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'''Fentanyl''' (also known as '''fentanil''' and brand names '''Sublimaze''',<ref>http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=fentanyl&SearchType=BasicSearch</ref> '''Actiq''', '''Durogesic''', '''Duragesic''', '''Fentora''', '''Matrifen''', '''Haldid''', '''Onsolis''',<ref>Improving Onsolosis | http://www.onsolis.com/</ref> '''Instanyl''',<ref>http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000959/WC500033142.pdf</ref> '''Abstral''',<ref> European public assessment report (EPAR) for Instanyl | http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000959/WC500033142.pdf</ref> '''Lazanda'''<ref>Lazanda: Fentanyl nasal spray | http://www.lazanda.com/</ref> and others<ref>http://www.drugs.com/international/fentanyl.html</ref>) is a potent synthetic [[Chemical class::piperidine]] [[Psychoactive class::opioid]] [[pain relief|analgesic]] with a rapid [[onset]] and short [[duration]] of action.<ref>http://aspi.wisc.edu/wpi/focus/spring96.htm</ref> It is a strong [[agonist]] at the [[μ-opioid]] [[receptors]] and approximately 40 to 50 times more potent than pharmaceutical grade (100% pure) [[heroin]]<ref>FENTANYL : Incapacitating Agent | http://www.cdc.gov/niosh/ershdb/EmergencyResponseCard_29750022.html</ref><ref>Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 286. ISBN 3-8047-1763-2.</ref> and roughly 80 to 100 times more potent than [[morphine]]. The subjective effects of fentanyl are similar to those of heroin, with the exception that many users report a noticeably less [[physical euphoria|euphoric]] "high" associated with the drug and stronger [[respiratory depression]], [[sedation]] and [[pain relief]].
A wide range of medical fentanyl preparations are available, including transdermal skin patches, lollipops, buccal tablets or patches, nasal sprays and inhalers.
'''Fentanyl''' (also known as '''Fentanil''' and by the brand names '''Sublimaze''',<ref>SUBLIMAZE Injection | https://web.archive.org/web/20170702004717/http://www.janssen.com/australia/sites/www_janssen_com_australia/files/prod_files/live/sublimaze_pi.pdf</ref> '''Actiq''', '''Durogesic''', '''Duragesic''', '''Fentora''', '''Matrifen''', '''Haldid''', '''Onsolis''', '''Instanyl''',<ref>http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000959/WC500033142.pdf</ref> '''Abstral''',<ref>European public assessment report (EPAR) for Instanyl | http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000959/WC500033142.pdf</ref> '''Lazanda'''<ref>Lazanda (Fentanyl) Nasal Spray CII | https://web.archive.org/web/20170216184309/https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022569s005lbl.pdf</ref> among others<ref>Drugs.com, Fentanyl | http://www.drugs.com/international/fentanyl.html</ref>) is a potent [[Psychoactive class::opioid]] substance of the [[Chemical class::anilidopiperidine]] class. It is a strong [[agonist]] at the [[μ-opioid]] [[receptors]] and approximately 40 to 50 times more potent than pharmaceutical grade (i.e. 100% pure) [[heroin]]<ref>{{Citation | year=2021 | title=Fentanyl: Incapacitating Agent, NIOSH, CDC | url=https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750022.html}}</ref><ref>{{cite book | veditors=((Mutschler, E.)) | date= 2001 | title=Arzneimittelwirkungen: Lehrbuch der Pharmakologie und Toxikologie ; mit einführenden Kapiteln in die Anatomie, Physiologie und Pathophysiologie | publisher=Wiss. Verl.-Ges | edition=8., völlig neu bearb. und erw. Aufl | isbn=9783804717633}}</ref> and roughly 80 to 100 times more potent than [[morphine]].{{citation needed}}
A wide range of pharmaceutical fentanyl preparations are available, including transdermal skin patches, lollipops, buccal tablets or patches, nasal sprays, and inhalers.<ref>Drugs.com Fentanyl Fact Sheet https://www.drugs.com/dosage/fentanyl.html</ref> On the street, it is typically encountered in powder form, where it is often cut into or sold as heroin and other drugs, which has resulted in numerous accidental overdoses and fatalities.<ref>SAMHSA "Fact Sheet: Fentanyl-Laced Heroin and Cocaine" https://www.samhsa.gov/sites/default/files/programs_campaigns/medication_assisted/dear_colleague_letters/2013-colleague-letter-fentanyl-analogues.pdf</ref> In 2016, fentanyl and analogues were the most common cause of overdose deaths in the United States at more than 20,000, about half of all opioid-related deaths.<ref>{{Citation | vauthors=((Abuse, N. I. on D.)) | year=2018 | title=Nearly half of opioid-related overdose deaths involve fentanyl | url=https://nida.nih.gov/news-events/news-releases/2018/05/nearly-half-of-opioid-related-overdose-deaths-involve-fentanyl | access-date=14 June 2018}}</ref><ref>{{cite journal | vauthors=((Hedegaard, H.)), ((Bastian, B. A.)), ((Trinidad, J. P.)), ((Spencer, M.)), ((Warner, M.)) | journal=National Vital Statistics Reports: From the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System | title=Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2011-2016 | volume=67 | issue=9 | pages=1–14 | date= December 2018 | issn=1551-8922}}</ref>
[[Subjective effects]] are similar to those of [[heroin]] and includes [[pain relief]] (analgesia), [[sedation]], [[respiratory depression]], and [[euphoria]]. However, it has a rapid [[onset]] and short [[duration]] of action relative to other opioids, which can lead to [[compulsive redosing]]. Additionally, many users report noticeably less [[euphoria]] with fentanyl and its analogs. As a result, it is generally considered to have lower recreational value.
Fentanyl is a highly dangerous substance due its addictiveness and the difficulty with which it can be safely dosed, a result of its incredible potency. Users are advised to be aware of the extreme risk they are placing themselves in if they choose to use fentanyl. It is also highly advised to use [[harm reduction practices]] if a user chooses to do fentanyl. Users are also advised to test all of their opioids (and substances in general) for fentanyl and other adulterants using [[reagent testing kits]].
==History and culture==
Fentanyl was first synthesized by Paul Janssen in 1960<ref>{{cite journal | vauthors=((Stanley, T. H.)) | journal=Journal of Pain and Symptom Management | title=The history and development of the fentanyl series | volume=7 | issue=3 Suppl | pages=S3-7 | date= April 1992 | issn=0885-3924 | doi=10.1016/0885-3924(92)90047-l}}</ref> following the medical inception of pethidine several years earlier. Janssen developed fentanyl by assaying analogues of the structurally related substance pethidine for opioid activity.<ref>{{cite journal | vauthors=((Black, J.)) | journal=Journal of Medicinal Chemistry | title=A personal perspective on Dr. Paul Janssen | volume=48 | issue=6 | pages=1687–1688 | date=24 March 2005 | issn=0022-2623 | doi=10.1021/jm040195b}}</ref> The widespread use of fentanyl triggered the production of fentanyl citrate which entered the clinical practice as a general anesthetic 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 carfentanil.
In the mid-1990s, fentanyl was first introduced for widespread palliative use with the clinical introduction of the Duragesic patch. It was 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 through the delivery method of estradiol Mylan transdermal patches. As of 2012, fentanyl was the most widely used synthetic opioid in clinical practice<ref>FENTANYL AND ANALOGUES | http://livertox.nih.gov/FentanylAndAnalogues.htm</ref> with several new delivery methods now available, including a sublingual spray for cancer patients.<ref>{{Citation | title=Subsys (fentanyl sublingual spray), CenterWatch | url=https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4226-subsys-fentanyl-sublingual-spray}}</ref><ref>{{Citation | vauthors=((INSYS Therapeutics Inc)) | year=2013 | title=Open-label Multi-center Safety Trial of Fentanyl Sublingual Spray (Fentanyl SL Spray) for the Treatment of Breakthrough Cancer Pain | publisher=clinicaltrials.gov | url=https://clinicaltrials.gov/ct2/show/NCT00538863}}</ref> In 2013, 1700 kilograms were used globally.<ref>Narcotic Drugs Report 2014, UN | https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2014/Narcotic_Drugs_Report_2014.pdf</ref>
==Chemistry==
==Chemistry==
Fentanyl is a member of the phenylpiperdine class of synthetic opioids. Its structure features a piperidine ring bound at its nitrogen constituent R<sub>N</sub> to a phenyl ring through an ethyl chain. The opposite carbon of the piperidine ring is bonded to the nitrogen member of a propanamide group, a 3 carbon chain with a nitrogen constituent adjacent to a carbon bonded to a ketone oxygen. This propanamide group is also substituted with an additional phenyl ring at R<sub>N</sub>.
Fentanyl is a member of the [[anilidopiperidine]] class of synthetic [[opioids]]. Its structure features a [[piperidine]] ring bound at its nitrogen constituent R<sub>N</sub> to a phenyl ring through an ethyl chain. The opposite carbon of the piperidine ring is bonded to the nitrogen member of a propanamide group, a three carbon chain with a nitrogen constituent adjacent to a carbon bonded to a ketone oxygen. This propanamide group is also substituted with an additional phenyl ring at R<sub>N</sub>.
==Pharmacology==
==Pharmacology==
The recreational effects of this compound occur because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their [[physical euphoria|euphoria]], [[pain relief]] and [[anxiolytic]] effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.
The recreational effects of fentanyl occur because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their [[physical euphoria|euphoria]], [[pain relief]] and [[anxiolytic]] effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.
Fentanyl's strong potency in relation to that of morphine is largely due to its high [https://en.wikipedia.org/wiki/Lipophilicity lipophilicity] (the ability of a chemical compound to dissolve in fats, oils, and lipids). Because of this, it can more easily penetrate the central nervous system in comparison to other opioids.
Fentanyl's strong potency compared to that of morphine is mainly due to its high [https://en.wikipedia.org/wiki/Lipophilicity lipophilicity] (the ability of a chemical compound to dissolve in fats, oils, and lipids). Because of this, it can more easily penetrate the central nervous system in comparison to other opioids.
==Subjective effects==
==Subjective effects==
{{Preamble/SubjectiveEffects}}
{{Preamble/SubjectiveEffects}}
===Physical effects===
{{effects/base
|{{effects/physical|
*'''[[Effect::Sedation]]''' - Fentanyl can be described as much more sedating then other opiates. Even at moderate dosages, fentanyl can result in overwhelming feelings of sedation and tiredness that is considerably more sedating than that of [[heroin]] and [[oxycodone]].
*'''[[Effect::Pain relief]]''' - In comparison to other opiates, fentanyl can be described as a strong analgesic, providing relief even at non-recreational doses.
*'''[[Effect::Pain relief]]''' - In comparison to other opiates, fentanyl can be described as a strong analgesic, providing relief even at non-recreational doses.
*'''[[Effect::Physical euphoria]]''' - This particular substance can be considered as less intense in its physical euphoria when compared with that of [[morphine]] or [[diacetylmorphine]] (heroin). The sensation itself can be described as strong feelings of intense physical comfort, warmth and bliss which spread throughout the body.
*'''[[Effect::Physical euphoria]]''' - Fentanyl can be considered as less intense in its physical euphoria when compared with that of [[morphine]] or [[diacetylmorphine]] (heroin). The sensation itself can be described as strong feelings of intense physical comfort, warmth and bliss which spread throughout the body.
*'''[[Effect::Itchiness]]''' - This compound presents very little itch response due to little to no amounts of histamines being released, unlike other [[opioids]].
*'''[[Effect::Itchiness]]''' - Unlike other [[opioids]], fentanyl presents very little itch response due to little to no amounts of released [[histamines]].
*'''[[Effect::Respiratory depression]]''' - In comparison to other opiates, fentanyl displays this effect at lower doses relative to euphoria then other opiates, and even at low doses results in the sensation that the breath is slowed down mildly to moderately, but does not cause noticeable impairment. At high doses and overdoses, opioid-induced respiratory depression can result in a shortness of breath, abnormal breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses can result in a coma or death without immediate medical attention.
*'''[[Effect::Respiratory depression]]''' - In comparison to other opiates, fentanyl displays this effect at lower doses relative to euphoria than other opiates, and even at low doses results in the sensation that the breath is slowed down mildly to moderately, but does not cause noticeable impairment. At high doses and overdoses, opioid-induced respiratory depression can result in a shortness of breath, abnormal breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses can result in a coma or death without immediate medical attention.
*'''[[Effect::Sedation]]''' - Fentanyl can be described as much more sedating then other opiates. Even at moderate dosages, this compound can result in overwhelming feelings of sedation and tiredness that is considerably more sedating than that of [[heroin]] and [[oxycodone]].
*'''[[Effect::Constipation]]'''
*'''[[Effect::Constipation]]'''
*'''[[Effect::Cough suppression]]'''
*'''[[Effect::Cough suppression]]'''
Line 33:
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*'''[[Effect::Pupil constriction]]'''
*'''[[Effect::Pupil constriction]]'''
*'''[[Effect::Increased perspiration]]'''
*'''[[Effect::Increased perspiration]]'''
*'''[[Effect::Low blood pressure]]'''
*'''[[Effect::Decreased blood pressure]]'''
*'''[[Effect::Appetite suppression]]'''
*'''[[Effect::Appetite suppression]]'''
*'''[[Effect::Orgasm suppression]]'''
*'''[[Effect::Orgasm suppression]]'''
===Cognitive effects===
}}
*'''[[Effect::Cognitive euphoria]]''' - This particular substance can be considered as less intense in its cognitive euphoria when compared with that of [[morphine]] or [[diacetylmorphine]] (heroin) due to the upper limit of how much can be converted into its active form through metabolism. It is still, however, capable of extreme intensity and overwhelming bliss at heavier dosages with a low tolerance. The sensation itself can be described as powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
|{{effects/cognitive|
*'''[[Effect::Cognitive euphoria]]''' - Fentanyl can be considered less intense in its cognitive euphoria when compared with that of [[morphine]] or [[diacetylmorphine|heroin]]. It is still, however, capable of extreme intensity and overwhelming bliss at heavier dosages with a low tolerance. The sensation itself can be described as powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
*'''[[Effect::Anxiety suppression]]'''
*'''[[Effect::Anxiety suppression]]'''
*'''[[Effect::Compulsive redosing]]'''
*'''[[Effect::Compulsive redosing]]'''
*'''[[Effect::Dream potentiation]]'''
*'''[[Effect::Dream potentiation]]'''
}}
{{effects/visual|
====Suppressions====
*'''[[Effect::Double vision]]''' - At high doses, the eyes un-focus and re-focus uncontrollably. This creates a blurred effect and double vision that is present no matter where one focuses their eyes.
}}
}}
===Experience reports===
===Experience reports===
There are currently no anecdotal reports which describe the effects of this compound within our [[experience index]]. Additional experience reports can be found here:
There are currently no anecdotal reports which describe the effects of this compound within our [[experience index]]. Additional experience reports can be found here:
[[File:Heroin-Fentanyl-vials-NHSPFL-1024x576.jpg|350px|thumbnail|'''Fentanyl''' by ''New Hampshire state police forensic lab'' - This image serves as a portrayal of lethal doses for heroin and fentanyl.]]
[[File:Heroin-Fentanyl-vials-NHSPFL-1024x576.jpg|350px|thumbnail|'''Fentanyl''' by ''New Hampshire state police forensic lab'' - This image serves as a portrayal of lethal doses for heroin and fentanyl.]]
Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.<ref>DEA: Deaths from fentanyl-laced heroin surging | http://www.usatoday.com/story/news/2015/03/18/surge-in-overdose-deaths-from-fentanyl/24957967/</ref><ref>Prince died of accidental overdose of opioid fentanyl, medical examiner says - http://www.cnn.com/2016/06/02/health/prince-death-opioid-overdose/</ref> It is [[Toxicity::potentially fatal at heavy dosages]] and 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. 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. It is also [[Toxicity::potentially [[respiratory depression|lethal]] when mixed with [[depressants]] like [[alcohol]] or [[benzodiazepines]]]].
Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.<ref>{{Citation | title=DEA: Deaths from fentanyl-laced heroin surging | url=https://www.usatoday.com/story/news/2015/03/18/surge-in-overdose-deaths-from-fentanyl/24957967/}}</ref><ref>{{Citation | vauthors=((Sidner, R. E., Sara)) | year=2016 | title=Prince died of accidental overdose of opioid fentanyl, medical examiner says | url=https://www.cnn.com/2016/06/02/health/prince-death-opioid-overdose/index.html}}</ref> It is [[Toxicity::potentially fatal at heavy dosages]] and 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. 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. It is also [[Toxicity::potentially [[respiratory depression|lethal]] when mixed with [[depressants]] like [[alcohol]] or [[benzodiazepines]]]].
Like most opioids, unadulterated fentanyl at appropriate dosages does not cause many long-term complications other than dependence and [[constipation]]. Outside of the extremely powerful addiction and physical dependence, the harmful or toxic aspects of opioid usage are exclusively associated with not taking the necessary precautions in regards to its administration, overdosing and using impure products.
Like most opioids, pure fentanyl at appropriate dosages does not cause many long-term complications other than dependence and [[constipation]]. Outside of the extremely powerful addiction and physical dependence, the harmful or toxic aspects of opioid usage are exclusively associated with not taking the necessary precautions in regards to its administration, overdosing and using impure products.
It is important to consider that particular care must be taken with fentanyl due to its extreme potency and ability to be absorbed through the skin. This means that simply [[Toxicity::unintentionally spilling a very small amount of fentanyl on one's skin could result in a fatal overdose.]]
Fentanyl is very potent and around 1000 times more permeable than morphine.<ref name="LarsenNielsen2003">{{cite journal|last1=Larsen|first1=Rikke H.|last2=Nielsen|first2=Flemming|last3=Sorensen|first3=Jens A.|last4=Nielsen|first4=Jesper B.|title=Dermal Penetration of Fentanyl: Inter- and Intraindividual Variations|journal=Pharmacology and Toxicology|volume=93|issue=5|year=2003|pages=244–248|issn=0901-9928|doi=10.1046/j.1600-0773.2003.pto930508.x}}</ref> Even though fentanyl uptake through skin is rather slow<ref name="VarvelShafer1989">{{cite journal|last1=Varvel|first1=J. R.|last2=Shafer|first2=S. L.|last3=Hwang|first3=S. S.|last4=Coen|first4=P. A.|last5=Stanski|first5=D. R.|title=Absorption Characteristics of Transdermally Administered Fentanyl|journal=Anesthesiology|volume=70|issue=6|year=1989|pages=928–934|issn=0003-3022|doi=10.1097/00000542-198906000-00008}}</ref>, [[Toxicity::unintentionally transporting the substance from the skin by touching the mouth, nose or eyes is dangerous]].
Heavy dosages of fentanyl can result in [[Respiratory depression|respiratory depression]], leading onto fatal or dangerous levels of anoxia (oxygen deprivation). This occurs because the breathing reflex is suppressed by [[agonists|agonism]] of [[µ-opioid receptors]] proportional to the dosage consumed.
Heavy dosages of fentanyl can result in [[Respiratory depression|respiratory depression]], leading onto fatal or dangerous levels of anoxia (oxygen deprivation). This occurs because the breathing reflex is suppressed by [[agonists|agonism]] of [[µ-opioid]] [[receptors]] proportional to the dosage consumed.
Fentanyl can also cause nausea and vomiting; a significant number of deaths attributed to opioid overdose are caused by aspiration of vomit by an unconscious victim. This is when an unconscious or semi-conscious user who is lying on their back vomits into their mouth and unknowingly suffocates. It can be prevented by ensuring that one is lying on their side with their head tilted downwards so that the airways cannot be blocked in the event of vomiting while unconscious (also known as the [[recovery position]]). In case of overdose, it is advised to administer a dose of [[naloxone]] intravenously or intramuscularly to reverse the effects of opioid agonism.
Fentanyl can also cause nausea and vomiting; a significant number of deaths attributed to opioid overdose are caused by aspiration of vomit by an unconscious victim. This is when an unconscious or semi-conscious user who is lying on their back vomits into their mouth and unknowingly suffocates. It can be prevented by ensuring that one is lying on their side with their head tilted downwards so that the airways cannot be blocked in the event of vomiting while unconscious (also known as the [[recovery position]]). In the case of an overdose, it is advised to administer a dose of [[naloxone]] intravenously or intramuscularly to counteract the effects of the substance.
It is strongly recommended that one use [[responsible drug use|harm reduction practices]] when using this drug.
It is strongly recommended that one use [[responsible drug use|harm reduction practices]] when using this substance.
===Tolerance and addiction potential===
===Tolerance and addiction potential===
As with other [[opioids]], the chronic use of fentanyl can be considered [[Addiction potential::extremely addictive with a high potential for abuse]] and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and [[Opioids#Discontinuation|withdrawal symptoms]] may occur if a person suddenly stops their usage.
As with other [[opioids]], the chronic use of fentanyl can be considered [[Addiction potential::extremely addictive with a high potential for abuse]] and is capable of causing psychological and physical dependence among certain users. When addiction has developed, cravings and [[Opioids#Discontinuation|withdrawal symptoms]] may occur if a person suddenly stops their usage.
Tolerance to many of the effects of fentanyl [[Time to full tolerance::develops with prolonged and repeated use]]. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about [[Time to half tolerance::3 - 7 days]] for the tolerance to be reduced to half and [[Time to zero tolerance::1 - 2 weeks]] to be back at baseline (in the absence of further consumption). Fentanyl presents cross-tolerance with [[Cross-tolerance::all other [[opioids]]]], meaning that after the consumption of fentanyl all [[opioid]]s will have a reduced effect.
Tolerance to many of the effects of fentanyl [[Time to full tolerance::develops with prolonged and repeated use]]. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about [[Time to half tolerance::3 - 7 days]] for the tolerance to be reduced to half and [[Time to zero tolerance::1 - 2 weeks]] to be back at baseline (in the absence of further consumption). Fentanyl presents cross-tolerance with [[Cross-tolerance::all other [[opioids]]]], meaning that after the consumption of fentanyl all [[opioid]]s will have a reduced effect.
The risk of fatal opioid overdoses rise sharply after a period of cessation and [[relapse]], largely because of reduced tolerance.<ref>Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider) | http://www.businessinsider.com.au/philip-seymour-hoffman-overdose-2014-2</ref> To account for this lack of tolerance, it is safer to only dose a fraction of one's usual [[dosage]] if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment.<ref>Siegel, S., Hinson, R., Krank, M., & McCully, J. (1982). Heroin “overdose” death: contribution of drug-associated environmental cues. Science, 216(4544), 436–437. https://doi.org/10.1126/science.7200260</ref>
The risk of fatal opioid overdoses rise sharply after a period of cessation and [[relapse]], largely because of reduced tolerance.<ref>Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider) | http://www.businessinsider.com.au/philip-seymour-hoffman-overdose-2014-2</ref> To account for this lack of tolerance, it is safer to only dose a fraction of one's usual [[dosage]] if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the substance in contrast to a familiar environment.<ref>{{cite journal | vauthors=((Siegel, S.)), ((Hinson, R. E.)), ((Krank, M. D.)), ((McCully, J.)) | journal=Science | title=Heroin “Overdose” Death: Contribution of Drug-Associated Environmental Cues | volume=216 | issue=4544 | pages=436–437 | date=23 April 1982 | url=https://www.science.org/doi/10.1126/science.7200260 | issn=0036-8075 | doi=10.1126/science.7200260}}</ref>
===Dangerous interactions===
===Dangerous interactions===
Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. [https://www.google.com/ Independent research] should always be done to ensure that a combination of two or more substances is safe before consumption.
{{DangerousInteractions/Intro}}
*'''[[Depressants]]''' (''[[1,4-Butanediol]], [[2m2b]], [[alcohol]], [[barbiturates]], [[benzodiazepines]], [[GHB]]/[[GBL]], [[methaqualone]]'') - This combination can result in dangerous or even fatal levels of [[respiratory depression]]. These substances potentiate the [[muscle relaxation]], [[sedation]] and [[amnesia]] caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the [[recovery position]] or have a friend move them into it.
{{DangerousInteractions/Opioids}}
*'''[[Dissociatives]]''' - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the [[recovery position]] or have a friend move them into it.
*'''[[Stimulants]]''' - It is dangerous to combine fentanyl, a [[depressant]], with [[stimulant]]s due to the risk of excessive intoxication. Stimulants decrease the [[sedation|sedative]] effect of fentanyl, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of fentanyl will be significantly increased, leading to intensified [[disinhibition]] as well as [[fentanyl#Subjective effects|other effects]]. If combined, one should strictly limit themselves to taking a certain amount of fentanyl.
==Legal issues==
====[[Serotonin syndrome]] risk====
{{LegalStub}}
{{DangerousInteractions/SerotoninSyndrome}}
==History==
==Legal status==
Fentanyl was first synthesized by Paul Janssen in 1960<ref>The history and development of the fentanyl series (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/1517629</ref> following the medical inception of pethidine several years earlier. Janssen developed fentanyl by assaying analogues of the structurally related drug pethidine for opioid activity.<ref>A personal perspective on Dr. Paul Janssen (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/15771410</ref> The widespread use of fentanyl triggered the production of fentanyl citrate 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 carfentanil.
In the mid-1990s, fentanyl was first introduced for widespread palliative use with the clinical introduction of the Duragesic patch. It was 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 through the delivery method of estradiol Mylan transdermal patches. As of 2012, fentanyl was the most widely used synthetic opioid in clinical practice<ref>FENTANYL AND ANALOGUES | http://livertox.nih.gov/FentanylAndAnalogues.htm</ref> with several new delivery methods now available, including a sublingual spray for cancer patients.<ref>Subsys (fentanyl sublingual spray) | http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/1179/subsys-fentanyl-sublingual-spray</ref><ref>https://clinicaltrials.gov/ct2/show/NCT00538863</ref> In 2013, 1700 kilograms were used globally.<ref>https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2014/Narcotic_Drugs_Report_2014.pdf</ref>
*'''Austria:''' Fentanyl is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).{{citation needed}}
*'''Australia:''' Fentanyl is placed under Schedule 8, meaning that it is available for medical use, but possession, production or supply of it is illegal without authority. <ref>{{Citation | title=Poisons Standard February 2019 | url=https://www.legislation.gov.au/Details/F2019L00032/Html/Text#_Toc532805057}}</ref>
*'''Canada:''' Fentanyl is a Schedule I drug in Canada's Controlled Drugs and Substance Act.<ref>{{Citation | vauthors=((Branch, L. S.)) | year=2022 | title=Consolidated federal laws of Canada, Controlled Drugs and Substances Act | url=https://laws.justice.gc.ca/eng/acts/C-38.8/page-12.html#h-34}}</ref>
*'''Germany:''' Fentanyl is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.<ref>http://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html</ref>
*'''Netherlands:''' Fentanyl is a List I substance of the Opium Law.
*'''Russia:''' Fentanyl is a Schedule II controlled substance.<ref>{{Citation | title=Постановление Правительства РФ от 01.10.2012 N 1002 (ред. от 09.08.2019 | url=https://www.consultant.ru/cons/cgi/online.cgi?req=doc&base=LAW&n=331879&dst=100294&date=03.12.2019}}</ref>
*'''Switzerland''': Fentanyl is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.<ref>{{cite web|url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html|title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien|publisher=Bundeskanzlei [Federal Chancellery of Switzerland]|access-date=January 1, 2020|language=de}}</ref>
*'''Turkey''': Fentanyl is a 'red prescription' only substance<ref>KIRMIZI REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/K%C4%B1rm%C4%B1z%C4%B1%20Re%C3%A7eteye%20Tabi%20%C4%B0la%C3%A7lar%2005072019_ebcc7e92-6661-4983-870a-fe8983a9c2b7.pdf</ref> and illegal when sold or possessed without a prescription.{{citation needed}}
*'''United Kingdom:''' Fentanyl is a controlled Class A drug under the Misuse of Drugs Act 1971.<ref>{{Citation | title=Misuse of Drugs Act 1971 | url=https://www.legislation.gov.uk/ukpga/1971/38/schedule/2}}</ref>
*'''United States:''' 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. Health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.
It is strongly encouraged to wear gloves while handling, use volumetric dosing combined with a milligram scale, and to not consume either moderate or heavy dosages of other depressants in combination with this drug.
WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.
DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.
Fentanyl (also known as Fentanil and by the brand names Sublimaze,[2]Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis, Instanyl,[3]Abstral,[4]Lazanda[5] among others[6]) is a potent opioid substance of the anilidopiperidine class. It is a strong agonist at the μ-opioidreceptors and approximately 40 to 50 times more potent than pharmaceutical grade (i.e. 100% pure) heroin[7][8] and roughly 80 to 100 times more potent than morphine.[citation needed]
A wide range of pharmaceutical fentanyl preparations are available, including transdermal skin patches, lollipops, buccal tablets or patches, nasal sprays, and inhalers.[9] On the street, it is typically encountered in powder form, where it is often cut into or sold as heroin and other drugs, which has resulted in numerous accidental overdoses and fatalities.[10] In 2016, fentanyl and analogues were the most common cause of overdose deaths in the United States at more than 20,000, about half of all opioid-related deaths.[11][12]
Fentanyl is a highly dangerous substance due its addictiveness and the difficulty with which it can be safely dosed, a result of its incredible potency. Users are advised to be aware of the extreme risk they are placing themselves in if they choose to use fentanyl. It is also highly advised to use harm reduction practices if a user chooses to do fentanyl. Users are also advised to test all of their opioids (and substances in general) for fentanyl and other adulterants using reagent testing kits.
Fentanyl was first synthesized by Paul Janssen in 1960[13] following the medical inception of pethidine several years earlier. Janssen developed fentanyl by assaying analogues of the structurally related substance pethidine for opioid activity.[14] The widespread use of fentanyl triggered the production of fentanyl citrate which entered the clinical practice as a general anesthetic 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 carfentanil.
In the mid-1990s, fentanyl was first introduced for widespread palliative use with the clinical introduction of the Duragesic patch. It was 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 through the delivery method of estradiol Mylan transdermal patches. As of 2012, fentanyl was the most widely used synthetic opioid in clinical practice[15] with several new delivery methods now available, including a sublingual spray for cancer patients.[16][17] In 2013, 1700 kilograms were used globally.[18]
Chemistry
Fentanyl is a member of the anilidopiperidine class of synthetic opioids. Its structure features a piperidine ring bound at its nitrogen constituent RN to a phenyl ring through an ethyl chain. The opposite carbon of the piperidine ring is bonded to the nitrogen member of a propanamide group, a three carbon chain with a nitrogen constituent adjacent to a carbon bonded to a ketone oxygen. This propanamide group is also substituted with an additional phenyl ring at RN.
Pharmacology
The recreational effects of fentanyl occur because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their euphoria, pain relief and anxiolytic effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.
Fentanyl's strong potency compared to that of morphine is mainly due to its high lipophilicity (the ability of a chemical compound to dissolve in fats, oils, and lipids). Because of this, it can more easily penetrate the central nervous system in comparison to other opioids.
Subjective effects
Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWikicontributors. As a result, they should be viewed with a healthy degree of skepticism.
It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.
Physical effects
Sedation - Fentanyl can be described as much more sedating then other opiates. Even at moderate dosages, fentanyl can result in overwhelming feelings of sedation and tiredness that is considerably more sedating than that of heroin and oxycodone.
Pain relief - In comparison to other opiates, fentanyl can be described as a strong analgesic, providing relief even at non-recreational doses.
Physical euphoria - Fentanyl can be considered as less intense in its physical euphoria when compared with that of morphine or diacetylmorphine (heroin). The sensation itself can be described as strong feelings of intense physical comfort, warmth and bliss which spread throughout the body.
Itchiness - Unlike other opioids, fentanyl presents very little itch response due to little to no amounts of released histamines.
Respiratory depression - In comparison to other opiates, fentanyl displays this effect at lower doses relative to euphoria than other opiates, and even at low doses results in the sensation that the breath is slowed down mildly to moderately, but does not cause noticeable impairment. At high doses and overdoses, opioid-induced respiratory depression can result in a shortness of breath, abnormal breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses can result in a coma or death without immediate medical attention.
Cognitive euphoria - Fentanyl can be considered less intense in its cognitive euphoria when compared with that of morphine or heroin. It is still, however, capable of extreme intensity and overwhelming bliss at heavier dosages with a low tolerance. The sensation itself can be described as powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
Double vision - At high doses, the eyes un-focus and re-focus uncontrollably. This creates a blurred effect and double vision that is present no matter where one focuses their eyes.
Experience reports
There are currently no anecdotal reports which describe the effects of this compound within our experience index. Additional experience reports can be found here:
Fentanyl by New Hampshire state police forensic lab - This image serves as a portrayal of lethal doses for heroin and fentanyl.
Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.[19][20] It is potentially fatal at heavy dosages and 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. 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. It is also [[Toxicity::potentially lethal when mixed with depressants like alcohol or benzodiazepines]].
Like most opioids, pure fentanyl at appropriate dosages does not cause many long-term complications other than dependence and constipation. Outside of the extremely powerful addiction and physical dependence, the harmful or toxic aspects of opioid usage are exclusively associated with not taking the necessary precautions in regards to its administration, overdosing and using impure products.
Fentanyl is very potent and around 1000 times more permeable than morphine.[21] Even though fentanyl uptake through skin is rather slow[22], unintentionally transporting the substance from the skin by touching the mouth, nose or eyes is dangerous.
Heavy dosages of fentanyl can result in respiratory depression, leading onto fatal or dangerous levels of anoxia (oxygen deprivation). This occurs because the breathing reflex is suppressed by agonism of µ-opioidreceptors proportional to the dosage consumed.
Fentanyl can also cause nausea and vomiting; a significant number of deaths attributed to opioid overdose are caused by aspiration of vomit by an unconscious victim. This is when an unconscious or semi-conscious user who is lying on their back vomits into their mouth and unknowingly suffocates. It can be prevented by ensuring that one is lying on their side with their head tilted downwards so that the airways cannot be blocked in the event of vomiting while unconscious (also known as the recovery position). In the case of an overdose, it is advised to administer a dose of naloxone intravenously or intramuscularly to counteract the effects of the substance.
As with other opioids, the chronic use of fentanyl can be considered extremely addictive with a high potential for abuse and is capable of causing psychological and physical dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.
Tolerance to many of the effects of fentanyl develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Fentanyl presents cross-tolerance with [[Cross-tolerance::all other opioids]], meaning that after the consumption of fentanyl all opioids will have a reduced effect.
The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance.[23] To account for this lack of tolerance, it is safer to only dose a fraction of one's usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the substance in contrast to a familiar environment.[24]
Dangerous interactions
Warning:Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).
Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely
Stimulants - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the user and cause respiratory arrest.
Benzodiazepines - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position blackouts/memory loss likely.
DXM - Generally considered to be toxic. CNS depression, difficulty breathing, heart issues, and liver toxicity have been observed. Additionally if one takes DXM, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
GHB/GBL - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position
Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
MXE - MXE can potentiate the effects of opioids but also increases the risk of respiratory depression and organ toxicity.
Nitrous - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are common.
PCP - PCP may reduce opioid tolerance, increasing the risk of overdose.
Tramadol - Increased risk of seizures. Tramadol itself is known to induce seizures and it may have additive effects on seizure threshold with other opioids. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present.
Grapefruit - While grapefruit is not psychoactive, it may affect the metabolism of certain opioids. Tramadol, oxycodone, and fentanyl are all primarily metabolized by the enzyme CYP3A4, which is potently inhibited by grapefruit juice[25]. This may cause the drug to take longer to clear from the body. it may increase toxicity with repeated doses. Methadone may also be affected[25]. Codeine and hydrocodone are metabolized by CYP2D6. People who are on medicines that inhibit CYP2D6, or that lack the enzyme due to a genetic mutation will not respond to codeine as it can not be metabolized into its active product: morphine.
Combinations with the following substances can cause dangerously high serotonin levels. Serotonin syndrome requires immediate medical attention and can be fatal if left untreated.
Austria: Fentanyl is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).[citation needed]
Australia: Fentanyl is placed under Schedule 8, meaning that it is available for medical use, but possession, production or supply of it is illegal without authority. [27]
Canada: Fentanyl is a Schedule I drug in Canada's Controlled Drugs and Substance Act.[28]
Germany: Fentanyl is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.[29]
Netherlands: Fentanyl is a List I substance of the Opium Law.
Russia: Fentanyl is a Schedule II controlled substance.[30]
Switzerland: Fentanyl is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.[31]
Turkey: Fentanyl is a 'red prescription' only substance[32] and illegal when sold or possessed without a prescription.[citation needed]
United Kingdom: Fentanyl is a controlled Class A drug under the Misuse of Drugs Act 1971.[33]
United States: 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. Health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.
↑Mutschler, E., ed. (2001). Arzneimittelwirkungen: Lehrbuch der Pharmakologie und Toxikologie ; mit einführenden Kapiteln in die Anatomie, Physiologie und Pathophysiologie (8., völlig neu bearb. und erw. Aufl ed.). Wiss. Verl.-Ges. ISBN9783804717633.
↑Hedegaard, H., Bastian, B. A., Trinidad, J. P., Spencer, M., Warner, M. (December 2018). "Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2011-2016". National Vital Statistics Reports: From the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System. 67 (9): 1–14. ISSN1551-8922.
↑Stanley, T. H. (April 1992). "The history and development of the fentanyl series". Journal of Pain and Symptom Management. 7 (3 Suppl): S3–7. doi:10.1016/0885-3924(92)90047-l. ISSN0885-3924.
↑Black, J. (24 March 2005). "A personal perspective on Dr. Paul Janssen". Journal of Medicinal Chemistry. 48 (6): 1687–1688. doi:10.1021/jm040195b. ISSN0022-2623.
↑Larsen, Rikke H.; Nielsen, Flemming; Sorensen, Jens A.; Nielsen, Jesper B. (2003). "Dermal Penetration of Fentanyl: Inter- and Intraindividual Variations". Pharmacology and Toxicology. 93 (5): 244–248. doi:10.1046/j.1600-0773.2003.pto930508.x. ISSN0901-9928.
↑Varvel, J. R.; Shafer, S. L.; Hwang, S. S.; Coen, P. A.; Stanski, D. R. (1989). "Absorption Characteristics of Transdermally Administered Fentanyl". Anesthesiology. 70 (6): 928–934. doi:10.1097/00000542-198906000-00008. ISSN0003-3022.
. eISSN 1471-6771. ISSN 0007-0912. OCLC 01537271. PMID 16051647.