Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for preventing migraine

Migraine is a common condition that can significantly impair people's quality of life. Individuals who experience frequent or severe migraine may benefit from preventive medications taken prior to an attack and before the pain starts. Studies have suggested the potential role of neurotransmitters in the genesis of headache. Accordingly, drugs that inhibit the passage of neurotransmitters in brain cells and, therefore, increase their levels, have been examined for their potential benefit in preventing migraine. Two classes of inhibitors, the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), typically used to treat depression, are evaluated in this review.

This is an update of a previous review that included studies on migraine and tension-type headache. This original review has been split in two separate reviews: this update addresses only studies on migraine, while a second focuses on tension-type headache. In November 2014, we identified three new studies. Eight studies were already included in the previous version of the review. Overall, we analysed a total of 585 participants. All the studies had a small number of participants and were conducted over a period of two to three months. Only a few were of high quality.

The results suggest that SSRIs and SNRIs are no better than placebo (sugar pill) for reducing the number of migraine attacks. There were no differences in minor side effects between participants treated with SSRIs or SNRIs versus those treated with placebo. SSRIs and SNRIs seem not to offer advantages when compared to other active treatments, specifically the tricyclic antidepressant amitriptyline. The participants treated with SSRIs or SNRIs suffered fewer minor side effects than those who took amitriptyline, however the number of people who stopped taking one drug or the other due to side effects was approximately equal. These results are based on short-term trials (no more than three months), which are not properly sized and feature serious methodological deficiencies. We did not find studies comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. antiepileptics and anti-hypertensives).

Authors' conclusions: 

Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine as preventive drugs for migraine. There is no evidence to consider SSRIs or venlafaxine as more effective than placebo or amitriptyline in reducing migraine frequency, intensity, and duration over two to three months of treatment. No reliable information is available at longer-term follow-up. Our conclusion is that the use of SSRIs and SNRIs for migraine prophylaxis is not supported by evidence.

Read the full abstract...

This is an updated version of the original Cochrane review published in 2005 on selective serotonin reuptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards migraine prevention. Another updated review is under development to cover tension-type headache.

Migraine is a common disorder. The chronic forms are associated with disability and have a high economic impact. In view of discoveries about the role of serotonin and other neurotransmitters in pain mechanisms, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of migraine.


To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic migraine in adults.

Search strategy: 

For the original review, we searched MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), and Headache Quarterly (1990 to 2003). For this update, we applied a revised search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10), MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials.

Selection criteria: 

We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older of either sex with migraine.

Data collection and analysis: 

Two authors independently extracted data (migraine frequency, index, intensity, and duration; use of symptomatic/analgesic medication; days off work; quality of life; mood improvement; cost-effectiveness; and adverse events) and assessed the risk of bias of trials. The primary outcome of this updated review is migraine frequency.

Main results: 

The original review included eight studies on migraine. Overall, we now include 11 studies on five SSRIs and one SNRI with a total of 585 participants. Six studies were placebo-controlled, four compared a SSRI or SNRI to amitriptyline, and one was a head-to-head comparison (escitalopram versus venlafaxine). Most studies had methodological or reporting shortcomings (or both): all studies were at unclear risk of selection and reporting bias. Follow-up rarely extended beyond three months. The lack of adequate power of most of the studies is also a major concern.

Few studies explored the effect of SSRIs or SNRIs on migraine frequency, the primary endpoint. Two studies with unclear reporting compared SSRIs and SNRIs to placebo, suggesting a lack of evidence for a difference. Two studies compared SSRIs or SNRIs versus amitriptyline and found no evidence for a difference in terms of migraine frequency (standardised mean difference (SMD) 0.04, 95% confidence interval (CI) -0.72 to 0.80; I2 = 72%), or other secondary outcomes such as migraine intensity and duration.

SSRIs or SNRIs were generally more tolerable than tricyclics. However, the two groups did not differ in terms of the number of participants who withdrew due to adverse advents or for other reasons (one study, odds ratio (OR) 0.39, 95% CI 0.10 to 1.50 and OR 0.42, 95% CI 0.13 to 1.34).

We did not find studies comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. antiepileptics and anti-hypertensives).