Nefopam: A Review of its Pharmacological Properties and Therapeutic Efficacy

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.