Selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension‐type headache in adults
This is an updated version of the Cochrane review published in 2005 on selective serotonin re‐uptake inhibitors (SSRIs) for preventing migraine and tension‐type headache. The original review has been split in two parts and this review now only regards tension‐type headache prevention. Another updated review covers migraine. Tension‐type headache is the second most common disorder worldwide and has high social and economic relevance. As serotonin and other neurotransmitters may have a role in pain mechanisms, SSRIs and serotonin‐norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of tension‐type headache.
To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic tension‐type headache in adults.
For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), and Headache Quarterly (1990 to 2003). For this update, we revised the original search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10) on the Cochrane Library, 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.
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 tension‐type headache.
Data collection and analysis
Two authors independently extracted data (headache frequency, index, intensity, and duration; use of symptomatic/analgesic medication; quality of life; and withdrawals) and assessed the risk of bias of trials. The primary outcome is tension‐type headache frequency, measured by the number of headache attacks or the number of days with headache per evaluation period.
The original review included six studies on tension‐type headache. We now include eight studies with a total of 412 participants with chronic forms of tension‐type headache. These studies evaluated five SSRIs (citalopram, sertraline, fluoxetine, paroxetine, fluvoxamine) and one SNRI (venlafaxine). The two new studies included in this update are placebo controlled trials, one evaluated sertraline and one venlafaxine. Six studies, already included in the previous version of this review, compared SSRIs to other antidepressants (amitriptyline, desipramine, sulpiride, mianserin). Most of the included studies had methodological and/or reporting shortcomings and lacked adequate power. Follow‐up ranged between two and four months.
Six studies explored the effect of SSRIs or SNRIs on tension‐type headache frequency, the primary endpoint. At eight weeks of follow‐up, we found no difference when compared to placebo (two studies, N = 127; mean difference (MD) ‐0.96, 95% confidence interval (CI) ‐3.95 to 2.03; I2= 0%) or amitriptyline (two studies, N = 152; MD 0.76, 95% CI ‐2.05 to 3.57; I2= 44%).
When considering secondary outcomes, SSRIs reduce the symptomatic/analgesic medication use for acute headache attacks compared to placebo (two studies, N = 118; MD ‐1.87, 95% CI ‐2.09 to ‐1.65; I2= 0%). However, amitriptyline appeared to reduce the intake of analgesic more efficiently than SSRIs (MD 4.98, 95% CI 1.12 to 8.84; I2= 0%). The studies supporting these findings were considered at unclear risk of bias. We found no differences compared to placebo or other antidepressants in headache duration and intensity.
SSRIs or SNRI were generally more tolerable than tricyclics. However, the two groups did not differ in terms of number of participants who withdrew due to adverse events or for other reasons (four studies, N = 257; odds ratio (OR) 1.04; 95% CI 0.41 to 2.60; I2= 25% and OR 1.55, 95% CI 0.71 to 3.38; I2= 0%).
We did not find any study comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. botulinum toxin) or non‐drug therapies (e.g. psycho‐behavioural treatments, manual therapy, acupuncture).
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 (a SNRI) as preventive drugs for tension‐type headache. Over two months of treatment, SSRIs or venlafaxine are no more effective than placebo or amitriptyline in reducing headache frequency in patients with chronic tension‐type headache. SSRIs seem to be less effective than tricyclic antidepressants in terms of intake of analgesic medications. Tricyclic antidepressants are associated with more adverse events; however, this did not cause a greater number of withdrawals. No reliable information is available at longer follow‐up. Our conclusion is that the use of SSRIs and venlafaxine for the prevention of chronic tension‐type headache is not supported by evidence.
Rita Banzi, Cristina Cusi, Concetta Randazzo, Roberto Sterzi, Dario Tedesco, Lorenzo Moja
Plain language summary
Selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs) for preventing tension‐type headache
Tension‐type headache is a common type of headache that can significantly impair people's quality of life. Individuals who experience frequent or severe headaches may benefit from medications taken before the pain starts. Two classes of medication, 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. The original review has been split into two separate reviews: this update addresses only studies on tension‐type headache, while a second focuses on migraine. When we updated this review (November 2014), we identified two new studies. Six studies were already included in the previous version of the review. Overall, we analysed a total of 412 adults participants. All the studies had a small number of participants and were conducted over a period of two to four months. Only a few were of high quality.
Results suggest that SSRIs or SNRIs are no better than placebo (sugar pill) in reducing the number of days with tension‐type headache. There were no differences in minor side effects between participants treated with SSRIs or SNRIs versus those treated with placebo. SSRIs and SNRIs do not seem 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 poor quality, small, short‐term trials (no more than four months). We did not find a study comparing SSRIs or SNRIs with other medications (e.g. botulinum toxin) or non‐drug therapies (e.g. psycho‐behavioural treatments, manual therapy, acupuncture).
Rita Banzi, Cristina Cusi, Concetta Randazzo, Roberto Sterzi, Dario Tedesco, Lorenzo Moja
Implications for practice
Since the last version of this review, we included two new relevant studies which have provided little new evidence on the effectiveness of SSRIs and SNRIs in patients with tension‐type headache. The usefulness of SSRIs and SNRIs to prevent headache attacks is unclear and it is likely that these drugs do not represent an efficacious option for the prevention of chronic tension‐type headache, the population in which pharmacological prophylaxis is more appropriate. We did not find information on the use of these drugs in the prevention of episodic tension‐type headache. Considering the most relevant outcomes (headache frequency, intensity and duration) these new antidepressants did not show a superiority over placebo, and seem to be less efficacious than tricyclic antidepressants, particularly amitriptyline, in terms of duration of the headache and use of symptomatic medications.There is some evidence that SSRIs are better tolerated than other antidepressants with respect to minor adverse events, however, this does not impact on the total number of dropouts.
We cannot draw any conclusions on the place in therapy of antidepressants with respect to other non‐pharmacological prophylactic treatments, or other preventive drug classes, for the prevention of tension‐type headache in adults.
Implications for research
Overall, the standard in terms of design and reporting still needs to be improved, as does the protection against random error. For example, open design is unacceptable in this context. Headache frequency should be the primary efficacy measure in any new trial (Bendtsen 2009). Because tension‐type headache is often a chronic condition, longer follow‐up and harder outcomes that relate to real life (headache frequency, acute headache medication, days off work and quality of life) should be assessed (Bendtsen 2009). This will also avoid the use of non‐validated indexes, discouraging multiple comparisons at different time points, with the warning that multiple data testing easily results in misleading statistically significant findings that appear by chance (Moja 2005; Thornley 1998). Standardised collection of outcomes as suggested by the COMET (Core Outcome Measures in Effectiveness Trials) Initiative, which is engaged in developing, applying and promoting core outcomes sets (COS), using rigorous consensus methods, for effectiveness trials (Williamson 2012) could be helpful. The sample size should be carefully estimated on the basis of the available evidence and the expected effect, in order to protect the study against random error. Amitriptyline should be considered a reference comparator in terms of efficacy in clinical trials comparing antidepressants for patients with chronic headache disorders, however the value of new studies comparing different antidepressants in this setting is questionable.
During the current update, we noticed a clear reduction in the number of publications testing SSRIs and SNRIs in the prophylaxis of tension‐type headache. Other preventive strategies, especially non‐drug treatments, are likely to be the target of future research. For several clinically relevant outcomes, we reported a low level of evidence. This indicates that “further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate”. However, we think that a small, or large, RCT comparing a SSRI or a SNRI versus another drug or another non‐pharmacological intervention is not a priority and might not exert a significant impact on the overall evidence. In the field of antidepressants, it might be of greater interest exploring the efficacy and safety of drugs belonging to different classes (e.g. mirtazapine) and focus on depressed patients with tension‐type headache, as optimal treatments and the role of weak antidepressants are still debatable.