Those assigned to surgery had more complications (dural tears, excessive bleeding, repeat surgery). 99
TENS A meta-analysis of three trials comparing TENS vs. placebo in 78 patients with diabetic neuropathy found reduced pain severity at four weeks and six weeks but not at 12 weeks. 106 An analysis by the Agency for Healthcare Research and Quality (AHRQ), however, did not find significant or compelling evidence to suggest TENS was more effective than placebo for diabetic neuropathy. 107 Cognitive and behavioral interventions Little data support cognitive and behavioral interventions for patients with diabetic neuropathy. A small trial of 20 patients receiving CBT showed a greater decrease in pain scores at 4-month follow- up, compared with usual care. 108 A small study of 20 patients found no difference with mindfulness meditation versus placebo on pain or quality of life. 109 Pharmacologic options Pregabalin, duloxetine, and tapentadol are FDA- approved for the treatment of neuropathic pain in diabetes. Other medications, such as gabapentin, oxcarbazepine, TCAs, topical lidocaine or capsaicin have been used off-label with varying degrees of success. Acetaminophen and NSAIDs No published trials have evaluated the use of acetaminophen alone or NSAIDs, either oral or topical, for diabetic neuropathy. SNRIs Both duloxetine and venlafaxine have been shown to reduce pain related to diabetic neuropathy compared to placebo. A network meta-analysis found relatively large effect sizes for pain reduction for duloxetine vs. placebo, and venlafaxine vs. placebo. 110 A 12-week study randomized 457 patients with painful diabetic neuropathy to three duloxetine groups (20 mg/day, 60 mg/day, and 120 mg/day) or placebo. 111 At follow-up, the mean daily pain severity score in the placebo group had dropped 1.91 points (on a 0-10 scale), with greater reductions in the three duloxetine groups: 2.36 points in the 20 mg group (not significant vs. placebo), 2.89 points in the 60 mg group (P<0.001 vs. placebo), and 3.24 points in the 120 mg group (P<0.001 vs. placebo). 111 TCAs TCAs studied for diabetic neuropathy include amitriptyline, imipramine, and desipramine. A meta- analysis of five RCTs found a modest effect size for pain reduction for amitriptyline. 110 Adverse effects with TCAs included somnolence and dizziness, which may be particularly important in older patients.
Anticonvulsants The
American Association recommends using pregabalin or gabapentin, noting that gabapentin may be less expensive than pregabalin, although it is not FDA-approved for the indication of neuropathic pain. 101 Other anticonvulsants (e.g., carbamazepine, topiramate, valproic acid, lacosamide, lamotrigine) lack clear evidence of benefit but have documented harms. 112 Gabapentin is a commonly prescribed off-label to treat diabetic neuropathy. Based on a review of five RCTs with 766 patients, gabapentin had a large overall effect on pain severity, however, the result was not statistically significant. A 2019 Cochrane review of 20 randomized trials found that pregabalin 300 mg/day modestly reduced pain intensity. 113 Rates of fatigue and dizziness were significantly higher with pregabalin. Diabetes Topical lidocaine Although lidocaine patches are FDA approved for post-herpetic neuralgia, no RCTs of patches have been conducted in diabetic neuropathy. One open-label, 4-week trial of 300 patients with painful diabetic polyneuropathy or post-herpetic neuralgia evaluated 5% lidocaine medicated plaster vs. pregabalin. In post-herpetic neuralgia more patients responded to 5% lidocaine medicated plaster treatment than to pregabalin (62.2% vs. 46.5% [no P value reported]), while response was comparable for patients with painful diabetic polyneuropathy (in the per-protocol set): 66.7% vs. 69.1% (no P value reported). 114 Cannabinoids for diabetic neuropathy Weak evidence suggests that medical marijuana and cannabinoids may reduce pain related to diabetic neuropathy. A Cochrane review of 16 randomized trials published through November 2017 comparing cannabis-based treatments to placebo in 1,750 adults with chronic neuropathic pain found slight reductions in pain intensity and increased numbers of patients achieving 50% or greater reductions in pain (21% vs. 17%). 43 The results, however, are limited by poor trial quality (only 2 trials were judged high-quality) and heterogeneity in treatments (10 trials evaluated an oromucosal spray containing THC or CBD, 2 trials evaluated a synthetic THC, 2 trials evaluated plant-derived THC, and 2 trials evaluated inhaled herbal cannabis). There were no significant differences in the rates of serious adverse events, but more people reported sleepiness, dizziness, or confusion in the cannabis groups. A study of high and low potency cannabis cigarettes (7% or 3.5% THC) in 44 patients with neuropathic pain showed reduced pain scores in both cannabis cigarette groups vs. placebo cigarettes (P<0.01) with no significant differences between the two doses of cannabis. 115
Diabetic neuropathy
Diabetic neuropathy most commonly affects the distal extremities in a symmetric fashion causing numbness, tingling, pain, loss of vibratory sensation, and altered proprioception. Improved glucose control may reduce the risk of acquiring diabetic neuropathy and slow its progression, 100 and in those who have neuropathy, pain management may improve quality of life. 101 Current American Diabetes Association guidelines suggest initial management with pregabalin, duloxetine, or gabapentin. 100 Second- line options include TCAs (use cautiously in older adults), venlafaxine, or carbamazepine. Opioids, and particularly tapentadol, are not recommended to treat neuropathy due to their risk for addiction and limited evidence for efficacy. 100 Tapentadol is FDA-approved to treat diabetic neuropathy, but the approval was based on two trials that used a design enriched for patients who responded to tapentadol, therefore the results are not generalizable. 100 Because tapentadol incurs similar risks of addiction and safety compared to typical opioids, it’s use is generally not recommended as first- or second-line therapy for neuropathic pain. 100
Non-drug options
Movement-based options A small RCT of 39 Korean patients with type 2 diabetes and neuropathy found tai chi improved quality of life on five domains, including pain, physical functioning, social functioning, vitality and a mental component score, compared with usual care, but there was no significant difference in neuropathy scores. 102 Acupuncture and massage Small studies suggest a possible effect of acupuncture and massage on pain and function. A pilot study of 46 patients found overall symptom improvement from baseline with acupuncture in 77% of patients with 67% discontinuing medication. However, the study didn’t have a control group nor did it specifically identify pain as an endpoint. 103 A 4-week trial involving 46 patients who received aromatherapy and massage had reduced pain and improved quality of life compared to usual care. 104 A 2014 trial randomized 45 patients to acupuncture vs. sham acupuncture for 10 weeks and found no significant differences in pain outcomes. 105 Further studies are required to provide a more clear understanding of the role of acupuncture and massage in managing pain in diabetic neuropathy.
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