Neuropathic Pain

Amanda Macone, MD; James A. D. Otis, MD, FAAN, DABPM


Semin Neurol. 2018;38(6):644-653. 

In This Article


Tricyclic antidepressants (TCAs) have been used for many years in the management of neuropathic pain. Their analgesic effect appears to be independent of their antidepressant actions.[7] Evidence suggests that their effect is through enhancing the body's own pain-modulating pathways and the opioid effect at the opioid receptors.[8] Their onset of action is slow, requiring several weeks for the full drug effect to be achieved. TCAs are most effective for continuous, burning, or dysesthetic pain.[9] There is level A evidence supporting the use of amitriptyline, nortriptyline, desipramine, and maprotiline in the treatment of postherpetic neuralgia.[10] Although TCAs are a first-line therapy for many forms of neuropathy, they appear to have poor efficacy in HIV neuropathy.[11,12] This may be secondary to the rapid degeneration of nerve fibers in HIV. The greatest analgesic effect is seen with the older, tertiary amine antidepressants, such as amitriptyline, imipramine, and doxepin. Of these three agents, amitriptyline has the most evidence supporting its use in the management of neuropathic pain,[13] with one class 1 randomized control trial,[14] and two class 2 RCTs[15,16] finding it more effective than placebo and maprotiline[14] in pain reduction. Secondary amine tricyclics, such as desipramine and nortriptyline, also are effective and have less sedation and anticholinergic side effects.[17] The selective serotonin reuptake inhibitor (SSRI) class is helpful in managing associated depression and insomnia but does not appear to be as effective for the management of neuropathic pain.[18,19] Tricyclics have few interactions with most medications and are absorbed well from the gastrointestinal tract; they do, however, have a significant number of side effects, including sedation. Sedation with TCAs may be reduced by starting at a low dose and instructing the patient to take the medication 10 to 12 hours before rising, rather than at bedtime. A typical starting dose for amitriptyline is between 10 and 25 mg, with most patients finding benefit between 50 and 150 mg doses daily. Other common side effects seen with TCAs are related to their anticholinergic properties. These include dry mouth, visual blurring, urinary retention, orthostatic hypotension, and cardiac arrhythmias. Patients frequently become tolerant to these after some time. Starting at a low dose of 10 mg can reduce the likelihood of significant side effects. In the elderly, amitriptyline has significant cardiac effects compared with desipramine and nortriptyline.[10] TCAs are contraindicated in patients with glaucoma, cardiac arrhythmias, and prolonged QT syndrome, and should be used with caution in patients with urinary outlet obstruction. The risk for QT prolongation is increased if tricyclics are combined with methadone, which both increases blood level of the tricyclic and independently prolongs the QT interval. Therefore, this combination is best avoided.

Some patients are unable to tolerate TCAs and may benefit from some of the newer antidepressants. In general, serotonin–norepinephrine reuptake inhibitors (SNRIs) are superior for pain reduction to SSRIs, and typically, the more selective the antidepressant is for serotonin, the less analgesic effect it has. In fact, the tricyclics are SNRIs. Some studies have shown benefit, for example, of paroxetine in certain forms of painful peripheral neuropathy.[20] Other SSRIs do not have similar evidence supporting their use in neuropathy. Venlafaxine and duloxetine (SNRIs) have shown efficacy in peripheral neuropathy.[21] In a well-designed crossover study, both venlafaxine (225 mg/day) and imipramine (150 mg/day) improved symptoms of painful polyneuropathy where patients rated pain paroxysms, constant pain, and pressure-evoked pain. The number needed to treat was lower in the imipramine group than in those given venlafaxine (2.7 vs. 5.2).[21] Multiple clinical trials have demonstrated the efficacy of duloxetine in restoration of functional status and decreasing pain scores in diabetic peripheral neuropathy at doses of 60 mg daily or twice daily.[22,23] In a randomized, blinded trial of diabetic neuropathy, duloxetine was found to be comparable to amitriptyline in efficacy, but overall, participants preferred duloxetine.[23] Duloxetine and venlafaxine have evidence suggesting that they may be the preferred drugs for the treatment of depression with comorbid pain syndromes, regardless of whether these pain syndromes have classic etiologies (e.g., diabetic peripheral neuropathy, radicular pain) or nonspecific pain associated with depression.[24] Notable advantages over classic TCAs include fewer anticholinergic effects, less α-blockade leading to less orthostatic hypotension, and absence of QT prolongation (Table 1 and Table 2).