Nefopam

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Nefopam is a centrally-acting analgesic agent belonging to the benzoxazocine chemical class. It is structurally distinct from opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), bearing closer resemblance to orphenadrine and diphenhydramine. Initially developed in the 1960s under the name fenazocine and explored as a potential antidepressant and muscle relaxant, its primary clinical application evolved towards analgesia.

Applications

Nefopam is utilised predominantly for the management of moderate to severe acute pain, particularly in the postoperative setting. Its analgesic efficacy in this context has been reported to be comparable to moderate doses of opioids like morphine or pethidine, and oral analgesics such as aspirin or pentazocine, although a potential ceiling effect at higher doses may limit its efficacy compared to higher opioid doses.

While the underlying pharmacology provides a strong theoretical case for nefopam's utility in chronic pain, particularly neuropathic and nociplastic pain, the available clinical evidence remains sparse, often derived from small studies, focused on short-term outcomes (even when assessing chronic conditions like PHN or CPSP incidence), and yielding mixed or inconsistent results.

Mechanisms

The precise molecular mechanisms underlying nefopam's analgesic effects are complex and remain incompletely understood. Evidence suggests a multi-target profile involving actions at both spinal and supraspinal levels. The primary proposed mechanisms include the inhibition of the reuptake of monoamine neurotransmitters—serotonin (5-hydroxytryptamine, 5-HT), noradrenaline (NA), and dopamine (DA)—similar to triple reuptake inhibitor (TRI) antidepressants.

Additionally, nefopam is reported to modulate voltage-gated ion channels, specifically voltage-gated sodium channels (VGSCs) and voltage-sensitive calcium channels (VSCCs). These actions on ion channels are thought to lead to downstream effects on glutamatergic transmission, including modulation of N-methyl-D-aspartate (NMDA) receptor-mediated events (not direct NMDA antagonism). This mechanism shares similarities with gabapentinoids (gabapentin, pregabalin), which modulate VSCC function via binding to the alpha-2-delta subunit.

Nefopam also exhibits anticholinergic activity, though its contribution to analgesia is less well-defined compared to its other mechanisms. This activity is consistent with its structural similarity to known anticholinergic agents like orphenadrine and diphenhydramine.

Nefopam's well-documented anti-shivering effect appears to be mediated via alpha-2 adrenoceptors, specifically the alpha-2A subtype. Interestingly, nefopam reduces the shivering threshold significantly without substantially altering the vasoconstriction threshold, a pattern distinct from most other centrally acting thermoregulatory drugs like alpha-2 agonists or opioids.

Adverse Effects

Mainly anti-cholinergic, also some nausea. There has been some concern with addiction.

Literature Review

Literature Review

Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf

Articles from all years: PubMed search, Google Scholar search.

TRIP Database: clinical publications about evidence-based medicine.

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