Antidepressants and chronic pain

Effective analgesia in neuropathic pain and other syndromes

Antidepressants are used widely to treat symptoms other than depression, many of which fit into a general category of pain. They include neuropathic pain (postherpetic neuralgia, diabetic neuropathy (p 827)1), irritable bowel syndrome, temporomandibular joint dysfunction, atypical facial pain, and fibromyalgia. In Britain no antidepressant is licensed for these indications. Do they work?

There is strong evidence from systematic reviews of randomised trials that tricyclic antidepressants are effective treatments for several of these conditions.2 3 4 For established postherpetic neuralgia, tricyclic antidepressants seem to be the only drugs of proved benefit,4 and the number needed to treat to achieve at least 50% pain relief after three to six weeks compared with placebo was 2.3 (95% confidence interval 1.7 to 3.3).2 This means that two patients in five will achieve this (high) level of relief who would not have done so with placebo. Numbers needed to treat of two to three compare well with the most effective analgesics in acute pain, and with anticonvulsants in neuropathic pain.5

Figure 1 shows results from individual randomised trials of diabetic neuropathy and postherpetic neuralgia, each point representing one randomised trial.2 All the points fall in the upper segment, showing treatment to be better than placebo. Overall, about 50-90% of patients can expect to achieve at least 50% pain relief with antidepressants, while others will achieve a lower level of relief that may still be worth while for them.

Fig 1

L'Abbé plot for trials of antidepressants in diabetic neuropathy and postherpetic neuralgia, showing percentage of patients achieving at least 50% pain relief when taking antidepressants versus placebo1

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Antidepressants also work in other neuropathic pain syndromes. In 13 randomised studies of diabetic neuropathy the number needed to treat to achieve at least 50% pain relief was 3.0 (2.4 to 4), and in two studies of atypical facial pain it was 2.8 (2.0 to 4.7). The estimated number needed to treat from one study of pain after stroke was 1.7.3

The analgesic effects of antidepressants differ in several ways from classic descriptions of their action on depression itself. Amitriptyline, for example, has proved analgesic efficacy with a median preferred dose of 75 mg (with a clear dose response6) in a range of 25-150 mg daily. This range is lower than traditional doses for depression of 150-300 mg. The speed of onset of effect is much faster (one to seven days) than that reported in depression, and the analgesic effect is distinct from any effect on mood.7

The commonest adverse effects are drowsiness and dry mouth, which occur in one in three cases. About one in 30 patients has to stop taking the drug because of intolerable or unmanageable side effects. The profile of adverse effects is the same as when the drugs are used to treat depression.

Antidepressants have two roles in managing chronic pain. The primary role is when pain relief with conventional analgesics (from aspirin or paracetamol through to morphine) is inadequate or when pain relief is combined with intolerable or unmanageable adverse effects. The failure of conventional analgesics should justify a therapeutic trial of antidepressants, particularly if the pain is neuropathic (pain in a numb area). There used to be a dogma that the character of the neuropathic pain was predictive of response, so that burning pain should be treated with antidepressants and shooting pain with anticonvulsants. Max showed that this was wrong; in his study both burning and shooting pain responded to tricyclic antidepressants.7

A secondary role of antidepressants in treating chronic pain is their use in addition to conventional analgesics. This can be particularly effective in patients with cancer who have pain in multiple sites, some nociceptive and some neuropathic. Improved sleep is a huge bonus.

So which antidepressant should be chosen and at what dose? Tricyclic antidepressants have proved efficacy in chronic pain, but there is little evidence that one drug is better than another, though some patients troubled by adverse effects may benefit from changing drug. The common first choice is amitriptyline, with a starting dose of 25 mg (10 mg in frail patients) to be taken as a single night time dose one hour before lights out. We advise patients to increase the dose by 25 mg at weekly intervals until they either achieve pain relief or adverse effects become problematic. The maximum dose is 150 mg. Patients are warned to expect a dry mouth and drowsiness, which is why they should take the drug at night. If they are still drowsy first thing in the morning they should take the drug earlier in the evening.

There is no evidence that the newer antidepressants have greater analgesic effect than tricyclic drugs. The number needed to treat to achieve at least 50% pain relief was five for paroxetine and 15.3 for fluoxetine, while mianserin showed no difference from placebo.1 There is still insufficient evidence from trials to be sure about this. The lower incidence of adverse effects for selective serotonin reuptake inhibitors (fluoxetine and paroxetine) than with tricyclic drugs may make them worth trying for those patients who cannot take tricyclics because of adverse effects.

One obvious question is what happens in the long term. Most evidence of efficacy comes from short term trials (lasting weeks to months), and, although many patients continue to achieve pain relief with antidepressants for months to years, this is not true for everybody. Another puzzle is how antidepressants work as analgesics. The standard (but not compelling) explanation is that they act on descending tracts from the brain via noradrenaline and serotonin systems to modulate signalling of pain in the spinal cord. This sounds, and is, an unsatisfactory explanation. But in the meantime it is clear that antidepressants have an important role to play in relieving chronic pain.