Definition

Neuropathic pain is pain caused by a lesion or dysfunction in the nervous system. In peripheral neuropathic pain, the lesion is located in the peripheral nervous system, and painful polyneuropathies (diabetic and non-diabetic), post-herpetic neuralgia and chronic pain after surgery (e.g. post-mastectomy pain syndrome) are prominent examples of this category of neuropathic pain. Post-stroke pain, pain after spinal cord injury, and pain in multiple sclerosis represent examples of central neuropathic pain conditions.

Antidepressants are drugs primarily developed to treat depression. The antidepressants that have been found to relieve neuropathic pain are tricyclic antidepressants (TCAs), serotonin noradrenaline reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs) and a dopamine noradrenaline reuptake inhibitor (DNRI). Within the pain field, the important drugs in these categories are TCAs: amitriptyline, imipramine, clomipramine, nortriptyline, desipramine and maprotyline; SNRIs: venlafaxine and duloxetine; SSRIs: paroxetine, fluoxetine and citalopram (see Table 1).

Table 1 Pharmacological profile of antidepressant drugs tried in neuropathic pain
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Characteristics

TCAs were among the first evidence-based treatments for neuropathic pain and this drug class is still, together with anticonvulsants, the mainstay of treatment for this type of pain. TCAs have been tested in various peripheral and central neuropathic pain conditions and there are also some data on SNRIs, SSRIs and a DNRI (Sindrup et al. 2005).

Pharmacology of Antidepressants

TCAs have a genuine analgesic effect, since 1) they have analgesic efficacy in experimental pain in humans and animals; 2) relieve neuropathic pain in patients both with and without concomitant depression; and 3) have a more prompt effect at lower doses in pain than in depression (Sindrup 1997). The pharmacological actions of TCAs are numerous (Table 1): inhibition of presynaptic reuptake of serotonin and noradrenaline, postsynaptic blockade of α-adrenergic and NMDA receptors, and blockade of sodium and possibly also calcium channels (Baldessarini 2001; Sindrup et al. 2005). All of these actions have a potential for relief of neuropathic pain, due to the specific mechanisms of this type of pain (Woolf and Mannion 1999) (Fig. 1). However, it is thought that the pain-relieving effect is mainly attributed to the TCA action on monoamines and sodium channels. The more selective antidepressants, SNRIs, SSRIs and one DNRI (bupropion), have an effect on the reuptake of amines, apparently without other actions. Therefore, the latter drug classes may only interfere with parts of the neuropathic pain mechanisms (Table 1).

Figure 1
figure _1_978-3-540-29805-2_249

Mechanisms and sites of action of tricyclic antidepressants (TCA) in neuropathic pain on peripheral nerves, in the dorsal horn of the spinal cord and at supraspinal levels. NA, noradrenaline; 5-HT, serotonin; DOPA, dopamine; NMDA, N-methyl-D-aspartate.

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Evidence

Numerous randomised, double-blind, placebo-controlled clinical trials have shown that TCAs relieve painful polyneuropathies and post-herpetic neuralgia, and a few trials have indicated that TCAs also have the potential to relieve central post-stroke pain and post-mastectomy pain syndrome (Sindrup et al. 2005). Lack of effect of the TCA amitriptyline in spinal cord injury pain in a single trial may have been caused by insufficient dosing, and a negative outcome in a study on amitriptyline in post-amputation pain could be related to inclusion of a number of patients with minimal pain. Thus, TCAs appear to be effective in central and peripheral neuropathic pain. The SNRIs venlafaxine and duloxetine relieve painful diabetic polyneuropathy, and SSRIs also apparently have a weak effect in this condition (Sindrup et al. 2005). In a study including a mixture of different types of peripheral neuropathic pain, bupropion provided astonishing pain relief (Semenchuck et al. 2001).

Efficacy of Antidepressants in Neuropathic Pain

Numbers needed to treat (NNT) to obtain one patient with more than 50% pain relief, calculated from pooled data from randomised placebo-controlled trials, is used to give a rough estimate of the efficacy of different antidepressants in peripheral and central neuropathic pain and some of their subcategories (Table 2) (Sindrup et al. 2005). For TCAs, the NNT is 4.0 (CI 2.6–8.5) in central pain and 2.3 (2.1–2.7) in peripheral neuropathic pain, and there are only minor differences between the efficacy of TCAs in different peripheral neuropathic pain conditions. The SNRI venlafaxine seems to have lower efficacy than TCA in painful polyneuropathy, whereas preliminary reports have indicated that duloxetine, another SNRI, has the potential to relieve painful diabetic polyneuropathy more efficiently. The SSRIs have been tested in painful diabetic polyneuropathy and appear to have rather low efficacy, with an NNT value of 6.8. A surprisingly low NNT of 1.6 was calculated for the DNRI bupropion in a group of patients with a range of different etiologies to their neuropathic pain. In general, the efficacy ranking in peripheral neuropathic pain is in line with the supposed mechanism of action of the different antidepressants, i.e. multiple mechanisms for TCAs versus more selective effects of the other antidepressants.

Table 2 Efficacy of antidepressants in neuropathic pain as estimated by Numbers Needed to Treat (NNT) for one patient with more than 50% pain relief
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Data on the effects of antidepressants on specific neuropathic pain symptoms are sparse. The TCA imipramine and the SNRI venlafaxine apparently relieve some spontaneous pain symptoms (constant deep aching pain and lancinating pain), and at least one type of stimulus-evoked pain (pain on pressure) in painful polyneuropathy (Sindrup et al. 2003). A general effect of TCAs on different pain symptoms has also been reported for amitriptyline and desipramine in postherpetic neuralgia (Kishore-Kumar et al. 1990; Max et al. 1988) and painful diabetic polyneuropathy (Max et al. 1987; Max et al. 1991).

Dosing of Antidepressants in Neuropathic Pain

TCAs exhibit a large interindividual variability in pharmacokinetics (Baldessarini 2001), and concentration-response relations have been found for some of these drugs, e.g. imipramine and amitriptyline (Rasmussen 2004; Sindrup 2005). Thus, standard dosing may cause toxicity in some patients due to the relatively low therapeutic index of TCAs, and leave others at subtherapeutic drug levels. Dosing according to effect and side-effect is not expected to be successful, since side-effects are often present even at subtherapeutic concentrations, and not all patients will obtain a pain-relieving effect at all. Dosing guided by measurements of serum drug concentrations (therapeutic drug monitoring) is suggested to improve therapeutic outcome, i.e. a start dose of 50 mg/d and dose adjustment according to a drug level measured after 2–3 weeks on the start dose.

The pharmacokinetics of SNRIs, DNRI and SSRIs show less interindividual variability and the therapeutic index is probably higher. Dosing according to effect and side-effects is therefore feasible. The studies on venlafaxine showed that a dose of 75 mg/d was ineffective, whereas 225 mg/d relieved pain (Rowbotham et al. 2004), and low serum drug levels were associated with non-response (Sindrup et al. 2003). This result fits with the experimental data showing that noradrenaline reuptake inhibition is first present at higher drug concentration, and the noradrenergic effect is expected to be important for the analgesic effect. The preliminary data on duloxetine indicate that 60–120 mg/d provides pain relief, whereas 20 mg/d is ineffective.

Side-Effects of Antidepressants in Neuropathic Pain

TCAs cannot be used in patients with cardiac conduction disturbances, cardiac incompensation and epilepsy. Side-effects including dry mouth, sweating, dizziness, orthostatic hypotension, fatigue, constipation and problems with micturition are often bothersome and will lead to discontinuation of TCAs in a number of patients. The SSRIs and SNRI are better tolerated, but drugs from these groups also cause side-effects. The SSRIs may induce nausea, vomiting and dyspepsia, and the same types of side-effects are seen with the SNRIs. Bupropion may cause gastric upset like the SNRIs and like the TCAs dry mouth. The SNRI venlafaxine may also lead to rising blood pressure.

Drop-outs due to side-effects during clinical trials with antidepressants in neuropathic pain can be used to calculate Number Needed to Harm (NNH), as the reciprocal value of the difference in drop-out rates on active and placebo treatment, and this provides a rough estimate of tolerability of the drugs. The overall NNHs are 13.6 (9.8–22.5) for TCAs, 19 (8.1–∞) for SSRIs and 21.5 (11.2–270) for SNRIs and bupropion together. The somewhat better tolerability of SSRIs and SNRIs than of TCAs is reflected in these figures. Treatment discontinuation may be more frequent in daily clinical practice than in the setting of a clinical trial.

Discussion and Conclusion

To summarize, TCAs and SNRIs are evidence-based treatments of peripheral neuropathic pain and TCAs appear to be more efficacious than SNRIs. SSRIs relieve peripheral neuropathic pain with low efficacy, whereas a limited amount of data indicates that the DNRI bupropion could be very effective for this type of pain. TCAs may work for central pain, whereas none of the other antidepressants have been tried for this category of neuropathic pain. Thus, antidepressants are, together with anticonvulsants, first line treatments for peripheral (TCAs and SNRIs) and central (TCAs) neuropathic pain. Our present knowledge does not allow us to predict which patients with neuropathic pain will respond to treatment with antidepressants.