Dihydromorphine: Difference between revisions

{{Short description|Semi-synthetic opioid analgesic drug}}

{{Distinguish|text=[[dihydromorphinone]] (Dilaudid, etc.) or [[dehydromorphine]]}}

{{More citations needed|date=November 2012}}

{{Drugbox

| =

| =

| verifiedrevid = 443686436

| IUPAC_name = 3,6-dihydroxy-(5α,6α)-4,5-epoxy-17-methylmorphinan

| image = Dihydromorphine 2D structure.svg

| alt = Skeletal formula of dihydromorphine

| width = 280

| image2 = Dihydromorphine 3D ball.png

| alt2 = Ball-and-stick model of the dihydromorphine molecule

| width2 = 220

| =

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

| =

| legal_AU = S8

| legal_BR = A1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule I

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_US = Schedule I

|

| dependency_liability = High

| addiction_liability = High

<!--Pharmacokinetic data-->| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion = <!--Identifiers-->

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 509-60-4

| ATC_prefix = none

| ATC_suffix =

| PubChem = 5359421

| IUPHAR_ligand = 1616

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01565

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4514282

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = C11782

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1500

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = C3S5FRP6JW

<!--Chemical data-->| C = 17

| H = 21

| N = 1

| O = 3

| smiles = O[C@@H]4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@H]3CC4)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C17H21NO3/c1-18-7-6-17-10-3-5-13(20)16(17)21-15-12(19)4-2-9(14(15)17)8-11(10)18/h2,4,10-11,13,16,19-20H,3,5-8H2,1H3/t10-,11+,13-,16-,17-/m0/s1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = IJVCSMSMFSCRME-KBQPJGBKSA-N

| synonyms = Dihydromorphine, Paramorphan

'''Dihydromorphine''' ('''Paramorfan''', '''Paramorphan''') is a semi-synthetic [[opioid]] structurally related to and derived from [[morphine]]. The 7,8-double bond in morphine is reduced to a single bond to get dihydromorphine.<ref name="Nadendla_2005">{{cite book | vauthors = Nadendla R | title = Principles of Organic Medicinal Chemistry | date = 2005 | pages = 215–216 | oclc = 938923816 }}</ref> Dihydromorphine is a moderately strong [[analgesic]] and is used clinically in the treatment of pain and also is an active metabolite of the analgesic opioid drug [[dihydrocodeine]].<ref name="DrugBank">{{cite web | url = http://www.drugbank.ca/drugs/DB01565 | work = DrugBank | title = Dihydromorphine | id = DB01565 }}</ref><ref name="PubChem">{{cite web | url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5359421&loc=ec_rcs | title = Dihydromorphine | work = PubChem | publisher = U.S. National Library of Medicine }}</ref><ref name="DihydrocodeinePharmacokinetics">{{cite journal | vauthors = Ammon S, Hofmann U, Griese EU, Gugeler N, Mikus G | title = Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing | journal = British Journal of Clinical Pharmacology | volume = 48 | issue = 3 | pages = 317–322 | date = September 1999 | pmid = 10510141 | pmc = 2014322 | doi = 10.1046/j.1365-2125.1999.00042.x | name-list-style = amp }}</ref> Dihydromorphine occurs in trace quantities in assays of opium on occasion, as does dihydrocodeine, dihydrothebaine, tetrahydrothebaine, etc. The process for manufacturing dihydromorphine from morphine for pharmaceutical use was developed in Germany in the late 19th century, with the synthesis being published in 1900 and the drug introduced clinically as Paramorfan shortly thereafter. A high-yield synthesis from tetrahydrothebaine was later developed.<ref name="pmid12608825">{{cite journal | vauthors = Przybyl AK, Flippen-Anderson JL, Jacobson AE, Rice KC | title = Practical and high-yield syntheses of dihydromorphine from tetrahydrothebaine and efficient syntheses of (8S)-8-bromomorphide | journal = The Journal of Organic Chemistry | volume = 68 | issue = 5 | pages = 2010–3 | date = March 2003 | pmid = 12608825 | doi = 10.1021/jo0206871 }}</ref>

==Uses==

===Medical===

Dihydromorphine is used for the management of moderate to severe pain such as that occurring in cancer; however, it is less effective in treating neuropathic pain and is generally considered inappropriate and ineffective for psychological pain.<ref name="DrugBank" /><ref>{{cite book | vauthors = Dureja GP | title = Handbook of Pain Management | publisher = Elsevier, a division of Reed Elsevier India Private Limited | location = New Delhi, India | page = 67 | oclc = 884520261 }}</ref>

===Research===

Dihydromorphine, often labelled with the isotope [[tritium]] in the form of [3H]-dihydromorphine, is used in scientific research to study binding of the [[opioid receptor]]s in the [[nervous system]].<ref>{{cite journal | vauthors = Antkiewicz-Michaluk L, Vetulani J, Havemann U, Kuschinsky K | title = 3H-dihydromorphine binding sites in subcellular fractions of rat striatum | journal = Polish Journal of Pharmacology and Pharmacy | volume = 34 | issue = 1–3 | pages = 73–78 | year = 1982 | pmid = 6300816 }}</ref><ref>{{cite journal | vauthors = Savage DD, Mills SA, Jobe PC, Reigel CE | title = Elevation of naloxone-sensitive 3H-dihydromorphine binding in hippocampal formation of genetically epilepsy-prone rats | journal = Life Sciences | volume = 43 | issue = 3 | pages = 239–246 | year = 1988 | pmid = 2840539 | doi = 10.1016/0024-3205(88)90313-x }}</ref>

==Strength==

Dihydromorphine is slightly stronger than morphine as an analgesic with a similar side effect profile. The relative potency of dihydromorphine is about 1.2 times that of morphine. In comparison, the relative potency of [[dihydrocodeine]] is around 1.2 to 1.75 times that of [[codeine]].<ref name="Nadendla_2005" />

==Pharmacology==

Dihydromorphine acts as an agonist at the [[mu opioid receptor|μ-opioid]] with a K_i value of 2.5&nbsp;nM compared to 4.9&nbsp;nM of [[morphine]], [[delta opioid receptor|δ-opioid]] with a K_i value of 137&nbsp;nM compared to 273&nbsp;nM of morphine and [[kappa opioid receptor|κ-opioid]] with a K_i value of 223&nbsp;nM compared to 227&nbsp;nM of morphine. Dihydromorphine is therefore slightly more μ-selective than morphine.<ref name="DrugBank" /><ref name="PubChem" /> Agonism of the μ-opioid and δ-opioid receptors is largely responsible for the clinical effects of opioids like dihydromorphine, with the μ-agonism providing more analgesia than the δ.<ref>{{cite journal | vauthors = Costantino CM, Gomes I, Stockton SD, Lim MP, Devi LA | title = Opioid receptor heteromers in analgesia | journal = Expert Reviews in Molecular Medicine | volume = 14 | issue = 9 | pages = e9 | date = April 2012 | pmid = 22490239 | pmc = 3805500 | doi = 10.1017/erm.2012.5 }}</ref><ref name="pmid15567186">{{cite journal | vauthors = Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI | title = Agonist-specific regulation of the delta-opioid receptor | journal = Life Sciences | volume = 76 | issue = 6 | pages = 599–612 | date = December 2004 | pmid = 15567186 | doi = 10.1016/j.lfs.2004.07.020 }}</ref>

===Pharmacokinetics===

Dihydromorphine's onset of action is more rapid than morphine and it also tends to have a longer duration of action, generally 4–7 hours.{{citation needed|date=November 2012}}

==Legality==

Under the 1961 international [[Single Convention on Narcotic Drugs]] treaty dihydromorphine is a [[Single Convention on Narcotic Drugs#Schedule I|Schedule I]] [[narcotic]] subject to control, and other countries' laws may vary.<ref>[http://www.unodc.org/pdf/convention_1961_en.pdf Single Convention on Narcotic Drugs, 1961] - Page 40 of 44</ref>

===United States===

Under the [[Controlled Substances Act]], dihydromorphine is listed as a [[Controlled Substances Act#Schedule I controlled substances|Schedule I]] substance along with [[heroin]].<ref>{{cite web | url = http://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf | title = Controlled Substances (in alphabetical order) | date = 8 February 2016 | archive-url = https://web.archive.org/web/20160417085659/http://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf | archive-date=2016-04-17 | page = 5 | work = Diversion Control Division | publisher = U.S. Drug Enforcement Agency, Department of Justice }}</ref> In the United States, its role in the production of dihydrocodeine and other related drugs make it a Schedule I substance with one of the higher annual manufacturing quotas granted by the US [[Drug Enforcement Administration]]: 3300 kilograms in 2013. Manufacturers, distributors, and importers with the correct DEA license and state permits related thereto are able to use Schedule I drugs in this fashion when they are transformed into something of a lower schedule.<ref>DEA Website: Forms, Retrieved 26. April 2014</ref> The DEA has assigned dihydromorphine and all of its salts, esters, etc. the [[ACSCN]] of 9145. As with nicomorphine, MDMA and heroin, dihydromorphine is also used in research in properly licensed facilities. US DEA Form 225, the most common and least expensive individual researcher's license, does not include Schedule I drugs, and so the lab must have a higher-level DEA registration.<ref>DEA Web Site, retrieved 30. April 2014</ref> As with other licit opioids used for medical purposes in other countries, including even much weaker opioids like [[nicocodeine]], [[benzylmorphine]], and [[tilidine]], the reason for dihydromorphine being in Schedule I is that it was not in medical use in the US at time the Controlled Substances Act of 1970 was drawn up.{{cn|date=October 2023}}

===Europe===

Dihydromorphine is regulated in the same fashion as morphine in Germany under the BtMG,<ref>Deutsche Betäbungsmittelgesetz, accessed 27. April 2014</ref> Austrian SMG,<ref>SMG, 30. April 2014</ref> and Swiss BtMG, where it is still used as an analgesic.<ref>UNODC Bulletin On Narcotics, 1953, Issue 2</ref> The drug was invented in Germany in 1900 and marketed shortly thereafter. It is often used in Patient Controlled Analgesia units.<ref>''Opioids for Pain Control'' (Cambridge Press, 2002)</ref><ref>{{cite book |last1=Hardman JG, Limbird LE |title=Goodman & Gilman's The pharmacological basis of therapeutics |date=2001 |publisher=McGraw-Hill Med. Publ |location=New York, NY |isbn=978-0-07-135469-1 |edition=10th}}</ref>

===Japan===

Dihydromorphine and morphine are also used alongside each other in clinical use in Japan and is regulated as such <ref>UNODC Bulletin On Narcotics, 1955</ref>

== See also ==

* [[Dihydroheroin]]

* [[Acetyldihydrocodeine]]

* [[Morphine]]

* [[Nicodicodeine]]

* [[Nicocodeine]]

* [[Thebacon]]

== References ==

{{Reflist}}

== External links ==

* [http://www.drugbank.ca/drugs/DB01565 Various information about dihydromorphine] at the [[DrugBank]]

{{Analgesics}}

{{Opioidergics}}

[[Category:Opioid metabolites]]

[[Category:4,5-Epoxymorphinans]]

[[Category:Euphoriants]]

[[Category:Hydroxyarenes]]

[[Category:Cyclohexanols]]

[[Category:Mu-opioid receptor agonists]]

[[Category:Semisynthetic opioids]]