A case of naloxone reversed acute coma after a single nefopam intramuscular administration. A link with opioids is sustained by naltrexone-sensitive nefopam analgesic effect in mice

摘要

Nefopam is a well-known analgesic drug widely used since 1976. It is supposed to act within the centralnervous system in a non-opioid dependent manner. Among the common reported side effects, the main aretachycardia, blood pressure increase, atropinic symptoms and convulsions, malaise or sedative effects. We reporta case of an acute and profound central depression after a single 20 mg intramuscular (IM) administration ofnefopam rapidly reversed by 0.4mg of naloxone IV. Since the mechanisms of nefopam are still discussed, wetested mice on the hot plate test, with addition or not of 2mg/kg of naltrexone [NTX]. Clinical report: a 40-yearoldman had an acute abdominal pain. He had no antecedent and did not take any medication. The diagnosis ofrenal colic is no doubt with the clinical exam. Firefighters were called to drive him to the hospital emergency.The physician administered 2 tablets of phloroglucinol per os and injected a bulb of 20 mg IM of nefopam(Acupan?). During the transport (10 – 15 minutes) the patient became unconscious with a Glasgow score of 7.He was dramatically hypotonic and progressively lacked of spontaneous breathing but he was not intubated. Hehad no tachycardia, nor convulsion. He displayed a sudden resuscitation after a single injection of naloxone (0.4mg IV). He transiently relapsed in drowsiness with a decreased respiratory frequency (9 breaths/min) whichdisappeared after a short perfusion of naloxone. The patient reported he remembered he was unable to moveduring the ambulance ride. This severe side effect with near death experience is not described in the drugdictionaries and the only 4 fatal cases previously reported are related to voluntary intoxications. We found onlytwo cases with vegetative breakdown and loss of consciousness In the French pharmacovigilance database: (i) a67-year-old man who had history of an operated carcinoid tumor and was treated by somatostatin plus lisinoprilfor hypertension. During a painful episode of occlusion, he received 20 mg of IV nefopam. He had loss ofconsciousness and coma during 2 hours, spontaneously regressive; (ii) a 78-year-old male who had hypothermia(32.7°C) without feeling cold or shivering and a Glasgow score of 6. He received for postoperative pain a singlemorphine dose and a perfusion of nefopam (80 mg /d). He recovered in 6 hours. The literature shows pro andcons for an opioid link in nefopam effect. Using tail-lick test in mice Piercey and Schroeder (1981) concludedthat nefopam was a non-narcotic centrally analgesic because its effect was unaffected by naloxone pretreatment(0.5mg/kg, ip). But, Gary and al. (1999) using abdominal constriction assay and tail immersion test in mice havesuggested an opioidergic component in nefopam antinociceptive effects. Thus, we tested mice on hot-plate(55°C) with nefopam (30mg/kg, ip) or saline (in presence of NTX (2mg/kg, sc)) or saline. NTX alone did notmodify the jump latency (32.4-2.0 vs 40.0-5.4s) while it reversed the increased latency induced by nefopam(64-8.8 vs 131.6-15.5 s; p<0.01). We concluded that (i) the rare vital failures induced by nefopam have to bereverse by naloxone (ii) in mice, the opioid effect of high dosage nefopam is clear because antagonized by NTX.Further studies are needed to explore whether or not release of endogenous opioids is the main source of thisunexpected effect.