These are the most effective medications for the neuropathic pain (NNT 3.1). They also help with depression associated with pain. The most commonly used drugs are amitriptyline, imipramine, nortriptyline, desipramine and clomipramine. They have a three-ring structure with a side chain. They inhibit norepinephrine transport and inhibit reuptake of serotonin. They have selective affinity for α1 receptors. As the reuptake is inhibited, serotonin levels rise and indirect transmission of serotonin is mediated by α2 and D2 receptors. They also block sodium channels, histamine channels and calcium channels. Clinical improvement in pain takes between 2 and 3 weeks after the start of the medication.

They are well absorbed after first-pass metabolism from the small intestine. Peak levels are seen in 2–6 h. Metabolism is in the liver by demethylation and conjugation. The excretion is through urine and faeces.

Side effects include urinary retention, tachycardia, blurred vision, weight gain, drowsiness, hypotension and sleep disturbance.

They are mostly useful in neuropathic pain, chronic low back pain, fibromyalgia, postherpetic neuralgia and diabetic neuropathy. Clinical effect takes between 2 and 3 min to appear. Their efficacy is less in HIV neuropathy and phantom pain.

They inhibit uptake of serotonin and norepinephrine by blocking the sodium-potassium ATP pump. The drugs include duloxetine, venlafaxine and milnacipran. Serotonin reuptake is inhibited leading to increase in serotonin and norepinephrine which leads to activation of descending inhibitory pathways. All drugs are metabolised by the liver and excreted renally. Venlafaxine has an active metabolite which has a long half-life of 10 h. Duloxetine should be avoided in patients with renal deficit as it is 70 % excreted in the urine. Adverse effects include nausea, vomiting, constipation, drowsiness, dry mouth, decreased appetite, tremors, insomnia, diarrhoea, ejaculatory delay and impotence. The NNT of venlafaxine for diabetic neuropathy is 4.6 and 5.2 for duloxetine. Duloxetine has been widely used for neuropathic pain and fibromyalgia.