Download Removal of Nefopam from formulary letter

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 our region 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-acute low 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.
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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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