Effects of treatments for symptoms of painful diabetic neuropathy: systematic review
BMJ 2007; 335 doi: https://doi.org/10.1136/bmj.39213.565972.AE (Published 12 July 2007) Cite this as: BMJ 2007;335:87
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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
Competing interests: No competing interests
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
Competing interests: No competing interests
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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2007
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Competing interests:
Søren H. Sindrup has received advisory or speakers fee from Eli Lilly, Boehringer Ingelheim, Novartis, Grünenthal, 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.
Competing interests: No competing interests