Fentanyl is a highly potent syntheticpiperidineopioid primarily used as ananalgesic (pain medication). It is 30 to 50 times morepotent thanheroin and 50 to 100 times more potent thanmorphine.[10] Its primaryclinical utility is in pain management for cancer patients and those recovering from painful surgeries.[11][12] Fentanyl is also used as asedative.[13] Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose.[14] Fentanyl works by activatingμ-opioid receptors.[8] Fentanyl is sold under the brand namesActiq,Duragesic, andSublimaze, among others.[15]
Pharmaceutical fentanyl's adverse effects are similar to those of other opioids andnarcotics,[16] including addiction, confusion,respiratory depression (which, if extensive and untreated, may lead torespiratory arrest), drowsiness, nausea, visual disturbances,dyskinesia, hallucinations, delirium, a subset of the latter known as "narcotic delirium",narcotic ileus,muscle rigidity,constipation, loss of consciousness,hypotension,coma, and death.[13] Alcohol and other drugs (e.g.,cocaine andheroin) can synergistically exacerbate fentanyl's side effects.Naloxone (also known as Narcan) can reverse the effects of an opioid overdose, but because fentanyl is so potent, multiple doses may be necessary.[15]
Fentanyl was first synthesized byPaul Janssen in 1959 and was approved for medical use in the United States in 1968.[8][17] In 2015, 1,600 kilograms (3,500 pounds) were used in healthcare globally.[18] As of 2017[update], fentanyl was the most widely usedsynthetic opioid in medicine;[19] in 2019, it was the 278th most commonly prescribed medication in the United States, with more than a million prescriptions.[20][21] It is on theWorld Health Organization's List of Essential Medicines.[22]
Fentanyl fuels anepidemic of synthetic opioid drug overdose deaths in the United States. From 2011 to 2021, deaths from prescription opioid (natural and semi-synthetic opioids andmethadone) per year remained stable, while synthetic opioid (primarily fentanyl) deaths per year increased from 2,600overdoses to 70,601.[23] Since 2018, fentanyl and its analogues have been responsible for most drug overdose deaths in the United States, causing over 71,238 deaths in 2021.[24][23][25] Fentanyl constitutes the majority of all drug overdose deaths in the United States since it overtookheroin in 2018.[24]The United States National Forensic Laboratory estimates fentanyl reports by federal, state, and localforensic laboratories increased from 4,697 reports in 2014 to 117,045 reports in 2020.[26] Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin.[26] Fentanyl has been reported in pill form, including pills mimickingpharmaceutical drugs such asoxycodone.[26] Mixing with other drugs or disguising as a pharmaceutical makes it difficult to determine the correct treatment in the case of an overdose, resulting in more deaths.[13] In an attempt to reduce the number of overdoses from taking other drugs mixed with fentanyl, drug testing kits, strips, and labs are available.[27][28] Fentanyl's ease of manufacture and high potency makes it easier to produce and smuggle, resulting in fentanyl replacing other abusednarcotics and becoming more widely used.[29]
For pain relief after surgery, use can decrease the amount of inhalational anesthetic needed for emergence from anesthesia.[31] Balancing this medication and titrating the drug based on expected stimuli and the person's responses can result in stable blood pressure and heart rate throughout a procedure and a faster emergence from anesthesia with minimal pain.[31]
Fentanyl is the most commonly usedintrathecal opioid because its lipophilic profile allows a quick onset of action (5–10 min) and intermediate duration of action (60–120 min).[34] Spinal administration of hyperbaricbupivacaine with fentanyl may be the optimal combination. The almost immediate onset of fentanyl reduces visceral discomfort and even nausea during the procedure.[35]
Fentanyl is sometimes given intrathecally as part ofspinal anesthesia or epidurally forepidural anaesthesia andanalgesia. Because of fentanyl's high lipid solubility, its effects are more localized than morphine, and some clinicians prefer to use morphine to get a wider spread of analgesia.[36] It is widely used inobstetrical anesthesia because of its short time to action peak (about 5 minutes), the rapid termination of its effect after a single dose, and the occurrence of relative cardiovascular stability.[37] In obstetrics, the dose must be closely regulated to prevent large amounts of transfer from mother to fetus. At high doses, the drug may act on the fetus to cause postnatalStimulant.[37] For this reason, shorter-acting agents such asalfentanyl orremifentanil may be more suitable in the context of inducing general anaesthesia.[38]
A fentanyl nasal spray with a strength of 100μg per use
The bioavailability of intranasal fentanyl is about 70–90% but with some imprecision due to clotted nostrils, pharyngeal swallow, and incorrect administration. For both emergency and palliative use, intranasal fentanyl is available in doses of 50, 100, 200, 400(PecFent)μg. In emergency medicine, safe administration of intranasal fentanyl with a low rate of side effects and a promising pain-reducing effect was demonstrated in a prospective observational study in about 900out-of-hospital patients.[39]
In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.[40] Furthermore, a 2017 study suggested the efficacy of fentanyl lozenges in children as young as five, weighing as little as 13kg. Lozenges are more inclined to be used as the child is in control of sufficient dosage, in contrast to buccal tablets.[41]
It is also used in themanagement ofchronic pain.[42] Often,transdermal patches are used.[26] The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72hours, allowing for long-lasting pain management.[43] Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature.[43] Each patch should be changed every 72hours.[44] Rate of absorption is dependent on a number of factors. Body temperature, skin type, amount of body fat, and placement of the patch can have major effects. The different delivery systems used by different makers will also affect individual rates of absorption, and route of administration. Under normal circumstances, the patch will reach its full effect within 12 to 24hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine or oxycodone) to handle breakthrough pain.[43] It is unclear if fentanyl gives long-term pain relief to people withneuropathic pain.[45]
Sublingual fentanyl dissolves quickly and is absorbed through thesublingual mucosa to provide rapid analgesia.[46] Fentanyl is a highly lipophilic compound,[46][47] which is well absorbed sublingually and generally well tolerated.[46] Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration, and severe in intensity.[48]
A fentanyl transdermal patch with a release rate of 12 micrograms per hour, on a person's arm
Inpalliative care, transdermal fentanyl patches have a definitive, but limited role for:
people already stabilized on other opioids who have persistent swallowing problems and cannot tolerate other parenteral routes such as subcutaneous administration.
When using the transdermal patch, patients must be careful to minimize or avoid external heat sources (direct sunlight, heating pads, etc.), which can trigger the release and absorption of too much medication and cause potentially deadly complications.[52]
USAFPararescuecombat medics in Afghanistan used fentanyl lozenges in the form of lollipops on combat casualties fromIED blasts and other trauma.[53] The stick is taped to a finger and the lozenge put in thecheek of the person. When enough fentanyl has been absorbed, the (sedated) person generally lets the lollipop fall from the mouth, indicating sufficient analgesia and somewhat reducing the likelihood of overdose and associated risks.[53]
Fentanyl is used to help relieve shortness of breath (dyspnea) when patients cannot tolerate morphine, or whose breathlessness is refractory to morphine. Fentanyl is useful for such treatment inpalliative care settings where pain and shortness of breath are severe and need to be treated with strong opioids.Nebulized fentanyl citrate is used to relieve end-of-life dyspnea inhospice settings.[54][55]
Someroutes of administration such as nasal sprays and inhalers generally result in a faster onset of high blood levels, which can provide more immediate analgesia but also more severe side effects, especially in overdose. The much higher cost of some of these appliances may not be justified by marginal benefit compared with buccal or oral options. Intranasal fentanyl appears to be equally effective as IV morphine and superior to intramuscular morphine for the management of acute hospital pain.[40]
A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow patients to control the administration of fentanyl through the skin to treat postoperative pain.[56] The technology consists of a "preprogrammed, self-contained drug-delivery system" that useselectrotransport technology to administer on-demand doses of 40μg of fentanyl hydrochloride over ten minutes. In a 2004 experiment including 189 patients with moderate to severe postoperative pain up to 24hours after major surgery, 25% of patients withdrew due to inadequate analgesia. However, the PCTS method proved superior to the placebo, showing lower meanVAS pain scores and having no significant respiratory depression effects.[57]
Overall, drug overdose deaths in the United States rose from 2019 to 2021 with more than 106,000 drug overdose deaths reported in 2021. Deaths involving synthetic opioids other than methadone (primarily fentanyl) continued to rise with 70,601 overdose deaths reported in 2021. Those involving stimulants, including cocaine or psychostimulants with abuse potential (primarily methamphetamine), also continued to increase with 32,537 overdose deaths in 2021 (Source: CDC WONDER).[23]
Fentanyl's most common side effects, which affect more than 10% of people, include nausea, vomiting, constipation, dry mouth,somnolence, confusion, andasthenia (weakness). Less frequently, in 3–10% of people, fentanyl can cause abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, anxiety, depression, flu-like symptoms,dyspepsia (indigestion),shortness of breath,hypoventilation,apnoea, and urinary retention. Fentanyl use has also been associated withaphasia.[58] Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as lesshistamine-mediated itching, than morphine.[59] In rare cases,serotonin syndrome is associated with fentanyl use. Existing studies advise medical practitioners to exercise caution when combiningselective serotonin reuptake inhibitor (SSRI) drugs with fentanyl.[60][61]
The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context.[62][63][64][65] In 2006, theUnited States Food and Drug Administration (FDA) began investigating several respiratory deaths, but doctors in the United Kingdom were not warned of the risks with fentanyl until September 2008.[66] The FDA reported in April 2012 that twelve young children had died and twelve more had become seriously ill from separate accidental exposures to fentanyl skin patches.[67]
The most dangerous adverse effect of fentanyl is respiratory depression,[68] that is, decreased sensitivity to carbon dioxide leading to reduced rate of breathing, which can cause anoxic brain injury or death. This risk is decreased when the airway is secured with anendotracheal tube (as during anesthesia).[69] This risk is higher in specific groups, like those withobstructive sleep apnea.[69]
Other factors that increase the risk of respiratory depression are:[69]
Sustained release fentanyl preparations, such as patches, may also produce unexpected delayedrespiratory depression.[70][71][72] The precise reason for sudden respiratory depression is unclear, but there are several hypotheses:
Saturation of the body fat compartment in people with rapid and profound body fat loss (people with cancer, cardiac or infection-inducedcachexia can lose 80% of their body fat).
Early carbon dioxide retention causes cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces the protein binding of fentanyl, releasing yet more fentanyl.
Reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory-depressant levels.
Another related complication of fentanyl overdoses includes the so-calledwooden chest syndrome, which quickly induces complete respiratory failure by paralyzing the thoracic muscles, explained in more detail in theMuscle rigidity section below.
Bradycardia: Fentanyl decreases the heart rate by increasingvagal nerve tone in the brainstem, which increases theparasympathetic drive.[69]
Vasodilation: It also vasodilates arterial and venous blood vessels through a central mechanism, by primarily slowing down vasomotor centers in the brainstem. To a lesser extent, it does this by directly affecting blood vessels.[69] This is much more profound in patients who have an already increased sympathetic drive, like patients who have high blood pressure or congestive heart failure.[69] It does not affect the contractility of the heart when regular doses are administered.[69]
If high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult.[69] The exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers.[69]
A prominent idiosyncratic adverse effect of fentanyl also includes a sudden onset of rigidity of the abdominal muscles and the diaphragm, which induces respiratory failure; this is seen with high doses and is known aswooden chest syndrome.[73] The syndrome is believed to be the main cause of death as a result of fentanyl overdoses.[74]
Wooden chest syndrome is unique to the most powerful opioids—which today comprise fentanyl and its analogs—while other less-powerful opioids like heroin produce mild rigidity of the respiratory muscles to a much lesser degree.[76][75]
There are many reports of fentanyl users adopting a "folded" posture.[77]
Daniel Ciccarone of UCSF said what he calls the “nod” is a common side effect of opioid use, and later notes that "nods have always happened to varying degrees with other opioids, particularly heroin. The nods with fentanyl, however, seem to be more extreme. And it's often a sign that a person has taken too strong a dose".[78] He also said "the fentanyl fold falls into the umbrella of a severe spinal deformity that can cause functional disability and can drive mental anguish" which is a factor given the socioeconomic status and more fragile mental health of drug users typically when compared to non-users.
Adulteration of fentanyl withxylazine, also known as 'tranq', can exacerbate postural problems.[79][80]
A two milligram dose of fentanyl powder (onpencil tip) is a lethal amount for most people.[81][82]
Fentanyl poses an exceptionally high overdose risk in humans since the amount required to causetoxicity is unpredictable.[13] In its pharmaceutical form, most overdose deaths attributed solely to fentanyl occur atserum concentrations at a mean of 0.025μg/mL, with a range 0.005–0.027μg/mL.[83] In contexts of poly-substance use, blood fentanyl concentrations of approximately 7ng/mL or greater have been associated with fatalities.[84] Over 85% of overdoses involved at least one other drug, and there was no clear correlation showing at which level the mixtures were fatal. The dosages of fatal mixtures varied by over three magnitudes in some cases. This extremely unpredictable volatility with other drugs makes it especially difficult to avoid fatalities.[85]
Naloxone (sold under the brand name Narcan) can completely or partially reverse an opioid overdose.[86] In July2014, theMedicines and Healthcare products Regulatory Agency (MHRA) of the UK issued a warning about the potential for life-threatening harm from accidental exposure to transdermal fentanyl patches, particularly in children,[87] and advised that they should be folded, with the adhesive side in, before being discarded. The patches should be kept away from children, who are most at risk from fentanyl overdose.[88] In the US, fentanyl andfentanyl analogs caused over 29,000deaths in 2017, a large increase over the previous four years.[89][90]
A package of 30 lozenges, 600mcg of fentanyl, each
Some increases in fentanyl deaths do not involve prescription fentanyl but are related to illicitly made fentanyl that is being mixed with or sold as heroin.[91] Death from fentanyl overdose continues to be a public health issue of national concern in Canada since September 2015.[92] In 2016, deaths from fentanyl overdoses in the province ofBritish Columbia averaged two persons per day.[93] In 2017 the death rate increased by more than 100% with 368 overdose-related deaths in British Columbia between January and April 2017.[94]
Illegal fentanyl flow to the US from various regions in 2019
Fentanyl has started to make its way into heroin as well as illicitly manufactured opioids and benzodiazepines. Fentanyl contamination in cocaine, methamphetamine,ketamine, MDMA, and other drugs is common.[95][96] A kilogram of heroin laced with fentanyl may sell for more than US$100,000, but the fentanyl itself may be produced far more cheaply, for about US$6,000 per kilogram. While Mexico and China are the primary source countries for fentanyl and fentanyl-related substances trafficked directly into the United States, India is emerging as a source for finished fentanyl powder and fentanyl precursor chemicals.[97][98] The United Kingdom illicit drug market is no longer reliant on China, as domestic fentanyl production is replacing imports.[99]
The intravenous dose causing 50% of opioid-naive experimental subjects to die (LD50) is "3mg/kg in rats, 1mg/kg in cats, 14mg/kg in dogs, and 0.03mg/kg in monkeys."[100] The LD50 in mice has been given as 6.9mg/kg by intravenous administration, 17.5mg/kg intraperitoneally, 27.8mg/kg by oral administration.[101] The LD50 in humans is unknown.[102]
In 2023, overdose deaths in the U.S. and Canada again reached record numbers.[103] While overdoses involving fentanyl in the United States have decreased in 2024, the overall percentage of overdoses involving fentanyl has remained stable between 70% and 80% from 2021-2024.[103] According to a 2023 report from theUnited Nations Office on Drugs and Crime (UNODC), the increased numbers of deaths are not related to an increased number of users but to the lethal effects of fentanyl itself. Fentanyl would require a special status as it is considerably more toxic than other widely abused opioids and opiates.[104] Overdose deaths in pediatric cases are also concerning. In a report published inJAMA Pediatrics, 37.5% of all fatal pediatric cases between 1999 and 2021 were related to fentanyl; most of the deaths were among adolescents (89.6%) and children aged 0 to 4 years (6.6%). According to the UNODC, "the opioid crisis in North America is unabated, fueled by an unprecedented number of overdose deaths."[105]
False reports by police of poisonings through secondary exposure
In the late 2010s, some media outlets began to report stories of police officers being hospitalized after touching powdered fentanyl, or after brushing it from their clothing.[106][107]Topical (or transdermal; via the skin) andinhalative exposure to fentanyl is extremely unlikely to cause intoxication or overdose (except in cases of prolonged exposure with very large quantities of fentanyl), and first responders such as paramedics and police officers are at minimal risk of fentanyl poisoning through accidental contact with intact skin.[108][109] A 2020 article from theJournal of Medical Toxicology stated that "the consensus of the scientific community remains that illness from unintentional exposures is extremely unlikely, because opioids are not efficiently absorbed through the skin and are unlikely to be carried in the air."[110] TheAmerican College of Medical Toxicology and theAmerican Academy of Clinical Toxicology issued a joint report in 2017 asserting the risk of fentanyl overdose via incidental transdermal exposure is very low, and it would take 200 minutes of breathing fentanyl at the highest airborne concentrations to yield a therapeutic dose, but not a potentially fatal one.[111][112] The effects being reported in these cases, including rapid heartbeat,hyperventilation and chills, were not symptoms of a fentanyl overdose, and were more commonly associated with apanic attack.[113]
A 2021 paper expressed concern that these physical fears over fentanyl may inhibit effective emergency response to overdoses by causing responding officers to spend additional time on unnecessary precautions and that the media coverage could also perpetuate a wider social stigma that people who use drugs are dangerous to be around.[112] A 2020 survey of first responders inNew York found that 80% believed “briefly touching fentanyl could be deadly.”[114]
Many experts in toxicology are skeptical of police truly overdosing through mere touch. "This has never happened," said Dr. Ryan Marino, anemergency andaddiction medicine physician atCase Western Reserve University. "There has never been an overdose through skin contact or accidentally inhaling fentanyl."[115]
Public health advisories to prevent fentanyl misuse and fatal overdose have been issued by the U.S. Centers for Disease Control (CDC). An initial HAN Advisory, also known as a Health Alert Network Advisory ("provides vital, time-sensitive information for a specific incident or situation; warrants immediate action or attention by health officials, laboratorians, clinicians, and members of the public; and conveys the highest level of importance") was issued during October 2015.[116] A subsequent HAN Alert was issued in July 2018, warning of rising numbers of deaths due to fentanyl abuse and mixing with non-opioids.[117] A December 2020 HAN Advisory warned of:
substantial increases in drug overdose deaths across the United States, primarily driven by rapid increases in overdose deaths involving ... illicitly manufactured fentanyl; a concerning acceleration of the increase in drug overdose deaths, with the largest increase recorded from March 2020 to May 2020, coinciding with the implementation of widespread mitigation measures for the COVID-19 pandemic; significant increases in overdose deaths involving methamphetamine.[118]
81,230 drug overdose deaths occurred during the 12 months from May 2019 to May 2020, the largest number of drug overdoses for a 12-month interval ever recorded for the U.S. The CDC recommended the following four actions to counter this rise:[118]
Local need to expand the distribution and use of naloxone and overdose prevention education,
Expand awareness, access, and availability of treatment for substance use disorders,
Intervene early with individuals at the highest risk for overdose, and
improve detection of overdose outbreaks to facilitate more effective response.[118][119]
Another initiative is asocial media campaign from the United StatesDrug Enforcement Administration (DEA) called "One Pill Can Kill".[81] This social media campaign's goal is to spread awareness of the prevalence of counterfeit pills that are being sold in America that is leading to the large overdose epidemic in America. This campaign also shows the difference between counterfeit pills and real pills.
The chemical structure of fentanyl has been used as a basis in modern chemistry for the discovery and nomenclature of many new fentanyl analogues, sometimes called fentalogs.
The structures of opioids share many similarities. Whereas opioids likecodeine,hydrocodone,oxycodone, andhydromorphone are synthesized by simple modifications of morphine, fentanyl, and its relatives are synthesized by modifications ofmeperidine.[69] Meperidine is a fully synthetic opioid, and other members of the phenylpiperidine family like alfentanil and sufentanil are complex versions of this structure.[69]
Fentanyl analogs are types of fentanyl with various chemical modifications on any number of positions of the molecule, but still maintain, or even exceed, its pharmacological effects. Many fentanyl analogs are termed "designer drugs" because they are synthesized solely to be used illicitly.Carfentanil, a fentanyl analog, has an additionalcarboxylic acid group attached to the 4 position. Carfentanil is 20–30 times as potent as fentanyl and is common in the illicit drug chain. The drug is commonly used to tranquilize elephants and other large animals.[123]
Fentanyl, like other opioids, acts on opioid receptors. These receptors areG-protein-coupled receptors, which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus.[69] The extracellular N-terminus is important in differentiating different types of binding substrates.[69] When fentanyl binds, downstream signaling leads to inhibitory effects, such as decreasedcAMP production, decreased calcium ion influx, and increased potassium efflux.[69] This inhibits the ascending pathways in the central nervous system to increase pain threshold by changing the perception of pain; this is mediated by decreasing propagation ofnociceptive signals, resulting in analgesic effects.[125][126][unreliable medical source?]
As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine.[125] It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to penetrate more easily thecentral nervous system.[120][59] It attenuates "second pain" with primary effects on slow-conducting, unmyelinated C-fibers and is less effective on neuropathic pain and "first pain" signals through small, myelinated A-fibers.[69]
Fentanyl can produce the following clinical effects strongly, through μ-receptor agonism:[127]
Pain relief: Primarily, fentanyl provides the relief of pain by acting on the brain and spinal μ-receptors.[69]
Sedation: Fentanyl produces sleep and drowsiness, as the dosage is increased, and can produce theδ-waves often seen in natural sleep onelectroencephalogram.[69]
Suppression of thecough reflex: Fentanyl can decrease the struggle against anendotracheal tube and excessive coughing by decreasing the cough reflex, becoming useful when intubating people who are awake and have compromised airways.[69] After receiving a bolus dose of fentanyl, people can also experience paradoxical coughing, which is a phenomenon that is not well understood.[69]
Fentanyl may be measured in blood or urine to monitor for abuse, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Commercially availableimmunoassays are often used as initial screening tests, but chromatographic techniques are generally used for confirmation and quantitation. TheMarquis Color test may also be used to detect the presence of fentanyl. Usingformaldehyde andsulfuric acid, the solution will turn purple when introduced to opium drugs. Blood orplasma fentanyl concentrations are expected to be in a range of 0.3–3.0 μg/L in persons using the medication therapeutically, 1–10 μg/L in intoxicated people, and 3–300 μg/L in victims of acute overdosage.[128]Paper spray-mass spectrometry (PS-MS) may be useful for initial testing of samples.</ref>[129]
Image of testing strip instructions from the harm reduction organization Dance Safe
Fentanyl and fentanyl analogues can be qualitatively detected in drug samples using commercially available fentanyl testing strips or spot reagents. Following the principles of harm reduction, this test is to be used directly on drug samples as opposed to urine. To prepare a sample for testing, approximately 10 mg of the drug, about the size of hair on Abraham Lincoln's head on a penny, should be diluted into 1 teaspoon, or 5 mL, of water.[130] Research in Dr. Lieberman's lab at the University of Notre Dame has reported false positive results on BTNX fentanyl testing strips withmethamphetamine,MDMA, anddiphenhydramine.[131] Thesensitivity and specificity of fentanyl test strips vary depending on the concentration of fentanyl tested, particularly from 10 to 250 ng/mL.[132]
Fentanyl is a 4-anilinopiperidine class synthetic opioid.[133] The synthesis of Fentanyl is accomplished by one of four main methods as reported in the scientific literature: the Janssen, Siegfried, Gupta, or Suh method.[134][135]
Portion of the Janssen Method of synthesis, to synthesize a related opioid
The original synthesis as patented in 1964 by Paul Janssen involves the synthesis ofbenzylfentanyl from N-benzyl-4-Piperidone. The resulting benzylfentanyl is used as feedstock tonorfentanyl. It is norfentanyl that forms fentanyl upon reaction with phenethyl chloride.[136]
Siegfried Method from NPP through 4-ANPP to fentanyl
The Siegfried method involves the initial synthesis ofN-phenethyl-4-piperidone (NPP). This intermediate isreductively aminated to4-anilino-N-phenethylpiperidine (4-ANPP). Fentanyl is produced following the reaction of 4-ANPP with an acyl chloride.[137] The Siegfried method was used in the early 2000s to manufacture fentanyl in both domestic and foreign clandestine laboratories.[138]
The Gupta (or 'one-pot') method starts from4-Piperidone and skips the direct use of 4-ANPP/NPP; rather, the compounds are formed only as impurities or temporary intermediates.[139] For the first half of 2021, theU.S. Drug Enforcement Administration found the Gupta method was the predominant synthesis route in their samples of seized fentanyl.[140] In 2022, Braga and coworkers described a synthesis of fentanyl involving continuous flow that uses reagents similar to the ones described for the Gupta procedure.[141]
Fentanyl was first synthesized in Belgium byPaul Janssen under the label of his relatively newly formedJanssen Pharmaceutica in 1959.[143] It was developed by screening chemicals similar topethidine (Demerol) for opioid activity.[144] The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1stoichiometric ratio).[145][146] Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured byMcNeil Laboratories under the brand name Sublimaze.[147]
In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formulation of an inert alcohol gel infused with select fentanyl doses, which are worn to provide constant administration of the opioid over 48 to 72hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.[148]
Following the patch, a flavoredlollipop of fentanyl citrate mixed with inert fillers was introduced in 1998 under the brand name Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain.[149]
In 2009, the USFood and Drug Administration (FDA) approved Onsolis (fentanyl buccal soluble film), a fentanyl drug in a new dosage form for cancer pain management in opioid-tolerant subjects.[150] It uses a medication delivery technology called BEMA (BioErodible MucoAdhesive), a small dissolvable polymer film containing various fentanyl doses applied to the inner lining of thecheek.[150]
Estonia is known to have been home to the world's longest documented fentanyl epidemic, especially following theTaliban ban on opium poppy cultivation in Afghanistan.[161]
A 2018 report byThe Guardian indicated that many major drug suppliers on thedark web have voluntarily banned the trafficking of fentanyl.[162]
The fentanyl epidemic has erupted in a highly acrimonious dispute between the U.S. and Mexican governments. While U.S. officials blame the flood of fentanyl crossing the border primarily on Mexican crime groups, then-PresidentAndrés Manuel López Obrador insisted that the main source of this synthetic drug isAsia. He stated that the crisis of a lack of family values in the United States drives people to use the drug.[163]
Illicit use of pharmaceutical fentanyl and its analogues first appeared in the mid-1970s in the medical community and continues in the present. More than 12 different analogues of fentanyl, all unapproved andclandestinely produced, have been identified in the U.S. drug traffic. In February 2018, the U.S. Drug Enforcement Administration indicated that illicit fentanyl analogs have no medically valid use, and thus applied a "Schedule I" classification to them.[164]
Fentanyl analogues may be hundreds of times more potent than heroin. Fentanyl is used orally, smoked, snorted, or injected. Fentanyl is sometimes sold as heroin oroxycodone, which can lead to overdose. Many fentanyl overdoses are initially classified as heroin overdoses.[165] Recreational use is not particularly widespread in the EU except for Tallinn, Estonia, where it has largely replaced heroin.Estonia has the highest rate of3-methylfentanyl overdose deaths in the EU, due to its high rate of recreational use.[166]
Fentanyl is sometimes sold on the black market in the form of transdermal fentanyl patches such asDuragesic, diverted from legitimate medical supplies. The gel from inside the patches is sometimes ingested or injected.[167]
Another form of fentanyl that has appeared on the streets is the Actiq lollipop formulation. The pharmacy retail price ranges from US$15 to US$50 per unit based on the strength of the lozenge, with the black market cost ranging from US$5 to US$25, depending on the dose.[168] The attorneys general of Connecticut and Pennsylvania have launched investigations into its diversion from the legitimate pharmaceutical market, including Cephalon's "sales and promotional practices for Provigil, Actiq and Gabitril."[168]
Non-medical use of fentanyl by individuals without opioid tolerance can be very dangerous and has resulted in numerous deaths.[167] Even those with opiate tolerances are at high risk for overdoses. Like all opioids, the effects of fentanyl can be reversed withnaloxone, or other opiate antagonists. Naloxone is increasingly available to the public. Long-acting or sustained-release opioids may require repeat dosage. Illicitly synthesized fentanyl powder has also appeared on the United States market. Because of the extremely high strength of pure fentanyl powder, it is very difficult to dilute appropriately, and often the resulting mixture may be far too strong and, therefore, very dangerous.[169]
Some heroin dealers mix fentanyl powder with heroin to increase potency or compensate for low-quality heroin. In 2006, illegally manufactured, non-pharmaceutical fentanyl often mixed withcocaine orheroin caused an outbreak of overdose deaths in the United States andCanada, heavily concentrated in the cities ofDayton, Ohio;Chicago, Illinois;Detroit, Michigan; andPhiladelphia, Pennsylvania.[170]
Fentanyl powder (23% fentanyl) seized by police inOhio, United States[171]
The fentanyl supply chain in Mexico consists of a vast and elusive network, potentially involving hundreds of players. U.S. and Mexican anti-narcotics officials acknowledge that the exact number is unknown. Some brokers operate as specialists within major cartels, while others act independently. However, the majority remain unknown to authorities and operate below the radar. A major challenge in disrupting this trade lies in the global chemical industry. Many of the compounds used to manufacture fentanyl have legitimate industrial applications, classifying them as dual-use chemicals. These substances are often unregulated or only lightly controlled in key countries such as the United States, Mexico, and China. This regulatory gap enables brokers to evade detection, seamlessly navigating between the legal chemical trade and the illicit drug market to acquire the necessary precursors.[172]
Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In November2016, the DEA uncovered an operation making counterfeit oxycodone andXanax from a home inCottonwood Heights, Utah. They found about 70,000pills in the appearance of oxycodone and more than 25,000 in the appearance of Xanax. The DEA reported that millions of pills could have been distributed from this location over the course of time. The accused owned atablet press and ordered fentanyl in powder form from China.[173][174] A seizure of a record amount of fentanyl occurred on 2 February 2019, byU.S. Customs and Border Protection inNogales, Arizona. The 254 pounds (115 kg) of fentanyl, which was estimated to be worth US$3.5M, was concealed in a compartment under a false floor of a truck transporting cucumbers.[175] The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especiallyα-methylfentanyl (AMF).[176] One US Department of Justice publication lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,[177] which today are classified asSchedule I drugs in the United States.[176] Part of the motivation for AMF is that, despite the extra difficulty from a synthetic standpoint, the resultant drug is more resistant to metabolic degradation. This results in a drug with an increased duration.[178]
In June 2013, the United StatesCenters for Disease Control and Prevention (CDC) issued a health advisory[179] to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated withacetylfentanyl, a synthetic opioid analog of fentanyl that has never been licensed for medical use. In a separate study conducted by the CDC, 82% of fentanyl overdose deaths involved illegally manufactured fentanyl, while only 4% were suspected to originate from a prescription.[180]
Beginning in 2015, Canada has seen several fentanyl overdoses. Authorities suspected that the drug was being imported from Asia to the western coast by organized crime groups in powder form and being pressed into pseudo-OxyContin tablets.[181] Traces of the drug have also been found in other recreational drugs, including cocaine,MDMA, and heroin. The drug has been implicated in the deaths of people from all walks of life—from homeless individuals to professionals—including teens and young parents.[182] Because of the rising deaths across the country, especially inBritish Columbia where 1,716deaths were reported in 2020 and 1,782 from January to October2021,[183]Health Canada is putting a rush on a review of the prescription-only status ofnaloxone in an effort to combat overdoses of the drug.[184] In 2018,Global News reported allegations thatdiplomatic tensions between Canada and China hindered cooperation to seize imports, with Beijing being accused of inaction.[185]
Fentanyl has been discovered for sale in illicit markets in Australia in 2017[186] and in New Zealand in 2018.[187] In response, New Zealand experts called for wider availability of naloxone.[188]
In May 2019, China regulated the entire class of fentanyl-type drugs and two fentanyl precursors. Nevertheless, it remains the principal origin of fentanyl in the United States: Mexican cartels source fentanylprecursors from Chinese suppliers such asYuancheng Group, which are finished in Mexico and smuggled to the United States.[189][190][191] Following the2022 visit by Nancy Pelosi to Taiwan, China halted cooperation with the United States on combatting drug trafficking.[192] Bilateral talks on fentanyl later resumed in San Francisco in 2024 when then U.S. President Joe Biden and Chinese President Xi Jinping met. In the past several months before February 2025, China had also began scheduling fentanyl precursors that are internationally banned, aligning with efforts to restrict the flow of chemicals used in fentanyl production as well as the drug itself. These actions are intended to strengthen efforts to curb drug trafficking and disrupt the supply chain more effectively. In February 2025, US president Trump imposed a 10%tariff on Chinese imports, claiming the move as a way "to pressure China into taking action on fentanyl". But experts have expressed concern that these tariffs could reverse the progress made under the Biden administration and weaken the international cooperation necessary to combat global drug trafficking.[193][194][195]
India has also emerged as a source of fentanyl and fentanyl precursors,[191] where Mexican cartels have already developed networks for the import of synthetic drugs. It is possible that fentanyl and precursor production may disperse to other countries, such asNigeria,South Africa,Indonesia,Myanmar, and theNetherlands.[190]
In 2020, theMyanmar military and police confiscated 990 gallons of "methyl fentanyl" [sic], as well asprecursors for the illicit synthesis of the drug. According to theUnited Nations Office on Drugs and Crime, theShan State of Myanmar has been identified as a major source for fentanyl derivatives. In 2021, the agency reported a further drop in opium poppy cultivation in Burma, as the region's synthetic drug market continues to expand and diversify.[196][197]
In 2023, a California police union director was charged with importing synthetic opioids, including fentanyl andtapentadol disguised aschocolate. U.S. law enforcement had been slow in their response to the fentanyl crisis, according to the Washington Post. The response by the federal government to the fentanyl crisis had also faltered, according to the press release. Overdose deaths by fentanyl and other illegally imported opioids were surging since 2019 and are presently a major cause of death in all U.S. states.[198][199]
According to the national archives and theDEA, direct fentanyl shipments from China have stopped since 2022.[200][201] The majority of illicit fentanyl and analogues now entering the U.S. from Mexico are final products in form of "tablets" and adulterated heroin from previously synthesized fentanyl. From the sophistication of fullfentanyl synthesis and acute toxicity in laboratory environments, 'clandestine' labs in Mexico relate to making an illicit dosage form from available fentanyl rather than the synthesis itself. Based on further research by investigators, fentanyl and analogues are likely synthesized in labs that have the appearance of a legal entity, or are diverted from pharmaceutical laboratories.[202][203][204]
Recent investigations and convictions of members of theSinaloa drug cartel by federal agencies made a clear connection between illegal arms trafficking from the U.S. to Mexico and the smuggling of fentanyl into the U.S. Mexico had repeatedly made official complaints since illegal guns are easily purchased for example in Arizona and as far north as Wisconsin and even Alaska, according to U.S. intelligence sources, and transported onto Mexican territory through a chain of American brokers and couriers often financed by those drug cartels that also engage in money laundering. Therefore, the lack of arms controls in the U.S. has directly contributed to the U.S. opioid overdose crisis.[205][206][207]
In the United States, the 800 mcg tablet was 6.75 times more expensive as of 2020 than the lozenge.[213][214] As of 2023, the average cost for an injectable fentanyl solution (50 mcg/mL) is aroundUS$17 for a supply of 20 milliliters, depending on the pharmacy.[215] In a 2020 report by theAustralian Institute of Criminology, a 100-microgram transdermal patch was valued from betweenAU$75 and AU$450 on illicit markets.[216] Furthermore, in another 2020 study, the average price per gram of non-pharmaceutical fentanyl on variouscryptomarkets was US$1,470.40 for offerings of less than five grams; the average for offers over five grams was US$139.50. In addition, onDreamMarket furanfentanyl (Fu-F), the most common analog on said market, the average price per gram was US$243.10 for retail listings and US$26.50 per gram for wholesale listings.[217]
The fentanyl patch is one of a few medications that may be especially harmful, and in some cases fatal, with just one dose, if misused by a child.[218][219] Experts have advised that any unused fentanyl patches be kept in a secure location out of children's sight and reach, such as a locked cabinet.
InBritish Columbia,Canada, where there are environmental concerns about toilet flushing or garbage disposal,pharmacists recommend that unused patches be sealed in achild-proof container that is then returned to apharmacy.[220] In the United States where patches cannot always be returned through a medication take-back program,flushing is recommended for fentanyl patches, because it is the fastest and surest way to remove them from the home to prevent ingestion by children, pets or others not intended to use them.[219][221]
On 24 May 2010,Slipknot bassistPaul Gray died from an overdose of morphine and fentanyl.[226]
On 21 April 2016, musicianPrince died and medical examiners concluded he had accidentally overdosed on fentanyl.[227] Fentanyl was among many substances identified in counterfeit pills recovered from his home, including some that were mislabeled as Watson 385, a combination ofhydrocodone and paracetamol.[227][228]
On 21 April 2016, American author and journalistMichelle McNamara died from an accidental overdose. Medical examiners determined fentanyl was a contributing factor.[229][230]
On 11 November 2016, Canadian video game composerSaki Kaskas died of a fentanyl overdose.[231] He had been battling heroin addiction for over a decade.[231]
On 15 November 2017, American rapperLil Peep died of an accidental fentanyl overdose.[232][233]
On 19 January 2018, theLos Angeles County Department of Medical Examiner said that musicianTom Petty's 2017 death was an accidental drug overdose as a result of mixing medications that included fentanyl, acetyl fentanyl, and despropionyl fentanyl (among others). He was reportedly treating "many serious ailments" that included a broken hip.[234]
On 7 September 2018, American rapperMac Miller died from an accidental overdose of fentanyl, cocaine and alcohol.[235]
On 16 December 2018, American tech entrepreneurColin Kroll, founder of social media video-sharing appVine and quiz appHQ Trivia, died from an overdose of fentanyl, heroin, and cocaine.[236]
On 1 January 2020, American rapper, singer, and songwriterLexii Alijai died from accidental toxicity resulting from the combination of alcohol and fentanyl.[238]
On 20 August 2020, American singer, songwriter, and musicianJustin Townes Earle died from an accidental overdose caused by cocaine laced with fentanyl.[239]
On 24 August 2020,Riley Gale, frontman for the Texas metal bandPower Trip, died as a result of the toxic effects of fentanyl in a manner that was ruled accidental.[240]
On 2 March 2021, American musicianMark Goffeney, also known as "Big Toe" (because being bornwithout arms, he playedguitar with his feet), died from an overdose of fentanyl.[241][242]
On 22 April 2021,Digital Underground frontman, rapper, and musicianShock G died from an accidental overdose of fentanyl, meth, and alcohol.[243]
On 28 September 2022, rapperCoolio (Artis Leon Ivey, Jr.) died from an accidental overdose of fentanyl, heroin, and methamphetamine.[246]
On 31 July 2023,Angus Cloud, best known for his portrayal ofFezco on theHBO drama seriesEuphoria, died from an accidental overdose of methamphetamine, cocaine, fentanyl, and benzodiazepines.[247]
On 15 September 2023, an infant died at a daycare center in The Bronx, New York City, due to fentanyl contamination, which is also believed to have caused sickness in other children.[248]
On 22 March 2024, Luke D'Wit was sentenced to a minimum of 37 years imprisonment for murdering Stephen and Carol Baxter inEssex, England on 9 April 2023 by giving them drinks laced with fentanyl.[249]
RussianSpetsnaz security forces are suspected to have used a fentanyl analogue, or derivative (suspected to be carfentanil and remifentanil),[256] to rapidly incapacitate people in theMoscow theater hostage crisis in 2002. The siege was ended, but many hostages died from the gas after their health was severely taxed during the days long siege.[257][258] The Russian Health Minister later stated that the gas was based on fentanyl,[259] but the exact chemical agent has not been clearly identified.[260]
In February2004, a leading fentanyl supplier, Janssen Pharmaceutica Products recalled one lot, and later, additional lots of fentanyl (brand name: Duragesic) patches because of seal breaches that might have allowed the medication to leak from the patch. A series of classII recalls was initiated in March2004, and in February2008, theALZA Corporation recalled their 25μg/h Duragesic patches due to a concern that small cuts in the gel reservoir could result in accidental exposure of patients or health care providers to the fentanyl gel.[261] In April 2023,Teva Pharmaceuticals USA recalled 13 lots of their Fentanyl Buccal Tablets CII due to missing safety information sheets on how to properly administer their product. The corporation issued a consumer recall report[262] and stressed the importance of safety in the use and administration of opioid therapeutics.[263]
Fentanyl is commonly used for analgesia and as a component of balancedsedation and generalanesthesia in small animal patients. In addition, its efficacy is higher than many other pure-opiate and synthetic pure-opioid agonists regarding vomiting, depth of sedation, and cardiovascular effects when given as a continuous infusion as well as atransdermal patch.[264][265][266] As with other pure-opioid agonists, fentanyl has been associated withdysphoria in dogs.[267]
Furthermore,transdermal fentanyl's potency and short duration of action make it popular as an intra-operative and post-operative analgesic in cats and dogs.[268] This is usually done with off-label fentanyl patches manufactured for humans with chronic pain. In 2012, a highly concentrated (50mg/mL)transdermal solution, brand name Recuvyra, has become commercially available for dogs only. It is approved by theFood and Drug Administration to provide four days of analgesia after a single application before surgery. It is not approved for multiple doses or other species.[269] The drug is also approved in Europe.[270]
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