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The Back Pain Revolution : Waddell DSc MD FRCS, Gordon: Amazon.co.uk: Books

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Analysis of Real-World Implementation of the Biopsychosocial Approach to Healthcare: Evidence From a Combination of Qualitative and Quantitative Methods

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Analysis of Real-World Implementation of the Biopsychosocial Approach to Healthcare: Evidence From a Combination of Qualitative and Quantitative Methods

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Abstract

Aims: The modern medical model has been transformed into a biopsychosocial model. The integration of the biopsychosocial approach in healthcare can help improve the effectiveness of diagnosis and treatment. This study explored the actual application of the biopsychosocial approach in healthcare and provides a basis for targeted interventions to promote the biopsychosocial approach in healthcare.

Methods: Study 1 involved one-on-one interviews with 30 medical staff and focus group interviews with 16 recent patients. Study 2 was a cross-sectional survey of 13,105 medical staff in Hangzhou, China that analyzed the status quo implementation of the biopsychosocial approach in healthcare.

Results: Study 1 found that medical staff did not welcome patients to report information unrelated to their disease, hoping patients did not express their emotions. In the treatment process, patients believed that medical staff refused to attend to or did not encourage reporting of any information other than the disease, and that patients should have reasonable expectations for medical staff. Study 2 found that medical staff had a 37.5% probability of actively paying attention to the patient's psychosocial status. Female medical staff (38.5%) were actively concerned about the patient's psychosocial status significantly more than male medical staff (34.2%) ( P < 0.01). The medical staff in the psychiatric department (58.4%) paid more active attention to the patient's psychosocial status than staff in the non-psychiatric departments (37.2%). Gender, department, hospital level, and professional title were the factors associated with the medical staff's attention to the patient's psychosocial status ( P < 0.05). The influence of age on the probability of medical staff actively paying attention to the psychosocial status of patients increased with the number of years of employment. Participants that were 31-40 years old, had an intermediate professional title, and 11-15 years of employment were the least likely to actively pay attention to patients' psychosocial status.

Conclusion: Although the biopsychosocial approach has been popularized for many years, it has not been widely used in medical care. Medical staff pay more attention to patients' physical symptoms and less attention to patients' psychosocial status. It is recommended that training will be provided to medical personnel on implementing a biopsychosocial approach with particular attention to the sociodemographic characteristics of medical personnel. Additionally, we propose helping patients set reasonable expectations, and formulating guidelines for implementing the biopsychosocial approach.

Keywords: biopsychosocial approach, healthcare, medical staff, psychosocial status, qualitative and quantitative methods

Introduction

With the changes in the spectrum of human diseases, understanding psychological disorders and symptoms continue to deepen. People have become increasingly aware that no single reason could cause the appearance of symptoms, and psychological and social factors need to be considered. Therefore, a purely biomedical model cannot serve and meet the needs of contemporary medical care. In 1977, Engel ( 1) pointed out the limitations of the biomedical model, integrated psychological and social dimensions, and proposed a biopsychosocial approach. Engel held the view that disease is the result of the interaction of biological, psychological, and social subsystems on multiple levels and highlighted the indispensable role of psychosocial factors, which explained such phenomena as the effect of living conditions on the development of the disease. The premise of the biopsychosocial approach is that the patient's disease cannot be divorced from his or her psychosocial causes, personality, and surroundings ( 2). Evidence has shown that social/environmental and psychological factors matter in the development of psychiatric disorders ( 3). In the following decades, the biopsychosocial approach was mentioned in many disciplines and practical fields, including medical traumatic stress, anorexia nervosa, addiction treatment, daily pain, elderly frailty, disability, and health psychology ( 4- 10). With the recognition that some risk factors of the disease are psychosocial rather than biomedical, and that some non-pharmacologic and non-surgical treatment modalities have a therapeutic effect, the biopsychosocial approach potentially improves clinical outcomes for chronic diseases and functional illnesses seen in primary care ( 11). The biopsychosocial approach in healthcare can improve the effectiveness of diagnosis and treatment ( 12), which enhances patient satisfaction and can ease conflicts between doctors and patients.

In clinical training such as medical schools and graduate schools, the biopsychosocial approach has been widely taught to arouse attention to the interaction between various factors that affect health and cause diseases ( 13). However, integrating the biopsychosocial approach into healthcare practice has not been as successful as integrating the approach into research and medical education ( 14). Most modern healthcare is still based on the biomedical model of disease, which can help identify and treat many diseases. However, it has difficulty recognizing the multi-factor and complexity of many (including non-organic) diseases. In addition, it is easy to ignore the psychosocial status of patients, which may trigger unnecessary disease behaviors in patients ( 15). Although the biomedical model promotes many healthcare innovations, a biomedical perspective alone cannot guarantee favorable results, nor can it explain the placebo effect and health gaps. It must also include psychological and social factors ( 10). Suls and Rothman ( 16) proposed that applying the biopsychosocial framework has not been fully utilized and should be considered in health psychology theories and clinical practice. Fava and Sonino ( 17) pointed out that although the biopsychosocial framework has been implemented for many years and the evidence base has grown over time, the implementation of this framework in healthcare has been slow. According to Adler ( 14), studies have found that many medical staff, such as the staff in pain clinics and on medical psychiatric wards, do not adhere to Engel's biopsychosocial approach. The application of the biopsychosocial approach needs thorough evaluation of the psychological, behavioral, sociocultural, and spiritual dimensions of patients' problems, which is time-consuming ( 18). For physicians who are already overburdened with clinical, administrative, and possibly research tasks, it is a formidable task ( 11).

However, as diseases become more complicated and multi-factorial, studying the status quo implementation of the biopsychosocial approach has far-reaching significance in health care. Surprisingly, we know very little about the practical application of the biopsychosocial approach in healthcare. To fill this gap in the literature, we explored the practical application of the biopsychosocial approach in healthcare through qualitative and quantitative research methods. Qualitative research in this area can provide us with valuable and comprehensive information and deepen our understanding of the practical application of the biopsychosocial approach in healthcare. Carrying out large-scale quantitative research complements the qualitative data, by investigating and analyzing the current status of implementing the biopsychosocial approach in healthcare and related factors. The knowledge gained would provide a scientific basis for how to carry out effective interventions to promote the status quo implementation of the biopsychosocial approach in healthcare. Specifically, the study could serve as a reference and provide direction for promoting doctor-patient communication; improving patient participation, acceptance, and compliance; improving the effectiveness of diagnosis and treatment; and promoting the harmony in the doctor-patient relationship.

The primary purpose of this study was to explore the implementation of biopsychosocial approach in healthcare and any differences associated with the psychosocial status of patients with different sociodemographic variables. One important factor is the gender of the medical professional. During the consultation process, female doctors have been shown to provide a longer consultation time than male doctors ( 19). In addition, women were found to use more emotion-focused coping strategies than men ( 20). Therefore, female doctors may pay more attention to patients' emotions and social factors. Thus, we examined the following hypothesis.

H1: Female medical staff pay more attention to the psychosocial status of patients than male medical staff.

The organizations in which people work affect their thoughts, feelings, and actions in the workplace ( 21). Hence, the difference in working environments may affect the thoughts and behaviors of medical staff. In a psychiatric department, because the working environment involves patients with mental illness, psychiatric staff may pay more attention to the psychosocial status of patients than in an environment where the medical staff are working with non-psychiatric patients. Therefore, we examined the following hypothesis.

H2: Psychiatric medical staff pay more attention to the psychosocial status of patients than non-psychiatric medical staff.

In China, hospitals are divided into three levels according to their functions and tasks ( 22). The first-level hospitals provide the community with primary healthcare, prevention, rehabilitation, and health care services. The second-level hospital is responsible for providing diagnosis and treatment of common and frequently occurring diseases for the community. The tertiary hospital is a comprehensive medical institution that provides specialized medical services ( 23). Medical staff at different hospital levels face different workloads, different kinds or parts of training, and different working environments, which may affect their attention to the psychosocial status of patients. Among them, tertiary hospitals provide diagnosis and treatment services for acute, critical, and difficult and complex diseases, which require comprehensive evaluation of patients. As such, medical staff in tertiary hospitals may pay more attention to the psychosocial status of patients than medical staff in secondary hospitals and first-level hospitals. Consequently, we proposed the following hypothesis.

H3: Medical staff in tertiary hospitals pay more attention to the psychosocial status of patients than medical staff in first- and second-level hospitals.

Lastly, it has been shown that burnout symptoms among doctors are prevalent and associated with age, professional title, and long working hours ( 24). Age and years of employment are related to the psychosocial workload of medical staff ( 25), which may affect the attention of medical staff to the psychosocial status of patients. Medical staff may face pressure from job tasks and their promotion to professional titles, and the professional title may affect their attention to the psychosocial status of patients. Medical staff with senior professional titles may pay more attention to the psychosocial status of patients. However, medical staff with junior and intermediate titles are faced with heavy workloads and the pressure to be promoted. Therefore, they may pay less attention to the psychosocial aspects of patients. Given these differences, our last hypothesis was as follows:

H4: Medical staff's attention to patients' psychosocial status will be associated with their age, years of employment, and professional title.

Materials and Methods

Design and Participants

This research study used a combination of qualitative and quantitative research methods. Study 1 conducted one-on-one interviews with 30 medical staff and conducted focus group interviews with 16 recent patients to summarize the views of both doctors and patients on the biopsychosocial approach. Participants in the one-on-one interviews were selected through random sampling from medical staff in the outpatient and ward areas of a large tertiary hospital in Zhejiang, China in September 2019. The researcher introduced himself to the interviewees who met the inclusion criteria and explained the purpose and methods of the study. After obtaining consent, the interview was conducted according to a semi-structured interview outline determined in advance. The interview began by asking for basic information on the participant, such as department and years of employment, which was followed by the interview questions, such as "What information do you want the patient to tell you when you are providing treatment?" and "What about the patient's behavior do you think will hinder the diagnosis and treatment?" The participants included 13 men and 17 women. Their average working experience was 9.84 ± 8.08 years and they were from diverse medical fields (e.g., internal medicine, urology, endocrinology).

Two focus group interviews were conducted in June 2020, and each group included eight participants. A semi-structured interview outline was prepared in advance for the purposes of the group interview, which asked the participants to "Please talk about your most recent medical experience," and questions such as "During the treatment, what behaviors or reactions do you think will promote or hinder the medical treatment process?" Inclusion criteria for the focus group were clear verbal expression and medical experience in the past 6 months. The participants were 6 men and 10 women with an average age of 22.9 ± 2.11 years. The researcher introduced himself to the patients who met the inclusion criteria and explained the purpose and methods of the research. The researcher obtained informed consent from each participant before conducting the focus group. Focus group interviews were recorded and the researcher took notes.

From December 2020 to January 2021, Study 2 was carried out in Hangzhou, Zhejiang Province. An anonymous online questionnaire was used to gather data on the current status of implementing the biopsychosocial approach in healthcare. The questionnaire asked for demographic information including gender, department, hospital level, professional title, age, years of employment, and the probability of actively paying attention to the patients' psychosocial status. To assess the probability of medical staff actively paying attention to the patient's psychosocial status, participants were asked, "During the consultation process, in ()% of the cases, I will actively pay attention to the patient's psychosocial status rather than just the physical symptoms." A total of 13,105 medical staff were surveyed.

Table 1 shows detailed information on the participants' characteristics. Of the 13,105 eligible medical staff that were included in this study, 23.5% ( n = 3,084) were men and 76.5% ( n = 10,021) were women. A total of 1.6% ( n = 206) were psychiatric medical staff and 98.4% ( n =12,899) were non-psychiatric. There were 2,681 (20.5%) medical staff from tertiary hospitals, 5,064 (38.6%) medical staff from second-level hospitals, and 5,360 (40.9%) medical staff from first-level hospitals. Approximately half (50.8%) of the medical staff had junior titles and 4,627 (35.3%) had intermediate titles. In terms of age, 27.6% ( n = 3,614) were ages 20-30, 41.7% ( n = 5,466) were 31-40, 20.3% ( n = 3,018) were 41-50, and 7.7% ( n = 1,007) were ages 51 or older. With regard to years of employment, 19.6% ( n = 2,567) were employed 0-5 years, 19.9% ( n = 2,603) 6-10 years, 25.2% ( n = 3,305) 11-15 years, 9.8% ( n = 1,289) 16-20 years, and 25.5% ( n = 3,341) were employed for 21 years or more.

Table 1

Demographic characteristics

n (%)

M

SD

t

P

Gender

Department

Hospital level

Professional title

Age

Years of employment

Statistical Analyses

In Study 1, we used thematic analysis to analyze the qualitative data. Initially, we transcribed the recorded interview then reviewed the transcribed data three times to obtain a general understanding. Next, we extracted semantic units and classified them as compact units. We then honed the important parts of each unit and what aspects of the qualitative data it covered. Next, the compact unit was further summarized and marked with appropriate headings. In addition, we searched for overlapping areas between topics, identified emerging subtopics, provided more detailed topic descriptions and described the hierarchical structure in the data, and clearly defined the scope of each topic. Finally, the sub-categories were grouped according to similarities and differences, and appropriate titles that could represent the resulting categories were selected.

In Study 2, we analyzed the sociodemographic variables and calculated the number and percentage distribution of the categorical variables. The independent t-test and one-way analysis of variance were used to determine sociodemographic differences among medical staff with regard to actively paying attention to patients' psychosocial status. Lastly, all variables were included in a stepwise linear regression model (the entry/clearance criterion was P = 0.05/0.1) for analysis. All statistical analyses were performed using IBM SPSS Version 26.0, and P < 0.05 (two-tailed) was considered statistically significant.

Results

Study 1

Medical Staff Do Not Welcome Patients to Report Information That Is Not Related to the Disease

During the consultation process, some medical staff paid more attention to the patient's physical symptoms. Patients were not welcome to report information that was not related to the disease. Medical staff hoped that the patient would grasp the key points when explaining their condition.

"The patients only need to talk about the disease and what is related to the disease during the communication with medical staff, and not mention other content." (A male orthopedic doctor who has worked for 10 years)

"During the treatment, the patient does not need to say too much that has nothing to do with the symptom." (A female doctor in the urology department who has worked for 7 years)

"I hope that the patient's parents can accurately provide the child's medical history and clearly describe the condition."(A female neonatologist who has worked for 7 years)

"The patient should focus on the critical points in the process of describing the condition." (A female internal medicine outpatient doctor who has worked for 1 year)

Medical Staff Hope That Patients Will Not Confide in Them

The medical staff said that although they can understand the patients' mood, they hoped that the patient would not confide their emotions to them and that they need to a maintain a rational attitude.

"Although the patient's mood is understandable, the patient does not need to say many things that have nothing to do with the patient's condition and only need to answer my questions accurately." (A respiratory physician who has worked for 9 years)

"I hope that the patients will not confide their emotions to the medical staff." (A female doctor in the gastroenterology department who has worked for 3 years)

"The patient's anxiety is understandable, but the patient should maintain a rational attitude during the treatment process." (A female doctor in the endocrinology department who has worked for 8 years)

The Patient Felt That Medical Staff Refused to Pay Attention to the Patient's Psychosocial Status

Some patients expressed their desire to get the attention of medical staff, thinking that the medical staff refused to pay attention to the patient's psychosocial status, which made patients feel dissatisfied.

"I want to describe my symptoms perfectly to the medical staff, but the medical staff seems to know me well, and the medical staff do not let me say too much. I feel a little dissatisfied. I want to talk to the medical staff, but the medical staff refuse to understand me." (Patient Y, male)

"The patients are eager to get the kind of attention from the medical staff. But if there is no particular situation, the medical staff will not pay attention to the patient deliberately." (Patient Z, female)

"I feel obstructed when communicating with some doctors, and the doctors may not listen carefully to what I say." (Patient C, female)

Patients Should Have Reasonable Expectations for Medical Staff

Most doctors believed that patients' high expectations would impact the effectiveness of diagnosis and treatment, so patients should have reasonable expectations. Some patients held the view that the patient's expectations for medical staff should be reasonable.

"Excessive expectations of patients have an impact on the effectiveness of diagnosis and treatment. I hope patients have reasonable expectations." (A male dentist who has worked for 7 years)

"Medical staff have as part of their responsibilities to take care of patients' emotions, but do not expect clinical medical staff to comfort patients like psychological medical staff." (Patient A, female)

"Patients are emotionally sensitive, which may hinder the doctor's diagnosis and treatment. Sometimes patients need to control their emotions and calm their minds to some extent." (Patient D, female)

Study 2

Comparison of the Probability of Medical Staff Actively Paying Attention to the Psychosocial Status of Patients

There were significant differences in the probability of actively paying attention to the psychosocial status of patients according to gender, department, hospital level, professional title, age, and years of employment ( P < 0.01). Female medical staff (38.5%) were more likely to pay attention to the psychosocial status of patients than male medical staff (34.2%) ( P < 0.01). The medical staff in the psychiatry department (58.4%) paid more attention to patients' psychosocial status than the medical staff in other departments (37.2%).

Table 2 provides the results of the comparisons according to hospital level, professional title, age, and years of employment. The probability of medical staff in second-level and tertiary hospitals actively paying attention to the psychosocial status of patients was significantly higher than that of medical staff in first-level hospitals, and medical staff in tertiary hospitals were more likely to pay attention to psychosocial status than medical staff in second-level hospitals.

The probability of medical staff 20-30 years old actively paying attention to the patient's psychosocial status was significantly higher than that of medical staff 31-40 years old and those who were 41-50 years old. Medical staff aged 41-50 and over 50 were more likely to pay attention to the psychosocial status of patients than those who were 31-40. The medical staff over the age of 50 were more likely to actively pay attention to the psychosocial status of patients than those aged 41-50. Medical staff aged 31-40 were the least likely to pay attention to patients' psychosocial status.

The probability of medical staff with junior professional titles actively paying attention to the psychosocial status of patients was significantly higher than that of the medical staff with intermediate professional titles and deputy senior professional titles. The probability that medical staff with deputy senior professional titles and senior professional titles actively pay attention to the psychosocial status of patients was significantly higher than that of the medical staff with intermediate professional titles. Medical staff with intermediate professional titles were the least likely to pay attention to the psychosocial status of patients.

Medical staff who had worked for 0-5 years were more likely to actively pay attention to the psychosocial status of patients than other medical staff who had worked for more years. Medical staff who had worked for 6-10 years were more likely to pay attention to the psychosocial status of patients than those who had worked for 11-15 years. Medical staff who had worked for more than 21 years were more likely to pay attention to the psychosocial status of patients than those who had worked for 11-15 years. Medical staff who had worked for 11-15 years were the least likely to actively pay attention to the psychosocial status of patients.

Regression Analysis on the Probability of Medical Staff Actively Paying Attention to the Psychosocial Status of Patients

In order to identify the statistical significant characteristics of medical staff who actively pay attention to the psychosocial status of patients, we first included all sociodemographic variables into the stepwise linear regression analysis. Gender was indexed as 0 = male, 1 = female. Then, considering the possible interaction between hospital level and professional title, and between age and years of employment, we included the interaction terms "hospital level × professional title" and "age × years of employment" into the regression equation. The results are shown in Table 3 . Gender [β = 0.05, CI (2.66, 5.19), P < 0.01], department [β = 0.07, CI (13.48, 21.93), P < 0.01], hospital level [β = 0.10, CI (3.51, 4.92), P < 0.01], and professional title [β = −0.04, CI (−2.41, −0.68), P < 0.01] were statistical significant predictors of the probability of medical staff actively paying attention to the psychosocial status of patients. Age and years of employment were not statistical significant. Age and working years cannot independently predict the probability of medical staff actively paying attention to the psychosocial state of patients. But the interaction of age and years of employment was statistical significant [β = 0.11, CI (0.03, 0.04), P < 0.01]. The influence of age on the probability of medical staff actively paying attention to the psychosocial status of patients increased with the increase in years of employment. The interaction of hospital level and professional title level was not statistical significant.

Discussion

In this study, we explored the implementation of the biopsychosocial approach in healthcare through a combination of qualitative and quantitative research methods. Our focus was to understand the experience of medical staff and patients with regard to the attention given to the psychosocial status of patients, and determine what sociodemographic factors were associated with differences among medical staff in the active attention they give to patients' psychosocial status. One qualitative research finding was that medical staff do not welcome patients to report information unrelated to the disease and hope that patients will not confide in them. Quantitative research found that medical staff had a 37.5% probability of actively paying attention to the patient's psychosocial status. This shows that medical staff focus on the patient's physical symptoms and tend to ignore the patient's psychosocial status. Based on the sample in the present study, it can be concluded that the biopsychosocial approach is not sufficiently applied in healthcare.

Another finding from the qualitative study was that some patients held the view that medical staff refused to pay attention to the patients' psychosocial status. The patients were eager to get such attention from the medical staff, which is consistent with previous research results. Vinson found that patients increasingly wanted to interact emotionally with medical staff ( 26). In the eyes of patients, the medical staff take care of the patient's emotions to a certain extent, which helps patients to relax. Patients feel helpless and hopeless in the face of the disease, and medical staff play an essential role in providing support to patients ( 27). The integration of biopsychosocial methods in healthcare needs to be established within medical staff ( 14).

In addition, according to the results of the qualitative study, patients should have reasonable expectations of the medical staff. Patients who go to the hospital generally have expectations regarding the care that they will receive. These expectations range from a desire for information or psychosocial support to expectations for specific tests or treatments. Fulfillment of patients' expectations may influence health care utilization, affect patient satisfaction, and be used to indicate quality of care ( 28). Health care expectations may be positive or negative ( 29). Particular emphasis should be placed on patients with excessive expectations, as the lack of an achievable balance between expectations and fulfillment may lead to dissatisfaction ( 30). Therefore, in routine medical services, medical staff should discuss the treatment plan with patients and the realization of short- and long-term goals to ensure that patients' expectations are realistic and reasonable ( 31). Medical staff should actively listen to determine patients' understanding and concerns about the disease, respond to patients' concerns, and help set reasonable expectations, which is helpful to establish a harmonious doctor-patient relationship.

The quantitative study results verified our first hypothesis. Female medical staff (38.5%) were more likely to actively pay attention to the psychosocial status of patients than male medical staff (34.2%). Our findings are consistent with prior studies indicating that the gender of the doctor is a relevant factor in the differences in medical care provided. For example, it was found that female doctors take an average of 2 min longer to see a patient than male doctors ( 32), are more likely to ask patients about health risks and unhealthy behaviors and provide more psychological support ( 33).

In addition, department and hospital level were factors associated with medical staff actively paying attention to the psychosocial status of patients. Psychiatric medical staff actively paid more attention to the psychosocial status of patients than non-psychiatric medical staff. This verifies our hypothesis that psychiatrists would pay more attention to the psychosocial status of patients due to the particularity of the department. However, our results showed that only 58.4% of the psychiatric medical staff paid attention to the patient's psychosocial status. Regarding hospital level, medical staff in tertiary and second-level hospitals were more likely to actively pay attention to the psychosocial status than medical staff in first-level hospitals. To a certain extent, our results are consistent with Meretoja et al.'s ( 34) finding that competence profiles differed in both the level and infrequency of using competencies according to work environment. There are differences in the work environments of hospitals of different levels, including the competence of the medical staff, which may affect the degree to which medical staff pay attention to the psychosocial status of patients.

The hypothesis that medical staff's active attention to patients' psychosocial status is related to age, years of employment, and professional title was also supported. Professional title and the interaction of age and years of employment had predictive effects on the probability of medical staff actively paying attention to the patient's psychosocial status. The influence of age increased with the increase in years of employment. We found that the medical staff aged 31-40 years, with an intermediate professional title, and 11-15 years of employment were least likely to actively pay attention to the patient's psychosocial status. Previous studies have found that age, working years, and work burden were essential predictors of job burnout for doctors and nurses ( 35). Compared with other occupations, occupational stress and burnout symptoms were more common among doctors ( 36). The job burnout of doctors was related to changes in the professional environment, such as financial pressure, increased workload, and index assessment ( 37). Therefore, we speculate that medical staff aged 31-40 with intermediate professional titles and 11-15 years of employment may have a heavier workload, more tremendous pressure for promotion, and face more severe job burnout. Thus, they have the lowest probability of actively focusing on the patient's psychosocial status.

Based on the findings mentioned above in this study, the biopsychosocial approach has not been widely used in healthcare. Most medical staff tend to only focus on the patients' physical symptoms and not pay attention to the patients' psychosocial status. Hence, it is recommended that the biopsychosocial approach be promoted in medical treatment through training and interventions for medical staff, primarily geared to those with the lowest probability of actively focusing on the patients' psychosocial status. Further, it is suggested to comprehensively popularize the knowledge of medical psychology among medical staff and carry out the research of disease psychology, which will help strengthen the medical staff's attention to the biopsychosocial medical model. Then, in medical practice, guidelines for implementing the biopsychosocial medical model should be formulated so that the patients' disease's biological, psychological, and social components are considered and managed as a whole. For example, medical and psychology departments could establish an efficient consultation, referral, or a multi-disciplinary treatment team to enhance patient diagnosis and treatment.

Strengths and Limitations

This research explored the integration of the biopsychosocial approach into health care from the perspective of medical staff and patients. Using qualitative and quantitative methods, the study provides comprehensive information and fills a gap in the research on the application of the biopsychosocial approach. The study included a diverse and extensive sample of medical staff, as well as interviewing doctors and patients for their perspective on the issue. Furthermore, the study investigated sociodemographic variables in relation to medical staff's attention to patients' psychosocial status. As such, the study provides scientific evidence for carrying out effective interventions to promote the implementation of the biopsychosocial approach in healthcare.

This study has some limitations. Firstly, although the sample included 13,105 medical staff in Hangzhou City, the results may not be generalizable to the situation of medical staff in other countries and regions. Future research should focus on other countries and regions with comparative analyses. Secondly, Study 2 used self-report questionnaires, which are subject to response bias such as social desirability. Lastly, this is a cross-sectional study which does not show how these variables behave over time. Future studies should consider using longitudinal designs.

Conclusion

Although the biopsychosocial approach has been popularized for many years, it has not been widely used in medical care. The results of the present study suggest that medical staff tend to focus their attention on the patients' physical symptoms and are less inclined to attend to patients' psychosocial status. Gender, department, hospital level, professional title and the interaction of age and years of employment can play a predictive role in the extent to which medical staff pay attention to patients' psychosocial status. Therefore, it is recommended that training and interventions be provided for medical staff on integrating the biopsychosocial approach into the provision of health care. In developing and implementing any in-service training for medical staff, it would be important to consider how the factors identified in this study may impact the ability and motivation of medical staff to attend to the psychosocial status of patients. Additionally, we propose guidelines be formulated for implementing the biopsychosocial approach, and helping patients set reasonable expectations regarding what the medical staff is able to do given their job responsibilities and the timeframe they have to provide diagnosis and treatment.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics Statement

The studies involving human participants were reviewed and approved by ethical review institutions of Zhejiang University and related hospitals. The participants provided their informed consent to participate in this study.

Author Contributions

QY, XX, and HS contributed to the conception of the study. HS, TS, and ZW collected the data. YX and XX carried out data cleaning. XX performed the data analyses and wrote the manuscript. QY and HS contributed to critically revising the manuscript for important content. All authors have read and agreed to the published version of the manuscript and contributed to the article and approved the submitted version.

Funding

This research was funded by National Natural Science Foundation of China (Grant Numbers 71974170), Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (Grant Numbers 2019R01007) and Public Projects of Science and Technology Department of Zhejiang Province (Grant Numbers LGF21H090006) to HS.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Articles from Frontiers in Psychiatry are provided here courtesy of Frontiers Media SA

# data[].attributes.attachment_link.title
Analysis of Real-World Implementation of the Biopsychosocial Approach to Healthcare: Evidence From a Combination of Qualitative and Quantitative Methods

# data[].attributes.attachment_link.description
Aims: The modern medical model has been transformed into a biopsychosocial model. The integration of the biopsychosocial approach in healthcare can help improve the effectiveness of diagnosis and treatment. This study explored the actual application of ...

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https://www.iasp-pain.org/publications/iasp-news/iasp-announces-revised-definition-of-pain/

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International Association for the Study of Pain (IASP)

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For the first time since 1979, IASP introduced a revised definition of pain, the result of a two-year process that the association hopes will lead to revised ways of assessing pain.

"IASP and the Task Force that wrote the revised definition and notes did so to better convey the nuances and the complexity of pain and hoped that it would lead to improved assessment and management of those with pain," said Srinivasa N. Raja, MD, Chair of the IASP Task Force and Director of Pain Research, Professor of Anesthesiology & Critical Care Medicine, Professor of Neurology, Johns Hopkins University School of Medicine.

The definition is: "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and is expanded upon by the addition of six key Notes and the etymology of the word pain for further valuable context.

Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.

Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.

Through their life experiences, individuals learn the concept of pain.

A person's report of an experience as pain should be respected.

Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.

Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.

A multi-national, multidisciplinary Task Force developed the revised definition with input from all potential stakeholders, including persons in pain and their caregivers.

The revised definition was introduced in this article in the journal PAIN and a via a press release. An infographic also illustrates the changes.

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IASP Announces Revised Definition of Pain - International Association for the Study of Pain (IASP)

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For the first time since 1979, IASP introduced a revised definition of pain, the result of a two-year process that the association hopes will lead to revised ways of assessing pain.

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https://www.youtube.com/watch?v=IGQmdoK_ZfY

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The role of the bio-psychosocial model in public health

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The role of the bio-psychosocial model in public health

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https://www.youtube.com/watch?v=sxwn1w7MJvk

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The Rubber Hand Illusion - Horizon: Is Seeing Believing? - BBC

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Co-activation of SAM and HPA Responses to Acute Stress: A Review of the Literature and Test of Differential Associations with Preadolescents’ Internalizing and Externalizing

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Co-activation of SAM and HPA Responses to Acute Stress: A Review of the Literature and Test of Differential Associations with Preadolescents’ Internalizing and Externalizing

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Co-activation of SAM and HPA Responses to Acute Stress- A Review of the Literature and Test of Differential Associations with Preadolescents’ Internalizing and Externalizing

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The Biopsychosocial Model 25 Years Later: Principles, Practice, and Scientific Inquiry

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The Biopsychosocial Model 25 Years Later: Principles, Practice, and Scientific Inquiry

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Abstract

The biopsychosocial model is both a philosophy of clinical care and a practical clinical guide. Philosophically, it is a way of understanding how suffering, disease, and illness are affected by multiple levels of organization, from the societal to the molecular. At the practical level, it is a way of understanding the patient's subjective experience as an essential contributor to accurate diagnosis, health outcomes, and humane care. In this article, we defend the biopsychosocial model as a necessary contribution to the scientific clinical method, while suggesting 3 clarifications: (1) the relationship between mental and physical aspects of health is complex-subjective experience depends on but is not reducible to laws of physiology; (2) models of circular causality must be tempered by linear approximations when considering treatment options; and (3) promoting a more participatory clinician-patient relationship is in keeping with current Western cultural tendencies, but may not be universally accepted. We propose a biopsychosocial-oriented clinical practice whose pillars include (1) self-awareness; (2) active cultivation of trust; (3) an emotional style characterized by empathic curiosity; (4) self-calibration as a way to reduce bias; (5) educating the emotions to assist with diagnosis and forming therapeutic relationships; (6) using informed intuition; and (7) communicating clinical evidence to foster dialogue, not just the mechanical application of protocol. In conclusion, the value of the biopsychosocial model has not been in the discovery of new scientific laws, as the term "new paradigm" would suggest, but rather in guiding parsimonious application of medical knowledge to the needs of each patient.

Keywords: Biopsychosocial model, clinical practice patterns, personal autonomy, empathy, communication, education

GEORGE ENGEL'S LEGACY

The late George Engel believed that to understand and respond adequately to patients' suffering-and to give them a sense of being understood-clinicians must attend simultaneously to the biological, psychological, and social dimensions of illness. He offered a holistic alternative to the prevailing biomedical model that had dominated industrialized societies since the mid-20th century. His new model came to be known as the biopsychosocial model. He formulated his model at a time when science itself was evolving from an exclusively analytic, reductionistic, and specialized endeavor to become more contextual and cross-disciplinary. Engel did not deny that the mainstream of biomedical research had fostered important advances in medicine, but he criticized its excessively narrow (biomedical) focus for leading clinicians to regard patients as objects and for ignoring the possibility that the subjective experience of the patient was amenable to scientific study. Engel championed his ideas not only as a scientific proposal, but also as a fundamental ideology that tried to reverse the dehumanization of medicine and disempowerment of patients (Table 1). His model struck a resonant chord with those sectors of the medical profession that wished to bring more empathy and compassion into medical practice.

Table 1.

1. A biochemical alteration does not translate directly into an illness. The appearance of illness results from the interaction of diverse causal factors, including those at the molecular, individual, and social levels. And the converse, psychological alterations may, under certain circumstances, manifest as illnesses or forms of suffering that constitute health problems, including, at times, biochemical correlates

2. The presence of a biological derangement does not shed light on the meaning of the symptoms to the patient, nor does it necessarily infer the attitudes and skills that the clinician must have to gather information and process it well

3. Psychosocial variables are more important determinants of susceptibility, severity, and course of illness than had been previously appreciated by those who maintain a biomedical view of illness

4. Adopting a sick role is not necessarily associated with the presence of a biological derangement

5. The success of the most biological of treatments is influenced by psychosocial factors, for example, the so-called placebo effect

6. The patient-clinician relationship influences medical outcomes, even if only because of its influence on adherence to a chosen treatment

7. Unlike inanimate subjects of scientific scrutiny, patients are profoundly influenced by the way in which they are studied, and the scientists engaged in the study are influenced by their subjects

In this article we critically examine and update 3 areas in which the biopsychosocial model was offered as a "new medical paradigm": (1) a world view that would include the patient's subjective experience alongside objective biomedical data, (2) a model of causation that would be more comprehensive and naturalistic than simple linear reductionist models, and (3) a perspective on the patient-clinician relationship that would accord more power to the patient in the clinical process and transform the patient's role from passive object of investigation to the subject and protagonist of the clinical act. We will also explore the interface between the biopsychosocial model and evidence-based medicine.

DUALISM, REDUCTIONISM, AND THE DETACHED OBSERVER

In advancing the biopsychosocial model, Engel was responding to 3 main strands in medical thinking that he believed were responsible for dehumanizing care. First, he criticized the dualistic nature of the biomedical model, with its separation of body and mind (which is popularly, but perhaps inaccurately, traced to Descartes). This conceptualization (further discussed in the supplemental appendix, available online at http:// www.annfammed.org/cgi/content/full/2/6/576/DC1) included an implicit privileging of the former as more "real" and therefore more worthy of a scientific clinician's attention. Engel rejected this view for encouraging physicians to maintain a strict separation between the body-as-machine and the narrative biography and emotions of the person-to focus on the disease to the exclusion of the person who was suffering-without building bridges between the two realms. His research in psychosomatics pointed toward a more integrative view, showing that fear, rage, neglect, and attachment had physiologic and developmental effects on the whole organism.

Second, Engel criticized the excessively materialistic and reductionistic orientation of medical thinking. According to these principles, anything that could not be objectively verified and explained at the level of cellular and molecular processes was ignored or devalued. The main focus of this criticism-a cold, impersonal, technical, biomedically-oriented style of clinical practice-may not have been so much a matter of underlying philosophy, but discomfort with practice that neglected the human dimension of suffering. His seminal 1980 article on the clinical application of the biopsychosocial model examines the case of a man with chest pain whose arrhythmia was precipitated by a lack of caring on the part of his treating physician.

The third element was the influence of the observer on the observed. Engel understood that one cannot understand a system from the inside without disturbing the system in some way; in other words, in the human dimension, as in the world of particle physics, one cannot assume a stance of pure objectivity. In that way, Engel provided a rationale for including the human dimension of the physician and the patient as a legitimate focus for scientific study.

Engel's perspective is contrasted with a so-called monistic or reductionistic view, in which all phenomena could be reduced to smaller parts and understood as molecular interactions. Nor did he endorse a holistic-energetic view, many of whose adherents espouse a biopsychosocial philosophy; these views hold that all physical phenomena are ephemeral and controllable by the manipulation of healing energies. Rather, in embracing Systems Theory, Engel recognized that mental and social phenomena depended upon but could not necessarily be reduced to (ie, explained in terms of) more basic physical phenomena given our current state of knowledge. He endorsed what would now be considered a complexity view, in which different levels of the biopsychosocial hierarchy could interact, but the rules of interaction might not be directly derived from the rules of the higher and lower rungs of the biopsychosocial ladder. Rather, they would be considered emergent properties that would be highly dependent on the persons involved and the initial conditions with which they were presented, much as large weather patterns can depend on initial conditions and small influences. This perspective has guided decades of research seeking to elucidate the nature of these interactions.

COMPLEXITY SCIENCE: CIRCULAR AND STRUCTURAL CAUSALITY

Engel objected to a linear cause-effect model to describe clinical phenomena. Clinical reality is far more complex. For example, although genetics may have a role in causing schizophrenia, no clinician would ignore the sociologic factors that might unleash or contain the manifestations of the illness.

Complexity and Causality

Few morbid conditions could be interpreted as being of the nature "one microbe, one illness"; rather, there are usually multiple interacting causes and contributing factors. Thus, obesity leads to both diabetes and arthritis; both obesity and arthritis limit exercise capacity, adversely affecting blood pressure and cholesterol levels; and all of the above, except perhaps arthritis, contribute to both stroke and coronary artery disease. Some of the effects (depression after a heart attack or stroke) can then become causal (greater likelihood of a second similar event). Similar observations can be made about predictors of relapse in schizophrenia. These observations set the stage for models of circular causality, which describes how a series of feedback loops sustain a specific pattern of behavior over time. Complexity science is an attempt to understand these complex recursive and emergent properties of systems and to find interrelated proximal causes that might be changed with the right set of interventions (family support and medications for schizophrenia; depression screening and cholesterol level reduction after a heart attack).

Structural Causality

In contrast to the circular view, structural causality describes a hierarchy of unidirectional cause-effect relationships-necessary causes, precipitants, sustaining forces, and associated events. For instance, a necessary cause for tuberculosis is a mycobacterium, precipitants can be a low body temperature, and a sustaining force a low caloric intake. Complexity science can facilitate understanding of a clinical situation, but most of the time a structural model is what guides practical action. For example, if we think that Mr. J is hypertensive because he consumes too much salt, has a stressful job, poor social supports, and an overresponsible personality type, following a circular causal model, possibly all of these factors are truly contributory to his high blood pressure. But, when we suggest to him that he take an antihypertensive medication, or that he consume less salt, or that he take a stress-reduction course, or that he see a psychotherapist to reduce his sense of guilt, we are creating an implicit hierarchy of causes: Which cause has the greatest likely contribution to his high blood pressure? Which would be most responsive to our actions? What is the added value of this action, after having done others? Which strategy will give the greatest result with the least harm and with the least expenditure of resources?

Interpretations, Language, and Causality

Causal attributions have the power to create reality and transform the patient's view of his/her own world. A physician who listens well might agree when a patient worries that a family argument precipitated a myocardial infarction; although this interpretation may have meaning to the patient, it is inadequate as a total explanation of why the patient suffered a myocardial infarction. The attribution of causality can be used to blame the patient for his or her illness ("If only he had not smoked so much...."), and also may have the power of suggestion and might actually worsen the patient's condition ("Every time there is a fight, your dizziness worsens, don't you see?").

TOWARD A RELATIONSHIP-CENTERED MODEL

Power and Emotions in the Clinical Relationship

Patient-centered, relationship-centered, and client-centered approaches propose that arriving at a correct biomedical diagnosis is only part of the clinician's task; they also insist on interpreting illness and health from an intersubjective perspective by giving the patient space to articulate his or her concerns, finding out about the patient's expectations, and exhorting the health professional to show the patient a human face. These approaches represent movement toward an egalitarian relationship in which the clinician is aware of and careful with his or her use of power.

This "dialogic" model suggests that the reality of each person is not just interpreted by the physician, but actually created and recreated through dialogue; individual identities are constructed in and maintained through social interaction. The physician's task is to come to some shared understanding of the patient's narrative with the patient. Such understanding does not imply uncritical acceptance of whatever the patient believes or hypothesizes, but neither does it allow for the uncritical negation of the patient's perspective, as so frequently occurs, for example, when patients complain of symptoms that physicians cannot explain. The patient's story is simultaneously a statement about the patient's life, the here-and-now enactment of his life trajectory, and data upon which to formulate a diagnosis and treatment plan.

Underlying the analysis of power in the clinical relationship is the issue of how the clinician handles the strong emotions that characterize everyday practice. On the one hand, there is a reactive clinical style, in which the clinician reacts swiftly to expressions of hostility or distrust with denial or suppression. In contrast, a proactive clinical style, characterized by a mindful openness to experience, might lead the clinician to accept the patient's expressions with aplomb, using the negative feelings to strengthen the patient-clinician relationship. The clinician must acknowledge and then transcend the tendency to label patients as "those with whom I get along well" or "difficult patients." By removing this set of judgments, true empathy can devolve from a sense of solidarity with the patient and respect for his or her humanity, leading to tolerance and understanding. Thus, in addition to the moral imperative to treat the patient as a person, there is a corresponding imperative for the physician to care for and deepen knowledge of himself or herself. Without a sufficient degree of self-understanding, it is easy for the physician to confuse empathy with the projection of his or her needs onto the patient.

Implications for Autonomy

Most patients desire more information from their physicians, fewer desire direct participation in clinical decisions, and very few want to make important decisions without the physician's advice and consultation with their family members. This does not mean that patients wish to be passive, even the seriously ill and the elderly. In some cases, however, clinicians unwittingly impose autonomy on patients. Making a reluctant patient assume too much of the burden of knowledge about an illness and decision making, without the advice from the physician and support from his or her family, can leave the patient feeling abandoned and deprived of the physician's judgment and expertise. The ideal, then, might be "autonomy in relation"-an informed choice supported by a caring relationship. The clinician can offer the patient the option of autonomy while considering the possibility that the patient might not want to know the whole truth and wish to exercise the right to delegate decisions to family members.

The Social Milieu

There is an ecological dimension of each encounter-it is not just between patient and physician, but rather an expression of social norms. Sometimes clinicians face a dilemma: can or should a private clinical relationship between patient and physician be a vehicle for social transformation? Or, should the relationship honor and conform to the cultural norms of patients? Our view is that adaptation normally should occur before transformation-the physician must first understand and accommodate to the patient's values and cultural norms before trying to effect change. Otherwise, the relationship becomes a political battleground and the focus of a process to which the patient has not consented and may not desire. This debate, however, becomes much more difficult in situations in which patients have suffered abuse-for example domestic violence or victims of torture. In those cases, not trying to remedy the social injustices that resulted in the patient seeking care may interfere with the formation of a trusting relationship. The physician may be tempted to effect a social transformation in these cases, for example, to advise the patient to leave an abusive situation, even though the patient may state that she only wants care for the bruises. Premature advice may interfere with enabling the patient to be the agent of change, however. Stopping short of attempting to transform social relationships until the patient has given consent should not be interpreted as indifference to, acceptance of, or complicity in such situations; rather, it should be viewed as a prudent course of action that will ultimately be validating and empowering.

Caring, Paternalism, and Empathy

Taking Engel's view, perhaps it is not paternalism that is the problem but practicing as a cold technician rather than a caring healer. The physician who sees his or her role as nothing more than a technical adviser can regard empathy as a useless effort that has no influence on clinical decisions, or, worse, a set of linguistic tricks to get the patient to comply with treatment. Because it is entirely possible to advocate for shared decision making without challenging the notion of the cold technician, we propose to move the emphasis to an approach that emphasizes human warmth, understanding, generosity, and caring.

THE BIOPSYCHOSOCIAL MODEL AND RELATIONSHIP-CENTERED CARE

The practical application of the biopsychosocial model, which we will call biopsychosocially oriented clinical practice does not necessarily evolve from the constructs of interactional dualism or circular causality. Rather, it may be that the content and emotions that constitute the clinician's relationship with the patient are the fundamental principles of biopsychosocial-oriented clinical practice, which then inform the manner in which the physician exercises his or her power. The models of relationship that have tended to appear in the medical literature, with a few notable exceptions, have perhaps focused too much on an analysis of power and too little on the underlying emotional climate of the clinical relationship. For this reason, we suggest a reformulation of some of the basic principles of the biopsychosocial model according to the emotional tone that engraves the relationship with such characteristics as caring, trustworthiness, and openness. Some principles of biopsychosocial-oriented clinical practice are outlined below.

Calibrating the Physician

The biopsychosocial model calls for expanding the number and types of habits to be consciously learned and objectively monitored to maintain the centrality of the patient. The physician is in some ways like a musical instrument that needs to be calibrated, tuned, and adjusted to perform adequately. The physician's skills should be judged on their ability to produce greater health or to relieve the patient's suffering-whether they include creating an adequate emotional tone, gathering an accurate history, or distinguishing between what the patient needs and what the patient says he or she wants. In that regard, a clinical skill includes the ethical mandate not only to find out what concerns the patient, but to bring the physician's agenda to the table and influence the patient's behavior. Sometimes doing so may include uncovering psychosocial correlates of otherwise unexplained somatic symptoms (such as ongoing abuse or alcoholism) to break the cycle of medicalization and iatrogenesis. To abandon this obligation, in our view, is breaking an implicit social contract between physicians and society. This deliberative and sometimes frankly physician-centered approach has its perils, however. The physician must be capable of an ongoing self-audit simply because his or her performance is never the same from moment to moment. Weick and Sutcliffe regard this constant vigilance as a fundamental requirement for professions that require high reliability in the face of unexpected events. Mindfulness-the habits of attentive observation, critical curiosity, informed flexibility, and presence-underlies the physician's ability to self-monitor, be vigilant, and respond with compassion.

Creating Trust

The expert clinician considers explicitly, as a core skill, the achievement in the encounter of an emotional tone conducive to a therapeutic relationship. For that reason, all consultations might be judged on the basis of cordiality, optimism, genuineness, and good humor. By receiving a hostile patient with respect, it clarifies for the clinician that the patient's emotions are the patient's-and not the physician's-and also sets the stage for the patient to reflect as well. Similarly, the physician must know how to recognize and when to express his or her own emotions, sometimes setting limits and boundaries in the interest of preserving a functional relationship.

Cultivating Curiosity

The next step in the application of clinical evidence to medical care is the cultivation of curiosity. Thus, cultivated naïvete might be considered one of the fundamental habits characteristic of expert practitioners. Another aspect of this emotional tone is an empathic curiosity about the patient as person. Empathic curiosity allows the clinician to maintain an open mind and not to consider that any case is ever closed. If the patient does not surprise us today, perhaps he or she will tomorrow. We have described this capacity using the term, beginner's mind. It is the capacity for expecting the unexpected, just as if the physician were another clinician seeing the patient for the first time. There is also an ethical component of this emotional tone-there are no "good" or "bad" patients, nor are there "interesting" and "boring" diseases. Patients should not have to legitimize their suffering by describing illnesses that make the clinician feel comfortable or confident.

Recognizing Bias

The grounding of medical decisions based on scientific evidence while also integrating the clinician's professional experience is now a well-accepted tenet of the founders of the evidence-based medicine movement. The method for incorporation of experience, however, has been less well described than the method for judging the quality of scientific evidence. For example, clinicians should learn how their decisions might be biased by the race and sex of the patient, among other factors, and also the tendency to close the case prematurely to rid oneself of the burden of attempting to solve complex problems.

Educating the Emotions

There are methods for emotional education, just as there are for learning new knowledge and skills. Tolerance of uncertainty, for example, is amenable to observation and calibration-making decisions in the absence of complete information is a characteristic of an expert practitioner, in contrast to the technician who views his role as simply following protocols.

Using Informed Intuition

The role of intuition is central. Just as Polanyi and Schön maintain that professional competence is based in tacit, rather than explicit, knowledge, expertise often is manifest in insights that are difficult to track on a strictly cognitive level. If a clinician, encountering a situation in which he normally would use a particular treatment, has the intuition, for a reason that has not yet become clear, that treatment might not be the best for this particular patient, we suggest, rather than considering it a feeling from nowhere that might be discarded, perhaps the intuition can later be traced to a set of concrete observations about the patient that were not easy for the clinician to describe at the time. Because these observations often are manifest only when cases are reviewed after the fact does not diminish the ethical obligation that the clinician use all of his or her capabilities, not only those which can be readily explained.

Communicating Clinical Evidence

Evidence should be communicated in terms the patient can understand, in small digestible pieces, at a rate at which it can be assimilated. Information overload may have two effects-reduction in comprehension and increasing the emotional distance between physician and patient. Communication of clinical evidence should foster understanding, not simply answers.

FURTHER DEVELOPMENT OF THE BIOPSYCHOSOCIAL MODEL

George Engel formulated the biopsychosocial model as a dynamic, interactional, but dualistic view of human experience in which there is mutual influence of mind and body. We add to that model the need to balance a circular model of causality with the need to make linear approximations (especially in planning treatments) and the need to change the clinician's stance from objective detachment to reflective participation, thus infusing care with greater warmth and caring. The biopsychosocial model was not so much a paradigm shift-in the sense of a crisis of the scientific method in medicine or the elaboration of new scientific laws-as it was an expanded (but nonetheless parsimonious) application of existing knowledge to the needs of each patient.

In the 25 years that have elapsed since Engel first proposed the biopsychosocial model, two new intellectual trends have emerged that could make it even more robust. First, we can move beyond the problematic issue of mind-body duality by recognizing that knowledge is socially constructed. To some extent, such categories as "mind" or "body" are of our own creation. They are useful to the extent that they focus our thinking and action in helpful ways (eg, they contribute to health, well-being, and efficient use of resources), but when taken too literally, they can also entrap and limit us by creating boundaries that need not exist. By maintaining what William James called "fragile" categories, we can alter or dispose of categories as new evidence accumulates and when there is a need to engage in flexible, out-of-the-box thinking.

Second, we can move beyond the multidimensional and multifactorial linear thinking to consider complexity theory as a more adequate model for understanding causality, dualism, and participation in care. Complexity theory shows how, in open systems, it is often impossible to know all of the contributors to and influences on particular health outcomes. By describing the ways in which systems tend to self-organize, it provides guideposts to inform the clinician's actions. It also buffers the tendency to impose unrealistic expectations that one can know and control all of these contributors and influences.

George Engel's most enduring contribution was to broaden the scope of the clinician's gaze. His bio-psychosocial model was a call to change our way of understanding the patient and to expand the domain of medical knowledge to address the needs of each patient. It is perhaps the transformation of the way illness, suffering, and healing are viewed that may be Engel's most durable contribution.

Acknowledgments

The following people have provided important critiques of this article. We thankfully acknowledge their contributions, but do not infer that they take responsibility for the content of the article: Drs. Rogelio Altisent, Lucy M. Candib, Jordi Cebrià, José Corrales, Blas Coscollar, Javier García-Campayo, Salvador García-Sánchez, Diego Gracia, Maria León, Susan McDaniel, Fernando Orozco, Vicente Ortún, Timothy Quill, Roger Ruiz, Jorge Tizón, and Lyman Wynne.

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# data[].attributes.attachment_link.title
The Biopsychosocial Model 25 Years Later: Principles, Practice, and Scientific Inquiry

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The biopsychosocial model is both a philosophy of clinical care and a practical clinical guide. Philosophically, it is a way of understanding how suffering, disease, and illness are affected by multiple levels of organization, from the societal to the ...

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Pain and depression: A neurobiological perspective of their relationship

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Pain and depression: A neurobiological perspective of their relationship

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Pain and Depression- A Neurobiological Perspective of Their Relationship

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https://www.amazon.co.uk/Psychologically-Informed-Physiotherapy-psychosocial-perspectives/dp/0702068179

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Psychologically Informed Physiotherapy is a key new textbook for those who need a trusted and comprehensive resource to guide them in applying psychosocial perspectives to their physiotherapy practice.

The first of its kind, this textbook brings together an international and interdisciplinary team of leading experts in the field. Together they present an evidence-based range of ideas and concepts around the psychologically informed practice framework, bringing psychosocial aspects of physiotherapy to the fore alongside the established biomedical model. By applying these aspects to screening, exploration and triaging, physiotherapists are better able to identify the origins of pain and barriers to rehabilitation; and so are more likely to achieve consistently good clinical outcomes for their patients. Throughout, clinical case studies ensure that the theory is then grounded in a variety of practical scenarios after which some reflective exercises and clinically relevant scenarios reinforce learning and understanding.

Chapters on:

Psychology of professional identity in health care

The biopsychosocial model

Screening for red flags

Adapting interactions with others to form empowering relationships and influence behavioural change

Neuro-immune-endocrine interactions and clinical practice in stress, pain and recovery

Care of the anxious patient through cognitive and person-centred strategies

Alternative and evolving models of practice, including the clinical flag system

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A global study of pain prevalence across 52 countries: examining the role of country-level contextual factors

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A global study of pain prevalence across 52 countries: examining the role of country-level contextual factors

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Pain. Author manuscript; available in PMC 2023 Sep 1.

Published in final edited form as:

1. Introduction

Globally, pain impacts billions of people daily [ 10, 37, 59]. Given its ubiquity, and its accompanying disability and mortality, there is ample reason to regard pain as a major global health burden and priority [ 3, 29]. Estimating prevalence across countries, and assessing whether and how these estimates vary, is an important step in understanding the global challenge of pain.

Studies around the world that use survey data to estimate pain prevalence suggest there is wide cross-national variation [ 4, 24, 25, 33, 40, 41]. A meta-analysis of 25 studies estimating prevalence of chronic widespread pain across countries and cultural groups in Europe, Asia, and the Americas, found estimates ranging between 0% and 24% [ 50]. This variation may be partly explained by methodological difference across studies and partly by cultural idiosyncrasies [ 5, 15, 29]. It may also be explained by 'compositional' individual-level factors [ 6]. For instance, variations in the prevalence of any health condition cross-nationally is frequently a function of several demographic characteristics that are important determinants of health. Studies have consistently shown that women report pain more frequently than men, that pain prevalence increases with age, and that pain prevalence tends to be higher in rural as opposed to urban areas [ 4, 7, 25, 26, 33, 40, 50, 57]. As a result, older populations with a higher proportion of women and rural residents would be expected to have higher pain prevalence.

While research frequently considers these types of individual factors in studies of prevalence, they are unlikely to fully explain cross-national variations and run the risk of underrepresenting the impact of systemic processes on cross-national inequalities, which in turn has implications for the development of appropriate health policies [ 6]. Research on global health inequalities has identified a number of consequential 'contextual' country-level factors [ 64, 70]. In particular, research has implicated macro political and economic factors as determinants of health. These include the impact of national health expenditures, national income, and quality of governance on life expectancy and mortality [ 39, 43, 44, 49]. Social inequalities are also an important factor when considering health disparities [ 2]. Studies demonstrate significant relationships between within-country income inequality, as measured by indicators like the Gini coefficient, and a variety of health outcomes [ 56]. Gender inequality has also been associated with some health outcomes [ 61] including musculoskeletal pain [ 11], child mortality [ 14], mental health and overall self-rated health [ 45]. While these studies have focused on other health outcomes, we hypothesize that these types of country-level contextual factors would also impact pain, given that there is a close association between chronic pain and other health conditions [ 9, 13, 21, 22, 31, 62]. The extent to which country-level factors influence pain prevalence has, however, not been adequately examined.

The current study estimates country-level pain prevalence from a single global survey with a consistent definition of pain and instrumentation protocol. We combine survey data with country-level indicators gathered from global databases to create a multilevel dataset for 52 countries. The study uses these data to: (a) estimate and compare pain prevalence across countries, and (b) explore the degree to which variations in prevalence are explained by country-level contextual factors commonly considered as macro-determinants of health.

2. Methods

2.1. Ethical clearance

The study protocol was approved by the Mount Saint Vincent University Research Ethics Board [2021-014].

2.2. World Health Survey

Data on pain and individual-level demographic characteristics were obtained from the World Health Survey (WHS), implemented between 2002 and 2004 by the World Health Organization. The WHS involved cross-sectional data collection in 70 countries across five continents. Countries participating in the WHS were chosen to provide a range of different national income categories, and to include countries with large adult populations. These data have been commonly used for comparative research on health [ 35, 36, 66]. Details of the WHS survey and data are provided elsewhere [ 68, 74].

Each respective Ministry of Health within the 70 countries designed a local sampling strategy based on World Health Organization guidelines, and administered standardized questionnaires. A nationally representative, multistage cluster design was used in all countries except China, Comoros, Cote d'Ivoire, Croatia, India, and Russia, where the WHS was carried out in more geographically limited regions. Designs were based on probability strategies, with sampling frames covering 100% of eligible adults aged 18+ stratified by gender, age, and urban/rural setting [ 68]. Weights that account for sampling design and non-response and assure that prevalence estimates are representative of total country populations are provided for most countries. These sampling weights are applied as in other publications using these data [ 72].

Questionnaires went through back- and forward- translations into multiple languages, with end results being checked by linguists. Data collection was completed by trained interviewers, either face-to-face or by telephone. The individual country response rates ranged from 63% to 99% [ 72]. Ethics boards at each study site reviewed study protocols. Informed consent was obtained from all participants. The WHS was carried out in accordance with the latest version of the Declaration of Helsinki.

Of the 70 initial countries, 18 were excluded from the current analysis. One country did not make data available publicly. Ten countries do not include sampling weights, and since these are required for prevalence estimates, these countries were excluded. Five were excluded because of a high level of missing data (>20%) on the pain item used to estimate prevalence. Norway was excluded because its data did not include information on rural versus urban residence, a variable we use in our modeling of pain prevalence. After preliminary analysis, Comoros (population of <600,000 in 2003) was excluded because it was an outlier with respect to pain prevalence; its prevalence was more than 3.5 standard deviations above the cross-country mean.

For the purpose of these analyses, we considered all respondents aged 25+ from the remaining 52 countries. Starting the sample at this age maximizes the chance that the sample would be comprised of working age adults with completed education. Completed education level is one of the contextual variables in the analysis. Sensitivity analyses that included respondents 18+ yielded comparable results. This provided an initial sample size of 210,763 possible respondents. A small percentage of these respondents had missing data in variables of interest. Respondents with missing data in one variable of interest tended to have missing data across multiple variables. Subjects with any missing information were excluded (N=10,901), resulting in a final sample of N=199,862 for all analyses. The average within-country sample size was 3,844, with numbers ranging from a low of 620 in Luxembourg to a high of 32,028 in Mexico. Thirty-seven countries included at least 2,000 observations. See Supplementary Table 1 for a list of sample sizes by country and region.

2.3. Measuring pain

Pain is assessed by the following WHS question asked of all participants: "Overall in the last 30 days, how much of bodily aches or pains did you have?" with answer options being none, mild, moderate, severe, and extreme. The question did not specify the location of pain in the body or specific length of time for which pain has been present. We dichotomized the variable as none or mild versus moderate, severe, or extreme pain; a threshold meant to capture meaningful levels of pain. Previous research has indicated that compared to mild pain, moderate and severe pain strongly predict mortality [ 30] and the development of functional limitations at much earlier ages [ 20]. Thus, we followed the 'no worse than mild pain' model of pain, a designation that is indicative of analgesic control and carries significant health and economic benefits to patients [ 55]. Sensitivity analyses were conducted to calculate pain prevalence resulting from alternate measurement treatments (e.g. no pain vs. any pain) and to assess whether these alternate categorizations of pain resulted in different rank orderings of countries. Spearman's rank correlations indicated a strong, positive monotonic correlation between pain prevalence rankings across different categorizations of pain, indicating a congruence across these.

2.4. Demographic predictors

Models first adjust prevalence for three individual-level demographic variables that come from WHS data. These include interviewer-observed gender (dichotomized as woman=1 or man=0), self-reported age in years (categorized in ten-year increments as 25-34, 35-44, 45-54, 55-64, and 65 or older), and rural/urban setting (rural=1 or urban=0). We avoided over-controlling for individual-level variables as the current study prioritizes the impact of contextual variables on pain.

2.5. Country-level contextual predictors

We combined individual-level information from the WHS with country-level contextual covariates assembled from a series of global data banks, such as World Bank and United Nations Development Programme, to derive a dataset for the analysis. The contextual variables represent domains of socioeconomic, political, cultural, and environmental conditions, selected based on availability of data, and previous literature on contextual factors considered to impact population health [ 2, 71].

When available, these measures are taken for the year 2003, the midpoint of the WHS data collection. In a small number of instances, for a few of the country-level variables, information for the year 2003 was not available. In these cases, the measure came from the closest year for which data were available. Additional sensitivity analyses tested for the impact of including data from different years by modeling a variable that measured the difference between the year 2003 and the year in which data was observed. No bias was identified.

The following are the country-level contextual variables:

1) The Gini Index (Gini): a measure of economic inequality that ranges from 0 (no inequality) to 100 (totally unequal) [ 54].

2) Gross National Income (GNI): measured in current U.S. dollars per capita.

3) Average years of education completed by those age 25+ (Education).

4) Total labour force participation rate (TLFP): expressed as a percentage of the population.

5) Life expectancy at birth (LE), which serves as a proxy for the overall population health.

6) Health expenditure (HE%GDP): annual health expenditure expressed as a percentage of GDP.

7) Population density (Pop Density): number of residents per square kilometre.

6) The Gender Inequality Index (GII): ranges from 0 to 1, with higher scores indicating more inequalities between genders and greater disadvantages for women [ 27]. The index is derived from a series of dimensions that include educational attainment, economic and political participation, and reproductive health issues.

7) Quality of Government index (QoG). constructed using a principal-component factor analysis, with promax rotation, of six worldwide governance indicators (WGI) provided by the World Bank. These indicators are commonly used as proxies for governance quality [ 42, 44]. The factor analysis resulted in one factor containing all six governance indicators (alpha=0.948). High internal consistency and correlation between the predicted factor and a summed score of the six items (r=0.999, p=0.000) indicated that a summed, factor-based score was an appropriate and parsimonious choice. All governance indicators have values of −2.5 to 2.5; these are summed with a higher score indicating better governance.

To allow for comparability across these country-level contextual variables, all were standardized to have a mean of 0 and standard deviation of 1 in multivariate regression equations.

Finally, to account for potential regional heterogeneity in pain reporting across world regions, the 52 countries were categorized into one of six world regions according to the World Health Organization regional groupings [ 73]: the Americas, Africa, Europe, Eastern Mediterranean, Western Pacific, and South-East Asia. These were entered into models as dummy variables with Western Pacific, the region that was found to have the overall lowest levels of pain prevalence, as the comparison category. Since the WHO regional groupings differ from other standard ways of grouping countries, supplemental analyses tested other reasonable combinations and the overall pattern of findings did not differ from those reported herein.

Supplementary Tables 2, 3, and 4 provide details on country-level variables, unstandardized raw data by country, and results of the factor analysis used to create the Quality of Government variable, respectively.

2.6. Statistical analysis

We first calculate a standardized pain prevalence for each country, with the standardization being based on the global age and sex distribution for the year 2003 obtained from the United Nations Population Database [ 67]. This allows for a comparison of prevalence and an assessment of variation after accounting for cross-national age and sex differences.

Next, we examined associations between each separate individual- and country-level variable and pain by pooling data from all countries and calculating zero-order correlations. Using these pooled data, we then modeled the variation in the prevalence across countries by fitting nested multilevel random intercept logistic regression models predicting the odds that an individual living in a particular country reports pain. Because odds can be used to calculate predicted probabilities of reporting pain, and these probabilities translate into prevalence rates, higher odds are interpreted directly as higher prevalence. Multilevel models fit two types of equations. The first is the individual-level equation that estimates fixed effects, which capture the influence of covariates on the odds that an individual in any country reports pain. The covariates are both at the individual- and country-level. The second is the country-level equation to assess the random effect of country, which quantifies the variance in the odds of reporting pain that is a function of the unmeasured country-specific heterogeneity that remains after controlling for fixed effect covariates. This random effect accounts for the idiosyncratic likelihood of reporting pain that is unique to each country.

We tested a series of nested models, each of which adds different variables to a base model. The base model (Model 1) is an individual-level only model that adjusts for age, sex, and urban/rural residence. The magnitude of the random effect is expected to change as country-level variables are added, indicating the degree to which contextual covariates account for the variation in pain prevalence. Because a high correlation between a number of the contextual country-level variables is likely, we assessed the potential for, and developed models to avoid, collinearity. To do this, bivariate correlations were first examined across predictors. These are shown Table 1 . As can be seen, there are some very high correlations. For instance, higher average education is negatively and very strongly correlated with the Gender Inequality Index, meaning that these two variables will share a degree of variance that may be too large to adequately assess the independent impact of either variable when both are included in the same model. Thus, we tested variance inflation factors (VIF) to obtain a statistical basis for determining variables to be included in the same models [ 65]. There is little consensus on a cut-off that is most appropriate; however, most conventions dictate that a VIF greater than 10 indicates a danger of collinearity [ 17, 53, 69]. The VIF results are provided in Supplementary Table 5. Based on the VIF findings, the final presentation comprises several models, all of which have VIF values below the cut-off of 10. As noted, Model 1 is the base that includes only the individual-level variables: age, sex, and rural/urban setting. Model 2 adds a set of country-level contextual variables that do not pose shared variance problems. In Models 3 to 5, other contextual variables are added to Model 2 that individually do not pose issues, but would if entered together. In this way, the analysis examines the largest set of predictor variables possible while avoiding collinearity.

Table 1.

Gini

GNI

Education

TLFP

QoG

HE%GDP

LE

GII

Pop Density

In a final procedure, results of the multilevel analysis were used to calculate an adjusted pain prevalence for each of the 52 countries in the data. The country-level prevalence rates that adjust for the effects of the individual- and country-level variables included in particular models were computed by summing the resulting fixed and random effects from logistic regression models with random effects (i.e. intercepts) by country [ 25] such that:

P r e v a l e n c e=1 ∕(1 +e x p(-1 ∗(l i n e a r p r e d i c t i o n f o r f i x e d e f f e c t+l i n e a r p r e d i c t i o n f o r r a n d o m e f f e c t))).

We calculated the coefficient of variation (CV) to assess the disparity in prevalence estimates across countries for each model's predicted country-level prevalence rates. Thus, the coefficient of variation, which is the ratio of the standard deviation in prevalence to mean prevalence, allows us to assess how much variation in prevalence is explained by the contextual factors included in each model.

Data manipulations and descriptive analyses were performed using Stata 16.1 [ 63], while multilevel effects models were estimated using SPSS 26 software [ 38].

3. Results

Table 2 presents unweighted descriptive statistics for study variables. For the individual-level variables, we report statistics for samples pooled across countries within regions, and the total sample pooled across all countries. Sample sizes are also shown. The overall unweighted prevalence of reported pain for the total combined sample is 28%. Regionally, the lowest unweighted prevalence is for the sample that combines observations from across the five Western Pacific countries at 21%, and the highest prevalence is for the 18 European countries at 34%.

Table 2.

Europe

Africa

Americas

SE Asia

E Mediterranean

W Pacific

Total

Individual-Level (proportions)

Country-Level (means)

For the country-level contextual variables, we report means for countries grouped within regions and the total for all 52 countries prior to standardization. There is variation in country-level variables across regions. Generally, the 18 countries in Europe have the least income and gender inequality as measured by the Gini and the GII, and the highest gross national income (per capita GNI), average years of education, quality of government (QoG), health expenditure as a proportion of GDP, and life expectancy. The highest income inequality is found across countries in the Americas, while African countries display the highest gender inequalities. Gross National Income, Quality of Government, and health expenditures are lowest, and population density is highest, in the South-East Asian countries.

The prevalence of pain in each country, standardized by age and sex, is displayed as the proportion reporting pain, with 95% confidence intervals, in Figure 1 . The figure clearly shows a wide range in prevalence. China has the lowest proportion with pain at 0.099 (95% CI: 0.090 - 0.108) and Morocco has the highest proportion at 0.503 (95% CI: 0.487 - 0.519). However, aside from some countries on the higher and lower end, most report a prevalence within a somewhat narrower range. The average for the combined sample across the 52 countries is 0.275 with a cross-country standard deviation of 0.084. Thirty-eight countries fall within one standardized unit from the cross-country mean with a prevalence between 0.191 and 0.359. Eight countries fall under a prevalence of 0.191 and six countries have a prevalence over 0.359. Supplementary Table 6 provides details for both unstandardized (crude) and standardized point prevalence estimates.

The first column of results in Table 3 shows the zero-order correlations with 95% confidence intervals and p-values that indicate whether there is an association between each individual covariate and the probability of reporting pain for the total sample. Without controls, all of the variables, with the exception of Quality of Government and life expectancy, appear to have an association with reported pain.

Table 3.

Zero-Order
Correlation

Model 1
OR (95% CI)

Model 2
OR (95% CI)

Model 3
OR (95% CI)

Model 4
OR (95% CI)

Model 5
OR (95% CI)

Intercept

0.126 (0.109-0.145)
0.000

0.068 (0.042-0.110)
0.000

0.088 (0.058-0.134)
0.000

0.069 (0.042-0.112)
0.000

0.076 (0.048-0.121)
0.000

Age

25-34

−0.140 (−0.144-0.135)
0.000

-

-

-

-

-

GII ¹

0.049 (0.045-0.053)
0.000

1.307 (1.073-1.437)
0.001

QoG ²

−0.001(−0.006-−0.003)
0.534

0.918 (0.796-1.059)
0.242

LE ³

0.003 (−0.001-−0.008)
0.134

0.785 (0.620-0.995)
0.045

Region

W Pacific

−0.046 (−0.050-−0.042)
0.000

-

-

-

-

N

199861

199861

199861

199861

199861

Random Intercept

0.256

0.188

0.161

0.188

0.179

0.000

0.000

0.000

0.000

0.000

AIC

1575838859.653

1575838917.394

1575838916.776

1575838921.395

1575838917.504

The remaining columns in Table 3 present the odds ratios of reporting pain for five multilevel logistic regression models with 95% confidence intervals and p-values. Model 1 shows associations between pain and individual-level covariates. Women (OR=1.973), older persons (OR=4.850), and rural residents (OR=1.199) have higher odds of reporting pain. The magnitude of these associations is consistent across all our models.

Models 2-5 present associations that include both individual- and country-level covariates. Model 2 shows that living in a country with a higher level of income inequality (i.e., higher Gini Index) predicts higher odds of reporting pain (OR=1.242; 95% CI: 1.073-1.437). This effect remains stable across models 3-5. Because contextual covariates are standardized, odds are interpreted as the expected change in pain prevalence given a standard deviation change in the predictor. A one standard deviation change in GNI is associated with 21-26% higher odds of pain. Population density (Pop Density) is also associated with a 26% higher odds of reporting pain (OR=1.264; 95% CI: 1.049-1.523) in model 2, and this effect persists in every following model (26-30% higher odds). The Gender Inequality Index (GII) in Model 3 is associated with pain (OR=1.307; 95% CI: 1.073-1.437), indicating that pain prevalence is 31% higher for each standard unit of gender inequality. We subsequently tested an interaction between gender (woman=1) and the Gender Inequality Index. The result (OR=1.085; 95% CI: 0.999-1.177) indicates that the disadvantage that women have in experiencing pain may be even greater in countries with more gender inequality. However, both men and women are disadvantaged by country-level gender inequality such that both are more likely to report pain in countries with high gender inequality compared to countries with low gender inequality. A standard unit increase in life expectancy (LE) is associated with 21% lower odds of pain in Model 5 (OR=0.785; 95% CI: 0.620-0.995). Covariates not associated with the odds of reporting pain in multilevel models include Quality of Government (QoG), average level of education (Education), Total Labor Force Participation (TLFP) and health expenditures as a proportion of GDP (HE%GDP). Gross National Income (GNI) is associated with slightly lower odds of reporting pain in Model 2 (OR=0.935; 95% CI: 0.873-1.001), but this is a small effect, and does not carry over in other models.

Region is associated with the odds of reporting pain. The main finding here is that, adjusting for other factors, living in a European country predicts higher odds of reporting pain relative to living in the Western Pacific region, which has the lowest odds. This finding remains stable across models 2-5. Otherwise, living in an Eastern Mediterranean country is associated with higher odds in pain compared to the Western Pacific, although the strength of effect is less consistent across models compared to living in Europe. Living in Africa and the Americas is associated with the odds of reporting pain in some of the models and not others, with greater odds of pain in comparison to the Western Pacific.

The random effect in model 1 is 0.256 and indicates substantial variance in the odds of reporting pain between countries. The random effect is reduced when country-level variables are added to models. For instance, the random intercept reduces by about 27% between models 1 and 2, after country-level variables are added to the model in addition to individual-level variables. The random intercept is at its lowest point in Model 3, having reduced by 37% from model 1. This occurs when adjusting for the Gender Inequality Index, suggesting that this model accounts for more cross-country variance than others. However, a large portion of the heterogeneity in pain prevalence remains unexplained by covariates across the models.

To illustrate the unexplained variation further, we present in Figure 2 the range and variance in pain across countries in the age-/sex-standardized prevalence and the predicted prevalence based on each of the multilevel models. Each dot in the figure is the prevalence of pain in one country given the specific type of estimate. The countries with the highest and lowest predicted values are listed with their predicted prevalence, shown as the proportion reporting pain, in order to assess the range. The Figure illustrates graphically the wide range in prevalence in age- and sex-standardized estimates. Notably, adjustment for age, gender, and rural/urban setting in Model 1 produces no reduction in the large variation of prevalence across countries. In fact, based on the Coefficient of Variation (CV) and the range, the variation increases, likely due to how controlling for age, gender, and rural setting interacts with the unique population distributions in each country to shift pain prevalence further from the grand mean. However, when additionally adjusted for country-level factors, the estimated variance in prevalence decreases, as can be seen in a narrowing of the range and a decrease in CV. Consistent with the random effect in the multilevel model, the smallest variation is seen in model 3. This model included individual-level factors, the Gini index, Gross National Income, average education, Total Labor Force Participation, health expenditures, population density, and the Gender Inequality Index. There is a definite tightening in the predicted values for this model. Nonetheless, a substantial amount of variation remains. The adjusted rates in Model 3 vary from a predicted low of 0.152 in Ireland to a predicted high of 0.432 in Morocco. The CV drops to .252 for this model, which represents a 25% reduction in the CV in comparison to Model 1.

We conducted sensitivity analyses in which we dichotomized the pain outcome as no pain versus any pain. The pain prevalence estimated for this definition is shown in Supplementary Figure 1. The average prevalence for the combined sample across 52 countries doubles to 0.532, with a standard deviation of 0.077. However, the wide range in pain prevalence across countries remains, ranging from 0.237 to 0.784, in Ireland and Bangladesh respectively. The ranking of pain across countries is also largely the same (r s=0.81). Likewise, with the no vs. any pain categorization as outcome, the inclusion of country-level variables in multilevel models results in a reduction in the CV of up to 20% compared to model 1, even though there is an overall lower level of variation between countries. This confirms that the country-level variables are largely insensitive to the categorization of pain.

4. Discussion

We examined prevalence of moderate to extreme pain among adults aged 25+ across 52 countries using data from the 2002 - 2004 World Health Survey (WHS). The cross-country average reporting pain over the 30 days preceding the interview was 27.5%, and ranged from a minimum of 9.9% in China to a maximum of 50.3% in Morocco. Though not directly comparable, this pain prevalence is not radically different from that in Jackson et al. [ 40], who reported pooled prevalence of unspecified persistent pain to be 34% across studies and lower- and middle- income countries. Also consistent with previous literature, we found substantial variation in pain prevalence across countries [ 4, 24, 26, 33, 40, 50, 60]. This variation exists despite the information on pain coming from a single data source - the World Health Survey - that used a standardized measure across countries.

Like previous research, this study found that the odds of experiencing pain is higher for women, older persons, and those living in rural settings [ 8, 19, 26, 28, 40, 50, 60]. These individual-level characteristics -age, sex, and rural/urban residence-did not explain the cross-country variation in pain prevalence. Also comparable to the findings of similar research, the observed cross-national variation could not be completely explained with the inclusion of higher-level variables. For instance, research based on the Cultural and Psychosocial Influences on Disability (CUPID) study found marked variation in musculoskeletal pain across 18 countries, and though reduced, between-country variance was not completely accounted for by the inclusion of group-level variables [ 18, 19]. This indicates a complex interaction between individual- and country-level factors, as well as other factors, in explaining variation in pain, and highlights a need to better understand why people in some countries appear to be more prone to pain. However, five contextual country-level factors were associated with pain: region, population density, life expectancy, gender inequality, and income inequality. Moreover, they explained some of the cross-country variation in pain levels. Residents of European countries were most likely to report pain, while those living in countries in the Western Pacific region were least likely. These regional variations may partly reflect the distinctive subjective nature of pain reporting on surveys.

With respect to population density, the environment in which people live, shaped by factors such as urbanization, is a major factor influencing public health [ 47]. The World Health Organization, for instance, has highlighted the negative impact of high population density on mental and physical health [ 75]. Inadequate housing, congested public transport, poor hygiene, high pollution levels, a lack of safe spaces for active living, and greater perceived stress may all increase the likelihood of experiencing physical and mental health conditions. Thus, though living in a rural area may contribute to more adverse health outcomes due to the reduced availability and accessibility of health care [ 58], the quality of the built environment in urban areas also matters, having possible implications for health conditions such as pain. Given the lack of research on population density and pain prevalence, these results must be interpreted cautiously, although it seems likely that population density may be reflecting one or more of the detrimental conditions associated with rapid urbanization.

Life expectancy is a key metric for assessing population health. However, life expectancy may also be a proxy representing other determinants that support a longer life expectancy beyond the country-level variables included in this study. Hauck, Martin, and Smith [ 32] suggested that life expectancy may be robustly associated with a variety of possible social determinants, including gender equality, agricultural production, political stability, access to clean water and sanitation, good governance, primary school enrolment, private health expenditure, overseas development assistance, control of armed conflict, and HIV prevalence. Thus, beyond the determinants that were already included in this analysis, it is possible that life expectancy may be representing one or more of these, and should be researched further.

Importantly, this study found two different forms of social inequality, income and gender, to be independently and strongly associated with the probability of reporting pain. Research attests that income inequality affects population health and wellbeing [ 56], and that individual income is related to health as a marker of individual social status [ 1, 51]. Moreover, not only may income inequality have a direct impact on health outcomes across countries [ 56], but greater inequality also likely worsens other outcomes that impact health, such as social mobility and mental health conditions, all of which contribute to a cycle of inequality, and therefore worse health outcomes, through fewer resources [ 16, 52, 56].

It has also long been known that pervasive gender inequality and restrictive gender norms result in a range of negative health outcomes for the total population, not only for women and girls [ 61]. Subsequent testing of the interaction between gender and the Gender Inequality Index in the current data indicated that greater gender inequality increases the probability of pain among both women and men, although the association is stronger for women. This is a promising area of future research to explore, as gender inequalities and gender discrimination can contribute to poor health outcomes through complex pathways including how the gender system interacts with other axes of power and privilege across the gender spectrum to shape an individual's social position throughout life [ 61].

Some theories have attempted to explain the impact of inequality on health as solely the result of indirect forces, including the availability of "neo-materials", such as societal investment in education, occupation, and health services [ 48]. However, this study has suggested that income inequality and gender inequality have negative impacts on health outcomes such as pain even when accounting for possible effects of social inputs, such as GNI, education, health expenditure, and labour force participation. It is possible that psychosocial factors, such as social capital and trust [ 56], or consequences of feeling socially inferior, lacking control, and feeling unsafe [ 12] may mediate the relationship, contributing to a physiological chain of events that translate into heightened risk of mental and physical health conditions over time. While these effects are felt most among the marginalized groups, they may also extend to other strata of the population due to generally higher levels of stress and distrust. Our findings about gender and income inequalities are of particular concern at time of writing given gender inequalities that are being exacerbated by a global pandemic lockdown [ 46], and income inequalities that are on the rise globally [ 23, 34]. Thus, social inequalities remain a critical area for future research and health policy, including in, but not restricted to the realm of pain.

Strengths of our study include a large sample size and substantial number of countries representing a variety of country regions and income levels. Moreover, due to rigorous sampling and survey protocol in the WHS, the survey was conducted using standardized measures among representative samples.

Our study also had limitations. Though the WHS survey provides a unique opportunity as a standardized source of international health data when there are few comparable data sources available for examining global variations in pain prevalence [ 33], it is an older dataset, which may limit its current generalizability. In addition, due to the way pain was assessed in the WHS survey, only accounting for pain experienced in the previous 30 days, it may be difficult to conclude that these results point to prevalence of chronic pain (which is often assessed with respect to a longer time frame), making it challenging to compare to other studies. Likewise, due to a lack of data, we could only assess the general intensity of pain, and not the frequency of pain experienced within the month. Finally, the WHS was cross-sectional and causal relationships cannot be assumed. However, even with these challenges, this study has contributed unique insight into the potential impacts of contextual factors on pain around the world, and presents a starting point for further research.

In conclusion, prevalence of pain varied substantially across countries (9.9 - 50.3%). A portion of this variation was explained by contextual country-level social and economic factors. Importantly, these factors included two indicators of social inequality, income inequality and gender inequality. However, residual variation in pain prevalence across countries remains even in our most robust model. Given the consistency of measurement across the surveys, the remaining variation in pain across countries points to a complex interaction between known and unknown personal, local, economic and political impacts on pain prevalence, as well as inherent differences in language, interpretations of health, and other difficult-to-assess cultural idiosyncrasies. The frequency with which individuals around the world report moderate to severe pain, and the association of pain reporting with social, economic, and political determinants, provides further justification for regarding pain as a global public health priority. It also suggests that global attention and resources be shifted to the macrosocial determinants that shape patterns of pain and differentially impact quality of life on a larger scale. Future research should delve further into the complex association between inequality and pain in order to obtain a more complete picture of the possible explanatory power of social and political determinants of pain around the world.

Supplementary Material

Supplementary Materials: figures, tables

Supplementary Materials: movies, audio

Acknowledgements

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG065351 (PI: HGP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Financial support was also provided by the Social Sciences and Humanities Research Council of Canada through the Canada Research Chairs Program to ZZ.

Footnotes

Conflict of interest statement

The authors have no conflicts of interest to declare.

References

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A global study of pain prevalence across 52 countries: examining the role of country-level contextual factors

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Pain. Author manuscript; available in PMC 2023 Sep 1. Published in final edited form as: Globally, pain impacts billions of people daily [ 10, 37, 59]. Given its ubiquity, and its accompanying disability and mortality, there is ample reason to regard pain as a major global health burden and priority [ 3, 29].

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35.2 million

Estimated working days lost due to work-related ill health and non-fatal workplace injuries in 2022/23 (LFS)

Working days lost, 2022/23

Stress, depression or anxiety and musculoskeletal disorders accounted for the majority of days lost due to work-related ill health in 2022/23, 17.1 million and 6.6 million respectively.

On average, each person suffering took around 15.8 days off work. This varies as follows:

6.6 days for Injuries

17.8 days for Ill health cases

19.6 days for Stress, depression or anxiety

13.9 days for Musculoskeletal disorders

Change over time

Prior to the coronavirus pandemic, working days lost per worker due to self-reported work-related illness or injury had been broadly flat. The current rate (1.31 working days lost per worker) is higher than the 2018/19 pre-coronavirus level.

A chart showing how the working days lost rates have changed over time can be found in the Historical picture statistics in Great Britain report.

More information on working days lost

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Provides estimates of work-related days lost from self-reporting household surveys: the Labour Force Survey (LFS) for workplace injuries and the Self-reported Work-related Illness (SWI) surveys from work related ill health.

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A new view of pain as a homeostatic emotion

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A new view of pain as a homeostatic emotion

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A new view of pain as a homeostatic emotion

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The Infancy of Infant Pain Research: The Experimental Origins of Infant Pain Denial

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The Infancy of Infant Pain Research: The Experimental Origins of Infant Pain Denial

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Theories of pain: from specificity to gate control

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Theories of pain: from specificity to gate control

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Complexity, reductionism and the biomedical model,” in Rethinking Causality, Complexity and Evidence for the Unique Patient: A CauseHealth Resource for Healthcare Professionals and the Clinical Encounter. pp. 75-94

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Complexity, reductionism and the biomedical model,” in Rethinking Causality, Complexity and Evidence for the Unique Patient: A CauseHealth Resource for Healthcare Professionals and the Clinical Encounter. pp. 75-94

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Biomedical models can be of many types-from animal models of human diseases to animal, in vitro, or modelling systems for studying any aspect of human biology or disease. A detailed discussion of various types of models appeared in a National Research Council study, Models for Biomedical Research (NRC 1985), and is appended to this report.

A biomedical model is a surrogate for a human being, or a human biologic system, that can be used to understand normal and abnormal function from gene to phenotype and to provide a basis for preventive or therapeutic intervention in human diseases. For example, characterization of mouse models of various dwarfing syndromes, cloning of mutated genes, and parallel comparative genetic mapping and cloning of genes for similar human syndromes have led to an understanding of various human dwarfing conditions and have suggested therapies based on biologic knowledge, rather than shotgun testing. Mouse models with targeted mutations in the cystic fibrosis gene are providing a means for testing gene therapy delivered by aerosol into the lungs (Dorin and others 1996). The use of nonhuman primates that are genomically similar is beginning to shed light on complex human diseases. Squid giant axons are important model systems in neurobiologic research because their size allows a variety of manipulations not possible with vertebrate axons and because there are 40 years of data on the anatomy, physiology, biophysics, and biochemistry of those neurons. Clams, sea urchins, and fishes are models in developmental biology (for example, for study of transcriptional regulation during early cell differentiation) because they have high fecundity, short generation times, and transparent eggs that develop externally. Those are but a few examples among thousands that illustrate the breadth and utility of comparative models in biomedicine.

A model need not be an exact replica of a human condition or disease. For example, mice with mutations in the homologue of the human Duchenne-Becker muscular dystrophy gene are less severely affected than human patients and can regenerate degenerating muscle (Anderson and others 1988); they have been used successfully to test muscle implantation therapy for this debilitating disease (Ragot and others 1993). Many targeted-mutation (so-called knockout) mice exhibit unexpected phenotype, revealing previously unidentified roles for known genes (Homanics and others 1995 Shastry 1994). Finally, to the extent that biologic processes in living organisms are predictable, computer modelling might be able to predict the outcome of perturbing a metabolic pathway or treating a metabolic disease; this can lead to hypothesis-driven research with an animal model.

This report tends to emphasize genetic models because the dramatic success of the Human Genome Initiative has created a strong bias in biomedical research toward research on functional genomics. The preponderance of survey and workshop participants were scientists who were using genetic animal models. This emphasis is not intended to downplay the value of nongenetic model systems. The information that we gathered from researchers who were using nongenetic systems strongly suggests that many of the same factors influence their success or failure.

The committee recognized the importance of in vitro models, but did not cover them in this report for several reasons. First, in vitro models, including cell culture, bacteria, viruses, and yeasts. are universally used by the scientific community, including those using animal models. In vitro models provide important perspectives on the continuum of biologic processes that ultimately must be investigated at the organismal level. Furthermore, in vitro systems provide a wealth of material for in vivo applications, including vectors, constructs, expression libraries, monoclonal antibodies, infectious agents (including genetically modified agents), and so on. Finally, in vitro models are used by scientists across all NIH institutes, and this committee focused on recommendations that would enhance NCRR's rich tradition of animal model development, maintenance, and support.

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Biomedical models can be of many types-from animal models of human diseases to animal, in vitro, or modelling systems for studying any aspect of human biology or disease. A detailed discussion of various types of models appeared in a National Research Council study, Models for Biomedical Research (NRC 1985), and is appended to this report.

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What are Yellow Flags and Why are They Important?

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What are Yellow Flags and Why are They Important?

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https://www.youtube.com/watch?v=QFkkxXQ7NIo

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What are Yellow Flags and Why are They Important?

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https://www.youtube.com/watch?v=gwd-wLdIHjs&t=46s

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TEDxAdelaide - Lorimer Moseley - Why Things Hurt

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A modern way to teach and practice manual therapy

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A modern way to teach and practice manual therapy

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Musculoskeletal (MSK) conditions are leading contributors to the burden of global disability and healthcare [ 1]. Amongst other interventions, manual therapy (MT) has been recommended for the management of people with MSK conditions in multiple clinical guidelines, for example [ 2, 3].

MT has been described as the deliberate application of externally generated force upon body tissue, typically via the hands, with therapeutic intent [ 4]. It includes touch-based interventions such as thrust manipulation, joint mobilisation, soft-tissue mobilisation, and neurodynamic movements [ 5]. For people with MSK conditions, this therapeutic intent is usually to reduce pain and improve movement, thus facilitating a return to function and improved quality of life [ 6]. Patient perceptions of MT are, however, vague and sit among wider expectations of treatment including education, self-efficacy and the role of exercise, and prognosis [ 7].

Although the teaching and practice of MT has invariably changed over time, its foundations arguably remain unaltered and set in biomedical and outdated principles. This paper sets out to review contemporary literature and propose a revised model to inform the teaching and practice of MT.

The aim of this paper is to stimulate debate about the future teaching and practice of manual therapy through the proposal of an evidence-informed re-conceptualised model of manual therapy. The new model dismisses traditional elements of manual therapy which are not supported by research evidence. In place, the model offers a structure based on common humanistic principles of healthcare.

Consenus methodology

We present the literature synthesis and proposed framework as a consensus document to motivate further professional discussion developed through a simple three-stage iterative process over a 5-year period. The consensus methodology was classed as educational development which did not require ethical approval. Stage 1: a change of teaching practice was adopted by some co-authors (VG, RK, EL) on undergraduate and postgraduate Physiotherapy programmes at a UK University in 2018. This was a result of standard institutional teaching practice development which includes consideration of evidence-informed teaching. Stage 2: Input from a broader spectrum of stakeholders was sought, so a group of experienced, internationally-based educators, clinicians, and researchers from across the spectrum of manual therapy was convened. Perspectives were elicited through discussions in an iterative process. Stage 3: Presentations were made by some of the co-authors (VG, RK, SV, KY) to multidisciplinary groups (UK, Europe, North America) and feedback via questions and discussions was incorporated into further co-author discussions on the development of the framework. Consensus was achieved through repeated discussion of relevant elements. Figure 1 summarises the consensus methodology.

Summary and timeline of iterative consensus process for development of framework (MT: Manual Therapy; UG: Undergraduate; PG: Postgraduate)

Clinical & cost effectiveness of manual therapy

Manual therapy has been suggested to be a valuable part of a multimodal approach to managing MSK pain and disability, for example [ 8]. The majority of recent systematic reviews of clinical trials report a beneficial effect of MT for a range of MSK conditions, with at least similar effect sizes to other recommended approaches, for example [ 9]. Some systematic reviews report inconclusive findings, for example [ 10], and a minority report effects that were no better than comparison or sham treatments, for example [ 11].

Potential benefits must always be weighed against potential harms, of course. Mild to moderate adverse events from MT (e.g. mild muscle soreness) are common and generally considered acceptable [ 12], whilst serious adverse events are very rare and their risk may be mitigated by good practice [ 13]. MT has been reported by people with MSK disorders as a preferential and effective treatment with accepted levels of post-treatment soreness [ 14].

MT is considered cost-effective [ 15] and the addition of MT to exercise packages has been shown to increase clinical and cost-effectiveness compared to exercise alone in several MSK conditions [ 16, 17, 18, 19, 20, 21, 22, 23]. Further, manual therapy has been shown to be less costly and more beneficial than evidence-based advice to stay active [ 24].

In summary, MT is considered a useful evidence-based addition to care packages for people experiencing pain and disability associated with MSK conditions. As such, MT continues to be included in national and international clinical guidelines for a range of MSK conditions as part of multimodal care.

Principles of traditional manual therapy (TMT)

Manual therapy has been used within healthcare for centuries [ 4] with many branches of MT having appeared (and disappeared) over time [ 25]. In developed nations today, MT is most commonly utilised by the formalised professional groups of physiotherapy, osteopathy, chiropractic, as well as groups such as soft tissue therapists. All of these groups have a history that borrows heavily from traditional healers and bone-setters [ 26].

Although there are many elements of MT, three principles appear to have become ubiquitous within what we shall now refer to as 'traditional manual therapy' (TMT): clinician-centred assessment, patho-anatomical reasoning, and technique specificity [ 27, 28, 29, 30]. These principles continue to influence the teaching and practice of manual therapy over recent years, for example [ 31].

However, they have become increasingly difficult to defend given a growing volume of empirical evidence to the contrary.

Traditional manual therapy (TMT) principles: origins and problems

Clinician-centred assessment

TMT has long had an emphasis on what we shall refer to as clinician-centred assessments. Within this, we claim, is an assumption that clinical information is both highly accurate and diagnostically important, for example [ 32]. Clinician-centred assessments include, for example, routine imaging, the search for patho-anatomical 'lesions' and asymmetries, and specialised palpation. Although the focus of this paper is on the 'hands-on' examples of client-centred assessment, the notion of imaging is presented below to expose some of the flaws in the underlying belief system for TMT.

Hands-on interventions are inextricably related to hands-on assessment [ 40], and often associated with claims of 'specialisation' [ 41]. By this we mean where a great level of training and precision are claimed to be necessary for influencing the interpretation of assessment findings, treatment decisions, and/or treatment outcomes. Implicit within this claim is that therapists who are unable to achieve such precision are not able to perform MT to an acceptable level (and thereby are not able to provide benefit to patients).

There are numerous studies that cast doubt over claims of highly specialised palpation skills. Palpation of anatomical landmarks does not reach a clinically acceptable level of validity [ 42]. Specialised motion palpation does not appear to be a good method for differentiating people with or without low back pain [ 43]. Poor content validity of specialised motion tests have been reported, in line with a lack of acceptable reference standards [ 44]. Palpable sensations reported by therapists are unlikely to be due to tissue deformation [ 45]. Furthermore, the delivery of interventions based on specialised palpatory findings is no better than non-specialised palpation [ 46]. Generally poor reliability of motion palpation skills has been reported, for example [ 47] and appear to be independent of clinician experience or training, for example [ 48]. Notably, person-centred palpation-for pain and tenderness for example-has slightly higher reliability, but is still fair at best [ 49].

This does not mean that palpation is of no use at all though; just that effective manual therapy does not depend upon it. For example, expert therapists can display high levels of interrater reliability during specialised motion palpation [ 50]. Focused training can improve the interrater reliability of specialised skills [ 51]. However, the validity of the phenomenon remains poor. Given the weight of the evidence and consistency of data over recent decades, we suggest that the role of clinician-centred hands-on assessment is no longer central to contemporary manual therapy.

Patho-anatomical reasoning

The justification for selecting particular MT interventions has historically been based upon the patho-anatomical status of local peripheral tissue [ 52, 53, 54, 55]. Patho-anatomical reasoning, we propose, is the framework that links clinician-centred assessments to the desire for highly specific delivery of MT interventionsKey to this is the relationship between a patho-anatomic diagnosis and the assumed mechanisms of action of the intervention employed.

Technique specificity

TMT techniques have been taught with an emphasis that a particular direction, 'grade' of joint movement, or deformation of tissue at a very specific location in a certain way, is required to achieve a successful treatment outcome.

One problem with a demand for technique specificity in manual therapy is that an intervention does not always result in the intended effect. For example, posteroanterior forces applied during spinal mobilization consistently induce sagittal rotation, as opposed to the assumed posteroanterior translation, for example [ 69]. Furthermore, irrespective of the MT intervention chosen, restricting movements to a particular spinal segment is difficult and a regional, non-specific motion is typically induced, for example [ 70].

To support technique specificity, comparative data must repeatedly and reproducibly show superiority of outcome from specific MT interventions over non-specific MT, which is consistently not observed [ 71, 72, 73]. Some studies have demonstrated localised effects of targeted interventions [ 74] but there appears to be no difference in outcome related to: the way in which techniques are delivered [ 75]; whether technique selection is random or clinician-selected [ 41]; or variations in the direction of force or targeted spinal level [ 76]. Conversely, there is evidence that non-specific technique application may improve outcomes [ 77, 78, 79]. Further, sham techniques produce comparable results to specialised approaches [ 11].

Passive movement and localised touch have been associated with significant analgesic responses [ 80]. These data indicate the presence of an analgesic mechanism. Unfortunately, mechanistic explanation for the therapeutic effects of MT upon pain and disability still remain largely in a 'black box' state [ 81]. Nevertheless, there are several plausible mechanisms of action to explain the analgesic action of MT interventions, including the activation of modulatory spinal and supraspinal responses [ 82, 83, 84, 85]. In support of this, MT interventions have been associated with a variety of neurophysiological responses [ 61]. However, it must be acknowledged that these studies provide mechanistic evidence based on association, which is insufficient to make causal claims [ 86]. Importantly, none of these neurophysiological responses have been directly related to either the analgesic mechanisms or clinical outcome and may therefore be incidental.

A modern framework for manual therapy

We propose a new direction for the future of MT in which the teaching and practice of this core dimension of MSK care are no longer based on the traditional principles of clinician-centred assessment, patho-anatomical reasoning, and technique specificity.

In doing so, this framework places MT more explicitly as part of person-centred care and appeals to common principles of healthcare, best available evidence, and contemporary theory which avoids unnecessary and over-complicated explanations of observed effects. The framework is simple in terms of implementation and delivery and contextualised by common elements of best practice for healthcare, in line with regulated standard of practice, e.g., [ 94, 95, 96, 97]. Our proposal simply illustrates the operationalisation of these common elements through manual therapy.

Too much emphasis has been given to clinician-centred assessments and this should be rebalanced with an increased use of patient-centred assessments, such as a thorough case history, the use of validated patient-reported outcome measures (PROMS), and real-time patient feedback during assessments.

The new framework considers fundamental and humanistic dimensions of touch-based therapies, such as non-specific neuromodulation, communication and sense-making, physical education, and contextual clinical effectiveness. This aligns to contemporary ideas regarding therapeutic alliance and a move towards genuinely holistic healthcare [ 98, 99]. The framework needs to be "open" in order to represent and allow expression of the complexity of the therapeutic encounter. However, to prevent the exploitation of this openness the framework is underpinned by evidence, and any manual therapy approaches without plausible and measurable mechanisms are not supported.

To provide the best care, common healthcare elements such as the safety and comfort of the person seeking help and therapist must be considered, and care should be provided as efficiently as possible. Our framework embraces these dimensions and employs an integration of current evidence. It is transdisciplinary in nature and may be adopted by all MT professions. Figure 1 provides a graphical representation of the framework. It is acknowledged that all components overlap, relate, and influence each. There are two main components: the practical elements on the inside, comprised of safety, comfort, and efficiency, and the conceptual themes on the outer regions, consisting of communication, context, and person-centred care Fig. 2.

Representation of a modern teaching and practice framework for manual therapy. The image is purposefully designed to be simple, and has been developed primarily to be used as a teaching aid. When displayed in a learning environment, learners and clinicians can quickly refer to the image to check their practice against each element. To keep the image clear, each element of the image is described in detail in the text below"

Practical elements

Safety

Safety for people seeking help is a primary concern for all healthcare providers, with the aims to " prevent and reduce risks, errors and harm that occur to patients [sic] during provision of health care... and to deliver quality essential health services" [ 100]. This, and the notion of safety more generally (including that of the therapist), should be central to way MT is taught and practised.

A fundamentally safe context should be created where there is an absence of any obvious danger or risk of harm to physical or mental health. Consideration should be given to ensuring that communication and consent processes are orientated towards the safety of both the person seeking help and the therapist. The therapist should pay attention to any sense of threat that could be present in the physical, emotional, cognitive and environmental domains of the clinical encounter, and use skilful communication to mitigate anxiety about the assessment or therapeutic process.

Safety should also be considered in the clinical context of the assessment and treatment approach, ensuring that relevant and meaningful safety screenings have been undertaken [ 67, 101]. There remains a need for good, skilful practice and development of manually applied techniques, but this can be achieved without reference to the principles of TMT and without the dogma of a proprietary therapeutic approach.

Comfort

Comfort suggests that both the person seeking help and the therapist are physically and emotionally content during the assessment and therapeutic process. For example, the person seeking help is agreeable with any necessary state of dress (sociocultural difference should be considered); the person is relaxed and untroubled in whatever position they are in, and is adequately supported whether sitting, standing or recumbent during assessment and treatment; the therapist is comfortable with their positioning and posture; any discomfort produced by the therapeutic process is negotiated and agreed. Any physical mobilisation or touch should be applied with respect to the feedback from the person in relation to their comfort, rather than a pre-determined force based on the notion of resistance. This process requires clinical phronesis, sensitivity, responsivity, dexterity, and embodied communication [ 102].

Efficiency

The therapeutic process should be undertaken in a well-organised, competent manner aiming to achieve maximum therapeutic benefit with minimum waste of effort, time, or expense. To enhance the efficiency dimension, the assessment and therapeutic process should be an integral part of a holistic educational and/or activity-based approach to the management of the people which might also address psychological, nutritional, or ergonomic aspects of care, while being aware of social determinants to health. Recommendations exist which serve as a useful guide for enhancing care and promoting self-management in an efficient way [ 103].

A principle of this new model of MT is that therapists should not lose sight of the goals they develop with the people they help and ensure that there is coherence between their management aims and their techniques. Therapists should aim to support a person's self-efficacy and use active approaches to empower them in their recovery. The overall number of therapeutic applications should be made in the context of fostering therapeutic alliance and supporting people to make sense of their situation and symptoms. This should be informed by contemporary views of the effects of manual therapy, emphasising a "physical education process" to promote sense-making and self-efficacy in alliance with the people they aim to help.

Clinical interactions need to be reproducible under a person's own volition, serving to enhance self-empowerment. For example, someone could be taught how to "self-mobilise" if a positive effect is found with a particular therapeutic application. This should be appropriately scaffolded with behavioural change principles and functional contextualism that promote autonomy and self-management, rather than inappropriate reliance on the therapist [ 103, 104].

An important and emergent notion from the proposed model is to question what constitutes indications for MT given that the model excludes traditional factors which would have informed whether manual therapy is indicated or not for a particular person. The response to this sits within the efficiency and safety dimensions: MT can be beneficial as part of a multi-dimensional approach to management across a broad population of people with musculoskeletal dysfunction, with no evidence to suggest any clinician-centered or patho-anatomical finding influences outcomes. The choice of whether or not to include MT as part of a management strategy should therefore be a product of a lack of contraindications and shared-decision making.

This framework aligns with evidence-based propositions that effectiveness and efficiency in assessment, diagnosis, and outcomes are not reliant on the therapist's skill set of specialised elements of TMT, but rather other factors-for example variations in pain phenotypes [ 5].

Conceptual themes

Communication

Communication is the overriding critical dimension to the whole therapeutic process and should be aimed at addressing peoples' fundamental needs to make sense of their symptoms and path to recovery. The delivery and uptake of the therapy should therefore be operationalised in a communication process that meaningfully represents shared-decision making and the best possible attempt to contextualise the therapy in positive and evidence-informed explanations of the process and desired effects [ 105].

Within a therapeutic encounter, practitioners must give the time to listen to peoples' accounts and explanations of their symptoms, including their ideas about their cause [ 106]. The assessment and diagnostic process should be a shared endeavour, for example, the negotiation of symptom reproduction. This should be done in a manner that facilitates sense-making, and which simultaneously encourages people to move on from unhelpful beliefs about their symptoms [ 107, 108], encouraging understanding of the uncertain nature of pain and injury. Person-centered communication requires attention to what we communicate and how we communicate across the entire clinical interaction including interview, examination, and management planning [ 109]. Therapists need to be open, reflective, aware and responsive to verbal and non-verbal cues, and demonstrate a balance between engaging with people (e.g. eye-gaze) and writing/typing notes during the interview [ 110, 111, 112].

People should be given the opportunity to discuss their understanding of the diagnosis and options for treatment and rehabilitation. The decision-making process is dialogical, in which alternative options to the offered therapy should also be discussed with the comparative risks and benefits of all available management options, including doing nothing [ 113, 114].

The therapist must fully appreciate the potential consequences of touch without consent. Continual dialogue should ensure that all parties are moving towards mutually agreed goals. The context of the therapy should be explicitly communicated to give appropriate context for any particular intervention as part of a holistic, evidence-based approach [ 115, 116, 117]. Therapists should be aware that their own beliefs can affect the way they communicate with their people; in the same way, a person's context affects how they communicate what they expect from their treatment [ 107, 118, 119, 120]. The construction of contextual healing scenarios which support positive outcomes, whilst minimising nocebic effects, is critical to effective healthcare [ 121, 122, 123].

There is a growing academic interest in the nature, role, and purpose of social and affective touch, and any re-framing of MT should consider touch as a means of communication to develop and enhance cooperative communications and strengthen the therapeutic relationship [ 124, 125, 126, 127, 128, 129]. It can be soothing for a person in pain to experience the caring touch of a professional therapist [ 130]; on the other hand, probing, diagnostic, and touch can be experienced as alienating [ 131, 132, 133]. Touch can alter a person's sense of body ownership and their ability to recognise and process their emotions by modulating interoceptive precision [ 129, 134, 135], and intentional touch may be perceived differently from casual, unfocussed touch [ 136, 137]. There is also a thesis that touch generates shared understanding and meaning [ 138, 139, 140]. This wider appreciation of touch should be embedded in modern MT communication.

Context

The contextual quality of a person's experience of the therapeutic encounter can affect satisfaction and clinical outcomes [ 141, 142, 143, 144, 145]. The context in which therapeutic care takes place should therefore be developed to enhance this experience. There could be very local, practical aspects of the context, such as the type of passive information available in the clinical space, e.g. replacing biomedical and pathological imagery and objects with positive, active artefacts; judicious and thoughtful organisation and use of treatment tables to discourage a sense of passivity and disempowerment; allocating a comfortable space where communication can take place; colour schemes and light sources which facilitate positivity; ensuring consistency through all clinical and administrative staff promoting encouraging and non-nocebic messages. Importantly, the way the therapist dresses influences peoples' perception of their healthcare experience [ 146, 147], and that in turn should be contextually and culturally sensitive [ 148, 149, 150].

Beyond the local clinical space is the broader social environment. The undertaking of MT should serve a role in a person's engagement with their social environment. For example, someone returning home after engaging with their therapist and disseminating positive health messages within their home and social networks; people acting as advocates for self-empowered healthcare. Furthermore, early data have demonstrated that aligning treatment with the beliefs and values of culturally and linguistically diverse communities enhances peoples' engagement with their healthcare [ 151].

Person-centred care

Here we borrow directly from one of the most established and clinically useful definitions of Person-Centered Medicine [ 152]:

"(Person-Centered Medicine is) an affordable biomedical and technological advance to be delivered to patients [sic] within a humanistic framework of care that recognises the importance of applying science in a manner that respects the patients [sic] as a whole person and takes full account of [their] values, preferences, aspirations, stories, cultural context, fears, worries and hopes and thus that recognises and responds to [their] emotional, social and spiritual necessities in addition to [their] physical needs" [ 152], p219.

Person-centred care incorporates a person's perspective as part of the therapeutic process. In practice, therapists need to communicate in a manner that creates adequate conversational space to elicit a person's agenda (i.e. understanding, impact of pain, concerns, needs, and goals), which guides clinical interactions. This approach encourages greater partnership in management [ 109, 153, 154].

A roadmap outlining key actions to implement person-centeredness in clinical practice has been outlined in detail elsewhere [ 155]. This includes screening for serious pathology, health co-morbidities and psychosocial factors; adopting effective communication; providing positive health education; coaching and supporting people towards active self-management; and facilitating and managing co-care (when needed) [ 154].

It is critical and necessary now to make these features explicit and central to the revised model of MT proposed in this paper. We wish to identify common ground across all MT professions in order to achieve a trans-disciplinary understanding of the evidence supporting the use of MT.

We acknowledge that our arguments here are rooted in empiricism and deliberately based on available research data from within the health science disciplines. We also acknowledge that there is a wider debate about future directions in person-centred care arising from the current evolution of the evidence-based health care movement, which has pointed to the need to learn more about peoples' lived experiences, to redefine the model of the therapeutic relationship. Although beyond the scope of this paper, a full exploration of modern health care provision involves reconsideration of the ethics and legal requirements of communication and shared decision-making [ 156, 157, 158, 159]. The authors envision this paper as a stimulus for self-reflection, stakeholder discussions, and ultimately change that can positively impact outcomes for people who seek manual therapy interventions.

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A modern way to teach and practice manual therapy - Chiropractic & Manual Therapies

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Background Musculoskeletal conditions are the leading contributor to global disability and health burden. Manual therapy (MT) interventions are commonly recommended in clinical guidelines and used in the management of musculoskeletal conditions. Traditional systems of manual therapy (TMT), including physiotherapy, osteopathy, chiropractic, and soft tissue therapy have been built on principles such as clinician-centred assessment, patho-anatomical reasoning, and technique specificity.

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Developing Manual Therapy Frameworks for Dedicated Pain Mechanism

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Developing Manual Therapy Frameworks for Dedicated Pain Mechanism

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Understanding Pain in less than five minutes

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Tame The Beast — It's time to rethink persistent pain

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Tame the Beast – It's time to rethink persistent pain

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Tame The Beast — It's time to rethink persistent pain

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Supercharge your understanding and treatment of pain Moseley and Butler's brand new book is for all health professionals treating pain. The authors apply their unique style to take the neuroimmune science of pain further and deeper. Explain Pain Supercharged will provide you with: Entirely origin...

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Recovery strategies pain guidebook by Dr Greg Lehman

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Constructing and Deconstructing the Gate Theory of Pain

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Constructing and Deconstructing the Gate Theory of Pain

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Pain. Author manuscript; available in PMC 2015 Feb 1.

Published in final edited form as:

Abstract

The Gate Theory of Pain, published by Ronald Melzack and Patrick Wall in Science in 1965, was formulated to provide a mechanism for coding the nociceptive component of cutaneous sensory input. The theory dealt explicitly with the apparent conflict in the 1960s between the paucity of sensory neurons that responded selectively to intense stimuli and the well-established finding that stimulation of the small fibers in peripheral nerves is required for the stimulus to be described as painful. It incorporated recently discovered mechanisms of presynaptic control of synaptic transmission from large and small sensory afferents which was suggested to "gate" incoming information depending on the balance between these inputs. Other important features included the convergence of small and large sensory inputs on spinal neurons that transmitted the sensory information to the forebrain as well as the ability of descending control pathways to affect the biasing established by the gate. The clarity of the model and its description gave this paper immediate visibility with numerous attempts made to test its various predictions. Although subsequent experiments and clinical findings have made clear that the model is not correct in detail, the general ideas put forth in the paper and the experiments they prompted in both animals and patients have transformed our understanding of pain mechanisms.

Keywords: Gate Theory, Dorsal root potentials, Presynaptic inhibition, Dorsal horn, TENS, Nociceptor, Substantia Gelatinosa

Introduction

It is approaching the 50 th year since the landmark paper advancing the Gate Theory of Pain was published [ 45]. Although this paper is only one of many very influential papers in the pain field, it holds a special place because of its very clear theoretical position on how pain is coded and its elaboration of a specific model to achieve this based on available electrophysiological evidence. Given its prominence it is valuable to review the findings that led up to its publication. Because Melzack and Wall provided such a clear statement about pain mechanisms, many of the subsequent developments in the field were evaluated with reference to the Gate Theory, and so a discussion of this paper can provide a window into the history of the field at that time and later. The paper made certain predictions that have been influential in the pain field and beyond. Other conclusions in the paper made using available experimental data turned out to be incorrect. A full evaluation of the Gate Theory requires discussion of both its successes and its failures; in so doing we provide a more complete perspective as to its role in the development of modern pain theory.

Early work based largely on lesions and electrical stimulation of peripheral nerves had provided an outline of what could be called a pain pathway projecting from the periphery to the cortex by way of the spinal cord, brainstem and thalamus. Despite this basic information it was not possible to permanently abolish pain in patients surgically or pharmacologically. Beginning with a series of papers by Ronald Melzack, joined later by Patrick Wall, a new conceptual framework for pain was advanced. This framework drew on provocative behavioral observations with important implications for pain mechanisms. Later work made use of new experimental evidence illuminating processing of sensory input by the spinal cord. This led to a simple, elegant mechanism for pain coding that stimulated new modalities of treatment for certain painful conditions. This mechanism, called The Gate, provoked a number of important experiments which advanced the study of pain without necessarily confirming the Gate mechanism.

Early studies

Modern studies leading to the Gate Theory Hypothesis began with the work of Ronald Melzack, a student of DO Hebb at McGill. He noted that dogs maintained in a restricted sensory environment would bump their head on exposed pipes when allowed to run freely and would not avoid these obstacles subsequently. This observation prompted a formal study of the effect of experience on the reaction to stimuli normally causing pain in dogs beginning at 4 weeks of age. The deficit was not in the ability to react immediately to the intense stimuli but rather in the subsequent avoidance behavior. The important conclusion was stated as follows [ 42]: "The results which have been reported here then, make it difficult to treat behavior related to pain simply in terms of frequency and intensity of stimulations or in terms of imperative reflex responses alone without regard to the earlier perceptual experience of the organism." This conclusion differs substantially from earlier ideas about pain, notably the iconic picture from Descartes suggesting that pain was an obligatory response to stimulation of elements responsive to the intense stimulus. As he stated "If...fire comes near the foot, the minute particles of this fire...set in motion the spot of the skin of the foot which they touch, and...pulling on the delicate thread...they open up at the same instant the pore against which the delicate thread ends, just as by pulling at one end of a rope one makes to strike at the same instant a bell which hangs at the other end" (from [ 45]). Apart from details about sensory transduction and axonal conduction, this formulation is identical to what we would now call the labeled line mechanism for pain.

In the early 1960s Melzack, now at MIT, began collaborating with Patrick Wall whose spinal cord physiology laboratory had been there since the mid-1950s. Their first joint effort was a theoretical paper [ 44] discussing sensory physiology including pain processing. From his previous work Melzack was already disposed towards the idea that sensory circuits were not labeled lines such that activation of a particular receptor resulted in a particular sensation- touch receptor/touch; pain receptor/ pain, etc. Wall had similar ideas based on his work on modification of sensory input at the first spinal synapse due to presynaptic inhibition [ 24, 64, see below]. They noted the ongoing controversy about cutaneous sensory mechanisms with one opinion originating with von Frey that cutaneous modalities were fixed beginning with anatomically distinct cutaneous receptors responsible for different modalities- touch, warm, cold and pain. The other view was championed by Weddell, Sinclair and others based on a lack of correspondence between anatomy and adequate stimulus of receptors. They suggested that stimulus modality was signaled by the spatiotemporal barrage of impulses in sensory fibers (see discussion in [ 44] for review of these concepts).

Melzack and Wall deconstructed von Frey's theory of specificity into 3 assumptions: Although they accepted the possibility that individual receptors might have a specific anatomy (The Anatomical Assumption) correlated with sensitivity to a specific physical stimulus (The Physiological Assumption), they were skeptical that the "psychological dimension of the somesthetic experience" could be identified with a specific skin receptor type (The Psychological Assumption). They argued in favor of a Pattern Theory where barrages of impulses produced in different sensory fibers initiated a computation in the central nervous system that was decoded into a somesthetic experience based in part on other ongoing brain activity. A corollary was the possibility that interference with the barrage or with the computation of its effects might prevent accurate interpretation, as for example the inability of experience- deprived dogs to react appropriately to intense stimuli.

In this paper Melzack and Wall drew special attention to Goldscheider's original proposal reemphasized by Livingston [ 11, 35] that central summation is important for generating impulse patterns interpreted as pain. They cited the lack of evidence for individual sensory fibers responding selectively to intense, presumptively painful stimuli. They suggested that pain might arise only when the number of responding fibers as well as their frequency of discharge exceeded some threshold.

Inhibition of cutaneous input to the spinal cord

Two major advances in the late 1950s were very influential in the development of the Gate Theory. The first was a clinical finding from analysis of patients with Herpes zoster. These patients experience excruciating pain in response to gentle stimulation of the affected area. Noordenbos [ 56] showed that the fraction of large fibers in nerves innervating these areas was diminished. He suggested that large fibers normally inhibit the effects of small fibers, and that this inhibition is reduced in the diseased nerves. This led to the idea, so important in the formulation of the Gate Theory, that the balance between the large and small fiber input was a major factor in determining the painfulness of a stimulus.

A second advance began with the seminal work of Frank and Fuortes [ 18] who demonstrated long lasting presynaptic inhibition of input to motor neurons elicited by volleys in large afferent fibers. Later, both Wall [ 65] and Eccles et al [ 16] both demonstrated that the central effects of volleys in cutaneous afferent fibers were presynaptically inhibited by conditioning volleys in other segmentally close cutaneous afferents. Up to this point studies of synaptic effects had been largely restricted to the effects of large diameter myelinated afferent fibers. Mendell and Wall [ 50] investigated the presynaptic effects of activity in small diameter unmyelinated afferent fibers. These were of interest because electrical stimulation of peripheral nerves in human subjects had shown that stimulus intensities high enough to activate unmyelinated fibers were required to elicit pain [ 9]. Mendell and Wall measured the presynaptic effect of small fiber stimulation by measuring the dorsal root potential (DRP) and by testing the excitability of the terminals of sensory fibers. Presynaptic inhibition is signaled as a negative DRP associated with depolarization of the fiber terminals and as an increase in electrical excitability of the depolarized terminals (reviewed in [ 57]). When unmyelinated fiber volleys were elicited in isolation using direct current anodal block to prevent conduction in the concomitantly activated large diameter afferents, the DRP was reversed in sign ( Figure 1 ), and the test of terminal excitability revealed a decline. Both of these were indicative of hyperpolarization of the terminals. This was interpreted as presynaptic facilitation.

The requirement to block inputs from large cutaneous Aβ fibers was due to the interference from the large negative DRPs they evoke. This was a technical limitation in these experiments that caused some controversy [ 76]. In later experiments where muscle nerves were activated, the positive DRP could be unambiguously observed in response to small fiber stimulation without the need for large fiber blockade because large proprioceptive afferent fibers evoke much smaller negative DRPs than large cutaneous afferent fibers [ 47].

Cells responsible for generating presynaptic inhibition of cutaneous sensory fibers

An important component of the Gate Hypothesis was the suggestion by Wall that cells of the substantia gelatinosa (SG) were responsible for the presynaptic effects [ 65, 66]. He drew upon anatomical evidence that these cells synapsed only with other cells in the SG in the same segment or in neighboring segments via Lissauer's Tract. This suggested that these cells acted as a modulatory system rather than as a system projecting directly or indirectly to the forebrain. The evidence linking the activity of these cells to presynaptic inhibition was based on correlating the timing of their activity to the generation of the DRP. Crucial was the observation that interrupting intersegmental conduction in the SG by cutting Lissauer's Tract interfered with the spread of the DRP to an adjacent segment. It was hypothesized that cells in the SG made axo-axonic synapses on terminals of sensory fibers in the dorsal horn, but no direct evidence was available on this point. Axo-axonic synapses were first identified in 1962 [ 19] but there was very little evidence for their distribution in the early 1960s.

The difference in small and large fiber inputs to the SG demonstrated by Szentagothai [ 61] played an important part in the elaboration of the Gate Theory. Szentagothai demonstrated that branches of large fibers entering the spinal cord dropped into the deeper laminae of the dorsal horn and then curved dorsally to enter the SG from the ventral side. Small diameter afferents entered SG directly from the dorsal side ( Figure 2A ). Melzack and Wall distilled the complex figure of Szentagothai focusing on the different patterns of small and large fiber projections to the SG ( Figure 2B ). They suggested that a single functional set of SG cells with axo-axonal projections to terminals of both large and small sensory fibers could be excited by large fibers or inhibited by small fibers. There was no specific evidence for this conclusion, but Mendell and Wall [ 50] had argued that this was the simplest interpretation of the different polarity of presynaptic control exerted by these fibers ( Figure 1 ) as well as the enhancement of the positive DRP during steady enhanced negative DRPs produced by high frequency stimulation of large diameter sensory fibers. Later work [ 48] indicating that both the negative and positive DRP are blocked by the GABA A antagonist picrotoxin was supportive of this conclusion although recent studies suggest that the synaptology and transmitters involved may be more complex [ 22].

These findings were the basis for the iconic gate mechanism diagram published in the 1965 paper ( Figure 3 ). Both large and small sensory fibers were assumed to project to cells (called T-cells) which projected to the forebrain. Selective activation of large fibers should reduce net input to T cells via the presynaptic gate located in the SG. It was proposed that prolonged high intensity stimulation caused an unbalanced small fiber input due to selective adaptation of large fibers (rather than the high threshold of receptors associated with small fibers). This unbalanced small fiber input removed presynaptic inhibition of sensory inputs, i.e., disinhibition which "opened the gate". Thus, as originally proposed by Noordenbos (see above), the balance between small and large fiber input, not the activity in in a special class of fibers responding to damage, would determine the output of the T cell via the gate. Once the integrated firing- level of T cells exceeded a critical preset level, the firing would trigger a sequence of responses by the Action System. This integrated response would be interpreted as "pain" and would not be an instantaneous response. The Central Control system was proposed to reset the Gate based on external contingencies, including sensory input reaching the brain rapidly via the large fibers in the dorsal columns or the very rapidly conducting spinocervical tract system, and thereby alter control over the sensory input. This implied descending control of the gate mechanism ( 21), a prediction that was confirmed later (see below).

Implicit in the Gate Control Hypothesis is the idea that pain is evoked when brain activity reaches a certain level due to sensory and/or central inputs. Melzack [ 39, 40] has expanded this idea into the Neuromatrix concept which for pain is a neural network with somatosensory, limbic and cognitive components ( 41). As in the Gate model, the output or "neurosignature" of the neuromatrix determining the painfulness of a sensory input is modulated by sensory input and differs in different individuals according to genotype and experiential variables. Thus the pain experience is not unique and can differ according to the individual as well as the injury. This was explored by Melzack and Torgerson [ 43] who classified painful experiences in terms of the words used to describe them. This is useful for investigating the efficacy of treatments in the clinic and led to the more formal McGill Pain Questionnaire [ 38], used widely in pain clinics.

Tests of closing and opening the gate

A major prediction of the Gate Control Hypothesis was that enhancing input selectively in large fibers would shut the Gate by reducing activity in T- cells; this would diminish any ongoing pain. This was tested initially by Wall and Sweet [ 70] who reported on 8 patients experiencing pain. Four had conditions indicative of peripheral nerve damage; high frequency stimulation of the large fibers in that nerve (Transcutaneous Nerve Electrical Stimulation- TENS) produced tingling referred to the distribution of that nerve and relief of the pain for the duration of the stimulation, and for 30 min after cessation of the stimulation. In 4 other cases where peripheral nerve damage was not suspected, stimulation of large diameter afferents also was analgesic but the reappearance of pain after stimulation was much faster, within 5-10 minutes. Pain abolition was attributed to closing the gate by selective stimulation of large fibers. Reappearance of pain was attributed to gradual reopening the gate by ongoing small fiber activity which was less intense in cases where peripheral nerves had been damaged and therefore took longer to be re-established. A similar protocol was attempted in a group of patients suffering from post-herpetic neuralgia and some success was observed in a subset whose pain was moderate [ 4, 55]. The relief from pain continued for up to 2 hours after the stimulation was stopped. Surprisingly, a few patients reported an improvement in their neuralgia over the course of treatment, and 2 of the patients considered themselves cured (one after 4 months; the other after 3 years of treatment). Because of its potential value in alleviating pain without the use of drugs, TENS has continued to be studied [ 60] with recent suggestions that its effects may be highly selective, e.g., deep pain vs cutaneous pain [ 31]. Relief from pain has also been obtained using high frequency stimulation of the dorsal columns [ 58] which is comprised largely of branches of large myelinated sensory fibers. Although the Gate Theory was the genesis of this treatment modality, it is not clear that it can account for the clinical effects, particularly the lingering after effects of the stimulation.

The question of opening the gate by small fiber stimulation has been explored at several different levels. Melzack and Wall proposed explicitly that this occurred by means of a presynaptic control mechanism although they made clear that they were open to other possibilities. Mendell and Wall ([ 50]- their Figure 6) did demonstrate that large cutaneous afferent fibers could be hyperpolarized but this was demonstrated under conditions where they were initially depolarized by high frequency burst stimulation of another sensory input. In reconsidering the interpretation of this experiment it is possible that the test stimulus interrupted the effects of the burst by presynaptically inhibiting its input, i.e., by closing the gate, rather than by inhibiting tonically active interneurons of the gate mechanism which would open the gate [ 49]. Furthermore, when intrafiber recording was used to search for changes in polarization from identified afferent fibers in response to peripheral nerve stimulation, the most reliable hyperpolarization was observed in muscle spindle group I afferent fibers of flexor afferents [ 23, 48] which probably contribute little to conscious pain. Burke and colleagues [ 49] also questioned the association of presynaptic hyperpolarization with pain by demonstrating that radiant heat stimulation in the noxious range (> 50°C) evoked primary afferent depolarization in cutaneous afferents, not hyperpolarization. So although stimulation of large fibers produced presynaptic depolarization which would be interpreted as closing the gate, the correspondence of gate opening (i.e., presynaptic hyperpolarization) and inputs producing pain was not confirmed.

Nonetheless, it became clear that the firing of second order cells in the spinal cord was selectively enhanced by volleys in small diameter afferents. Furthermore, the repetitive discharge of spinal neurons exhibited a phenomenon called windup [ 46, 51] whereby it became more prolonged in response to each successive C- fiber stimulus if it occurred within 4 seconds of the preceding one. At the time this was interpreted in terms of the gate model, i.e., as due to summation of presynaptic facilitation, but now it is recognized as due to the release of peptides by certain small diameter afferents which prolongs the synaptic potential thus allowing temporal summation over a period of seconds [ 29]; this depolarization activates NMDA receptors whose blockade abolishes windup without eliminating the response to C- fiber stimulation [ 13]. Windup is an early event in a process leading to central sensitization [ 72] and represents an increase in gain for the spinal system processing the nociceptive input [ 73]. Volleys in large diameter afferents also initiate a repetitive discharge in these postsynaptic cells but this is fixed in duration and often followed by a brief silent period [ 46, 51]. Thus small and large fibers elicit very different central effects that resemble what was suggested in the Gate Theory, but the mechanism responsible for the effects of small fiber stimulation is quite different.

Nociceptors

At the time the Gate Theory was proposed, there was very little evidence for high threshold afferent fibers. Based on reports of very few such fibers [e.g., 25, 27], Melzack and Wall [ 45] viewed them as the "extreme of a continuous distribution of receptor- fiber thresholds rather than a special category". The gate circuit was considered to provide a mechanism for enhancing the discharge of central neurons (T-cells) in response to intense stimulation without the need for a population of cells selectively activated by high intensity inputs. The discharge of T-cells was determined by the balance between small and large fiber input; maintained intense stimuli favored the discharge in small diameter afferent fibers because they exhibited little adaptation in contrast to large diameter afferent fibers.

At this time Burgess and Perl [ 6] published experiments which changed the landscape of the pain field again. They demonstrated a population of small diameter myelinated fibers innervating the skin that were activated only by stimuli that would be damaging to the skin. These became known as High Threshold Mechanoreceptors. Perl and his collaborators went on to describe a population of C-fibers activated by nociceptive stimuli of different modalities (mechanical, thermal and chemical (pH)). These were referred to as Polymodal Nociceptors [ 5], the term nociceptor denoting receptors activated by stimuli that were potentially damaging to the tissue in which they were embedded [ 59]. Nociceptors were later found to have important physiological properties such as sensitization [ 29], and to project into the superficial dorsal horn [ 34] where they synapse upon a population of cells called marginal cells that respond exclusively to noxious stimuli [ 8]. These cells in the marginal zone were found to contribute to the spinothalamic tract [ 71, 75] which gave them access to forebrain structures and thus presumably to conscious sensation. A population of nociceptors was also observed to be peptidergic (reviewed in [ 30]) and thus able to promote Windup.

This series of discoveries was at odds with the philosophy expressed in the Gate Theory since it suggested a labeled line for the projection of nociceptors and thus for "pain". Some cells in the VPL in thalamus are known to respond selectively to pinch stimuli [ 20, 32], at least under anesthesia, implying that labeled lines might account for some behavioral responses to nociceptive input. However, there are other cells in the spinal dorsal horn, the wide dynamic range cells [ 46],that receive excitatory input from both nociceptive and non-nociceptive sensory inputs. Therefore, it seems unlikely that the presumptive nociceptive circuit is acting in isolation to signal "pain". In fact, experiments in which pain intensity was rated while recordings were carried out in wide dynamic range cells or in lamina I nociceptive neurons in the medullary dorsal horn suggested that the former were more specialized for coding pain intensity [ 14]. Lamina I cells have been proposed to serve a homeostatic role with regard to pain by coordinating the organism's response to nociceptive stimulation in a way that maintains equilibrium [ 10].

Other gate mechanisms

Although later experiments took issue with some of the specific components of the gate hypothesis and its predictions, the value of the concept has been demonstrated by its extension to other systems. The clearest example of this comes from analysis of descending pathways from the rostroventromedial (RVM) nucleus of the medulla [ 1, 53]. This nucleus consists of 2 populations of neurons (ON and OFF) projecting to the superficial dorsal horn of the spinal cord. OFF cells are constitutively active and are turned off by nociceptive inputs. ON cells are constitutively silent but are turned on by nociceptive inputs. ON cells enhance transmission from nociceptors to lamina I neurons; OFF cells depress it. When the tail is subjected to an increasingly hot thermal stimulus [ 17], the motor response (tail flick) is immediately preceded by OFF cells turning off and ON cells turning on. Furthermore, OFF cells are excited by opiates whereas ON cells are inhibited; this is consistent with the antinociceptive effect of opiates. Thus the ON/OFF system acts as an opioid- dependent gate at nociceptor- driven synapses in the spinal dorsal horn.

Anatomy and function of lamina II

One of the major ideas underlying the Gate Theory as originally proposed was that the SG (or lamina II) is a closed network of cells whose activity can be turned on by large myelinated fibers and off by unmyelinated fibers. The other major point was that these cells make axo- axonic synapses on the terminals of incoming afferent fibers. New evidence consistent with the idea that the discharge of cells in the superficial dorsal horn is related to the negative DRP was obtained by Lidierth and Wall [ 33] who recorded from cells activated by microstimulation of Lissauer's Tract. They found that most of these cells could also be activated by muscle and skin afferents as well as by inputs from motor cortex. Using spike triggered averaging they demonstrated that the spontaneous discharge of cells activated by Lissauer's tract stimulation was correlated with the negative DRP. Because these experiments could not establish causation, they concluded that these superficially located neurons activated by Lissauer's Tract were very promising candidates for generating the negative DRP. It is interesting that in none of this later work was any attempt apparently made to determine the response of these cells to small diameter sensory fiber input.

Recent immunohistochemical work using newly available reagents to identify different populations of neurons within the superficial dorsal horn has made clear that glutamatergic cells in lamina II are activated by small diameter afferents and deliver significant output to projection neurons in lamina I [ 63], i.e., cells in the SG are part of a projection system. Similar synaptology was observed in electrophysiological studies [ 62] and further indicate that the projection from Aβ afferent fibers through lamina II to lamina I projection cells can be inhibited by a postsynaptic inhibitory mechanism.

Additional perspective

We have reviewed the ideas that went into the formulation of the Gate Hypothesis and have evaluated many of the experimental issues in the light of later experiments. It is easy to criticize bits and pieces of the theory as many did. Indeed, in a later paper, partly in answer to a critical review [ 54], Wall [ 68] re-evaluated the Gate Theory accepting some but not all of these criticisms. As in an earlier paper [ 44] he remained dismissive of the labeled line theory of sensation by emphasizing that although the response of sensory receptors is diagnostic in indicating the physical stimulus, it is not prognostic in predicting the resulting psychological modality.

However, Wall did accept the criticism of one of the initial pillars on which the Gate Theory was constructed, namely the idea initially advanced by Noordenbos from his work on Herpes zoster, that inputs restricted to small sensory fibers are always painful. Several clinical examples of large fiber degeneration e.g., Friederich's ataxia and polyneuropathy of renal failure, were listed where the resulting sensation is not painful [ 54] (see also [ 15]). Despite the lack of generality for the painful quality of small fiber inputs, Wall considered the inhibitory effects of large fiber inputs to be well verified by subsequent demonstration of the analgesic effect of TENS and dorsal column stimulation (see above) although the mechanism of that inhibition was still open to question. The iconic diagram published in 1965 indicated a presynaptic inhibitory mechanism, based largely on the then current work in Wall's laboratory, but Melzack and Wall were very careful to point out that postsynaptic inhibition might be responsible [ 45]. Wall [ 68] discussed possibilities for postsynaptic inhibition based on literature appearing since publication of the Gate Hypothesis. This change in mechanism gains further currency in a recent account of the Gate Theory by Basbaum and Jessell in the 4 th edition of Medical Neuroscience textbook [ 3] where the illustration of the Gate mechanism shows the inhibition as being postsynaptic, not presynaptic.

In their 1965 paper [ 45] Melzack and Wall provided a diagram (their Figure 1 ) illustrating the many surgical attempts that had been made to treat chronic pain. The inability to permanently abolish pain by cutting various tracts was a taken as evidence against the labeled line pain pathway and served as a stimulus to develop a pattern theory leading to the Gate Theory. We now know that damage to the nervous system or alterations in the sensory barrage due to inflammation can lead to structural and functional changes within the CNS that enhances the nociceptive input [ 26, 37]. Wall himself was a pioneer in the study of plasticity in the spinal cord [ 2, 52] dorsal column nuclei [ 36], and thalamus [ 69] and stimulated many others to explore these important issues which are central to our understanding of pain. In addition to structural plasticity there have been many new findings of functional plasticity related particularly to the central projections of C-fibers (reviewed in [ 73]).

Concluding comment

The Gate Theory of Pain was formulated using available physiological observations to explain certain behavioral and psychophysical observations related to pain. The combination of a remarkably clear and incisive paper and some simple diagrams captured the imagination of a generation of clinicians and neuroscientists [ 12]. Measures of its success are some of the predictions that have been useful clinically. In addition, its broad frame of reference attributing pain to multiple interacting circuits, formalized later by Melzack in the neuromatrix concept, has had numerous offshoots including pain genetics, affective components of pain and environmental contributions to the pain experience. The simple diagram of the gate circuit in the Science paper is what is remembered by most, but this was just a small part of discussions in that paper. It forced a re-evaluation of pain mechanisms and it is the outcome of this re-evaluation rather than the simple mechanistic diagram that represents the major significance of the Gate Control Theory. As Wall [ 67] himself wrote evaluating the Gate Theory in the light of further experiments: "The least, and perhaps the best, that can be said for the 1965 paper is that it provoked discussion and experiment".

Acknowledgement

I thank Drs. Pablo Rudomin and Rick Koerber for critically reviewing the manuscript and offering helpful comments. LMM was supported by The Christopher and Dana Reeve Foundation and by NIH 5 R01 NS 16996.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

I declare no conflict of interest in connection with this review article.

References

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18. Frank K, Fuortes MGF. Presynaptic and postsynaptic inhibition of monosynaptic reflexes. Fed. Proc. 1957;16:3940. [ Google Scholar]

40. Melzack R. From the gate to the neuromatrix. Pain. 1999 Aug;(Suppl 6):S121-S126. [[ PubMed] Google Scholar]

# data[].attributes.attachment_link.title
Constructing and Deconstructing the Gate Theory of Pain

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The Gate Theory of Pain, published by Ronald Melzack and Patrick Wall in Science in 1965, was formulated to provide a mechanism for coding the nociceptive component of cutaneous sensory input. The theory dealt explicitly with the apparent conflict in ...

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Theories of pain/ from specificity to gate control

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Theories of pain/ from specificity to gate control

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 Theories of pain: from specificity to gate control

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Tissue Adaptation to Physical Stress: A Proposed “Physical Stress Theory” to Guide Physical Therapist Practice, Education, and Research

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Tissue Adaptation to Physical Stress: A Proposed “Physical Stress Theory” to Guide Physical Therapist Practice, Education, and Research

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Abstract

The purpose of this perspective is to present a general theory-the Physical Stress Theory (PST). The basic premise of the PST is that changes in the relative level of physical stress cause a predictable adaptive response in all biological tissue. Specific thresholds define the upper and lower stress levels for each characteristic tissue response. Qualitatively, the 5 tissue responses to physical stress are decreased stress tolerance (eg, atrophy), maintenance, increased stress tolerance (eg, hypertrophy), injury, and death. Fundamental principles of tissue adaptation to physical stress are described that, in the authors' opinion, can be used to help guide physical therapy practice, education, and research. The description of fundamental principles is followed by a review of selected literature describing adaptation to physical stress for each of the 4 main organ systems described in the Guide to Physical Therapist Practice (ie, cardiovascular/pulmonary, integumentary, musculoskeletal, neuromuscular). Limitations and implications of the PST for practice, research, and education are presented.

Physical therapists have expertise in the application of interventions-such as exercise, postural instruction, orthotic devices, and modalities-that allow them to modify the physical stresses applied to tissues of the body. Physical stress is defined as the force applied to a given area of biological tissue. Exercise interventions that modify physical stress have been shown to decrease impairments, functional limitations, disability, and pain in a variety of patient populations. These same interventions can help people with and without disease increase muscle performance, bone mineral density, and fitness levels. An increasing amount of evidence indicates that exercise can have positive effects on disease processes such as diabetes, arthritis, and coronary artery disease.

We believe that the many different theories and approaches currently used in physical therapy share fundamental principles that can be organized into a general theory to guide prevention and treatment of a broad range of patient problems. The general theory we present is based on fundamental principles that appear to govern the adaptive response of biological tissues to physical stress. Therefore, we refer to this theory as the Physical Stress Theory (PST). The PST integrates existing knowledge into a deliberately broad theory with potential application to physical therapist practice, education, and research.

Physical therapists have emphasized the evaluation and treatment of movement dysfunction. Movement can be defined by the basic physical components ( mass × acceleration) of a segment or body. The mass × acceleration of a body segment is defined as force ( force=mass × acceleration, Newton's second law of motion). The application of force over a given area of tissue during movement results in stress to the tissue (s tress=force/area, where force may be applied in any direction [tension, shear, compression]). Although movement is a major source of physical stress on tissues, other forces generated both inside the body (eg, isometric muscle contractions) and outside of the body (eg, gravity) also may contribute to tissue stress. The PST was developed to address how tissues, organs, and organ systems adapt to varying levels of physical stress ( Tab. 1). In addition, this theory describes how other factors ( Tab. 2) can modify both the level of physical stress and the response of biological tissues to a given stress level.

The PST focuses on the physical stresses that influence all biological tissues. Tissues are formed from groups of similarly specialized cells that cooperate to perform one or more functions within the body. The 4 fundamental types of tissue are: (1) epithelial tissue, which covers internal and external surfaces of the body and forms glands, (2) connective tissue, which provides structural and functional support to other tissues of the body, (3) muscular tissue, which has specialized contractile properties for producing movement, and (4) nervous tissue, which collects, transmits, and integrates stimuli to control the functions of the body. These 4 basic tissues combine to form organs. Groups of anatomically or functionally related organs are referred to as "organ systems." Our discussion of the PST will be limited to tissues that form the organ systems identified as most relevant to physical therapists in the Guide to Physical Therapist Practice (ie, cardiovascular/pulmonary, integumentary, musculoskeletal, and neuromuscular systems). The PST does not address molecular or cellular mechanisms of adaptation. Rather, the PST identifies common principles from the literature that we suggest may be used to predict adaptive tissue changes that occur in response to physical stress.

The purpose of this perspective is to present a general theory, based on principles of adaptation to physical stress, that we believe can be used to help guide physical therapy practice, education, and research. First, we will describe the fundamental principles of the PST, followed by a review of selected literature describing adaptation to physical stress for each of the 4 main organ systems described in the Guide to Physical Therapist Practice. The fundamental principles are based on an analysis of the literature and our clinical experiences. Because the principles are general and represent what we contend are the "common denominators" of a variety of research findings and clinical approaches, references are not provided in the description of the theory or in the listing of Fundamental Principles in Table 1. Supporting literature is provided in the subsequent section and is summarized in Table 3. The literature review also will address how we believe the PST relates to other physical therapy theories and approaches. Limitations and implications of the PST for practice, research, and education will then be discussed.

Description of Physical Stress Theory

The basic premise of the PST is that changes in the relative level of physical stress cause a predictable adaptive response in all biological tissue ( Tab. 1). Figure 1 illustrates primary adaptive responses and thresholds for tissue adaptation in response to physical stress. Factors that may influence either the level of physical stress on tissues or the adaptive response of tissues to a given stress level are outlined in Table 2. The fundamental principles of the PST are summarized in Table 1 and are described in further detail below.

Fundamental Principle A-Changes in the relative level of physical stress cause a predictable response in all biological tissues. Physical stress is the force, or load, acting on a given area of tissue. In the PST, we propose that tissues accommodate to physical stresses by altering their structure and composition to best meet the mechanical demands of routine loading. Deviations from routine or steady-state loading provide a stimulus for tissue adaptation that allows tissues to meet the mechanical demands of a novel environment.

Fundamental Principle B-Biological tissues exhibit 5 characteristic responses to physical stress. Each response is predicted to occur within a defined range along a continuum of stress levels. Specific thresholds define the upper and lower stress levels for each characteristic tissue response. These thresholds can be viewed as boundaries for the effective dose-response to physical stress. The 5 qualitative responses to physical stress are decreased stress tolerance (eg, atrophy), maintenance, increased stress tolerance (eg, hypertrophy), injury, and death.

Fundamental Principle C-Physical stress levels that are lower than the maintenance range result in decreased tolerance of tissues to subsequent stresses. Atrophy is one common mechanism by which tissues become less tolerant of subsequent physical stresses ( Fig. 2). Atrophy occurs when tissue degeneration exceeds tissue production and has been observed in all 4 major organ systems in response to reduced stress levels ( Tab. 3). Other examples of adaptations that may reduce stress tolerance include hormonal changes, altered cell membrane excitability, and changes in the material properties of tissues ( Tab. 3).

Fundamental Principle D-Physical stress levels that are in the maintenance range result in no apparent tissue change. Tissue homeostasis occurs when tissue degeneration is equal to tissue production, resulting in tissue turnover without net gain or loss. The range of stress levels that promote tissue homeostasis is defined as the maintenance stress range and may be different for different people. This steady-state or equilibrium response occurs when tissues are exposed to the same levels of stress to which they have become accustomed.

Fundamental Principle E-Physical stress levels that exceed the maintenance range (ie, overload) result in increased tolerance of tissues to subsequent stresses. Hypertrophy is one common mechanism by which tissues become more tolerant of subsequent physical stresses ( Fig. 3). Hypertrophy occurs when tissue production exceeds tissue degeneration, and can be defined as a general increase in bulk of a tissue. In general, biological tissues adapt to increased levels of stress by increasing cross-sectional area, density, or volume ( Tab. 3). Other examples of adaptations that may increase tissue stress tolerance include hormonal changes, altered cell membrane excitability, and changes in the material properties of tissues ( Tab. 3). Although stress overload can promote tissue hypertrophy and improve stress tolerance, adequate recovery between bouts of increased stress is needed for this adaptive response to occur (see below).

Fundamental Principle F-Excessively high levels of physical stress result in tissue injury. For the purposes of this theory, injury is defined as tissue damage caused by excessive stress resulting in pain or discomfort, impaired function of the tissue, or both. Damages that are not felt or are not causing noticeable dysfunction are not considered clinically significant injuries. The maximum stress threshold is defined as the amount of stress the tissue can bear just before it fails, if the tissue is fully rested and recovered from previous stresses. Stress levels that exceed the maximum stress threshold are considered excessive and result in tissue injury.

Fundamental Principle G-Extreme deviations from the maintenance stress range that exceed the adaptive capacity of tissue result in tissue death. The PST represents the potential range of responses of viable tissues to a given level of physical stress. To the extent that the stress level can be altered, viable tissues exhibit a variable stress response. For example, healthy tissues that are injured as a result of exposure to high stress levels may return to the maintenance range if stress levels are appropriately reduced. In cases where stress levels deviate substantially from maintenance conditions, tissues may no longer be viable and tissue death can result. Thus, tissue death can occur when tissues are exposed to either extremely high or extremely low stress levels and are unable to adapt or recover.

Fundamental Principle H-The level of exposure to physical stress is a composite value, defined by the magnitude, time, and direction of stress application ( Fig. 4). Stress magnitude refers to the amount of stress (force per unit area) on a tissue at any given moment in time. Time factors include the duration, the number of repetitions, and the rate at which stress is applied to tissues of the body. Each of these factors has a direct relationship with the level of stress exposure. For example, a longer duration of stress application results in a greater level of stress on the tissue. The direction of stress application also influences tissue adaptation. Stress will have a different effect depending on whether it is applied in tension, compression, shear, or torsion. Use of a composite measure to quantify the level of stress exposure implies that stress levels may be altered by changing one or more of the stress-related variables that comprise this measure.

Fundamental Principle I-Individual stresses combine in complex ways to contribute to the overall level of stress exposure. Tissues are affected by the history of recent stresses. In the PST, the effect of any given stress will depend on the previous stress experience of the tissue. For example, 1 repetition of a biceps muscle curl against a resistance of 13.6 kg (30 lb) may have little effect on subsequent muscle performance. However, 3 sets of 10 repetitions, 3 times a week, for 2 weeks can lead to muscle hypertrophy and increase the muscle's ability to generate force. One consequence of the cumulative effect of repeated stresses is that tissues require periods of rest in which the level of stress exposure is substantially reduced so that they can adapt and recover from previous stresses.

Fundamental Principle J-Excessive physical stress that causes injury can occur through 1 or more of the following 3 mechanisms: (1) a high-magnitude stress applied for a brief duration, (2) a low-magnitude stress applied for a long duration, and (3) a moderate-magnitude stress applied to the tissue many times. This principle is closely related to Fundamental Principle H ( Tab. 1), which identifies stress magnitude and time factors (eg, duration and number of repetitions of stress application) as important variables used to determine the composite level of stress to which tissues are exposed.

Fundamental Principle K-Regardless of the mechanism of injury, inflammation occurs immediately following tissue injury and renders the injured tissue less tolerant of stress than it was prior to injury. In the context of the PST, the threshold for subsequent tissue injury is lowered as a result of previous injury and the presence of inflammation. Stress levels that did not cause pain before the tissue was injured would then have the potential to cause pain and further tissue damage. Injured and inflamed tissues must be protected from subsequent excessive stress until acute inflammation subsides. Continued stress, even at a level considered normal for uninjured tissue, can prevent tissue regeneration following injury.

Fundamental Principle L-The stress thresholds required to achieve a given tissue response may vary among individuals depending on the presence or absence of several modulating variables. In developing the PST, we identified 4 categories of variables ( Tab. 2) that can modulate either: (1) the level of stress on tissues, or (2) the response of tissues to a given level of physical stress (ie, threshold values for tissue adaptation and injury). Because of the complex interaction among variables, it is not yet possible to determine the absolute value of the thresholds for tissue adaptation proposed within this theory. However, we propose that the PST can be used to construct models that predict the relative influence of both stress-related and nonmechanical variables on tissue adaptation and injury. With additional research, it should be possible to estimate the relative threshold value, based on a percentage of maximum stress tolerance, that is required to promote a desired tissue response given the individual circumstances of each patient. Rehabilitation programs then could be tailored to enhance factors contributing to tissue repair and to minimize factors contributing to tissue failure.

Factors that can change the level of stress on tissues or the threshold values for tissue adaptation and injury are summarized in Table 2 and include movement and alignment, extrinsic, psychosocial, and physiological factors. Each of these factors is described below, and those factors that can be modified with physical therapy interventions are emphasized.

Movement and Alignment Factors

According to the PST, movement is the most important factor that physical therapists can use to influence tissue adaptation. As noted, movement occurs because of forces. Forces are applied to tissues over a given area that result in stresses, which contribute to tissue adaptation as outlined in this theory. Physical therapists often focus on the treatment of movement dysfunction, and one theory has designated movement as its core principle. By comparison, the core principle of the PST is tissue adaptation in response to physical stress. As summarized in Table 3, movement can have beneficial effects (eg, exercise-related tissue hypertrophy) as well as detrimental effects (eg, overuse injury) on tissues of the body. According to the PST, movement and alignment factors are considered primarily for their ability to place stress on biological tissue. The components of movement and alignment considered by this theory are muscle performance, motor control, posture and alignment, and physical activity.

Muscle Performance

Muscle performance (force generation, muscle length) is a critical aspect of movement that can influence tissue stress. Muscles are highly adaptable. They generate movement and, hence, forces that place stress on tissues. Muscle also is an important "shock absorber," and muscle contraction is well recognized for its ability to protect bones, cartilage, and ligaments from excessive stress. As a general theory, the PST can be used in combination with other theories and approaches that provide a more detailed analysis of the mechanisms by which muscle performance contributes to stress on tissues of the body.

Motor Control

Motor control has been defined as the study of the nature and cause of movement, and it, therefore, represents a major component of physical therapists' expertise. Evaluation of the ways in which people control their movements to accomplish tasks provides physical therapists with insight into how stresses are applied to tissues of the body during movement. For example, Maluf et al have proposed that the daily repetition of similar movements and postures may result in excessive stress on tissues of the low back. These authors suggest that physical therapists can identify and modify motor recruitment patterns which potentially contribute to patients' low back pain during the performance of daily activities. Maluf et al contend that an important role of physical therapists is to identify patterns of movement that contribute to excessive tissue stress and to teach patient-appropriate movement strategies to prevent tissue injury and pain.

Posture and Alignment

Some studies have questioned, and even refuted, a large relationship between these variables in people with and without back pain. Rather than emphasizing an ideal standard of posture and hypothesizing that there is a large relationship among specific postures, impairments, and pain patterns, the PST proposes that pain is caused by excessive tissue stress and that postural deviations are one of many potential variables that contribute to the excessive stress levels that result in pain. We commonly observe people with "poor" posture who are pain-free and other people with "good" posture who have pain. The types of activities performed by people varies widely, resulting in different stress demands on tissues of the body.

The PST predicts that no one ideal posture exists for all people because tissues will adapt to meet the unique stress demands of each person. Injury occurs when tissues are unable to adapt to meet the demands of a given posture or task. Therefore, rather than comparing a person's posture to an ideal standard, the therapist's examination should focus on the postures or movements that cause pain. Within this context, postural deviations become one of many potential factors that may place stress on injured tissues. In some people, the postural deviation may be the primary factor contributing to excessive tissue stress (see "Implications for Physical Therapist Practice" and "Implications for Research" sections). In our view, the PST expands upon the Kendalls' theory by proposing that postural deviations are one important component of musculoskeletal pain; however, pain patterns should be evaluated in a broader context that considers other potential sources of tissue stress.

Physical Activity

Physical activity is another component of movement that results in tissue stress. The US Department of Health and Human Services and the American College of Sports Medicine have adopted the definition of physical activity as "bodily movement that is produced by the contraction of skeletal muscle and that substantially increases energy expenditure." Physical activity may be divided into the specific subcategories of occupational, leisure, and self-care activities. The PST predicts that physical activity improves health because it increases stress on a broad range of tissues, making the tissues more tolerant of subsequent physical activity. Because the tissues are more tolerant of physical stress, they are less likely to be injured. This reduction in the likelihood of injury occurs regardless of whether the tissue is part of the cardiovascular/pulmonary, integumentary, musculoskeletal, or neuromuscular system. Increased physical activity has been linked to many positive health benefits, including lower risk for non-insulin-dependent diabetes mellitus, stroke, and obesity. The federal government, in Healthy People 2010, has set a number of goals to increase physical activity (Objective 22; Physical Activity and Fitness) in people who are otherwise healthy. We believe that physical therapists should use their expertise to provide instruction on how people can increase overall physical activity without injuring specific structures (ie, back or knee).

Extrinsic Factors

Extrinsic factors are factors outside of the body that can influence either the level of stress on tissues or the thresholds for tissue adaptation and injury. For the purpose of this perspective, those extrinsic factors that can be modified or utilized by physical therapists are emphasized.

Orthotic devices can be used to modify physical stress on biological tissues and can be used as an adjunct to other interventions in several phases of tissue adaptation. An orthotic device can be used to relieve stress from injured tissue (eg, a resting hand splint for patients with carpal tunnel syndrome, a lumbosacral corset for a person with low back pain). An orthotic device also can be used to apply stress to tissue to cause a change in the tissue (eg, orthotic devices that apply low loads for prolonged periods to increase muscle length and joint range of motion at the elbow). According to the PST, orthotic devices are an appropriate adjunct to treatment when other means of movement can not adequately control stress on the tissue to meet desired guidelines. We contend that components of the orthotic device should be chosen for their ability to achieve a desired stress level on the tissue. Likewise, taping and assistive devices (eg, crutches, walkers, canes) may be effective adjuncts to help modify stress on injured tissues.

Psychosocial Factors

Physiological Factors

Physiological factors influence the ability of tissue to respond to physical stress, but these factors often are difficult, if not impossible, to modify. Physiological factors assume a less important role in physical therapy treatment compared with the factors described previously because physical therapists usually can not modify or treat physiological factors directly. Physical therapists should be aware of the influence of physiological factors, however, because these factors will affect the prognosis of tissue adaptation and recovery from injury.

Age is another important physiological factor. Although it is beyond the scope of this perspective to discuss the effects of age on tissue adaptation, it is important to discuss several general points. Aging has a negative effect on tissue adaptation. The magnitude of this negative effect in humans, however, is not clear. Kohrt believes that a considerable portion of the negative effects that have been attributed to aging may be due to age-associated decreases in activity. Two predictions regarding the effects of age can be derived from the PST. The first prediction is that aging lowers the ability of tissues to tolerate stress and has a general tendency to lower the threshold for injury, similar to the effect illustrated in Figure 2. The level of stress required to promote tissue hypertrophy and increase stress tolerance generally is greater for young subjects who are healthy compared with older subjects. Young people, therefore, can exercise and stress their tissues more aggressively with less fear of injury than older people. The second prediction is that the negative effects of aging can be modified through increased stress on the tissue. Increased stress, applied through progressive increases in activity or exercise, theoretically can help prevent or reverse some of the negative effects of aging ( Fig. 3). Increasing evidence suggests that tissues remain responsive to physical stress well into old age and that positive adaptations to increased activity and exercise can result in decreases in functional limitations and disability.

Although the PST recognizes the negative impact of systemic pathology on tissue adaptation, it also proposes that carefully applied physical stresses can have positive effects for people with chronic disease. Growing evidence supports this prediction. Traditionally, people with rheumatoid arthritis have been excluded from vigorous activities that might exacerbate joint inflammation. However, studies have shown that progressive resistive exercises and aerobic exercise programs can increase muscle performance, fitness levels, and bone mineral density with no exacerbation of disease activity in patients with rheumatoid arthritis. The positive effects of aerobic exercise for patients with cardiovascular disease have been well documented. Likewise, evidence indicates that increased activity, even in small increments, can have positive effects on reducing the burden of hyperinsulinemia and diabetes. William H Herman, an associate editor for Clinical Diabetes, summarized the effect of exercise on diabetes:

An ideal treatment for type 2 diabetes would lower blood glucose concentrations acutely, improve long-term glycemic control, and enhance insulin sensitivity. It would improve mild to moderate hypertension, reduce low-density lipoprotein cholesterol and triglycerides, increase high-density lipoprotein cholesterol, and serve as an adjunct to caloric restriction for weight reduction. Finally, it would increase patients' sense of well-being and improve their quality of life. As a drug, such an agent would be a blockbuster, with greater than $1 billion per year sales potential. Yet such a treatment exists and has been recognized for centuries. It is regular physical activity-that is exercise.

Although systemic pathology may lower the threshold for tissue injury, many people with systemic pathology respond positively to exercise, both in terms of increased stress tolerance and reduction of disease complications.

We also consider obesity a physiological factor within the context of the PST that can be modified, but not easily. Obesity is defined as an increase in body weight beyond the limitation of skeletal and physical requirements, as the result of an excessive accumulation of fat. Body weight provides an indication of the stresses that must be borne by tissues of the body during physical activity. The PST predicts that obesity is a risk factor for certain types of injury and a negative factor for recovery from injury. In addition, obesity has been linked with low activity levels. People who are obese, therefore, may be at greater risk of injury than people who are not obese because high-stress, low-repetition activities are thought to be more damaging than low-stress, high-repetition activities. Evidence exists to support this prediction. For example, a population-based (n=350, 95 men and 255 women, 55 years of age or older) longitudinal study (mean follow-up duration=5.1 years) reported that the risk of incident radiographic knee osteoarthritis was significantly increased among subjects with higher baseline body mass index (odds ratio=18.3, 95% confidence interval=5.1-65.1).

Literature Review

The PST focuses on how biological tissues respond to physical stress. Existing evidence and approaches that share common principles with the PST will be described next for each of the 4 major systems described in the Guide to Physical Therapist Practice. Because physical therapists often work with patients with injuries, each section will begin by discussing how physical stress can contribute to injury. Discussion of the effects of physical stress on injury will then be followed by a discussion of the effects of physical stress on tissue atrophy, maintenance, and hypertrophy. These effects are summarized in Table 3.

Musculoskeletal System

Some authors have described mechanical principles involved in the management of patients with low back pain. McGill proposed that injury, or "failure of a tissue," occurs when the applied load exceeds the failure tolerance of the tissue. In addition, McGill contended that the structures of the back are influenced by the history of recent physical stresses, so that the accumulation of individual stresses can cause injury. He argued that the characteristics of the load (load rate, mode of load compression, bending, torsion, shear) and the properties of the tissue determine the type and extent of tissue damage.

McGill described the same 3 mechanisms of injury to low back tissues that are proposed within the PST (Principles H, I, and J, Tab. 1). One mechanism of injury to low back tissues is a single application of a relatively high load or stress. McGill provided the example of a person riding a snowmobile who is thrown from the machine and lands on a flexed spine and experiences a sudden posterior disk herniation. A second mechanism of injury to low back tissues is multiple moderate loads or stresses applied to the structures of the low back. In this case, injury is the result of accumulated trauma. McGill provided the example of a worker lifting boxes in which tissues of the low back are loaded repeatedly, causing a slow degradation of the tissue tolerance. A third mechanism of injury is low loads sustained by the low back over a long period of time. An example of this mechanism of injury is construction workers who install rods in the floors of a new building and remain in a flexed posture for prolonged periods of time.

Similar to bone, models of tendon and ligament adaptation predict that deviations from a typical range of strain (change in length relative to original length) stimulus values promote adaptive responses in these tissues. According to these models, strain values of 1.5% to 3.0% are required to maintain tissue homeostasis. Strain values above this range will lead to increases in the cross-sectional area and stiffness of tendon and ligament, whereas strain values below this range predict decreases in these parameters. The models further predict that the more the strain stimulus deviates from steady-state values, the faster adaptive responses occur in tissue. Model-based simulations of tissue adaptation are consistent with histology data for tendon and ligament in animals and humans. Other research has demonstrated that both tendon and ligament respond to exercise-induced stress with increases in cross-sectional area, stiffness, and tensile strength.

Evidence also supports the idea that tissues within the musculoskeletal system atrophy and become less tolerant of physical stress if stress on the tissue diminishes below a baseline level. Unfortunately, tissues typically atrophy at a faster rate than they hypertrophy. Muscle can lose 6% to 40% of its ability to generate force over a 4- to 6-week period of bed rest or immobilization. Bone mineral density also is lost in response to diminished physical stress. Leblanc et al found that BMD is reduced 3% to 4% at the femoral neck and lumbar spine after 17 weeks of bed rest in young men who are healthy. Holick summarized the current literature by indicating that unloading of the skeleton, either due to strict bed rest or in zero gravity, leads, on average, to a 1% to 2% reduction in BMD at selected skeletal sites each month.

Likewise, ligaments respond to reduced mechanical stress. Woo and colleagues have documented a decline in the mechanical properties of the rabbit medial collateral ligament in response to 9 weeks of immobilization. These researchers reported that the stiffness, the ultimate load before failure, and the energy-absorbing capacity of the immobilized medial collateral ligament-bone complex were approximately one third of those variables in the contralateral, nonimmobilized control limb.

Integumentary System

Tissues in the integumentary system also demonstrate patterns of response to physical stress similar to those described for the musculoskeletal system. Mechanisms of excessive stress resulting in injury to the skin have been described by Brand regarding his work with patients with Hansen disease and foot ulcers. Brand proposed the same 3 basic mechanisms of injury to skin that we describe for musculoskeletal tissues and that are outlined in this theory (Principle J, Tab. 1). According to Brand, direct mechanical damage to the skin can occur with high levels of pressure (100 kg/cm ² or 1,300 psi) applied for a brief duration, such as when a person steps on a tack. Ischemic skin lesions can occur when a relatively low magnitude of pressure (1-5 psi) is applied to the skin for a long duration, such as when people wear tight shoes or are confined to bed for prolonged periods of time. "Inflammatory autolysis," similar in concept to cumulative trauma injury, can occur when pressures of a moderate magnitude (20 psi) are applied to the skin hundreds or thousands of times each day, such as stresses applied to plantar tissues during normal walking. Integument failure due to repetitive stress was shown when repetitive stress (10,000 repetitions per day) was applied to denervated rat footpads in an attempt to simulate stress on the foot during walking. Footpad ulcers occurred within 7 to 10 days of commencing the simulated walking procedures. Brand and others subsequently documented similar relationships among time, pressure, and skin breakdown in patients with diabetes and peripheral neuropathy.

Cardiovasuclar/Pulmonary System

Training can enhance cardiovascular function in athletes, people who are sedentary, people with disabilities, and people with previous cardiac impairments. Training causes adaptations in tissues within the cardiovascular and pulmonary systems, including an increase in the weight and volume of the heart, an increase in the size of the left ventricular cavity and the thickening of its walls, an increase in plasma volume, an increase in maximum cardiac output, and an increase in lung volumes. Intensive training can increase aerobic capacity 15% to 30% during the first 3 months, with as much as a 50% increase over a 2-year period ( Tab. 3).

Similar to other systems described, the positive effects of physical stress (ie, aerobic exercise training) are quickly reversible for tissues in the cardiopulmonary system. Reductions in metabolic and exercise capacity can occur after only 1 to 2 weeks of detraining, and many other improvements are lost within several months of detraining. McArdle et al, for instance, reported a 25% reduction in maximum oxygen consumption in 5 subjects who remained bedridden for 20 consecutive days. Maximal stroke volume and cardiac output also decreased, resulting in a loss of aerobic capacity by an average of 1% per day.

Neuromuscular System

In our opinion, adaptation of the nervous system in response to physical stress has not been studied as extensively as the adaptive response of tissues in the musculoskeletal, integumentary, and cardiovascular/pulmonary systems. Increasing evidence, however, suggests that physical stress and activity affect the peripheral and central nervous systems in a manner similar to that of other tissues in the body. Excessive stress can cause injury to tissues within the nervous system via the 3 mechanisms discussed for other systems. Examples of nerve injuries caused by high-magnitude stress applied over a brief duration include spinal cord injuries resulting from gunshot wounds or motor vehicle accidents. Nerve injury also may be caused by lower-magnitude stresses applied repetitively or over a long duration. Examples of these mechanisms of nerve injury include carpal tunnel syndrome, tarsal tunnel syndrome, thoracic outlet syndrome, ulnar nerve palsy, spinal stenosis, and lumbar root lesions.

Novak and Mackinnon described excessive physical stress from various postural alignments and repetitive motions that can contribute to nerve injury and pain. The incidence of cumulative trauma disorders has risen dramatically over the last 15 years and has been linked to jobs that require high-force and high-repetition activities, especially when performed in awkward postures. The odds ratio for developing carpal tunnel syndrome has been reported to be greater than 15 for high-force, high-repetition jobs compared with jobs requiring low-force, low-repetition activities. Pressures within the carpal tunnel have been shown to be higher when the wrist is in extreme flexion or extension compared with a neutral position. Furthermore, jobs requiring excessive wrist deviations are considered a risk factor for injury to the median nerve.

Mechanical injury of nerve tissue can occur with low-magnitude stresses applied for a long duration (compression injury) or from repetitive bouts of moderate-magnitude stresses (cumulative trauma disorders). Although some nerve injuries may require surgical correction, we believe one role of the physical therapist is to determine how excessive stress on the nerve can be relieved in a conservative fashion to facilitate healing of the nervous tissue.

We have limited our discussion of the neuromuscular system to nerve injuries caused by mechanical stress on the nerve and surrounding structures. Although beyond the scope of this perspective, a growing body of literature suggests that neurons adapt to high and low levels of physical activity by altering their electrical activity ( Tab. 3; eg, rate of discharge, threshold of recruitment). The observation that physical activity can stimulate neural adaptation has important implications for the rehabilitation of patients with primary neurological disorders (eg, stroke, traumatic brain injury). We predict that the fundamental principles outlined in the PST can be used to describe neural adaptations following central or peripheral nervous system injury, and we encourage others to investigate this prediction.

Limitations of the Physical Stress Theory

The PST represents an effort to integrate common principles from the approaches and evidence described above. We also expand existing theories to place the role of tissue injury within a continuum of tissue viability so that the theory encompasses pathological conditions and principles of wellness and prevention. Like any theory, the PST has limitations. These limitations will be discussed next, followed by a discussion of the implications of the theory for physical therapist practice, education, and research.

We believe the PST provides an appropriate framework for investigating the influence of multiple factors on the level of physical stress required for tissue adaptation and injury avoidance. Despite the absence of specific values for thresholds of change, the PST currently provides an overall framework that outlines relative relationships along a continuum of tissue responses to physical stress. Elaboration and refinement of this preliminary framework should eventually allow for a quantitative understanding of the thresholds that indicate when atrophy, maintenance, hypertrophy, injury, and death of various tissues begin.

Certain areas within physical therapy are not well developed in the PST in its current form. For example, the PST does not address issues of adaptation in the central nervous system. In addition, the PST does not identify the specific psychosocial factors that most influence tissue adaptation and injury. We believe the current theory, however, does provide a useful framework a wide range of physical therapy issues and has implications for practice, research, and education.

Implications for Physical Therapist Practice

We believe the PST provides a useful framework to approach patient care. It emphasizes the role of physical stress by addressing factors known to influence the level of physical stress and the response of tissues to stress application. According to this theory, the primary role of the physical therapist is to modify physical stresses to achieve a desired goal. Two broad goals will be discussed. The first goal is to reduce pain and subsequent impairments, functional limitations, and disabilities that result from injury. The second goal is to increase activity tolerance. Each of these goals will be discussed further in subsequent sections.

Implications for Treating Patients With Tissue Injury

The PST provides a general model for evaluating and treating people with injury. Chronic tissue injury, defined as injury that results in pain lasting greater than 8 weeks, often is caused by stresses of moderate magnitude that are repeated hundreds or even thousands of times a day. Examples of injuries resulting from this mechanism include many forms of back and cervical pain, patellofemoral pain, tendinitis injuries (eg, Achilles tendon, posterior tibial tendon), impingement syndrome of the shoulder, stress fractures, neuropathic plantar ulcers, and carpal tunnel syndrome. The primary questions asked in the evaluation and treatment of these and other forms of tissue injury are: (1) What factors appear to be contributing to excessive stress on the injured tissue? and (2) How can these contributing factors be modified to reduce stress on the tissue and allow the tissue to heal?

We believe proper identification of the injured tissue usually can help determine the factors contributing to excessive stress on the tissue. For example, suspected tendinitis might lead the clinician to investigate sources of stress caused by movements that are controlled by the muscle and tendon. In many cases, however, physical therapists are not able to confirm injury of a specific tissue using the tools currently available to them. The PST describes general principles of tissue adaptation and injury, applicable to all types of biological tissue, that can be used to guide treatment regardless of whether the injury can be localized to a specific structure. In our view, appropriate treatment, therefore, does not always require accurate identification of the injured structure. For instance, if low back pain can be eliminated by teaching the patient to move at the hips rather than moving at the lumbar spine when movements of the lumbar spine cause pain, identifying the specific injured tissue is of little benefit.

We believe general principles that govern the response of all biological tissues to stress can be used to guide physical therapy intervention, even when pathology of a specific structure cannot be determined. In this context, we contend that the most important question to guide treatment becomes: What factors appear to be contributing to excessive stress on the injured tissue? This question relates to Fundamental Principles F, I, J, and K in Table 1. In our opinion, the factors in Table 2 should be systematically evaluated for their potential to contribute to excessive tissue stress or for their potential to modify the response of tissues to stress application. In our experience, various types of injury tend to be associated with a similar set of contributing factors. For example, we have observed that factors contributing to overuse injuries of the foot and ankle often include movement and alignment factors (ie, excessive pronation or supination, changes in activity) and extrinsic factors (ie, footwear). Factors that contribute to excessive tissue stress or modify the tissue response can be added to or subtracted from the model depending on individual characteristics of the patient and the therapist's current working set of hypotheses.

The basic principles discussed can be illustrated with several examples. Maluf et al described evaluation and treatment of a patient with chronic low back pain. The authors speculated that repetition of rotation and extension movements of the lumbar spine contributed to excessive stress and injury to structures within the low back region. Low back symptoms improved following instructions designed to restrict lumbar rotation and extension movements during the performance of daily activities. McPoil and Hunt described a similar approach in the treatment of a patient with heel pain. The authors speculated that a recent change in activity level, poor footwear, and excessive pronation at the subtalar joint contributed to excessive stress on the plantar fascia and resultant heel pain. The treatment plan, therefore, was designed to modify these factors to decrease stress on the plantar fascia (eg, modifying the patient's work schedule to limit weight-bearing time, purchasing shoes with cushioned midsoles, obtaining temporary orthotic devices to control excessive pronation).

Even after sources of excessive stress have been identified and removed, we contend that injured tissues will be less tolerant of stress than they were prior to injury due to pain, inflammation, and disuse associated with the injury (Principles C and K, Tab. 1). Therefore, after pain and inflammation have subsided, previously injured tissues, in our opinion, should be exposed to progressively higher levels of physical stress to gradually restore the tissues' ability to tolerate greater levels of stress (Principle E, Tab. 1). Stress, we contend, should be applied progressively, with attention paid to the body's need for rest and recovery.

Implications for Improving Activity Tolerance

The overload principle (Principle E, Tab. 1), in which maintenance stress levels are raised to the range of stress that promotes tissue hypertrophy, has tremendous implications for physical therapy and forms the basis for progressive resistance exercises to increase muscle performance and activity tolerance. Physical stress must be of sufficient magnitude and repetition to cause the desired change in performance. The role of the physical therapist, in our view, is to instruct people in the appropriate magnitude and repetition of exercise or activity to provide an adequate stimulus for hypertrophy of intended tissues without injuring other tissues. Although clinicians are accustomed to using the overload principle to achieve hypertrophy of muscle, these same principles can be applied to other tissues such as ligament, tendon, and skin ( Tab. 3).

Implications for Physical Therapist Education

In a time when scientific and medical knowledge is expanding at an exponential rate, we believe the PST can help educators focus on appropriate content for a substantial portion of the physical therapy curriculum. According to the PST, key elements of the curriculum should include a clear understanding of how the body adapts to physical stress and how physical therapists can apply or modify stress on the body to achieve desired outcomes ( Tabs. 1 and 3).

In the PST, we propose that several key content areas should be emphasized. Kinesiology, we argue, should be taught with an emphasis on tissue mechanics and how different types of movement contribute to stress on specific tissues. Classes related to exercise physiology, in our view, should present guidelines for exercise and activity prescription that are designed to fall within the range of stress that promotes tissue hypertrophy while avoiding injury. We contend that instruction about orthotic devices or modalities should focus on their use in modifying either the level of stress applied to the body or the body's response to stress. The content of classes related to medicine and pathology should focus on providing an understanding of how particular diseases or pathologies modify the body's response to various forms of physical stress including exercise and activity. Classes related to clinical diagnosis and management could be organized using the approach described in the section titled "Implications for Physical Therapist Practice." We contend that the list of factors in Table 2 could form the focus of factors to consider for evaluation and intervention. Although there are other content areas that must be addressed in a curriculum (eg, administration), we contend that the factors listed above are the most important and could serve as the focus of content unique to a physical therapy curriculum. Students should be trained to develop a clinical hypothesis that identifies the most important factors contributing to a patient's problem, to address each modifiable factor, and to revise the initial hypothesis based on evaluation of treatment outcomes.

Implications for Research

The PST provides a framework for generating research hypotheses that focus attention on what we believe to be the most important and basic treatment technique used by physical therapists: modifying physical stresses to facilitate tissue adaptation and prevent injury. Although emphasizing the role of physical stress ( Tab. 1), the PST also recognizes the multifactorial nature of tissue adaptation and injury ( Tab. 2).

We believe this theory helps to clarify and expand on documented theoretical approaches currently used in physical therapy. Disablement models have provided an excellent theoretical framework for studying the relationship among impairments, functional limitations, and disability. We agree that a limitation of these models, however, is that they often do not address the underlying cause of the patient's symptoms. For example, disablement models postulate that back pain leads to certain functional limitations, such as difficulty performing household chores. However, we believe these models do not encourage identification of the specific mechanisms that cause the pathology leading to low back pain. The PST helps to fill this theoretical void by proposing that excessive physical stress causes the pathology, resulting in pain and subsequent disability.

Another example of how the theory could be used to generate and test hypotheses put forth in the agenda is in the management of skin breakdown on the plantar surface of the foot in patients with diabetes and peripheral neuropathy. Question 2.2.1. asks, "What are the modifiable risk factors for cumulative trauma syndrome?" Neuropathic plantar ulcers are one of many conditions that can be considered cumulative trauma syndrome. Investigators have determined that the location of plantar ulcers corresponds with areas of high physical stress, identified by peak plantar pressure. Identifying the magnitude of pressure that predicts injury of plantar tissues, however, has been elusive. The PST predicts that there is no single threshold of peak pressure that predicts injury for all patients. Rather, the theory suggests that a combination of stress-related variables (eg, magnitude, duration, repetition, and direction of pressures) must be considered when assessing a patient's risk for skin breakdown (Fundamental Principles H and J, Tab. 1). Furthermore, the threshold for injury is influenced by individual movement and alignment factors (eg, activity level, foot deformities), extrinsic factors (eg, type of shoes), psychosocial factors (eg, adherence), and physiological factors (eg, severity of peripheral vascular disease and peripheral neuropathy) ( Tab. 1). Researchers who are attempting to investigate the complex issue of skin breakdown would need to account for these many factors. The PST provides a framework for connecting the factors that can be used to guide research questions for a broad range of problems encountered by physical therapists.

Conclusion

The PST emphasizes the application and modification of physical stress on tissues of the human body to elicit positive adaptations and avoid injury. Many of the thoughts presented in this article are not new. The summary and integration of these thoughts into a defined theory, however, does offer a comprehensive approach that we believe can help to direct physical therapist practice and research for a wide range of people with and without impairments. We assert that there is considerable evidence to support current physical therapist interventions directed at modifying physical stress. We challenge readers to test, modify, and develop this theory through practice and published research. Our hope is that readers will see common elements described in this perspective in their own areas of practice and that physical therapy can continue to move forward in a more systematic and evidence-based manner.

References

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Tissue Adaptation to Physical Stress: A Proposed "Physical Stress Theory" to Guide Physical Therapist Practice, Education, and Research

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Abstract. The purpose of this perspective is to present a general theory-the Physical Stress Theory (PST). The basic premise of the PST is that changes in

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Central sensitization: Implications for the diagnosis and treatment of pain

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Central sensitization: Implications for the diagnosis and treatment of pain

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Abstract

Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and postsurgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk both of developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

Introduction

In 1983 I published a study indicating that many features of the pain hypersensitivity accompanying peripheral tissue injury or inflammation were the direct result of an augmentation of sensory signaling in the central nervous system [ 255]. A central amplification during angina pectoris had been postulated exactly 100 years before by W Allen Sturge MD, who in an 1883 paper in Brain envisaged a possible central nervous system "commotion ...... passed up from below" that somehow contributed to the clinical features of ischemic cardiac pain. However, the importance of this clinical insight lay largely dormant for a century, except for one human volunteer study on secondary hyperalgesia that was recognized by the authors as suggestive of a possible central contribution to the spread of pain sensitivity [ 101]. What I found in a preclinical study on stimulus-response relations in the spinal cord was that the afferent activity induced by peripheral injury triggered a long-lasting increase in the excitability of spinal cord neurons, profoundly changing the gain of the somatosensory system [ 255]. This central facilitation manifested as a reduction in threshold (allodynia), an increase in responsiveness and prolonged aftereffects to noxious stimuli (hyperalgesia), and a receptive field expansion that enabled input from non-injured tissue to produce pain (secondary hyperalgesia) [ 255- 256; 273; 51; 268].

I have recently reviewed the circumstances surrounding the discovery of the activity-dependent synaptic plasticity in the spinal cord that generates post-injury pain hypersensitivity [ 259], and that became termed "central sensitization" [ 272], as well as the current state of understanding of the cellular and molecular mechanisms responsible for this form of neuronal plasticity [ 147]. What I would like to specifically address in this review are the clinical implications of the phenomenon. What has central sensitization taught us about the nature and mechanisms of pain in patients, and what are the implications of central sensitization for pain diagnosis and therapy? Before doing this though, it is important first to understand exactly what central sensitization represents, how it has changed our general understanding of pain mechanisms, as well as reviewing the substantial data on central sensitization derived from studies on experimental pain in human volunteers.

What is central sensitization?

Prior to the discovery of central sensitization, the prevailing view on pain processing in the central nervous system was of a largely passive neural relay that conveyed by encoded action potentials, information on the onset, duration, intensity, location and quality of peripheral noxious stimuli, much like a telephone wire, from one site to another. More specifically, the CNS pathway was seen to constitute particular anatomical connections in the spinal cord, brain stem, thalamus and cortex (the "pain pathway"), linking the sensory inflow generated in high threshold primary afferents with those parts of the cortex that lead to the conscious awareness of painful sensations. The spinal gate control theory by Melzack and Wall in 1965 had highlighted that this sensory relay system could be modulated in the spinal cord by inhibitory controls [ 163], and considerable progress had been made by the early 1980's in identifying such inhibitory circuits [ 18]. Indeed this, together the discovery of enkephalins and endorphins [ 109; 98], diffuse noxious inhibitory controls [ 150], transcutaneous nerve stimulation [ 224], and the rediscovery of acupuncture [ 25], generated a much greater emphasis at that time on endogenous inhibitory controls than on those factors that might increase excitation, and thereby produce pain hypersensitivity. However, there was one exception, that which related to the discovery of peripheral sensitization in the 1970's [ 178]. Work by Iggo [ 112; 28] and Perl [ 33; 177; 20] had identified specific high threshold sensory neurons tuned to respond only to noxious stimuli, hence their name nociceptors [ 265], a term first coined by Sherrington based on his studies on noxious stimulus evoked flexion reflexes. Furthermore, first Perl then others showed that nociceptor peripheral terminals could become "sensitized" after injury, reducing their threshold, mainly to heat stimuli, and only within the site of injury where the terminal was exposed to inflammatory modulators, the zone of primary hyperalgesia [ 178; 146; 138; 41; 23]. While this phenomenon clearly is a very important contributor to inflammatory pain hypersensitivity [ 22], it cannot account for dynamic tactile allodynia, the temporal summation of pain, or secondary hyperalgesia. Some other explanation was needed as the neurobiological basis for these symptoms, which turned out to be increased synaptic function triggered within the CNS by nociceptive inputs [ 257; 237; 268].

The realization that synapses were subject to a form of use-dependent plasticity that could increase their strength or efficacy had steadily gained ground by the early 1980's. The phenomenon had first been described in the CNS as short lasting a post-tetanic potentiation of mono synaptic IA synaptic input to motor neurons by Lloyd in 1949 [ 155], one that could spread to other synapses on motor neurons [ 21]. This was followed by the discovery of windup in dorsal horn neurons by Mendell and Wall in 1965 [ 164], where repeated low frequency stimulation of a nerve at constant C-fiber strength were found to elicit a progressive increase in action potential firing over the course of the stimulus. A transformative breakthrough was the first description of long term potentiation (LTP) in the hippocampus by Bliss and Lomo in 1973, where a brief high frequency coincident input produced a persistent increase in synaptic efficacy, opening the door for an extensive and still ongoing study into the molecular mechanisms of synaptic plasticity. LTP was first recorded in the spinal cord in 1993 [ 182], where it represents a particular component of the general phenomenon of central sensitization [ 113; 122; 114]. In 1976 Kandel and colleagues described a sensitization of the gill withdrawal reflex in the sea snail Aplysia, which was associated with a facilitation of the synapse between sensory and motor neurons [ 29]. However, this data was interpreted as reflecting memory and learning rather than an invertebrate model of pain hypersensitivity, although of course the two phenomena converge in this, and other model systems, although there are differences too [ 274; 122].

What I found in my original 1983 and subsequent pre-clinical studies with colleagues at University College London, was that a brief (~10-20 second), low frequency (1-10Hz) burst of action potentials into the CNS generated by electrical stimulation or natural activation of nociceptors increased synaptic efficacy in nociceptive neurons in the dorsal horn of the spinal cord and this lasted for tens of minutes after the end of the conditioning stimulus [ 255; 244; 256; 267; 50; 245; 273; 51; 272; 263; 230; 264]. This phenomenon differed from windup, which represented a progressively increasing output during the course of a train of identical stimuli (technically called homosynaptic potentiation); central sensitization was concerned instead with the facilitation that manifested after the end of the conditioning stimuli, and that once triggered remained autonomous for some time, or only required a very low level of nociceptor input to sustain it. Furthermore, central sensitization represented a condition where input in one set of nociceptor sensory fibers (the conditioning input) amplified subsequent responses to other non stimulated non-nociceptor or nociceptor fibers (the test input; this form of facilitation is termed heterosynaptic potentiation to distinguish it from homosynaptic potentiation where the test and conditioning input are the same) [ 231]. The classic form of LTP in the hippocampus is homosynaptic with changes in efficacy restricted to activated synapses, a convergent plasticity, and while this is a feature of some aspects of central sensitization [ 190], most of its clinically relevant attributes relate to its divergent heterosynaptic components [ 147]. The underlying neurobiological basis for central sensitization is that for most central circuits, the receptive field properties of neurons defined by the firing of action potentials is only the "tip of the iceberg". Most of the synaptic input to neurons is subthreshold [ 262- 263], acting subliminally either because synaptic input is too weak or membrane excitability is restrained by inhibitory inputs. Increasing synaptic strength by a presynaptic increase in an excitatory transmitter release or in the post synaptic response to the transmitter [ 264; 271; 231; 129; 247; 130; 133; 154; 46; 100; 151- 152; 227] or by reducing inhibition [ 208; 168; 12; 103; 180; 165; 226] or increasing membrane excitability can recruit these normally subthreshold inputs to suprathreshold action potentials, producing profound changes in functional properties [ 270]. More recently it has become appreciated that in addition to activity-dependent synaptic plasticity, changes in microglia, astrocytes, gap junctions, membrane excitability and gene transcription all can contribute to the maintenance of central sensitization [ 234; 189; 43; 48; 88; 104; 205; 44; 47; 186]. Figures 1 and ​and2 2 summarize sensory processing under normal circumstances and the changes that result from induction of central sensitization.

An important implication of these early basic science studies was the possibility that the pain we experience might not necessarily reflect the presence of a peripheral noxious stimulus. We learn from our everyday experience interfacing with the external environment to interpret pain as reflecting the presence of a peripheral damaging stimulus, and indeed this is critical to its protective function. Central sensitization introduces another dimension, one where the CNS can change, distort or amplify pain, increasing its degree, duration, and spatial extent in a manner that no longer directly reflects the specific qualities of peripheral noxious stimuli, but rather the particular functional states of circuits in the CNS. With the discovery of central sensitization, pain conceptually at least had become "centralized" instead of being exclusively peripherally driven. In this sense central sensitization represents an uncoupling of the clear stimulus response relationship that defines nociceptive pain. Nociceptive pain reflects the perception of noxious stimuli. In the absence of such potentially damaging stimuli there is no nociceptive pain. However, after the discovery of central sensitization it became clear that a noxious stimulus while sufficient was not necessary to produce pain. If the gain of neurons in the "pain pathway" in the CNS was increased, they could now begin to be activated by low threshold, innocuous inputs. In consequence pain, could in these circumstances become the equivalent of an illusory perception, a sensation that has the exact quality of that evoked by a real noxious stimulus but which occurs in the absence of such an injurious stimulus. This does not mean the pain is not real, just that it is not activated by noxious stimuli. Such pain can no longer be termed nociceptive, but rather reflects a state of induced pain hypersensitivity, with almost precisely the same "symptom" profile to that found in many clinical conditions. This raised the immediate obvious question, was central sensitization a contributor to clinical pain hypersensitivity?

These notions were generally not very well received initially, particularly by physicians who believed that pain in the absence of pathology was simply due to individuals seeking work or insurance-related compensation, opioid drug seekers, and patients with psychiatric disturbances; i.e. malingerers, liars and hysterics. That a central amplification of pain might be a "real" neurobiological phenomenon, one that contributes to diverse clinical pain conditions, seemed to them to be unlikely, and most clinicians preferred to use loose diagnostic labels like psychosomatic or somatoform disorder to define pain conditions they did not understand. We can now 30 years later, based on data from many studies in human volunteers and patients, address whether central sensitization, defined operationally as an amplification of neural signaling within the CNS that elicits pain hypersensitivity, is a real phenomenon or not, and can assess its relative contribution to inflammatory, neuropathic and dysfunctional pain disorders in patients [ 258; 53].

Central sensitization in human volunteers

The first clear demonstration of central sensitization in human volunteers came from a psychophysical study by LaMotte and colleagues on the secondary cutaneous hyperalgesia that is elicited by intradermal capsaicin injection (which activates the TRPV1 receptor). They found intense localized pain lasting minutes at the injection site, followed immediately by three zones of hyperalgesia; a small zone of heat hyperalgesia close to the injection site lasting 1-2 hours, an intermediate zone of dynamic tactile allodynia spreading beyond the area of heat hyperalgesia and lasting several hours, and the largest zone to pinprick, way outside of the injection site, which remained present for up to 24 hours [ 145]. The investigators then showed that the secondary mechanical hyperalgesia required sensory inflow to the CNS because local anesthesia prior to the capsaicin injection blocked it. In addition because the pain sensitivity crossed a tight band that prevented circulation in the skin, they concluded that it was not due to a local spread of the capsaicin or any peripheral inflammatory mediator. An even more direct demonstration that activity dependent central sensitization was responsible for tactile allodynia and secondary hyperalgesia in humans came from a second study by La Motte, this time with Torebjork in 1992 [ 233]. They again used intradermal injection of capsaicin to induce an area of tactile allodynia that lasted for 2 hours. Nerve block experiments revealed that while the capsaicin and heat pain was carried by C fibers, the mechanical allodynia was transferred to the CNS by low threshold myelinated fibers. The most elegant part of the study was their finding that electrical intraneural stimulation of single Aβ mechanoreceptive fibers that elicited a non painful tactile sensation before the capsaicin injection, began to produce pain if the fibers' receptive field fell within the zone of secondary mechanical hyperalgesia. Lidocaine anesthesia of the cutaneous innervation territory of the stimulated fiber did not reverse the pain, showing this was not peripheral in origin. They concluded that the pain evoked by stroking the skin area surrounding a painful intradermal injection of capsaicin "is due to reversible changes in the central processing of mechanoreceptive input from myelinated fibres which normally evoke non-painful tactile sensations".

Another early study, this time by Koltzenburg and Torebjork, using mustard oil (which activates TRPA1) as the pain conditioning stimulus, together again with differential nerve blocks, confirmed that brush-evoked mechanical allodynia was mediated by low threshold Aβ fibers that normally encode non-painful tactile sensations [ 140]. Unlike after capsaicin, however, the mustard oil evoked tactile allodynia required an ongoing low level input from C-nociceptors to sustain it, indicating that different sensory fibers may have different central actions, some short and others long lasting, and indeed further studies have shown differences in the duration of tactile allodynia after capsaicin and mustard oil [ 139], the significance of which was not appreciated a the time because it was not clear then that these irritants acted on quite different TRP receptors.

That central sensitization could cause a spread of pain sensitivity across peripheral nerve territories, the neurological dogma for diagnosing a disease of the central rather than peripheral nervous system, was shown by Max and colleagues using the intradermal capsaicin model in volunteers together with radial or ulnar nerve blocks to clearly identify individual nerve territory [ 192]. Complementing this, a study comparing skin hyperaemia induced by a skin burn injury found that the skin blood flow changes induced by the injury had disappeared by the time secondary mechanical hyperalgesia peaked, and the two were not correlated in time or space, supporting the conclusion that peripheral mechanisms do not contribute to secondary hyperalgesia [ 198]. Even more dramatic perhaps, was the relatively recent demonstration that intradermal capsaicin induces contralateral hyperalgesia and allodynia that is delayed in its manifestation and reduced in extent compared to the ipsilateral secondary hyperalgesia, but present in a majority of subjects [ 206], a form perhaps of "tertiary hyperalgesia" that cannot be peripheral in origin. What pain sensitivity we feel then, can be determined by the state of excitability of neurons in the CNS.

Central amplification of Aδ nociceptor fiber test input following a C-fiber conditioning input was shown to contribute to pinprick/punctate secondary hyperalgesia, again using the intradermal capsaicin model [ 279], underscoring the different identity of the afferent signals that elicit central sensitization as a conditioning stimulus (C-fibers) from those that elicit allodynia (Aβ) or hyperalgesia (Aδ), a further clear manifestation of heterosynaptic facilitation. In a similar vein, another study found that pin prick hyperalgesia induced in response to intradermal capsaicin was actually mediated by capsaicin-insensitive afferents, showing that the test and conditioning inputs in this setting are quite different [ 87], while the secondary hyperalgesia elicited by intradermal capsaicin was shown by yet other investigators, to be restricted to mechanical stimuli, with no correlation between the magnitude of capsaicin evoked pain and the extent of punctate or tactile secondary hyperalgesia [ 237]. Furthermore, temporal summation to pin prick in the zone of capsaicin injection (as model of homosynaptic facilitation/windup) was mechanistically independent of the development of secondary hyperalgesia, because while the gain of the stimulus-response relationship in the zone of secondary was increased, that of the windup was not changed, even though the actual pain was enhanced [ 158]. A similar conclusion was made after a study where repeated intradermal capsaicin injections were reported to produce a progressively diminishing pain, presumably due to desensitization, while the allodynia and punctate hyperalgesia continued to increase [ 254]. Two more recent studies using high frequency stimulation as the conditioning input to mimic conditions that elicit LTP, found that while changes in the conditioned site (homotopic site) do occur, they are accompanied by a development of pain hypersensitivity in the adjacent non-stimulated heterotopic site (reduction in threshold, pain evoked by light tactile stimuli, and exaggerated response to suprathreshold pinprick stimuli [ 136; 240], and both sets of investigators concluded that heterosynaptic facilitation predominates in this model of central sensitization, exactly as it does for the low frequency conditioning inputs that mimic the natural firing range of nociceptors. Generalizing, it seems clear that heterosynaptic changes are a major feature of the presentation of central sensitization.

Apart from changes in subjective pain measures, the consequences of central sensitization can also be detected using objective biomarkers. These include long-term changes in nociceptive withdrawal reflexes [ 24] and increases in cortical event related potential amplitudes [ 240]. Magnetic source imaging reveals an increase in the excitability of neurons in the somatosensory cortex evoked by low threshold Aβ stimulation within the capsaicin-induced zone of secondary hyperalgesia [ 17], while magnetoencephalography detects changes in the patterns of cerebral processing [ 159] and functional MRI, changes in BOLD signals in the cortex, both during secondary hyperalgesia [ 16]. Another MRI study found changes in the brainstem that are apparently specific to central sensitization, in addition to the changes in the primary somatosensory cortex that are related to the intensity of pain [ 153].

While most studies have looked at the effects of skin conditioning stimuli on skin pain sensitivity, experimental muscle pain produced by hypertonic saline injections produces long lasting changes in thermal sensitivity in the area of referred pain [ 203], while sustained nociceptive stimulation of myofascial trigger points induces a wide spread central sensitization [ 273; 275]. Interestingly, in preclinical models, muscle and joint conditioning afferents have a longer lasting action in producing central sensitization than those from skin [ 244]. A reverse approach has shown that cutaneous capsaicin increases myofascial trigger point pressure sensitivity in segmentally related muscles [ 211]. Conditioning nociceptive stimuli originating in viscera, such as exposure of the lower esophagus to acid, also induces central sensitization, leading to viscerovisceral (pain hypersensitivity in the upper esophagus) and viscerosomatic hypersensitivity (allodynia on the chest wall) [ 193] that can be captured by esophageal evoked potentials [ 194], and is associated with increased temporal summation [ 196]. A recent study has replicated this esophageal model of central sensitization using acid and capsaicin infusions, showing also thermal and mechanical pain hypersensitivity in the rectum after the esophageal stimulation [ 27], indicating how widespread the effects of central sensitization are in the gastro intestinal tract. These changes may be mechanistically related to widespread clinical pain syndromes [ 95].

One emerging area of considerable interest is the utility of experimental central sensitization in human volunteers to test efficacy in centrally acting drugs. Drugs with efficacy in preclinical models, such as NMDA receptor antagonists [ 271] can be tested in Phase 1b human proof of principle studies [ 212]. Ketamine inhibits central temporal summation [ 8] and secondary mechanical hyperalgesia [ 142] evoked by repetitive nociceptive electrical stimulation in humans as well as primary and secondary hyperalgesia after an experimental burn injury [ 116], visceral conditioning inputs [ 253; 251] and topical [ 6] or intradermal [ 204] capsaicin, but not A delta mediated nociceptive pain [ 181]. Ketamine's action on experimental pain can be detected by fMRI [ 210]. Similar activity is found for i.v. dextromethophan [ 115]. Collectively these data strongly support a role for the NMDA receptor in acute activity-dependent central sensitization [ 147]. However, the trials also indicate the lack of therapeutic index between reducing central sensitization and inducing psychotomimetic side effects. Another class of drugs that has been extensively studied in human experimental models of central sensitization is the gabapentanoids. Oral gabapentin at doses similar to that used for chronic neuropathic pain when given to human volunteers reduced tactile allodynia and decreased mechanical secondary hyperalgesia elicited by intradermal capsaicin [ 92]. Even single administration of gabapentin had an antihyperalgesic effect on capsaicin-induced secondary hyperalgesia and reduced fMRI signatures of central sensitization [ 110]. In another study gabapentin, interestingly reduced cutaneous evoked central sensitization but not muscle pain [ 201]. Two studies have looked at pregabalin's efficacy in experimental human central sensitization, one evoked by electrical stimuli [ 49] and the other by intradermal capsaicin [ 246]. Both of these double blind studies demonstrated efficacy for pregabalin in terms of experimental tactile allodynia and secondary hyperalgesia. These data suggest that a major component of gabapentin or pregabalin's mechanism of action is a reduction of central sensitization [ 238]. Many other centrally acting drugs with analgesic efficacy in patients reduce central sensitization preclinically, including duloxetine, milnacipran and lamotrigene [ 118; 170; 15] but have not been tested for this action in humans. Drugs that have failed to show efficacy in human studies of activity-dependent central sensitization are NK1 receptor antagonists [ 252] [ 49] and COX-2 inhibitors [ 35; 250; 49]. A COX-2 inhibitor does have efficacy though if the central sensitization is triggered by peripheral inflammation [ 225], as predicted by preclinical models [ 189].

Interestingly, while gender has been described as important for differences in nociceptive pain sensitivity, a study on the secondary hyperalgesia induced by heat and capsaicin did not reveal a gender difference [ 119]. Nevertheless, recent data show that pain sensitivity including secondary hyperalgesia and brush evoked allodynia is heritable, with an estimated 50% genetic contribution to the pain variance [ 172]. The genetic polymorphisms involved in the differential susceptibility to secondary hyperalgesia have not been comprehensively investigated, although some candidates are beginning to be identified in studies of experimental central sensitization [ 228]. This is an area that requires major research.

The following conclusions can be made from this survey of the published studies of experimental pain hypersensitivity in human volunteers. Central sensitization is a robust phenomenon, readily induced in human volunteers in response to diverse ways of activating nociceptors (electrical stimulation, capsaicin, mustard oil, acid, heat burn, UV burn, hypertonic saline). Generally this activity-dependent plasticity manifests immediately, but its effects persist for many hours beyond the inducing conditioning stimulus, eventually returning, however, back to baseline, indicating its usual full reversibility. The phenomenon can be elicited by conditioning skin, muscle or visceral organs, and typically presents as dynamic tactile allodynia and punctate hyperalgesia but also enhanced pressure, and in some cases, thermal sensitivity, spreading from the conditioning site to neighboring non stimulated sites, and even to very remote regions. Although there is a homosynaptic (homotopic) aspect to the phenomenon, its major manifestation is heterosynaptic (heterotopic), and for this reason and its reversibility, it is perhaps inaccurate to equate central sensitization with the LTP like phenomena in the cortex that are specifically associated with long term memory. Because central sensitization can be induced in almost all subjects and detected using subjective and objective outcome measures and is sensitive to pharmacological interventions, it is a useful tool for determining the activity of drugs on centrally driven pain hypersensitivity.

Globally, the data obtained in human volunteer studies demonstrate that induction of use-dependent central facilitation in nociceptive central pathways increases pain sensitivity and may, therefore, contribute to clinical pain syndromes. Experimental studies in human volunteers are necessarily restricted to using non-injurious conditioning inputs, and therefore are limited to studying only the activity-dependent components of pain hypersensitivity elicited by sensory inputs, and not those transcription-dependent and structural changes that manifest after inflammation or nerve injury, which may have different mechanisms, time courses and presentations [ 269; 171; 121; 160; 261; 189; 123; 229; 97; 53; 242]. The limited experience with more severe human experimental injury indicates that central sensitization also contributes to the late hyperalgesia present in this model [ 58; 176].

Central sensitization and the clinical pain phenotype

What features of the clinical phenotype may be contributed to, or generated exclusively by central sensitization? While the human experimental studies reviewed above indicate that if a patient has dynamic tactile allodynia, secondary punctuate/pressure hyperalgesia, temporal summation and sensory aftereffects, central sensitization may well be involved. Any sensory experience greater in amplitude, duration and spatial extent than that would be expected from a defined peripheral input under normal circumstances, qualifies as potentially reflecting a central amplification due to increased excitation or reduced inhibition. These changes could include a reduction in threshold, exaggerated response to a noxious stimulus, pain after the end of a stimulus, and a spread of sensitivity to normal tissue. However, because we cannot directly measure sensory inflow, and because peripheral changes can contribute to sensory amplification, as with peripheral sensitization, pain hypersensitivity by itself is not enough to make an irrefutable diagnosis of central sensitization. A further complication is that because peripheral input commonly is the trigger of central sensitization, a reduction in pain sensitivity produced by targeting a peripheral trigger with a local anesthetic does not exclude central amplification, but may rather indicate a role of peripheral input in maintaining it [ 140]. Nevertheless, there are some features of patient's symptoms which are more likely to indicate central rather than peripheral contribution to pain hypersensitivity. These include pain mediated by low threshold Aβ fibers (determined by nerve block or electrical stimulation), a spread of pain sensitivity to areas with no demonstrable pathology, aftersensations, enhances temporal summation, and the maintenance of pain by low frequency stimuli that normally do not evoke any ongoing pain. To assess how central sensitization may present in patients, we need a detailed phenotyping of different patient cohorts to capture exactly what changes in sensitivity occur, where and when [ 93; 188; 86; 9; 11; 197; 55]. Ideally this should be combined with objective measures of central activity, such as fMRI, so that clear diagnostic criteria for determining the presence of central sensitization in patients can be established. The utility of diagnostic criteria for the presence of central sensitization would not only be insight into the pathophysiological mechanisms responsible for producing pain, but more so in defining potential treatment strategies. If a particular patient's pain is primarily the result of abnormal activity in nociceptors, as in patients with primary erythromelalgia [ 74], the optimal therapy required is likely to be different from a patient whose tactile allodynia and secondary hyperalgesia are entirely maintained by central sensitization due to changes in synaptic efficacy in the spinal cord. This is the rationale for a mechanism-based approach to the diagnosis and treatment of pain [ 266; 258]. Indeed response to a trial treatment, such as to the NMDA receptor antagonist ketamine, can itself be a potential diagnostic for the presence central sensitization.

To which clinical syndromes does central sensitization contribute?

Given the caveats about the lack of absolute diagnostic criteria for identifying the presence of central sensitization in patients, a fairly large number of studies have nevertheless putatively identified this phenomenon as contributing to patients' pain phenotype. I will briefly review these, based on disease.

Rheumatoid arthritis (RA)

Patients with RA, the prototypic inflammatory joint disease, have extra-articular tenderness which is correlated with the extent of joint disease [ 141] but whether this is the result of peripheral or central sensitization has not been studied. A study on juvenile chronic arthritis reported enhanced sensitivity to noxious stimuli both at joints and in remote areas in patients with and without active disease, suggesting the possibility that the disease when active sets up a state of autonomous central sensitization [ 107]

Osteoarthritis (OA)

This degenerative joint disease with characteristic destruction of cartilage and alteration in bone is a very common cause of chronic pain, particularly in the elderly. The degree of pain does not always correlate with the extent of joint damage or presence of active inflammation raising the possibility that there may be a central component to the pain [ 26]. Supporting this is the enhanced degree and duration of pain and secondary hyperalgesia evoked by intramuscular injection of hypertonic saline in patients with OA compared to controls [ 13]. Patients with high pre-operative pain and a low pain threshold have a higher risk of persistent pain after total knee replacement for OA, which was interpreted as reflecting central sensitization [ 157]. Another study on 62 patients showed that pain of central neural origin (widespread reduced pressure pain thresholds) negatively impacted on knee functional capacity [ 117]. OA patients have a lower pain threshold and have punctate hyperalgesia in areas of referred pain, which is associated with greater activation in the brainstem as detected by fMRI, representing a possible biomarker for central changes [ 99]. The centrally acting amine uptake inhibitor duloxetine which reduces central sensitization in preclinical models [ 124; 15], significantly reduced pain more than placebo in an RCT in 231 patients with knee OA pain [ 45], indicating that drigs that target central sensitization are efficacious in this patient population. In a recent phenotyping study in 48 patients with painful knee OA and 24 age matched controls, the patients had reduced pressure pain thresholds both at the joint and in remote areas, and increased temporal summation. While the degree of sensitization correlated with the pain, it did not correlate with radiological findings, leading to the conclusion that central sensitization is an important contributor to knee OA pain [ 7]. Collectively, these data intriguingly suggest that the pain of OA, a peripheral pathology, has an important central component, and this is clearly deserving of more study to understand its extent, mechanism and therapeutic implications.

Temporomandibular disorders (TMD)

Unlike OA, the pathophysiology of this syndrome is much less well understood. However, TMD has been found to be associated with an increase in generalized pain sensitivity after isometric contraction of the orofacial muscles [ 166], and widespread bilateral mechanical [ 78] and thermal [ 175] pain sensitivity is reported in women with myofascial TMD compared to age matched controls, which was interpreted as suggesting widespread central sensitization. In addition, a greater referred pain is elicited from the more frequent trigger points that are found in these patients, than in controls [ 77].

As for other types of facial pain, mechanical allodynia is a major feature of periradicular inflammation (periradicular periodontitis) with reduced threshold also in contalateral non inflamed teeth, reflecting central sensitization [ 132]. After a third molar extraction evidence for central sensitization could be detected for at least a week (enhanced response to repetitive intraoral pinprick and electrical stimulation, aftersensations and extraoral hyperalgesia) [ 126].

Fibromyalgia (FM)

A quantitative sensory testing study in 85 fibromyalgia patients and 40 matched controls found that the patients had altered heat and cold thresholds and a reduced tolerance for pain, as well as a reduced nociceptive reflex threshold, a measure of central excitability [ 65]. The latter finding was sufficiently different from controls that the authors suggest it could be used as a diagnostic measure of central sensitization, identifying patients for whom centrally acting drugs may be particularly beneficial. Other studies have confirmed the increased generalized sensitivity in FM patients to pressure and thermal stimuli [ 179]; [ 94; 173] and to electrical stimulation of skin and muscle, with enhanced cortical evoked potentials [ 66]. The data overall seem to support a major role for central sensitization in the generation of the symptoms of FM, and the success of centrally acting treatments, such as pregabalin or duloxetine in treating these conditions, may reflect a reduction in central sensitization in these patients.

Miscellaneous Musculoskeletal Disorders

Chronic neck pain resulting from whiplash is associated with lowered pain thresholds in uninjured tissue [ 57; 222]. Injection of local anesthetic into myofascial trigger points in these patients results in an immediate increase in range of motion and elevation in pressure pain thresholds, which was felt to reflect dynamic maintenance of central sensitization by afferent triggers [ 85]. Patients with shoulder impingement syndrome also show widespread muscle sensitivity and an increased number of trigger points [ 105]. A widespread (bilateral) mechanical pain hypersensitivity is observed in patients with unilateral epicondylalgia (tennis elbow) interpreted as indicating central sensitization, possible induced by a peripheral trigger [ 75]. Similar generalized deep tissue hyperalgesia can also be demonstrated in patients with chronic radiating low back pain with intervertebral disc herniation [ 173]. Collectively these data indicate that diverse musculoskeletal disorders are characterized by a spread of pain sensitivity to deep uninjured tissue and that low level peripheral inputs may maintain this.

Headache

Neuropathic pain

The first demonstration of a likely contribution of central sensitization to neuropathic pain came from a study by Campbell and colleagues, who showed that an ischemic conduction block of large myelinated fibers specifically reduced dynamic tactile allodynia [ 42], a finding that was soon replicated [ 140]. Since then careful phenotyping studies of conditions like carpal tunnel syndrome have revealed enhanced bilateral sensitivity and an extraterritorial spread of symptoms in patients with unilateral or single nerve entrapment, supporting a contribution of central sensitization [ 61; 76; 82; 278]. Furthermore, ketamine reduces established peripheral neuropathic pain [ 125] and chronic phantom limb pain [ 73] indicating that ongoing activity- and NMDA receptor-dependent synaptic plasticity may contribute to maintaining neuropathic pain. That tricyclic antidepressants, dual uptake inhibitors and calcium channel alpha(2)-delta ligands, all centrally acting drugs that normalize enhanced neural activity, are the current first line treatments for neuropathic pain [ 72], reinforces the importance of the central component of the pain and its suitability as a target for treatment.

Complex regional pain syndrome (CRPS)

A prominent feature of chronic CRPS1 is tactile hyperesthesia and pressure hyperalgesia [ 241], which can be registered as enhanced S1 activation by a neuromagnetometer [ 243]. There is also thermal hyperalgesia in acute CRPS1 patients, which on the side ipsilateral to the diseased limb, may have a peripheral component due to ongoing aseptic inflammation, but the presence of contralateral hypersensitivity in the absence of any inflammatory changes points to an involvement of the CNS [ 108]. In a small randomized placebo controlled trial intravenous ketamine reduced CRPS pain [ 200].

Post-surgical pain

Visceral Pain Hypersensitivity Syndromes

Pain hypersensitivity is a feature of several common disorders of the gastro-intestinal tract including irritable bowel syndrome, non-cardiac chest pain and chronic pancreatitis, that all appear to have a central sensitization component. A majority of IBS patients have both rectal and somatic hypersensitivity [ 249]. Repetitive sigmoid stimulation in patients with IBS induces rectal hyperalgesia and viscerosomatic referral [ 169]. Local rectal anesthesia reduces rectal and somatic pain in irritable bowel syndrome patients, supporting the possibility that visceral hyperalgesia and secondary cutaneous hyperalgesia in irritable bowel syndrome is the result of central sensitization dynamically maintained by input from the GIT. Patients with non cardiac chest pain have esophageal hypersensitivity [ 195], with a reduced tolerance to repeated distension, increased size of referred pain and a greater propensity to show secondary hyperalgesia after acid infusion in their lower esophagus [ 69], all interpreted as reflecting the consequence of central sensitization. Chronic pancreatitis is associated with generalized deep pressure hyperalgesia [ 39; 174] and patients display greater degree and spatial extent secondary hyperalgesia elicited by repetitive experimental stimulation, suggesting enhanced central sensitization [ 67], that is reduced by a thorascopic splanchnic denervation [ 38], which may reflect that visceral input from the pancreas maintains the central sensitization.

In the urological tract, pain hypersensitivity is a feature of interstitial cystitis, chronic prostatitis, endometriosis, and vulvodynia, conditions whose pathophysiology and etiology is however, poorly understood. Although central sensitization has been hypothesized to contribute [ 137], not much data is available and few studies have been performed. Men with chronic prostatitis have though heightened pain sensitivity in the perineum [ 276; 239], while women with vulvodynia have an enhanced post capsaicin allodynia and secondary hyperalgesia compared to controls [ 84].

Co-morbidity of pain conditions characterized by pain hypersensitivity

Pain can be defined as nociceptive when it is generated by noxious stimuli, inflammatory when produced by tissue injury and/or immune cell activation, and neuropathic, when it is due to a lesion of the nervous system. What about pain conditions though, where there is no noxious stimulus, inflammation or damage to the nervous system? There are several common syndromes that present with pain hypersensitivity but no clear etiological factor, i.e. are considered "unexplained" and which might actually reflect not peripheral pathology but a primary dysfunction of the nervous system. These include fibromyalgia, tension-type headache, temporomandibular joint disease and irritable bowel syndrome, all of which may have a specific contribution to their phenotype by central sensitization, as detailed above. If a heightened sensitivity of the CNS or an increased propensity to develop central sensitization is a common feature of these syndromes, one would expect that there may be increased co-occurrence or comorbidity of the different conditions. It is also possible that an enhanced capacity to produce or maintain central sensitization is the primary defect in some of these syndromes.

In a study on almost 4,000 twins for comorbidity of chronic fatigue, low back pain, irritable bowel syndrome, chronic tension type headache, temporomandibular joint disease, major depression, panic attacks and post-traumatic stress disorder, associations were found that far exceeded those expected by chance, and the conclusion was that these conditions share a common etiology [ 199]. Another large epidemiological study on 44,000 individuals including twins for comorbidity with chronic widespread pain, found co-occurrence with chronic fatigue, joint pain, depressive symptoms, and irritable bowel syndrome, leading to the conclusion that associations between chronic widespread pain and its comorbidities may include genetic factors [ 127]. Yet another study on 2299 subjects for four unexplained syndromes; chronic wide spread pain, chronic orofacial pain, irritable bowel and chronic fatigue, again found that the occurrence of multiple syndromes was greater than expected by chance [ 2]. These epidemiological findings strongly suggest that there may be a common mechanistic basis for these diverse conditions, and that it may have a hereditary component.

The overwhelming conclusion from these diverse epidemiological studies is that chronic pain hypersensitivity in the absence of inflammation or nerve damage results in apparently phenotypically different syndromes depending on the tissue/organs affected. However, the overall similarity of the sensitivity changes may reflect a common contribution of central sensitization, and this may account for the unexpectedly high comorbid rate of the apparently different different syndromes. To test if there are indeed central sensitization syndromes, we will need a clear set of diagnostic criteria and biomarkers for the phenomenon. If this hypothesis is correct, the implications may be that treatment strategies targeted at normalizing hyperexcitability in the CNS may have a shared efficacy for the different manifestations of the central sensitization syndrome.

Conclusions

Clinical pain is not simply the consequence of a "switching on" of the "pain system" in the periphery by a particular pathology, but instead reflects to a substantial extent, the state of excitability of central nociceptive circuits. The induction of activity-dependent increases in synaptic function in these circuits, triggered and maintained by dynamic nociceptor inputs, shifts the sensitivity of the pain system such that normally innocuous inputs can activate it and the perceptual responses to noxious inputs are exaggerated, prolonged and spread widely. These sensory changes represent the manifestation of central sensitization, and extensive experimental medicine and clinical investigations over the past twenty years, have revealed it to be an important component of the pain hypersensitivity present many patients. While considerable progress has been made in teasing out the cellular and molecular mechanism responsible [ 148], much remains still to be learned, particularly which genetic and environmental contributors increase the risk of developing central sensitization in particular systems, exactly what triggers and sustains the phenomenon, and what is responsible in some individuals for its persistence. Nevertheless, the identification of the contribution of central sensitization to many "unexplained" clinical pain conditions has both provided a mechanistic explanation, and offered a therapeutic target.

Acknowledgments

Supported by research funds from the NIH. I thank all my colleagues whose work has over the past 25 years contributed to the study of central sensitization but particularly Alban Latremoliere for his careful reading of the MS and Christian von Hehn for making the two figures.

Footnotes

There is no conflict of interest.

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Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, ...

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