The full article is freely accessible.

The result of a systemic search in databases were: nine studies of pregabalin, seven studies of the lidocaine plaster, and only one study of duloxetine in treatment refractory neuropathic pain. Extremely dissapointing is the fact that not one head-to-head studies of these treatments could be identified. This is clearly due to company strategies and requirements for registration. Only double blind studies against placebo are planned and submitted for registration purposes. To conduct a straight head to head study within the pharmaceuticsl industry requires guts.. It can be that you find out that your own drug is inferior to the drug of the competition...Than you might want to move to another company...

Mostly these trials are founded by pharmaceutical companies, so what clinicians need, the direct comparison between drugs in order to be able to make a sound judgement what woud be the first drug of choice, are clearly lacking.

Definition treatment refractory neuropathic pain 

The authors could not identify published definitions of refractory neuropathic pain, apart from a proposed definition of pharmacoresistant NeP:

"A neuropathic pain condition is resistant to pharmacotherapy when mono-or a rational combination treatment using drugs proven efficacious in RCTs fails in inducing useful pain relief from the patient's/physician's point of view after an appropriate duration of treatment with adequate dosage, or if intolerable side effects occur" ^[1]

The authors selected a more pragmatic approach to define refractory NeP as patients who had failed to receive adequate pain relief from or were intolerant to previous therapy irrespective of the duration, dose and type of previous therapy. 

Refractory neuropathic pain is clearly an issue, and I found more than 500 hits with these three words in pubmed. And given the prevalence it is quite remarkable to find so few studies! ^[2]

.Low quality of studies and lack of full papers

Seven of the studies were published solely as conference abstracts, while the remaining studies were available as full journal publications at the time of searching in December 2008. 

The trial quality was not as we expected:

Approximately half of the studies did not define or clearly report the study question. Withdrawals, an important aspect to determine complete follow-up of patients, were reported in the majority of pregabalin trials (7/9) but less frequently in the lidocaine plaster studies (4/7). The duloxetine study did not report withdrawals [23]. Bias and confounding factors were not addressed in many of the studies, most likely due to the brevity of information presented in the abstracts. Almost all of the included studies were single arm trials, which prevented direct and indirect comparisons of the interventions of interest. 

Discussion

The findings of this comprehensive systematic review indicate little clinical evidence is available for the refractory treatment setting. Only seventeen studies met the inclusion criteria of which seven were available as conference abstracts only.

When considering the three included treatments in this review the evidence base for pregabalin in the refractory NeP population is stronger than for the lidocaine plaster or duloxetine. This is particularly apparent when considering only studies within UK licensing.

The studies included in this review were heterogenous in their design and reported outcomes. Patient populations enrolled were highly variable, ranging from a specific condition such as TN or chronic lower back pain with a neuropathic component to a "wide variety of NeP conditions".

Pregabalin and the lidocaine plaster were trialled in a wide variety of NeP conditions. The duloxetine study enrolled a specific TN patient group, limiting generalisability to a clinical practice setting.

Both within and between study differences in NeP types of included patients are important factors, which should be considered when drawing conclusions from the results of the review. Study durations varied considerably with long-term data on key efficacy outcomes available for pregabalin only. 

Wide variation between trials hinders comparison of the proportion of responders between treatments. Although treatment efficacy was reported in studies of a wide variety of NeP types, only one study carried out subgroup analysis, demonstrating efficacy of pregabalin in both DPN and PHN. 

So much still to be done, especially since we know that mutimodal therapy in refractory neuropathic pain patients is most probably the way to go....

Comments on definition refractory neuropathic pain (JMKH)

Treatment refractory depression is a much debated clinical entity and is defined as cases of major depressive disorder that do not respond to adequate courses of at least two antidepressants. In depression one prescribes in principle subsequently. In neuropathic pain one probably follows an other principle, of combining 2 or 3 analgesics.

The pragmatic approach to define refractory NeP as patients who had failed to receive adequate pain relief from or were intolerant to previous therapy irrespective of the duration, dose and type of previous therapy is clearly a field definition.

Therefore this definition is more apt to be used by clinicians compared to the definition of Attal and colleagues: A neuropathic pain condition is resistant to pharmacotherapy when mono-or a rational combination treatment using drugs proven efficacious in RCTs fails in inducing useful pain relief from the patient's/physician's point of view after an appropriate duration of treatment with adequate dosage, or if intolerable side effects occur.

For clinical trials, following the principles of Chalmers, one would select the pragmatic definition and as a descriptor for the patients add the Attal definition.

Most probably useful painrelief has to be defined as 50% reduction from baseline and/or reaching a cut off on the NRS predefined by the patient. Appropriate duration should probably be at least 6 weeks. Adequate dosing should be the minimal effective dose tested in the RCT 

January 2011, Jan M. Keppel Hesselink, MD, PhD

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