Effects of treatments for symptoms of painful diabetic neuropathy: systematic review

Abstract

Objective: To evaluate the effects of treatments for the symptoms of painful diabetic neuropathy.

Design: Systematic review.

Data sources: Articles (English and full text) on double blind randomised trials found by searching with the key words anticonvulsant, antidepressant, non-steroidal anti-inflammatory drugs, tramadol, opioid, ion channel blocker, diabetic neuropathy, diabetic peripheral neuropathy, peripheral neuropathy, and neuropathy. The search included Medline, Embase, EMB reviews-AP Journal club, and the Cochrane central register of controlled trials.

Study selection: Randomised controlled trials comparing topically applied and orally administered drugs with a placebo in adults with painful diabetic neuropathy.

Data extraction: Data were extracted to examine quality of methods, characteristics of studies and patients, efficacy, and side effects. The primary outcome was dichotomous information for 50% or moderate reduction of pain. Secondary outcomes were 30% reduction of pain and withdrawals related to adverse events.

Results: Odds ratios were calculated for achievement of 30%, 50%, or moderate pain relief and for withdrawals related to adverse effects. Twenty five reports were included and seven were excluded. The 25 included reports compared anticonvulsants (n=1270), antidepressants (94), opioids (329), ion channel blockers (173), N-methyl-D-aspartate antagonist (14), duloxetine (805), capsaicin (277), and isosorbide dinitrate spray (22) with placebo. The odds ratios in terms of 50% pain relief were 5.33 (95% confidence interval 1.77 to 16.02) for traditional anticonvulsants, 3.25 (2.27 to 4.66) for newer generation anticonvulsants, and 22.24 (5.83 to 84.75) for tricylic antidepressants. The odds ratios in terms of withdrawals related to adverse events were 1.51 (0.33 to 6.96) for traditional anticonvulsants, 2.98 (1.75 to 5.07) for newer generation anticonvulsants, and 2.32 (0.59 to 9.69) for tricylic antidepressants. Insufficient dichotomous data were available to calculate the odds ratios for ion channel blockers.

Conclusion: Anticonvulsants and antidepressants are still the most commonly used options to manage diabetic neuropathy. Oral tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants. Evidence of the long term effects of oral antidepressants and anticonvulsants is still lacking. Further studies are needed on opioids, N-methyl-D-aspartate antagonists, and ion channel blockers.

Fig 1 Identification and inclusion of studies. RCT=randomised controlled trial

Fig 2 Treatment efficacy of traditional anticonvulsants versus placebo

Fig 3 Withdrawals related to adverse events for traditional anticonvulsants versus placebo

Fig 4 Treatment efficacy of newer generation anticonvulsants versus placebo

Fig 5 Withdrawals related to adverse events for newer generation anticonvulsants versus placebo

Fig 6 Treatment efficacy of tricyclic antidepressants (TCA) versus placebo

Fig 7 Withdrawals related to adverse events for tricyclic antidepressants (TCA) versus placebo

Fig 8 Treatment efficacy of duloxetine 60 mg versus placebo

Fig 9 Withdrawals related to adverse events for duloxetine 60 mg versus placebo

Fig 10 Treatment efficacy of duloxetine 120 mg versus placebo

Fig 11 Withdrawals related to adverse events for duloxetine 120 mg versus placebo

Fig 12 Weighted mean differences in mean visual analogue scale score for pain intensity with mexiletine versus placebo

Fig 13 Withdrawals related to adverse events for mexiletine versus placebo

Fig 14 Treatment efficacy of opioids versus placebo

Fig 15 Withdrawals related to adverse events of opioids versus placebo

Fig 16 Proposed treatment algorithm for painful diabetic neuropathy