bmj.com Rapid Responses for Wong et al., 335 (7610) 87

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RESEARCH:
Man-chun Wong, Joanne W Y Chung, and Thomas K S Wong
Effects of treatments for symptoms of painful diabetic neuropathy: systematic review
BMJ 2007; 335: 87 [Abstract] [Full text]

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Rapid Responses published:

Older drugs are still the main choices: Rizaldy Pinzon (20 June 2007)

Effects of treatments for symptoms of painful diabetic neuropathy: systematic review: Fenella Lemonsky (13 July 2007)

Systematic review on treatments for painful diabetic neuropathy skips important studies and accepts dubious findings in others leading to an invalid treatment algorithm: S�ren H Sindrup, Solomon Tesfaye, Marit Otto, Flemming W. Bach (22 August 2007)

Older drugs are still the main choices 20 June 2007

Rizaldy Pinzon,
Neurologist
Neurology Department Bethesda Hospital Yogyakarta INDONESIA 55224
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Re: Older drugs are still the main choices

This review concludes that among different drugs to manage neuropathic pain, anticonvulsants and antidepressants are still the options most commonly used for painful diabetic neuropathy. Newer drugs tend to be least effective, with superior safety. The important question can we trade off good clinical efficacy against only minor side effects (like drowsiness)?
The important question about the review is Why don't the authors describe the efficacy of the drugs with NNT (Number needed to be Treated)? Using NNT seems to be more easily understood in clinical settings.
One of the strengths of this article is the suggested clinical algorithm. The critical question is can we use drug combinations with different mechanisms of action? One drug is sodium channel blocker, and the other is NMDA receptor antagonist or enhancing the inhibition system. There is a need for further randomized clinical trials for answering the question.
Competing interests: None declared

Effects of treatments for symptoms of painful diabetic neuropathy: systematic review 13 July 2007

Fenella Lemonsky,
Expert by Experience,
North London Hub, Mental Health Research Network, Imperial College, London
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Re: Effects of treatments for symptoms of painful diabetic neuropathy: systematic review

Although older generation anticonvulsants may seem preferable, patient compliance is very important as well as patient satisfaction. Many patients for example will prefer pregabalin over gabapentin because of the fewer side effects and there is increased tolerability. Patient choice has got to be included in the management of DPN.
Competing interests: None declared

Systematic review on treatments for painful diabetic neuropathy skips important studies and accepts dubious findings in others leading to an invalid treatment algorithm 22 August 2007

S�ren H Sindrup,
Professor, consultant
Department of Neurology, Odense University Hospital, DK-5000 Odense C,
Solomon Tesfaye, Marit Otto, Flemming W. Bach
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Re: Systematic review on treatments for painful diabetic neuropathy skips important studies and accepts dubious findings in others leading to an invalid treatment algorithm

Wong et al. recently published a systematic review on treatments for painful diabetic neuropathy.1 The review has in our opinion several weaknesses which deserve attention, since the review suggests a treatment algorithm based on the results.
1. A number of studies cited in a review published two years ago2 or published later3, 4, 5 were not included in the present review even though they appear to fulfill the inclusion criteria and have no exclusion criteria. The search strategy seems not to have considered previous reviews although this is recommended in the Cochrane Handbook. Some of the older antidepressant studies cited in the previous review2 may have been excluded due to lack of a pure pain measure, but this did not lead to the exclusion of a trial with a similar outcome measure.6 Mixed patient populations have led to the exclusion of one study with both diabetic and non-diabetic polyneuropathy.7 However, others with similar populations are not mentioned as exclusions, i.e. they may not have been identified,8, 9 and the authors did not withhold from including other mixed studies.10 We feel, this non-transparent selection of studies and omissions has biased the results and hence the conclusions of this systematic review.
2. The review includes both older cross-over trials with small sample sizes and more recent large scale parallel group trials, which is also recognized as a problem. It is becoming more and more evident that the small cross-over trials may over-estimate efficacy2 which is probably mainly related to less pronounced placebo responses and lack of methodology for performing intention to treat analyses. The true difference in efficacy between e.g. tricyclic antidepressants tested in cross-over trials and serotonin noradrenaline reuptake inhibitors (SNRI) tested in large parallel group trials may therefore be much smaller than indicated here.
3. The Kochar et al trials11, 12 on sodium valproate are a special concern. Methodology with respect to randomization and blinding may be inadequate. The studies show a surprisingly high efficacy considering the limited benefit experienced in clinical practice and negative findings in a study9 not included in the current review. Moreover, there was no placebo effect,12 when this phenomenon is well recognized in painful diabetic neuropathy,13 resulting in higher odds ratio. In addition, this systematic review presents incorrect numbers from the sodium valproate trial included in the analysis. The original paper11 comprises 57 patients but the present analysis only includes 30.
4. The lumping of different drugs as presented may be problematic. From a pharmacological action point of view, the groups should be carbamazepine/oxcarbazepine vs. gabapentin/pregabalin vs. sodium valproate vs. tricyclic antidepressants vs. SNRIs. With carbamazepine together with sodium valproate, the dubious findings with the latter drug may cause an unfounded recommendation of carbamazepine.
5. A paper published this year on lamotrigine14 reports two large trials that have not been able to replicate the positive results with this drug in the initial smaller trial15 included in the current review.
6. Within each group of drugs the efficacy results are weighted according to the amount of available data. In the next step, i.e. construction of the algorithm it should also be recognized that treatment with the SNRI duloxetine and the anticonvulsant pregabalin rely on huge amounts of data mainly from trials of high quality as compared to limited data of variable quality supporting some of the other drugs studied with less robust end- points, decades ago.
Taken together the points presented here seriously question the validity of the algorithm suggested for the treatment of painful diabetic neuropathy. In particular the recommendation of the traditional anticonvulsants as being more effective pain relieving agents than the newer anticonvulsants and SNRIs is based on small studies and lumping disparate compounds. Further, within the pain field the trend is towards taking different peripheral neuropathic pain conditions together16 and the algorithm proposed by Finnerup et al. 20052 is probably more appropriate, although it may be argued that with the current knowledge SNRIs could be given first line status together with tricyclic antidepressants and gabapentin/pregabalin.17 Finally, it has to be pointed out that the best way to settle this issue is by well designed and adequately powered head- to-head trials.
References
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Competing interests: S�ren H. Sindrup has received advisory or speakers fee from Eli Lilly, Boehringer Ingelheim, Novartis, Gr�nenthal, NorPharma and Pfizer. Marit Otto is partly funded by H. Lundbeck as a research fellow. Solomon Tesfaye has received advisory and speakers fee from Eli Lilly and Boehringer Ingelheim and speakers fee from Pfizer and Schwarz Pharma. Flemming W. Bach has received advisory and speakers fee from Pfizer and advisory fee from NorPharma.