By Marcello Cherchi, MD PhD
For patients
Serotonin-norepinephrine reuptake inhibitors (SNRIs) are pills you can take by mouth. They are sometimes used for problems with mood (like depression or anxiety), but some doctors also prescribe them to protect against migraine.
For clinicians
Overview
Serotonin-norepinephrine reuptake inhibitors (SNRIs) are sometimes used in otoneurology for migraine prophylaxis, though evidence in support of this application is mixed. Generally these drugs are well-tolerated.
Introduction
Serotonin-norepinephrine reuptake inhibitors (SNRIs) were originally developed and approved for the treatment of various mood disorders. Over the years they have found a number of off-label uses, such as in the management of neuropathic pain, migraine, menopausal symptoms, and others. The SNRIs approved by the FDA include venlafaxine, desvenlafaxine, duloxetine and levomilnacipran.
Pharmacology
Although the nomenclature for class of medications suggests that they only inhibit the reuptake of serotonin and norepinephrine, their pharmacologic mechanism is probably be more complex; for instance, venlafaxine also partially inhibits the reuptake of dopamine (Holliday and Benfield 1995; Wellington and Perry 2001).
Cautions and contraindications
As with any drugs that have serotonergic activity, SNRIs post the risk of inducing serotonin syndrome. The risk of serotonin syndrome is very small, but becomes non-trivial if these drugs are used in high doses, especially if used simultaneously with other serotonergic medications.
SNRIs should not be taken during pregnancy and lactation.
Relevance in otoneurology
Probably the main application of SNRIs in otoneurology is in the management of migraine with migraine associated vertigo (MAV).
For the purpose of migraine prophylaxis, venlafaxine was shown to be superior to placebo (Ozyalcin et al. 2005), not inferior to amitriptyline (Hedayat et al. 2022), equivalent to propranolol (Salviz et al. 2016), and similar to flunarizine and valproate (Liu et al. 2017). Venlafaxine is generally well-tolerated, and appears to be better tolerated than tricyclic compounds such as amitriptyline (Bulut et al. 2004; Hedayat et al. 2022). As with most medications used off-label for migraine prophylaxis, the dose of venlafaxine used is generally lower than the drug’s original (psychiatric) purpose. At the low dose, the side effect profile is fairly favorable; if patients experience adverse effects, they usually include “jitteriness” and dyspepsia, which are usually transient.
As of this writing there were no published studies regarding desvenlafaxine for migraine prophylaxis. However, since desvenlafaxine is a catabolite of venlafaxine, some clinicians prescribe it in a similar fashion. Many patients report desvenlafaxine to be somewhat better tolerated than venlafaxine.
Duloxetine appears to have some efficacy for migraine prophylaxis (Taylor et al. 2007) independently of any effects on mood (Young et al. 2013), though overall it has not been studied as well as venlafaxine.
As of this writing there were no published studies on the use of levomilnacipran for migraine prophylaxis.
A Cochrane review of SNRIs concluded that there is insufficient evidence of efficacy for migraine (Banzi et al. 2015), though some investigators have reached different conclusions (Wang et al. 2020).
References
Banzi R, Cusi C, Randazzo C, Sterzi R, Tedesco D, Moja L (2015) Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults. Cochrane Database Syst Rev 4: CD002919. doi: 10.1002/14651858.CD002919.pub3
Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B (2004) Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg 107: 44-8. doi: 10.1016/j.clineuro.2004.03.004
Hedayat M, Nazarbaghi S, Heidari M, Sharifi H (2022) Venlafaxine can reduce the migraine attacks as well as amitriptyline: A noninferiority randomized trial. Clin Neurol Neurosurg 214: 107151. doi: 10.1016/j.clineuro.2022.107151
Holliday SM, Benfield P (1995) Venlafaxine. A review of its pharmacology and therapeutic potential in depression. Drugs 49: 280-94. doi: 10.2165/00003495-199549020-00010
Liu F, Ma T, Che X, Wang Q, Yu S (2017) The Efficacy of Venlafaxine, Flunarizine, and Valproic Acid in the Prophylaxis of Vestibular Migraine. Front Neurol 8: 524. doi: 10.3389/fneur.2017.00524
Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R (2005) The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 45: 144-52.
Salviz M, Yuce T, Acar H, Karatas A, Acikalin RM (2016) Propranolol and venlafaxine for vestibular migraine prophylaxis: A randomized controlled trial. Laryngoscope 126: 169-74. doi: 10.1002/lary.25445
Taylor AP, Adelman JU, Freeman MC (2007) Efficacy of duloxetine as a migraine preventive medication: possible predictors of response in a retrospective chart review. Headache 47: 1200-3. doi: 10.1111/j.1526-4610.2007.00886.x
Wang F, Wang J, Cao Y, Xu Z (2020) Serotonin-norepinephrine reuptake inhibitors for the prevention of migraine and vestibular migraine: a systematic review and meta-analysis. Reg Anesth Pain Med 45: 323-330. doi: 10.1136/rapm-2019-101207
Wellington K, Perry CM (2001) Venlafaxine extended-release: a review of its use in the management of major depression. CNS Drugs 15: 643-69. doi: 10.2165/00023210-200115080-00007
Young WB, Bradley KC, Anjum MW, Gebeline-Myers C (2013) Duloxetine prophylaxis for episodic migraine in persons without depression: a prospective study. Headache 53: 1430-7. doi: 10.1111/head.12205
