Fentanyl

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This substance is extraordinarily potent (i.e. active in the microgram range). For this reason, it should be handled with extreme care and never be eyeballed. Fentanyl can also be fatal when combined with depressants such as opiates, benzodiazepines, barbiturates, gabapentinoids, thienodiazepines or other GABAergic substances.[1]

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.

Summary sheet: Fentanyl
Fentanyl
Fentanyl.svg
Chemical Nomenclature
Common names Fentanyl, fentanil, Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis, Instanyl, Abstral, Lazanda
Systematic name N-(1-(2-Phenylethyl)-4-piperidinyl)-N-phenylpropanamide
Class Membership
Psychoactive class Opioid
Chemical class Piperidine
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.





⇣ Sublingual
Dosage
Bioavailability 50%[citation needed]
Threshold 5 - 10 μg
Light 10 - 25 μg
Common 25 - 50 μg
Strong 50 - 75 μg
Heavy 75 μg +
Duration
Total 1 - 4 hours
Onset 15 - 30 minutes
⇣ Insufflated
Dosage
Bioavailability 89%[citation needed]
Threshold 5 - 10 μg
Light 10 - 25 μg
Common 25 - 50 μg
Strong 50 - 75 μg
Heavy 75 μg +
Duration
Total 1 - 4 hours
Onset 15 - 30 minutes


⇣ Transdermal
Dosage
Bioavailability 92%[citation needed]
Threshold 5 - 12 μg
Light 12 - 25 μg
Common 25 - 50 μg
Strong 50 - 100 μg
Heavy 100 μg +
Duration
Total 48 - 72 hours
Onset 2 - 4 hours




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.

Interactions
MAOIs
Nitrous
PCP
Stimulants
SNRIs
Alcohol
Benzodiazepines
DXM
GHB
GBL
Ketamine
MXE
Tramadol
Grapefruit
MAOIs
Serotonin releasers
SSRIs
5-HTP


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-opioid receptors 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]

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 low 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. 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[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 PsychonautWiki contributors. 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.
    • Constipation
    • Cough suppression
    • Decreased libido
    • Difficulty urinating
    • Pupil constriction
    • Increased perspiration
    • Decreased blood pressure
    • Appetite suppression
    • Orgasm suppression

Cognitive effects
 

    • Cognitive euphoria - Fentanyl can be considered less intense in its cognitive euphoria when compared with that of morphine or 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.
    • Anxiety suppression
    • Compulsive redosing
    • Dream potentiation

Visual effects
 

  • Suppressions

    • 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:

Toxicity and harm potential

 
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 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-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 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 harm reduction practices when using this substance.

Tolerance and addiction potential

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 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.

Serotonin syndrome risk

Combinations with the following substances can cause dangerously high serotonin levels. Serotonin syndrome requires immediate medical attention and can be fatal if left untreated.

Legal status

  • 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.

See also

External links

References

  1. ↑ Risks of Combining Depressants - TripSit 
  2. ↑ 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
  3. ↑ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000959/WC500033142.pdf
  4. ↑ 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
  5. ↑ Lazanda (Fentanyl) Nasal Spray CII | https://web.archive.org/web/20170216184309/https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022569s005lbl.pdf
  6. ↑ Drugs.com, Fentanyl | http://www.drugs.com/international/fentanyl.html
  7. ↑ Fentanyl: Incapacitating Agent, NIOSH, CDC, 2021 
  8. ↑ 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. ISBN 9783804717633. 
  9. ↑ Drugs.com Fentanyl Fact Sheet https://www.drugs.com/dosage/fentanyl.html
  10. ↑ 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
  11. ↑ Abuse, N. I. on D. (2018), Nearly half of opioid-related overdose deaths involve fentanyl, retrieved 14 June 2018 
  12. ↑ 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. ISSN 1551-8922. 
  13. ↑ 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. ISSN 0885-3924. 
  14. ↑ Black, J. (24 March 2005). "A personal perspective on Dr. Paul Janssen". Journal of Medicinal Chemistry. 48 (6): 1687–1688. doi:10.1021/jm040195b. ISSN 0022-2623. 
  15. ↑ FENTANYL AND ANALOGUES | http://livertox.nih.gov/FentanylAndAnalogues.htm
  16. ↑ Subsys (fentanyl sublingual spray), CenterWatch 
  17. ↑ INSYS Therapeutics Inc (2013), Open-label Multi-center Safety Trial of Fentanyl Sublingual Spray (Fentanyl SL Spray) for the Treatment of Breakthrough Cancer Pain, clinicaltrials.gov 
  18. ↑ Narcotic Drugs Report 2014, UN | https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2014/Narcotic_Drugs_Report_2014.pdf
  19. ↑ DEA: Deaths from fentanyl-laced heroin surging 
  20. ↑ Sidner, R. E., Sara (2016), Prince died of accidental overdose of opioid fentanyl, medical examiner says 
  21. ↑ 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. ISSN 0901-9928. 
  22. ↑ 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. ISSN 0003-3022. 
  23. ↑ Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider) | http://www.businessinsider.com.au/philip-seymour-hoffman-overdose-2014-2
  24. ↑ Siegel, S., Hinson, R. E., Krank, M. D., McCully, J. (23 April 1982). "Heroin "Overdose" Death: Contribution of Drug-Associated Environmental Cues". Science. 216 (4544): 436–437. doi:10.1126/science.7200260. ISSN 0036-8075. 
  25. ↑ 25.0 25.1 Ershad, M., Cruz, M. D., Mostafa, A., Mckeever, R., Vearrier, D., Greenberg, M. I. (March 2020). "Opioid Toxidrome Following Grapefruit Juice Consumption in the Setting of Methadone Maintenance". Journal of Addiction Medicine. 14 (2): 172–174. doi:10.1097/ADM.0000000000000535. ISSN 1932-0620. 
  26. ↑ Gillman, P. K. (2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia. 95 (4): 434–441. doi:10.1093/bja/aei210  . eISSN 1471-6771. ISSN 0007-0912. OCLC 01537271. PMID 16051647. 
  27. ↑ Poisons Standard February 2019 
  28. ↑ Branch, L. S. (2022), Consolidated federal laws of Canada, Controlled Drugs and Substances Act 
  29. ↑ http://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html
  30. ↑ Постановление Правительства РФ от 01.10.2012 N 1002 (ред. от 09.08.2019 
  31. ↑ "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020. 
  32. ↑ 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
  33. ↑ Misuse of Drugs Act 1971 


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