The tricyclic antidepressants (TCAs) inhibit the reuptake of monoamines, have anticholinergic properties, and also inhibit sodium channel function, potentially modulating both central (serotonergic and other neurotransmitters) and peripheral (neuronal membrane depolarization) factors contributing to neuropathic pain. Although developed as antidepressants, the pain relief they provide has been proven independent of any effect on mood. Their most common side effects relate to their anticholinergic action, including dry mouth, constipation, sweating, blurred vision, sedation, orthostatic hypotension (with attendant fall risk), and urinary retention, which often limit their clinical use in some diabetic and many elderly subjects. Cognitive clouding or frank confusion may also occur. Sedation during initial therapy is also common in all age groups, but usually improves over the first 1 or 2 weeks of continuous therapy [7, 13].

TCAs were one of the very first classes of agents proven effective for diabetic painful neuropathy (DPN) and also work in a number of other neuropathic pain states, including postherpetic neuralgia (PHN). Amitriptyline was effective in double-blind, placebo-controlled trials, and desipramine was proven more effective than placebo and equally as effective when compared to amitriptyline, with somewhat better tolerability [14, 15]. Imipramine and nortriptyline may also be effective and may work in individual patients even after amitriptyline fails.

The average effective dosage of amitriptyline for DPN is lower than that required for the treatment of depression, typically 10–25 mg at bedtime for 2 weeks. This low dose may adequately control mild to moderate pain. If it is not effective, it may be increased by 10–25 mg every 2 weeks as tolerated, up to a maximum of 150 mg/day. The TCAs are often especially helpful for the common nocturnal symptoms of DPN, relieving pain and improving sleep quality.

Duloxetine and venlafaxine are serotonin and norepinephrine reuptake inhibitors (SNRIs). The efficacy of SNRIs duloxetine and venlafaxine is well established in controlled trials of DPN. Duloxetine has been studied in several randomized, double-blind, placebo-controlled trials for relief of pain in patients with DPPN and is approved by the FDA for treatment of DPN [16, 17]. The most common adverse events are nausea, somnolence, dizziness, constipation, dry mouth, hyperhidrosis, increased appetite, anorexia, and weakness with higher doses. Rare cases of hepatotoxicity have been reported with duloxetine, while the side effects of venlafaxine are mainly gastrointestinal. Elevated blood pressure and clinically significant ECG changes occur in 5% of patients [16, 17]. Duloxetine is contraindicated for patients with uncontrolled narrow-angle glaucoma and for patients being treated with monoamine oxidase inhibitors [16, 17].

Treatment with duloxetine may be initiated at 30 mg daily, and then increased by 30 mg/day after 1 week as tolerated to avoid nausea. The recommended total daily dose of duloxetine is 60 mg/day, but may be increased to a maximum of 120 mg/day. Treatment with venlafaxine should be initiated at 37.5 mg once or twice a day and increased by 37.7–75 mg/day each week as tolerated. High doses of venlafaxine (150–225 mg/day) are typically effective.

Gabapentin and pregabalin are thought to work through activation of the alpha-2-delta subunit of L-type voltage-regulated calcium channels, decreasing neuronal excitation and diminishing central sensitization and nociceptive transmission. Side effects include dizziness, somnolence, peripheral edema, weight gain, asthenia, headache, and dry mouth. Gabapentin, extended-release gabapentin, and pregabalin have proven effective for treatment of DPN and PHN in randomized, double-blind, placebo-controlled trials [7].

Treatment with gabapentin is typically initiated at 300–600 mg/day in three divided doses, and then gradually increased as tolerated to efficacy over several weeks to minimize sedation. Pain control is achieved for most at total daily doses of 1,000–2,000 mg/day but doses of 3,600 mg/day may be required in a minority of cases. Effects may not be seen for 1–2 weeks after dosage adjustment. Treatment with pregabalin begins with 25–75 mg once at bedtime, followed by increases of 75 mg daily for 3–7 days, then by 150 mg/day every 3–7 days as tolerated, to a maximum dose of 600 mg daily (200 mg TID or 300 mg BID). Dosage should be adjusted for renal impairment.

The remaining antiepileptic drugs have proven variable effective in clinical trials. Carbamazepine was one of the first AEDs studied for the treatment of DPN. However, although early small studies supported its efficacy, larger placebo-­controlled trials have shown limited to no benefit. Common adverse effects of carbamazepine include somnolence, dizziness, and gait disturbances, and rarely, leukopenia, hepatotoxicity, and inappropriate secretion of antidiuretic hormone. Oxcarbazepine also may be effective, with fewer side effects [7]. Lamotrigine, a voltage-dependent sodium channel blocker, proved effective in treating the pain of HIV neuropathy and in trigeminal neuralgia, but was negative in a large controlled neuropathic pain trial, at doses of 200–400 mg/day [18]. The most common adverse events were nausea, epigastric pain, headache, ataxia, drowsiness, and dizziness.

Topiramate is a sulfamate-substituted monosaccharide which blocks voltage-dependent Na⁺ and Ca²⁺ channels, increases GABA activity, and inhibits α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors. The largest positive trial of any of the agents not FDA approved for DPN was done using topiramate [19], but this evidence must be weighed against three smaller negative trials published in the same year [20].

Lidocaine is an anesthetic agent which works primarily through voltage-gated sodium channel inhibition, making it particularly useful for stabilizing injured peripheral nerve membranes in which sodium channels are upregulated. Topical lidocaine 5% has proven efficacy in small randomized and open-label studies for the relief of DPN [21–23] and has been FDA approved for PHN. The only significant side effects reported with the 5% lidocaine patch are mild skin reactions, such as erythema and localized rash. However, as this drug transiently worsens numbness, it may increase the likelihood of insensate skin injury, especially in diabetics who must exercise care with its use.

5% lidocaine patch should be applied to cover the painful area up to four times per day, but total hours of use should not exceed 12 h within a 24-h period. However, its use should be avoided in patients receiving oral Class I antiarrhythmic medications (e.g., mexiletine) to avoid potentially harmful synergy, and also in patients with severe hepatic dysfunction who may develop toxic drug levels.

Topical capsaicin depletes substance P from the cutaneous sensory nerves with chronic topical use, diminishing activation of cutaneous pain receptors. Low-concentration (0.025–0.075%) creams have been proven effective for alleviating DPN in blinded controlled trials [24–26]. Capsaicin is not associated with any severe systemic adverse effects. However, topical application is inconvenient, as it must be applied three times per day. Furthermore, it causes increased pain initially during the first week of therapy as substance P is depleted. Its moderate efficacy in DPN makes it unsatisfactory for use as a sole agent.

A high-concentration patch (8%) was developed to enable longer duration of effect and proved efficacious in both PHN and painful HIV neuropathy for periods up to 3 months following a single application [27]. It is a rapid-delivery dermal patch containing 8% of transcapsaicin, which acts as an antagonist of the transient receptor potential vanilloid 1 (TRPV1). Side effects are mainly related local at the application site, including pain, erythema, edema, and itching. Initial application may cause severe pain with high blood pressure and may necessitate opioid analgesia for transition. Long-term data on efficacy and safety, particularly on the effect on nerve fiber structure within the skin, are still needed. High-concentration capsaicin patch may be applied 30 min (to the feet) to 60 min (in other areas), up to a maximum of four patches and repeated every 90 days.

Tramadol is a centrally acting analgesic with unique properties as a weak inhibitor of norepinephrine and serotonin reuptake and low-affinity binding to μ-opioid receptors (at approximately 1/10th the strength of codeine). Its beneficial effects in neuropathic pain are attributed primarily to serotonergic modulation of pain transmission within the brain and spinal cord and secondarily to opioid effect. The efficacy of tramadol has been established predominantly in DPN in a randomized, double-blind, placebo-controlled trial, and was significant even after the control of potential antidepressant effects of serotonin reuptake inhibition.