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Abstract
Nefopam hydrochloride (Acupan) is a potent non-opioid analgesic widely used for the relief of moderate to severe postoperative pain. The drug is generally well tolerated, but it has a broad spectrum of side effects including tachycardia, sweating, nausea, seizures and hallucinations. When taken in overdose, nefopam has been reported to cause cardiac conduction abnormalities, cerebral oedema, fever and renal failure. The case is presented of a previously healthy 19-year-old man who presented to the emergency department in cardiac arrest following intentional nefopam overdose. It is only the fourth reported case of fatal nefopam overdose in the literature.
- Nefopam
- overdose
- fatal outcome
- mental health, overdose
- poisoning, deliberate self
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Introduction
Nefopam hydrochloride is a centrally acting benzoxazocine analgesic with a structure distinct from non-steroidal anti-inflammatory drugs and opioids. It was initially developed as a muscle relaxant but it is now primarily used for the relief of moderate to severe pain, particularly in the postoperative setting. It is also used in reducing postoperative shivering following general anaesthesia.
Nefopam has been found to strongly depress the nociceptive reflex in human subjects, with recent studies showing that the drug causes inhibition of N-methyl-D-aspartate (NMDA)-mediated excitotoxicity following activation of voltage-sensitive sodium and calcium channels.
Oral nefopam has approximately 10 times the potency of an equivalent dose of aspirin, although in patients with severe pain it has been shown to be less effective than morphine and oxycodone when administered via the parenteral route.
Adverse reactions include effects on the cardiovascular (palpitations and tachycardia), renal (urinary retention and dysuria), gastrointestinal (diarrhoea, dyspepsia, nausea and vomiting) and neurological (dizziness, paraesthesia, tremor and hallucinations) systems. Seven cases of generalised tonic-clonic seizures have been reported to the Medicines and Healthcare products Regulatory Agency (MHRA), so the use of nefopam is contraindicated in patients with convulsive disorders and caution is advised in those taking medications that lower the seizure threshold. Nefopam use is rarely associated with dependence or withdrawal symptoms, however cases of abuse have been reported.
Nefopam has been commercially available in the UK for 30 years, during which time 11 fatalities have been notified to the MHRA. Five of these were secondary to overdose, either with a single agent or in conjunction with weak opioids (in two patients). Other causes of death listed include coronary artery thrombosis, haematemesis, peptic ulcer perforation, aspiration pneumonia and hepatic necrosis although, in the latter two cases, at least eight other medications were taken alongside nefopam.
To our knowledge, only four cases of death due directly to nefopam overdose have been reported in the literature.1–3
Case report
A previously well 19-year-old man was brought into the emergency department at 20.01 h, approximately 1 h after ingestion of 60×30 mg nefopam hydrochloride and 14×50 mg diclofenac sodium tablets. According to the attending ambulance crew, the patient had been alert and communicating upon their arrival but had deteriorated rapidly, having one generalised seizure at home followed by three further seizures during transfer to hospital.
As the patient entered the emergency department he became unresponsive and cyanosed. Cardiorespiratory arrest was confirmed, with cardiac monitoring demonstrating pulseless electrical activity at a rate of 40 beats/min. Intubation was performed within 1 min of arrival and full ALS protocol was followed. No potentially reversible causes of cardiac arrest were identified. A total of 5 mg epinephrine, 3 mg atropine, 10 ml calcium chloride 10%, 400 μg naloxone, 50 ml sodium bicarbonate 8.4% and 1.5 l colloid fluid were administered intravenously but no response was observed. Resuscitation was unsuccessful and the patient was declared dead at 20.24 h.
Post-mortem toxicology revealed a serum nefopam concentration of 7.45 mg/l and diclofenac concentration of 69 mg/ml. Histological examination showed evidence of pulmonary congestion, but there were no other significant findings on macroscopic or microscopic examination. The cause of death was directly attributed to overdosage of nefopam.
Discussion
Within the Sheffield Teaching Hospitals NHS foundation trust, nefopam is prescribed regularly with approximately 200 packs (each containing 90 tablets) being dispensed monthly from discharge and outpatient prescriptions. Awareness of the potential consequences of nefopam overdose is therefore important within our emergency department setting.
Oral nefopam is readily absorbed from the gastrointestinal tract, reaching peak plasma concentrations between 1 and 3 h after administration. It has a half-life of approximately 5 h following either oral or parenteral administration. Unfortunately, there is little information available regarding the toxicology of nefopam in either human or animal studies. Case et al administered 40 and 80 mg/kg/day nefopam to dogs over a 12-month period and reported central nervous system stimulation in the form of convulsions and excitable behaviour.4
Known effects of nefopam overdosage include tachycardia, convulsions, agitation, hallucinations, oliguria, dilated pupils, hyporeflexia and hyper-reflexia. Table 1 summarises the reported cases of nefopam overdose in the literature, together with the clinical findings observed in each case.
Reported cases of fatal nefopam overdose
There is no specific antidote available for nefopam, hence treatment of overdosage is supportive. Activated charcoal (adults 50 g, children 1 g/kg) is recommended for patients who present within 1 h of ingestion of 7.5 mg/kg or above. Beta-blockade is recommended for the treatment of supraventricular tachycardias, and benzodiazepines may be used for the control of frequent/prolonged seizures or hallucinations.
Conclusion
Nefopam is an effective analgesic which is generally well tolerated, despite its broad side effect profile. Overdosage is uncommon but can be rapidly fatal, as demonstrated in this case report and those preceding it. Features which may identify patients presenting with potentially fatal overdose include generalised seizures, cardiac conduction defects and oliguria/anuria. Treatment at present remains supportive.
Footnotes
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; not externally peer reviewed.