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United Nations's Office on Drugs and Crime 

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UNODC launches strategy in 2018 to protect public health

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UNODC launches strategy in 2018 to protect public health

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Misuse of opioid's, such as fentanyl as well as tramadol are a growing concern and have outlined the opioid crisis.

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New England Jornal of Health: Fentanyl Threat to Public Health

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New England Jornal of Health: Fentanyl Threat to Public Health

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Peer Reviewed

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Video

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Canada has fastest growing overdose mortality rate in the world, experts say

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Harvid Health Publishing: Fentanyl (Peer Reviewed) 

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Harvid Health Publishing: Fentanyl (Peer Reviewed) 

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Pills made to look like painkillers or anxiety medication are actually Fentanyl.

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Health Alerts from Harvard Medical School

Get helpful tips and guidance for everything from fighting inflammation to finding the best diets for weight loss...from exercises to build a stronger core to advice on treating cataracts. PLUS, the latest news on medical advances and breakthroughs from Harvard Medical School experts.

Plus, get a FREE copy of the Best Diets for Cognitive Fitness.

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Fentanyl: The dangers of this potent "man-made" opioid - Harvard Health

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Fentanyl is a powerful synthetic opioid. It is far more potent - and potentially more dangerous - than heroin and morphine. Overdose deaths related to fentanyl are on the rise. The drug is cheaper than heroin and recently is being used to dilute heroin or substitute for it.

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World Heath Organization, Opioid overdose (News Article)

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World Heath Organization, Opioid overdose (News Article)

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Fentanyl in various forms is on the WHO Model List of Essential Medicines. Its 50-100 times more potent than morphine, can be cancer treater. WHO

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Opioids

The term "opioids" includes compounds that are extracted from the poppy seed as well as semisynthetic and synthetic compounds with similar properties that can interact with opioid receptors in the brain. Opioids have analgesic and sedative effects, and are commonly used for the management of pain. Opioid medicines such as methadone and buprenorphine are used for maintenance treatment of opioid dependence. After intake, opioids can cause euphoria, which is one of the main reasons why they are taken for non-medical reasons. Opioids include heroin, morphine, codeine, fentanyl, methadone, tramadol, and other similar substances. Due to their pharmacological effects, they can cause difficulties with breathing, and opioid overdose can lead to death.

Their regular non-medical use, prolonged use, misuse and use without medical supervision can lead to opioid dependence and other health problems. Opioid dependence is a disorder of regulation of opioid use arising from repeated or continuous use of opioids. The characteristic feature of dependence is a strong internal drive to use opioids, which manifests itself by impaired ability to control use, increasing priority given to use over other activities and persistence of use despite harm or negative consequences. Physiological features of dependence may also be present, including increased tolerance to the effects of opioids, withdrawal symptoms following cessation or reduction in use, or repeated use of opioids or pharmacologically similar substances to prevent or alleviate withdrawal symptoms.(1)

Worldwide, about 275 million people (or 5.5% of the global population aged 15-64 years) used drugs at least once in 2019. Among them, about 62 million people used opioids. About 36.3 million people suffered from drug use disorders in 2019.(2) Most people dependent on opioids used illicitly cultivated and manufactured heroin, but the proportion of those using prescription opioids is growing.

Opioid overdose

Opioid use can lead to death due to the effects of opioids on the part of the brain which regulates breathing. An opioid overdose can be identified by a combination of three signs and symptoms:

pinpoint pupils;

unconsciousness; and

difficulties with breathing.

Worldwide, about 500 000 deaths are attributable to drug use. More than 70% of these deaths are related to opioids, with more than 30% of those deaths caused by overdose. According to WHO estimates, approximately 115 000 people died of opioid overdose in 2017. Opioid overdoses that do not lead to death are several times more common than fatal overdoses.

The number of opioid overdoses has increased in recent years in several countries, in part due to the increased use of opioids in the management of chronic pain and increasing use of highly potent opioids appearing on the illicit drug market. In the United States of America (USA) the number of people dying from opioid overdose increased by 120% between 2010 and 2018, and two-thirds of opioid-related overdose deaths in 2018 in the USA involved synthetic opioids, including fentanyl and its analogues.(3) During the COVID-19 pandemic, a further substantial increase in drug overdose deaths was reported in the USA, primarily driven by rapid increases in overdose deaths involving synthetic opioids.(4)

Fentanyl is a potent synthetic opioid that is used as a pain reliever and as an anaesthetic. It is approximately 50-100 times more potent than morphine. Fentanyl in various formulations is on the WHO Model List of Essential Medicines. However, fentanyl and its chemically-similar analogues (including carfentanil, acetylfentanyl, butyrfentanyl, and furanyl fentanyl) have been associated with a spike in deaths from opioid overdose. There is evidence that drug dealers may be adding fentanyl to increase the potency of their products (such as heroin) and selling fentanyl as counterfeit tablets, created to look like authentic prescription medications. Therefore, many users who test positive for fentanyl and its analogues do not realize that they took the substance.

Risk factors for opioid overdose

There are a number of risk factors for opioid overdose. These include:

having an opioid use disorder;

taking opioids by injection;

resumption of opioid use after an extended period of abstinence (e.g. following detoxification, release from incarceration, cessation of treatment);

using prescription opioids without medical supervision;

high prescribed dosage of opioids (more than 100 mg of morphine or equivalent daily).

using opioids in combination with alcohol and/or other substances or medicines that suppress respiratory function such as benzodiazepines, barbiturates, anesthetics or some pain medications; and

having concurrent medical conditions such as HIV, liver or lung diseases or mental health conditions.

Males, people of older age and people with low socio-economic status are at higher risk of opioid overdose than women, people of young age groups and people with higher socio-economic status.

Emergency responses to opioid overdose

Death following opioid overdose is preventable if the person receives basic life support and the timely administration of the drug naloxone. Naloxone is an antidote to opioids that will reverse the effects of an opioid overdose if administered in time. Naloxone has virtually no effect in people who have not taken opioids.

Access to naloxone is generally limited to health professionals. In many countries there is still limited availability of naloxone even in medical settings, including in ambulances. On the other hand, some countries have already made naloxone available in pharmacies without prescription. Several countries (Australia, Canada, Italy, the United Kingdom of Great Britain and Northern Ireland and Ukraine) have introduced naloxone as over-the-counter medication and have also started proactive dissemination in communities.

In recent years, a number of programmes around the world have shown that providing naloxone to people likely to witness an opioid overdose, in combination with training on the use of naloxone and on the resuscitation of people following an opioid overdose, could substantially reduce the number of deaths resulting from opioid overdose. This is particularly relevant for people with opioid use disorder and leaving prison, as they have very high rates of opioid overdose during the first four weeks after release.

People most likely to witness an opioid overdose

People who are most likely to witness an opioid overdose are:

people at risk of an opioid overdose themselves;

friends and families of people who use opioids on a regular basis; and

health-care workers, the emergency services, people providing accommodation to people who use opioids, and peer education and outreach workers as well as others whose work brings them into contact with people who are at risk of overdose.

Prevention of opioid overdose

Beyond approaches to reducing drug use in general in the community, there are specific measures to prevent opioid overdose. These include:

increasing the availability of opioid dependence treatment, including for those dependent on prescription opioids;

reducing and preventing irrational or inappropriate opioid prescribing;

monitoring opioid prescribing and dispensing; and

limiting inappropriate over-the-counter sales of opioids.

The gap between recommendations and practice is significant. Only half of countries provide access to effective treatment options for opioid dependence and less than 10% of people worldwide in need of such treatment are receiving it.(5)

WHO response and recommendations

WHO supports countries in their efforts to ensure rational use of opioids and their optimal availability for medical purposes and minimization of their misuse and non-medical use. Following the recommendation of WHO's Expert Committee on Drug Dependence, a number of fentanyl analogues have been placed under international control, which means rigorous regulation for their availability.

WHO continues to monitor several fentanyl analogues through its surveillance system for new psychoactive substances, alerting countries to the potential dangers associated with these substances. Collection of such data is important as information about the patterns of use, misuse and non-medical use of opioids is very limited.

WHO also supports countries in monitoring trends in drug use and related harm, to better understand the scale of opioid dependence and opioid overdose.

WHO recommends that naloxone be made available to people likely to witness an opioid overdose, as well as training in the management of opioid overdose. In suspected opioid overdose, first responders should focus on airway management, assisting ventilation and administering naloxone. After successful resuscitation following the administration of naloxone, the level of consciousness and breathing of the affected person should be closely observed until full recovery has been achieved.

WHO recommends the use of a range of treatment options for opioid dependence. These include opioid agonist maintenance treatment (with medicines such as methadone and buprenorphine), which has the strongest evidence of effectiveness and cost-effectiveness, as well as psychosocial treatment and support, and pharmacological treatment with opioid antagonists (such as naltrexone). WHO supports countries in improving the coverage and quality of treatment programmes for opioid dependence and introducing them where they do not already exist.

WHO also issues normative guidance to promote the appropriate use of opioids for pain and palliative care. Appropriate use and regulation of opioid analgesics ensures that they are available where needed whilst preventing their diversion and harm related to misuse.

In 2016, under the framework of the WHO/UNODC Programme on Drug Dependence Treatment and Care, the "Stop Overdose Safely (S-O-S)" Initiative was launched, to provide training on recognizing the risk of overdose and providing emergency care in the event of an overdose. As part of this Initiative, a multi-site study on community management of opioid overdose was implemented in Kazakhstan, Kyrgyzstan, Tajikistan, and Ukraine in 2019-2020. About 40 000 kits of naloxone were distributed, more than 14 000 people were trained as part of the project and around 90% of those participants who witnessed an overdose reported using naloxone. In almost all instances, it was recorded that the person with overdose survived. Evaluation of the project showed that it was widely accepted by stakeholders, ranging from people who use drugs through to health and law enforcement officials. .

References

1. WHO (2019). International Classification of Diseases for Mortality and Morbidity Statistics. Eleventh Revision.

2. UNODC (2021). World Drug Report 2021. Available at: https://www.unodc.org/unodc/data-and-analysis/wdr2021.html

3. CDC WONDER (2020). National Center on Health Statistics

4. CDC Emergency Preparedness and Response: Increase in Fatal Drug Overdoses Across the United States Driven by Synthetic Opioids Before and During the COVID-19 Pandemic, 17 December 2020. Available at: https://emergency.cdc.gov/han/2020/han00438.asp

5. Degenhardt L, Glantz M, Evans-Lacko S, et al. (2017). Estimating treatment coverage for people with substance use disorders: an analysis of data from the World Mental Health Surveys. World Psychiatry. 2017;16(3):299-307. doi:10.1002/wps.2045

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The term "opioids" includes compounds that are extracted from the poppy seed as well as semisynthetic and synthetic compounds with similar properties that can interact with opioid receptors in the brain. Opioids have analgesic and sedative effects, and are commonly used for the management of pain.

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5 West Point cadets overdosed in Florida during their 2022 spring break, leaving 2 in critical condition. The drug is not only laced with heroin but cocaine as well, a well-known party drug. Making it twice as dangerous to society

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CNN  —

A suspect is in custody after five West Point cadets overdosed – four of whom were hospitalized – on the drug fentanyl while they were on spring break in Fort Lauderdale earlier this week, according to police.

Authorities in Broward County, Florida, have made the arrest of the 21-year-old man in connection to the sale of a fentanyl-laced powder substance that allegedly triggered overdoses, according to CNN affiliate WPLG.

The incident occurred in a vacation rental house in Wilton Manors, according to a news release from the Wilton Manors Police Department (WMPD).

The Fort Lauderdale Fire Rescue (FLFR) responded to the house around 5 p.m. Thursday and aided six men who were feeling overdose symptoms. A seventh patient, who is a woman, was later transported to the hospital after feeling sick, police said.

A hazmat team tested the powdered material and found that it was laced with fentanyl, an opioid drug, according to the department.

Police said Friday that six West Point cadets on spring break in Fort Lauderdale were hospitalized after overdosing on a powder substance laced with the drug fentanyl. However, Lt. Col. Beth Smith, West Point director of public affairs and communications, told CNN on Saturday morning that only five of the six individuals involved in the overdose incident are cadets.

Four of the cadets required hospitalization after the incident, according to Smith.

According to the arrest report, Broward County Drug Task Force detectives responded to an overdose investigation involving multiple victims. Detectives were able to get the cellphone number “of the alleged dealer who supplied the narcotics to the victims,” as part of the investigation.

An undercover detective made contact with Axel Giovany Casseus on Friday and “purchased 43 grams of cocaine” from him in exchange for $1,000, the report said. Casseus was later arrested on charges of trafficking cocaine.

During a Saturday bond hearing, a Broward County deputy identified Casseus as the man they believe sold the laced substance to the cadets and indicated that Casseus admitted to the transaction involving the West Point students after being taken into custody, according to the CNN-affiliate WPLG.

Casseus is being held in the Broward County Jail in lieu of a $50,000 bond, according to BCSO online records. It is unclear whether he has an attorney.

Police did not provide information on the suspect or the charges in Friday’s press release.

The names of the patients have not been released, though police said the college students are from New York who were vacationing in Fort Lauderdale on spring break.

“This incident serves as a stark reminder to all, especially those visiting for Spring Break, of the deadly impacts of Fentanyl,” Wilton Manors police said in the news release.

Beth Smith, a spokesperson for the US Military Academy at West Point, acknowledged to CNN the college students were cadets and said the academy is investigating.

Local authorities are investigating the overdose incident, police said.

WMPD officers “took precautionary measures by evacuating and securing the residence due to the unidentified powdery substance,” said the press release.

Fentanyl is a synthetic drug that can be up to 50 times stronger than heroin, up to 100 times stronger than morphine and commonly resembles prescription drugs, according to the US Centers for Disease Control and Prevention. It is often added to other drugs by dealers “because of its extreme potency, which makes drugs cheaper, more powerful, more addictive, and more dangerous,” the CDC said.

On Friday, Wilton Manors police warned in a tweet about the dangers of fentanyl.

“WMPD wants to warn spring breakers about the dangers of using illicit drugs & to avoid mixing drugs with alcohol or other forms of drugs. Protect yourself from the dangers of Fentanyl,” police said.

Last year saw a record high of drug overdose deaths, with more than 100,000 people dying from April 2020 to April 2021, according to provisional data published in November by the CDC. It was a 28.5% spike compared to the same period a year earlier and nearly doubling over the past five years.

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5 west point cadets overdose on fentanyl during spring break

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5 West Point cadets overdose on fentanyl during spring break, police say

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A suspect is in custody after five West Point cadets overdosed -- four of whom were hospitalized -- on the drug fentanyl while they were on spring break in Fort Lauderdale earlier this week, according to police.

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(Peer Reviewed) Deaths from illicit fentanyl use have also occurred in Estonia, Germany, Canada, Finland, UK, and Australia. 

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(Peer Reviewed) Deaths from illicit fentanyl use have also occurred in Estonia, Germany, Canada, Finland, UK, and Australia. 

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Fentanyl's high potency leads to its higher risk of overdose and death mainly related to cocaine. Deaths increased nearly 55% from 2015-2017.

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Abstract

Fentanyl is a powerful opioid anesthetic and analgesic, the use of which has caused an increasing public health threat in the United States and elsewhere. Fentanyl was initially approved and used for the treatment of moderate to severe pain, especially cancer pain. However, recent years have seen a growing concern that fentanyl and its analogs are widely synthesized in laboratories and adulterated with illicit supplies of heroin, cocaine, methamphetamine, and counterfeit pills, contributing to the exponential growth in the number of drug-related overdose deaths. This review summarizes the recent epidemic and evolution of illicit fentanyl use, its pharmacological mechanisms and side effects, and the potential clinical management and prevention of fentanyl-related overdoses. Because social, economic, and health problems that are related to the use of fentanyl and its analogs are growing, there is an urgent need to implement large-scale safe and effective harm reduction strategies to prevent fentanyl-related overdoses.

Subject terms: Addiction, Pharmacodynamics

Introduction

Fentanyl was first developed in 1960 by Paul Janssen as a potent opioid anesthetic and analgesic. At the time, fentanyl was the fastest-acting opioid discovered to date and more powerful than morphine (50-100 times) and heroin (30-50 times)1,2. Transdermal, intravenous, and transbuccal fentanyl administration and several other drugs with chemical structures that are similar to fentanyl have been developed, approved, and used for surgical anesthesia and the management of severe cancer pain and perioperative pain, eventually becoming the most often used synthetic opioid in clinical practice3-5. Since 1979, fentanyl and its analogs have been synthesized in laboratories and sold as heroin substitutes or mixed with other illicitly sourced drugs, leading to an increase in fentanyl-related overdose deaths6,7. Postmortem studies have consistently found pulmonary edema, congestion, and needle puncture sites in these victims. Based on data from the National Vital Statistics System, 599,255 drug overdose deaths occurred from 1979 to 2016 in the United States, and the overall mortality rate has seen exponential growth. Fentanyl-related overdose deaths predominantly occurred in the northeastern United States, mostly affecting younger people (20-40 years of age), and grew sharply since 20138.

Rapid death from ingesting fentanyl has become increasingly more common. Its high potency, fast onset of action, and duration of the desired effect may be particularly important contributing factors to the higher risk of overdose deaths and social consequences9. Fentanyl has become a major contributor to cocaine-related fatal overdoses. The rate of fentanyl-related overdose deaths increased 55% between 2015 and 2017 in New York city10,11. Synthetic opioids are also increasingly detected in illicit supplies of heroin, methamphetamine, and counterfeit pills. Analysis of a sampling of 1 million unique patients' urine drug test (UDT) specimens showed that positivity rates for fentanyl have increased by 1850% among cocaine positive UDT results and increased by 798% among methamphetamine-positive UDT results between January 2013 and September 201812. This mixture may lead to the increases in cocaine-related and methamphetamine-related overdoses. Moreover, the number of fatal overdoses from synthetic opioids, primarily fentanyl and its analogs, was 19,547 in 2016 in the United States, and this rate increased by 88% per year from 2013 to 201613-16. The incidence of heroin-related overdose deaths stabilized in 2017, whereas deaths that involved other synthetic opioids continued to increase17. Given the substantial individual and public health threats of this emerging problem, the present review summarizes the epidemic and evolution of illicit fentanyl use, its pharmacological mechanism of action, its adverse consequences, and the clinical management and prevention of fentanyl-related overdoses.

Epidemic and evolution of illicit fentanyl use

Fentanyl is currently approved and commonly used to treat breakthrough pain in cancer patients and various other clinical conditions that involve noncancer pain, such as postoperative pain. However, its potential for abuse and the rise in overdose deaths pose a serious challenge to public health18-21. Deaths that were attributable to illicit fentanyl use were first reported in the early 1980s and occurred sporadically in the United States. A surge in the occurrence of fentanyl-related fatalities among illicit drug users occurred in 2006. A total of 1013 deaths in six states occurred from April 4, 2005, to March 28, 200723. Since then, the prevalence of opioid-related mortality has increased persistently, and the number of reported fentanyl-related deaths more than doubled (from 2628 to 5544) between 2012 and 2014. The rate of fentanyl-related overdose deaths increased from <15% in 2010 to ~50% in 2017 in Marion County, Indiana26. Overall overdose deaths and first-responder calls increased in a community-based sample in an impoverished neighborhood in Vancouver, Canada, in 2017, and fentanyl was detected in 52% of the subjects who were prescribed opioid agonist therapy27. At the same time, fentanyl-related deaths also increased in Australia28,29.

The presence of fentanyl and its analogs has become a central contributor to the increase in the number of opioid-related overdose deaths. Preliminary estimates of opioid overdose deaths in the United States in 2016 revealed that fentanyl and its analogs (e.g., acetylfentanyl, furanylfentanyl, and carfentanil) have contributed to nearly half of opioid overdose deaths. Moreover, the number of deaths that were attributable to illicitly manufactured fentanyl and its analogs nearly quadrupled between July 2015 and June 2017 in Montgomery County, Ohio32. Heroin-positive cases declined while methamphetamine-positive cases increased in these victims. Urine drug screens showed that the prevalence of recent fentanyl use in patients who received opioid agonist treatment in England was 3%, and multiple fatalities with synthetic fentanyl analogs were reported in northern England in early 201733,34.

Fentanyl is ~30-50 times more potent than heroin, and smaller volumes of heroin and other drugs that are adulterated with fentanyl can produce powerful effects with lower production costs. Detecting fentanyl and its analogs in used syringes can reveal exposure risk35. The fentanyl detection rate was significantly higher among drug users who injected drugs in the past 6 months compared with non-injection drug users. The prevalence of non-fatal overdose is very high among people who inject drugs36-38. The prevalence of intravenous fentanyl use among people who inject drugs in Australia is 8%. Given the narrow range between effective and lethal doses, this population is at high risk of overdose. The opioid crisis is likely attributable to illicitly manufactured fentanyl and its analogs around the world, especially when they are mixed with heroin and other drugs, and the route of administration41,42.

Many people who have survived fentanyl overdose appear to be unaware that they ever took the drug. Surveys from 17 harm reduction sites in British Columbia, Canada, revealed that the prevalence of fentanyl use was 29% (70/242; based on urine drug screen), 73% of whom report that they did not knowingly use fentanyl43. Urine drug screens in methadone-maintained patients in Wayne County, Michigan, showed that 38% of 368 unique patients tested positive for fentanyl, and 67.3% of 113 patients reported that they did not know anyone who sought to obtain fentanyl in a subsequent anonymous survey44. A high risk of overdose and deaths was found among this vulnerable population that exhibited high fentanyl exposure, thus highlighting the pressing need to develop appropriate harm-reduction strategies, such as surveillance, the development of early-warning systems, pill-testing technology about the presence of fentanyl in various drug products, naloxone training and distribution, overdose education, and urine screens. The vast majority of people reported their willingness to use rapid test strips to detect the presence of fentanyl in drugs or urine at home or utilize drug-checking services at supervised injection clinics47,48. Multiplex ultrahigh-performance liquid chromatography (UHPLC-MS)/liquid chromatography tandem mass spectrometry (LC-MS-MS)/liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS) analyses have also been developed and validated for the detection of fentanyl and its analogs and metabolites in blood, hair, and oral fluid, which will be helpful for informing harm reduction behaviors and combating the fentanyl crisis49-52. A newly developed lateral flow immunoassay was also evaluated for effectiveness in the detection of fentanyl analogs53.

Pharmacological mechanisms and side effects of fentanyl

Despite the beneficial clinical anesthetic and pain-relieving effects of fentanyl, the frequent use of fentanyl primarily affects the central nervous system (CNS) and gastrointestinal, cardiovascular, and pulmonary systems and can cause several side effects54. Digestive symptoms, such as nausea, vomiting, and constipation, are common in patients who repeatedly use fentanyl55,56. Immunosuppression was also shown to be precipitated by analgesic opioid drugs, including fentanyl, in preclinical and clinical studies. Such immunosuppression can be especially dangerous in the elderly and already immunocompromised patients57-59. Additionally, fentanyl and synthetic opioids have other frequently reported side effects, including migraine, dizziness, vertigo, confusion, hallucinations, and a higher risk of fractures in the elderly59-63. Fentanyl has rewarding effects and thus high abuse potential. Its repeated use leads to the development of tolerance and drug dependence64,65. Analyses of adverse-event reporting systems in the United States, Europe, and the United Kingdom have shown that cases of fentanyl-related misuse, abuse, dependence, and withdrawal steadily increased between 2004 and 2018, resulting in prolonged hospitalization or death66. Other mental disorders, such as depression, insomnia, and suicidality, can also occur with fentanyl abuse, contributing to relapse and a higher risk of respiratory depression or overdose death65,67. The treatment of these mental disorders may help prevent fentanyl-related fatalities and achieve abstinence.

Fentanyl is a full μ-opioid receptor agonist, but it also acts on δ- and κ-opioid receptors68,69. Fentanyl has been shown to exert its analgesic and lethal effects through different receptor populations in the CNS. It is eliminated from cerebrospinal fluid at approximately the same rate as morphine70,71. Acute naloxone administration antagonizes fentanyl-induced analgesia more than fentanyl-induced lethality. β-funaltrexamine was shown to inhibit both fentanyl-induced analgesia and lethality71. Overdose-related concentrations of fentanyl were shown to block human ether-a-go-go-related gene (hERG) potassium channels in ventricular myocytes that were isolated from neonatal rats, which may contribute to fentanyl-related overdose death or sudden death72.

Respiratory depression is the most dangerous adverse reaction to fentanyl that can result in lethality. In rats, intravenous injections of fentanyl dose-dependently decreased oxygen levels in the nucleus accumbens, basolateral amygdala, and subcutaneous space, followed by a delayed increase in glucose and fluctuations in brain temperature and metabolic brain activity73-75. Neuronal hypermetabolism that is induced by fentanyl and its analogs may damage the hippocampus and limbic system, causing an amnestic syndrome in patients who use fentanyl76-79. With regard to brain hypoxia and hypothermia, fentanyl has synergistic effects with heroin, which is consistent with the higher risk of overdose death that is associated with heroin-fentanyl mixtures73,80. Fentanyl-related respiratory depression is also dose-dependent, which reaches a peak 5 min after administration and requires 4 h to recover in humans. Such effects can lead to prolonged apnea and sudden death. Epidural fentanyl infusion has been shown to cause postoperative adult respiratory distress syndrome83. The μ ₁-opioid receptor is involved in respiratory depression that is induced by fentanyl and its analogs but not morphine84. Selective α4β2 nicotinic receptor agonist A85380 reversed fentanyl-induced respiratory depression in rats without significant side effects85. The calcium-activated potassium channel blocker GAL021 was shown to attenuate morphine-induced respiratory depression in rats, mice, and nonhuman primates, and it produced stimulatory effects during alfentanil-induced respiratory depression, without affecting sedation in humans86-88. However, more studies are needed to confirm the efficacy and potential toxicity of A85380 and GAL021.

Many studies have reported cardiovascular symptoms after fentanyl-induced analgesia, such as myocardial ischemia, QTc interval prolongation, and bradycardia89-91. Fentanyl is commonly used during percutaneous coronary interventions, but the relative safety of its use requires further investigation because intravenous fentanyl has been reported to induce hypothermia, impair ticagrelor absorption, and cause antiplatelet effects92-94. Autopsy and toxicological analyses indicated that chronic fentanyl use may be responsible for hypertrophy, cardiac fibrosis, and atherosclerosis. Neither sigma nor opioid receptors are essential for the fentanyl-induced attenuation of muscarinic coronary contraction97.

Fentanyl administration provides effective pain relief, but its long-term use can result in a lowering of pain thresholds98,99. This phenomenon of fentanyl-induced hyperalgesia is a challenge in the clinical management of perioperative and chronic pain. Recent studies showed that fentanyl-induced hyperalgesia was modulated by the activation of extracellular signal-regulated kinase in the laterocapsular division of the central nucleus of the amygdala (CeLC) and CaMKIIα in the CeLC-periaqueductal gray-rostral ventromedial medulla-spinal cord descending facilitative pain pathway in rats100,101.

Interventions for the management and prevention of fentanyl overdose

Similar treatments are prescribed for opioid use disorder and opioid overdose, including the Food and Drug Administration (FDA)-approved medications methadone, buprenorphine, extended-release naltrexone, and naloxone102. Lofexidine, a central α ₂-adrenergic receptor agonist, was the first non-opioid medication that was approved by the United States FDA for the treatment of opioid withdrawal103,104. Lofexidine has fewer prescriptive barriers and comparable efficacy and safety relative to other opioid receptor agonizts, but it is generally more expensive. Sparse data are available on the effectiveness of interventions to prevent overdoses that are caused by illicitly manufactured fentanyl (Table ​(Table1). 1 ). Compared with other opioid-related overdoses, illicit fentanyl-related overdoses appear to be accompanied by distinct symptoms, such as body and chest rigidity, dyskinesia, and slow or irregular heart rate, which can affect overdose management, such as oxygen provisions and appropriate doses of naloxone105,106. To avoid or reduce the adverse effects of fentanyl, the FDA proposed to control the duration of use and doses of fentanyl107. One study showed that the majority of patients who were presumed to experience fentanyl overdose could be discharged after brief emergency room observation, thus unlikely requiring additional naloxone dosing in the emergency room108.

Table 1

Medication

Mechanism of action

Treatment

Limitations

Implications for fentanyl overdose

Methadone

Full MOR agonist

Reduces cravings and withdrawal symptoms.

Risk of dependence and acute withdrawal after abrupt discontinuation.

Respiratory depression and QTc prolongation as a result of methadone overdose or illicit use.

Protects against death and promotes abstinence in fentanyl-exposed patients, but relapse rates are still high.

Buprenorphine

MOR partial agonistKOR antagonist

Reduces cravings and withdrawal symptoms.

Risk of acute withdrawal in OUD patients with high levels of tolerance.

Promotes treatment retention and opioid abstinence in fentanyl-exposed patients.

Extended-release naltrexone

MOR antagonistKOR antagonist

Reduces cravings, promotes abstinence, promotes treatment retention, and prevents relapse.

Requires detoxification before initiating naltrexone treatment.High risk of early induction failure.

Adverse events, including overdoses, did not differ between extended-release naltrexone and buprenorphine-naloxone combination.

Naloxone

MOR antagonist

Reduces craving, promotes abstinence, promotes treatment retention, and prevents relapse.

Risk of precipitating opioid withdrawal.

Mostly utilized to reverse the overdose epidemic, but its efficacy needs improvement, and safe dosing needs further investigation.

Lofexidine

Central α ₂-adrenergic receptor agonist

Reduces withdrawal symptoms but not drug craving.

Hypotension and bradycardia.

Not effective for all withdrawal symptoms.

N/A

There are limited data on the efficacy of methadone or buprenorphine for the treatment of illicit fentanyl use. A retrospective study in Rhode Island showed that 6 months of methadone maintenance protected against death and promoted abstinence in fentanyl-exposed patients, but relapse rates were still high109. Buprenorphine is a μ-opioid receptor partial agonist and κ-opioid receptor antagonist that is commonly used to treat opioid use disorder. It also exerts antidepressant and anxiolytic activity and is a promising treatment for neonatal opioid withdrawal syndrome110. A retrospective cohort study showed that 6-month treatment retention rates and opioid abstinence rates were not different between individuals who were positive for fentanyl or heroin at baseline before initiating buprenorphine treatment, indicating that buprenorphine may still be beneficial for treating fentanyl exposure111. Repeated treatment with buprenorphine produced a greater magnitude of antinociceptive tolerance than higher-efficacy agonizts (e.g., morphine and etonitazene) in rats112. Studies in pigeons and rhesus monkeys showed that the amount of tolerance that develops to the reinforcing potency of opioids depends on their efficacy, and the higher-efficacy μ-opioid receptor agonist sufentanil was more difficult to antagonize than the low-efficacy μ-opioid receptor agonist morphine113-115. These data indicate that buprenorphine may have lower efficacy for the treatment of fentanyl overdose compared with heroin overdose, although no human trials have been performed to date116.

Naloxone is a μ-opioid receptor antagonist that is used to treat fentanyl-related overdose, regardless of the suspected route of administration. However, its efficacy is inconsistent, and safe dosing needs to be considered from the perspective of precipitating opioid withdrawal117-119. Recent studies also showed that extended-release naltrexone was equally safe and effective as a buprenorphine-naloxone combination at promoting abstinence and treatment retention once treatment was initiated, but fewer participants successfully initiated naltrexone treatment120,121. Larger or repeated doses of naloxone are speculated to be required for the treatment of fentanyl overdose because of its higher affinity for μ-opioid receptors. However, a study of a community naloxone distribution program in Allegheny County showed that the average doses of naloxone that were administered to reverse overdose did not change between 2013 and 2016, although the incidence of overdoses that were related to fentanyl and its analogs increased during the same time122. A retrospective study of the fentanyl epidemic in Chicago showed that doses of naloxone up to 12 mg may effectively treat fentanyl overdose123. Naloxone was shown to reverse transdermal fentanyl overdose-induced sedation, the reduction of body temperature, and the reduction of heart rate in dogs124. A systematic review found a low incidence of mortality or serious adverse events that were caused by prehospital naloxone administration in opioid overdose patients, although the source of overdose was mostly heroin and not fentanyl125. Additionally, seeking emergency medical help was positively associated with overdose victims who received higher doses of naloxone and rescue breathing in British Columbia, Canada126. A survey of 316 street-recruited people who used opioids in Baltimore showed that the majority of them perceived the high risk of fentanyl-adulterated heroin and overdose, but most of them did not often carry naloxone with them127. The early adoption and distribution of take-home naloxone have been reported to effectively prevent opioid overdose deaths128-130. Therefore, harm reduction strategies, such as safe injection sites, the expansion of available opioid agonist treatment, and overdose prevention training (e.g., carrying naloxone and not use drugs alone, higher dose or multiple administrations of naloxone), are needed to control the adverse effects of fentanyl and reduce overdoses131.

Additionally, more potent, longer-acting opioid receptor antagonists are needed to prevent fentanyl-related overdose deaths. Compared with naloxone, nalmefene has been shown to have superior efficacy in reversing the carfentanil-induced loss of righting reflex and respiratory depression in rats132. Nalmefene is generally well tolerated and is a recent option for patients with alcohol dependence133-135. Additionally, novel, selective, and potent μ-opioid receptor antagonists, such as 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ) and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN), have been reported to produce less opioid tolerance, dependence, and withdrawal signs. Furthermore, NAN pretreatment was shown to block the discriminative stimulus effects of fentanyl in rats. The orexin-1 receptor antagonist SB-334867 was also shown to decrease motivation and demand for fentanyl in rats136. Therefore, these drugs could be considered candidates for the treatment of opioid use disorder137. Chronic anticonvulsant carbamazepine therapy was shown to increase fentanyl clearance and decrease plasma concentrations in neurosurgical patients, which may attenuate the actions of fentanyl138. A case report showed that treatment with slow-release oral morphine in a near-fatal fentanyl overdose patient was successful, despite the patient's previous failures with methadone and buprenorphine/naloxone-based opioid agonist therapies, which could be considered potential alternative treatments139.

Previous studies have reported the vaccine consisting of fentanyl hapten conjugated to tetanus toxoid or keyhole limpet hemocyanin carrier protein, and immunization with these vaccines reduced fentanyl biodistribution to the brain, and blunted its antinociceptive effects and respiratory depression in rodents140,141. Moreover, the conjugate vaccine stimulated the endogenous generation of antibodies with high affinity for a variety of fentanyl analogs140, and was shown to blunt fentanyl reinforcement142. A recent study screened and purified monoclonal antibodies (mAbs) from vaccinated mice, and found that the 6A4 mAb prevented the acute lethality of fentanyl, and reversed both fentanyl and carfentanil-induced antinociception as effective as naloxone143. These findings suggest that immunopharmacotherapies including active vaccine or its combination with passive mAb may be potential and promising treatment strategies to address the current opioid crisis. Accumulating evidence also implicate the dysbiosis of gut microbiome in the pathophysiology of drug addiction, however data regarding fentanyl use is rare144. Manipulating the compositions of the gut microbiome or its products may guide new adjuvant therapies for opioid addiction in the future.

A United States FDA Risk Evaluation and Mitigation Strategy (REMS) program was also implemented to assess transmucosal immediate-release fentanyls (TIRFs) and found that substantial rates of TIRFs were prescribed inappropriately145,146. With the findings of deficiencies in the structure and administration of TIRFs, the development of other REMSs is needed to ensure the safe and appropriate use of approved drugs, especially dangerous opioid drugs147.

In conclusion, the crisis of opioid-related overdoses, especially fentanyl and its analogs, is a major threat to both individual and public health. Respiratory depression, cardiovascular effects, and neuropsychiatric symptoms are associated with fentanyl overdose and lethality. Naloxone is the standard rescue drug for fentanyl overdose, but its efficacy is inconsistent. Further clinical research is needed to optimize individualized medication-assisted treatments in patients who overdose on fentanyl and its analogs. To address the social, economic, and health problems that are associated with fentanyl and its analogs, coordinated efforts are needed to implement large-scale harm reduction strategies (e.g., naloxone distribution, innovative studies, and the development of novel drugs).

Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (nos. 81701312 and 81521063).

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

17. Scholl, L., Seth, P., Kariisa, M., Wilson, N. & Baldwin, G. Drug and opioid-involved overdose deaths-United States, 2013-2017. [ Morb. Mortal. Wkly Rep. 67, 1419-1427 (2018). PMC free article] [ PubMed]

46. Strike, C. & Watson, T. M. Losing the uphill battle? Emergent harm reduction interventions and barriers during the opioid overdose crisis in Canada. Int. J. Drug Policy.10.1016/j.drugpo.2019.02.005 (2019). [ PubMed]

80. Solis, E., Jr., Cameron-Burr, K. T. & Kiyatkin, E. A. Heroin contaminated with fentanyl dramatically enhances brain hypoxia and induces brain hypothermia. [ eNeuro 4, ENEURO.0323-17.2017 (2017). PMC free article] [ PubMed]

126. Karamouzian, M., Kuo, M., Crabtree, A. & Buxton, J. A. Correlates of seeking emergency medical help in the event of an overdose in British Columbia, Canada: findings from the Take Home Naloxone program. Int. J. Drug Policy.10.1016/j.drugpo.2019.01.006 (2019). [ PubMed]

139. Prinsloo, G., Ahamad, K. & Socias Me, Md M. Successful treatment with slow-release oral morphine following afentanyl-related overdose: a case report. [ Subst. Abus.10.1080/08897077.2019.1576086 (2019). PMC free article] [ PubMed]

Articles from Translational Psychiatry are provided here courtesy of Nature Publishing Group

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The rising crisis of illicit fentanyl use, overdose, and potential therapeutic strategies

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Fentanyl is a powerful opioid anesthetic and analgesic, the use of which has caused an increasing public health threat in the United States and elsewhere. Fentanyl was initially approved and used for the treatment of moderate to severe pain, especially ...