Nefopam

Nefopam
Clinical data
Trade names Acupan
AHFS/Drugs.com International Drug Names
Routes of
administration		 Oral, Intravenous, Intramuscular
ATC code N02BG06 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Pharmacokinetic data
Protein binding 73%
Metabolism Hepatic
Biological half-life 4-6 hours
Excretion Urine, faeces (6%)
Identifiers
CAS Number 13669-70-0 YesY
PubChem (CID) 4450
ChemSpider 4295 N
UNII 4UP8060B7J YesY
KEGG D08258 YesY
ChEBI CHEBI:88316 N
ECHA InfoCard 100.033.757
Chemical and physical data
Formula C17H19NO
Molar mass 253.34 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Nefopam (brand names: Acupan, Silentan, Nefadol and Ajan) is a centrally-acting non-opioid analgesic drug of the benzoxazocine chemical class which was developed by Riker Laboratories in the 1960s.[1] It is widely used, mainly in European countries, for the relief of moderate to severe pain as an alternative to opioid analgesic drugs. Animal studies have shown that nefopam has a potentiating (analgesic-sparing) effect on morphine and other opioids by broadening the antinociceptive action of the opioid and possibly other mechanisms, generally lowering the dose requirements of both when they are used concomitantly.[2]

Use

Nefopam has additional action in the prevention of shivering, which may be a side effect of other drugs used in surgery.[3] Nefopam was significantly more effective than aspirin as an analgesic in one clinical trial,[4] although with a greater incidence of side effects such as sweating, dizziness and nausea, especially at higher doses.[5][6] Nefopam is around a third to half the potency and slightly less effective as an analgesic compared to morphine,[7][8][9] or oxycodone,[10] but tends to produce fewer side effects, does not produce respiratory depression,[11] and has much less abuse potential, and so is useful either as an alternative to opioids, or as an adjunctive treatment for use alongside opioid(s) or other analgesics.[9][12] Nefopam is also used to combat severe hiccups.[13]

Side effects

Common side effects include nausea, nervousness, dry mouth, light-headedness and urinary retention.[14] Less common side effects include vomiting, blurred vision, drowsiness, sweating, insomnia, headache, confusion, hallucinations, tachycardia, aggravation of angina and rarely a temporary and benign pink discolouration of the skin or erythema multiforme.[14]

Contraindications

It is contraindicated in people with convulsive disorders, those that have received treatment with irreversible monoamine oxidase inhibitors such as phenelzine, tranylcypromine or isocarboxazid within the past 30 days and those with myocardial infarction pain, mostly due to a lack of safety data in these conditions.[14]

Interactions

It has additive anticholinergic and sympathomimetic effects with other agents with these properties.[14] Its use should be avoided in people receiving some types of antidepressants (tricyclic antidepressants or monoamine oxidase inhibitors) as there is the potential for serotonin syndrome or hypertensive crises to result.[14]

Recreational use and overdose

Recreational use of nefopam and death from overdose have both been reported,[15] although these events are less common with nefopam than with opioid analgesic drugs.[16] Overdose usually manifests with convulsions, hallucinations, tachycardia and hyperdynamic circulation.[14] Treatment is usually supportive, managing cardiovascular complications with beta-blockers and limiting absorption with activated charcoal.[14]

Pharmacology

The mechanism of action of nefopam is not well understood, although inhibition of serotonin, dopamine and noradrenaline reuptake is thought to be involved in its analgesic effects,[17][18][19] and there may be other modes of action such as through histamine H3 receptors[20] and glutamate.[21] Recently, like its analogue orphenadrine which also has analgesic effects, nefopam has been found to act as a voltage-gated sodium channel blocker, and this may in part or fully mediate its antinociceptive effects.[22]

Ki values (Human)[23]
Receptor Ki (nM)
5-HT2A 1685
5-HT2B 329.5
5-HT2C 56
DAT 531
NET 33
SERT 29

See also

References

  1. ↑ US Patent 3830803
  2. ↑ Girard, P; Pansart, Y; Gillardin, JM (April 2004). "Nefopam potentiates morphine antinociception in allodynia and hyperalgesia in the rat.". Pharmacology, Biochemistry, and Behavior. 77 (4): 695–703. doi:10.1016/j.pbb.2004.01.018. PMID 15099914.
  3. ↑ Alfonsi P, Adam F, Passard A, Guignard B, Sessler DI, Chauvin M (January 2004). "Nefopam, a Non-sedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold". Anesthesiology. 100 (1): 37–43. doi:10.1097/00000542-200401000-00010. PMC 1283107Freely accessible. PMID 14695722.
  4. ↑ Cohen A, Hernandez CM (1976). "Nefopam hydrochloride: new analgesic agent". Journal of International Medical Research. 4 (2): 138–43. PMID 799984.
  5. ↑ Wang RI, Waite EM (July 1979). "The clinical analgesic efficacy of oral nefopam hydrochloride". Journal of Clinical Pharmacology. 19 (7): 395–402. doi:10.1002/j.1552-4604.1979.tb02498.x. PMID 479385.
  6. ↑ Pillans PI, Woods DJ (September 1995). "Adverse reactions associated with nefopam". New Zealand Medical Journal. 108 (1008): 382–4. PMID 7566787.
  7. ↑ Sunshine A, Laska E (November 1975). "Nefopam and morphine in man". Clinical Pharmacology and Therapeutics. 18 (5 Pt 1): 530–4. PMID 1102231.
  8. ↑ Phillips G, Vickers MD (October 1979). "Nefopam in postoperative pain". British Journal of Anaesthesia. 51 (10): 961–5. doi:10.1093/bja/51.10.961. PMID 391253.
  9. 1 2 Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS (1980). "Nefopam: a review of its pharmacological properties and therapeutic efficacy". Drugs. 19 (4): 249–67. doi:10.2165/00003495-198019040-00001. PMID 6991238.
  10. ↑ Tigerstedt I, Tammisto T, Leander P (December 1979). "Comparison of the analgesic dose-effect relationships of nefopam and oxycodone in postoperative pain". Acta Anaesthesiologica Scandinavica. 23 (6): 555–60. doi:10.1111/j.1399-6576.1979.tb01486.x. PMID 397711.
  11. ↑ Gasser JC, Bellville JW (August 1975). "Respiratory effects of nefopam". Clinical Pharmacology and Therapeutics. 18 (2): 175–9. PMID 1097153.
  12. ↑ Kapfer B, Alfonsi P, Guignard B, Sessler DI, Chauvin M (January 2005). "Nefopam and Ketamine Comparably Enhance Postoperative Analgesia". Anesthesia and Analgesia. 100 (1): 169–74. doi:10.1213/01.ANE.0000138037.19757.ED. PMC 1283103Freely accessible. PMID 15616073.
  13. ↑ Bilotta, F; Rosa, G (December 2000). "Nefopam for severe hiccups.". The New England Journal of Medicine. 343 (26): 1973–4. doi:10.1056/nejm200012283432619. PMID 11186682.
  14. 1 2 3 4 5 6 7 "Data Sheet ACUPAN™ Nefopam hydrochloride 30 mg tablets 20 mg intramuscular injection" (PDF). Medsafe New Zealand. iNova Pharmaceuticals (New Zealand) Limited. 3 September 2007. Retrieved 10 March 2014.
  15. ↑ Bismuth, C; Fournier, PE; Bavoux, E; Husson, O; Lafon, D (September 1987). "[Chronic abuse of the analgesic nefopam (Acupan)].". Journal de Toxicologie Clinique et Experimentale (in French). 7 (5): 343–6. PMID 3448182.
  16. ↑ Tracqui, A; Berthelon, L; Ludes, B (May 2002). "Fatal overdosage with nefopam (Acupan)." (PDF). Journal of Analytical Toxicology. 26 (4): 239–43. doi:10.1093/jat/26.4.239. PMID 12054367.
  17. ↑ Esposito, E; Romandini, S; Merlo-Pich, E; Mennini, T; Samanin, R (September 9, 1986). "Evidence of the involvement of dopamine in the analgesic effect of nefopam". European Journal of Pharmacology. 128 (3): 157–64. doi:10.1016/0014-2999(86)90762-4. PMID 3098570.
  18. ↑ Marazziti, D; Rotondo, A; Ambrogi, F; Cassano, GB (1991). "Analgesia by nefopam: does it act through serotonin?". Drugs under Experimental and Clinical Research. 17 (5): 259–61. PMID 1756689.
  19. ↑ Fuller RW, Snoddy HD (October 1993). "Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice". Neuropharmacology. 32 (10): 995–9. doi:10.1016/0028-3908(93)90064-A. PMID 7507578.
  20. ↑ Girard, P; Pansart, Y; Coppé, MC; Verniers, D; Gillardin, JM (October 25, 2004). "Role of the histamine system in nefopam-induced antinociception in mice". European Journal of Pharmacology. 503 (1–3): 63–9. doi:10.1016/j.ejphar.2004.09.030. PMID 15496297.
  21. ↑ Verleye, M; André, N; Heulard, I; Gillardin, JM (July 9, 2004). "Nefopam blocks voltage-sensitive sodium channels and modulates glutamatergic transmission in rodents". Brain Research. 1013 (2): 249–55. doi:10.1016/j.brainres.2004.04.035. PMID 15193535.
  22. ↑ Verleye, M; André, N; Heulard, I; Gillardin, JM (July 2004). "Nefopam blocks voltage-sensitive sodium channels and modulates glutamatergic transmission in rodents". Brain Research. 1013 (2): 249–55. doi:10.1016/j.brainres.2004.04.035. PMID 15193535.
  23. ↑ Gregori-Puigjané, E.; Setola, V; Hert, J; Crews, BA; Irwin, JJ; Lounkine, E; Marnett, L; Roth, BL; Shoichet, BK (18 June 2012). "Identifying mechanism-of-action targets for drugs and probes" (PDF). Proceedings of the National Academy of Sciences. 109 (28): 11178–11183. doi:10.1073/pnas.1204524109. PMID 22711801.
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