TCAs as Painkillers: Proof That You Can Teach an Old Dog New Tricks

medium_4882443448 The creation of a new drug that is safer, more effective, and has fewer side effects than the current treatment surely renders the current treatment obsolete, right? Well, not necessarily.

Take tricyclic antidepressants (TCAs) for instance. TCAs are a class of antidepressant that work by blocking the serotonin and noradrenaline transporters, leading to an increase in the amount of serotonin and noradrenaline in the synapse. As the current theory says that depression is caused by low levels of serotonin and noradrenaline in the brain, you would assume that TCAs were a good choice of treatment for depression.

However, while effective, TCAs can cause a variety of side effects including drowsiness, dry mouth, blurred vision, sexual dysfunction, and irregular heartbeat. The most problematic (although uncommon) side effect is suicidal thoughts – not something you want any patient to experience, but particularly worrisome if the patient is depressed. Coupled with a low therapeutic index that makes accidental or deliberate overdose easy (some patients take up to 300mg/day, while the lowest reported toxic dose is around 6.7mg/kg of body weight – about 422mg for a 10st adult), TCAs are now rarely used to treat depression, having been replaced by newer drugs like SSRIs (selective serotonin reuptake inhibitors) and SNRIs (selective noradrenaline reuptake inhibitors).

You’d think that that would be the end of the road for TCAs, but it turns out that they can be an effective treatment for a variety of conditions including chronic neuropathic pain, for which they are a first-line treatment. Neuropathic pain arises as a result of damage to the somatosensory system – the system responsible for our sense of touch – and is a common complication of diseases such as diabetes and multiple sclerosis.

So how do TCAs work as painkillers? First of all, it’s thought that pain and depression share some biochemical mechanisms, as many depression patients experience pain and many chronic pain patients experience depression. The precise way in which TCAs alleviate pain isn’t fully understood, but the fact that SNRIs are also effective at treating neuropathic pain indicates that noradrenaline reuptake inhibition has a role in analgesia. The increased amount of serotonin and noradrenaline in the synapse is one proposed mechanism for the analgesic properties of TCAs, due to the drug blocking the transporters of these neurotransmitters. Serotonin and noradrenaline are already known to regulate nociceptive pain (pain as a result of noxious stimuli such as being pinched or burnt), so it has been suggested that TCAs may enhance pain control in neuropathic pain by inhibiting reuptake of serotonin and noradrenaline.  Recent studies have shown that neuropathic pain can be alleviated by b2-adrenoreceptor mediated inhibition of TNFa. Noradrenaline acts on the b2-adrenorecpetor and produces analgesic effects by decreasing TNFa production. Release of TNFa from non-neuronal cells causes and maintains neuropathic pain, and mRNA expression of TNFa is increased in mouse models of neuropathy. Treatment with TCAs reduces the mRNA overexpression and thus decreases TNFa levels, reducing pain

Neuronal hyperexcitability has also been shown to cause spontaneous neuropathic pain. Over-expression of NMDA receptor-operated ion channels in the spinal cord and over-expression of sodium channels in the peripheral nervous system are known causes of hyperexcitability-induced pain. TCAs block both of these channels, thus preventing hyperexcitation from occurring. Another possibility is that TCAs relieve neuropathic pain by blocking calcium channels in a similar way to the anticonvulsant drug gabapentin. Gabapentin reduces the release of neurotransmitters into the synaptic cleft by binding to the a2-d-subunit of the calcium channel. While we still don’t know for sure how TCAs act as analgesics for neuropathic pain, there are several promising directions being explored by researchers. What we do know is that TCAs are incredibly good at their new job, leading to this obsolete antidepressant being reinvented as the gold standard of neuropathic pain treatment.

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Sindrup, S., Otto, M., Finnerup, N., & Jensen, T. (2005). Antidepressants in the Treatment of Neuropathic Pain Basic Clinical Pharmacology Toxicology, 96 (6), 399-409 DOI: 10.1111/j.1742-7843.2005.pto_96696601.x

Bohren Y, Tessier LH, Megat S, Petitjean H, Hugel S, Daniel D, Kremer M, Fournel S, Hein L, Schlichter R, Freund-Mercier MJ, Yalcin I, & Barrot M (2013). Antidepressants suppress neuropathic pain by a peripheral β2-adrenoceptor mediated anti-TNFα mechanism. Neurobiology of disease, 60, 39-50 PMID: 23978467

Micó JA, Ardid D, Berrocoso E, & Eschalier A (2006). Antidepressants and pain. Trends in pharmacological sciences, 27 (7), 348-54 PMID: 16762426

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