By Marcello Cherchi, MD PhD
For patients
Tricyclic compounds are medications that were originally designed to treat depression, but over the years they have come to be used for other problems as well. Some doctors prescribe them to protect against migraine, with the most common ones being amitriptyline and nortriptyline. Common side effects include drowsiness, dry mouth and dry eyes.
For clinicians
Practical summary
Tricyclic compounds inhibit the presynaptic uptake of serotonin and norepinephrine, though they also antagonize muscarinic acetylcholine receptors. These drugs were originally developed as antidepressants, but eventually found a variety of off-label uses, such as migraine prophylaxis and neuropathic pain. Their side effects result from their anticholinergic properties. Their main application in otoneurology is in migraine prophylaxis, for which amitriptyline has been best studied, though its active catabolite nortriptyline is often better tolerated.
Introduction
Tricyclic compounds were originally developed in the 1950s and marketed for the treatment of depression.
Holroyd and Bendtsen (Holroyd and Bendtsen 2010) state that the original interest regarding the application of tricyclic compounds in the management of headache disorders arose following the publication by Lance and Curran (Lance and Curran 1964) of the efficacy of amitriptyline for chronic tension type headache. The first publication regarding amitriptyline and migraine appeared in 1973 (Gomersall and Stuart 1973).
Since then various tricyclic compounds have been studied as migraine prophylactics (Xu et al. 2017); these are reviewed by Jackson and colleagues (Jackson et al. 2010).
Pharmacology
Tricyclic compounds inhibit the presynaptic reuptake of the monoamine neurotransmitters serotonin and norepinephrine.
Probably the best studied tricyclic compound for migraine prophylaxis is amitriptyline, which has been studied in randomized trials against placebo and against other treatments (Bruno and Krymchantowski 2018; Bulut et al. 2004; Couch and Amitriptyline Versus Placebo Study 2011; Couch and Hassanein 1979; Couch et al. 1976; Gomersall and Stuart 1973; Hedayat et al. 2022; Kalita et al. 2013; Kalita et al. 2021; Wu et al. 2012; Ziegler et al. 1987; Ziegler et al. 1993). The efficacy of amitriptyline for treating migraine in the pediatric population has been questioned (Ahmad 2017; Dalrymple and Wacogne 2017; Ebell 2017; Powers et al. 2017).
Studies in animals (Norkus et al. 2015), human cell lines (Coutts et al. 1997), and humans (Baumann et al. 1986; Breyer-Pfaff 2004; Vandel et al. 1978) show that the amitriptyline is hepatically catabolized into several compounds, of which nortriptyline is the active metabolite. Having recognized this, pharmaceutical companies developed nortriptyline as a separate drug, and it has proved popular because its overall efficacy appears similar to amitriptyline but it is often better tolerated. Given that nortriptyline is a catabolite of amitriptyline, relatively few studies have been conducted focusing specifically on nortriptyline for migraine prophylaxis (Krymchantowski et al. 2012).
There are numerous other tricyclic compounds, but they have either proven inefficacious for migraine — such as clomipramine (Langohr et al. 1985; Noone 1980) — or have not been studied.
Adverse effects
Adverse effects of tricyclic compounds are thought to result from their antagonistic effect at muscarinic acetylcholine receptors. The adverse effects are those that would be expected from anticholinergic drugs, with the most common including fatigue, dry mouth, dry eyes, etc.
Cautions and contraindications
Tricyclic compounds should not be taken during pregnancy and nursing.
Relevance in otoneurology
The main application of tricyclic compounds in otoneurology is in the management of migraine and migraine associated vertigo.
References
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