Fentanyl: Difference between revisions

Fentanyl

Clinical data
Pronunciation	/ˈfɛntənɪl/ or /ˈfɛntənəl/
Trade names	Actiq, Duragesic, Fentora, others
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN
Pregnancy category	AU: C
Dependence liability	High[1]
Routes of administration	Buccal, epidural, IM, IT, IV, sublingual, skin patch
Drug class	Opioid
ATC code	N01AH01 (WHO) N02AB03 (WHO)
Legal status
Legal status	AU: S8 (Controlled drug) CA: Schedule I DE: Anlage III (Special prescription form required) UK: Class A US: WARNING[2]Schedule II
Pharmacokinetic data
Bioavailability	92% (transdermal) 89% (intranasal) 50% (buccal) 33% (ingestion) 100% intramuscular
Protein binding	80–85%
Metabolism	Liver, primarily by CYP3A4
Onset of action	5 minutes[3]
Elimination half-life	IV: 6 mins (T1/2 α) 1 hours (T1/2 β) 16 hours (T1/2 ɣ) Intranasal: 6.5 hours Transdermal: 20–27 hours[4] Sublingual/buccal (single dose): 2.6–13.5 hours[4]
Duration of action	IV: 30–60 minutes[3][5]
Excretion	Mostly urinary (metabolites, <10% unchanged drug)[4]
Identifiers
IUPAC name N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide
CAS Number	437-38-7 Y
PubChem CID	3345
IUPHAR/BPS	1626
DrugBank	DB00813 Y
ChemSpider	3228 Y
UNII	UF599785JZ
KEGG	D00320 Y
ChEBI	CHEBI:119915 Y
ChEMBL	ChEMBL596 Y
CompTox Dashboard (EPA)	DTXSID9023049
ECHA InfoCard	100.006.468
Chemical and physical data
Formula	C22H28N2O
Molar mass	336.471 g·mol−1
3D model (JSmol)	Interactive image
Density	1.1 g/cm3
Melting point	87.5 °C (189.5 °F)
SMILES O=C(CC)N(C1CCN(CC1)CCc2ccccc2)c3ccccc3
InChI 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 Y Key:PJMPHNIQZUBGLI-UHFFFAOYSA-N Y
(verify)

Fentanyl, also spelled fentanil, is a synthetic opioid used as a pain medication and together with other medications for anesthesia.^[6][4] Fentanyl is also used as a recreational drug, often mixed with heroin or cocaine.^[7] It has a rapid onset and its effects generally last less than two hours.^[4] Medically, fentanyl is used by injection, as a patch on the skin, as a nasal spray, or in the mouth.^[4]

Common side effects include vomiting, constipation, sedation, confusion, hallucinations, and injuries related to poor coordination.^[4][8] Serious side effects may include decreased breathing (respiratory depression), serotonin syndrome, low blood pressure, addiction, or coma.^[4][8] Fentanyl works primarily by activating μ-opioid receptors.^[4] It is around 100 times stronger than morphine, and some analogues such as carfentanil are around 10,000 times stronger.^[9]

Fentanyl was first made by Paul Janssen in 1960 and approved for medical use in the United States in 1968.^[4][10] In 2015, 1,600 kilograms (3,500 lb) were used in healthcare globally.^[11] As of 2017^[update], fentanyl was the most widely used synthetic opioid in medicine.^[12] Fentanyl patches for cancer pain are on the WHO List of Essential Medicines, which lists the most effective and safe medicines needed in a health system.^[13] For a 100 microgram vial, the average wholesale cost in the developing world was US$0.66 in 2015.^[14] In 2017, the price in the United States was US$0.49 for that same amount.^[15] In 2016, it was the 218th most prescribed medication in the United States, with more than 2 million prescriptions.^[16] In 2016, fentanyl and analogues were the most common cause of overdose deaths in the United States at more than 20,000, about half of all opioid-related deaths.^[17][18][19] Most of these overdose deaths were due to illegally made fentanyl.^[20]

Intravenous fentanyl is often used for anesthesia and analgesia.^[21] It is also administered in combination with a benzodiazepine, such as midazolam, to produce sedation for procedures such as endoscopy, cardiac catheterization, and oral surgery, or in emergency rooms.^[22][23] During anesthesia in surgery, it is often used along with a hypnotic agent like propofol.^[24]

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.^[25] However, it's widely used in obstetrical anesthesia because of its short time to action peak (about 5 min), the rapid termination of its effect after a single dose, and the occurrence of relative cardiovascular stability.^[26] In obstetrics, the dose must be closely regulated in order to prevent large amounts of transfer from mother to fetus. At high doses, the drug may act on the fetus to cause postnatal respiratory distress.^[26]

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, and 200 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.^[27]

In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.^[28]

USAF Pararescue combat medics in Afghanistan use fentanyl lozenges in the form of lollipops on combat casualties from IED blasts and other trauma.^[29] 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 let the lollipop fall from the mouth, indicating sufficient analgesia and somewhat reducing the likelihood of overdose and associated risks.^[29]

It is also used in the management of chronic pain including cancer pain.^[30] Often, transdermal patches are used.^[31] The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours, allowing for long-lasting pain management.^[32] Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature.^[32] 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. 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.^[32] Yet, it is unclear if fentanyl gives long-term pain relief to people with neuropathic pain.^[33]

Sublingual fentanyl solves quickly and is absorbed through the sublingual mucosa to provide rapid analgesia.^[34] Fentanyl is a highly lipophilic compound,^[34][35] which is well absorbed sublingually and generally well tolerated.^[34] Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration and severe in intensity.^[36]

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.
• troublesome side effects of oral morphine, hydromorphone, or oxycodone.^{[citation needed]}

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 of too much medications and cause potentially deadly complications.

The fentanyl patch is one of a few medications that may be especially harmful, and in some cases fatal, with just one dose, if used by someone other than the person for whom the medication was prescribed.^[37] Unused fentanyl patches should 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 which is then returned to a pharmacy.^[38] 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 them from ingestion by children, pets or others not intended to use them.^[37][39]

Some routes of administration such as nasal sprays and inhalers generally result in 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 as equally effective as IV morphine and superior to intramuscular morphine for management of acute hospital pain.^[28]

A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow people to control administration of fentanyl through the skin to treat postoperative pain.^[40]

Fentanyl's most common side effects (more than 10% of people) include diarrhea, nausea, constipation, dry mouth, somnolence, confusion, asthenia (weakness), sweating, and less frequently (3 to 10% of people) abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, hallucinations, anxiety, depression, flu-like symptoms, dyspepsia (indigestion), shortness of breath, hypoventilation, apnoea, and urinary retention. Fentanyl use has also been associated with aphasia.^[42]

Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, than morphine.^[43]

Sustained release fentanyl preparations, such as patches, may produce unexpected delayed respiratory depression.^[44][45][46] 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 causing cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces 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.

The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context.^{[47][48][49][50]} In 2006, the U.S. 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.^[51] The FDA reported in April 2012 that twelve young children had died and twelve more made seriously ill from separate accidental exposures to fentanyl skin patches.^[52]

Fentanyl has a therapeutic index of 270.^[53]

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,^[55] 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.^[56]

In the US, fentanyl and fentanyl analogs caused over 29,000 deaths in 2017, a large increase over the previous four years.^[57][41]

Death from fentanyl overdose was declared a public health crisis in Canada in September 2015, and it continues to be a significant public health issue.^[58] In 2016, deaths from fatal fentanyl overdoses in British Columbia, Canada, averaged two persons per day.^[59] In 2017 the death rate rose over 100% with 368 overdose related deaths in British Columbia between January and April 2017.^[60]

Fentanyl has started to make its way into heroin and oxycodone, and more recently, cocaine.^[61] 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. Fentanyl is often produced in China and exported illegally to the U.S.^[62][63]

As of 2018 fentanyl was the most commonly listed opioid in overdose drug deaths, surpassing heroin. Between 2013–2016 overdose deaths involving fentanyl increased 113% per year.^[64]

The intravenous dose causing 50% of 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."^[65] 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.^[66] The LD₅₀ in humans is unknown,^[67][68] but a lethal dose for the average person is estimated to be 2 mg.^[54][69]

Fentanyl is a synthetic opioid in the phenylpiperidine family, which includes sufentanil, alfentanil, remifentanil, and carfentanil.^[6][71]

Fentanyl provides some of the effects typical of other opioids through its agonism of the opioid receptors. As a Mu-receptor agonist, it binds 50 to 100 times more strongly than morphine.^[72] Fentanyl 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.^[6][43]

Fentanyl binds to opioid receptors⁠ ⁠— G-protein coupled receptors (GPCR) which regulate synaptic transmission. Binding of fentanyl activates the GPCR which initiates signalling to result in the inhibition of the release of nociceptive neurotransmitters. 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.^[72][73]

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. 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.^[74] Paper spray-mass spectrometry (PS-MS) may be useful for initial testing of samples.^[75][76]

Fentanyl was first synthesized in Belgium by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959.^[77] It was developed by screening chemicals similar to pethidine (meperidine) for opioid activity.^[78] 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).^[79] Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by McNeil Laboratories under the trade name Sublimaze.^[80]

In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formation of an inert alcohol gel infused with select fentanyl doses, which are worn to provide constant administration of the opioid over a period of 48 to 72 hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.

Following the patch, a flavoured lollipop of fentanyl citrate mixed with inert fillers was introduced in 1998 under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain.^[81]

In 2009, the US Food and Drug Administration approved Onsolis (fentanyl buccal soluble film), a fentanyl drug in a new dosage form for cancer pain management in opioid-tolerant subjects.^[82] 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.^[82]

Fentanyl has a US DEA ACSCN of 9801 and a 2013 annual aggregate manufacturing quota of 2,108.75 kg, unchanged from the prior year.

In the UK, fentanyl is classified as a controlled Class A drug under the Misuse of Drugs Act 1971.^[83]

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

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.^[84][85] In order to curb misuse, many health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.^[86][87][88]

In Canada, fentanyl is considered a Schedule I drug as listed in Canada's Controlled Drugs and Substances Act.^[89]

A 2018 report by The Guardian indicated that many major drug suppliers on the dark web have voluntarily banned the trafficking of fentanyl.^[90]

The US Food and Drug Administration (FDA) has issued public health advisories related to fentanyl patch dangers. Among these, in July 2005, the FDA issued a Public Health Advisory,^[91] which advised that "deaths and overdoses have occurred in patients using both the brand name product Duragesic and the generic product." In December 2007, as part of this continuing investigation, the FDA issued a second Public Health Advisory^[91] stating, "The FDA has continued to receive reports of deaths and life-threatening side effects in patients who use the fentanyl patch. The reports indicate that doctors have inappropriately prescribed the fentanyl patch... In addition, the reports indicate that patients are continuing to incorrectly use the fentanyl patch..."

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.^[92] The biological effects of the fentanyl analogues are similar to those of heroin, although often with less euphoria and stronger sedative and analgesic effects.^{[citation needed]}

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, sometimes leading to overdoses. Many fentanyl overdoses are initially classified as heroin overdoses.^[93] The recreational use is not particularly widespread in the EU with the exception of 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.^[94]

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.^[95]

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.^[96] 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".^[96]

Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.^[95] 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.^[97]

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; Detroit; and Philadelphia.^[98]

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.^[100][101] A seizure of a record amount of fentanyl occurred on February 2, 2019 by U.S. Customs and Border Protection in Nogales, Arizona.^[102] The 254 pounds (115 kg) of fentanyl, which was estimated to be worth US$3.5M, was buried under a pile of cucumbers and stowed under a special floor compartment.

The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF).^[103] One US Department of Justice publication lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,^[104] which today are classified as Schedule I drugs in the United States.^[103] 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.^[105]

In June 2013, the United States Centers for Disease Control and Prevention (CDC) issued a health advisory^[106] 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.^[107]

Beginning in 2015, Canada has seen a number of 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.^[108] Traces of the drug have also been found in other recreational drugs including cocaine, MDMA, and heroin. The drug has been implicated in multiple deaths from the homeless to young professionals, including multiple teens and young parents.^[109] Because of the rising deaths across the country, especially in British Columbia where the deaths for 2016 is 668 and deaths for 2017 (January to October) is 999,^[110]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.^[111]

Fentanyl has been discovered for sale in illicit markets in Australia in 2017^[112] and in New Zealand in 2018.^[113] In response, New Zealand experts called for wider availability of naloxone.^[114]

In February 2004, a leading fentanyl supplier, Janssen Pharmaceutica Products, L.P., recalled one lot, and later, additional lots of fentanyl (brand name: Duragesic) patches because of seal breaches which 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 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.^[115]

In February 2011, the manufacturer suspended production of all Duragesic patches due to quality control issues involving unspecified "microscopic crystallization" detected during the manufacturing process of the 100 µg/h strength.^{[citation needed]}

Brand names include Sublimaze,^[42] Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis,^[116] Instanyl,^[117] Abstral,^[118] Lazanda^[119] and others.^[120] Subsys is a sublingual spray of fentanyl manufactured by Insys Therapeutics.^[121]

The wholesale cost in the developing world as of 2015^[update] is between US$0.08 and US$0.81 per 100 microgram vial.^[14] In the United States this amount costs about US$0.40 as of 2017^[update].^[15] In the United States the patches cost US$11.22 for a 12 µg/hr version and US$8.74 for a 100 µg/hr version.^[15]

Medical examiners concluded that musician Prince died on April 21, 2016, from an accidental fentanyl overdose.^[122] Fentanyl was among many substances identified in counterfeit pills recovered from his home, especially some that were mislabeled as Watson 385, a combination of hydrocodone and paracetamol.^[122][123] American rapper Lil Peep also died of an accidental fentanyl overdose on November 15, 2017.^[124][125] On January 19, 2018, the medical examiner-coroner for the county of Los Angeles said 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.^[126] Additionally in 2018, American rapper Mac Miller died from an accidental overdose of fentanyl, cocaine and alcohol.^[127]

Russian Spetsnaz security forces used a fentanyl analogue or derivative to incapacitate people rapidly in the Moscow theater hostage crisis in 2002. The siege was ended, but about 130 of the 850 hostages died from the gas. The Russian Health Minister later stated that the gas was based on fentanyl,^[128] but the exact chemical agent has not been identified.

In August 2018, the United States used fentanyl for the first time to execute a prisoner.^{[129][130][131]} Carey Dean Moore, at the time one of the United States' longest-serving death row inmates,^[132] 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.^[133][134]

The use of fentanyl in execution caused concern among death penalty experts because it was part of a previously untested drug cocktail.^[129][131] The execution was also protested by anti-death penalty advocates at the prison during the execution and later at the Nebraska capitol building.^[133][134]

Fentanyl in injectable formulation is commonly used for analgesia and as a component of balanced sedation and general anesthesia in small animal patients. Its potency and short duration of action make it particularly useful in critically ill patients. In addition, it tends to cause less vomiting and regurgitation than other pure-opiate (codeine, morphine) and synthetic pure-opioid agonists (oxycodone, hydromorphone) when given as a continuous post-operative infusion. As with other pure-opioid agonists, fentanyl can be associated with dysphoria in both dogs and cats.

Transdermal fentanyl has also been used for many years in dogs and cats for post-operative analgesia. 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, trade name Recuvyra, has become commercially available for dogs only. It is FDA approved to provide four days of analgesia after a single application prior to surgery. It is not approved for multiple doses or other species.^[135] The drug is also approved in Europe.^[136]

• List of fentanyl analogues

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• National Institute of Health (NIH) Medline Plus: Fentanyl Buccal (Transmucosal)
• US DEA information: Fentanyl
• Fentanyl: Emergency Response Database. National Institute for Occupational Safety and Health
• U.S. National Library of Medicine: Drug Information Portal – Fentanyl