Fentanyl

Fentanyl
Clinical data
Trade names Actiq, Duragesic, Fentora, others
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Dependence
liability		 Very high
Routes of
administration		 TD, IM, IV, oral transmucosal, sublingual, buccal
ATC code N01AH01 (WHO) N02AB03 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 92% (transdermal)
89% (intranasal)
50% (buccal)
33% (ingestion)
Protein binding 80–85%
Metabolism hepatic, primarily by CYP3A4
Onset of action 5 min[1]
Biological half-life IV: 10–20 mins (T1/2 β)
2–4 hours (T1/2 ɣ)
Intranasal: 6.5 mins
Transdermal: 20–27 h[2]
Sublingual/buccal (single dose): 5.4–6.3 h[3]
Duration of action IV: 30–60 minutes[4]
30–40 min[1]
Excretion 60% urinary (metabolites, <10% unchanged drug)[5]
Identifiers
CAS Number 437-38-7 YesY
PubChem (CID) 3345
IUPHAR/BPS 1626
DrugBank DB00813 YesY
ChemSpider 3228 YesY
UNII UF599785JZ YesY
KEGG D00320 YesY
ChEBI CHEBI:119915 YesY
ChEMBL CHEMBL596 YesY
ECHA InfoCard 100.006.468
Chemical and physical data
Formula C22H28N2O
Molar mass 336.471 g/mol
3D model (Jmol) Interactive image
Melting point 87.5 °C (189.5 °F)
  (verify)
Listen to this article (info/dl)


This audio file was created from a revision of the "Fentanyl" article dated 2011-12-01, and does not reflect subsequent edits to the article. (Audio help)
More spoken articles

Fentanyl (also known as fentanil) is a potent, synthetic opioid pain medication with a rapid onset and short duration of action.[6] It is a strong agonist at the μ-opioid receptors. Fentanyl is estimated to be between 50 and 100 times as potent as morphine.[7]

Fentanyl was first made by Paul Janssen in 1960,[8] following the medical inception of pethidine (also known as meperidine, marketed as Demerol) several years earlier. Janssen developed fentanyl by assaying analogues of the structurally related drug pethidine for opioid activity.[9] The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1 stoichiometry),[10] which entered medical use as a general anaesthetic under the trade name Sublimaze in the 1960s. Following this, many other fentanyl analogues were developed and introduced into medical practice, including sufentanil, alfentanil, remifentanil, and lofentanil.

In the mid-1990s, fentanyl was introduced for palliative use with the fentanyl patch, followed in the next decade by the introduction of the fentanyl lollipop, dissolving tablets, and sublingual spray which are resorbed through the skin inside the mouth.[11][12] As of 2012 fentanyl was the most widely used synthetic opioid in medicine.[13] In 2013, 1700 kilograms were used globally.[14]

Fentanyl is also used as a recreational drug, and this use has led to thousands of overdose deaths each year from 2000 to 2015.[15][16] Deaths have also resulted from improper medical use.[17] Fentanyl has a relatively wide therapeutic index (270)[18] which makes it a very safe surgical anesthetic when monitored carefully; however, its extreme potency requires careful measurements of highly diluted fentanyl in solution; attempting to accurately measure a dose of pure fentanyl powder is impractical without advanced scientific equipment as an effective dose and a lethal dose of fentanyl powder placed next to each other would be difficult or impossible to differentiate with the naked eye.

Medical uses

Intravenous

Intravenous fentanyl is often used for anesthesia and analgesia. During anaesthesia it is often used along with a hypnotic agent like propofol. Fentanyl may be included in a solution along with local anesthetic for neuraxial administration (epidural or intrathecal/spinal). 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. It is often used in the management of chronic pain including cancer pain.

Patches

A fentanyl patch from Israel

Fentanyl transdermal patches (Durogesic/Duragesic) are used in chronic pain management. The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours, allowing for long-lasting pain management.[19] Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature.[19] 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 opiate (such as morphine or oxycodone) to handle breakthrough pain.[19]

It is unclear if fentanyl gives pain relief to people with neuropathic pain.[20]

In palliative care, transdermal fentanyl has a definite, but limited, role for:

Care must be taken to guard against the application of external heat sources (such as direct sunlight, heating pads, etc.) which in certain circumstances can trigger the release of too much medication and cause life-threatening complications.

Duragesic was first approved by the College ter Beoordeling van Geneesmiddelen, the Medicines Evaluation Board in the Netherlands, on 17 July 1995 as 25, 50, 75 and 100 µg/h formulations after a set of successful clinical trials, and on October 27, 2004 the 12 µg/h formulation was approved as well. On Jan 28, 2005, the U.S. Food and Drug Administration approved first-time generic formulations of 25, 50, 75, and 100 µg/h fentanyl transdermal systems (made by Mylan Technologies, Inc.; brand name Duragesic, made by Alza Corp.) through an FTC consent agreement derailing the possibility of a monopoly in the treatment of Breakthrough Chronic Pain by Alza Corp. In some cases, physicians instruct patients to apply more than one patch at a time, giving a much wider range of possible dosages. For example, a patient may be prescribed a 37.5 µg dosage by applying one 12 µg patch and one 25 µg patch simultaneously, or contingent on the large size of the (largest) 100 μg/h patch, multiple patches are commonly prescribed for doses exceeding 100μg/h, such as two 75 μg/h patches worn to afford a 150 μg/h dosage regimen. Although the commonly referred to dosage rates are 12/25/50/75/100 µg/h, the "12 µg" patch actually releases 12.5 µg/h.[21] It is designed to release half the dose of the 25 µg/h dose patch.

Duragesic is manufactured by ALZA Corporation and marketed by Janssen Pharmaceutica (both subsidiaries of Johnson & Johnson). During the period of June 2002 through June 2003, Duragesic sales totaled over one billion.

As of July 2009, construction of the Duragesic patch had been changed from the gel pouch and membrane design to "a drug-in-adhesive matrix designed formulation", as described in the prescribing information.[21] This construction makes illicit use of the fentanyl more difficult.

Storage and Disposal

The fentanyl patch is one of a small number of drugs 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 drug was prescribed.[22] Unused fentanyl patches should be kept in a secure location that is out of children’s sight and reach, such as a locked cabinet.

When they cannot be disposed of through a drug take-back program, flushing is recommended for fentanyl patches because it is the fastest and surest way to remove them from the home so they cannot harm children, pets, and others who were not intended to use them.[22][23][24]

Recalls

In February 2004, a leading fentanyl supplier, Janssen Pharmaceutica Products, L.P. recalled one lot of fentanyl (brand name: Duragesic) patches because of seal breaches which may allow the drug to leak from the patch. Janssen also later recalled additional lots; a series of Class II Recalls were then initiated in March 2004 due to a potentially life-threatening manufacturing defect.

The 25 µg/h Duragesic patches manufactured by ALZA Corporation were also recalled in February 2008 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.[25]

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.

Intranasal

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 micrograms. 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 around 900 out-of-hospital patients.[26]

In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.[27]

Sublingual

Abstral dissolves quickly and is absorbed through the sublingual mucosa to provide rapid analgesia.[28] Fentanyl is a highly lipophilic compound,[28][29] which is well absorbed sublingually[28] and generally well tolerated.[28] Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration and severe in intensity.[30]

Lozenges

Package and example of fentanyl lollipop (brand: Actiq), 400 micrograms.

Fentanyl lozenges (Actiq) are a solid formulation of fentanyl citrate on a stick in the form of a lollipop that dissolves slowly in the mouth for transmucosal absorption. These lozenges are intended for opioid-tolerant individuals and are effective in treating breakthrough cancer pain.[31] It has also been used for breakthrough pain for patients with nonmalignant (not cancer related) pain, but this application is controversial.[32] The unit is a berry-flavored lozenge on a stick swabbed on the mucosal surfaces inside the mouth — inside of the cheeks, under and on the tongue and gums — to release the fentanyl quickly into the system. It is most effective when the lozenge is consumed within 15 minutes. About 25% of the drug is absorbed through the oral mucosa, resulting in a fast onset of action, and the rest is swallowed and absorbed in the small intestine, acting more slowly. The lozenge is less effective and acts more slowly if swallowed as a whole, as despite good absorbance from the small intestine there is extensive first-pass metabolism, leading to an oral bioavailability of about 33% as opposed to 50% when used correctly (25% via the mouth mucosa and 25% via the gut).[31]

However, most people find that it takes 10–15 minutes to use all of one lozenge, and those with a dry mouth cannot use this route. In addition, medical personnel are unable to document how much of a lozenge has been used by a person, making drug records inaccurate.

Actiq is produced by the pharmaceutical company Cephalon on a plastic stick that dissolves slowly in the mouth for absorption across the buccal mucosa, in a manner similar to sublingual buprenorphine/naloxone film strips. An Actiq lozenge contains 2 grams of sugar[33] (8 calories). Actiq has been linked to dental decay, with some users who previously had no dental issues, having had teeth loss and in the U.S many users have started their own Facebook page in educating users to the severe dental issues caused by the so-called fentanyl lollipops. CBS News reported the issue 28 September 2009. The status of a sugar-free version, called Actiq-SF, is unclear. Since the release of Fentora—an effervescent buccal fentanyl tablet for breakthrough cancer pain—Cephalon has indefinitely postponed plans to release a sugar free version of Actiq.

Beginning late September, 2006, a generic "oral transmucosal fentanyl citrate" has been available, made by Barr Pharmaceuticals.[34]

The United States Air Force Pararescue and Swedish armed forces combat medics utilize lollipops with fentanyl.[35] Navy corpsmen working with the United States Marine Corps in Afghanistan use Fentanyl lollipops on combat casualties from IED blasts and other mechanisms of injury. The lollipop is taped to the casualty's finger and inserted in between the teeth and cheek (buccal area) of the patient. When enough of the medication has been absorbed the finger will generally fall from the patient's mouth, thereby indicating that the medication has become effectively administered.

Other

A wide range of fentanyl preparations are available, including buccal tablets or patches, nasal sprays, inhalers, and active transdermal patches (heat or electrical). Some preparations such as nasal sprays and inhalers may result in a rapid response, but the fast onset of high blood levels may compromise safety. In addition, the expense of some of these appliances may greatly reduce their cost-effectiveness. In children it is unclear if intranasal fentanyl is as good as or the same as morphine.[36]

Fentanyl is sometimes given intrathecally as part of spinal anesthesia or epidurally for epidural anesthesia 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.

A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow patients to control administration of fentanyl through the skin during the treatment of perioperative pain.[37]

The Danish Army uses the fentanyl stick in military operations as a painkiller. The war documentary Armadillo (2010) features an interview with a Danish medic who tells of using fentanyl on a severely wounded soldier in Afghanistan.

Adverse effects

Fentanyl's most common side effects (more than 10% of patients) include diarrhea, nausea, constipation, dry mouth, somnolence, confusion, asthenia (weakness), sweating, and less frequently (3 to 10% of patients) abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, hallucinations, anxiety, depression, flu-like symptoms, dyspepsia (indigestion), dyspnea (shortness of breath), hypoventilation, apnea, and urinary retention. Fentanyl use has also been associated with aphasia.[38]

Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, in relation to morphine.[39]

Fentanyl may produce more prolonged respiratory depression than other opioid analgesics.[40][41][42][43][44][45][46] 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.[47] 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.[48]

The precise reason for sudden respiratory depression is unclear, but there are several hypotheses:

Fentanyl has a therapeutic index of 270.[18]

Overdose

In July 2014, the Medicines and Healthcare Products Regulatory Agency (MHRA) issued a warning about the potential for life-threatening harm from accidental exposure to transdermal fentanyl patches, particularly in children,[49] 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.[50]

Death from fentanyl overdose was declared a public health crisis in Canada in September 2015, and it continues to be a major killer drug.[51] In 2016, deaths from fatal fentanyl overdoses in British Columbia, Canada, averaged two persons per day.[52]

Medical examiners concluded that musician Prince died in April 2016 from an accidental fentanyl overdose. The drug was among many identified in counterfeit pills recovered from his home, especially some that were mislabeled as Watson 385, a combination of hydrocodone and paracetamol.[53][54]

Pharmacology

Fentanyl provides some of the effects typical of other opioids through its agonism of the opioid receptors. Its strong potency in relation to that of morphine is largely due to its high lipophilicity, per the Meyer-Overton correlation. Because of this, it can more easily penetrate the CNS.[39]

History

Fentanyl was first synthesized by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959.[55] In the 1960s, fentanyl was introduced as an intravenous anesthetic under the trade name of Sublimaze. 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 flavored lollipop of fentanyl citrate mixed with inert fillers was introduced under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain. Fentanyl has been developed into an effervescent tab for buccal absorption much like the Actiq lollipop, followed by a buccal spray device for fast-acting relief and other delivery methods currently in development.

A fentanyl product has been approved by the US Food and Drug Administration (FDA) for breakthrough cancer pain called Onsolis. It uses a drug delivery technology called BEMA (fentanyl buccal soluble film) on a small disc placed in the mouth. Unlike many other fentanyl products, the drug cannot be abused by crushing and inhaling.

Fentanyl has a US DEA ACSCN of 9801 and a 2013 annual aggregate manufacturing quota of 2108.75 kilos, unchanged from the prior year.

Society and culture

Brand names

Brand names include Sublimaze,[38] Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis,[56] Instanyl,[57] Abstral,[58] Lazanda[59] and others.[60]

In the UK, fentanyl is classified as a controlled Class A drug under the Misuse of Drugs Act 1971.[61] 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.[62][63] In order to curb misuse, many health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.[64][65][66]

On June 19, 2007, a $5.5 million jury verdict was awarded in a US case against Johnson & Johnson subsidiaries, Alza Corporation and Janssen Pharmaceutica Products, the manufacturers of the Duragesic fentanyl transdermal pain patch. This case, the first Federal trial involving the Duragesic fentanyl patch, was tried in the Federal District Court for the Southern District of Florida, West Palm Beach Division.

J&J has filed an opposition[67] to the trademark application Dermogesic filed by Minnesota High Tech Resources, LLC for their iontophoretic transdermal patch. The litigation has been ongoing since 2002. The trial has been completed. The parties are now drafting and filing their final briefs. J&J's main argument is that the Dermogesic mark dilutes their Durogesic brand and adds confusion in the marketplace. Obviously, Minnesota High Tech Resources, LLC disagrees with this position. Minnesota High Tech Resources, LLC is a very small biomedical research company owned by two individuals in Red Wing, MN.

Public Health Advisories

The U.S. Food and Drug Administration (FDA) has issued public health advisories related to fentanyl patch dangers. Among these, in July 2005, the US Food and Drug Administration (FDA) issued a Public Health Advisory,[68] 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[68] 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..."

Recreational use

Fentanyl powder seized by a Sheriff.[69]

Illicit use of pharmaceutical fentanyl and its analogues first appeared in the mid-1970s in the medical community and continues in the present. United States authorities classify fentanyl as a narcotic and an opioid. To date, more than 12 different analogues of fentanyl have been produced clandestinely and identified in the U.S. drug traffic. The biological effects of the fentanyl analogues are similar to those of heroin, with the exception that many users report a noticeably less euphoric "high" associated with the drug and stronger sedative and analgesic effects.

Fentanyl analogues may be hundreds of times more potent than street heroin, and tend to produce significantly more respiratory depression, making it somewhat more dangerous than heroin to users. Fentanyl is used orally, smoked, snorted, or injected. Fentanyl is sometimes sold as heroin, often leading to overdoses. Many fentanyl overdoses are initially classified as heroin overdoses.[70] Estonia has the highest rate of 3-methylfentanyl overdose deaths in the EU, due to its high rate of recreational use.[71]

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 may be ingested or injected.[72]

Another dosage form of fentanyl that has appeared on the streets is the Actiq fentanyl lollipops, which are sold under the street name of "percopop". The pharmacy retail price ranges from US$15 to US$50 per unit (based on strength of lozenge), with the black market cost ranging from $5–25, depending on its dose.[73] 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".[73]

Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.[72] Even those with opiate tolerances are at high risk for overdoses. Once the fentanyl is in the user's system, it is extremely difficult to stop its course because of the nature of absorption. 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.

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.[74]

Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In June 2006, 945 grams of 83%-pure fentanyl powder was seized by Border Patrol agents in California from a vehicle that had entered from Mexico.[75] Mexico is the source of much of the illicit fentanyl for sale in the U.S. However, in April 2006, there was one domestic fentanyl lab discovered by law enforcement in Azusa, California. The lab was a source of counterfeit 80-mg OxyContin tablets containing fentanyl instead of oxycodone, as well as bulk fentanyl and other drugs.[76][77] In November of 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 over 25,000 more 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 pill press and ordered fentanyl in powder form from China.[78][79]

The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF).[80] This Department of Justice document lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,[81] which today are classified as Schedule I drugs in the United States.[82] Part of the motivation for AMF is that, despite the extra difficulty from a synthetic standpoint, the resultant drug is relatively more resistant to metabolic degradation. This results in a drug with an increased duration.[83]

In June 2013, the United States' Centers for Disease Control and Prevention (CDC) issued a health advisory[84] 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.

Beginning in 2015, Canada has seen a widespread issue of fentanyl overdoses country-wide. Authorities suspect that the drug is being imported from Asia to the western coast by organized crime groups in powder form and being pressed into pseudo-OxyContin tablets.[85] 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.[86] Because of the rising deaths across the country, 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.[87]

Incapacitating agent

Russian spetsnaz security forces used a "fentanyl gas" to incapacitate people rapidly in the Moscow theater hostage crisis. 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,[88] but the exact chemical agent has not been identified.

Veterinary use

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-opioid agonists (morphine, hydromorphone) when given as a continuous post-operative infusion. As with other pure opioids, 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.[89] The drug is also approved in Europe.[90]

References

  1. 1 2 Clinically Oriented Pharmacology (2 ed.). Quick Review of Pharmacology. 2010. p. 172.
  2. ↑ "DURAGESIC® (fentanyl transdermal system) CII Pain Patch". Retrieved 28 March 2016.
  3. ↑ Lennernäs B, Hedner T, Holmberg M, Bredenberg S, Nyström C, Lennernäs H (Feb 2005). "Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain". Br J Clin. Pharmacol. doi:10.1111/j.1365-2125.2004.02264.x. PMID 1884753.
  4. ↑ "Guideline for administration of fentanyl for pain relief in labour" (PDF). RCP. Retrieved 7 October 2015. Onset of action after IV administration of Fentanyl is 3–5 minutes; duration of action is 30–60 minutes.
  5. ↑ Hess R, Stiebler G, Herz A (June 1972). "Pharmacokinetics of fentanyl in man and the rabbit". Eur. J. Clin. Pharmacol. 4 (3): 137–41. doi:10.1007/BF00561135. PMID 4655287.
  6. ↑ "WCPI Focus on Pain Series: The Three Faces of Fentanyl". Aspi.wisc.edu. Retrieved 2010-07-28.
  7. ↑ "Fentanyl". NIH. Retrieved 2016-11-06.
  8. ↑ Stanley TH (April 1992). "The history and development of the fentanyl series". J Pain Symptom Manage. 7 (3 Suppl): S3–7. doi:10.1016/0885-3924(92)90047-L. PMID 1517629.
  9. ↑ Black J (March 2005). "A personal perspective on Dr. Paul Janssen" (PDF). J. Med. Chem. 48 (6): 1687–8. doi:10.1021/jm040195b. PMID 15771410.
  10. ↑ "DailyMed: About DailyMed". Dailymed.nlm.nih.gov. Retrieved 2010-07-28.
  11. ↑ "Subsys (fentanyl sublingual spray)".
  12. ↑ "Long Term Safety and Efficacy Study of Fentanyl Sublingual Spray for the Treatment of Breakthrough Cancer Pain - Full Text View". ClinicalTrials.gov. Retrieved 2010-07-28.
  13. ↑ "Fentanyl and Analogues".
  14. ↑ Narcotic Drugs 2014 (pdf). INTERNATIONAL NARCOTICS CONTROL BOARD. 2015. p. 21. ISBN 9789210481571.
  15. ↑ "'It is a huge issue': 145 fentanyl-related deaths in Alberta so far in 2015". globalnews.ca. August 11, 2015. Retrieved 16 November 2015.
  16. ↑ Vestal, Christine (1 April 2016). "As Fentanyl Deaths Spike, States and CDC Respond". Pew Charitable Trusts. Retrieved 13 July 2016.
  17. ↑ Serna, Joseph; Karlamangla, Soumya. "Death toll rises to 9 in suspected fentanyl overdoses in Northern California". latimes.com. The Los Angeles Times. Retrieved 2016-04-01.
  18. 1 2 Stanley, Theodore Henry; Petty, William Clayton (1983-03-31). New Anesthetic Agents, Devices, and Monitoring Techniques. Springer. ISBN 978-90-247-2796-4. Retrieved 20 October 2007.
  19. 1 2 3 Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 2621f. ISBN 978-3-85200-181-4.
  20. ↑ Derry, Sheena; Stannard, Cathy; Cole, Peter; Wiffen, Philip J.; Knaggs, Roger; Aldington, Dominic; Moore, R. Andrew (2016-10-11). "Fentanyl for neuropathic pain in adults". The Cochrane Database of Systematic Reviews. 10: CD011605. doi:10.1002/14651858.CD011605.pub2. PMID 27727431.
  21. 1 2 http://www.duragesic.com/duragesic/shared/pi/duragesic.pdf Official Duragesic Full Prescribing Information
  22. 1 2 "Disposal of Unused Medicines: What You Should Know". U.S. Food and Drug Administration. Retrieved 2013-09-10.
  23. ↑ "Medicines Recommended for Disposal by Flushing". U.S. Food and Drug Administration. Retrieved 2013-09-10.
  24. ↑ "Medication Guide and Instructions for Use – Duragesic (fentanyl) Transdermal System" (PDF). U.S. Food and Drug Administration. Retrieved 2013-09-10.
  25. ↑ "PRICARA RECALLS 25 mcg/hr DURAGESIC (fentanyl transdermal system) CII PAIN PATCHES". FDA. 2008-02-12.
  26. ↑ Karlsen, A. P.; Pedersen, D. M.; Trautner, S; Dahl, J. B.; Hansen, M. S. (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.
  27. ↑ Murphy A, O'Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N (Oct 10, 2014). "Intranasal fentanyl for the management of acute pain in children". The Cochrane database of systematic reviews. 10: CD009942. doi:10.1002/14651858.CD009942.pub2. PMID 25300594.
  28. 1 2 3 4 Abstral Summary of Product Characteristics. February 2010. http://www.medicines.org.uk/emc/medicine/21371/SPC/Abstral+Sublingual+Tablets/
  29. ↑ "Abstral (Fentanyl Sublingual Tablets for Breakthrough Cancer Pain)". P T. 36 (2): 2–28. February 2011. PMC 3086091Freely accessible. PMID 21560267.
  30. ↑ http://spcare.bmj.com/content/1/Suppl_1/A24.1.abstract
  31. 1 2 Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 89–92. ISBN 978-3-85200-181-4.
  32. ↑ O'Connor AB (2008). "Is actiq use in noncancer-related pain really "a recipe for success"?". Pain Medicine. 9 (2): 258–60; author reply 261–5. doi:10.1111/j.1526-4637.2008.00413.x. PMID 18298711.
  33. ↑ Actiq Information from Drugs.com
  34. ↑ Barr Pharmaceuticals (2006-09-27). Barr Launches Generic ACTIQ(R) Cancer Pain Management Product. Press release.
  35. ↑ Shachtman, Noah (September 10, 2009). "Airborne EMTs Shave Seconds to Save Lives in Afghanistan". Danger Room. Wired. Retrieved July 1, 2010.
  36. ↑ Murphy A, O'Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N (10 October 2014). "Intranasal fentanyl for the management of acute pain in children.". The Cochrane database of systematic reviews. 10: CD009942. doi:10.1002/14651858.CD009942.pub2. PMID 25300594.
  37. ↑ "Medscape: Medscape Access". Retrieved 28 March 2016.
  38. 1 2 "fentanyl". Drugs@FDA: FDA Approved Drug Products. U.S. Food and Drug Administration.
  39. 1 2 Stacey Mayes, PharmD MS, Marcus Ferrone, PharmD BCNSP, 2006.Fentanyl HCl Patient-Controlled Iontophoretic Transdermal System for Pain: Pharmacology The Annals of Pharmacotherapy
  40. ↑ Smydo, J. (1979). "Delayed respiratory depression with fentanyl". Anesth Prog. 26 (2): 47–8. PMC 2515983Freely accessible. PMID 295585.
  41. ↑ van Leeuwen, L.; Deen, L.; Helmers, J. H. (August 1981). "A comparison of alfentanil and fentanyl in short operations with special reference to their duration of action and postoperative respiratory depression". Anaesthesist. 30 (8): 397–9. PMID 6116461.
  42. ↑ Brown, D. L. (November 1985). "Postoperative analgesia following thoracotomy. Danger of delayed respiratory depression". Chest. 88 (5): 779–80. doi:10.1378/chest.88.5.779. PMID 4053723.
  43. ↑ Bülow, H. H.; 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 Anaesthesiol Scand. 39 (6): 835–9. doi:10.1111/j.1399-6576.1995.tb04180.x. PMID 7484044.
  44. ↑ Nilsson, C.; Rosberg, B. (June 1982). "Recurrence of respiratory depression following neurolept analgesia". Acta Anaesthesiol Scand. 26 (3): 240–1. doi:10.1111/j.1399-6576.1982.tb01762.x. PMID 7113633.
  45. ↑ McLoughlin, R.; McQuillan, R. (September 1997). "Transdermal fentanyl and respiratory depression". Palliat Med. 11 (5): 419. doi:10.1177/026921639701100515. PMID 9472602.
  46. ↑ Regnard, C.; Pelham, A. (December 2003). "Severe respiratory depression and sedation with transdermal fentanyl: four case studies". Palliat Med. 17 (8): 714–6. PMID 14694924.
  47. ↑ "Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use". Drug Safety Update. 2 (2): 2. September 2008.
  48. ↑ "Fentanyl Patch Can Be Deadly to Children". FDA Consumer Information on drugs.com site. U.S. FDA(Drugs.com). April 19, 2012. Retrieved July 30, 2013.
  49. ↑ "Fentanyl patches warning". Pharmaceutical Journal. Retrieved 28 March 2016.
  50. ↑ "MHRA warns about fentanyl patches after children exposed". Pharmaceutical Journal. Retrieved 28 March 2016.
  51. ↑ "Fentanyl Overdose". Huffington Post. May 20, 2016.
  52. ↑ "Fentanyl-Detected in Illicit Drug Overdose Deaths January 1, 2012 to April 30, 2016" (PDF). British Columbia Coroners Service.
  53. ↑ John Eligon and Serge F Kovaleski for The New York Times. June 2, 2016. Prince Died From Accidental Overdose of Opioid Painkiller
  54. ↑ "Official: Mislabeled pills found at Prince's estate contained fentanyl". Chicago Tribune. Retrieved 22 August 2016.
  55. ↑ Lopez-Munoz, Francisco; Alamo, Cecilio (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.
  56. ↑ "Introducing Onsolis". Onsolis.com. Retrieved 2010-07-28.
  57. ↑ "EPAR summary for the public: Instanyl" (PDF). European Medicines Agency. Retrieved 2010-07-28.
  58. ↑ "Abstral: Prescribing Information". Retrieved 2011-01-07.
  59. ↑ "Lazanda (fentanyl nasal spray) CII". Lazanda.com. Retrieved 2012-05-14.
  60. ↑ "Fentanyl". International Drug Names. Drugs.com.
  61. ↑ http://www.legislation.gov.uk/ukpga/1971/38/schedule/2
  62. ↑ "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. Retrieved 5 November 2015.
  63. ↑ Shelley, Suzanne (22 April 2011). "With a Few Stumbles, REMS Begins to Hit Its Stride". Pharmaceutical Commerce. Retrieved 5 November 2015.
  64. ↑ "Aetna notice regarding precertification requirement", Aetna, May, 2007
  65. ↑ "BlueCross BlueShield of Arizona notice regarding precertification requirement", Blue Cross Blue Shield of Arizona, November 5, 2007
  66. ↑ "Medications Requiring Precertification", Oxford Health Plans
  67. ↑ http://ttabvue.uspto.gov/ttabvue/v?pno=91152039&pty=OPP
  68. 1 2 "Fentanyl Transdermal System (marketed as Duragesic) Information". U.S. Food and Drug Administration. Retrieved 2013-09-10.
  69. ↑ "DEA Microgram Bulletin, June 2006". US Drug Enforcement Administration, Office of Forensic Sciences Washington, D.C. 20537. June 2006. Retrieved 22 June 2009.
  70. ↑ Boddiger, D. (2006, August 12).Fentanyl-laced street drugs "kill hundreds". The Lancet. Retrieved June 15, 2010.
  71. ↑ "Synthetic drug fentanyl causes overdose boom in Estonia". BBC News. 30 March 2012.
  72. 1 2 "Fentanyl" (PDF). Drug Enforcement Administration. March 2015.
  73. 1 2 "Painkiller is topic of inquiry", Bob Mims, The Salt Lake Tribune, 11 November 2004
  74. ↑ "CDC Nonpharmaceutical Fentanyl-Related Deaths - Multiple States, April 2005-March 2007". Cdc.gov. Retrieved 2010-07-28.
  75. ↑ Intelligence alert: High purity fentanyl seized near Westmoreland, California, DEA Microgram, June 2006
  76. ↑ Intelligence alert: Large fentanyl / MDA / TMA laboratory in Azuza, California - possibly the "OC-80" tablet source, DEA Microgram, April 2006.
  77. ↑ Intelligence alert: Oxycontin mimic tablets (containing fentanyl) near Atlantic, Iowa, DEA Microgram, January 2006.
  78. ↑ Tribune, Courtney Tanner The Salt Lake. "Thousands of fentanyl pills confiscated in Utah drug raid". The Salt Lake Tribune. Retrieved 2016-11-23.
  79. ↑ "Cottonwood Heights drug bust one of the largest in Utah history". fox13now.com. 2016-11-22. Retrieved 2016-11-23.
  80. ↑ List of Schedule I Drugs, U.S. Department of Justice. Archived January 9, 2010, at the Wayback Machine.
  81. ↑ Behind the Identification of China White Analytical Chemistry, 53(12), 1379A-1386A (1981)
  82. ↑ List of Schedule I Drugs, U.S. Department of Justice.
  83. ↑ Van Bever, Willem F. M.; Niemegeers, Carlos J. E.; Janssen, Paul A. J. (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". J. Med. Chem. 17 (10): 1047–51. doi:10.1021/jm00256a003. PMID 4420811.
  84. ↑ CDC Health Alert Network (June 20, 2013). "Recommendations for Laboratory Testing for Acetyl Fentanyl and Patient Evaluation and Treatment for Overdose with Synthetic Opioids". Centers for Disease Control and Prevention. Retrieved June 20, 2013.
  85. ↑ Lethal fentanyl profiting gangs in Western Canada while deaths climb, Metro News Edmonton, August 6, 2015.
  86. ↑ Fentanyl doesn’t discriminate, killing the homeless and young professionals, Edmonton Journal, August 22, 2015.
  87. ↑ Winnipeg Naloxone-distribution program could prevent fentanyl deaths, CBC News Manitoba, August 20, 2015.
  88. ↑ "Russia names Moscow Siege Gas". BBC. October 31, 2002.
  89. ↑ Original new animal drug application: Recuvyra
  90. ↑ "European Medicines Agency - Veterinary medicines - Recuvyra". Retrieved 28 March 2016.
This article is issued from Wikipedia - version of the 12/2/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.