Drugs

, Volume 19, Issue 4, pp 249–267 | Cite as

Nefopam: A Review of its Pharmacological Properties and Therapeutic Efficacy

  • R. C. Heel
  • R. N. Brogden
  • G. E. Pakes
  • T. M. Speight
  • G. S. Avery
Evaluations on New Drugs

Summary

Synopsis: Nefopam1 is a non-narcotic analgesic not structurally related to other analgesic drugs. It is effective by the oral and parenteral routes, and when appropriate dose ratios were compared in short term studies it was shown to produce analgesia comparable to that with the oral analgesics aspirin, dextropropoxyphene and pentazocine, as well as that with ‘moderate’ doses of parenteral morphine, pethidine and pentazocine. However, when ‘higher’ dose ratios were compared, morphine and pethidine were usually more effective than nefopam, possibly due to a ‘ceiling effect’ for analgesia which may occur with higher doses of nefopam, as with other simple analgesics. Although a few patients with chronic pain have received nefopam for several weeks, further studies are needed to clarify its continued effectiveness and safety when used over long periods. In most patients nefopam has been relatively well tolerated, the most frequent side effects being sweating, nausea and in some studies sedation.

Pharmacodynamic Studies: Although structurally related to the antihistamine, diphenhydramine, and the antiparkinson drug, orphenadrine, nefopam has no antihistaminic activity, and in contrast to orphenadrine it may enhance motor neurone excitability. In most healthy subjects usual analgesic doses have not caused respiratory depression. However, data in ‘at risk’ patients (such as those with bronchopulmonary disease or heart failure), or following overdosage, have not been reported. In contrast to morphine, nefopam appears to have a slight positive chronotropic and inotropic effect on the heart.

The relative analgesic potency of nefopam hydrochloride compared with morphine sulphate has not been consistent in various studies, possibly due to the confounding effect of a ‘ceiling effect’ for analgesia which may occur with higher doses of nefopam (as with other simple analgesics); but the potency ratio lies in the range of 0.2 to 0.6 : 1 (nefopam : morphine potency). The mechanism of nefopam’s analgesic action Is not known, but it does not bind to opiate receptors.

Studies in animal models suggest that nefopam may have a low dependence liability and abuse potential, but only wider use over longer periods will determine this with certainty.

Pharmacokinetic Studies: Only limited pharmacokinetic data are available. Following a 60mg oral dose in healthy subjects peak blood concentrations of 29 to 67ng/ml occurred at about 2 hours. Similar peak concentrations were achieved about 1.5 hours after an intramuscular dose of 20mg. Nefopam is about 75% protein bound. Biotransformation of nefopam is extensive, less than 5% being excreted in the urine in unchanged form. The elimination half-life in healthy subjects is 3 to 8 hours (mean 4 hours) after an oral or intravenous dose.

Therapeutic Trials: Nefopam has been studied primarily in single dose or short term studies in patients with postoperative or musculoskeletal pain. Most comparative studies have made reasonable efforts to overcome the inherent difficulties in evaluating an analgesic drug.

When oral nefopam in the dose range of 30 to 90mg was compared with approximately equianalgesic doses of aspirin, dextropropoxyphene or oral pentazocine, few important differences emerged. Similarly, when intramuscular (15 or 30mg) or intravenous (10 or 15mg) nefopam was compared with ‘moderate’ equianalgesic doses of morphine, pethidine or pentazocine the analgesia produced was usually similar. At the ‘higher’ dose levels, however, morphine and pethidine were more effective in relieving pain, morphine 8mg and pethidine 100mg producing greater analgesia than nefopam 30mg, although the duration of analgesia was sometimes longer with nefopam at these doses.

Side Effects: In the short term studies reported to date nefopam has usually been relatively well tolerated. The adverse effects profile during chronic use has not been clearly determined. The most frequent side effects encountered have been nausea and sweating, each occurring in about 10 to 30% of patients; the reported incidence in individual studies probably depending to some extent on the method used to elicit side effect information, as well as the dosage used. Parenteral administration does not appear to reduce the incidence of nausea. Sedation also was reported to occur frequently in some studies (about 20 to 30% of patients), and pain at the site of intramuscular or intravenous injection has occurred in 20% of patients in some series. Tachycardia has been reported following parenteral administration.

In comparative studies the overal profile of side effects with nefopam usually resembled that with other analgesic drugs tested. However, nefopam usually caused more sweating (and in some studies tachycardia) but less sedation than the narcotic analgesics such as morphine. Unlike aspirin, oral nefopam does not cause gastrointestinal blood loss, but it may produce a higher incidence of nausea and sweating than aspirin.

Dosage and Administration: The initial oral dose of nefopam is 30mg 3 to 4 times daily, as required. If this is inadequate, single doses may be increased to 60mg, or to 90mg if pain is very severe. If parenteral administration is indicated, 20mg every 4 to 6 hours, as necessary, may be given intramuscularly. By the intravenous route the dosage is 10 to 20mg by slow injection up to every 4 to 6 hours or, alternatively, 10 to 30mg by intravenous infusion over a 2 to 6 hour period. The maximum recommended dose in a 24-hour period is 300mg orally and 120mg parenterally.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aluja Deu, J.R.; Vazquez Garcia, J.A. and Melgareja Carrion, J.S.: Investigacion clinica sobre el analgésico no narcotico R-738. Investigacion Médica Internacional 3: 37–42 (1976).Google Scholar
  2. Baltes, B.J.: Gastrointestinal blood loss study with a new analgesic compound: nefopam hydrochloride. Journal of Clinical Pharmacology 17: 120–124 (1977).PubMedGoogle Scholar
  3. Bassett, J.R.; Cairncross, K.D.; Hacket, N.B. and Story, M.: Studies on the peripheral pharmacology of fenazoxine, a potential antidepressant drug. British Journal of Pharmacology 37: 69–78 (1969).PubMedCrossRefGoogle Scholar
  4. Beaver, W.T.: Mild analgesics — A review of their clinical pharmacology, Part I. American Journal of Medical Sciences 250: 577–604 (1965).CrossRefGoogle Scholar
  5. Beaver, W.T. and Feise, G.A.: A comparison of the analgesic effect of intramuscular nefopam and morphine in patients with postoperative pain. Journal of Clinical Pharmacology 17: 579–591 (1977).PubMedCrossRefGoogle Scholar
  6. Belleville, J.P.; Dorey, F. and Belleville, J.W.: Effects of nefopam on visual tracking. Clinical Pharmacology and Therapeutics 26: 457–463 (1979).PubMedGoogle Scholar
  7. Bloomfield, S.S.; Barden, T.P. and Mitchell, J.: Nefopam and propoxyphene in episiotomy pain. Clinical Pharmacology and Therapeutics 25: 214 (1979).Google Scholar
  8. Campos, V.M.: The analgesic nefopam (Acupan) lowers body temperature. Current Therapeutic Research 22: 790–791 (1977).Google Scholar
  9. Case, M.T.; Smith, J.K. and Nelson, R.A.: Reproductive, acute and subacute toxicity studies with nefopam in laboratory animals. Toxicology and Applied Pharmacology 33: 46–51 (1975).PubMedCrossRefGoogle Scholar
  10. Case, M.T.; Smith, J.K. and Nelson, R.A.: Chronic oral toxicity studies of nefopam hydrochloride in rats and dogs. Toxicology and Applied Pharmacology 36: 301–306 (1976).PubMedCrossRefGoogle Scholar
  11. Cohen, A.: Nefopam hydrochloride pain relief. Current Therapeutic Research 16: 184–193 (1974).PubMedGoogle Scholar
  12. Cohen, A. and Hernandez, C.M.: Nefopam hydrochloride: New analgesic agent. Journal of International Medical Research 4: 138–143 (1976).PubMedGoogle Scholar
  13. Cole, J.O.; Pope, H.G.; LaBrie, R. and Ionescu-Pioggia, M.: Assessing the subjective effects of stimulants in casual users. A methodology and preliminary results. Clinical Pharmacology and Therapeutics 24: 243–252 (1978).PubMedGoogle Scholar
  14. Conway, A.C. and Mitchell, C.L.: Analgesic studies with nefopam hydrochloride. Archives internationale de Pharmacodynamie et de Therapie 226: 156–171 (1977).Google Scholar
  15. de Thibault de Boesinghe, L.: Double-blind study of the analgesic effect of nefopam hydrochloride (Acupan) and pentazocine (Fortal) in cancer patients with pain. Current Therapeutic Research 24: 646–655 (1978).Google Scholar
  16. de Thibault de Boesinghe, L.; Van Daele, M.J. and Van Severen, G.: Open study of the analgesic effects of nefopam hydrochloride (Acupan) on cancer patients with pain. Current Therapeutic Research 20: 59–61 (1976).PubMedGoogle Scholar
  17. Fassolt, A.: Acupan® (nefopam) zur Schmerzbehandlung in der postoperativen Frühphase. Schweizerische Rundschau für Medizin (Praxis) 68: 1333–1337 (1979).Google Scholar
  18. Ferguson, R.K. and Turek, D.M.: Double-blind comparison of nefopam and pethidine in post-operative pain. Pharmatherapeutica 1: 523–527 (1977).Google Scholar
  19. Frey, L.G. and Winter, J.C.: Comparison of the discriminative stimulus properties of nefopam and morphine. Psychopharmacology 61: 231–232 (1979).PubMedCrossRefGoogle Scholar
  20. Garcés, M.A.; Beitran, M. and Montes, R.F.: Evaluacion de un nuevo analgésico. Actualidades Médicas, p.53, November (1975).Google Scholar
  21. Gassel, M.M.: An objective technique for the analysis of the clinical effectiveness and physiology of action of drugs in man; in Desmedt (Ed) New Developments in Electromyography and Clinical Neurophysiology, volume 3, pp.342–359 (Karger, Basel 1973).Google Scholar
  22. Gassel, M.M.; Diamantopoulos, E.; Petropoulos, V.; Hughes, A.C.R.; Fernandez Ballesteros, M.L. and Re, O.N.: Controlled clinical trial of oral and parenteral nefopam hydrochloride. A novel and potent analgesic drug. Journal of Clinical Pharmacology 16: 34–42 (1976).PubMedGoogle Scholar
  23. Gasser, J.C. and Bellville, J.W.: Respiratory effects of nefopam. Clinical Pharmacology and Therapeutics 18: 175–197 (1975).PubMedGoogle Scholar
  24. Hagemann, K.; Platte, G.; Meyer, J. and Effert, S.: Hamodynamische Wirkung von Nefopam. Deutsch Medizinische Wochenschrift 103: 1040–1043 (1978).CrossRefGoogle Scholar
  25. Hammerbeck, D.M.; Conway, A.C. and Mitchell, C.L.: Pharmacologic evaluation of nefopam hydrochloride (Acupan). Pharmacologist 16: 247 (1974).Google Scholar
  26. Hedges, A.; Wadsworth, J. and Turner, P.: A double-blind comparison of nefopam and placebo in post-operative pain. Current Medical Research and Opinion 5: 614–617 (1978).PubMedCrossRefGoogle Scholar
  27. Heel, R.C.; Brogden, R.N.; Speight, T.M. and Avery, G.S.: Butorphanol: A review of its pharmacological properties and therapeutic efficacy. Drugs 16: 473–505 (1978).PubMedCrossRefGoogle Scholar
  28. Heel, R.C.; Brogden, R.N.; Speight, T.M. and Avery, G.S.: Buprenorphine: A review of its pharmacological properties and therapeutic efficacy. Drugs 17: 81–110 (1979).PubMedCrossRefGoogle Scholar
  29. Houde, R.W.; Wallenstein, M.S.; Rogers, A. and Kaiko, R.F.: Annual report of the Memorial Sloan-Kettering Cancer Center analgesic studies section; from Problems of Drug Dependence, proceedings of 39th Annual Scientific Meeting, Committee on Problems of Drug Dependence, July 6–9 (1977).Google Scholar
  30. Jasinski, D.R.; Griffith, J.D. and Pevnick, J.: Nefopam (n), morphine (m), and d-amphetamine (a) in man: Subjective, behavioral, and physiologic effects. Pharmacologist 19: 230 (1977a).Google Scholar
  31. Jasinski, D.R.; Griffith, J.D.; Pevnick, J.; Gorodetzky, C; Cone, E. and Kay, D.: Progress report from the clinical pharmacology section of the NIDA research center. U.S. Department of Health, Education and Welfare (1977b).Google Scholar
  32. Kaiko, R.F.; Houde, R.W.; Rogers, A.; Inturrisi, C.E.; Wallenstein, S.L.; Grabinski, P. and Foley, K.M.: Annual report of the Memorial Sloan-Kettering Cancer Center, analgesic studies section: Disposition and action of narcotic analgesics; from Problems of Drug Dependence, proceedings of the 40th Annual Scientific Meeting, Committee on Problems of Drug Dependence, June 3–6 (1978).Google Scholar
  33. Klohs, M.W.; Draper, M.D.; Petracek, F.J.; Ginzel, K.H. and Re, O.N.: Benzoxazocines: A new chemical class of centrally acting skeletal muscle relaxants. Arzneimittel-Forschung 22: 132–133 (1972).PubMedGoogle Scholar
  34. Klotz, A.L.: Long-term safety of nefopam hydrochloride (Acupan), a new analgesic formulation. Current Therapeutic Research 16: 602–608 (1974).PubMedGoogle Scholar
  35. Knaus, U.: Cardiovascular effect of nefopam in nitrous oxide anaesthesia. Inaugural dissertation for doctorate of the medical faculty of Zurich University, Zurich (1977).Google Scholar
  36. Kolodny, A.L. and Winter, L.: Further clinical evaluations of nefopam hydrochloride, a new analgesic. Current Therapeutic Research 17: 519–524 (1975).PubMedGoogle Scholar
  37. Mok, M.S.; Lippmann, M. and Steen, S.N.: Nefopam in the relief of postoperative pain. IRCS Medical Science 5: 39 (1977).Google Scholar
  38. Mok, M.S.; Lippmann, M. and Steen, S.N.: Intravenous nefopam for post-operative pain: Preliminary investigation. IRCS Medical Science 6: 408 (1978).Google Scholar
  39. Mok, M.S.; Lippmann, M. and Steen, S.N.: Comparison of intravenous nefopam versus morphine for the relief of postoperative pain. Clinical Pharmacology and Therapeutics 25: 237–238 (1979).Google Scholar
  40. Phillips, G. and Vickers, M.D.A.: Nefopam in postoperative pain. British Journal of Anaesthesia 51. 961–965 (1979).PubMedCrossRefGoogle Scholar
  41. Rosen, M.: The measurement of pain; in Harcus, A.W. et al. (Eds) Pain, New Perspectives in Measurement and Management, p. 13–20 (Churchill Livingstone, Edinburgh 1977).Google Scholar
  42. Schietzel, M.: Analgesie mit geringen Nebenwirkungen. Fortschritte der Medezin 95: 2743–2746 (1977).Google Scholar
  43. Schmidt, M. and Fuhrer, R.: Ajan bei postoperativen Schmerzzustanden. Munchener Medizinische Wochenschrift 119: 991–992 (1977).PubMedGoogle Scholar
  44. Steen, S.N.; Mok, M.S.; Lippmann, M.; Smith, R.L.; Jeretin, S. and Kozjek, F.: Effect of intravenous nefopam on the human respiratory center. IRCS Medical Science 6: 483 (1978).Google Scholar
  45. Steen, S.N.; Smith, R.; Kuo, J.; Mok, M.S. and Lippmann, M.: Effects of nefopam and pentazocine on the human respiratory center. IRCS Medical Science 5: 490 (1977).Google Scholar
  46. Sunshine, A. and Laska, E.: Nefopam and morphine in man. Clinical Pharmacology and Therapeutics 18: 530–534 (1975).PubMedGoogle Scholar
  47. Sunshine, A.; Laska, E. and Slafta, J.: Oral nefopam and aspirin. Clinical Pharmacology and Therapeutics 24: 555–559 (1978).PubMedGoogle Scholar
  48. Tigerstedt, I.; Sipponen, J.; Tammisto, T. and Turunen, M.: Comparison of nefopam and pethidine in postoperative pain. British Journal of Anaesthesia 49: 1133–1138 (1977).PubMedCrossRefGoogle Scholar
  49. Tigerstedt, I.; Tammisto, T. and Leander, P.: Comparison of the analgesic dose-effect relationships of nefopam and oxycodone in postoperative pain. Acta Anesthesiologica Scandinavica. In press (1980).Google Scholar
  50. Tresnak-Rustad, N.J. and Wood, M.B.: Opiate receptor binding activity and effect on synaptosomal uptake of dopamine, norepinephrine and serotonin of nefopam hydrochloride (Acupan). Federation Proceedings 37: 764 (1978).Google Scholar
  51. Trop, D.: A study of potency and side-effects of nefopam hydrochloride. Clinical Therapeutics: Nefopam (Exerpta Medica, Princeton 1979).Google Scholar
  52. Trop, D.; Kenny, L. and Grad, B.R.: Comparison of nefopam hydrochloride and propoxyphene hydrochloride in the treatment of postoperative pain. Canadian Anaesthetist’s Society Journal 26: 296 (1979).CrossRefGoogle Scholar
  53. Wade, A.G. and Hosie, J.: A new oral analgesic in general practice. Practitioner 223: 129–132 (1979).PubMedGoogle Scholar
  54. Wallenstein, S.L.; Kaiko, R.F.; Rogers, A. and Houde, R.W.: A clinical assay of nefopam and morphine. Clinical Pharmacology and Therapeutics 23: 134 (1978).Google Scholar
  55. Wang, R.I.H. and Waite, E.M.: The clinical analgesic efficacy of oral nefopam hydrochloride. Journal of Clinical Pharmacology 19: 395–402 (1979).PubMedGoogle Scholar
  56. Workmon, F.C. and Winter, L.: A clinical evaluation of nefopam hydrochloride (Acupan): A new analgesic. Current Therapeutic Research 16: 609–616 (1974).PubMedGoogle Scholar

Copyright information

© ADIS Press Australasia Pty Ltd 1980

Authors and Affiliations

  • R. C. Heel
    • 1
  • R. N. Brogden
    • 1
  • G. E. Pakes
    • 1
  • T. M. Speight
    • 1
  • G. S. Avery
    • 1
  1. 1.Australasian Drug Information ServicesBirkenhead, Auckland 10New Zealand

Personalised recommendations