Evaluating Treatments for Painful Diabetic Neuropathy

Painful diabetic neuropathy (PDN) affects the small nerve fibers and is characterized by the sensations of uncomfortable burning, numbness, tingling, warmth, cold, or electric-shock, as well as exaggerated painful sensations to painful stimuli (hyperalgesia) and perception of pain to non-painful stimuli (allodynia).² This form of neuropathy typically occurs in a length-dependent or stocking-glove distribution affecting the distal legs and arms, and diabetes is the most common etiology.³ According to “Comparative Efficacy and Safety of Six Antidepressants and Anticonvulsants in Painful Diabetic Neuropathy: A Network Meta-analysis,” published in Pain Physician by Rudroju et al, painful diabetic neuropathy remains one of the most unreported (12.5%) and untreated (39.3%) ailments. Given that the astounding prevalence of painful diabetic neuropathy is 10-20% of those suffering from diabetes (prevalence of diabetes in the USA is 25.8 million, or 8.3% of the population, according to the CDC), more than five million Americans are experiencing PDN.^1,4

In this network (multiple treatment) meta-analysis and benefit-risk analysis, Rudroju et al compared various antidepressants and anticonvulsants head-to-head with one another or with placebo to rank their safety and efficacy in the management of PDN. After reviewing the literature from 1980 to 2012, the authors identified several randomized controlled studies of both the open-labeled and blinded type for inclusion in the systemic review. They analyzed data for patients age 18 years and older who were exclusively diagnosed with PDN and not combined forms of neuropathy (ie, with post-herpetic neuralgia). The primary outcome measure of efficacy was pain reduction by greater than or equal to 50% using ordinal descriptive scales of improvement. The primary outcome measure of safety was the number of patient withdrawals due to adverse events.

Statistical analysis was conducted in this network meta-analysis using intention-to-treat analysis in a Bayesian model using Markov chain Monte Carlo methods. For the study, the authors labeled efficacy and safety differences between active treatment and another treatment or compared with placebo as statistically-significant when the lower limit of 95% confidence intervals of the odds ratio was greater than one. They performed benefit-risk analysis, with the number of patients with 50% reduction in pain as criteria for benefit and number of withdrawals as standard risk.

After these methods were undertaken, 21 randomized control trials were included in the meta-analysis comparing six active treatments (monotherapy or dual therapy) in a total of 4,219 study participants. Compared with placebo, duloxetine, gabapentin, pregabalin, and venlafaxine exhibited PDN treatment superiority with odds ratios (OR) of 95% confidence intervals (CI) that exceeded 1. However, there was no difference when these active treatments were compared head-to-head. The most efficacious agent was found to be gabapentin followed by venlafaxine, pregabalin, duloxetine/gabapentin, duloxetine, amitriptyline, and placebo. Compared with placebo, the number of withdrawals due to adverse events was higher for amitriptyline, duloxetine, duloxetine/gabapentin, and pregabalin with OR that exceeded 1. The rank order of safety starting with safest was placebo, gabapentin, pregabalin, venlafaxine, duloxetine/gabapentin, duloxetine, and amitriptyline. The final rank order of benefit-risk analysis was as follows: gabapentin, venlafaxine, pregabalin, duloxetine/gabapentin, placebo, duloxetine, and amitriptyline.

Commentary from Dr. Mitchell

Though all 21 studies included in this network meta-analysis were “randomized-controlled trials,” five studies were not placebo-controlled trials, which brings into question the true effect of either medication in this head-to-head trial without a control for comparison. The inclusion of open-label studies in the data may have confounded the results. Having foreknowledge of combination regimens may bias the subjects and investigators into expecting superior outcomes compared with monotherapy or placebo. Also, one may argue that despite the rigor of meta-analysis, patients are not actually being compared head-to-head given the diversity of study locations and actual study conditions (investigators, etc).

Another factor to consider (and not mentioned in the article) is the possibility of polypharmacy in the form of other anticonvulsants and antidepressants used by study participants and unknown to the investigators, which may have modulated outcomes. For example, it was not mentioned whether other pharmaceuticals, such as topical capsaicin creams, topical lidocaine patches, or other alternative medicines used for depression, such as St. John’s Wort, were used concomitantly in these studies.

Interestingly, duloxetine (a serotonin and norepinephrine dual reuptake inhibitor) and pregabalin are FDA-approved for peripheral diabetic neuropathy, though the data from this meta-analysis underscores the unfavorable benefit-risk balance for these agents compared with gabapentin and venlafaxine, also a serotonin-norepinephrine reuptake inhibitor.⁵ In addition, though the combination of duloxetine and gabapentin proved unfavorable in this analysis, other studies of small fiber neuropathy have shown that combination dual therapy can be beneficial when monotherapy fails.⁶ There is Level A evidence for combination therapy of tricyclic antidepressants (TCA) with gabapentin and gabapentin with opioids for treatment of diabetic neuropathy and post-herpetic neuralgia.^6,7 Three class I studies showed a greater analgesic effect of the gabapentin/opioids (morphine, oxycodone) and gabapentin/nortriptyline combinations compared to each drug alone in patients with diabetic small fiber neuropathy. The combination of gabapentin and venlafaxine has also been shown to be more effective than gabapentin alone.⁸ Future prospective studies should be undertaken to evaluate the benefit-risk balance of combination trials for PDN.

Valproate was excluded from the analysis. Given its mechanism of action, valproate may actually serve as an efficacious agent for PDN in selected patients who may benefit from its concomitant anticonvulsant and mood-stabilizing effects. Otherwise, this study does not support its first-line use for isolated PDN.

A flaw of the analysis was the overall short duration of the trial (mean of 10.8 weeks). Diabetic neuropathy is a chronic condition that may evolve and progress over time depending on glycemic control. As such, an individual patient’s clinical symptomatology may be dynamic over time, something that could be best captured by evaluating treatment effect over six months or longer. There was also weak power of the trial with a mean sample size of 82.7 patients per group. Due to the dearth of longitudinal data and low power of the study, the validity of the study is reduced despite its methodological rigor and demonstration of statistical significance.

Amber N. Mitchell is a neurology resident at Albany Medical Center Hospital.

REFERENCES

1. Rudroju N, Bansal D, Talakokkula S, et al. Comparative Efficacy and Safety of Six Antidepressants and Anticonvulsants in Painful Diabetic Neuropathy: A Network Meta-analysis. Pain Physician. 2013 Nov; 16 (E705-E714).

2. McArthur JC. Painful Small Fiber Neuropathies. Continuum (Minneapolis, Minn.). 2012 Feb; 18(1):106-25.

3. Tavee J, Zhou L. Small Fiber Neuropathy: A Burning Problem. Cleve Clin J Med. 2009 May; 76(5): 297—305.

4. The Facts About Diabetes: A Leading Cause of Death in the U.S. CDC.gov. 2013.

5. Attal N, Cruccu G, Haanpää M, et al. EFNS Task Force. EFNS Guidelines On Pharmacological Treatment of Neuropathic Pain. Eur J Neurol. 2006 Nov; 13(11):1153—1169. (class I SR).

6. Gilron I, Baley JM, Tu D, et al. Nortriptyline and Gabapentin, Alone and in Combination for Neuropathic Pain: A Double-Blind, Randomised Controlled Crossover Trial. Lancet 2009 Oct; 374(9697):1252—1261.

7. Hanna M, O’Brien C, Wilson MC. Prolonged-release Oxycodone Enhances The Effects of Existing Gabapentin Therapy in Painful Diabetic Neuropathy Patients. Eur J Pain. 2008 Aug; 12(6):804—813. (class I).

8. Simpson DA. Gabapentin and Venlafaxine for the Treatment of Painful Diabetic Neuropathy. J Clin Neuromuscul Dis 2001 Dec; 3(2):53—62. (class II).