Rediscovery of Nefopam for the Treatment of Neuropathic Pain

Abstract

Nefopam (NFP) is a non-opioid, non-steroidal, centrally acting analgesic drug that is derivative of the non-sedative benzoxazocine, developed and known in 1960s as fenazocine. Although the mechanisms of analgesic action of NFP are not well understood, they are similar to those of triple neurotransmitter (serotonin, norepinephrine, and dopamine) reuptake inhibitors and anticonvulsants. It has been used mainly as an analgesic drug for nociceptive pain, as well as a treatment for the prevention of postoperative shivering and hiccups. Based on NFP's mechanisms of analgesic action, it is more suitable for the treatment of neuropathic pain. Intravenous administration of NFP should be given in single doses of 20 mg slowly over 15-20 min or with continuous infusion of 60-120 mg/d to minimize adverse effects, such as nausea, cold sweating, dizziness, tachycardia, or drowsiness. The usual dose of oral administration is three to six times per day totaling 90-180 mg. The ceiling effect of its analgesia is uncertain depending on the mechanism of pain relief. In conclusion, the recently discovered dual analgesic mechanisms of action, namely, a) descending pain modulation by triple neurotransmitter reuptake inhibition similar to antidepressants, and b) inhibition of long-term potentiation mediated by NMDA from the inhibition of calcium influx like gabapentinoid anticonvulsants or blockade of voltage-sensitive sodium channels like carbamazepine, enable NFP to be used as a therapeutic agent to treat neuropathic pain.

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

“…nefopam during phase 1, but not during phase 2, of a formalin test (47). Furthermore, it has been confirmed in an in vivo animal pain model that monoamine depletion inhibited nefopam antinociception, which indicated the involvement of neuromediators in nefopam-induced analgesia (6). More recently, a number of studies have been conducted on the receptor subtypes that are involved in nefopam antinociception.…”

“…Nevertheless, it effectively elicits antinociception in the majority of noxious and thermal models in rodents (3,4). The mechanisms of action of nefopam may involve inhibition of monoamine reuptake in the central nervous system and glutamatergic pathway, in which calcium channels serve a role (5,6). Certain adverse reactions of nefopam, including dizziness, headache, nausea, vomiting and sweating, have been associated with its central mechanisms (7).…”

Combination of nefopam and remifentanil is more effective to reduce rocuronium-induced withdrawal response compared with remifentanil alone: a prospective, double-blinded, randomized control study

“…elucidated [11,18,19]. Studies of serotonin receptor antagonists reported that ondansetron and palonosetron were effective in the prevention of rocuronium-induced withdrawal response [5][6][7][8].…”

“…Nefopam has several potential adverse events, including sedation, dry mouth, tachycardia, dizziness, sweating, nausea and vomiting, dysphoria, diplopia, and dizziness [11,[20][21][22][23].…”

“…We cannot ignore the fact that preoperative treatment with these analgesics influences rocuroniuminduced withdrawal response. Nefopam (a non-narcotic, nonsteroidal, centrally acting analgesic) is usually used for the treatment of nociceptive pain and the prevention of postoperative shivering and hiccups with a similar mechanism to that of serotonin, norepinephrine, and dopamine reuptake inhibitors, although the mechanism of nefopam has not been clearly demonstrated [11]. In critically ill patients with moderate-to-severe pain, nefopam is also reported to be an effective alternative to opioids without significant changes in Richmond Agitation Sedation Scale score, ventilatory frequency, or oxygen saturation [12].…”