Jump to content

Fentanyl

Listen to this article
From Wikipedia, the free encyclopedia
(Redirected from Duragesic®)
"Fent" redirects here. For other uses, see Fent (disambiguation).

Fentanyl
Clinical data
Pronunciation/ˈfɛntənɪl/ or /ˈfɛntənəl/
Trade namesActiq, Duragesic, Sublimaze, others
AHFS/Drugs.comMonograph
MedlinePlusa605043
License data
Pregnancy
category
  • AU: C
Dependence
liability		High[1]
Addiction
liability		Very High[2]
Routes of
administration		Buccal, epidural, intramuscular, intrathecal, intravenous, sublingual, transdermal
Drug classOpioid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability
Protein binding80–85%[7]
MetabolismLiver, primarily by CYP3A4
Onset of action5 minutes[8]
Elimination half-lifeIV: 6 mins (T1/2 α)
1 hours (T1/2 β)
16 hours (T1/2 ɣ)
Intranasal: 15–25 hours[9]
Transdermal: 20–27 hours[9]
Sublingual (single dose): 5–13.5 hours[9]
Buccal: 3.2–6.4 hours[9]
Duration of actionIV: 30–60 minutes[8][10]
ExcretionMostly urinary (metabolites, < 10% unchanged drug)[9]
Identifiers
  • N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.006.468 Edit this at Wikidata
Chemical and physical data
FormulaC22H28N2O
Molar mass336.479 g·mol−1
3D model (JSmol)
Density1.1 g/cm3
Melting point87.5 °C (189.5 °F)
  • O=C(CC)N(C1CCN(CC1)CCc2ccccc2)c3ccccc3
  • InChI=1S/C22H28N2O/c1-2-22(25)24(20-11-7-4-8-12-20)21-14-17-23(18-15-21)16-13-19-9-5-3-6-10-19/h3-12,21H,2,13-18H2,1H3 checkY
  • Key:PJMPHNIQZUBGLI-UHFFFAOYSA-N checkY
  (verify)

Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic. It is 30 to 50 times more potent than heroin and 100 times more potent than morphine;[11] its primary clinical utility is in pain management for cancer patients and those recovering from painful surgeries.[12][13] Fentanyl is also used as a sedative.[14] Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose.[15] Fentanyl works by activating μ-opioid receptors.[9] Fentanyl is sold under the brand names Actiq, Duragesic, and Sublimaze, among others.[16]

Pharmaceutical fentanyl's adverse effects are identical to those of other opioids and narcotics,[17] including addiction, confusion, respiratory depression (which, if extensive and untreated, may lead to respiratory 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.[14] Alcohol and other drugs (e.g., cocaine and heroin) 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 might be necessary.[16]

Fentanyl was first synthesized by Paul Janssen in 1959 and was approved for medical use in the United States in 1968.[9][18] In 2015, 1,600 kilograms (3,500 pounds) were used in healthcare globally.[19] As of 2017, fentanyl was the most widely used synthetic opioid in medicine;[20] in 2019, it was the 278th most commonly prescribed medication in the United States, with more than a million prescriptions.[21][22] It is on the World Health Organization's List of Essential Medicines.[23]

Fentanyl continues to fuel an epidemic of synthetic opioid drug overdose deaths in the United States. From 2011 to 2021, prescription opioid deaths per year remained stable, while synthetic opioid deaths per year increased from 2,600 overdoses to 70,601.[24] 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.[25][24][26] Fentanyl constitutes the majority of all drug overdose deaths in the United States since it overtook heroin in 2018.[25] The United States National Forensic Laboratory estimates fentanyl reports by federal, state, and local forensic laboratories increased from 4,697 reports in 2014 to 117,045 reports in 2020.[27] Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin.[27] Fentanyl has been reported in pill form, including pills mimicking pharmaceutical drugs such as oxycodone.[27] 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.[14] In an attempt to reduce the number of overdoses from taking other drugs mixed with fentanyl, drug testing kits, strips, and labs are available.[28][29] Fentanyl's ease of manufacture and high potency makes it easier to produce and smuggle, resulting in fentanyl replacing other abused narcotics and becoming more widely used.[30]

Medical uses

[edit]

Anesthesia

[edit]

Intravenous fentanyl is often used for anesthesia and as an analgesic.[31] To induce anesthesia, it is given with a sedative-hypnotic, like propofol or thiopental, and a euphoriant.[32] To maintain anesthesia, inhaled anesthetics and additional fentanyl may be used.[32] These are often given in 15–30 minute intervals throughout procedures such as endoscopy and surgeries and in emergency rooms.[33][34]

For pain relief after surgery, use can decrease the amount of inhalational anesthetic needed for emergence from anesthesia.[32] 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.[32]

Regional anesthesia

[edit]

Fentanyl is the most commonly used intrathecal opioid because its lipophilic profile allows a quick onset of action (5–10 min) and intermediate duration of action (60–120 min).[35] Spinal administration of hyperbaric bupivacaine with fentanyl may be the optimal combination. The almost immediate onset of fentanyl reduces visceral discomfort and even nausea during the procedure.[36]

Obstetrics

[edit]

Fentanyl is sometimes given intrathecally as part of spinal anesthesia or epidurally for epidural anaesthesia and analgesia. 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.[37] It is widely used in obstetrical 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.[38] 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 postnatal Stimulant.[38] For this reason, shorter-acting agents such as alfentanyl or remifentanil may be more suitable in the context of inducing general anaesthesia.[39]

Pain management

[edit]
A fentanyl nasal spray with a strength of 100 μg 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 900 out-of-hospital patients.[40]

In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.[41] Furthermore, a 2017 study suggested the efficacy of fentanyl lozenges in children as young as five, weighing as little as 13 kg. Lozenges are more inclined to be used as the child is in control of sufficient dosage, in contrast to buccal tablets.[42]

Chronic pain

[edit]

It is also used in the management of chronic pain.[43] Often, transdermal patches are used.[27] The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours, allowing for long-lasting pain management.[44] Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature.[44] Each patch should be changed every 72 hours.[45] 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 24 hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine or oxycodone) to handle breakthrough pain.[44] It is unclear if fentanyl gives long-term pain relief to people with neuropathic pain.[46]

Breakthrough pain

[edit]

Sublingual fentanyl dissolves quickly and is absorbed through the sublingual mucosa to provide rapid analgesia.[47] Fentanyl is a highly lipophilic compound,[47][48] which is well absorbed sublingually and generally well tolerated.[47] Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration, and severe in intensity.[49]

Palliative care

[edit]
A fentanyl transdermal patch with a release rate of 12 micrograms per hour, on a person's arm

In palliative 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.
  • people with moderate to severe kidney failure.[50]
  • troublesome side effects of oral morphine, hydromorphone, or oxycodone.[51][52]

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.[53]

Combat medicine

[edit]

USAF Pararescue combat medics in Afghanistan used fentanyl lozenges in the form of lollipops on combat casualties from IED blasts and other trauma.[54] The stick is taped to a finger and the lozenge put in the cheek 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.[54]

Breathing difficulties

[edit]

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 in palliative 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 in hospice settings.[55][56]

Other

[edit]

Some routes 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.[41]

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.[57] The technology consists of a "preprogrammed, self-contained drug-delivery system" that uses electrotransport technology to administer on-demand doses of 40 μg of fentanyl hydrochloride over ten minutes. In a 2004 experiment including 189 patients with moderate to severe postoperative pain up to 24 hours after major surgery, 25% of patients withdrew due to inadequate analgesia. However, the PCTS method proved superior to the placebo, showing lower mean VAS pain scores and having no significant respiratory depression effects.[58]

Adverse effects

[edit]
A two milligram dose of fentanyl powder (on pencil tip) is a lethal amount for most people.[59]
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).[24]

Fentanyl's most common side effects, which affect more than 10% of people, include nausea, vomiting, constipation, dry mouth, somnolence, confusion, and asthenia (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 with aphasia.[60] Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, than morphine.[61] In rare cases, serotonin syndrome is associated with fentanyl use. Existing studies advise medical practitioners to exercise caution when combining selective serotonin reuptake inhibitor (SSRI) drugs with fentanyl.[62][63]

The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context.[64][65][66][67] In 2006, the United 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.[68] 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.[69]

Respiratory depression

[edit]

The most dangerous adverse effect of fentanyl is respiratory depression,[70] 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 an endotracheal tube (as during anesthesia).[71] This risk is higher in specific groups, like those with obstructive sleep apnea.[71]

Other factors that increase the risk of respiratory depression are:[71]

  • High fentanyl doses
  • Simultaneous use of methadone
  • Sleep
  • Older age
  • Simultaneous use of CNS depressants like benzodiazepines (i.e. alprazolam, diazepam, clonazepam), barbiturates, alcohol, and inhaled anesthetics
  • Hyperventilation
  • Decreased CO2 levels in the serum
  • Respiratory acidosis
  • Decreased fentanyl clearance from the body
  • Decreased blood flow to the liver
  • Renal insufficiency

Sustained release fentanyl preparations, such as patches, may also produce unexpected delayed respiratory depression.[72][73][74] 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-induced cachexia 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-called wooden chest syndrome, which quickly induces complete respiratory failure by paralyzing the thoracic muscles, explained in more detail in the Muscle rigidity section below.

Heart and blood vessels

[edit]
  • Bradycardia: Fentanyl decreases the heart rate by increasing vagal nerve tone in the brainstem, which increases the parasympathetic drive.[71]
  • 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.[71] 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.[71] It does not affect the contractility of the heart when regular doses are administered.[71]

Muscle rigidity

[edit]

If high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult.[71] The exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers.[71]

Wooden chest syndrome

[edit]

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 as wooden chest syndrome.[75] The syndrome is believed to be the main cause of death as a result of fentanyl overdoses.[76]

Wooden chest syndrome is reversed by naloxone and is believed to be caused by a release of noradrenaline, which activates α-adrenergic receptors and also possibly via activation of cholinergic receptors.[77]

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.[78][77]

"Fentanyl fold" posture

[edit]

There are many reports of fentanyl users adopting a "folded" posture.

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".[79] 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.

Overdose

[edit]
Further information: Opioid overdose and U.S. drug overdose death rates and totals over time
2 mg of fentanyl (white powder to the right) is a lethal dose in most people.[80] A US penny is 19 mm (0.75 in) wide.

Fentanyl poses an exceptionally high overdose risk in humans since the amount required to cause toxicity is unpredictable.[14] In its pharmaceutical form, most overdose deaths attributed solely to fentanyl occur at serum concentrations at a mean of 0.025 μg/mL, with a range 0.005–0.027 μg/mL.[81] In contexts of poly-substance use, blood fentanyl concentrations of approximately 7 ng/mL or greater have been associated with fatalities.[82] 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.[83]

Naloxone (sold under the brand name Narcan) can completely or partially reverse an opioid overdose.[84] In July 2014, the Medicines 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,[85] 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.[86] In the US, fentanyl and fentanyl analogs caused over 29,000 deaths in 2017, a large increase over the previous four years.[87][88]

A package of 30 lozenges, 600 mcg 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.[89] Death from fentanyl overdose continues to be a public health issue of national concern in Canada since September 2015.[90] In 2016, deaths from fentanyl overdoses in the province of British Columbia averaged two persons per day.[91] In 2017 the death rate increased by more than 100% with 368 overdose-related deaths in British Columbia between January and April 2017.[92]

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.[93][94] 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.[95][96] The United Kingdom illicit drug market is no longer reliant on China, as domestic fentanyl production is replacing imports.[97]

The intravenous dose causing 50% of opioid-naive experimental subjects to die (LD50) is "3 mg/kg in rats, 1 mg/kg in cats, 14 mg/kg in dogs, and 0.03 mg/kg in monkeys."[98] The LD50 in mice has been given as 6.9 mg/kg by intravenous administration, 17.5 mg/kg intraperitoneally, 27.8 mg/kg by oral administration.[99] The LD50 in humans is unknown.[100]

In 2023, overdose deaths in the U.S. and Canada again reached record numbers.[101] While overdoes involving fentanyl in the United States have decreased in 2024, the overall percentage of overdoes involving fentanyl has remained stable between 70% and 80% from 2021-2024.[101] According to a 2023 report from the United 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.[102] Overdose deaths in pediatric cases are also concerning. In a report published in JAMA 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."[103]

False reports by police of poisonings through secondary exposure

[edit]

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.[104][105] Topical (or transdermal; via the skin) and inhalative 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.[106][107] A 2020 article from the Journal 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."[108] The American College of Medical Toxicology and the American 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.[109][110] 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 a panic attack.[111]

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 in New York found that 80% believed “briefly touching fentanyl could be deadly.”[113]

Many experts in toxicology are skeptical of police truly overdosing through mere touch. "This has never happened," said Dr. Ryan Marino, an emergency and addiction medicine physician at Case Western Reserve University. "There has never been an overdose through skin contact or accidentally inhaling fentanyl."[114]

Prevention

[edit]

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.[115] A subsequent HAN Alert was issued in July 2018, warning of rising numbers of deaths due to fentanyl abuse and mixing with non-opioids.[116] 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.[117]

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:[117]

  1. Local need to expand the distribution and use of naloxone and overdose prevention education,
  2. Expand awareness, access, and availability of treatment for substance use disorders,
  3. Intervene early with individuals at the highest risk for overdose, and
  4. improve detection of overdose outbreaks to facilitate more effective response.[117][118]

Another initiative is a social media campaign from the United States Drug Enforcement Administration (DEA) called "One Pill Can Kill".[59] 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.

Pharmacology

[edit]
See also: Opioid § Pharmacology

Classification

[edit]

Fentanyl is a synthetic opioid in the phenylpiperidine family, which includes sufentanil, alfentanil, remifentanil, and carfentanil.[119][120] Some fentanyl analogues, such as carfentanil, are up to 10,000 times stronger than morphine.[121]

Structure-activity

[edit]
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 like codeine, hydrocodone, oxycodone, and hydromorphone are synthesized by simple modifications of morphine, fentanyl, and its relatives are synthesized by modifications of meperidine.[71] Meperidine is a fully synthetic opioid, and other members of the phenylpiperidine family like alfentanil and sufentanil are complex versions of this structure.[71]

Like other opioids, fentanyl is a weak base that is highly lipid-soluble, protein-bound, and protonated at physiological pH.[71] All of these factors allow it to rapidly cross cellular membranes, contributing to its quick effect in the body and the central nervous system.[61][119]

Fentanyl analogs

[edit]

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 additional carboxylic 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.[122]

Mechanism of action

[edit]
Fentanyl at opioid receptors[123]
Affinities, KiTooltip Inhibitor constant Ratio
MORTooltip μ-opioid receptor DORTooltip δ-opioid receptor KORTooltip κ-opioid receptor MOR:DOR:KOR
0.39 nM >1,000 nM 255 nM 1:>2564:654

Fentanyl, like other opioids, acts on opioid receptors. These receptors are G-protein-coupled receptors, which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus.[71] The extracellular N-terminus is important in differentiating different types of binding substrates.[71] When fentanyl binds, downstream signaling leads to inhibitory effects, such as decreased cAMP production, decreased calcium ion influx, and increased potassium efflux.[71] 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 of nociceptive signals, resulting in analgesic effects.[124][125][unreliable medical source?]

As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine.[124] It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to more easily penetrate the central nervous system.[119][61] 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.[71]

Fentanyl can produce the following clinical effects strongly, through μ-receptor agonism:[126]

  • Supraspinal analgesia (μ1)
  • Respiratory depression (μ2)
  • Physical dependence
  • Muscle rigidity

It also produces sedation and spinal analgesia through Κ-receptor agonism.[126]

Therapeutic effects

[edit]
  • Pain relief: Primarily, fentanyl provides the relief of pain by acting on the brain and spinal μ-receptors.[71]
  • Sedation: Fentanyl produces sleep and drowsiness, as the dosage is increased, and can produce the δ-waves often seen in natural sleep on electroencephalogram.[71]
  • Suppression of the cough reflex: Fentanyl can decrease the struggle against an endotracheal tube and excessive coughing by decreasing the cough reflex, becoming useful when intubating people who are awake and have compromised airways.[71] After receiving a bolus dose of fentanyl, people can also experience paradoxical coughing, which is a phenomenon that is not well understood.[71]

Detection in biological fluids

[edit]

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 available immunoassays are often used as initial screening tests, but chromatographic techniques are generally used for confirmation and quantitation. The Marquis Color test may also be used to detect the presence of fentanyl. Using formaldehyde and sulfuric acid, the solution will turn purple when introduced to opium drugs. Blood or plasma 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.[127] Paper spray-mass spectrometry (PS-MS) may be useful for initial testing of samples.[128][129]

Detection for harm reduction purposes

[edit]
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 with methamphetamine, MDMA, and diphenhydramine.[131] The sensitivity and specificity of fentanyl test strips vary depending on the concentration of fentanyl tested, particularly from 10 to 250 ng/mL.[132]

Synthesis

[edit]

Fentanyl is a 4-anilopiperidine 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]

Janssen

[edit]
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 of benzylfentanyl from N-Benzyl-4-Piperidone. The resulting benzylfentanyl is used as feedstock to norfentanyl. It is norfentanyl that forms fentanyl upon reaction with phenethyl chloride.[136]

Siegfried

[edit]
Siegfried Method from NPP through 4-ANPP to fentanyl

The Siegfried method involves the initial synthesis of N-phenethyl-4-piperidone (NPP). This intermediate is reductively aminated to 4-anilino-N-phenethylpiperidine (4-ANPP). Fentanyl is produced following the reaction of 4-ANPP with an acyl chloride.[137] The Siegfried method has been used in the early 2000s to manufacture fentanyl in both domestic and foreign clandestine laboratories.[138]

Gupta

[edit]
Gupta Method from 4-Piperidone to fentanyl

The Gupta (or 'one-pot') method starts from 4-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, the U.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]

Suh

[edit]

The Suh (or 'total synthesis') method skips the direct use of piperidine precursors in favor of creating the ring system in-situ.[142]

History

[edit]

Fentanyl was first synthesized in Belgium by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959.[143] It was developed by screening chemicals similar to pethidine (meperidine) 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 1:1 stoichiometric ratio).[145][146] Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by McNeil 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 72 hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.[148]

Following the patch, a flavored lollipop 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 US Food 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 the cheek.[150]

Fentanyl has a US Drug Enforcement Administration (DEA) Administrative Controlled Substances Code Number (ACSCN) of 9801. Its annual aggregate manufacturing quota has significantly reduced in recent years from 2,300,000 kg in 2015 and 2016 to only 731,452 kg in 2021, a nearly 68.2% decrease.[151]

Society and culture

[edit]
[edit]

In the UK, fentanyl is classified as a controlled Class A drug under the Misuse of Drugs Act 1971.[152]

In the Netherlands, fentanyl is a List I substance of the Opium Law.[153]

In the U.S., fentanyl is a Schedule II controlled substance per the Controlled Substance Act. Distributors of Abstral are required to implement an FDA-approved risk evaluation and mitigation strategy (REMS) program.[154][155] In order to curb misuse, many health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.[156][157][158]

In Canada, fentanyl is considered a schedule I drug as listed in Canada's Controlled Drugs and Substances Act.[159]

Estonia is known to have been home to the world's longest documented fentanyl epidemic, especially following the Taliban ban on opium poppy cultivation in Afghanistan.[160]

A 2018 report by The Guardian indicated that many major drug suppliers on the dark web have voluntarily banned the trafficking of fentanyl.[161]

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-President Andrés Manuel López Obrador insisted that the main source of this synthetic drug is Asia. He stated that the crisis of a lack of family values in the United States drives people to use the drug.[162]

Recreational use

[edit]

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 and clandestinely 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.[163]

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 or oxycodone, which can lead to overdose. Many fentanyl overdoses are initially classified as heroin overdoses.[164] Recreational use is not particularly widespread in the EU except for Tallinn, Estonia, where it has largely replaced heroin. Estonia has the highest rate of 3-methylfentanyl overdose deaths in the EU, due to its high rate of recreational use.[165]

Fentanyl is sometimes sold on the black market in the form of transdermal fentanyl patches such as Duragesic, diverted from legitimate medical supplies. The gel from inside the patches is sometimes ingested or injected.[166]

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.[167] 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."[167]

Non-medical use of fentanyl by individuals without opioid tolerance can be very dangerous and has resulted in numerous deaths.[166] Even those with opiate tolerances are at high risk for overdoses. Like all opioids, the effects of fentanyl can be reversed with naloxone, 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.[168]

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 with cocaine or heroin caused an outbreak of overdose deaths in the United States and Canada, heavily concentrated in the cities of Dayton, Ohio; Chicago, Illinois; Detroit, Michigan; and Philadelphia, Pennsylvania.[169]

Enforcement

[edit]
Further information: Anti-fentanyl legislation in the United States, United States sanctions against China § Sanctions on producers of fentanyl precursors, and China and the opioid epidemic in the United States
Fentanyl powder (23% fentanyl) seized by police in Ohio, United States[170]

Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In November 2016, the DEA uncovered an operation making counterfeit oxycodone and Xanax from a home in Cottonwood Heights, Utah. They found about 70,000 pills 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 a tablet press and ordered fentanyl in powder form from China.[171][172] A seizure of a record amount of fentanyl occurred on 2 February 2019, by U.S. Customs and Border Protection in Nogales, 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.[173] The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF).[174] One US Department of Justice publication lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,[175] which today are classified as Schedule I drugs in the United States.[174] 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.[176]

In June 2013, the United States Centers for Disease Control and Prevention (CDC) issued a health advisory[177] to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated with acetylfentanyl, 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.[178]

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.[179] 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.[180] Because of the rising deaths across the country, especially in British Columbia where 1,716 deaths were reported in 2020 and 1,782 from January to October 2021,[181] Health Canada is putting a rush on a review of the prescription-only status of naloxone in an effort to combat overdoses of the drug.[182] In 2018, Global News reported allegations that diplomatic tensions between Canada and China hindered cooperation to seize imports, with Beijing being accused of inaction.[183]

Fentanyl has been discovered for sale in illicit markets in Australia in 2017[184] and in New Zealand in 2018.[185] In response, New Zealand experts called for wider availability of naloxone.[186]

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 fentanyl precursors from Chinese suppliers such as Yuancheng Group, which are finished in Mexico and smuggled to the United States.[187][188][189] Following the 2022 visit by Nancy Pelosi to Taiwan, China halted cooperation with the United States on combatting drug trafficking.[190]

India has also emerged as a source of fentanyl and fentanyl precursors,[189] 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 as Nigeria, South Africa, Indonesia, Myanmar, and the Netherlands.[188]

In 2020, the Myanmar military and police confiscated 990 gallons of "methyl fentanyl" [sic], as well as precursors for the illicit synthesis of the drug. According to the United Nations Office on Drugs and Crime, the Shan 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.[191][192]

In 2023, a California police union director was charged with importing synthetic opioids, including fentanyl and tapentadol disguised as chocolate. 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.[193][194]

According to the national archives and the DEA, direct fentanyl shipments from China have stopped since 2022.[195][196] 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 full fentanyl 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.[197][198][199]

Recent investigations and convictions of members of the Sinaloa 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.[200][201][202]

Brand names

[edit]

Brand names include Sublimaze,[60] Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis,[203] Instanyl,[204] Abstral,[205] Lazanda[206] and others.[207]

Economics

[edit]

In the United States, the 800 mcg tablet was 6.75 times more expensive as of 2020 than the lozenge.[208][209] As of 2023, the average cost for an injectable fentanyl solution (50 mcg/mL) is around US$17 for a supply of 20 milliliters, depending on the pharmacy.[210] In a 2020 report by the Australian Institute of Criminology, a 100-microgram transdermal patch was valued from between AU$75 and AU$450 on illicit markets.[211] Furthermore, in another 2020 study, the average price per gram of non-pharmaceutical fentanyl on various cryptomarkets 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, on DreamMarket 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.[212]

Storage and disposal

[edit]

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.[213][214] 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.

In British Columbia, Canada, where there are environmental concerns about toilet flushing or garbage disposal, pharmacists recommend that unused patches be sealed in a child-proof container that is then returned to a pharmacy.[215] 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.[214][216]

Notable deaths

[edit]
  • On 25 September 2003, American professional wrestler Anthony Durante, also known as "Pitbull #2", died from a fentanyl-induced overdose.[217]
  • On 24 May 2009, Wilco guitarist Jay Bennett died from an accidental overdose of fentanyl.[218][219][220]
  • On 24 May 2010, Slipknot bassist Paul Gray died from an overdose of morphine and fentanyl.[221]
  • On 21 April 2016, musician Prince died and medical examiners concluded he had accidentally overdosed on fentanyl.[222] Fentanyl was among many substances identified in counterfeit pills recovered from his home, including some that were mislabeled as Watson 385, a combination of hydrocodone and paracetamol.[222][223]
  • On 21 April 2016, American author and journalist Michelle McNamara died from an accidental overdose; medical examiners determined fentanyl was a contributing factor.[224][225]
  • On 11 November 2016, Canadian video game composer Saki Kaskas died of a fentanyl overdose;[226] he had been battling heroin addiction for over a decade.[226]
  • On 15 November 2017, American rapper Lil Peep died of an accidental fentanyl overdose.[227][228]
  • On 19 January 2018, the Los Angeles County Department of Medical Examiner said musician Tom Petty died from 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.[229]
  • On 7 September 2018, American rapper Mac Miller died from an accidental overdose of fentanyl, cocaine and alcohol.[230]
  • On 16 December 2018, American tech entrepreneur Colin Kroll, founder of social media video-sharing app Vine and quiz app HQ Trivia, died from an overdose of fentanyl, heroin, and cocaine.[231]
  • On 1 July 2019, American baseball player Tyler Skaggs died from pulmonary aspiration while under the influence of fentanyl, oxycodone, and alcohol.[232]
  • On 1 January 2020, American rapper, singer, and songwriter Lexii Alijai died from accidental toxicity resulting from the combination of alcohol and fentanyl.[233]
  • On 20 August 2020, American singer, songwriter, and musician Justin Townes Earle died from an accidental overdose caused by cocaine laced with fentanyl.[234]
  • On 24 August 2020, Riley Gale, frontman for the Texas metal band Power Trip, died as a result of the toxic effects of fentanyl in a manner that was ruled accidental.[235]
  • On 2 March 2021, American musician Mark Goffeney, also known as "Big Toe" (because being born without arms, he played guitar with his feet), died from an overdose of fentanyl.[236][237]
  • On 22 April 2021, Digital Underground frontman, rapper, and musician Shock G died from an accidental overdose of fentanyl, meth, and alcohol.[238]
  • On 6 September 2021, actor Michael K. Williams, who performed as Omar Little on the HBO drama series The Wire, died from an overdose of fentanyl, parafluorofentanyl, heroin, and cocaine.[239][240]
  • On 28 September 2022, rapper Coolio (Artis Leon Ivey, Jr.) died from an accidental overdose of fentanyl, heroin, and methamphetamine.[241]
  • On 31 July 2023, Angus Cloud, best known for his portrayal of Fezco on the HBO drama series Euphoria, died from an accidental overdose of methamphetamine, cocaine, fentanyl, and benzodiazepines.[242]
  • 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.[243]
  • On 22 March 2024, Mark D'Wit was sentenced to a minimum of 37 years imprisonment for murdering Stephen and Carol Baxter in Essex, England on 9 April 2023 by giving them drinks laced with fentanyl.[244]

Governmental usage

[edit]

In August 2018, Nebraska became the first American state to use fentanyl to execute a prisoner.[245][246][247] Carey Dean Moore, at the time one of the longest-serving death row inmates in the United States,[248] was executed at the Nebraska State Penitentiary. Moore received a lethal injection, administered as an intravenous series of four drugs that included fentanyl citrate, to inhibit breathing and render the subject unconscious. The other drugs included diazepam as a tranquilizer, cisatracurium besylate as a muscle relaxant, and potassium chloride to stop the heart.[249][250] The use of fentanyl in execution caused concern among death penalty experts because it was part of a previously untested drug cocktail.[245][247] The execution was also protested by anti-death penalty advocates at the prison during the execution and later at the Nebraska State Capitol.[249][250]

Russian Spetsnaz security forces are suspected to have used a fentanyl analogue, or derivative (suspected to be carfentanil and remifentanil),[251] to rapidly incapacitate people in the Moscow 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.[252][253] The Russian Health Minister later stated that the gas was based on fentanyl,[254] but the exact chemical agent has not been clearly identified.[255]

Recalls

[edit]

In February 2004, 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 class II recalls was initiated in March 2004, and in February 2008, the ALZA Corporation recalled their 25 μg/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.[256] 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[257] and stressed the importance of safety in the use and administration of opioid therapeutics.[258]

Veterinary use

[edit]

Fentanyl is commonly used for analgesia and as a component of balanced sedation and general anesthesia 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 a transdermal patch.[259][260][261] As with other pure-opioid agonists, fentanyl has been associated with dysphoria in dogs.[262]

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.[263] This is usually done with off-label fentanyl patches manufactured for humans with chronic pain. In 2012, a highly concentrated (50 mg/mL) transdermal solution, brand name Recuvyra, has become commercially available for dogs only. It is approved by the Food 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.[264] The drug is also approved in Europe.[265]

References

[edit]
  1. ^ Bonewit-West K, Hunt SA, Applegate E (2012). Today's Medical Assistant: Clinical and administrative procedures. Elsevier Health Sciences. p. 571. ISBN 978-1-4557-0150-6. Archived from the original on 10 January 2023. Retrieved 20 August 2019.
  2. ^ Ciccarone D (August 2017). "Fentanyl in the US heroin supply: A rapidly changing risk environment". The International Journal on Drug Policy. 46: 107–111. doi:10.1016/j.drugpo.2017.06.010. PMC 5742018. PMID 28735776.
  3. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  4. ^ "Instanyl EPAR". European Medicines Agency (EMA). 20 July 2009. Retrieved 11 September 2024.
  5. ^ "Effentora EPAR". European Medicines Agency (EMA). 4 April 2008. Retrieved 12 October 2024.
  6. ^ Valtola A, Laakso M, Hakomäki H, Anderson BJ, Kokki H, Ranta VP, et al. (9 March 2021). "Intranasal Fentanyl for Intervention-Associated Breakthrough Pain After Cardiac Surgery". Clinical Pharmacokinetics. 60: 907–919 – via SpringerLink. Intranasal fentanyl 100 µg or 200 µg was used to manage breakthrough pain on the first and third postoperative mornings in a randomised order [...] Bioavailability of intranasal fentanyl was high (77%){{cite journal}}: CS1 maint: date and year (link)
  7. ^ Bista SR, Haywood A, Hardy J, Lobb M, Tapuni A, Norris R (March 2015). "Protein binding of fentanyl and its metabolite nor-fentanyl in human plasma, albumin and α-1 acid glycoprotein". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 45 (3): 207–212. doi:10.3109/00498254.2014.971093. PMID 25314012. S2CID 21109003.
  8. ^ a b Clinically Oriented Pharmacology (2nd ed.). Quick Review of Pharmacology. 2010. p. 172.
  9. ^ a b c d e f g "Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 14 December 2017. Retrieved 8 December 2017.
  10. ^ "Guideline for administration of fentanyl for pain relief in labour" (PDF). RCP. Archived (PDF) from the original on 4 March 2016. Retrieved 7 October 2015. Onset of action after I.V. administration of Fentanyl is 3–5 minutes; duration of action is 30–60 minutes.
  11. ^ Han Y, Yan W, Zheng Y, Khan MZ, Yuan K, Lu L (14 November 2018). "Fentanyl". Nature.com. 9 (1): 282. doi:10.1038/s41398-019-0625-0. PMC 6848196. PMID 31712552.
  12. ^ "Fentanyl". U.S. Centers for Disease Control and Prevention (CDC). 7 October 2022. Archived from the original on 28 April 2022. Retrieved 20 February 2023.
  13. ^ "Fentanyl: MedlinePlus Drug Information". MedlinePlus. Archived from the original on 27 November 2023. Retrieved 5 November 2023.
  14. ^ a b c d Ramos-Matos CF, Bistas KG, Lopez-Ojeda W (2022). "Fentanyl". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 29083586. Archived from the original on 15 March 2023. Retrieved 20 February 2023.
  15. ^ "Fentanyl". National Institute on Drug Abuse. 21 December 2021. Archived from the original on 20 February 2023. Retrieved 20 February 2023.
  16. ^ a b "Fentanyl DrugFacts". National Institute on Drug Abuse. 1 June 2021. Archived from the original on 11 May 2023. Retrieved 20 February 2023.
  17. ^ "Fentanyl: Uses, Warnings & Side Effects". Cleveland Clinic. Archived from the original on 5 November 2023. Retrieved 5 November 2023.
  18. ^ Stanley TH (April 1992). "The history and development of the fentanyl series". Journal of Pain and Symptom Management. 7 (3 Suppl): S3–S7. doi:10.1016/0885-3924(92)90047-L. PMID 1517629.
  19. ^ Narcotic Drugs Estimated World Requirements for 2017 / Statistics for 2015 (PDF) (Report). New York: United Nations. 2016. p. 40. ISBN 978-92-1-048163-2. Archived (PDF) from the original on 22 October 2017. Retrieved 14 December 2017.
  20. ^ "Fentanyl and analogues". LiverTox. 16 October 2017. Archived from the original on 7 January 2017. Retrieved 14 December 2017.
  21. ^ "The Top 300 of 2019". ClinCalc. Archived from the original on 12 February 2021. Retrieved 7 October 2022.
  22. ^ "Fentanyl Drug Usage Statistics". ClinCalc. Archived from the original on 11 April 2020. Retrieved 7 October 2022.
  23. ^ Organization WH (2021). World Health Organization model list of essential medicines (22nd list (2021) ed.). Geneva, CH: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  24. ^ a b c "Drug Overdose Death Rates". National Institute on Drug Abuse. 9 February 2023. Archived from the original on 23 February 2023. Retrieved 20 February 2023.
  25. ^ a b Reinberg S (12 December 2018). "Fentanyl overtakes heroin as the No. 1 opioid overdose killer". CBS News. CBS Interactive Inc. Archived from the original on 12 December 2018. Retrieved 20 February 2023.
  26. ^ "U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 – But Are Still Up 15%". U.S. Centers for Disease Control and Prevention (CDC). 11 May 2022. Archived from the original on 10 August 2022. Retrieved 5 May 2023.
  27. ^ a b c d "Fentanyl" (factsheet). Drug Enforcement Administration. Archived from the original on 4 December 2018. Retrieved 4 December 2018.
  28. ^ "DrugsData.org: Lab Analysis / Drug Checking for Recreational Drugs". DrugsData. Retrieved 12 December 2023.
  29. ^ Nasir A. "Drug Checking". DanceSafe. Retrieved 12 December 2023.
  30. ^ Falco G (8 January 2023). "China's Role in Illicit Fentanyl Running Rampant on US Streets". Congressman David Trone. Archived from the original on 16 February 2023. Retrieved 20 February 2023.
  31. ^ Brunton LL, Hilal-Dandan R, Knollmann BC (5 December 2017). Goodman & Gilman's: The pharmacological basis of therapeutics (13th ed.). New York, NY: McGraw-Hill Education. ISBN 978-1-259-58473-2. OCLC 993810322.
  32. ^ a b c d Gropper MA, Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Cohen LH, et al. (7 October 2019). Miller's Anesthesia (9th ed.). Philadelphia, PA: Elsevier. ISBN 978-0-323-61264-7. OCLC 1124935549.
  33. ^ Godwin SA, Burton JH, Gerardo CJ, Hatten BW, Mace SE, Silvers SM, et al. (February 2014). "Clinical policy: procedural sedation and analgesia in the emergency department". Annals of Emergency Medicine. 63 (2): 247–58.e18. doi:10.1016/j.annemergmed.2013.10.015. PMID 24438649.
  34. ^ Smith HS, Colson J, Sehgal N (April 2013). "An update of evaluation of intravenous sedation on diagnostic spinal injection procedures". Pain Physician. 16 (2 Suppl): SE217–SE228. doi:10.36076/ppj.2013/16/SE217. PMID 23615892. Archived from the original on 19 October 2015. Retrieved 1 May 2017.
  35. ^ Gudin MA, López R, Estrada J, Ortigosa E (28 November 2011). "Neuraxial Blockade: Subarachnoid Anesthesia". Essentials of Regional Anesthesia. New York, NY: Springer New York. pp. 261–291. doi:10.1007/978-1-4614-1013-3_11. ISBN 978-1-4614-1012-6. Archived from the original on 8 February 2023. Retrieved 4 July 2021.
  36. ^ Buggy D (1 July 2008). "Anesthesiology: Longnecker DE, Brown DL, Newman MF, Zapol WM, Editors, McGraw Hill, New York (2007) ISBN: 978-0-07-145984-6, 2278 pp, hardcover, $249 ..." Regional Anesthesia and Pain Medicine (book review). 33 (4). BMJ Journals: 380. doi:10.1016/j.rapm.2008.03.003. ISSN 1098-7339. Archived from the original on 18 July 2021. Retrieved 18 July 2021.
  37. ^ Bujedo BM (July 2014). "Current evidence for spinal opioid selection in postoperative pain". The Korean Journal of Pain. 27 (3): 200–209. doi:10.3344/kjp.2014.27.3.200. PMC 4099232. PMID 25031805.
  38. ^ a b Moisés EC, de Barros Duarte L, de Carvalho Cavalli R, Lanchote VL, Duarte G, da Cunha SP (August 2005). "Pharmacokinetics and transplacental distribution of fentanyl in epidural anesthesia for normal pregnant women". European Journal of Clinical Pharmacology. 61 (7): 517–522. doi:10.1007/s00228-005-0967-9. PMID 16021436. S2CID 26065578.
  39. ^ White LD, Hodsdon A, An GH, Thang C, Melhuish TM, Vlok R (November 2019). "Induction opioids for caesarean section under general anaesthesia: a systematic review and meta-analysis of randomised controlled trials". International Journal of Obstetric Anesthesia. 40: 4–13. doi:10.1016/j.ijoa.2019.04.007. hdl:10072/416502. PMID 31230994. S2CID 181816438. Archived from the original on 22 May 2022. Retrieved 23 May 2022.
  40. ^ Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS (June 2014). "Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study". Annals of Emergency Medicine. 63 (6): 699–703. doi:10.1016/j.annemergmed.2013.10.025. PMID 24268523.
  41. ^ a b Murphy A, O'Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, et al. (October 2014). "Intranasal fentanyl for the management of acute pain in children". The Cochrane Database of Systematic Reviews. 10 (10): CD009942. doi:10.1002/14651858.CD009942.pub2. PMC 6544782. PMID 25300594.
  42. ^ Coombes L, Burke K, Anderson AK (October 2017). "The use of rapid onset fentanyl in children and young people for breakthrough cancer pain". Scandinavian Journal of Pain. 17 (1): 256–259. doi:10.1016/j.sjpain.2017.07.010. PMID 29229211. S2CID 8577873.
  43. ^ Plante GE, VanItallie TB (October 2010). "Opioids for cancer pain: the challenge of optimizing treatment". Metabolism. 59 (Suppl 1): S47–S52. doi:10.1016/j.metabol.2010.07.010. PMID 20837194.
  44. ^ a b c Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna, AU: Österreichischer Apothekerverlag. pp. 2621 ff. ISBN 978-3-85200-181-4.
  45. ^ "Fentanyl patches (Durogesic) for chronic pain". NPS Medicinewise. August 2006. Archived from the original on 7 December 2021. Retrieved 7 December 2021.
  46. ^ Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, et al. (October 2016). "Fentanyl for neuropathic pain in adults". The Cochrane Database of Systematic Reviews. 10 (5): CD011605. doi:10.1002/14651858.CD011605.pub2. PMC 6457928. PMID 27727431.
  47. ^ a b c "Abstral sublingual tablets". UK Electronic Medicines Compendium. May 2016. Archived from the original on 23 March 2017. Retrieved 1 May 2017.
  48. ^ "Abstral (Fentanyl Sublingual Tablets for Breakthrough Cancer Pain)". P & T. 36 (2): 2–28. February 2011. PMC 3086091. PMID 21560267.
  49. ^ Ward J, Laird B, Fallon M (2011). "The UK breakthrough cancer pain registry: Origin, methods and preliminary data". BMJ Supportive & Palliative Care. 1: A24. doi:10.1136/bmjspcare-2011-000020.71. S2CID 73185220.
  50. ^ Roy PJ, Weltman M, Dember LM, Liebschutz J, Jhamb M (November 2020). "Pain management in patients with chronic kidney disease and end-stage kidney disease". Current Opinion in Nephrology and Hypertension. 29 (6): 671–680. doi:10.1097/MNH.0000000000000646. PMC 7753951. PMID 32941189.
  51. ^ Aurilio C, Pace MC, Pota V, Sansone P, Barbarisi M, Grella E, et al. (May 2009). "Opioids switching with transdermal systems in chronic cancer pain". Journal of Experimental & Clinical Cancer Research. 28 (1): 61. doi:10.1186/1756-9966-28-61. PMC 2684533. PMID 19422676.
  52. ^ Minami S, Kijima T, Nakatani T, Yamamoto S, Ogata Y, Hirata H, et al. (8 October 2014). "Opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch for patients with stable thoracic malignancy-related pain". BMC Palliative Care. 13 (1): 46. doi:10.1186/1472-684X-13-46. PMC 4195703. PMID 25313295.
  53. ^ "Fentanyl (Transdermal Route) Precautions". Mayo Clinic. Archived from the original on 19 January 2023. Retrieved 19 January 2023.
  54. ^ a b Shachtman N (10 September 2009). "Airborne EMTs Shave Seconds to Save Lives in Afghanistan". Danger Room. Wired. Archived from the original on 6 July 2010. Retrieved 1 July 2010.
  55. ^ van Dijk M, Mooren KJ, van den Berg JK, van Beurden-Moeskops WJ, Heller-Baan R, de Hosson SM, et al. (September 2021). "Opioids in patients with COPD and refractory dyspnea: literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD)". BMC Pulmonary Medicine. 21 (1): 289. doi:10.1186/s12890-021-01647-8. PMC 8431258. PMID 34507574.
  56. ^ Simon ST, Köskeroglu P, Gaertner J, Voltz R (December 2013). "Fentanyl for the relief of refractory breathlessness: a systematic review". Journal of Pain and Symptom Management. 46 (6): 874–886. doi:10.1016/j.jpainsymman.2013.02.019. PMID 23742735.
  57. ^ Koo PJ (June 2005). "Postoperative pain management with a patient-controlled transdermal delivery system for fentanyl". American Journal of Health-System Pharmacy. 62 (11): 1171–1176. doi:10.1093/ajhp/62.11.1171. PMID 15914877. Archived from the original on 6 August 2018. Retrieved 28 March 2016.
  58. ^ Chelly JE, Grass J, Houseman TW, Minkowitz H, Pue A (February 2004). "The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial". Anesthesia and Analgesia. 98 (2): 427–433. doi:10.1213/01.ANE.0000093314.13848.7E. PMID 14742382. S2CID 24551941.
  59. ^ a b "One Pill Can Kill". U.S. Drug Enforcement Administration. Archived from the original on 15 November 2023. Retrieved 15 November 2023.
  60. ^ a b "Fentanyl". U.S. Food and Drug Administration (FDA). Archived from the original on 13 March 2013. Retrieved 4 September 2013.
  61. ^ a b c Mayes S, Ferrone M (December 2006). "Fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain". The Annals of Pharmacotherapy. 40 (12): 2178–2186. doi:10.1345/aph.1H135. PMID 17164395. S2CID 24454875. Archived from the original on 1 October 2012. Retrieved 17 December 2010.
  62. ^ Kirschner R, Donovan JW (May 2010). "Serotonin syndrome precipitated by fentanyl during procedural sedation". The Journal of Emergency Medicine. 38 (4): 477–480. doi:10.1016/j.jemermed.2008.01.003. PMID 18757161.
  63. ^ Ailawadhi S, Sung KW, Carlson LA, Baer MR (April 2007). "Serotonin syndrome caused by interaction between citalopram and fentanyl". Journal of Clinical Pharmacy and Therapeutics. 32 (2): 199–202. doi:10.1111/j.1365-2710.2007.00813.x. PMID 17381671.
  64. ^ Smydo J (1979). "Delayed respiratory depression with fentanyl". Anesthesia Progress. 26 (2): 47–48. PMC 2515983. PMID 295585.
  65. ^ van Leeuwen L, Deen L, Helmers JH (August 1981). "A comparison of alfentanil and fentanyl in short operations with special reference to their duration of action and postoperative respiratory depression". Der Anaesthesist. 30 (8): 397–399. PMID 6116461.
  66. ^ Brown DL (November 1985). "Postoperative analgesia following thoracotomy. Danger of delayed respiratory depression". Chest. 88 (5): 779–780. doi:10.1378/chest.88.5.779. PMID 4053723. S2CID 1836168.
  67. ^ Nilsson C, Rosberg B (June 1982). "Recurrence of respiratory depression following neurolept analgesia". Acta Anaesthesiologica Scandinavica. 26 (3): 240–241. doi:10.1111/j.1399-6576.1982.tb01762.x. PMID 7113633. S2CID 9232457.
  68. ^ "Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use". Drug Safety Update. 2 (2): 2. September 2008. Archived from the original on 1 January 2015.
  69. ^ "Fentanyl patch can be deadly to children". U.S. Food and Drug Administration (FDA). 19 April 2012. Archived from the original on 25 July 2013. Retrieved 30 July 2013.
  70. ^ Topacoglu H, Karcioglu O, Cimrin AH, Arnold J (November 2005). "Respiratory arrest after low-dose fentanyl". Annals of Saudi Medicine. 25 (6): 508–510. doi:10.5144/0256-4947.2005.508. PMC 6089740. PMID 16438465.
  71. ^ a b c d e f g h i j k l m n o p q r s t Hemmings HC, Egan TD (19 October 2018). Pharmacology and Physiology for Anesthesia: Foundations and clinical application (2nd ed.). Philadelphia, PA: Elsevier. ISBN 978-0-323-56886-9. OCLC 1063667873.
  72. ^ McLoughlin R, McQuillan R (September 1997). "Transdermal fentanyl and respiratory depression". Palliative Medicine. 11 (5): 419. doi:10.1177/026921639701100515. PMID 9472602.
  73. ^ Bülow HH, Linnemann M, Berg H, Lang-Jensen T, LaCour S, Jonsson T (August 1995). "Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl". Acta Anaesthesiologica Scandinavica. 39 (6): 835–839. doi:10.1111/j.1399-6576.1995.tb04180.x. PMID 7484044. S2CID 22781991.
  74. ^ Regnard C, Pelham A (December 2003). "Severe respiratory depression and sedation with transdermal fentanyl: four case studies". Palliative Medicine. 17 (8): 714–716. doi:10.1191/0269216303pm838cr. PMID 14694924. S2CID 32985050.
  75. ^ Chambers D, Huang CL, Matthews G (1 September 2019) [2015]. "Section 2 – Respiratory physiology: Chapter 25: Anaesthesia and the lung". Basic Physiology for Anaesthetists (2nd ed.). Cambridge, UK: Cambridge University Press. pp. 107–110. doi:10.1017/CBO9781139226394.027. ISBN 978-1-108-46399-7. OCLC 1088737571. Archived from the original on 8 February 2023. Retrieved 9 August 2021 – via Google Books.
  76. ^ Burns G, DeRienz RT, Baker DD, Casavant M, Spiller HA (June 2016). Seifert SA, Buckley N, Seger D, Thomas S, Caravati EM (eds.). "Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse?". Clinical Toxicology. 54 (5). McLean, VA: American Academy of Clinical Toxicology (AACT) / European Association of Poisons Centres and Clinical Toxicologist / Taylor & Francis: 420–423. doi:10.3109/15563650.2016.1157722. OCLC 8175535. PMID 26999038. S2CID 23149685.
  77. ^ a b Torralva R, Janowsky A (November 2019). Trew KD, Dodenhoff R, Vore M, Siuciak JA, Perry J, Wood C, Blumer J (eds.). "Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 371 (2). Rockville, Maryland, United States of America: American Society for Pharmacology and Experimental Therapeutics: 453–475. doi:10.1124/jpet.119.258566. LCCN sf80000806. OCLC 1606914. PMC 6863461. PMID 31492824. Archived from the original (PDF) on 9 March 2020. Retrieved 9 August 2021.
  78. ^ Petrou I (1 September 2016). Levine L, Tan TQ, Shippoli J (eds.). "Chest wall rigidity in fentanyl abuse: illicit fentanyl could be a major factor in sudden onset of this potentially lethal adverse event". Contemporary Pedriatics. 33 (9). Cranbury, New Jersey, United States of America: Intellisphere, LLC./ MJH Life Sciences (Multimedia Medical LLC). ISSN 8750-0507. OCLC 10956598. Retrieved 9 August 2021 – via Gale Academic OneFile.[permanent dead link‍]
  79. ^ Toledo A, Greene CM (17 July 2024). "Here's why fentanyl users on S.F.'s streets are bent over". San Francisco Chronicle.
  80. ^ "Fentanyl. Image 4 of 17". U.S. Drug Enforcement Administration. Archived from the original on 8 October 2018. photo illustration of 2 milligrams of fentanyl, a lethal dose in most people
  81. ^ Cheema E, McGuinness K, Hadi MA, Paudyal V, Elnaem MH, Alhifany AA, et al. (7 December 2020). "Causes, Nature and Toxicology of Fentanyl-Associated Deaths: A Systematic Review of Deaths Reported in Peer-Reviewed Literature". Journal of Pain Research. 13: 3281–3294. doi:10.2147/JPR.S280462. PMC 7732170. PMID 33324089.
  82. ^ "Fentanyl drug profile". European Monitoring Centre for Drugs and Drug Addiction. Archived from the original on 10 September 2022. Retrieved 10 September 2022.
  83. ^ Drummer OH (2019). "Fatalities caused by novel opioids: a review". Forensic Sciences Research. 4 (2): 95–110. doi:10.1080/20961790.2018.1460063. PMC 6609322. PMID 31304441.
  84. ^ "Narcan (Naloxone hydrochloride injection)". RxList. Archived from the original on 24 October 2019. Retrieved 3 March 2020.
  85. ^ "Fentanyl patches warning". Pharmaceutical Journal. Archived from the original on 8 April 2016. Retrieved 28 March 2016.
  86. ^ "MHRA warns about fentanyl patches after children exposed". Pharmaceutical Journal. Archived from the original on 9 April 2016. Retrieved 28 March 2016.
  87. ^ Katz J (2 September 2017). "The first count of Fentanyl deaths in 2016 – up 540% in three years". The New York Times. Archived from the original on 4 September 2017. Retrieved 4 September 2017.
  88. ^ Overdose Death Rates (Report). National Institute on Drug Abuse (NIDA). 29 January 2021. Archived from the original on 28 November 2015. Retrieved 22 November 2017.
  89. ^ "Reported law enforcement encounters testing positive for Fentanyl increase across U.S." (Press release). U.S. Centers for Disease Control and Prevention (CDC). 9 August 2021. Archived from the original on 2 March 2022. Retrieved 3 March 2022.
  90. ^ "Fentanyl Overdose". The Huffington Post. 20 May 2016. Archived from the original on 5 June 2016. Retrieved 4 June 2016.
  91. ^ Fentanyl-detected in illicit drug overdose deaths, January 1, 2012 to April 30, 2016 (PDF) (Report). British Columbia Coroners Service. Archived from the original (PDF) on 25 June 2016. Retrieved 9 June 2016.
  92. ^ "Fentanyl contributed to hundreds of deaths in Canada so far this year". Global News. 31 July 2017. Archived from the original on 14 September 2017. Retrieved 14 September 2017.
  93. ^ Scaccia A (9 October 2018). "How Fentanyl is contaminating America's cocaine supply". Rolling Stone. Archived from the original on 6 November 2018. Retrieved 5 November 2018.
  94. ^ Daly M (30 July 2019). "Exclusive data reveals just how often Fentanyl is in cocaine". Vice. Archived from the original on 24 January 2020. Retrieved 9 January 2020.
  95. ^ Chang A (3 December 2018). "What it means for the U.S. that China will label Fentanyl as 'a controlled substance'". All Things Considered. NPR. Archived from the original on 6 December 2018. Retrieved 6 December 2018.
  96. ^ "Fentanyl Flow to the United States" (PDF). U.S. Drug Enforcement Administration. January 2020. Archived (PDF) from the original on 30 September 2022. Retrieved 24 July 2019.
  97. ^ Grierson J (12 April 2020). "Coronavirus triggers UK shortage of illicit drugs". Society. The Guardian. Archived from the original on 9 May 2020. Retrieved 23 April 2020.
  98. ^ "Fentanyl citrate injection, USP" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on 31 October 2020. Retrieved 3 March 2019.
  99. ^ Gupta PK, Yadav SK, Bhutia YD, Singh P, Rao P, Gujar NL, et al. (1 August 2013). "Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice". Medicinal Chemistry Research. 22 (8): 3888–3896. doi:10.1007/s00044-012-0390-6. ISSN 1554-8120.
  100. ^ "Fentanyl". Drugbank. Archived from the original on 11 July 2017. Retrieved 18 January 2019.
  101. ^ a b Tanz LJ, Stewart A, Gladden RM, Ko JY, Owens L, O'Donnell J (December 2024). "Detection of Illegally Manufactured Fentanyls and Carfentanil in Drug Overdose Deaths - United States, 2021-2024". MMWR. Morbidity and Mortality Weekly Report. 73 (48): 1099–1105. doi:10.15585/mmwr.mm7348a2. PMC 11620336. PMID 39636782.
  102. ^ United Nations Office on Drugs and Crime (2023). World Drug Report 2023 (PDF). United Nations publication. p. 44. ISBN 9789210028233. The opioid crisis in North America has not been associated with a sizeable increase in the number of opioid users but driven by overdose deaths, mainly attributed to the use of fentanyls. In the United States in 2021, following a year-on-year trend of increase, there were more than 80,000 opioid overdose deaths. Most of those deaths, 70,000, were attributed to any pharmaceutical opioid with synthetic opioids (primarily fentanyls). Women constituted approximately 30 per cent of all those who died from an overdose and of those attributed to opioids in the United States.
  103. ^ Gaither JR (8 May 2023). "National Trends in Pediatric Deaths From Fentanyl, 1999-2021". JAMA Pediatrics. 177 (7): 733–735. doi:10.1001/jamapediatrics.2023.0793. PMC 10167597. PMID 37155161 – via JAMA Network. Fentanyl was implicated in 5194 of 13 861 (37.5%) fatal pediatric opioid poisonings between 1999 and 2021. Most deaths were among adolescents aged 15 to 19 years (89.6%) and children aged 0 to 4 years (6.6%). For all ages, 43.8% of deaths occurred at home, and 87.5% were unintentional. Coingestion of benzodiazepines was implicated in 17.1% of deaths [.]
  104. ^ Ross C (9 August 2017). "Are people really falling ill from touching fentanyl? In most cases, scientists say no". Stat News. Archived from the original on 7 August 2021. Retrieved 7 August 2021.
  105. ^ Bump P (15 July 2022). "Analysis | Why you're hearing so much about fentanyl these days". The Washington Post. Archived from the original on 15 July 2022. Retrieved 16 September 2022.
  106. ^ "Position Statement on Fentanyl Exposure". American College of Medical Toxicology (Press release). 18 July 2017. Archived from the original on 31 August 2018.
  107. ^ Thors L, Öberg L, Forsberg E, Wigenstam E, Larsson A, Bucht A (September 2020). "Skin penetration and decontamination efficacy following human skin exposure to fentanyl". Toxicology in Vitro. 67: 104914. Bibcode:2020ToxVi..6704914T. doi:10.1016/j.tiv.2020.104914. PMID 32540164. S2CID 219704174.
  108. ^ Herman PA, Brenner DS, Dandorf S, Kemp S, Kroll B, Trebach J, et al. (April 2020). "Media Reports of Unintentional Opioid Exposure of Public Safety First Responders in North America". Journal of Medical Toxicology. 16 (2): 112–115. doi:10.1007/s13181-020-00762-y. PMC 7099103. PMID 32096007.
  109. ^ Moss MJ, Warrick BJ, Nelson LS, McKay CA, Dubé PA, Gosselin S, et al. (April 2018). "ACMT and AACT position statement: preventing occupational fentanyl and fentanyl analog exposure to emergency responders". Clinical Toxicology. 56 (4): 297–300. doi:10.1080/15563650.2017.1373782. PMC 5711758. PMID 28872357.
  110. ^ Del Pozo B, Sightes E, Kang S, Goulka J, Ray B, Beletsky LA (November 2021). "Can touch this: training to correct police officer beliefs about overdose from incidental contact with fentanyl". Health & Justice. 9 (1): 34. doi:10.1186/s40352-021-00163-5. PMC 8612110. PMID 34817717.
  111. ^ "State Departments Issue Guidance Around Fentanyl Exposure". State of Tennessee. Archived from the original on 13 September 2022. Retrieved 16 September 2022.
  112. ^ Del Pozo B, Sightes E, Kang S, Goulka J, Ray B, Beletsky LA (November 2021). "Can touch this: training to correct police officer beliefs about overdose from incidental contact with fentanyl". Health & Justice. 9 (1): 34. doi:10.1186/s40352-021-00163-5. PMC 8612110. PMID 34817717.
  113. ^ Persaud E, Jennings CR (August 2020). "Pilot Study on Risk Perceptions and Knowledge of Fentanyl Exposure Among New York State First Responders". Disaster Medicine and Public Health Preparedness. 14 (4): 437–441. doi:10.1017/dmp.2019.95. PMID 31571559.
  114. ^ Mann B. "Cops say they're being poisoned by fentanyl. Experts say the risk is 'extremely low'". Archived from the original on 27 November 2023. Retrieved 27 November 2023.
  115. ^ "Increases in Fentanyl Drug Confiscations and Fentanyl-related Overdose Fatalities HAN 00384". Health Alert Network. U.S. Centers for Disease Control and Prevention. 15 October 2015. Archived from the original on 21 December 2022. Retrieved 21 December 2022.
  116. ^ "Rising Numbers of Deaths Involving Fentanyl and Fentanyl Analogs, Including Carfentanil, and Increased Usage and Mixing with Non-opioids – 00413". Health Alert Network (HAN). U.S. Centers for Disease Control and Prevention. 11 July 2018. Archived from the original on 21 December 2022. Retrieved 21 December 2022.
  117. ^ a b c "Increase in Fatal Drug Overdoses Across the United States Driven by Synthetic Opioids Before and During the COVID-19 Pandemic – HAN 00438 – Health Alert Network Advisory". U.S. Centers for Disease Control and Prevention (CDC). 17 December 2020. Archived from the original on 20 December 2022. Retrieved 21 December 2022.
  118. ^ "Fentanyl | CDC's Response to the Opioid Overdose Epidemic | CDC". U.S. Centers for Disease Control and Prevention (CDC). 2 October 2021. Archived from the original on 28 April 2022. Retrieved 27 April 2022.
  119. ^ a b c Yaksh T, Wallace M (2011). Goodman & Gilman's: The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill. ISBN 978-0-07-162442-8.
  120. ^ Katzung BG (2017). Basic & Clinical Pharmacology (14th ed.). New York, NY: McGraw-Hill. ISBN 978-1-259-64115-2. OCLC 1015240036.
  121. ^ "Commission on Narcotic Drugs takes decisive step to help prevent deadly fentanyl overdoses" (Press release). Commission on Narcotic Drugs, United Nations Office on Drugs and Crime. 16 March 2017. Archived from the original on 20 March 2017. Retrieved 19 March 2017.
  122. ^ Zawilska JB, Kuczyńska K, Kosmal W, Markiewicz K, Adamowicz P (March 2021). "Carfentanil – from an animal anesthetic to a deadly illicit drug". Forensic Science International. 320: 110715. doi:10.1016/j.forsciint.2021.110715. PMID 33581655. S2CID 231918983.
  123. ^ Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, et al. (February 1994). "Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors". Molecular Pharmacology. 45 (2): 330–334. PMID 8114680.
  124. ^ a b Suzuki J, El-Haddad S (February 2017). "A review: Fentanyl and non-pharmaceutical fentanyls". Drug and Alcohol Dependence. 171: 107–116. doi:10.1016/j.drugalcdep.2016.11.033. PMID 28068563.
  125. ^ "Fentanyl". www.drugbank.ca. Archived from the original on 11 July 2017. Retrieved 18 January 2019.
  126. ^ a b Butterworth IV JV, Wasnick JD, MacKey DC (21 August 2018). Morgan & Mikhail's Clinical Anesthesiology (6th ed.). New York, NY: McGraw-Hill Education. ISBN 978-1-259-83442-4. OCLC 1039081701.
  127. ^ Baselt, R. (2017) Disposition of Toxic Drugs and Chemicals in Man, 11th edition, Biomedical Publications, Foster City, CA, pp. 883–886.
  128. ^ Vandergrift GW, Hessels AJ, Palaty J, Krogh ET, Gill CG (April 2018). "Paper spray mass spectrometry for the direct, semi-quantitative measurement of fentanyl and norfentanyl in complex matrices". Clinical Biochemistry. 54: 106–111. doi:10.1016/j.clinbiochem.2018.02.005. PMID 29432758.
  129. ^ Vandergrift GW, Hessels AJ, Palaty J, Krogh ET, Gill CG (April 2018). "Paper spray mass spectrometry for the direct, semi-quantitative measurement of fentanyl and norfentanyl in complex matrices". Clinical Biochemistry. 54: 106–111. doi:10.1016/j.clinbiochem.2018.02.005. PMID 29432758. 10.25316/IR-4343.
  130. ^ Cunningham C (22 March 2023). "Fentanyl Test Strip Guidance" (PDF). State of New York. Archived (PDF) from the original on 19 April 2023. Retrieved 3 October 2023.
  131. ^ Lockwood TE, Vervoordt A, Lieberman M (March 2021). "High concentrations of illicit stimulants and cutting agents cause false positives on fentanyl test strips". Harm Reduction Journal. 18 (1): 30. doi:10.1186/s12954-021-00478-4. PMC 7941948. PMID 33750405.
  132. ^ Bergh MS, Øiestad ÅM, Baumann MH, Bogen IL (April 2021). "Selectivity and sensitivity of urine fentanyl test strips to detect fentanyl analogues in illicit drugs". The International Journal on Drug Policy. 90: 103065. doi:10.1016/j.drugpo.2020.103065. PMID 33333419.
  133. ^ Vardanyan RS, Hruby VJ (March 2014). "Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications". Future Medicinal Chemistry. 6 (4): 385–412. doi:10.4155/fmc.13.215. PMC 4137794. PMID 24635521.
  134. ^ Valdez CA (17 November 2022). "Gas Chromatography-Mass Spectrometry Analysis of Synthetic Opioids Belonging to the Fentanyl Class: A Review". Critical Reviews in Analytical Chemistry. 52 (8): 1938–1968. doi:10.1080/10408347.2021.1927668. PMID 34053394. S2CID 235255612.
  135. ^ "News: April 2022 – UNODC: Three precursors of the most common synthesis routes used in illicit fentanyl manufacture now under international control". www.unodc.org. Archived from the original on 15 November 2023. Retrieved 15 November 2023.
  136. ^ "Fentanyl Synthesis". GPTA India. 18 June 2020. Archived from the original on 28 December 2022.
  137. ^ "Synthesis of Fentanyl". Rhodium. Siegfried. Archived from the original on 5 August 2022. Retrieved 24 January 2023.
  138. ^ "Designation of Benzylfentanyl and 4-Anilinopiperidine, Precursor Chemicals Used in the Illicit Manufacture of Fentanyl, as List I Chemicals". Federal Register. 15 April 2020. Archived from the original on 5 November 2021. Retrieved 28 January 2023.
  139. ^ Gupta P (9 November 2005). "A Convenient One-Pot Synthesis of Fenta4nyl". ChemInform. 36 (49). doi:10.1002/chin.200549130. Archived from the original on 24 January 2023. Retrieved 24 January 2023.
  140. ^ "Fentanyl Profiling Program Report" (PDF). Drug Enforcement Administration. pp. 1–2. Archived (PDF) from the original on 25 January 2023. Retrieved 25 January 2023.
  141. ^ Braga FC, Ramos TO, Brocksom TJ, de Oliveira KT (November 2022). "Synthesis of Fentanyl under Continuous Photoflow Conditions". Organic Letters. 24 (45): 8331–8336. doi:10.1021/acs.orglett.2c03338. PMID 36346151. S2CID 253396263.
  142. ^ Suh YG, Cho KH, Shin DY (February 1998). "Total synthesis of fentanyl". Archives of Pharmacal Research. 21 (1): 70–2. doi:10.1007/BF03216756. PMID 9875518. S2CID 31408546.
  143. ^ López-Muñoz F, Alamo C (April 2009). "The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice". Brain Research Bulletin. 79 (2): 130–141. doi:10.1016/j.brainresbull.2009.01.005. PMID 19186209. S2CID 7720401.
  144. ^ Black J (March 2005). "A personal perspective on Dr. Paul Janssen" (PDF). Journal of Medicinal Chemistry. 48 (6): 1687–1688. doi:10.1021/jm040195b. PMID 15771410. Archived from the original (PDF) on 10 October 2007.
  145. ^ "Sublimaze- fentanyl citrate injection, solution". DailyMed. 21 April 2008. Retrieved 10 July 2024.
  146. ^ "Actiq- fentanyl citrate lozenge". DailyMed. 18 December 2023. Retrieved 10 July 2024.
  147. ^ "Fentanyl (sublimaze)". Clinical Pharmacology and Therapeutics. 9 (5): 704–706. September 1968. doi:10.1002/cpt196895704. PMID 5676808. S2CID 9743189.
  148. ^ Mandal A (11 April 2010). SRobertson S (ed.). "Fentanyl History". News-Medical.net. AZoNetwork. Archived from the original on 27 January 2023. Retrieved 27 January 2023.
  149. ^ "ACTIQ® (fentanyl citrate) oral transmucosal lozenge (1968 version revised in 2011)" (PDF). U.S. Food and Drug Administration (FDA). December 2011. Archived (PDF) from the original on 10 February 2017. Retrieved 26 December 2017.
  150. ^ a b "Questions and Answers about Onsolis (fentanyl buccal soluble film)". U.S. Food and Drug Administration (FDA). 16 July 2009. Archived from the original on 22 July 2017. Retrieved 26 December 2017.
  151. ^ "2022 Aggregate Production Quota History for Selected Substances" (PDF). Archived (PDF) from the original on 19 January 2023.
  152. ^ "Misuse of Drugs Act 1971". Archived from the original on 14 November 2012. Retrieved 22 March 2017.
  153. ^ "Opiumwet" [Opium Act]. Ministerie van Binnenlandse Zaken en Koninkrijksrelaties [Ministry of the Interior and Kingdom Relations] (in Dutch). Archived from the original on 19 January 2023. Retrieved 19 January 2023.
  154. ^ "RelayHealth's pharmacy connectivity network and reach, aligned with McKesson Specialty Care Solutions' REMS expertise, expands cancer patients' access to pain therapy". Atlanta. 20 January 2011. Archived from the original on 29 January 2016. Retrieved 5 November 2015.
  155. ^ Shelley S (22 April 2011). "With a few stumbles, REMS begins to hit its atride". Pharmaceutical Commerce. Archived from the original on 29 January 2016. Retrieved 5 November 2015.
  156. ^ "Procedures, programs and drugs that require precertification: Participating provider precertification list" (PDF). Aetna Inc. Archived from the original (PDF) on 9 July 2021. Retrieved 4 July 2021.
  157. ^ "Notice regarding precertification requirement" (PDF). BlueCross BlueShield of Arizona. 5 November 2007. Archived from the original (PDF) on 28 August 2008.
  158. ^ "Medications requiring precertification". Oxford Health Plans. Archived from the original on 15 October 2006.
  159. ^ "Canada's Controlled Drugs and Substances Act". Canada Justice Laws Website. Archived from the original on 28 September 2018. Retrieved 8 September 2018.
  160. ^ Naylor A (6 January 2020). "What we can learn from a tiny Baltic country's two-decade Fentanyl crisis". Vice. Archived from the original on 8 March 2021. Retrieved 31 January 2021.
  161. ^ Townsend M (1 December 2018). "Dark web dealers voluntarily ban deadly fentanyl". The Guardian. Archived from the original on 2 December 2018. Retrieved 3 December 2018.
  162. ^ "As fentanyl crisis grows, U.S.-Mexico divide deepens". The Washington Post. Archived from the original on 29 April 2023. Retrieved 1 May 2023.
  163. ^ Ducharme J (3 December 2018). "China has promised to crack down on Fentanyl. Here's what that could mean for overdose deaths in the U.S." Time. Archived from the original on 6 December 2018. Retrieved 6 December 2018.
  164. ^ Boddiger D (August 2006). "Fentanyl-laced street drugs "kill hundreds"". Lancet. 368 (9535): 569–570. doi:10.1016/S0140-6736(06)69181-2. PMID 16909503. S2CID 39788629.
  165. ^ "Synthetic drug fentanyl causes overdose boom in Estonia". BBC News Online. 30 March 2012. Archived from the original on 28 July 2018. Retrieved 21 June 2018.
  166. ^ a b "Fentanyl" (PDF). U.S. Drug Enforcement Administration. March 2015. Archived (PDF) from the original on 11 June 2016. Retrieved 2 June 2016.
  167. ^ a b "Mims B (11 November 2004). "Painkiller is topic of inquiry". The Salt Lake Tribune. Archived from the original on 24 December 2007.
  168. ^ Mars SG, Rosenblum D, Ciccarone D (May 2019). "Illicit fentanyls in the opioid street market: desired or imposed?". Addiction. 114 (5): 774–780. doi:10.1111/add.14474. PMC 6548693. PMID 30512204.
  169. ^ Centers for Disease Control Prevention (CDC) (July 2008). "Nonpharmaceutical fentanyl-related deaths—multiple states, April 2005 – March 2007" (PDF). MMWR Morb Mortal Wkly Rep. 57 (29): 793–6. PMID 18650786. Archived (PDF) from the original on 2 December 2022. Retrieved 2 December 2022.
  170. ^ "DEA Microgram Bulletin". Office of Forensic Sciences. Washington, DC: U.S. Drug Enforcement Administration. June 2006. Archived from the original on 21 July 2009. Retrieved 22 June 2009.
  171. ^ Tanner C (2016). "Thousands of fentanyl pills confiscated in Utah drug raid". The Salt Lake Tribune. Archived from the original on 24 November 2016. Retrieved 23 November 2016.
  172. ^ "Cottonwood Heights drug bust one of the largest in Utah history". Fox 13. 22 November 2016. Archived from the original on 23 November 2016. Retrieved 23 November 2016.
  173. ^ "U.S. border officers make largest-ever fentanyl bust: 254 pounds hidden under cucumbers". The Washington Post. 31 January 2019. Archived from the original on 8 June 2020. Retrieved 8 June 2020.
  174. ^ a b "List of Schedule I Drugs". U.S. Department of Justice. Archived from the original on 9 January 2010.
  175. ^ Kram TC, Cooper DA, Allen AC (October 1981). "Behind the identification of China White". Analytical Chemistry. 53 (12): 1379A–1386A. doi:10.1021/ac00235a003. PMID 7294353.
  176. ^ Van Bever WF, Niemegeers CJ, Janssen PA (October 1974). "Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4-piperidyl)-N-phenylpropanamide and N-(3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide". Journal of Medicinal Chemistry. 17 (10): 1047–1051. doi:10.1021/jm00256a003. PMID 4420811.
  177. ^ CDC Health Alert Network (20 June 2013). "Recommendations for Laboratory Testing for Acetyl Fentanyl and Patient Evaluation and Treatment for Overdose with Synthetic Opioids". U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 24 June 2013. Retrieved 20 June 2013.
  178. ^ Characteristics of Fentanyl overdose — Massachusetts, 2014–2016 (Report). U.S. Centers for Disease Control and Prevention (CDC). 14 April 2017.
  179. ^ Burgmann T (6 August 2015). "Lethal fentanyl profiting gangs in Western Canada while deaths climb". CTV News. Archived from the original on 17 July 2022. Retrieved 16 July 2022.
  180. ^ "Fentanyl doesn't discriminate, killing the homeless and young professionals". Edmonton Journal. 22 August 2015. Archived from the original on 20 December 2016.
  181. ^ Mangione K, Hasegawa R (9 December 2021). "2021 is now B.C.'s deadliest year in the opioid crisis, with 2 months of data left to collect". CTV News. Archived from the original on 25 December 2021. Retrieved 25 December 2021.
  182. ^ "Winnipeg Naloxone-distribution program could prevent fentanyl deaths". CBC News. Archived from the original on 31 May 2018. Retrieved 16 January 2018.
  183. ^ Cooper S, Bell S, Russell A (1 December 2018). "China won't stop flood of fentanyl into Canada, sources say". National. Global News. Canada. Archived from the original on 13 June 2021. Retrieved 21 July 2021.
  184. ^ Bonini T (13 October 2017). "Could fentanyl be Australia's next deadly drug epidemic?". ABC News (Australia). Archived from the original on 8 May 2018. Retrieved 6 April 2018.
  185. ^ "Fentanyl found at New Zealand festival". KnowYourStuffNZ. 20 March 2018. Archived from the original on 7 April 2018. Retrieved 6 April 2018.
  186. ^ Buchanan J (27 March 2018). "NZ's 'deadly' indifference to drug overdose antidote". HealthCentral NZ. Archived from the original on 7 April 2018. Retrieved 6 April 2018.
  187. ^ Feng E (17 November 2020). "'We Are Shipping To The U.S.': Inside China's Online Synthetic Drug Networks". NPR. Archived from the original on 1 October 2022. Retrieved 1 October 2022.
  188. ^ a b Felbab-Brown V (23 March 2022). "China and synthetic drugs control: Fentanyl, methamphetamines, and precursors". Brookings. Archived from the original on 23 September 2022. Retrieved 23 September 2022.
  189. ^ a b "Fentanyl Flow to the United States" (PDF). U.S. Drug Enforcement Administration. January 2020. Archived (PDF) from the original on 30 September 2022. Retrieved 4 October 2022.
  190. ^ Lo K (29 September 2022). "White House confirms China has stopped cooperating on anti-drug measures". South China Morning Post. Archived from the original on 1 October 2022. Retrieved 1 October 2022.
  191. ^ Beech H, Nang S (19 May 2020). "Raids reveal massive fentanyl production in Myanmar". The New York Times. Archived from the original on 8 June 2021. Retrieved 2 May 2021.
  192. ^ UNODC report: Opium production drops again in Myanmar as the synthetic drug market expands. UNODC (Myanmar) (Report). Archived from the original on 4 March 2021. Retrieved 2 May 2021.
  193. ^ "A California police union director is being charged with importing opioids, including fentanyl, disguised as chocolate and wedding favors". CNN. 31 March 2023. Archived from the original on 2 April 2023. Retrieved 2 April 2023.
  194. ^ "Cause of death: Washington faltered as fentanyl gripped America". The Washington Post. Archived from the original on 25 March 2023. Retrieved 2 April 2023.
  195. ^ "DEA zeroes in on China as fentanyl deaths soar – CBS News". CBS News. 10 May 2022. Archived from the original on 15 November 2023. Retrieved 15 November 2023.
  196. ^ "DHS Investigation Leads to Indictments Against China-Based Companies and Employees for Fentanyl Trafficking | Homeland Security". U.S. Department of Homeland Security. Archived from the original on 15 November 2023. Retrieved 15 November 2023.
  197. ^ "U.S. indicts major Chinese traffickers and three Americans for selling fentanyl online". Reuters. 17 October 2017. Archived from the original on 5 April 2023. Retrieved 4 April 2023.
  198. ^ "China's Role in Illicit Fentanyl Running Rampant on US Streets". trone.house.gov. 8 January 2023. Archived from the original on 16 February 2023. Retrieved 4 April 2023.
  199. ^ "Briefing on the Senate Foreign Relations Committee Countering Illicit Fentanyl Trafficking Hearing". Wilson Center. Archived from the original on 5 April 2023. Retrieved 4 April 2023.
  200. ^ "Felon Arrested for Attempting To Trade Fentanyl for Four Firearms". ATF.gov. 6 September 2023. Retrieved 16 December 2023.
  201. ^ "Treasury Sanctions Individuals Linked to CJNG's Arms Trafficking, Fuel Theft, and Money Laundering". home.treasury.gov. Retrieved 16 December 2023.
  202. ^ "Mexican drug cartels pay Americans to smuggle weapons across the border, intelligence documents show". CBS News. 18 September 2023. Retrieved 16 December 2023.
  203. ^ "Introducing Onsolis". Onsolis.com. Archived from the original on 22 July 2010. Retrieved 28 July 2010.
  204. ^ Instanyl (PDF) (Report). European Medicines Agency. Archived (PDF) from the original on 20 May 2012. Retrieved 28 July 2010.
  205. ^ "Abstral". Archived from the original on 14 July 2011. Retrieved 7 January 2011.
  206. ^ "Lazanda (fentanyl nasal spray) CII". Lazanda.com. Archived from the original on 25 April 2012. Retrieved 14 May 2012.
  207. ^ "Fentanyl". Drugs.com. Archived from the original on 16 June 2018. Retrieved 23 January 2018.
  208. ^ "Fentanyl Buccal". Archived from the original on 31 July 2020. Retrieved 27 May 2020.
  209. ^ "Fentanyl Citrate Generic Actiq". GoodRx. Archived from the original on 31 July 2020. Retrieved 27 May 2020.
  210. ^ "Fentanyl Prices, Coupons, Copay & Patient Assistance". Drugs.com. Archived from the original on 26 January 2023. Retrieved 26 January 2023.
  211. ^ Broadhurst R, Ball M, Trivedi H (February 2020). "Fentanyl availability on darknet markets" (PDF). p. 1. Archived (PDF) from the original on 26 January 2023. Retrieved 26 January 2023.
  212. ^ Lamy FR, Daniulaityte R, Barratt MJ, Lokala U, Sheth A, Carlson RG (June 2020). "Listed for sale: Analyzing data on fentanyl, fentanyl analogs and other novel synthetic opioids on one cryptomarket". Drug and Alcohol Dependence. 213: 108115. doi:10.1016/j.drugalcdep.2020.108115. PMC 7736148. PMID 32585419.
  213. ^ Office of the Commissioner (26 January 2022). "Accidental Exposures to Fentanyl Patches Continue to Be Deadly to Children". FDA. Archived from the original on 12 April 2022. Retrieved 12 April 2022.
  214. ^ a b "Disposal of Unused Medicines: What You Should Know". U.S. Food and Drug Administration (FDA). 1 February 2019. Archived from the original on 2 September 2019. Retrieved 2 September 2019.
  215. ^ "Safe Disposal of Fentanyl Patches". College of Pharmacists of British Columbia. 2019. Archived from the original on 2 September 2019. Retrieved 2 September 2019.
  216. ^ "Drug Disposal: Flush Potentially Dangerous Medicine (Flush list)". U.S. Food and Drug Administration (FDA). 19 December 2018. Archived from the original on 4 September 2019. Retrieved 2 September 2019.
  217. ^ Williams SE (1 March 2006). Hardcore History: The Extremely Unauthorized Story of ECW. Sports Publishing. p. 211. ISBN 978-1-59670-021-5.
  218. ^ Lisle A (14 May 2009). "Is Wilco's Jeff Tweedy Living the Life He Sings About?". Memphis Flyer. Retrieved 24 May 2009.
  219. ^ Kot G (23 June 2009). "Coroner: Painkiller killed ex-Wilco member". Chicago Tribune. Archived from the original on 25 June 2009. Retrieved 23 June 2009.
  220. ^ "Ex-Wilco guitarist died of a drug overdose, says coroner: Jay Bennett had been taking pain medication". NME. Archived from the original on 3 March 2016.
  221. ^ Crumb MJ (21 June 2010). "Slipknot bassist died of an overdose of morphine". MSNBC. Associated Press. Archived from the original on 24 June 2010. Retrieved 21 June 2010.
  222. ^ a b Eligon J, Kovaleski SF (2 June 2016). "Prince died from accidental overdose of opioid painkiller". The New York Times. Archived from the original on 5 August 2017. Retrieved 1 March 2017.
  223. ^ "Official: Mislabeled pills found at Prince's estate contained fentanyl". Chicago Tribune. 22 August 2016. Archived from the original on 22 August 2016. Retrieved 22 August 2016.
  224. ^ Mizoguchi K (3 February 2017). "Patton Oswalt reveals wife died due to prescription medications and undiagnosed heart condition". People. Archived from the original on 11 April 2018. Retrieved 5 November 2017.
  225. ^ McCartney A (3 February 2017). "Oswalt says heart condition, meds killed wife". Associated Press. Archived from the original on 30 April 2018. Retrieved 30 April 2018.
  226. ^ a b Kurucz J (18 June 2019). "Completing Vancouver musician's album cathartic for those he left behind". Vancouver Courier. Archived from the original on 21 October 2020. Retrieved 21 January 2020.
  227. ^ "Toxic combo of prescription drugs killed rapper". The New York Times. 8 December 2017. Archived from the original on 10 December 2017. Retrieved 9 December 2017.
  228. ^ Brown A (16 November 2017). "Lil Peep, hero to the emo and hip-hop scenes, dies of suspected overdose at 21". Los Angeles Times. Archived from the original on 18 November 2017. Retrieved 16 November 2017.
  229. ^ Coscarelli J (2018). "Tom Petty Died From Accidental Drug Overdose Involving Opioids, Coroner Says". The New York Times. ISSN 0362-4331. Archived from the original on 20 January 2018. Retrieved 20 January 2018.
  230. ^ "Mac Miller's cause of death: Accidental Fentanyl, cocaine overdose". Rolling Stone. 5 November 2018. Archived from the original on 5 November 2018. Retrieved 5 November 2018.
  231. ^ Paybarah A (3 October 2019). "'Mike's candyshop': Behind the overdose death of HQ Trivia's Colin Kroll". The New York Times. ISSN 0362-4331. Archived from the original on 3 October 2019. Retrieved 29 April 2021.
  232. ^ "Tyler Skaggs' autopsy: Fentanyl, oxycodone and alcohol led to death by choking on vomit". Los Angeles Times. 30 August 2019. Archived from the original on 30 August 2019. Retrieved 30 August 2019.
  233. ^ "Accidental overdose killed St. Paul rapper Lexii Alijai". MPR News. 28 January 2020. Archived from the original on 26 June 2021. Retrieved 26 June 2021.
  234. ^ Bernstein J (1 December 2020). "Justin Townes Earle death ruled an accidental drug overdose". Rolling Stone. Archived from the original on 9 November 2021. Retrieved 29 December 2020.
  235. ^ "Riley Gale, Singer for Thrash Metal Band Power Trip, Dead at 34". Rolling Stone. 25 May 2021. Archived from the original on 8 November 2021. Retrieved 19 May 2022.
  236. ^ Goffeney A. "Statement from a family member". Big Toe Rocks. Retrieved 18 August 2021.
  237. ^ Raferty M (14 March 2021). "PASSAGES: MARK GOFFENEY, 'BIG TOE' MUSICIAN WITHOUT ARMS". East County Magazine. Archived from the original on 18 February 2023. Retrieved 18 February 2023.
  238. ^ Atkinson K (10 June 2021). "Digital Underground's Shock G Cause of Death Revealed". Billboard. Archived from the original on 31 August 2022. Retrieved 16 July 2022.
  239. ^ Moshtaghian A (24 September 2021). "Michael K. Williams' cause of death determined by medical examiner". CNN. Archived from the original on 17 March 2022. Retrieved 8 March 2022.
  240. ^ Cordero R, Hipes P (24 September 2021). "Michael K. Williams' Died From Accidental Overdose, New York Medical Examiner Says". Deadline Hollywood. Archived from the original on 24 September 2021. Retrieved 24 September 2021.
  241. ^ "Coroner says rapper Coolio died at 59 from effects of several drugs". ABC7 Los Angeles. 6 April 2023. Archived from the original on 26 April 2023. Retrieved 15 June 2023.
  242. ^ Franklin M (21 September 2023). "Angus Cloud's Cause of Death Revealed: Actor Overdosed on Fentanyl, Cocaine and More". Variety. Archived from the original on 21 September 2023. Retrieved 25 September 2023.
  243. ^ "US child dies from fentanyl kept under nursery nap mat". BBC News. 19 September 2023. Archived from the original on 20 September 2023. Retrieved 20 September 2023.
  244. ^ Rawlinson K (22 March 2024). "Fentanyl poisoner jailed for at least 37 years for murder of couple in Essex". The Guardian.
  245. ^ a b "Nebraska first to use fentanyl in execution". BBC News. 14 August 2018. Archived from the original on 15 August 2018. Retrieved 15 August 2018.
  246. ^ "Nebraska becomes first state to use fentanyl in execution". NBC News. 14 August 2018. Archived from the original on 14 August 2018. Retrieved 15 August 2018.
  247. ^ a b "Nebraska carries out 1st execution using Fentanyl in U.S." National Public Radio. Archived from the original on 14 August 2018. Retrieved 15 August 2018.
  248. ^ "Nebraska will make history in its execution of a death row inmate". Newsweek. 14 August 2018. Archived from the original on 14 August 2018. Retrieved 15 August 2018.
  249. ^ a b "Fentanyl used to execute Nebraska inmate, in a first for U.S.". The New York Times. 14 August 2018. Archived from the original on 14 August 2018. Retrieved 15 August 2018.
  250. ^ a b "Nebraska executes inmate using powerful opioid fentanyl". PBS NewsHour. Public Broadcasting System. 14 August 2018. Archived from the original on 15 August 2018. Retrieved 15 August 2018.
  251. ^ Riches JR, Read RW, Black RM, Cooper NJ, Timperley CM (2012). "Analysis of clothing and urine from Moscow theatre siege casualties reveals carfentanil and remifentanil use". Journal of Analytical Toxicology. 36 (9): 647–656. doi:10.1093/jat/bks078. PMID 23002178.
  252. ^ "Gas 'killed Moscow hostages'". 27 October 2002. Archived from the original on 31 July 2017. Retrieved 7 April 2023.
  253. ^ "115 Hostages in Moscow Killed by Gas". The Washington Post. 27 October 2002. Archived from the original on 13 March 2007.
  254. ^ "Russia names Moscow siege gas". BBC News. 31 October 2002. Archived from the original on 19 June 2018. Retrieved 18 May 2018.
  255. ^ "How Opioids Were Used as Weapons During the Moscow Theater Hostage Crisis". 5 October 2023. Archived from the original on 15 November 2023. Retrieved 15 November 2023.
  256. ^ "Pricara recalls 25 mcg/hr Duragesic (Fentanyl transdermal system) c II pain patches". U.S. Food and Drug Administration (FDA). 12 February 2008. Archived from the original on 13 May 2008. Retrieved 10 May 2008.
  257. ^ "Teva Issues Voluntary Nationwide Recall of Specific Lots of FENTANYL Buccal Tablets CII to the Consumer Level" (PDF). Teva Pharmaceuticals USA, Inc. 27 April 2023.
  258. ^ "Teva Initiates Voluntary Nationwide Recall of Specific Lots of FENTANYL Buccal Tablets CII Due to a Labeling Error". Office of Regulatory Affairs. U.S. Food and Drug Administration. 28 April 2023. Archived from the original on 15 November 2023. Retrieved 15 November 2023.
  259. ^ Kukanich B, Clark TP (August 2012). "The history and pharmacology of fentanyl: relevance to a novel, long-acting transdermal fentanyl solution newly approved for use in dogs". Journal of Veterinary Pharmacology and Therapeutics. 35 (Suppl 2): 3–19. doi:10.1111/j.1365-2885.2012.01416.x. PMID 22731771.
  260. ^ Gutierrez-Blanco E, Victoria-Mora JM, Ibancovichi-Camarillo JA, Sauri-Arceo CH, Bolio-González ME, Acevedo-Arcique CM, et al. (May 2015). "Postoperative analgesic effects of either a constant rate infusion of fentanyl, lidocaine, ketamine, dexmedetomidine, or the combination lidocaine-ketamine-dexmedetomidine after ovariohysterectomy in dogs". Veterinary Anaesthesia and Analgesia. 42 (3): 309–318. doi:10.1111/vaa.12215. PMID 25039918.
  261. ^ Pettifer GR, Dyson DH (April 1993). "Comparison of medetomidine and fentanyl-droperidol in dogs: sedation, analgesia, arterial blood gases and lactate levels". Canadian Journal of Veterinary Research. 57 (2): 99–105. PMC 1263601. PMID 8490814.
  262. ^ Becker WM, Mama KR, Rao S, Palmer RH, Egger EL (April 2013). "Prevalence of dysphoria after fentanyl in dogs undergoing stifle surgery". Veterinary Surgery. 42 (3): 302–307. doi:10.1111/j.1532-950X.2012.01080.x. PMID 23231071.
  263. ^ Lee L. "Perioperative Pain Management" (PDF). p. 11. Archived (PDF) from the original on 19 January 2023. Retrieved 19 January 2023.
  264. ^ "Original new animal drug application: Recuvyra" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on 4 September 2015. Retrieved 22 September 2014.
  265. ^ "Recuvyra". European Medicines Agency. Archived from the original on 4 March 2016. Retrieved 28 March 2016.

Further reading

[edit]
[edit]
Listen to this article (24 minutes)
Spoken Wikipedia icon
This audio file was created from a revision of this article dated 1 December 2011 (2011-12-01), and does not reflect subsequent edits.
(Audio help · More spoken articles)
Wikimedia Commons has media related to Fentanyl.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fentanyl&oldid=1265505259#Patches"