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Journal ofNeurology, Neurosurgery, and Psychiatry 1996;61:285-290 285 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.3.285 on 1 September 1996. Downloaded from A non-selective (), but not a selective (citalopram), inhibitor is effective in the prophylactic treatment of chronic tension-type

Lars Bendtsen, Rigmor Jensen, Jes Olesen

Abstract cemed, the most important type of headache.' Objectives-Although the anti- Yet remarkably little is known about its patho- depressant amitriptyline is extensively physiology and the treatment available is lim- used in the prophylactic treatment of ited. The only established prophylactic chronic tension-type headache, only few treatment is the tricyclic studies have investigated the efficacy of amitriptymine, a non-selective serotonin reup- this treatment and the results are contra- take inhibitor. The efficacy of this treatment dictory. In addition, the new selective has, however, only been investigated in a few serotonin reuptake inhibiting antidepres- placebo controlled studies,3-6 which have sants, which are widely used in depres- reported conflicting results. The scientific sup- sion and of potential value in pain port for the widespread use of amitriptyline in management, have never been investi- the treatment of chronic tension-type gated in a placebo controlled study often- headache, therefore, is scant. sion-type headache. The aim was to The mechanism of action of amitriptyline in evaluate the efficacy of amitriptyline and chronic tension-type headache, as well as in of the selective serotonin reuptake other non-depressive chronic pain states, is inhibitor citalopram in chronic tension- largely unknown, but it is assumed that the type headache. blockage of serotonin reuptake in the CNS Methods-Forty non-depressed patients plays an essential part in its analgesic effect.7-'0 with chronic tension type headache were The selective serotonin included in a 32 week, double blind, citalopram, which has antidepressant proper- placebo controlled, threeway crossover ties comparable with the tricyclic drugs but a study. far better side effect profile," might therefore Results-Thirty four patients completed be of value in the treatment of chronic tension the trial. Amitriptyline reduced area type headache. In addition, a comparison of under the headache curve by 30% com- amitriptyline and citalopram could provide pared with placebo (P = 0.002), whereas information on the mechanism of action of citalopram had no significant effect (P = these drugs in chronic pain. The aim of the

0.68). Explanatory analyses showed that present study was to evaluate the prophylactic http://jnnp.bmj.com/ amitriptyline significantly reduced the effect of amitriptyline and citalopram in duration of headache (P = 0.01), chronic tension-type headache. headache frequency (P = 0.01), and intake of analgesics (P = 0.02) but not headache intensity (P = 0.12). Materials and methods Conclusion-Although amitriptyline did PATIENTS not eliminate the headache, it provided a Forty patients with chronic tension type clinically important reduction of headache diagnosed according to the criteria on September 29, 2021 by guest. Protected copyright. headache in the majority of otherwise of the International Headache Society'2 were treatment resistant patients. The differ- recruited from the outpatient headache clinic ential effect of amitriptyline and citalo- at Glostrup University Hospital, Copenhagen, pram indicates that mechanisms other Denmark. Seven patients had coexisting infre- than inhibition of serotonin reuptake are quent migraine ( < one day a month) whereas Department of Neurology, Glostrup involved in the analgesic effect of the tri- 33 never had migraine. The patients under- Hospital, University of cyclic . Amitriptyline, but went a general and a neurological examina- Copenhagen, not citalopram, is valuable in the prophy- tion, including 12 channel ECG and Glostrup, Denmark lactic treatment of chronic tension type laboratory screening, and completed a diag- L Bendtsen R Jensen headache. nostic headache diary'3 during a four week run J Olesen in period. Table 1 gives detailed clinical infor- Correspondence to: (7 Neurol Neurosurg Psychiatry 1996;61:285-290) mation. Dr Lars Bendtsen, Department of Neurology, The inclusion criteria were a diagnosis of Glostrup Hospital, chronic tension type headache and age University of Copenhagen, Keywords: antidepressants; pain; tension type head- DK 2600 Glostrup, ache between 18 and 65 years. Women of child- Denmark. bearing potential had to use adequate contra- Received 2 January 1996 ceptive measures throughout the study. The and in revised form 18 March 1996 Tension type headache is the most common exclusion criteria were previous participation Accepted 22 March 1996 and, as far as socioeconomic impact is con- in a , migraine more than one day a 286 Bendtsen, _Jensen, Olesen J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.3.285 on 1 September 1996. Downloaded from Table 1 Clinical characteristics (Cipramil®), and placebo tablets. In the first Patients who week of treatment with amitriptyline the Patients included completed the study patients received a daily dose of one 25 mg No of patients 40 34 amitriptyline tablet and one placebo tablet, in Sex (women/men) 25/15 22/12 the second week they received two 25 mg Age (y) 40-0 (18-60) 40 7 (18-60) Area under the headache curve 982 (145-3331) 973 (145-3331) amitriptyline tablets, and in weeks 3-8 they Headache duration (hours/four weeks) 217 (27-487) 220 (27-487) received one 25 mg and one 50 mg amitripty- Headache intensity 4-2 (1 8-7 3) 4 1 (1-8-7-3) Headache frequency (days/four weeks) 24-5 (16-28) 24 7 (16-28) line tablet corresponding to a daily dose of 75 Analgesics (doses/four weeks) 41 8 (0-106) 41 3 (0-93) mg amitriptyline. During the eight weeks of Hamilton depression score 3 3 (2-11) 3 5 (2-11) Years with headache 12 2 (1-36) 11-7 (1-36) treatment with citalopram the patients Frequency of migraine (days/year (n = 7)) 7 6 (2-12) 7-6 (2-12) received a daily dose of one citalopram tablet to a Values are means (range). There were no significant differences in any of the clinical characteris- and one placebo tablet corresponding between the 34 patients who completed the study and the six drop outs (P = 0-32-0 98). daily dose of 20 mg citalopram. During the eight weeks of treatment with placebo and during the wash out periods the patients received a daily dose of two placebo tablets. month, serious somatic or psychiatric The patients thus received two tablets daily including depression (Hamilton depression during all 28 weeks of treatment. All tablets score'4 >s 17), misuse of simple analgesics were of identical look and taste, and the (corresponding to more than 2 g a patients were told to take the tablets two to day), regular intake of opiates or benzodi- three hours before bedtime. azepines, and previous treatment with antide- pressants. All patients gave written informed RECORDING OF EFFICACY VARIABLES consent to participate in the study, which was Throughout the study the patients kept a approved by the regional ethics committee. headache diary with recordings of intensity The patients were informed that the study and duration of headache, intake of analgesics, included placebo periods, but no further infor- and side effects. Intensity was recorded on an mation about the study design was given. 11 point scale (0-10), in which 0 indicated the headache free condition, 5 indicated a moder- STUDY DESIGN AND MEDICATION ate headache, and 10 indicated the worst The study was designed as a double blind, headache imaginable. Localisation and quality placebo controlled, three way crossover trial. of the headache, whether the headache was After a four week run in period, the patients aggravated by physical activity, and presence were randomly allocated to one of the six pos- or absence of , photophobia, and sible treatment sequences (fig 1). Randomisa- phonophobia were also recorded. tion was done in blocks of six patients. Each of the three drugs was given for eight weeks and CLINICAL VISITS the treatment periods were separated by two- Follow up visits were performed at four-week week wash out periods. intervals (fig 1). At each visit, the headache The study medication was tablets contain- diary was checked, medication supplies were ing 25 mg or 50 mg amitriptyline (Saroten®), handed over, side effects reported by the tablets containing 20 mg citalopram patients were recorded, and compliance was http://jnnp.bmj.com/

Citalopram Placebo Figure 1 Study design of a the 32 week, double blind, placebo controlled, three Amitriptyline ----X------way crossover trial. Each Placebo Citalopram patient was randomly .. ******************** D allocated to one of the six treatment sequences a-f. Clinical visits are indicated on September 29, 2021 by guest. Protected copyright. by *. Placebo Amitriptyline c Citalopram 1- Amitriptyline Placebo Amttn********** * *******ta*opram d

Amitriptyline Citalopram e l Placebo Citalopram Amitriptyline ------s.J f

Run-in Period 1 Wash out Period 2 Wash out Period 3 * * * * * * * I I m 0 4 12 14 22 24 -32I Time (weeks) Serotonin reuptake inhibitors and tension-type headache 287 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.3.285 on 1 September 1996. Downloaded from Figure 2 Area under the Whitney two tailed test.'5 A possible headache curve (duration x intensity) in 34 patients time/period effect was tested for by comparing with chronic tension type a) the difference in AUC in periods when drug A headache during eight was followed by drug B with the negative dif- weeks of treatment with C.) ference in AUC in periods when B was amitriptyline (circles), drug citalopram (triangles), and C.) followed by drug A.'5 Comparison of clinical placebo (squares). 'a characteristics between patients who com- Asterisks indicate * pleted the study and drop outs was done by differences a) significant U test. between amitriptyline and .C Mann-Whitney Comparison of clinical placebo. JP = 0-02; L- characteristics between the groups of patients **P < 0008; a) allocated to the six different treatment ***P = 0 001. sequences was made by Kruskal-Wallis test. McNemar's test was used for comparison of the number of patients reporting side effects. iJ Spearman's test was used for calculation of Run-in 1 2 3 4 5 6 7 8 correlation coefficients, R. Two sided P values Time (weeks) were calculated and significance was accepted at the 5% level. tested by asking the patients w]hether they remembered to take the tablets regularly. Results EVALUATION OF EFFICACY TREATMENT EFFECT: PRIMARY VARIABLE The efficacy variables were det:ermined in In the 34 patients who completed the study, advance. The primary efficacy vari;able was the the area under the headache curve (AUC) was area under the headache currve (AUC) 973 (136) in the run in period, 616 (129) dur- recorded in the last four weeks ofF each treat- ing treatment with amitriptyline, 772 (142) ment period. The AUC was calculated as the during treatment with citalopram, and 877 sum of the daily recordings of headache dura- (171) during treatment with placebo. Placebo tion x headache intensity. SecondLary efficacy decreased AUC by 10% compared with the variables were (a) headache duraition in the run in period (P = 0-12). There was a signifi- last four weeks of each treatment period, (b) cant difference in AUC among the three treat- mean headache intensity per headaLche day, (c) ment groups (P = 0-003). The AUC was 30% headache frequency in the last foiur weeks of lower on amitriptyline than on placebo (P = each treatment period, (d) numb)er of anal- 0 002). The absolute difference between gesic doses, equivalent to 500 mg aspirin, amitriptyline and placebo was 261 (95% CI taken in the last four weeks of eac-h treatment 103-419). In the 27 patients who had never period, and (e) number of patients reporting had migraine, the AUC was 28% lower on side effects in each treatment perioAd. The effi- amitriptyline than on placebo (P = 0002). cacy of amitriptyline compared writh placebo The AUC was 12% lower on citalopram than was calculated as: efficacy = (1- AUCmiti,,pt,y,,ne / on placebo (P = 0 68). The absolute differ- AUCplacebo) x 100%. ence between citalopram and placebo was 105 (-42-253). The AUC was 20% lower on

STATISTICS amitriptyline than on citalopram (P = 0 12 (P = http://jnnp.bmj.com/ Results are presented as meaLn (SEM). 0 04 without Bonferroni correction)). The Patients who dropped out of the study were absolute difference between amitriptyline and excluded from the analyses except Xwhen calcu- citalopram was 156 (95% CI 36-275). Figure 2 lating side effects. Friedman's tuvo way test shows the course of headache over time for was used to compare efficacy variaibles among each treatment. The effect of amitriptyline was the three drugs. If Friedman's tes;t showed a significant already in week 3 (the first week of significant difference between g;roups, the treatment with full dose), and continued to be groups were compared with Wilco, Kon's paired significant in the rest of the treatment period on September 29, 2021 by guest. Protected copyright. rank sum test. To correct for mulitiple testing except for week 6. There was no carryover the P values were multiplied accoi rding to the effect (P = 0-06 to 0 39) or time period effect method of Bonferroni.'5 Ninety fi yve per cent (P = 0-63 to 1-00). confidence intervals (95% CIs) are given. Migraine days were excluded fronra the analy- TREATMENT EFFECT: SECONDARY VARIABLES ses. A possible carryover effect walS tested for Table 2 presents the secondary efficacy vari- by comparing mean AUC recordecd in periods ables. The effect of amitriptyline was primarily when drug A was followed by d.rug B with due to a decrease in duration of headache (P = mean AUC in periods when drug B was fol- 0-01), whereas headache intensity decreased lowed by drug A by means of the Mann- only marginally (P = 0-12). In addition,

Table 2 Treatment effects, secondary variables Run in Amirriptyline Citalopram Placebo Headache duration (hours/four weeks) 220 (25) 151 (24)** 182 (26) 184 (27) Headache intensity 4-1 (0-2) 3-8 (0 3) 3-6 (0-3) 3 9 (0-3) Headache frequency (days/four weeks) 24 7 (0 7) 18 6 (1 6)** 21 5 (1-4) 21 7 (1 3) Intake of analgesics (doses/four weeks) 41 3 (5-1) 25-3 (4.2)* 34-8 (5-7) 33 8 (5 2) Values are means (SEM). *P = 0 02; **P = 0 01; amitriptyline v placebo (n = 34). 288 Bendtsen, J7ensen, Olesen J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.3.285 on 1 September 1996. Downloaded from Table 3 Side effects Diamond and Baltes4 reported superiority of Amitriptyline Citalopram Placebo amitriptyline over placebo. The studies are important as they are the first ones in this Dry mouth 30*** 5 3 Drowsiness 21 *** 7 6 field, but none of them meet modem method- 7 2 4 ological standards and they should therefore Nausea 1 6 3 Obstipation 3 1 0 be interpreted with care. Recently, Gobel et a16 Weight gain 5 0 0 evaluated amitriptyline in chronic tension type Sleep disturbances 0 1 4 Abdominal pain 0 1 3 headache. Compared with placebo, duration Various 9 5 7 of headache was reduced only in the last week Number of patients reporting one or more side effects 33*** 15 15 of the six week study while the intake of anal- gesics was unaltered. Unfortunately, the study The number of patients reporting side effects during each of the three treatments are given. ***P < 0-001; amitriptyline v placebo; amitriptyline v citalopram. There was no significant was of short duration, it did not include a run difference between citalopram and placebo (n = 40). in period, and neither frequency nor intensity of headache were presented. Nevertheless, as headache duration decreased consistently headache frequency and intake of analgesics throughout all six weeks of active treatment were decreased significantly by amitriptyline but not throughout placebo treatment, the (P = 0 01 and P = 0-02 respectively). study indicates that amitriptyline has an effect in chronic tension type headache. By contrast SIDE EFFECTS AND DROP OUTS with the above studies, a recent multicentre None of the clinical characteristics presented study by Pfaffenrath et al5 could not detect any in table 1 differed between the 34 patients who differences between amitriptyline, amitriptyli- completed the study and the six drop outs (P noxide, and placebo in chronic tension type = 032 to 098) or between the groups of headache. However, the frequencies of side patients allocated to the six different treatment effects were similar on amitriptyline and sequences (P = 0-20 to 0 89). The reasons for placebo. Usually, amitriptyline has pro- drop out were side effects (one patient on nounced side effects and the inability to detect amitriptyline reporting drowsiness, dizziness, known side effects suggests insensitivity of the and dry mouth), (one patient on trial for reasons which remain obscure. placebo), and lack of effect (two patients on The present study shows a highly significant placebo and two on citalopram). All drop outs effect of amitriptyline in chronic tension type occurred during the first treatment period, headache. The effect was found both for the except for one patient who dropped out primary efficacy variable and for a range of because of lack of effect of citalopram in the secondary efficacy variables. The mean total second treatment period after having been vir- relief on amitriptyline was 30% compared with tually headache free on amitriptyline. placebo. Amitriptyline, therefore, did not Amitriptyline induced significantly more completely alleviate the patients headache, but side effects than both citalopram and placebo in evaluating the size of the effect it must be (P < 0 001), whereas there was no difference remembered that the patients had had tension between citalopram and placebo (P > 0-2; type headache for many years and had tried table 3). The difference between amitriptyline numerous other treatments. They thus repre- and placebo was due to a higher number of sented a rather severe, treatment resistant

patients complaining of dry mouth group. Given also that patients with depres- http://jnnp.bmj.com/ (P < 0-001) and of drowsiness (P < 0 001) sion were excluded from this trial, we find the during the former treatment. Six patients had improvement obtained on amitriptyline a total of 19 days with migraine during the 28 impressive. Amitriptyline induced far more weeks of treatment. There was no difference in side effects than placebo but they were gener- the number of migraine days among the three ally mild and the number of drop outs was treatments (P = 0-50). actually lower on amitriptyline than on placebo. RELATION BETWEEN EFFICACY AND CLINICAL How can the physician identify the patients on September 29, 2021 by guest. Protected copyright. CHARACTERISTICS who will benefit from amitriptyline? Our Of the 34 patients who completed the study, results indicate that the efficacy of amitripty- 27 had a better effect from amitriptyline than line cannot be predicted on the basis of clinical from placebo. No significant correlations or characteristics. Nevertheless, the present find- tendencies were detected between the efficacy ing of a clear and early treatment effect com- of amitriptyline and any of the clinical charac- bined with mild side effects suggests that all teristics listed in table 1 (R = 0 19 to 0-23, P = patients with chronic tension-type headache 0-25 to 0 95). The efficacy of amitriptyline did should have a trial of amitriptyline. In the pre- not differ between women and men (P = sent trial all patients received a fixed daily dose 0 59). of 75 mg. It is, however, a common clinical experience that many patients respond well to a daily dose of 25 or 50 mg amitriptyline and Discussion that only very few patients benefit from EFFICACY AND TOLERABILITY OF increasing the dose above 75 mg. In the AMITRIPTYLINE absence of dose response studies, we recom- The placebo effect must be taken into account mend starting with 25 mg, increasing the dose in any study of treatment for headache 2 and every 14th day depending on effect and side therefore only placebo controlled studies will effects. The maintenance dose is usually 50 or be discussed here. Lance and Curran' and 75 mg daily. The efficacy of prolonged treat- Serotonin reuptake inhibitors and tension-type headache 289 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.3.285 on 1 September 1996. Downloaded from ment of tension type headache with amitripty- In addition, calculation of an area under a line has never been investigated and such curve is a statistically valid and simple method studies are much needed. On the basis of clin- for analysing serial measurements.25 ical experience, we suggest that a successful Unfortunately, the multiplication of two vari- treatment should be discontinued after six ables conceals some information and it is months to one year and that treatment should therefore essential also to present duration, be restarted in the event of relapse. intensity, and frequency of headache, as well as intake of analgesics. Until further method- EFFICACY AND TOLERABILITY OF CITALOPRAM ological studies have identified the best effi- The new selective serotonin reuptake cacy variable, future studies should select in inhibitors are of potential value in the manage- advance one of the above mentioned variables ment of chronic pain, but only a few placebo as the primary efficacy variable24 and present controlled studies have been performed.'6 the others as secondary variables. These studies have shown moderate17-20 or no The clearly identifiable side effects of the effects21 22 of the selective serotonin reuptake tricyclic antidepressants make effective blind- inhibitors, which is in line with the present ing difficult. We found, however, the three study. We found a non-significant trend way crossover design very useful in this regard. towards an effect of citalopram as all variables, Generally, the patients thought that the med- except intake of analgesics, were improved ications changed many times during the trial during treatment with citalopram compared and also the observer, who knew the design, with placebo. In addition, the AUC was lower was effectively blinded because of the many during all of the eight weeks of treatment with possible treatment sequences. In addition, the citalopram compared with placebo. A signifi- side effects were usually most prominent in the cant effect of citalopram might therefore possi- first week of treatment and then gradually bly have been detected, if we had examined a decreased, contrary to the treatment effect. larger number of patients. Thirty four Although we did not formally record data on patients, however, provide comfortable power efficacy of blinding, we are assured that the in a crossover study, which is 5-10 times as blinding was effective in this study. powerful as a parallel study.2' Even if an effect could be shown in a larger study it is therefore MODE OF ACTION unlikely to be clinically relevant. There is general agreement that the analgesic Saper et aP0 reported the selective serotonin effect of the tricyclic drugs is independent of reuptake inhibitor to be moderately their antidepressant effect2-29 and this was effective in patients with so-called chronic supported by the present finding of an effect of daily headache. Their patients could have amitriptyline in non-depressed patients with migraine twice a week, which makes it difficult headache. The mechanism of action is, how- to compare the two studies. Infrequent coex- ever, not clarified. Previously it was assumed isting migraine does not seem to indicate a that the analgesic properties of the tricyclic more favourable response to citalopram, as the antidepressants could be ascribed to the block- seven patients with coexisting infrequent age of serotonin reuptake in the CNS,7-'0 but migraine were improved less (0%) on citalo- this has recently been questioned. In an ani- pram than the 27 patients who had never had mal model, Ardid et al'0 found that both nora-

migraine (14%) in the present study. drenaline reuptake inhibitors and selective http://jnnp.bmj.com/ We used a fixed daily dose of 20 mg citalo- serotonin reuptake inhibitors had analgesic pram-that is, the lowest dose recommended effects, but that amitriptyline was more effec- for the treatment of depression. By compari- tive than both of these drugs. Watson and son, we used half of the lowest dose of Evans3" found amitriptyline more effective amitriptyline recommended for the treatment than the selective serotonin reuptake inhibitor of depression. We cannot exclude the possibil- zimeldine in postherpetic neuralgia, and ity that a better effect would have been Sindrup et al'8 reported that the tricyclic anti- obtained with a higher dose of citalopram, but depressant was more effective on September 29, 2021 by guest. Protected copyright. previous studies in other pain disorders con- than the selective serotonin reuptake inhibitor tradict this.'9 22 Despite the excellent side effect in diabetic neuropathy. These profile, citalopram (and probably also other results are in line with the present finding of a selective serotonin reuptake inhibitors) cannot clear effect of amitriptyline but only a trend be recommended in the treatment of chronic towards an effect of citalopram in tension-type tension-type headache. headache. Together the present and previous studies indicate that the selective serotonin METHODOLOGICAL CONSIDERATIONS reuptake inhibitors are less effective than the The selection of efficacy variables in clinical tricyclic antidepressants in pain management. trials on tension-type headache is difficult.24 Whereas citalopram is an extremely specific The International Headache Society serotonin reuptake inhibitor,'2 amitriptyline Committee on Clinical Trials24 suggests that also has effects on reuptake of noradrenaline33 frequency of headache should be used as the as well as effects on serotonergic,34 adrener- primary efficacy variable. However, this rates gic,'5 cholinergic,'4 and histaminergic recep- headache days lasting, for example, 30 min- tors. Of these effects, inhibition of utes and 16 hours the same.6 To the patients, noradrenaline reuptake33 and activation of var- the duration and the severity of their headache ious serotonin receptor subtypes37 may be are the most important features and AUC is especially important. The present study does therefore the clinically most relevant variable. not allow any firm conclusions on this issue, 290 Bendtsen, Jensen, Olesen J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.3.285 on 1 September 1996. Downloaded from but it indicates that mechanisms other than effective in the treatment of diabetic neuropathy symp- toms. Pain 1990;42:135-44. inhibition of serotonin reuptake are involved 19 Sindrup SH, Bjerre U, Dejgaard A, Brosen K, Aaes in the analgesic effect of the tricyclic antide- Jorgensen T, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of pressants. diabetic neuropathy. Clin Pharmacol Ther 1992;52: 547-52. We thank Mrs Hanne Andresen for skilful technical assistance 20 Saper JR, Silberstein SD, Lake AE, Winters ME. Double- and H for providing the medication. The study was blind trial of fluoxetine: chronic daily headache and supported by the Lundbeck Foundation (145/91) migraine. Headache 1994;34:497-502. 21 Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of , amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326:1250-6. 22 N0rregaard J, Volkmann H, Danneskiold-Samsoe B. A 1 Rasmussen BK, Jensen R, Olesen J. Impact of headache on randomized controlled trial of citalopram in the treat- sickness absence and utilisation of medical services: a ment of fibromyalgia. Pain 1995;61:445-9. Danish population study. J Epidemiol Community Health 23 Tfelt-Hansen P, Olesen J. Methodological aspects of 1992;46:443-6. drug trials in migraine. Neuroepidemiology 1985;4: 2 Couch JR, Micieli G. Prophylactic Pharmacotherapy. In: 204-26. 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