Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies

Abstract

SUMMARYNefopam is a non-opioid, non-steroidal, centrally acting analgesic drug used to prevent postoperative pain, primarily in the context of multimodal analgesia. This paper reviews preclinical and clinical studies in which nefopam has been combined with opioids, non-steroidal anti-inflammatory compounds, and paracetamol. This report focuses on the literature during the last decade and discusses the translational efforts between animal and clinical studies in the context of multimodal or balanced analgesia. In preclinical rodent models of acute and inflammatory pain, nefopam combinations including opioids revealed a synergistic interaction or enhanced morphine analgesia in six out of seven studies. Nefopam combinations including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, ketoprofen or nimesulide) or paracetamol likewise showed enhanced analgesic effects for the associated compound in all instances. Clinical studies have been performed in various types of surgeries involving different pain intensities. Nefopam combinations including opioids resulted in a reduction in morphine consumption in 8 out of 10 studies of severe or moderate pain. Nefopam combinations including NSAIDs (ketoprofen or tenoxicam) or paracetamol also demonstrated a synergic interaction or an enhancement of the analgesic effect of the associated compound. In conclusion, this review of nefopam combinations including various analgesic drugs (opioids, NSAIDs and paracetamol) reveals that enhanced analgesia was demonstrated in most preclinical and clinical studies, suggesting a role for nefopam in multimodal analgesia based on its distinct characteristics as an analgesic. Further clinical studies are needed to evaluate the analgesic effects of nefopam combinations including NSAIDs or paracetamol.

Preventive Analgesic Efficacy of Nefopam in Acute and Chronic Pain After Breast Cancer Surgery

“…The analgesic efficacy of nefopam during the acute postoperative period was known from several preclinical and clinical studies. 5 – 7 Our results were also similar to previous studies examining acute postoperative pain, which showed that patients treated with nefopam reported severe pain less often. All patients received ketorolac routinely at the end of the surgery and meloxicam in the acute postoperative period.…”

“…Nefopam has been studied in several animal models and various clinical settings, where it was found to be an effective analgesic adjuvant. 5 Perioperative use of nefopam reduced the postoperative consumption of morphine, with surgical pain relief after abdominal and orthopedic surgeries, 6 , 7 and it enhanced the analgesic effect of NSAIDs. 8 However, to our knowledge, no reported clinical study has evaluated the analgesic efficacy of nefopam in breast cancer surgery.…”

Nefopam and its Role in Modulating Acute and Chronic Pain

“…It inhibit the central synaptosomal reuptake of serotonin (5-hydroxytryptamine, 5-HT), norepinephrine and dopamine, it interacts directly with á2 -adrenoreceptors and modulate the calcium and sodium channels of the glutamatergic pathway and therefore decreasing the activation of postsynaptic glutamatergic receptors, like N-methyl-D-aspartate (NMDA), which has a specific role in hyperalgesia appearance [9]. In the first place, it was used as an antidepressant and as an antispasmodic drug due to its myorelaxant properties [10] but studies have shown its effectiveness in preventing acute postsurgical hyperalgesia [11] and modulation of non-surgical neuropathic pain [12]. It is a benzoxazocine known as 5-methyl-1-phenyl-1,3,4,6tetrahydro-2,5-benzoxazocine (C 17 H 19 NO) obtained from a non-sedative benzoxazocine and is a cyclized analogue of an antihistamine (diphenhydramine -C 17 H 21 NO) [13].…”

Neither nefopam nor acetaminophen can be used as postoperative analgesics in a rat model of ischemic stroke

“…The demonstration of the neuroprotective effect of acetaminophen finds echoes in the cardiology literature, where it is reported for antioxidant and anti-inflammatory properties [11]. In the brain, acetaminophen's mechanism of action may involve the inhibition of central cyclo-oxygenase COX-2 and COX-3 enzymes and the modulation of serotonergic system [12,13]. As well, acetaminophen enabled the lowering of oxidative stress-induced brain neuron damage through the inhibition of superoxide anion production, and an increased synthesis of anti-apoptotic protein Bcl-2 [14,15].…”

“…It is tempting to speculate that nefopam did not interfere with the binding of MK801 to NMDA receptors in the glutamate pathway [18]. Indeed, it has been demonstrated that nefopam act on the glutamatergic pathway via modulations of calcium and sodium channels, that leads to decreased activation of postsynaptic glutamatergic receptors such as NMDA receptors [13]. To end, our observation suggests that an acute administration of nefopam at a dose of 20 mg/kg may induce postoperative analgesia without masking the pharmacological effect of a neuroprotective agent such as MK801.…”