Dihydromorphine

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.[1] 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.[2][3][4] 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.[5]

Not to be confused with dihydromorphinone (Dilaudid, etc.) or dehydromorphine.
Dihydromorphine
Clinical data
Other namesDihydromorphine, Paramorphan
Routes of
administration		Oral, Intravenous, Intranasally, Sublingually
ATC code
  • none
Legal status
Legal status
  • AU: S8 (Controlled drug)
  • CA: Schedule I
  • DE: Anlage II (Authorized trade only, not prescriptible)
  • US: Schedule I
Identifiers
IUPAC name
  • 3,6-dihydroxy-(5α,6α)-4,5-epoxy-17-methylmorphinan
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.007.365
Chemical and physical data
FormulaC17H21NO3
Molar mass287.359 g·mol−1
3D model (JSmol)
SMILES
  • O[C@@H]4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@H]3CC4)C
InChI
  • InChI=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 Y
  • Key:IJVCSMSMFSCRME-KBQPJGBKSA-N Y
 NY (what is this?)  (verify)

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.[2][6]

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 receptors in the nervous system.[7][8]

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.[9]

Pharmacology

Dihydromorphine acts as an agonist at the μ-opioid (mu) with a ki value of 2.5nM compared to 4.9nM of Morphine, δ-opioid (delta) with a ki value of 137nM compared to 273nM of Morphine and κ-opioid (kappa) with a ki value of 223nM compared to 227nM of Morphine. Dihydromorphine is therefore slightly more Mu selective than Morphine .[2][3] Agonist 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.[10][11]

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.

Legality

Under the 1961 international Single Convention on Narcotic Drugs treaty dihydromorphine is a Schedule I narcotic subject to control, and other countries' laws may vary.[12]

United States

Under the Controlled Substances Act, dihydromorphine is listed as a Schedule I substance along with heroin.[13] 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 kilos 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.[14] The DEA has assigned dihydromorphine and all of its salts, esters, &c the ACSCN of 9145. As with nicomorphine, MDMA, heroin (DEA 2013 production quota: 25 grammes)[15] and the like, dihydromorphine is also used in research such as that mentioned above in properly licensed facilities; Form 225, the most common and least expensive individual researcher's license, does not include Schedule I so the lab must have a higher-level DEA registration [16] 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.

Europe

Dihydromorphine is regulated in the same fashion as morphine in Germany under the BtMG,[17] Austrian SMG,[18] and Swiss BtMG, where it is still used as an analgesic.[19] The drug was invented in Germany in 1900 and marketed shortly thereafter. It is often used in Patient Controlled Analgesia units.[20][21]

Japan

Dihydromorphine and morphine are also used alongside each other in clinical use in Japan and is regulated as such [22]

See also

References
  1. Rama Rao Nadendla. Principles Of Organic Medicinal Chemistry pp. 215
  2. DrugBank: Dihydromorphine (DB01565)
  3. Dihydromorphine - PubChem
  4. Susanne Ammon; Ute Hofmann; Ernst-Ulrich Griese; Nadja Gugeler & Gerd Mikus (1999). "Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing". British Journal of Clinical Pharmacology. 48 (3): 317–322. doi:10.1046/j.1365-2125.1999.00042.x. PMC 2014322. PMID 10510141.
  5. "Dihydromorphine | Thin Layer Chromatography | Chemistry".
  6. Dureja. Handbook Of Pain Management pp. 67
  7. Antkiewicz-Michaluk L, Vetulani J, Havemann U, Kuschinsky K (1982). "3H-dihydromorphine binding sites in subcellular fractions of rat striatum". Pol J Pharmacol Pharm. 34 (1–3): 73–78. PMID 6300816.
  8. Savage DD, Mills SA, Jobe PC, Reigel CE (1988). "Elevation of naloxone-sensitive 3H-dihydromorphine binding in hippocampal formation of genetically epilepsy-prone rats". Life Sci. 43 (3): 239–246. doi:10.1016/0024-3205(88)90313-x. PMID 2840539.
  9. Rama Rao Nedendla. Principles Of Organic Medicinal Chemistry pp. 216
  10. Costantino CM, Gomes I, Stockton SD, Lim MP, Devi LA (2012). "Opioid receptor heteromers in analgesia". Expert Rev Mol Med. 14 (9): e9. doi:10.1017/erm.2012.5. PMC 3805500. PMID 22490239.
  11. Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI (2004). "Agonist-specific regulation of the delta-opioid receptor". Life Sci. 76 (6): 599–612. doi:10.1016/j.lfs.2004.07.020. PMID 15567186.
  12. Single Convention on Narcotic Drugs, 1961 - Page 40 of 44
  13. Controlled Substances (in alphabetical order) Archived 2016-04-17 at the Wayback Machine - Page 5 of 12
  14. DEA Website: Forms, Retrieved 26. April 2014
  15. Federal Register, linked from DEA site
  16. DEA Web Site, retrieved 30. April 2014
  17. Deutsche Betäbungsmittelgesetz, accessed 27. April 2014
  18. SMG, 30. April 2014
  19. UNODC Bulletin On Narcotics, 1953, Issue 2
  20. Opioids for Pain Control (Cambridge Press, 2002)
  21. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition5n
  22. UNODC Bulletin On Narcotics, 1955
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