3.3.2.0 Neuropathic Pain
Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dysfunction (118). No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or prediabetes, which leaves only pharmaceutical interventions (119).
Pregabalin and duloxetine have received regulatory approval by the FDA, Health Canada, and the European Medicines Agency for the treatment of neuropathic pain in diabetes. The opioid tapentadol has regulatory approval in the U.S. and Canada, but the evidence of its use is weaker (120). Comparative effectiveness studies and trials that include quality-of-life outcomes are rare, so treatment decisions must consider each patient’s presentation and comorbidities and often follow a trial-and-error approach. Given the range of partially effective treatment options, a tailored and stepwise pharmacologic strategy with careful attention to relative symptom improvement, medication adherence, and medication side effects is recommended to achieve pain reduction and improve quality of life (121-123).
Pregabalin, a calcium channel α2-δsubunit ligand, is the most extensively studied drug for DPN. The majority of studies testing pregabalin have reported favorable effects on the proportion of participants with at least 30–50% improvement in pain (120,122,124–127). However, not all trials with pregabalin have been positive (120,122,128,129), especially when treating patients with advanced refractory DPN (126). Adverse effects may be more severe in older patients (130) and may be attenuated by lower starting doses and more gradual titration. The related drug, gabapentin, has also shown efficacy for pain control in diabetic neuropathy and may be less expensive, although it is not FDA approved for this indication (131).
Duloxetine is a selective norepinephrine and serotonin reuptake inhibitor. Doses of 60 and 120 mg/day showed efficacy in the treatment of pain associated with DPN in multicenter randomized trials, although some of these had high drop-out rates (120,122,127,129). Duloxetine also appeared to improve neuropathy-related quality of life (132). In longer-term studies, a small increase in A1C was reported in people with diabetes treated with duloxetine compared with placebo (133). Adverse events may be more severe in older people but may be attenuated with lower doses and slower titrations of duloxetine.
Tapentadol is a centrally acting opioid analgesic that exerts its analgesic effects through both μ-opioid receptor agonism and noradrenaline reuptake inhibition. Extended-release tapentadol was approved by the FDA for the treatment of neuropathic pain associated with diabetes based on data from two multicenter clinical trials in which participants titrated to an optimal dose of tapentadol were randomly assigned to continue that dose or switch to placebo (134,135). However, both used a design enriched for patients who responded to tapentadol and therefore their results are not generalizable. A recent systematic review and meta-analysis by the Special Interest Group on Neuropathic Pain of the International Association for the Study of Pain found the evidence supporting the effectiveness of tapentadol in reducing neuropathic pain to be inconclusive (120). Therefore, given the high risk for addiction and safety concerns compared with the relatively modest pain reduction, the use of extende-release tapentadol is not generally recommended as a first- or second-line therapy. The use of any opioids for management of chronic neuropathic pain carries the risk of addiction and should be avoided.
Tricyclic antidepressants, venlafaxine, carbamazepine, and topical capsaicin, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN (107,120,122).