Prescribing for Neuropathic Pain

Today's post is an honest summary of the role of antidepressants and anticonvulsants in treating neuropathic problems and comes from the Prescribing Bulletin, a UK bulletin produced on the island of Guernsey(see link below). Its findings are based on information from the UK National Prescribing Centre (npc.co.uk). It compares and contrasts the drugs which are used, based on the results of the few trials and studies that have been done. Whether you agree with the conclusion that amitriptyline is the best all round option is a matter of choice. Certainly, since the article was written, Pregabalin is much more widely used to treat neuropathy than suggested here. The article is however, a very useful base from which to start your own research.

Neuropathic Pain Part 2
Written by: Geraldine O’Riordan, Prescribing Advisor. Issue 05/09

Neuropathic pain is an ill-understood and distressing condition which may be life-long in many people. March’s Prescribing Bulletin looked at the pathology of neuropathic pain. This month’s bulletin provides a brief overview of the roles of antidepressants and anticonvulsants in the care of patients with neuropathic pain.

What are the drug treatment options?
Neuropathic pain is not as receptive to opioids and other analgesics as nociceptive pain is, so unusual classes of drugs are used. Many treatments are not licensed for use or have restricted licenses for neuropathic pain. However some have been prescribed for neuropathic pain for up to forty years so we have plenty of experience of their use.

The treatment options include
􀂾 Antidepressants
􀂾 Anticonvulsants
􀂾 Opioids and Tramadol
􀂾 Topical treatments
􀂾 “Other” treatments

Despite the fact that neuropathic pain is a relatively common condition the evidence base is poor. Trials, even for the newly licensed drugs made by large pharmaceutical companies, include very small numbers. The short follow-up is particularly unhelpful as neuropathic pain can be life-ling. There are also few head-to-head studies and little information on combinations of different treatments, which is common in clinical practice. The evidence to support the use of drug treatment were summarised in a
Cochrane review published in 2005.

Antidepressants
The key Cochrane findings were as follows:
1) Compared with placebo, tricyclic antidepressants (TCAs) were better than placebo in most studies. The NNT for neuropathic pain was 2 with amitriptyline. However the treatment periods and the follow-up were unclear.
2) The best evidence is for amitriptyline and the benefit were usually seen after a few days.
3) There was no significant difference between different different TCAs and compared with other active treatments TCAs had mixed results.
4) Capsacin cream was found to be as effective as amitriptyline in diabetic neuropathy.
5) Most of the studies comparing SSRIs with placebo were very small.
6) Fluoxetine 20mg and 40mg daily were more effective than placebo in idiopathic facial pain and diabetic neropathy.
7) Paroxetine and imipramine were found to be more effective than placebo for diabetic neuropathy.
8) Across the trials about 20% of patients dropped out for reasons including adverse effects.
9) With TCAs caution is required with cardiac disease and in the elderly.
10) SSRIs appear to be better tolerated, but more studies are required on their efficacy in neuropathic pain.
11) The Cochrane reviewers recommend that treatment should be initiated with amitriptyline and the patient switched to an alternative TCA if pain relief is obtained but ADRs are a problem.

Anticonvulsants
These drugs have been used in pain management since the 1960s. Carbamazepine is licensed for trigeminal neuralgia, gabapentin is licensed for neuropathic pain and phenytoin is licensed for trigeminal neuralgia.

The key findings of the Cochrane review were as follows:
1) NNT from eleven trials of carbamazepine for any pain relief in trigeminal neuralgia was 1.9.
2) The combined NNT for moderate relief in any neuropathic pain was 2.5.
3) The authors concluded that “there is evidence to show that carbamazepine is effective but trials are small. Use of carbamazepine for neuropathic pain has stood the test of time but the evidence is limited and mainly of poor quality”.
4) There were fourteen trials of gabapentin, mostly placebo-controlled
5) The NNT in diabetic neuropathy was 2.9 and in post-herpetic neuralgia it was 3.9.
6) The combined NNT for improvement in any neuropathic pain was 3.9.
7) The authors concluded that “gabapentin is effective for a variety of neuropathic pain. However it needs to be considered alongside other treatments such as carbamazepine and tricyclic antidepressants” i.e. effective and less expensive alternatives.
8) There are two very small studies( n= 12 and n=40) involving phenytoin in diabetic neuropathy.
9) One showed that 30% of patients improved on phenytoin.
10) Overall the Cochrane authors concluded that “the evidence here dose not support the use of anticonvulsants as first-line treatment” and the “in chronic pain syndromes other than trigeminal neuralgia, anticonvulsants should be withheld until other interventions have been tried.”
11) Pregabalin is licensed for neuropathic pain but is not currently prescribable on States prescriptions. It is structurally related to gabapentin and was launched just as the patent on
gabapentin expired.
12) There have been twelve randomised controlled trials comparing pregabalin with placebo.
13) Despite some creative inclusion criteria the NNT averaged just 6 for peripheral neuropathic pain and 7 for central neuropathic pain.
14) One study had an active arm in diabetic neuropathy. Placebo, 600mg od pregabalin and 75mg od amitriptyline were compared. Amitriptyline was found to be more effective than placebo but pregabalin was not.
15) The use of pregabalin has been rejected by the SMC for NHS patients in Scotland on three occasions.
16) The North Yorkshire New Drug Evaluation committee stated that “amitriptyline and carbamazepine remain first line choices for the treatment of neuropathic pain”.
17) Gabapentin and pregabalin are made by the same company, yet nearly five years after its launch there are still no published head-to-head studies.
18) Many of the pregabalin studies pre-screened the participants and excluded patients who failed to respond to gabapentin, the very group for whom it is being heavily promoted.
19) At the time of writing no credible evidence exists that patients who fail to respond to gabapentin will respond to pregabalin.

In summary
• The best evidence to date is for amitriptyline.
• Carbamazepine is a reasonable first choice second line drug if treatment fails with antidepressants
• A future bulletin will examine the role of opioids and other treatments in the management of neuropathic pain.

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