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.

Keywords: adverse drug reactions; molecular mechanisms of pharmacological action; nefopam; neuropathic pain; nonopioid analgesics.

Figures

Fig. 1

Similarity of structural formulae of (A) orphenadrine, (B) diphenhydramine, and (C) nefopam.

Fig. 2

Schematic presentation of dopamine (DA), noradrenalin (NA), and 5-hydroxytryptamine (5-HT) synaptic terminals drawn in the same neuron. In human body, they are actually located in the different neurons and locations: (1) The dopamine transporter (DAT) expression is dominant in the cell bodies of the substantia nigra and ventral tegmental area: (2) The noradrenalin transporter (NET) expression is abundant in the locus coeruleus and other brain stem nuclei; (3) The 5-HT transporter (SERT) expression is frequently found in the median and dorsal raphe nuclei. They are also found peripherally, especially in the dorsal root ganglia related to descending inhibition of pain. Monoamine transporters are localized to presynaptic sites, where they are crucial for the termination of monoamine transmission and the maintenance of presynaptic monoamine storage. Nefopam (NFP) has an ability of these 3 receptors reuptake inhibition (Modified from Torres GE, Gainetdinov RR, Caron MG. Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 2003; 4: 13-25.).

Fig. 3

Model synapse illustrating interaction of Na+ channel blocking anticonvulsants with voltage-activated Na+ channels and putative sites of action of newer anticonvulsants (gabapentin, pregabalin, and levetiracetam) that may more directly interact with release machinery. Gabapentin and pregabalin bind to α2-δ, which may inhibit voltage-activated Ca2+ entry through high voltage-activated Ca2+ channels or affect the way in which Ca2+ channels interact with vesicular release. Levetiracetam may also affect release by binding to synaptic vesicles protein SV2A. In contrast, action potentials are mediated by voltage-activated Na+ and K+ channels; Na+ channel blocking anticonvulsants suppress epileptiform action potential firing, which leads to inhibited release. Smaller yellow circles represent glutamate within synaptic vesicles (larger blue circles) and free in the synaptic cleft. Glutamate acts on ionotropic receptors of the NMDA, AMPA and kainate types to generate an excitatory postsynaptic potential (EPSP) in the postsynaptic neuron. Nefopam (NFP) shows an activity of the 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 (Modified by Löscher W, Schmidt D. New Horizons in the development of antiepileptic drugs: Innovative strategies. Epilepsy Res 2006; 69: 183-272.).

Fig. 4

The roles and deficit states of 3 important neurotransmitters (serotonin, norepinephrine, and dopamine) and balanced and unbalanced states of these neurotransmitters in human body.