Nicomorphine

Nicomorphine (Vilan, Subellan, Gevilan, MorZet) is the 3,6-dinicotinate ester of morphine. It is a strong opioid agonist analgesic two to three times as potent as morphine with a side effect profile similar to that of dihydromorphine, morphine, and diamorphine.

Nicomorphine
Clinical data
Other namesMorphine dinicotinate, 3,6-dinicotinoylmorphine
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral, Intravenous, Rectal
ATC code
Legal status
Legal status
  • AU: S9 (Prohibited substance)
  • CA: Schedule I
  • DE: Anlage I (Authorized scientific use only)
  • US: Schedule I
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.010.326
Chemical and physical data
FormulaC29H25N3O5
Molar mass495.535 g·mol−1
3D model (JSmol)
SMILES
  • O=C(O[C@H]2\C=C/[C@H]6[C@@H]5N(CC[C@@]61c4c(O[C@H]12)c(OC(=O)c3cccnc3)ccc4C5)C)c7cccnc7
InChI
  • InChI=1S/C29H25N3O5/c1-32-13-10-29-20-7-9-23(36-28(34)19-5-3-12-31-16-19)26(29)37-25-22(8-6-17(24(25)29)14-21(20)32)35-27(33)18-4-2-11-30-15-18/h2-9,11-12,15-16,20-21,23,26H,10,13-14H2,1H3/t20-,21+,23-,26-,29-/m0/s1 Y
  • Key:HNDXBGYRMHRUFN-CIVUWBIHSA-N Y
 NY (what is this?)  (verify)

Nicomorphine was first synthesized in 1904 and was patented as Vilan by Lannacher Heilmittel G.m.b.H. of Austria in 1957.

Medical Use

The hydrochloride salt is available as ampoules of 10 mg/ml solution for injection, 5 mg tablets, and 10 mg suppositories. It is possible that other manufacturers distribute 10  mg tablets and other concentrations of injectable nicomorphine in ampoules and multidose vials. It is used, particularly in the German-speaking countries and elsewhere in Central Europe and some other countries in Europe and the former USSR in particular, for post-operative, cancer, chronic non-malignant and other neuropathic pain. It is commonly used in patient-controlled analgesia (PCA) units. The usual starting dose is 5–10 mg given every 3–5 hours.

Side effects

Nicomorphine's side effects are similar to those of other opioids and include itching, nausea and respiratory depression. It is considered by doctors to be one of the better analgesics for the comprehensive mitigation of suffering, as opposed to purely clouding the noxious pain stimulus, in the alleviation of chronic pain conditions.[1]

Chemistry

The method for synthesis of nicomorphine, which involves treating anhydrous morphine base with nicotinic anhydride at 130 °C, was published by Pongratz and Zirm in Monatshefte für Chemie in 1957,[2] simultaneously with the two analogues nicocodeine and nicodicodeine in an article about amides and esters of various organic acids.[2][3]

Legality

Nicomorphine is regulated in much the same fashion as morphine worldwide but is a Schedule I controlled substance in the United States and was never introduced there.

Nicomorphine may appear on rare occasions on the European black market and other channels for unsupervised opioid users. It can be produced as part of a mixture of salts and derivatives of morphine by end users by means of treating morphine with nicotinic anhydride or related chemicals in an analogue of the heroin homebake process.

CAS number of hydrochloride: 35055-78-8
US DEA ACSCN: 9312
Free base conversion ratios of salts:
Nicomorphine Hydrochloride: 0.93

Pharmacology

Pharmacodynamics

The 3,6-diesters of morphine are drugs with more rapid and complete central nervous system penetration due to increased lipid solubility and other structural considerations. The prototype for this subgroup of semi-synthetic opiates is heroin and the group also includes dipropanoylmorphine, diacetyldihydromorphine, disalicylmorphine and others. Whilst this produces an enhanced "bang" when the drug is administered intravenously, it cannot be distinguished from morphine via other routes, although the different side effect profile, including lower incidence of nausea, is very apparent.

Pharmacokinetics

Nicomorphine is rapidly metabolized when administered by the I.V. route, having a half-life of 3 minutes, into morphine and 6-nicotinoylmorphine, the secondary active metabolite. Half lives of the metabolites were 3–15 minutes for the nicotinoyl metabolite, and 135–190 minutes for morphine.[4]

Via the epidural route, a much slower release from epidural space occurs and nicomorphine remains detectable for 1.5 hours or so, and has a longer effect of 18.2 +/- 10.1 hours due to slower release of the active metabolites, morphine and 6-nicotinoylmorphine. Half lives for those compounds is listed in the IV route.[5]

Pharmacokinetics via the rectal route differ, and change metabolism. Eight minutes after administration, morphine appeared rapidly, and had a half life of 1.48 +/- 0.48h. This was in turn metabolized to morphine-3- and morphine-6-glucoranides after another 12 minutes, which had similar half-lives to one-another, at about 2.8h. No 6-mononicotinoylmorphine was found, and bioavailability of morphine and metabolic actives was 88%. No remaining nicomorphine was found in urine.[6]

References
  1. Vadon P, Rehak P (April 1979). "[Comparison of the analgesic effect of nicomorphine in two different solutions (author's transl)]". Wiener Medizinische Wochenschrift (in German). 129 (8): 217–20. PMID 452619.
  2. List P, Hörhammer L (2013). Allgemeiner Teil. Wirkstoffgruppen I (in German). Springer-Verlag. ISBN 978-3-642-47985-4.
  3. Zirm KL, Pongratz A (May 1960). "[On the knowledge of new amides and esters of nicotinic acid. Part I. Chemistry and pharmacology of 4-nicotinylaminobenzoic acid-(beta-diethylamino)-ethyl ester monohydrochloride]". Arzneimittel-Forschung (in German). 10: 412–4. PMID 13847637.
  4. Koopman-Kimenai PM, Vree TB, Booij LH, Dirksen R, Nijhuis GM (March 1993). "Pharmacokinetics of intravenously administered nicomorphine and its metabolites in man". European Journal of Anaesthesiology. 10 (2): 125–32. PMID 8462537.
  5. Koopman-Kimenai PM, Vree TB, Hasenbos MA, Weber EW, Verweij-Van Wissen CP, Booij LH (June 1991). "Pharmacokinetics of nicomorphine and its metabolites in man after epidural administration". Pharmaceutisch Weekblad. Scientific Edition (in Dutch). 13 (3): 142–7. doi:10.1007/bf01981532. PMID 1923705. S2CID 27052829.
  6. Koopman-Kimenai PM, Vree TB, Booij LH, Dirksen R (December 1994). "Rectal administration of nicomorphine in patients improves biological availability of morphine and its glucuronide conjugates". Pharmacy World & Science. The Hague : KNMP, c1993-. 16 (6): 248–53. doi:10.1007/bf02178565. hdl:2066/21014. PMID 7889023. S2CID 2115715.
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