Overall, 1471 potential articles were identified. On the initial screen 443 full text articles were retrieved and assessed for eligibility (fig 1). Thirty seven studies met the inclusion criteria4 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
; 13 focused on migraine headaches,23 24 29 31 32 34 36 40 41 43 50 51 58
17 on tension-type headaches,4 25 26 28 33 35 37 38 39 42 44 45 47 53 55 56 57
six on chronic mixed headaches (components of migraine and tension-type headaches),27 30 46 48 49 54
and one on psychogenic headaches.52
Six studies used the 1988 criteria of the International Headache Society, 11 used the 1962 ad hoc committee criteria, and the remainder used the most recent criteria. All trials of migraine headaches would meet the most recent criteria. Among trials of tension-type headache, one met the criteria for infrequent episodic headaches, six for frequent episodic headaches, and 15 for chronic headache according to the most recent criteria. The six trials with mixed headaches were analysed as migraine headaches as they better met the criteria for migraine headache than for tension-type headache.
Fig 1Flow of articles through study
Twenty nine of the 37 studies used parallel group designs and eight crossover designs. None of the crossover studies provided sufficient data from which to calculate paired within patient results.4 25 29 36 43 48 51 58 59
All eight were, however, included as one trial,25
reported no carry-over effect, and the remainder had either more than four weeks of washout43 58
or sufficiently long treatment durations to minimise carry-over effects.36 43 48
A total of 3176 participants were enrolled across the 37 studies (table 1). Studies lasted an average of 10 weeks (range 4-26 weeks). A mean 70 participants (range 10-554) took part in the studies. Seventy three per cent of participants were women (range 28-98%); all but one study52
had more women than men. The mean age of participants was 39.6 years. Ten studies were carried out in the United States; five in Italy; four in the United Kingdom; three each in Denmark, Germany, and Turkey; two in Russia; and one each in Australia, Canada, Egypt, Greece, Hungary, Norway, and Spain. All but four studies were in English.23 30 45 55
Nine trials were sponsored by industry, and in 16 the source of funding was not stated.
Table 1 Characteristics of included studies
Among the 37 studies, 20 compared a tricyclic with placebo. Some studies had more than one comparison group. A few studies compared tricyclics with other modalities, including eight with selective serotonin reuptake inhibitors, three with β blockers, three with heterocyclics, and one each with buspirone,47
One study compared amitriptyline with cognitive behavioural therapy37
and one with stress management,38
one compared biofeedback with amitriptyline and propranolol,46
three compared amitriptyline with spinal manipulation,26 50 56
and one compared amitriptyline and fluvoxamine with transcranial brain electrostimulation.55
Measures of headache included frequency of headache (19 studies), headache intensity (n=5), and headache index (n=13). All the studies using headache index used frequency of headache as one component in the index calculation.
Most studies (n=29) titrated the study drugs. The maximum allowable daily dose for amitriptyline (30 studies) ranged from 10 mg30
to 150 mg,33 58
whereas the four studies of clomipramine ranged from 30 mg43
to 150 mg.42
Other maximum daily doses of tricyclics were opipramol 150 mg,40
doxepin 100 mg,48
amitriptylinoxide 90 mg,48 53
and desipramine 150 mg.57
Periods of dose titration ranged from none24 27 30 45 49
to four weeks.33 37 43 53 57 58
The mean pooled doses were amitriptyline 80.4 mg (95% confidence interval 70.1 to 90.7, range 25-150), amitriptylinoxide 90 mg (one study), clomipramine 116 mg (104 to 128, range 30-150), doxepin 50 mg (n=1), and opipramol 75 mg (n=1).
Seven studies excluded patients with depression.25 28 29 35 47 53 56
Eleven studies reported the number of patients at trial entry meeting criteria for depression, ranging from 21% to 98%. The remaining studies did not measure or report on depression.
Although quality varied among the studies, most had important limitations with design or reporting (table 2). Few studies reported the method of randomisation or allocation concealment. Although trials were often reported as double blind, blinding success was reported in only one trial57
and was often questionable, as treatment groups differed significantly in clinically recognisable adverse effects.
Tricyclics versus placebo
At baseline, participants with migraine averaged 4.7 headaches per month (95% confidence interval 4.3 to 5.1) and those with tension-type headaches 16.9 (15.8 to 18.0), with no difference between tricyclic and placebo groups (P=0.46). Tricyclics were more effective than placebo in reducing the burden from both tension-type headaches (average standardised mean difference −0.99, 95% confidence interval −1.66 to −0.32; 11 arms, I2=93.8%) and migraine headaches (−1.00, −1.52 to −0.48; 10 arms, I2=89.4%, fig 2). Tricyclics were equally efficacious between the two headache types. The studies combined yielded an overall average standardised mean difference for tricyclics of −0.96 (95% confidence interval −1.39 to −0.53, I2=90.1%). Therefore, regardless of the scale used to measure headaches, patients treated with a tricyclic experienced nearly 1 standard deviation of improvement, a clinically large effect. Efficacy did not differ among the different categories of tension-type headache (infrequent episodic v frequent episodic v chronic tension-type, P=0.39).
Fig 2Effect of tricyclic antidepressants on burden of headache for tension-type and migraine headaches compared with placebo. Trials of mixed and migraine headaches are combined
The number of headaches per month among studies reporting it were reduced on average by 6.9 for tension-type headaches (95% confidence interval −21.6 to 7.7, three studies) and 1.4 for migraine headaches (−3.3 to 0.5, four studies). For both headache types this beneficial effect increased over time (tension-type: β=−0.16, 95% confidence interval −0.23 to −0.10, P<0.0005, migraine: β=−0.09, −0.14 to −0.04, P=0.001, fig 3). Therefore for every additional week of treatment with a tricyclic, the number of headaches were reduced by 0.16 standard deviations. Among these trials, a range of tricyclic doses was used, with an average dose that was 50% of the maximum for the particular tricyclic studied. The effect of doses less than 50% of the maximum dose was lower than those with higher doses (average standardised mean difference −0.73, 95% confidence interval −1.14 to −0.32 v −0.92, −1.50 to −0.34), although the difference was not significant (P=0.34).
Fig 3Effect of tricyclic antidepressants compared with placebo over time. SMD=standardised mean difference
Patients taking tricyclics were more likely to experience at least 50% improvement in their headaches than those taking placebo for both tension-type headaches (relative risk 1.41, 95% confidence interval 1.02 to 1.89, four studies, I2=48.8%) and migraine headaches (1.80, 1.24 to 2.62, four studies, I2=0.0%, fig 4). Therefore, patients treated with tricyclics had a 40% and 80% increase in the probability of having 50% improvement in tension-type and migraine headaches, respectively. Overall, tricyclics improved the likelihood of achieving 50% improvement in headaches (1.53, 1.16 to 2.01, eight studies, I2=26.1%).
Fig 4Likelihood of experiencing at least 50% reduction in tension-type and migraine headaches compared with placebo. Trials of mixed and migraine headaches are combined
Tricyclics also reduced the number of doses of analgesics taken for acute headache pain for both tension-type headaches (average standardised mean difference −1.71, 95% confidence interval −3.37 to −0.05, six studies, I2=14.5%) and migraine headaches (−0.94, −1.87 to −0.02, four studies, I2=32.6%).
Individual adverse effects of tricyclics compared with placebo were variably reported among the studies. In seven comparison arms, patients taking tricyclics were more likely to report “any” side effect than those taking placebo (relative risk 1.89, 95% confidence interval 1.18 to 3.02, I2=85.9%, fig 5). Among 10 individual adverse effects, only dry mouth (2.34, 1.63 to 3.35, I2=43.3%) and drowsiness (1.87, 1.25 to 2.70, I2=55.1%) were statistically more frequent in patients receiving tricyclics than in those receiving placebo (table 3). The likelihood of withdrawing due to adverse effects, however, did not differ among 16 placebo controlled trials (1.21, 0.80 to 1.82, I2=74.1%, fig 5).
Fig 5Likelihood of adverse effects between tricyclic antidepressants and placebo
Table 3 Relative risk of adverse effects among tricyclic antidepressants compared with placebo or selective serotonin reuptake inhibitors Tricyclics versus selective serotonin reuptake inhibitors
In a limited number of trials the effectiveness between tricyclics and selective serotonin reuptake inhibitors did not differ for tension-type headaches (average standardised mean difference −0.80, 95% confidence interval −1.63 to 0.02, four studies, I2=89.5%, fig 6) or migraine headaches (−0.22, −0.75 to 0.31, four studies, I2=89.5%). Seven of these trials used amitriptyline and one used desipramine. The doses used were relatively low: the maximum dose of amitriptyline averaged 50 mg, ranging from 25 mg to 75 mg; the dose of desipramine was 150 mg. Despite low doses, tricyclics were more likely than selective serotonin reuptake inhibitors to produce at least 50% improvement in tension-type headaches (relative risk 1.73, 95% confidence interval 1.34 to 2.22, I2=0.0%, three studies, fig 7), and migraine headaches (1.72, 1.15 to 2.55, I2=9.2%, three studies). Tricyclic arms had higher rates of several adverse effects such as drowsiness and dry mouth (table 3), although they did not have higher withdrawal rates for tension-type headaches (1.05, 0.92 to 1.19, two studies, I2=0.0%) or migraine headaches (2.0, 0.90 to 4.47, three studies, I2=0.0%).
Fig 6Comparison of effectiveness of tricyclic antidepressants with selective serotonin reuptake inhibitors for tension-type and migraine headaches. Trials of mixed and migraine headaches are combined. SSRI=selective serotonin reuptake inhibitor (more ...)
Fig 7Likelihood of experiencing 50% clinical improvement with tricyclics compared with selective serotonin reuptake inhibitors. Trials of mixed and migraine headaches are combined. SSRI=selective serotonin reuptake inhibitor
Among three trials, tricyclic arms were more likely to have “any” side effect than the selective serotonin reuptake inhibitor arms (2.25, 1.52 to 3.32, I2
=0.0%).25 28 57
Specific side effects more common among tricyclics included abdominal distress (2.34, 1.31 to 4.95, four studies, I2
=6.6%), dizziness (2.52, 0.77 to 8.23, five studies, I2
=63.0%), and dry mouth (4.88, 2.26 to 10.52, five studies, I2
=67.8%), although the risk of withdrawing from the study did not differ (1.16, 0.81 to 2.97, five studies, I2
Tricyclics versus other drugs
Few studies compared tricyclics with other modalities. No studies compared β blockers and tricyclics for tension-type headaches; among three studies of migraine headaches, tricyclics and β blockers did not differ in reduction of number of headaches or attacks (average standardised mean difference 0.90, 95% confidence interval −0.38 to 2.18, I2=93.8%) and in two studies did not differ in the likelihood of experiencing at least 50% reduction in the number of headaches (relative risk 0.78, 95% confidence interval 0.42 to 1.44, I2=0.0%). Three of the studies used amitriptyline and one used clomipramine; the average dose for both was 100 mg.
Two studies of tension-type headaches compared tricyclics with buspirone (amitriptyline 50 mg) and found no differences (buspirone: average standardised mean difference −1.01, 95% confidence interval −1.83 to −0.18, I2=0.00%, table 4). Two studies compared tricyclics (amitriptyline 25 mg, clomipramine 150 mg) with tetracyclics and found no difference (average standardised mean difference −0.21, −0.65 to 0.22, I2=32.8%). A single study of tension-type headache found no difference between low dose amitriptyline (25 mg) and the serotonin antagonist ritanserin (−0.49, −1.70 to 0.71). One study found that amitriptyline (75 mg) was better than timed release dihydroergotamine for migraines (−6.57, −8.44 to −4.71). In addition, two trials compared amitriptyline (maximum doses 100 mg and 150 mg) with the anticonvulsant topiramate (0.05, −0.32 to 0.33, I2=29.2%, table 4) and one (amitriptyline 75 mg) with the calcium channel blocker flunarazine (relative risk 1.60, 95% confidence interval 0.83 to 3.10, table 5) in migraine headaches, and found no differences.
Table 4 Average standardised mean differences between tricyclic antidepressants and non-placebo treatments for tension-type and migraine headaches
Table 5 Effect of tricyclic antidepressants compared with non-placebo treatments on reduction in headache burden by 50% Tricyclics versus non-drug treatments
No differences were found between spinal manipulation and tricyclics in two studies of tension-type headaches (average standardised mean difference −0.25, 95% confidence interval −0.59 to 0.09, I2=0.0%, table 4) and one study of migraine headaches (−0.31, −0.69 to 0.08). All three studies used amitriptyline, with maximum doses of 25 mg, 30 mg, and 100 mg. Tricyclics were compared with cognitive behavioural therapy in one study of tension-type headaches and in two studies of migraine headaches, with no differences (tables 4 and 5). All three used amitriptyline at a dose of 75 mg.
Assessment of bias and sensitivity analyses
The Cochrane criteria seemed to show considerable risk of bias (table 2). On analysis of the components, we found no difference in effects between studies meeting or not meeting any Cochrane criteria for bias. We also found no effect of industry sponsorship or assessment of adherence on outcomes. We found evidence of publication bias for continuous outcomes (P=0.06) and dichotomous outcomes (P=0.04). Estimates based on Gleser’s method suggested that up to 10 unpublished trials reporting continuous outcomes and four unpublished trials reporting dichotomous outcomes could exist. Rosenthal’s fail safe suggests that 1467 unpublished trials with continuous outcomes and 691 unpublished trials with dichotomous outcomes with no effect would be required to reduce our effect to clinical insignificance (effect size <0.3). The meta-trim test did not affect the continuous outcome summary effect, but reduced the dichotomous outcome from a relative risk of 1.53 (95% confidence interval 1.16 to 2.01) to one of 1.50 (1.13 to 1.99). Metaregression found no effect of any other variables abstracted on summary outcomes, with the exception of study duration. Duration explained 32.4% of the heterogeneity for continuous outcomes and 27.3% of the variance for dichotomous outcomes.