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Dihydrocodeine: Difference between revisions
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{{DepressantOD|opiates}} | <br />{{headerpanel|{{DepressantOD|opiates}}}} | ||
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{{SubstanceBox/Dihydrocodeine}} | {{SubstanceBox/Dihydrocodeine}} | ||
'''Dihydrocodeine''' is a semi-synthetic [[chemical class::morphinan]] [[psychoactive class::opioid]] [[analgesic]] prescribed for pain, or as an [[antitussive]] (either alone or compounded with paracetamol or aspirin). It was developed in Germany in 1908 and first marketed in 1911.<ref>{{cite book | vauthors=((Stolerman, I.)) | date=31 July 2010 | title=Encyclopedia of Psychopharmacology | publisher=Springer Science & Business Media | isbn=9783540686989}}</ref> | |||
Dihydrocodeine is | Dihydrocodeine is also known as ''Drocode, Paracodeine and Parzone.'' Its many brand names include ''Synalgos DC, Panlor DC, Panlor SS, Contugesic, Bron Tablet, New Bron Solution-ACE, Pabron S Gold W Tablets, Huscode, Drocode, Paracodin,''<ref name=":0">{{Citation | year=2019 | title=Dihydrocodein - Wirkstoff & Medikamente, Gelbe Liste | url=https://web.archive.org/web/20190525105330/https://www.gelbe-liste.de/wirkstoffe/Dihydrocodein_1788}}</ref> ''Codidol, Dehace, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DHC,''<ref name=":0" /> ''DH-Codeine, Didrate, Dihydrin, Hydrocodin, Makatussin, Nadeine, Novicodin, Rapacodin, Paramol, Remedeine, Dico and DF-118''. | ||
Dihydrocodeine is used as an alternative or adjunct to [[codeine]] and is similar in chemical structure. | Dihydrocodeine is available as tablets, solutions, elixirs, and other oral forms. In some countries, the drug is available as an injectable solution for deep subcutaneous and intra-muscular administration. As with codeine, intravenous administration should be avoided as it could result in anaphylaxis and dangerous pulmonary edema. Dihydrocodeine is available in suppository form on prescription.{{citation needed}} | ||
Dihydrocodeine is used as an alternative or adjunct to [[codeine]] and is similar in chemical structure. Dihydrocodeine is generally considered to have up to twice as strong analgesic effects as codeine.<ref>{{cite journal | vauthors=((Leppert W. Dihydrocodeine as an opioid analgesic for the treatment of moderate to severe chronic pain. Curr Drug Metab. 2010 Jul;11(6):494-506. doi: 10.2174/138920010791636211. PMID: 20540693.}}</ref> It is also noteworthy that Dihydrocodeine has no ceiling effect unlike codeine (considered to be around 200-600mg/day) <ref>{{cite journal | vauthors=((Shiratsuchi T, Ogawa S. [Weak opioids]. Nihon Rinsho. 2001 Sep;59(9):1795-9. Japanese. PMID: 11554054.}}</ref>, meaning with Dihydrocodeine you can, theoretically, achieve more euphoria the higher the dose, which codeine can’t due to the so-called ceiling effect. | |||
==Chemistry== | ==Chemistry== | ||
Dihydrocodeine | Dihydrocodeine, or 4,5-alpha-epoxy-3-methoxy-17-methylmorphinan-6-ol, is an opioid of the morphinan class. Dihydrocodeine and other molecules of this class contain a polycyclic core of three benzene rings fused in a zig-zag pattern called a phenanthrene. A fourth nitrogen containing ring is fused to the phenanthrene at R<sub>9</sub> and R<sub>13</sub> with the nitrogen member looking at R<sub>17</sub> of the combined structure. This structure is called morphinan. | ||
Dihydrocodeine, along with other morphinans, contains an ether bridge between two of its rings, connecting R<sub>4</sub> and R<sub>5</sub> through an oxygen group. It also contains a hydroxy group (OH-) bound at R<sub>6</sub> and a methyl group located on the nitrogen atom at R<sub>17</sub>. On the same ring containing the hydroxy group, codeine contains a double bond, which dihydrocodeine lacks. This results in a much more stable chemical structure and also affects its metabolism. | |||
Dihydrocodeine can be synthesized from morphine by reduction of the 7,8-double bond. It readily converts to [[dihydromorphine]] with high yields (>95%) which can be methylated to create dihydrocodeine. Dihydrocodeine is analogous to the other morphinans including [[codeine]], [[heroin]], [[ethylmorphine]], [[hydrocodone]], and [[oxycodone]]. | |||
==Pharmacology== | ==Pharmacology== | ||
Dihydrocodeine | Dihydrocodeine exerts its effects by binding to and activating the [[Opioid#Mu_.28.CE.BC.29|μ-opioid]] [[receptor]]. This occurs 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.{{citation needed}} | ||
Dihydrocodeine is metabolized via CYP2D6 to the active metabolite dihydromorphine, which has a potency similar to morphine. Other weakly active metabolites include nordihydrocodeine (which is formed via CYP3A4) and dihydrocodeine-6-glucuronide.<ref>{{cite journal | vauthors=((Kirkwood, L. C.)), ((Nation, R. L.)), ((Somogyi, A. A.)) | journal=British Journal of Clinical Pharmacology | title=Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine | volume=44 | issue=6 | pages=549–555 | date= December 1997 | url=http://doi.wiley.com/10.1046/j.1365-2125.1997.t01-1-00626.x | issn=03065251 | doi=10.1046/j.1365-2125.1997.t01-1-00626.x}}</ref> Although dihydrocodeine does have extremely active metabolites in the form of dihydromorphine and dihydromorphine-6-glucuronide, these metabolites are produced in such a small amount that they do not have clinically important effects.<ref>{{cite journal | vauthors=((Schmidt, H.)), ((Vormfelde, S. V.)), ((Walchner-Bonjean, M.)), ((Klinder, K.)), ((Freudenthaler, S.)), ((Gleiter, C. H.)), ((Gundert-Remy, U.)), ((Skopp, G.)), ((Aderjan, R.)), ((Fuhr, U.)) | journal=International Journal of Clinical Pharmacology and Therapeutics | title=The role of active metabolites in dihydrocodeine effects | volume=41 | issue=3 | pages=95–106 | date= March 2003 | issn=0946-1965 | doi=10.5414/cpp41095}}</ref> | |||
===Binding affinities (K<sub>i</sub>)<ref name="Schmidt2002">{{cite journal | vauthors=((Schmidt, H.)), ((Vormfelde, S. V.)), ((Klinder, K.)), ((Gundert-Remy, U.)), ((Gleiter, C. H.)), ((Skopp, G.)), ((Aderjan, R.)), ((Fuhr, U.)) | journal=Pharmacology & Toxicology | title=Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors: DIHYDROCODEINE BINDING TO OPIOID RECEPTORS | volume=91 | issue=2 | pages=57–63 | date= August 2002 | url=http://doi.wiley.com/10.1034/j.1600-0773.2002.910203.x | issn=09019928 | doi=10.1034/j.1600-0773.2002.910203.x}}</ref>=== | |||
*Mu opioid agonist - 325 nM | |||
*Kappa opioid agonist - 14242 nM | |||
*Delta opioid agonist - 5905 nM | |||
Dihydrocodeine itself is a weak ligand for the opioid receptors however its main active metabolite - [[dihydromorphine]] and one of its metabolites - dihydromorphine-6-O-glucuronide show much stronger agonistic effects.<ref name="Schmidt2002"/> | |||
==Subjective effects== | ==Subjective effects== | ||
{{Preamble/SubjectiveEffects}} | |||
{{effects/base | |||
|{{effects/physical| | |||
*'''[[Effect::Pain relief]]''' - This | In comparison to [[codeine]], this compound can be generally described as significantly more euphoric and with less itchiness. | ||
*'''[[Effect::Physical euphoria|Euphoria]]''' - This particular substance can be considered as less intense in its physical euphoria when compared with that of [[morphine]] or [[diacetylmorphine]] | |||
*'''[[Effect::Pain relief]]''' | |||
*'''[[Effect::Itchiness]]''' - This effect is less intense in comparison to [[codeine]]. | |||
*'''[[Effect::Physical euphoria|Euphoria]]''' - This particular substance can be considered as less intense in its physical 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. However, may be considered more euphoric than [[codeine]] due to its more powerful analgesic effects. The sensation itself can be described as extreme feelings of intense physical comfort, warmth and bliss which spreads throughout the body. | |||
*'''[[Effect::Respiratory depression]]''' - At low to moderate doses, this effect 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]]''' - At low to moderate doses, this effect 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]]''' - | *'''[[Effect::Sedation]]''' - At higher dosages, this compound can result in feelings of sedation and is considerably more sedating than that of [[oxycodone]] and [[hydrocodone]]. | ||
*'''[[Effect::Constipation]]''' | *'''[[Effect::Constipation]]''' | ||
*'''[[Effect::Cough suppression]]''' | *'''[[Effect::Cough suppression]]''' | ||
*'''[[Effect::Difficulty urinating]]''' | *'''[[Effect::Difficulty urinating]]''' | ||
*'''[[Effect::Pupil constriction]]''' | *'''[[Effect::Pupil constriction]]''' | ||
*'''[[Effect:: | *'''[[Effect::Decreased libido]]''' | ||
*'''[[Effect::Appetite suppression]]''' | |||
*'''[[Effect::Orgasm suppression]]''' | |||
}} | |||
|{{effects/cognitive| | |||
The general head space of dihydrocodeine is described by many as one of intense euphoria, relaxation, anxiety suppression and pain relief. | |||
*'''[[Effect::Cognitive euphoria|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 can be overwhelming at heavier dosages with a low tolerance. The sensation itself can be described as powerful and overwhelming feelings of emotional bliss, contentment, and happiness. | |||
*'''[[Effect::Cognitive euphoria|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 | |||
*'''[[Effect::Anxiety suppression]]''' | *'''[[Effect::Anxiety suppression]]''' | ||
*'''[[Effect::Compulsive redosing]]''' | *'''[[Effect::Compulsive redosing]]''' | ||
*'''[[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<ref>{{Citation | title=Dihydrocodeine Tablets 30mg - Patient Information Leaflet (PIL) - (emc) | url=https://www.medicines.org.uk/emc/medicine/18064}}</ref> 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: | |||
*[https://www.erowid.org/experiences/subs/exp_Pharms_Dihydrocodeine.shtml Erowid Experience Vaults: Dihydrocodeine] | |||
==Toxicity and harm potential== | ==Toxicity and harm potential== | ||
Dihydrocodeine has a [[Toxicity::low toxicity]] relative to dose. As with all opiates, long-term effects can vary but can include diminished libido, apathy and memory loss. Some people may also have an allergic reaction to dihydrocodeine, such as the swelling of skin and rashes. It is also [[Toxicity::potentially [[respiratory depression|lethal]] when mixed with [[depressants]] like [[alcohol]] or [[benzodiazepines]]]]. | |||
It is strongly recommended that one use [[responsible drug use|harm reduction practices]] when using this drug. | |||
===Tolerance and addiction potential=== | ===Tolerance and addiction potential=== | ||
Tolerance to many of the effects of | As with other [[opioids]], the chronic use of dihydrocodeine can be considered [[Addiction potential::moderately 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. | ||
Tolerance to many of the effects of dihydrocodeine [[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). Dihydrocodeine presents cross-tolerance with [[Cross-tolerance::all other [[opioids]]]], meaning that after the consumption of dihydrocodeine all [[opioids]] will have a reduced effect. | |||
===Dangerous interactions=== | |||
{{DangerousInteractions/Intro}} | |||
{{DangerousInteractions/Opioids}} | |||
==Legal | ==Legal status== | ||
====Hong Kong | |||
In Hong Kong, dihydrocodeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. A pharmacist can dispense Dihydrocodeine when furnished with a doctors prescription. Anyone who supplies the substance without a prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption, without a licence from the Department of Health, is illegal and carries a $1,000,000 (HKD) fine and/or 7 years imprisonment. | *'''Austria:''' Dihydrocodeine 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:''' Dihydrocodeine is a Schedule 3 medicine meaning it is available without prescription but is stored behind the counter at a pharmacy. Consultation with pharmacist is required for purchase. It is most commonly available as an oral liquid (Brand name Rikodeine) at a dose of 19mg/10mL in 100 or 200mL bottles. | |||
In Japan, dihydrocodeine is available without a prescription; used in cough medicines such as New Bron Solution-ACE. Dihydrocodeine is used as an antitussive in many products as a Dextromethorphan alternative. Medicines in Japan which contain dihydrocodeine are coupled with caffeine to offset the sedative effects and discourage recreational use. Cough medicines containing dihydrocodeine are controlled similarly to | <ref>https://www.nps.org.au/medicine-finder/rikodeine-oral-liquid </ref> | ||
==== | <ref>https://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=10587</ref> | ||
In the United Kingdom, dihydrocodeine is a Class B drug; but, it is available over-the-counter in small amounts (less than 8 mg), when combined with paracetamol (see co-dydramol). Dihydrocodeine is listed in Schedule 5 of the Misuse of Drugs Regulations 2001 whereby it is exempt from prohibition on possession provided that it is in the form of a single preparation not being designed for injection and less than 100 mg (calculated as free base) or with a total concentration less than 2.5% (calculated as free base). Illegal possession of dihydrocodeine can result in up to 5 years in prison and/or | *'''Germany:''' Dihydrocodeine is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form. There is an exception for preperations, containing up to 2,5% or 100mg dihydrocodeine per unit, which can be prescripted on a regular prescription, if not prescripted to an alcohol or drug dependent person.<ref>{{Citation | title=Anlage III BtMG - Einzelnorm | url=http://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html}}</ref> | ||
*'''Hong Kong:''' In Hong Kong, dihydrocodeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. A pharmacist can dispense Dihydrocodeine when furnished with a doctors prescription. Anyone who supplies the substance without a prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption, without a licence from the Department of Health, is illegal and carries a $1,000,000 (HKD) fine and/or 7 years imprisonment.{{citation needed}} | |||
In the USA, dihydrocodeine is a DEA Schedule II substance, although preparations containing small amounts of dihydrocodeine are classified as Schedule III or Schedule V, depending on the concentration of dihydrocodeine relative to other active constituents, such as paracetamol (acetaminophen). This scheduling is similar to the UK's. The DEA's ACSCN for dihydrocodeine free base and all salts is 9120. The 2013 annual aggregate manufacturing quota is 250 kilos. | *'''Japan:''' In Japan, dihydrocodeine is available without a prescription; used in cough medicines such as New Bron Solution-ACE. Dihydrocodeine is used as an antitussive in many products as a Dextromethorphan alternative. Medicines in Japan which contain dihydrocodeine are coupled with caffeine to offset the sedative effects and discourage recreational use. Cough medicines containing dihydrocodeine are controlled similarly to dextromethorphan in the United States, in that its sale is strictly limited by purchase quantity and is restricted to persons 20 and older for purchase.{{citation needed}} | ||
*'''Russia:''' Dihydrocodeine 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=100263&date=03.12.2019}}</ref> | |||
*'''Sweden''': Dihydrocodeine is a prescription only medication.<ref>Läkemedelsverkets föreskrifter (LVFS 1997:12) om förteckningar över narkotika, konsoliderad version t.o.m. LVFS 2010:1</ref> | |||
*'''Switzerland''': Dihydrocodeine is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted. Some preparations containing dihydrocodeine are included in Verzechnis C, while certain ones are excluded.<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> | |||
*'''United Kingdom:''' In the United Kingdom, dihydrocodeine is a Class B drug; but, it is available over-the-counter in small amounts (less than 8 mg), when combined with paracetamol (see co-dydramol). Dihydrocodeine is listed in Schedule 5 of the Misuse of Drugs Regulations 2001 whereby it is exempt from prohibition on possession provided that it is in the form of a single preparation not being designed for injection and less than 100 mg (calculated as free base) or with a total concentration less than 2.5% (calculated as free base).<ref>{{Citation | title=The Misuse of Drugs Regulations 2001 | url=https://www.legislation.gov.uk/uksi/2001/3998/schedule/5/made}}</ref> Illegal possession of dihydrocodeine can result in up to 5 years in prison and/or a fine.<ref>Misuse of Drugs Act 1971, s.5(2)</ref> | |||
*'''United States:''' In the USA, dihydrocodeine is a DEA Schedule II substance, although preparations containing small amounts of dihydrocodeine are classified as Schedule III or Schedule V, depending on the concentration of dihydrocodeine relative to other active constituents, such as paracetamol (acetaminophen). This scheduling is similar to the UK's. The DEA's ACSCN for dihydrocodeine free base and all salts is 9120. The 2013 annual aggregate manufacturing quota is 250 kilos.{{citation needed}} | |||
==See also== | ==See also== | ||
*[[Responsible use]] | |||
*[[Extraction of opioids from painkiller products]] | |||
*[[Codeine]] | *[[Codeine]] | ||
*[[Opioid]] | *[[Opioid]] | ||
==External links== | |||
*[http://en.wikipedia.org/wiki/Dihydrocodeine Dihydrocodeine (Wikipedia)] | *[http://en.wikipedia.org/wiki/Dihydrocodeine Dihydrocodeine (Wikipedia)] | ||
*[https://www.erowid.org/pharms/dihydrocodeine/ Dihydrocodeine (Erowid Vault)] | |||
*[https://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=7659 Dihydrocodeine (Isomer Design)] | |||
*[https://go.drugbank.com/drugs/DB01551 Dihydrocodeine (DrugBank)] | |||
*[http://www.drugs.com/international/dihydrocodeine.html Dihydrocodeine (Drugs.com)] | |||
==Literature== | |||
*Schmidt, H., Vormfelde, S. V., Klinder, K., Gundert-Remy, U., Gleiter, C. H., Skopp, G., Aderjan, R. and Fuhr, U. (2002), Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors. Pharmacology & Toxicology, 91: 57–63. https://doi.org/10.1034/j.1600-0773.2002.910203.x | |||
*Koch T, Höllt V (2008). Role of receptor internalization in opioid tolerance and dependence. Pharmacol. Ther. 117 (2): 199–206. https://doi.org/10.1016/j.pharmthera.2007.10.003 | |||
*Pert, C. B., Pasternak, G., & Snyder, S. H. (1973). Opiate Agonists and Antagonists Discriminated by Receptor Binding in Brain. Science, 182 (4119), 1359-1361. https://doi.org/10.1126/science.182.4119.1359 | |||
*Friswell J, Phillips C, Holding J, Morgan CJ, Brandner B, Curran HV (2008). Acute effects of opioids on memory functions of healthy men and women. Psychopharmacology (Berl.). 198 (2): 243–50. https://doi.org/10.1007/s00213-008-1123-x. | |||
*Stefano GB, Ptáček R, Kuželová H, Kream RM (2012). Endogenous morphine: up-to-date review (2011). Folia Biol. (Praha). 58 (2): 49–56. PMID 22578954. | |||
==References== | ==References== | ||
<references /> | <references /> | ||
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[[Category: | |||
[[Category: | [[Category:Naturally-occurring substance]] | ||
[[Category:Benzofuran]] | |||
[[Category:Morphinan]] | |||
[[Category:Opioid]] | |||
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