Painful diabetic neuropathy (pDPN) was initially described in 1885 as a “burning and unremitting quality, often with a nocturnal exacerbation.”² Risk factors for neuropathy among diabetics include age, duration of disease, and poor glycemic control.¹ Patients typically describe a constellation of positive and negative sensory symptoms, including dysesthesias (ie, burning, shooting, or electric shock-like pain), paresthesias, and numbness. The symptoms typically present in a symmetric, “stocking and glove” distribution but can extend proximally with disease progression.³ Common features on physical examination include impaired proprioception and sensation of light touch, temperature, vibration, and pinprick.¹ Ankle deep tendon reflexes are typically diminished or absent.¹

The differential diagnosis for peripheral neuropathy includes a variety of systemic illnesses (eg, chronic kidney or liver disease, monoclonal gammopathies, inflammatory polyneuropathies, vasculitides), medication side effects, toxic exposures, hereditary disorders, and nutritional deficiencies. Clinical features suggesting a nondiabetic cause of neuropathy include focal or asymmetric symptoms, rapid onset, nonlength dependence, and predominance of motor weakness. Relevant laboratory studies include fasting blood glucose, complete blood count, comprehensive metabolic profile, erythrocyte sedimentation rate, vitamin B₁₂, and thyroid-stimulating hormone. Further diagnostic testing may include screening for markers of rheumatologic disease or paraneoplastic syndromes and electrodiagnostic testing.

While glycemic control is a cornerstone of diabetes management, its impact on the development of neuropathic pain is variable. The Diabetes Control and Complications Trial found tight glycemic control resulted in a 60% reduction in the rate of neuropathic pain in type 1 diabetics, but the same does not appear to be true for patients with type 2 diabetes.⁶ There are currently no drugs recommended for prevention or reversal of pDPN. Management therefore centers on treatment of symptoms with the aim of improving functional status and quality of life.

Treatment guidelines recommend the following as first- or second-line agents: pregabalin, gabapentin, duloxetine, venlafaxine, and amitriptyline.⁷ Only pregabalin, duloxetine, fluoxetine, and tapentadol are FDA approved for pDPN (Table 20.1). Choice of agent is driven
by patient-specific consideration of side effect profile and comorbid conditions. For further information on use of antidepressants and gabapentinoids for pain, see Chapter 36.

Gabapentin and pregabalin are γ-aminobutyric (GABA) mimetics that cause analgesia via high affinity binding and modulation of calcium channel α2-δ proteins in the dorsal root ganglion.⁸ Modulation of these channels reduces the number of synaptic vesicles that fuse within the presynaptic membrane, thus limiting the release of neurotransmitters (GABA, glutamate, noradrenaline, substance P, and calcitonin gene-related peptide) into the synapse. Gabapentin has also been shown to inhibit ectopic discharge activity from injured peripheral nerves. Finally, there is some evidence to support its antiallodynic effects due to either enhanced inhibitory input of GABA-mediated pathways and antagonism of both NMDA receptors and calcium channels in the CNS.⁹

A systematic review and meta-analysis of trials of gabapentin for pDPN demonstrated an NNT for benefit (NNTB) of 5.9 to reduce pain intensity by at least 50% at gabapentin doses of 1200 mg or more.¹ Furthermore, a double-blind, placebo-controlled multicentre study of 165 patients with pDPN reported a statistically significant reduction in mean daily pain score in the gabapentin group, with an NNT being 3.8.⁹ Because of nonlinear pharmacokinetics, gabapentin is typically started at lower doses (eg, 100-300 mg three times daily) and gradually up-titrated to effect.¹⁰ Maximum dose is 1200 mg three times daily.

The evidence for pregabalin is equally strong. A systematic review and meta-analysis demonstrated an NNT of 7.8 to reduce pain by at least 50% using a pregabalin dose of 600 mg daily.¹¹ Pregabalin is more potent than gabapentin, is typically started at a dose of 75 mg twice daily, and increased as necessary to a maximum daily dose of 300 mg (although the maximum dose is 600 mg in Europe and pregabalin doses up to 600 mg per day are approved for other indications). Both gabapentin and pregabalin are renally excreted and require dose adjustment in patients with impaired renal function.

Nearly two-thirds of patients taking gabapentinoids for neuropathic pain report a side effect, the most common being dizziness, fatigue, drowsiness, and ataxia.¹¹ Although drug interactions are thought to be uncommon due to lack of protein binding and metabolism, coadministration of gabapentin and pregabalin with opioids and benzodiazepines does increase the risk of overdose and death. Concerns about recreational use of gabapentinoids has led to prescribing restrictions and further underlines the need for caution when prescribing these drugs in patients with substance use disorders.¹ Gabapentin and pregabalin’s side effect profile makes them rational options for patients with insomnia, essential tremor, or restless legs syndrome. Acute discontinuation of gabapentinoids can result in withdrawal symptoms including anxiety, insomnia, and headaches, so tapering prior to discontinuation is recommended.¹

Mirogabalin is an emerging α2-δ subunit ligand for the treatment of neuropathic pain, which has shown excellent analgesic effects and safety profiling in recent randomized controlled trials. Unlike gabapentin and pregabalin, which are nonselective ligands for the α2-δ-1 and α2-δ-2, mirogabalin is more selective for the α2-δ-1 subunit and may be a promising option for neuropathic pain in the future.¹