Dept. Pain Medicine

Sunderland Royal Hospital

Kayll Road

Sunderland

SR4 7TP

Tel 0191 5656256 ex. 49628

25th January 2016

RE: Information following removal of nefopam from formulary

Dear Colleagues,

The use of nefopam has increased substantially in ourregion over the last few years, (2010-14 an increase of 321%), a change which is out of proportion with the rest of England (124%). Doubts remain in pain medicine units about its efficacy and safety profile. The recent substantial price increase has prompted our review of its utility as an analgesic.

Chronic Pain

Nefopam’s efficacy profile is poorly understood in the management of chronic pain, due to a paucity of data. National guidelines exist in Scotland, (SIGN 136) which recommend it is not used in the context of chronic pain management. It is not endorsed in the guidelines issued by NICE (palliative analgesia, acute & sub-acutelow back pain, neuropathic pain). Nor is it included in the treatment protocols published by the British Pain Society or Faculty of Pain Medicine of the Royal College of Anaesthetists.

Acute Pain

In the context of acute post-operative pain,Cochrane concluded that the absence of placebo controlled trials using pain scores as a primary end point, meant that it could not be recommended. Studies have shown that although it is able to reduce intravenous opioid requirements by about 10% in post operative patients, the adverse effects of opioids were unchanged.

On-going Inflammatory Pain

Cochrane analysis suggested a small analgesic improvement (21%) in the on-going inflammatory condition rheumatoid arthritis, but that it could not be recommended in the context of the adverse event profile.

Side Effect Profile

Nefopam is associated with a number of unpleasant side effects.Cochrane meta-analysis showed 27% of patients reported at least one of:nausea, sweating, insomnia, pruritus and malaise when the drug was used for 4 consecutive weeks. In the acute setting, Tachycardia is common (number needed to harm = 7), making it less appropriate in those with ischaemic heart disease. In has been (rarely) associated with anaphylaxis. The MHRA have recorded 14 fatalities as the result of adverse drug reactions.

Addiction and Overdose

A number of case reports have described psychological dependence and addiction to nefopam resulting in prescription forgery and significant dose escalation. Misuse of nefopam should be considered if there is an unexplained increasing anti-cholinergic or extra pyramidal side effects, agitation or anxiety. Nefopam can be fatal in overdose, causing cerebral oedema and arrhythmias.

Conclusions

Nefopam is not recommended in any national pain protocols or by national institutions associated with the management of acute, sub-acute, chronic or palliative pain. It is a relatively poorly researched drug in terms of the volume of published data and methodology. Its mode of action is poorly understood, it may act centrally though inhibition of serotonin, norepinephrine, and dopamine reuptake. Its effect on central neurotransmitters may explain the association with addiction and dependence not seen with NSAID and paracetamol usage. It is frequently (up to 27%) associated with problematic side effects, which can be serious and infrequently fatal. It is of relatively low efficacy, typically cited as producing a 10-20% reduction in acute pain.

City Hospitals Sunderland
An application has been made to remove the drug from the joint formulary, based on the low efficacy and comparatively high side effect profile. Given the recent price increase, I believe it represents poor value for money in terms of analgesic efficacy and should not be used on a routine basis.

Dose reduction and cessation
Consultation of standard reference texts of clinical pharmacology revealed no specific guidance on reduction and cessation of nefopam.Given its likely action on dopaminergic, serotonergic and noradrenergic pathways, abrupt cessation is not recommended. I would suggest slow tapering of the dose with regular review, and vigilance for CNS effects. Psychological addiction should be considered if dose reduction triggers dysphoria, agitation or anxiety.

Alternative medication and strategies
In general, one should seek to optimize analgesia using the principles contained in the WHO “pain ladder”(paracetamol, NSAID’s, minor and strong opioids, and analgesic adjuncts (eg. Membrane stabilizing drugs, topical drugs) as necessary. If tolerated, the acute pain data suggest significantly greater efficacy if one uses simple analgesics than nefopam.

Some patients may benefit from a reassessment using a biopsychosocial model and consideration of active management of underlying psychological pathologies e.g. depression and anxiety. Finally a rehabilitative approach using CBT or physiotherapy may be considered.

Kind regards,

Dr Allistair Dodds

MB ChB FRCA FFPMRCA

Consultant in Pain Medicine.

Regional Advisor Pain Medicine (Northern Region)

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