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Tricyclic antidepressants (TCA's). Need to know.

Updated: Mar 20, 2021

Interesting history

- They were introduced in diabetic neuropathy around 30 years ago

- It has been shown repeatedly that these work not only in patients with comorbid depression, but also those without

- They have NO antinociceptive effects

- Analgesic onset is between 1 and 7 days usually

- They are called 'tricyclic antidepressants' because of their chemical structure of a three-ring central structure plus a side chain

Types of medication / Doses

- Response is achieved at much lower doses than would be used for antidepressant

- Amitryitpyline (imipramine and clomipramine) cause a BALANCED SSRI and NRI reuptake in vivo.

- HOWEVER, the NRI component comes from amitriptyline's metabolite - nortriptyline

Mechanism of action

NRI enhances analgesic effects through alpha2-adrenergic receptors.

1. Noradrenaline --> Alpha2-adrenergic receptors --> inhibitory G protein (Gi/o) --> inhibits presynaptic voltage-gated Ca2+ channels in the dorsal horn --> reduced excitatory neurotransmitters from activated primary afferent fibers

2. G protein coupled inward rectifying K+ channels are opened on post-synaptic spinal cord dorsal horn cells leading to hyperpolarisation and reduced excitability

This works well on neuropathic pain is because nerve injury changes the function of alpha2-adrenergic receptors in the dorsal horn of the spinal cord and the cholinergic interneurons strengthens.

They also likely affect the descending noradrenergic inhibitory system from the locus coeruleus

5-HT may work in the dorsal horn to cause pain modulation

Antidepressants may also work through: Na+ channel blockade, NMDA receptor antagonists. Or through a bunch of other changes less clear (Alpha1-adrenergic receptors, CCBs, K+ channel activators, adenosine system changes, GABA-B receptor changes, opioid receptors etc.

They also have anticholinergic effects

Number needed to treat

For peripheral neuropathic pain 2-3 for Amitriptyline (NRI and 5-HT reuptake inhib)

2.5 for Nortriptyline (which is an NRI)

SNRI = 5.0

SSRI = 6.8

Number needed to harm

TCAs - 13.6

Metabolism (UpToDate 2021)

Absorbed rapidly and nearly completely in the small intestine.

It undergoes first pass metabolism in the liver (50% in this manner).

The medication then enters the systemic circulation and binds to proteins (up to 90%).

Only the free fraction is active.

TCAs are lipophilic so diffuse widely throughout the body including the brain.

Metabolism occurs in the liver through CYP isoenzymes (including 2D6, 3A4 and others). This metabolises the drug to further active metabolites.

Half-life is about 24 hrs.



- Careful if risk of suicidality - can cause serotonin syndrome and fatal cardiac abnormalities

- Not recommended for patients with ECG abnormalities

- QTc prolongation at higher doses (1)


- Variable genetic polymorphism of metabolising enzyme CYP2D6 causes significant variability in steady state concentrations

- Side effects unfortunately often occur at sub-therapeutic doses so are not overly helpful

- 10-75 mg orally nocte is a recommended starting dose

Common side effects

- Dry mouth, sweating, dizziness, orthostatic hypotension, fatigue, constipation, and micturition issues

- Weight gain, blurred vision, palpitations, somnolence

- The falls have been shown to increase incidence of hip fracture!

- >100mg of amitriptyline / day have been shown to increase cardiac death

Rare side effects - be aware!

Liver and kidney issues?

Golden pearls


1. Urits, I., Li, N., Berardino, K., Artounian, K. A., Bandi, P., Jung, J. W., ... & Viswanath, O. (2020). The use of antineuropathic medications for the treatment of chronic pain. Best Practice & Research Clinical Anaesthesiology.

2. Sindrup, S. H., Otto, M., Finnerup, N. B., & Jensen, T. S. (2005). Antidepressants in the treatment of neuropathic pain. Basic & clinical pharmacology & toxicology, 96(6), 399-409.

3. Riediger, C., Schuster, T., Barlinn, K., Maier, S., Weitz, J., & Siepmann, T. (2017). Adverse effects of antidepressants for chronic pain: a systematic review and meta-analysis. Frontiers in neurology, 8, 307.

4. The Use of Antidepressants in Pain Management. (2019). Practical Pain Management.

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