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Pharmacologic Interventions for Painful Diabetic Neuropathy: An Umbrella Systematic Review and Comparative Effectiveness Network Meta-analysisPharmacologic Interventions for Painful Diabetic Neuropathy

Marcio L. Griebeler, MD; Oscar L. Morey-Vargas, MD; Juan P. Brito, MD; Apostolos Tsapas, MD, PhD; Zhen Wang, PhD; Barbara G. Carranza Leon, MD; Olivia J. Phung, PharmD; Victor M. Montori, MD; and M. Hassan Murad, MD, MPH
[+] Article, Author, and Disclosure Information

From Mayo Clinic, Rochester, Minnesota; Aristotle University, Thessaloniki, Greece; and Western University of Health Sciences College of Pharmacy and Western Diabetes Institute, Pomona, California.

Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health.

Financial Support: By the Mayo Foundation for Medical Education and Research and Clinical and Translational Science Awards grant UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health.

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0511.

Requests for Single Reprints: M. Hassan Murad, MD, MPH, Department of Medicine, Division of Preventive Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail, murad.mohammad@mayo.edu.

Current Author Addresses: Drs. Griebeler, Morey-Vargas, Brito, Carranza Leon, and Montori: Department of Medicine, Division of Diabetes, Endocrinology, Metabolism and Nutrition, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Dr. Tsapas: Second Medical Department, Aristotle University, Thessaloniki 54124, Greece.

Dr. Wang: Knowledge and Evaluation Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Dr. Phung: Western University of Health Sciences College of Pharmacy and Western Diabetes Institute, 309 East Second Street, Pomona, CA 91766-1854.

Dr. Murad: Department of Medicine, Division of Preventive Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Author Contributions: Conception and design: M.L. Griebeler, J.P. Brito, A. Tsapas, V.M. Montori, M.H. Murad.

Analysis and interpretation of the data: M.L. Griebeler, O.L. Morey-Vargas, Z. Wang, B.G. Carranza Leon, O.J. Phung, V.M. Montori, M.H. Murad.

Drafting of the article: M.L. Griebeler, O.L. Morey-Vargas, J.P. Brito, A. Tsapas, B.G. Carranza Leon, V.M. Montori, M.H. Murad.

Critical revision of the article for important intellectual content: M.L. Griebeler, O.L. Morey-Vargas, J.P. Brito, A. Tsapas, V.M. Montori, M.H. Murad.

Final approval of the article: M.L. Griebeler, J.P. Brito, A. Tsapas, Z. Wang, B.G. Carranza Leon, V.M. Montori, O.J. Phung, M.H. Murad.

Statistical expertise: Z. Wang, M.H. Murad.

Administrative, technical, or logistic support: M.L. Griebeler, M.H. Murad.

Collection and assembly of data: M.L. Griebeler, O.L. Morey-Vargas, J.P. Brito, B.G. Carranza Leon.


Ann Intern Med. 2014;161(9):639-649. doi:10.7326/M14-0511
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This article has been corrected. The original version (PDF) is appended to this article as a Supplement.

Background: Multiple treatments for painful diabetic peripheral neuropathy are available.

Purpose: To evaluate the comparative effectiveness of oral and topical analgesics for diabetic neuropathy.

Data Sources: Multiple electronic databases between January 2007 and April 2014, without language restriction.

Study Selection: Parallel or crossover randomized, controlled trials that evaluated pharmacologic treatments for adults with painful diabetic peripheral neuropathy.

Data Extraction: Duplicate extraction of study data and assessment of risk of bias.

Data Synthesis: 65 randomized, controlled trials involving 12 632 patients evaluated 27 pharmacologic interventions. Approximately one half of these studies had high or unclear risk of bias. Nine head-to-head trials showed greater pain reduction associated with serotonin–norepinephrine reuptake inhibitors (SNRIs) than anticonvulsants (standardized mean difference [SMD], −0.34 [95% credible interval {CrI}, −0.63 to −0.05]) and with tricyclic antidepressants (TCAs) than topical capsaicin 0.075%. Network meta-analysis showed that SNRIs (SMD, −1.36 [CrI, −1.77 to −0.95]), topical capsaicin (SMD, −0.91 [CrI, −1.18 to −0.08]), TCAs (SMD, −0.78 [CrI, −1.24 to −0.33]), and anticonvulsants (SMD, −0.67 [CrI, −0.97 to −0.37]) were better than placebo for short-term pain control. Specifically, carbamazepine (SMD, −1.57 [CrI, −2.83 to −0.31]), pregabalin (SMD, −0.55 [CrI, −0.94 to −0.15]), venlafaxine (SMD, −1.53 [CrI, −2.41 to −0.65]), duloxetine (SMD, −1.33 [CrI, −1.82 to −0.86]), and amitriptyline (SMD, −0.72 [CrI, −1.35 to −0.08]) were more effective than placebo. Adverse effects included somnolence and dizziness with TCAs, SNRIs, and anticonvulsants; xerostomia with TCAs; and peripheral edema and burning sensation with pregabalin and capsaicin.

Limitation: Confidence in findings was limited because most evidence came from indirect comparisons of trials with short (≤3 months) follow-up and unclear or high risk of bias.

Conclusion: Several medications may be effective for short-term management of painful diabetic neuropathy, although their comparative effectiveness is unclear.

Primary Funding Source: Mayo Foundation for Medical Education and Research.

Figures

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Appendix Figure 1.

Summary of evidence search and selection.

RCT = randomized, controlled trial.

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Figure 1.

Network of RCTs evaluating painful diabetic neuropathy within 3 mo, by drug class.

Width of the lines is proportional to the number of trials for that comparison. ARI = aldose reductase inhibitor; RCT = randomized, controlled trial; SNRI = serotonin–norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant.

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Appendix Figure 2.

Summarized risk of bias, by domains in the included RCTs.

RCT = randomized, controlled trial.

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Figure 2.

Agents for treatment of diabetic peripheral neuropathy compared with placebo, by class.

Combined direct and indirect estimates. ARI = aldose reductase inhibitor; CrI = credible interval; SMD = standardized mean difference; SNRI = serotonin–norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant.

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Comments

Submit a Comment/Letter
Treatment of painful diabetic polyneuropathy should be individualized
Posted on November 6, 2014
Gauranga Dhar
Bangladesh Institute of Family Medicine and Research
Conflict of Interest: None Declared
Although proper glycemic control is the number one management option for diabetic neuropathy, this diabetes related complication can be found even in pre-diabetic stage. Treatment of painful diabetic polyneuropathy is a big challenge for a diabetologist.
Different guidelines have different first line drug options and only two drugs; duloxetine and pregabaline are approved by FDA and European Medicines Agency but my practical experience shows that drug therapy for painful diabetic neuropathy should be individualized in terms of efficacy and side effect profile. More ever, long term use (>4months) leads to reduction of efficacy. For this reason switch from one group to another in specific interval (every 4 to 6 months) is a good option. NSAIDs should better be avoided.
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