Fentanyl

Fentanyl
Systematic (IUPAC) name
N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide
Clinical data
Trade names Actiq, Duragesic, Fentora, Sublimaze and others
AHFS/Drugs.com monograph
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
Dependence
liability		 Very high
Routes of
administration		 TD, IM, IV, oral transmucosal, sublingual, buccal
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
ATC code N01AH01 N02AB03
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
Chemical data
Formula C22H28N2O
Molar mass 336.471 g/mol
Physical data
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, brand names Sublimaze,[6] Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis,[7] Instanyl,[8] Abstral,[9] Lazanda[10] and others[11]) is a potent, synthetic opioid analgesic with a rapid onset and short duration of action.[12] It is a strong agonist at the μ-opioid receptors. Historically, it has been used to treat breakthrough pain and is commonly used in pre-procedures as a pain reliever as well as an anesthetic in combination with a benzodiazepine.

Fentanyl is approximately 80 to 100 times more potent than morphine and roughly 40 to 50 times more potent than pharmaceutical grade (100% pure) heroin.[13][14]

Fentanyl was first synthesized by Paul Janssen in 1960,[15] 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.[16] 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),[17] which entered the clinical practice 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 first introduced for widespread palliative use with the clinical introduction of the Duragesic patch, followed in the next decade by the introduction of the first quick-acting prescription formulations of fentanyl for personal use, the Actiq lollipop and Fentora buccal as well as through the delivery method of estradiol Mylan transdermal patches. As of 2012 fentanyl was the most widely used synthetic opioid in clinical practice,[18] with several new delivery methods now available, including a sublingual spray for cancer patients.[19][20] In 2013, 1700 kilograms were used globally.[21]

Fentanyl is used recreationally, whereby death is common.[22] Deaths have resulted from both recreational and improper medical use.[23]

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.

In children intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.[24]

Patches

A fentanyl patch from Israel

Fentanyl transdermal patch (Durogesic/Duragesic/Matrifen) is 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.[25] Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature.[25] 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.[25]

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

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]

Lozenges

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.[27] It has also been used for breakthrough pain for patients with nonmalignant (not cancer related) pain, but this application is controversial.[28] 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).[27]

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.

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.[29]

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.[30]

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 do other pure-opioid agonists (morphine, hydromorphone) when given as a continuous infusion post-operatively. 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. Most commonly this has been accomplished by off-label use of fentanyl patches manufactured for use in humans with chronic malignant pain. In 2012 a highly concentrated (50 mg/ml) transdermal solution, trade name Recuvyra, has become commercially available for use in dogs only. It is FDA approved to provide four days of analgesia (again in dogs only) after a single application prior to surgery. It is not approved for multiple doses or use in other species.[31] The drug is also approved in Europe.[32]

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.[6]

Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, in relation to morphine.[33]

Fentanyl may produce more prolonged respiratory depression than other opioid analgesics.[34][35][36][37][38][39][40] 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.[41] The FDA reported in April 2012 that young children had died or become seriously ill from accidental exposure to a fentanyl skin patch.[42]

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

Fentanyl has a therapeutic index of 270.[43]

Storage and disposal

Fentanyl 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.[44] All fentanyl medicine should be kept in a secure location such as a locked cabinet that is out of children’s sight and reach.

When they cannot be disposed of through a drug take-back program, flushing is recommended for fentanyl medicines because it is the fastest and surest way to remove these potent medicines from the home so they cannot harm children, pets, and others not intended to use them.[44][45]

Fentanyl patches should be flushed down the toilet as soon as they are removed from the body, and unused fentanyl patches should be flushed as soon as they are no longer needed. Detailed "Instructions for Use", with complete information on how to apply, use, and dispose of fentanyl patches, are available on the FDA website.[46]

Overdoses and fatalities

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,[47] 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.[48]

Analogues

Structural analogs of fentanyl include:

Mechanism of action

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.[33]

History

Fentanyl was first synthesized by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959.[49] 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 the 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. More recently, 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.

Recreational use

Fentanyl powder seized by a Lake County Deputy Sheriff in Painesville, Ohio, where a male subject had been discovered unresponsive and struggling to breathe.[50]

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.[51] In Estonia, due to its high rate of recreational use, fentanyl causes more deaths nationwide than traffic accidents.[52]

Fentanyl is sometimes sold on the black market in the form of transdermal fentanyl patches such as Duragesic, diverted from legitimate medical supplies. The patches may be cut up and eaten, or the gel from inside the patch smoked.

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 anywhere from US$20 to US$80 per unit, depending on the strength.

Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.[53] 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.[54] The mixture of fentanyl and heroin is known as "magic" or "the bomb", among other names, on the street.[55]

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.[56] 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.[57][58]

The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF).[59] This Department of Justice document lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,[60] which today are classified as Schedule I drugs in the United States.[61] 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.[62]

In June 2013, the United States' Centers for Disease Control and Prevention (CDC) issued a health advisory[63] 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 West Coast by organized crime groups in powder form and being pressed into pseudo-OxyContin tablets.[64] 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.[65] Due to 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.[66]

Military use

Analgesic

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.

The United States Air Force Pararescue and Swedish armed forces combat medics utilize lollipops with fentanyl.[67] 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 there by indicating that the medication has become effectively administered.

Incapacitating agent

Russian spetsnaz security forces used a fentanyl-based gas to incapacitate people rapidly in the Moscow theater hostage crisis. The siege was ended, but about 130 of the 850 hostages died due to the use of the gas. The deaths were mostly due to lack of proper medical intervention and the unconscious hostages being left to choke (as opposed to being placed in a recovery position).[68]

See also

References

  1. 1 2 Clinically Oriented Pharmacology (2 ed.). Quick Review of Pharmacology. 2010. p. 172.
  2. ↑ Janssen Pharmaceuticals (Duragesic)
  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. 1 2 "fentanyl". Drugs@FDA: FDA Approved Drug Products. U.S. Food and Drug Administration.
  7. ↑ "Introducing Onsolis". Onsolis.com. Retrieved 2010-07-28.
  8. ↑ "EPAR summary for the public: Instanyl" (PDF). European Medicines Agency. Retrieved 2010-07-28.
  9. ↑ "Abstral: Prescribing Information". Retrieved 2011-01-07.
  10. ↑ "Lazanda (fentanyl nasal spray) CII". Lazanda.com. Retrieved 2012-05-14.
  11. ↑ "Fentanyl". International Drug Names. Drugs.com.
  12. ↑ "WCPI Focus on Pain Series: The Three Faces of Fentanyl". Aspi.wisc.edu. Retrieved 2010-07-28.
  13. ↑ "FENTANYL : Incapacitating Agent". CDC. Retrieved 2014-09-18.
  14. ↑ Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 286. ISBN 3-8047-1763-2.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ "DailyMed: About DailyMed". Dailymed.nlm.nih.gov. Retrieved 2010-07-28.
  18. ↑ "Fentanyl and Analogues".
  19. ↑ "Subsys (fentanyl sublingual spray)".
  20. ↑ "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.
  21. ↑ Narcotic Drugs 2014 (pdf). INTERNATIONAL NARCOTICS CONTROL BOARD. 2015. p. 21. ISBN 9789210481571.
  22. ↑ "‘It is a huge issue’: 145 fentanyl-related deaths in Alberta so far in 2015". globalnews.ca. August 11, 2015. Retrieved 16 November 2015.
  23. ↑ Parry, William H.; Martorano, Frank; Cotton, Ernest K. (January 1976). "Management of life-threatening asthma with intravenous isoproterenol infusions". Am. J. Dis. Child. 130 (1): 39–42. doi:10.1001/archpedi.1976.02120020041006. PMID 2007.
  24. ↑ 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.
  25. 1 2 3 Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 2621f. ISBN 978-3-85200-181-4.
  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. 1 2 Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 89–92. ISBN 978-3-85200-181-4.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ http://www.medscape.com/viewarticle/505784_2
  31. ↑ Original new animal drug application: Recuvyra
  32. ↑ European Medicines Agency: Recuvyra
  33. 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
  34. ↑ Smydo, J. (1979). "Delayed respiratory depression with fentanyl". Anesth Prog. 26 (2): 47–8. PMC 2515983. PMID 295585.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ McLoughlin, R.; McQuillan, R. (September 1997). "Transdermal fentanyl and respiratory depression". Palliat Med 11 (5): 419. doi:10.1177/026921639701100515. PMID 9472602.
  40. ↑ 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.
  41. ↑ "Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use". Drug Safety Update 2 (2): 2. September 2008.
  42. ↑ "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.
  43. ↑ 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.
  44. 1 2 "Disposal of Unused Medicines: What You Should Know". U.S. Food and Drug Administration. Retrieved 2013-09-10.
  45. ↑ "Medicines Recommended for Disposal by Flushing". U.S. Food and Drug Administration. Retrieved 2013-09-10.
  46. ↑ "Medication Guide and Instructions for Use – Duragesic (fentanyl) Transdermal System" (PDF). U.S. Food and Drug Administration. Retrieved 2013-09-10.
  47. ↑ Fentanyl patches warning
  48. ↑ MHRA warns about fentanyl patches after children exposed
  49. ↑ 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.
  50. ↑ "DEA Microgram Bulletin, June 2006". US Drug Enforcement Administration, Office of Forensic Sciences Washington, D.C. 20537. June 2006. Retrieved 22 June 2009.
  51. ↑ Boddiger, D. (2006, August 12).Fentanyl-laced street drugs "kill hundreds". The Lancet. Retrieved June 15, 2010.
  52. ↑ "Synthetic drug fentanyl causes overdose boom in Estonia". BBC News. 30 March 2012.
  53. ↑ http://www.deadiversion.usdoj.gov/drugs_concern/fentanyl.htm[]
  54. ↑ "CDC Nonpharmaceutical Fentanyl-Related Deaths - Multiple States, April 2005-March 2007". Cdc.gov. Retrieved 2010-07-28.
  55. ↑ Fentanyl probe nets 3 suspects by Norman Sinclair and Ronald J. Hansen, The Detroit News, June 23, 2006. Retrieved June 25, 2006.
  56. ↑ Intelligence alert: High purity fentanyl seized near Westmoreland, California, DEA Microgram, June 2006
  57. ↑ Intelligence alert: Large fentanyl / MDA / TMA laboratory in Azuza, California - possibly the "OC-80" tablet source, DEA Microgram, April 2006.
  58. ↑ Intelligence alert: Oxycontin mimic tablets (containing fentanyl) near Atlantic, Iowa, DEA Microgram, January 2006.
  59. ↑ List of Schedule I Drugs, U.S. Department of Justice. Archived January 9, 2010 at the Wayback Machine
  60. ↑ Behind the Identification of China White Analytical Chemistry, 53(12), 1379A-1386A (1981)
  61. ↑ List of Schedule I Drugs, U.S. Department of Justice.
  62. ↑ 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.
  63. ↑ 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.
  64. ↑ Lethal fentanyl profiting gangs in Western Canada while deaths climb, Metro News Edmonton, August 06, 2015.
  65. ↑ Fentanyl doesn’t discriminate, killing the homeless and young professionals, Edmonton Journal, August 22, 2015.
  66. ↑ Winnipeg Naloxone-distribution program could prevent fentanyl deaths, CBC News Manitoba, August 20, 2015.
  67. ↑ Shachtman, Noah (September 10, 2009). "Airborne EMTs Shave Seconds to Save Lives in Afghanistan". Danger Room. Wired.com. Retrieved July 1, 2010.
  68. ↑ "Russia names Moscow Siege Gas". BBC. October 31, 2002.

External links

This article is issued from Wikipedia - version of the Sunday, February 14, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.