Fentanyl

From Wikipedia, the free encyclopedia - View original article

Fentanyl
Systematic (IUPAC) name
N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide
Clinical data
Trade namesActiq, Duragesic, Fentora, Sublimaze and others
AHFS/Drugs.commonograph
Pregnancy cat.C (US)
Legal statusControlled (S8) (AU) Class A (UK) Schedule II (US)
Dependence liabilityModerate – high
RoutesTD, IM, IV, oral transmucosal, sublingual, buccal
Pharmacokinetic data
Bioavailability92% (transdermal)
89% (intranasal)
50% (buccal)
33% (ingestion)
Protein binding80–85%
Metabolismhepatic, primarily by CYP3A4
Half-life(IV)= 10-20 mins (T1/2 β)
2-4 hours (T1/2 ɣ)
Intranasal = 6.5 mins
Transdermal = 20–27 h[1]
Excretion60% Urinary (metabolites, <10% unchanged drug)[2]
Identifiers
CAS number437-38-7 YesY
ATC codeN01AH01 N02AB03
PubChemCID 3345
IUPHAR ligand1626
DrugBankDB00813
ChemSpider3228 YesY
UNIIUF599785JZ YesY
KEGGD00320 YesY
ChEBICHEBI:119915 YesY
ChEMBLCHEMBL596 YesY
Chemical data
FormulaC22H28N2O 
Mol. mass336.471 g/mol
Physical data
Melt. point87.5 °C (190 °F)
 YesY (what is this?)  (verify)
 
Jump to: navigation, search
Fentanyl
Systematic (IUPAC) name
N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide
Clinical data
Trade namesActiq, Duragesic, Fentora, Sublimaze and others
AHFS/Drugs.commonograph
Pregnancy cat.C (US)
Legal statusControlled (S8) (AU) Class A (UK) Schedule II (US)
Dependence liabilityModerate – high
RoutesTD, IM, IV, oral transmucosal, sublingual, buccal
Pharmacokinetic data
Bioavailability92% (transdermal)
89% (intranasal)
50% (buccal)
33% (ingestion)
Protein binding80–85%
Metabolismhepatic, primarily by CYP3A4
Half-life(IV)= 10-20 mins (T1/2 β)
2-4 hours (T1/2 ɣ)
Intranasal = 6.5 mins
Transdermal = 20–27 h[1]
Excretion60% Urinary (metabolites, <10% unchanged drug)[2]
Identifiers
CAS number437-38-7 YesY
ATC codeN01AH01 N02AB03
PubChemCID 3345
IUPHAR ligand1626
DrugBankDB00813
ChemSpider3228 YesY
UNIIUF599785JZ YesY
KEGGD00320 YesY
ChEBICHEBI:119915 YesY
ChEMBLCHEMBL596 YesY
Chemical data
FormulaC22H28N2O 
Mol. mass336.471 g/mol
Physical data
Melt. point87.5 °C (190 °F)
 YesY (what is this?)  (verify)

Fentanyl (also known as fentanil, brand names Sublimaze,[3] Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis,[4] Instanyl,[5] Abstral,[6] Lazanda[7] and others[8]) is a potent, synthetic opioid analgesic with a rapid onset and short duration of action.[9] 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 100 times more potent than morphine,[10] with 100 micrograms of fentanyl approximately equivalent to 10 mg of morphine and 75 mg of pethidine (meperidine) in analgesic activity.[11][dead link] It has an LD50 of 3.1 milligrams per kilogram in rats, and an LD50 of 0.03 milligrams per kilogram in monkeys.

Fentanyl was first synthesized by Paul Janssen in 1960[12] following the medical inception of pethidine several years earlier. Janssen developed fentanyl by assaying analogues of the structurally related drug pethidine for opioid activity.[13] 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),[14] 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 formations of fentanyl for personal use, the Actiq lollipop and Fentora buccal tablets. Through the delivery method of transdermal patches, as of 2012 fentanyl was the most widely used synthetic opioid in clinical practice,[citation needed] with several new delivery methods currently in development, including a sublingual spray for cancer patients.[15]

Fentanyl and derivatives have been used as recreational drugs. Fatalities arising from its use have been recorded.

Medical uses[edit]

Intravenous fentanyl is extensively used for anesthesia and analgesia, most often in operating rooms, intensive care units and in the prehospital medical setting. The concept of a general anesthetic is based upon a balance between an opioid and a hypnotic agent. Hence, fentanyl is mainly used for induction of anaesthesia alongside a hypnotic agent like propofol. It is also administered in combination with a benzodiazepine, such as midazolam, to produce procedural sedation for endoscopy, cardiac catheterization, oral surgery, etc., and is often used in the management of chronic pain including cancer pain.

Fentanyl transdermal patch (Durogesic/Duragesic/Matrifen) is used in chronic pain management. The patches work by releasing fentanyl into body fats, which then slowly release the drug into the bloodstream over 48 to 72 hours, allowing for long-lasting relief from pain. The patches are available in generic form which has made them available at lower cost. Dosage is based on the size of the patch, since the transdermal absorption rate is generally constant at a constant skin temperature.

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. The typical patch will take effect under normal circumstances usually within 8–12 hours, thus fentanyl patches are often prescribed with another opiate (such as morphine or oxycodone) to handle breakthrough pain.

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. It is also useful for breakthrough pain for those suffering bone injuries, severe back pain, neuropathy, arthritis, and some other examples of chronic nonmalignant pain. The unit is a berry-flavored lozenge on a stick which is 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 in 15 minutes. The drug is less effective if swallowed, as despite good absorbance from the small intestine there is extensive first-pass metabolism, leading to an oral bioavailability of 33%. These are now available in the United States in generic form,[16] through an FTC consent agreement.[17] However, most patients find it takes 10–15 minutes to use all of one lozenge, and those with a dry mouth cannot use this route. In addition, nurses are unable to document how much of a lozenge has been used by a patient, making drug records inaccurate.

During 2008-09, a wide range of fentanyl preparations became available, including buccal tablets or patches, nasal sprays, inhalers and active transdermal patches (heat or electrical). High-quality evidence for their superiority over existing preparations is currently lacking. 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 (see below). In addition, the expense of some of these appliances may greatly reduce their cost-effectiveness.

On July 16, 2009, the FDA approved Onsolis (BEMA Fentanyl) for breakthrough cancer pain. Onsolis incorporates "bioerodible mucoadhesive" technology, a small soluble film that contains fentanyl which is placed on the inside cheek of the mouth.

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

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.

Adverse effects[edit]

Fentanyl's major side effects (more than 10% of patients) include diarrhea, nausea, constipation, dry mouth, somnolence, confusion, asthenia (weakness), and 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.[3]

Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, in relation to morphine.[18]

Like other lipid-soluble drugs, the pharmacodynamics of fentanyl are poorly understood. The manufacturers acknowledge there is no data on the pharmacodynamics of fentanyl in elderly, cachectic or debilitated patients, frequently the type of patient for whom transdermal fentanyl is being used. This may explain the increasing number of reports of respiratory depression events since the late 1970s.[19][20][21][22][23][24][25] 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.[26] The FDA reported in April 2012 that young children had died or become seriously ill from accidental exposure to a fentanyl skin patch.[27]

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

Fentanyl has a therapeutic index of 270.[28]

Storage and disposal[edit]

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.[29] All fentanyl medicine 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 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 who were not intended to use them.[29][30]

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.[31]

Overdoses and fatalities[edit]

A number of fatal fentanyl overdoses have been directly tied to the drug over a period of years. In particular, manufacturers of time-release fentanyl patches have come under scrutiny for defective products.[32] While the fentanyl contained in the patches was safe, a malfunction of the patches caused an excessive amount of fentanyl to leak and become absorbed by patients, resulting in life-threatening side effects and even death.[33][34] Manufacturers of fentanyl transdermal pain patches have voluntarily recalled numerous lots of their patches, and the U.S. Food and Drug Administration (FDA) has issued public health advisories related to fentanyl patch dangers.[33] Manufacturers affected include Janssen Pharmaceutica Products, L.P.; Alza Corporation; Actavis South Atlantic, LLC; Sandoz; and Cephalon, Inc.

In 2009, the former guitarist for the band Wilco, Jay Bennett, died in his sleep of an overdose of the drug via Duragesic time-release patches prescribed for him.[35] In 2010, band Slipknot's bassist Paul Gray overdosed and died after abusing a mixture of fentanyl and morphine, for which there was no evidence of a prescription.[36] An inquest jury found by a majority verdict of 3-2 that an overdose of fentanyl was responsible for the death by misadventure of Anita Chan Lai-ling, 69, who died on October 17, 2007, after she was given an overdose of fentanyl.[37] On June 27, 2005, Laurence Harvey's daughter Domino Harvey was found unconscious in her bathtub and the Los Angeles County Coroner's office determined that she had overdosed on fentanyl.[38] In 2009 27-year-old Hayley Fisher a midwife at King Edward Memorial Hospital for Women in Australia died after injecting herself fentanyl.[39]

Chemistry[edit]

Synthesis[edit]

The synthesis of fentanyl by Janssen Pharmaceutica was achieved in four steps, starting from 4-piperidinonehydrochloride. The sequence commenced with N-alkylation of 4-piperidinone with 2-phenylethylbromide to giveN-phenethyl-4-piperidinone (NPP). Reductive amination of NPP using aniline and sodium borohydride afforded 4-anilino-N-phenethylpiperidine (ANPP). Finally N-acylation of the secondary amine with propionic anhydride provided fentanyl.

Analog[edit]

Structural analogs of fentanyl include:

Mechanism of action[edit]

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.[18]

Fentanyl binds μ-opioid G-protein-coupled receptors, which inhibit pain neurotransmitter release by decreasing intracellular Ca2+ levels.

History[edit]

Fentanyl was first synthesized by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959. In the 1960s, fentanyl was introduced as an intravenous anesthetic under the trade name of Sublimaze.[citation needed] 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.

Recreational use[edit]

Fentanyl powder seized by a Lake County Deputy Sheriff in Painesville, Ohio, where a male subject had been discovered unresponsive and struggling to breathe.[40]

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.[citation needed]

The use of fentanyl has caused death. Fentanyl analogues may be hundreds of times more potent than street heroin, and tends 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.[41] In Estonia, due to its high rate of recreational use, fentanyl causes more deaths nationwide than traffic accidents.[42]

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 are 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.[43] 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, consequently, 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, heavily concentrated in the cities of Dayton, (Ohio), Chicago, Detroit, and Philadelphia,[44] as well as Baltimore, Pittsburgh, St. Louis, Milwaukee, and Camden (New Jersey).[45] Little Rock and Dallas[46] were also affected. The mixture of fentanyl and heroin is known as "magic" or "the bomb", among other names, on the street.[47]

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 which had entered from Mexico.[48] 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.[49][50]

The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF).[51] This Department of Justice document lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,[52] which today are classified as Schedule I drugs in the United States.[53] 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.[54]

In June 2013, the United States' Centers for Disease Control and Prevention (CDC) issued a health advisory[55] to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated with acetylfentanyl, a novel, injected, non-prescription synthetic opioid analog of fentanyl.

Military use[edit]

Analgesic[edit]

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.[citation needed]

United States Air Force Pararescue and Swedish armed forces combat medics uses lollipops with fentanyl.[56]

As weapon[edit]

Mossad agents allegedly used "levofentanyl" in their 1997 attempt to kill Hamas leader Khalid Mishal.[57] However, since fentanyl is achiral (i.e., has no "levo-" form), the substance was probably fentanyl itself, a fentanyl analogue, or another opioid. However, it could have been a non-opioid sedative or unknown drug.

A gas apparently based on a derivative of fentanyl was used in 2002 in the Moscow theatre hostage crisis to incapacitate Chechen terrorist attackers (and, unavoidably, their hostages) too quickly for them to retaliate. More than 15% of those affected died, including 117 of the 800 hostages.[58]

References[edit]

  1. ^ Janssen Pharmaceuticals (Duragesic)
  2. ^ 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. 
  3. ^ a b "fentanyl". Drugs@FDA: FDA Approved Drug Products. U.S. Food and Drug Administration. 
  4. ^ "Introducing Onsolis". Onsolis.com. Retrieved 2010-07-28. 
  5. ^ "London, 23 April 2009" (PDF). Retrieved 2010-07-28. 
  6. ^ "Abstral: Prescribing Information". Retrieved 2011-01-07. 
  7. ^ "Lazanda (fentanyl nasal spray) CII". Lazanda.com. Retrieved 2012-05-14. 
  8. ^ "Fentanyl". International Drug Names. Drugs.com. 
  9. ^ "WCPI Focus on Pain Series: The Three Faces of Fentanyl". Aspi.wisc.edu. Retrieved 2010-07-28. 
  10. ^ "DBL FENTANYL INJECTION". Medsafe. Retrieved 2010-07-28. 
  11. ^ "Data Sheet". Medsafe.govt.nz. 2008-03-01. Retrieved 2010-07-28. 
  12. ^ 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. 
  13. ^ Black J (March 2005). "A personal perspective on Dr. Paul Janssen". J. Med. Chem. 48 (6): 1687–8. doi:10.1021/jm040195b. PMID 15771410. 
  14. ^ "DailyMed: About DailyMed". Dailymed.nlm.nih.gov. Retrieved 2010-07-28. 
  15. ^ "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. 
  16. ^ "Barr Launches Generic ACTIQ(R) Cancer Pain Management Product" (Press release). Barr Pharmaceuticals. 27 September 2006. Retrieved 30 September 2006. 
  17. ^ "With Conditions, FTC Allows Cephalon’s Purchase of CIMA, Protecting Competition for Breakthrough Cancer Pain Drugs" (Press release). FTC. 9 August 2004. Retrieved 30 September 2006. 
  18. ^ a b Stacey Mayes, PharmD MS, Marcus Ferrone, PharmD BCNSP, 2006.Fentanyl HCl Patient-Controlled Iontophoretic Transdermal System for Pain: Pharmacology The Annals of Pharmacotherapy
  19. ^ Smydo J (1979). "Delayed respiratory depression with fentanyl". Anesth Prog 26 (2): 47–8. PMC 2515983. PMID 295585. 
  20. ^ van Leeuwen L, Deen L, Helmers JH (August 1981). "A comparison of alfentanil and fentanyl in short operations with special reference to their duration of action and postoperative respiratory depression". Anaesthesist 30 (8): 397–9. PMID 6116461. 
  21. ^ Brown DL (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. 
  22. ^ Bülow HH, Linnemann M, Berg H, Lang-Jensen T, LaCour S, Jonsson T (August 1995). "Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl". Acta Anaesthesiol Scand 39 (6): 835–9. doi:10.1111/j.1399-6576.1995.tb04180.x. PMID 7484044. 
  23. ^ 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. 
  24. ^ McLoughlin R, McQuillan R (September 1997). "Transdermal fentanyl and respiratory depression". Palliat Med 11 (5): 419. doi:10.1177/026921639701100515. PMID 9472602. 
  25. ^ 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. 
  26. ^ "Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use". Drug Safety Update 2 (2): 2. September 2008. 
  27. ^ "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. 
  28. ^ 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. 
  29. ^ a b "Disposal of Unused Medicines: What You Should Know". U.S. Food and Drug Administration. Retrieved 2013-09-10. 
  30. ^ "Medicines Recommended for Disposal by Flushing". U.S. Food and Drug Administration. Retrieved 2013-09-10. 
  31. ^ "Medication Guide and Instructions for Use – Duragesic (fentanyl) Transdermal System". U.S. Food and Drug Administration. Retrieved 2013-09-10. 
  32. ^ Waknine, Yael (February 19, 2008). "Fold-Over Defect Causes Another Recall of Fentanyl Pain Patches". Medical News . Medscape. Retrieved July 29, 2013. 
  33. ^ a b "Information for Healthcare Professionals: Fentanyl Transdermal System (marketed as Duragesic and generics) - 12/21/2007 Update". Postmarket Drug Safety Information for Patients and Providers. FDA. December 21, 2007. Retrieved July 30, 2013. 
  34. ^ "Duragesic 25 mcg/hr (fentanyl transdermal system) CII Pain Patches Recalled". pharmawatchdog. Sadaka Associates. February 27, 2008. Retrieved July 29, 2013. 
  35. ^ "Coroner: Painkiller killed ex-Wilco member". Chicago Tribune. 2009-06-23. Retrieved 2010-08-20. 
  36. ^ "Slipknot bassist Paul Gray died of morphine overdose". BBC News. 2010-06-21. Retrieved 2010-07-28. 
  37. ^ "Son vows to sue on painkiller death". 2010-12-03. Retrieved 2010-12-03. 
  38. ^ http://www.utsandiego.com/uniontrib/20051014/news_1c14harvey.html
  39. ^ http://www.abc.net.au/news/2013-09-12/coroner-calls-for-stricter-access-to-pain-medication/4953786
  40. ^ "DEA Microgram Bulletin, June 2006". US Drug Enforcement Administration, Office of Forensic Sciences Washington, D.C. 20537. June 2006. Retrieved 22 June 2009. 
  41. ^ Boddiger, D. (2006, August 12).Fentanyl-laced street drugs “kill hundreds”. The Lancet. Retrieved June 15, 2010.
  42. ^ "Synthetic drug fentanyl causes overdose boom in Estonia". BBC News. 30 March 2012. 
  43. ^ http://www.deadiversion.usdoj.gov/drugs_concern/fentanyl.htm[dead link]
  44. ^ "CDC Nonpharmaceutical Fentanyl-Related Deaths - Multiple States, April 2005-March 2007". Cdc.gov. Retrieved 2010-07-28. 
  45. ^ Press Release by the Chicago Police Department Police report about a death linked to heroin/fentanyl mixture August 24, 2006
  46. ^ "SMU student's death blamed on rare drug". Dallasnews.com. 2006-12-20. Retrieved 2010-07-28. 
  47. ^ Fentanyl probe nets 3 suspects by Norman Sinclair and Ronald J. Hansen, The Detroit News, June 23, 2006. Retrieved June 25, 2006.
  48. ^ Intelligence alert: High purity fentanyl seized near Westmoreland, California, DEA Microgram, June 2006
  49. ^ Intelligence alert: Large fentanyl / MDA / TMA laboratory in Azuza, California - possibly the “OC-80” tablet source, DEA Microgram, April 2006.
  50. ^ Intelligence alert: Oxycontin mimic tablets (containing fentanyl) near Atlantic, Iowa, DEA Microgram, January 2006.
  51. ^ List of Schedule I Drugs, U.S. Department of Justice.[dead link]
  52. ^ Behind the Identification of China White Analytical Chemistry, 53(12), 1379A-1386A (1981)
  53. ^ List of Schedule I Drugs, U.S. Department of Justice.
  54. ^ Van Bever WF, Niemegeers CJ, Janssen PA (October 1974). "Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4-piperidyl)-N-phenylpropanamide and N-(3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide". J. Med. Chem. 17 (10): 1047–51. doi:10.1021/jm00256a003. PMID 4420811. 
  55. ^ 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. 
  56. ^ Shachtman, Noah (September 10, 2009). "Airborne EMTs Shave Seconds to Save Lives in Afghanistan". Danger Room. Wired.com. Retrieved July 1, 2010. 
  57. ^ McGeough, Paul (2009) Kill Khalid - The Failed Mossad Assassination of Khalid Mishal and the Rise of Hamas. Quartet Books. ISBN 978-0-7043-7157-6. Page 184.
  58. ^ "Russia names Moscow siege gas". CNN. 2002-10-30. 

External links[edit]