Chemistry:Nefopam

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Nefopam, sold under the brand name Acupan among others, is a centrally acting, non-opioid analgesic medication, with stimulant and sympathomimetic properties that is primarily used to treat moderate to severe pain.[1]

History

Nefopam is based on a benzoxazocine compound. It was developed in the 1960s and marketed under the name fenazocine.[2] It was initially used in shivering, as a muscle relaxant and as an antidepressant, but then increasingly as an analgesic.[2]

Medical uses

Analgesic

Nefopam was significantly more effective than aspirin as an analgesic in one clinical trial,[3] although with a greater incidence of side effects such as sweating, dizziness and nausea, especially at higher doses.[4][5]

The estimated relative potency of nefopam to morphine indicates that 20 mg of nefopam HCl is the approximate analgesic equal of 12 mg of morphine with comparable analgesic efficacy to morphine,[6][7][8] or oxycodone.[9] Nefopam tends to produce fewer side effects, does not produce respiratory depression,[10] and has much less abuse potential, and so is useful either as an alternative to opioid analgesics, or as an adjunctive treatment for use alongside opioids or other types of analgesics.[8][11]

Postoperative pain

A 2025 review, covering 17 studies, found that nefopam was an effective adjunctive postoperative analgesic with benefits in pain management, and correlated with a mean decrease in opioid consumption across the studies of 38%. Adverse effects were not discussed in detail in the included studies.[12]

Chronic pain

For chronic pain nefopam may sometimes be used when common alternatives are contraindicated or ineffective, or as an add-on therapy.[13]

Other medical uses

Nefopam is used to treat severe hiccups.[14]

Nefopam is thought to have some efficacy for treating (off-label) Parkinson's disease, in a similar fashion to those of Bupropion and Methylphenidate. [15]

Nefopam is effective for prevention of shivering during surgery or recovery from surgery.[16][17]

Dosage

Dosage is normally 90-180mg per day. Maximum dose is regarded as 270mg/day.[18] One 1979 study found that a ceiling effect on post-operative pain relief occurred at 60mg/day.[19]

Contraindications

Nefopam 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.[20]

Side effects

Common side effects include nausea, nervousness, dry mouth, light-headedness and urinary retention.[20] 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.[20]

CNS side effects

Some side effects, such as feeling confused or hallucinating, are more likely in patients over 65 years old.[21][20]

Nefopam has been shown to have anticholinergic properties[20] and has a score of 2 on the anticholinergic burden (ACB)[22] scale.[23]Anticholinergic drugs have caused concerns about cognitive decline in older people.[24]

Overdose

Overdose and death have been reported with nefopam.[25] Overdose usually manifests with convulsions, hallucinations, tachycardia, and hyperdynamic circulation.[20] Treatment is usually supportive, managing cardiovascular complications with beta blockers and limiting absorption with activated charcoal.[20]

Interactions

Nefopam has additive anticholinergic and sympathomimetic effects with other agents with these properties.[20] 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.[20]

Mechanisms of action

The mechanism of action of nefopam and its analgesic effects are not well understood.

Analgesic mechanisms of action

Nefopam may have three analgesic mechanisms in the brain and spinal cord;

Pharmacology

A 2025 review noted a significant literature gap on the pharmacokinetic and pharmacodynamic properties of nefopam.[12]

Site Ki (nM)
SERT 29
NET 33
DAT 531
5-HT2A 1,685
5-HT2B 330
5-HT2C 56

Pharmacokinetics

The absolute bioavailability of nefopam is low.[28] It is reported to achieve therapeutic plasma concentrations between 49 and 183 nM.[29] The drug is approximately 73% protein-bound across a plasma range of 7 to 226 ng/mL (28–892 nM).[28] The metabolism of nefopam is hepatic, by N-demethylation and via other routes.[28] Its terminal half-life is 3 to 8 hours, while that of its active metabolite, desmethylnefopam, is 10 to 15 hours.[28] It is eliminated mostly in urine, and to a lesser extent in feces.[28]

Chemistry

Nefopam is a cyclized analogue of orphenadrine, diphenhydramine, and tofenacin, with each of these compounds different from one another only by the presence of one or two carbons.[30][31][32] The ring system of nefopam is a benzoxazocine system.[30][33]

Manufacture

A 2025 review highlighted the difficulties and environmental costs of current Nefopam manufacturing processes, but the potential for improvement.[34]

Use by country

Nefopam is used in the UK, under prescription only,[35] although some UK regions do not advise initiation of use.[36][37] It is used in France,[38] although some concerns have been raised.[39]

As of 2014 Nefopam was not FDA-approved in the US.[40]

Society and culture

Recreational use

Recreational use of nefopam has rarely been reported,[25] and is far less common than with opioid analgesics.[41]

See also

References

  1. ↑ "Nefopam hydrochloride". London, UK: Pharmaceutical Press. 27 October 2016. https://www.medicinescomplete.com/mc/martindale/current/2674-m.htm. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Rediscovery of nefopam for the treatment of neuropathic pain". The Korean Journal of Pain 27 (2): 103–111. April 3, 2014. doi:10.3344/kjp.2014.27.2.103. PMID 24748937. 
  3. ↑ "Nefopam hydrochloride: new analgesic agent". The Journal of International Medical Research 4 (2): 138–143. 1976. doi:10.1177/030006057600400211. PMID 799984. 
  4. ↑ "The clinical analgesic efficacy of oral nefopam hydrochloride". Journal of Clinical Pharmacology 19 (7): 395–402. July 1979. doi:10.1002/j.1552-4604.1979.tb02498.x. PMID 479385. 
  5. ↑ "Adverse reactions associated with nefopam". The New Zealand Medical Journal 108 (1008): 382–384. September 1995. PMID 7566787. 
  6. ↑ "Nefopam and morphine in man". Clinical Pharmacology and Therapeutics 18 (5 Pt 1): 530–534. November 1975. doi:10.1002/cpt1975185part1530. PMID 1102231. 
  7. ↑ "Nefopam in postoperative pain". British Journal of Anaesthesia 51 (10): 961–965. October 1979. doi:10.1093/bja/51.10.961. PMID 391253. 
  8. ↑ 8.0 8.1 "Nefopam: a review of its pharmacological properties and therapeutic efficacy". Drugs 19 (4): 249–267. April 1980. doi:10.2165/00003495-198019040-00001. PMID 6991238. 
  9. ↑ "Comparison of the analgesic dose-effect relationships of nefopam and oxycodone in postoperative pain". Acta Anaesthesiologica Scandinavica 23 (6): 555–560. December 1979. doi:10.1111/j.1399-6576.1979.tb01486.x. PMID 397711. 
  10. ↑ "Respiratory effects of nefopam". Clinical Pharmacology and Therapeutics 18 (2): 175–179. August 1975. doi:10.1002/cpt1975182175. PMID 1097153. 
  11. ↑ "Nefopam and ketamine comparably enhance postoperative analgesia". Anesthesia and Analgesia 100 (1): 169–174. January 2005. doi:10.1213/01.ANE.0000138037.19757.ED. PMID 15616073. 
  12. ↑ 12.0 12.1 "Efficacy of nefopam in postoperative pain management: A systematic review of opioid consumption". Journal of Applied Pharmaceutical Science 15 (5): 024–039. April 5, 2025. doi:10.7324/JAPS.2025.203223. 
  13. ↑ "Use of nefopam for chronic pain". January 5, 2024. https://www.sps.nhs.uk/articles/use-of-nefopam-for-chronic-pain/. 
  14. ↑ "Nefopam for severe hiccups". The New England Journal of Medicine 343 (26): 1973–1974. December 2000. doi:10.1056/nejm200012283432619. PMID 11186682. 
  15. ↑ "Biological Peculiarities of the Analgesic Drug Nefopam in Rats". Advances in Clinical and Experimental Medicine 1 (19). January 2010. https://www.researchgate.net/publication/228540898. Retrieved 18 December 2024. 
  16. ↑ "Comparative effectiveness of pharmacologic interventions to prevent shivering after surgery: a network meta-analysis". Minerva Anestesiologica 85 (1): 60–70. January 2019. doi:10.23736/S0375-9393.18.12813-6. PMID 30226340. 
  17. ↑ "Nefopam, a nonsedative benzoxazocine analgesic, selectively reduces the shivering threshold in unanesthetized subjects". Anesthesiology 100 (1): 37–43. January 2004. doi:10.1097/00000542-200401000-00010. PMID 14695722. 
  18. ↑ https://www.nhs.uk/medicines/nefopam/how-and-when-to-take-nefopam/
  19. ↑ https://onlinelibrary.wiley.com/doi/10.1111/j.1399-6576.1979.tb01486.x
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 "Data Sheet ACUPAN™ Nefopam hydrochloride 30 mg tablets 20 mg intramuscular injection". Medsafe New Zealand. iNova Pharmaceuticals (New Zealand) Limited. 3 September 2007. http://www.medsafe.govt.nz/profs/datasheet/a/acupantabinj.pdf. 
  21. ↑ "Side effects of nefopam". April 25, 2024. https://www.nhs.uk/medicines/nefopam/side-effects-of-nefopam/. 
  22. ↑ "Anticholinergic Burden (ACB)". January 6, 2022. https://www.hey.nhs.uk/patient-leaflet/anticholinergic-burden-acb/. 
  23. ↑ "ACB Calculator". https://www.acbcalc.com/. 
  24. ↑ "Association between anticholinergic (atropinic) drug exposure and cognitive function in longitudinal studies among individuals over 50 years old: a systematic review". European Journal of Clinical Pharmacology 75 (12): 1631–1644. December 2019. doi:10.1007/s00228-019-02744-8. PMID 31468067. 
  25. ↑ 25.0 25.1 "[Chronic abuse of the analgesic nefopam (Acupan)]" (in French). Journal de Toxicologie Clinique et Expérimentale 7 (5): 343–346. September 1987. PMID 3448182. 
  26. ↑ 26.0 26.1 "Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies". Clinical and Experimental Pharmacology & Physiology 43 (1): 3–12. January 2016. doi:10.1111/1440-1681.12506. PMID 26475417. 
  27. ↑ "New Zealand Data Sheet Acupan(TM)". Medsafe. New Zealand The Ministry of Health. 17 May 2017. http://www.medsafe.govt.nz/profs/Datasheet/a/acupantabinj.pdf. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Cite error: Invalid <ref> tag; no text was provided for refs named Sanga_2016
  29. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named GregoriPuigjane_2012
  30. ↑ 30.0 30.1 The Practice of Medicinal Chemistry. Elsevier Science. 1 July 2015. pp. 250–251. ISBN 978-0-12-417213-5. https://books.google.com/books?id=dtScBAAAQBAJ&pg=PA250. 
  31. ↑ Drug Discovery: A History. John Wiley & Sons. 23 June 2005. pp. 405–. ISBN 978-0-471-89979-2. https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA405. 
  32. ↑ Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective. John Wiley & Sons. 6 March 2006. pp. 54–. ISBN 978-3-527-60402-9. https://books.google.com/books?id=oxvYXJSCImUC&pg=PA54. 
  33. ↑ Therapeutic Hypothermia. CRC Press. 2014. pp. 176–. https://books.google.com/books?id=lpETxii5bjQC&pg=PA176. 
  34. ↑ https://www.researchgate.net/publication/394305223_Synthetic_strategies_toward_nefopam_a_short_review
  35. ↑ "Nefopam: a painkiller taken to treat moderate pain". April 25, 2024. https://www.nhs.uk/medicines/nefopam/. 
  36. ↑ "Medicines Safety Sub-Group Nefopam Bulletin". November 2017. https://www.wyicsapc.co.uk/wp-content/uploads/2017/11/Medicines-Safety-Sub-Group-Nefopam-Bulletin-Version-1.0.pdf. 
  37. ↑ "Barnsley APC Position Statement on Nefopam". August 2023. https://best.barnsleyccg.nhs.uk/media/x5ijxd1l/nefopam_barnsley_apc_position_statement.pdf?UNLID=. 
  38. ↑ "Nefopam prescribing preferences in French hospitals: results of a survey". The Pan African Medical Journal 41: 213. May 6, 2022. doi:10.11604/pamj.2022.41.213.33365. PMID 35721644. 
  39. ↑ "[Thirty years of nefopam abuse in France]". Therapie 76 (6): 527–537. May 6, 2021. doi:10.1016/j.therap.2021.01.058. PMID 33618914. 
  40. ↑ "Public Notification: Pro ArthMax Contains Several Hidden Drug Ingredients". Center for Drug Evaluation and Research. U.S. Food and Drug Administration. August 16, 2021. https://www.fda.gov/drugs/medication-health-fraud/public-notification-pro-arthmax-contains-several-hidden-drug-ingredients. 
  41. ↑ "Fatal overdosage with nefopam (Acupan)". Journal of Analytical Toxicology 26 (4): 239–243. May 2002. doi:10.1093/jat/26.4.239. PMID 12054367. 



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