Ce12halalgia. Effectiveness of oral diclofenac in the acute treatment of common migraine attacks: a double-blind study versus placebo

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1 Effectiveness of oral diclofenac in the acute treatment of common migraine attacks: a double-blind study versus placebo Helene Massiou, Dominique Serrurier, Odile Lasserre, Marie-Germaine Bousser Ce12halalgia Massiou H, Serrurier D, Lasserre 0, Bousser M-G. Effectiveness of oral diclofenac in the acute treatment of common migraine attacks: a double-blind study versus placebo. Cephalalgia 1991;11: Oslo. ISSN In a multicentre double-blind cross-over trial, oral diclofenac at a dose of 50 mg to 100 mg was compared to placebo in the acute treatment of migraine attacks. A hundred and seven patients suffering from migraine without aura were included, and 91 were analysed for efficacy; they had to treat four successive attacks-two with diclofenac and two with placebo. Diclofenac was significantly more effective than placebo (p < 0.05) on the main judgement parameter, which was the number of attacks aborted within 2 h of drug intake, as well as on the following secondary parameters: the necessity for an escape medication and the evaluation of global efficacy. Diclofenac was well tolerated. This trial demonstrates the efficacy of diclofenac in the acute treatment of migraine attacks. It confirms the good clinical relevance of the main judgement parameter chosen, which is the one recommended by the International Headache Society, but appears to be a severe one in terms of successes. D Clinical trial, dicloienac, migraine, placebo Helene Massiou, Marie-Germaine Bousser, Department of Neurology, Hopital Saint-Antoine, F Paris Cedex 12, France; Dominique Serrurier, Odile Lasserre, LaboratoiresCiba-Geigy, Medical Department, BP 308, F Rueil-Malmaison Cedex, France; Correspondence to Dominique Serrurier; Accepted 11 January 1991 Since the 1970s, several non-steroidal anti-inflammatory drugs have been studied in clinical trials in order to evaluate their therapeutic efficacy in migraine attacks, and found more effective than placebo in this indication (1-13). There are, however, important discrepancies between the methodologies used in these trials, especially concerning the judgement criteria on efficacy, which make their results difficult to compare. In 1987, Del Bene et al. (12) demonstrated the efficacy of intramuscular diclofenac sodium in the treatment of migraine attack in a double-blind study versus placebo. We decided to study oral diclofenac in this indication in a controlled trial versus placebo. Special attention was focused on methodology by taking into account the proposed guidelines of the International Headache Society for controlled trials of drugs in migraine, which were in process at the time we began the trial. Patients and methods Patients The study was a multicentre double-blind, placebo controlled, cross-over trial. Patients suffering from migraine without aura for at least two years, with 2 to 8 attacks monthly, were recruited after having given their informed consent according to the Declaration of Helsinki. Excluded from the study were patients who: (1) had more than lout of 4 attacks on waking; (2) had other types of migraine or other headaches, including migraine with aura and tension type headaches; (3) had a history of peptic ulcer; (4) had an allergy to non-steroidal anti-inflammatory drugs. Prophylactic treatments of migraine (except for non-steroidal anti-inflammatory drugs and aspirin), oral contraceptives and minor tranquilizers were allowed, if taken for at least two months before the beginning of the study, and not modified during the trial. Study design A cross-over design was chosen with two attacks treated by the same drug in order to reduce intrapatient variability, as recommended by Tfelt-Hansen and Olesen (14). The study was conducted in seven centres in France. Each patient had to treat four successive attacks, two with diclofenac and two with placebo. Patients were allocated to receive either diclofenac or placebo for the first two attacks and the other treatment for the last two attacks using a computergenerated randomization list stratified by the investigator centre. Each tablet contained either 50 mg of entericcoated diclofenac or matching placebo, the package being labelled with a research code number. The first tablet had to be taken in the 30 min following the onset of headache; a second tablet could be taken 1 h later if relief was judged insufficient by the patient. Escape medication (excluding non-steroidal

2 60 H Massiou et al. anti-inflammatory drugs and aspirin) was allowed 2 h after the first tablet intake. Table 1. Disposition of patients. CEPHALALGIA 11 (1991) Group I Group II Total Evaluations Therapeutic efficacy was assessed from the patient record forms. For each attack the patient recorded: the date and time of onset of the migraine attack, the time of test and escape medication intake, the intensity of headache on visual analogue scales just before the first tablet intake, 1 h, 2 hand 3 h later, the presence of nausea or vomiting, the duration of the attack and their average subjective evaluation of drug efficacy. Patients were also required to describe side effects, whose intensity and relation to the test drug were evaluated by the investigator. Statistical analysis Statistical analysis was conducted using the method described by Hills and Armitage (15) for the two-period cross-over clinical trial. Because two attacks were treated successively with the same drug in each period, the average of the two attacks was used in the analysis for interval and ordinal variables such as intensity, duration and efficacy assessment. Tests of interaction, period and treatment effects were then performed by appropriate comparisons between the two groups of randomization using a two-sided Student's t-test (duration, intensity) or Wilcoxon rank sum test (assessments on ordinal scale). Binary variables such as success/failure or presence/absence of a sign or a symptom were coded 0/1 for each attack and the number of Is in each period was used in the analysis. Differences between periods range from - 2 to +2, and groups were compared using a two-sided Wilcoxon rank sum test. When one of the two attacks had not been treated in a given period, it was assumed to be a failure for analysis on binary variables. However, an analysis on patients who treated the four attacks was also performed for the main efficacy parameter. No period effect nor treatment by period interaction was ever found to be significant at the 5% level. Because of the limited power of the interaction test, it does not necessarily imply absence of carryover from one period to the other. Nevertheless, there is no reason to suspect pharmacological carryover in this study, since the interval between attacks was long enough to ensure elimination of the test drug. Results Patient population A hundred and seven patients were included in Randomized Lost to follow-up Available for analysis Treated only one or two attacks Personal report form missing Cross-over analysis Fourth attack not treated Four treated attacks Four successive attacks treated in the following order: Group I: Diclofenac - diclofenac - placebo - placebo. Group II: Placebo - placebo - diclofenac - diclofenac. the trial, but three were lost to follow-up, permitting analysis on 104. Eleven of them treated only one or two attacks, i.e. used only one drug, and an additional two did not fill out their personal report form, allowing cross-over analysis on 91 patients. Eight out of the 91 did not treat the fourth attack but could be kept in the cross-over analysis since they used both treatments for at least one attack. These data are summarized in Table 1. Altogether the 104 analysed patients treated 382 attacks (191 in each group), of which 373 were self-evaluated by the patient, 186 with diclofenac and 187 with placebo. The characteristics of the patients are described in Table 2. Patients in the two treatment groups were comparable with respect to sex, age, duration of migraine history, frequency of attacks, prophylactic drug treatment, proportion of attacks on waking, photophonophobia and all other features shown in Table 2. Efficacy In most cases and more often with placebo (87% of attacks) than with diclofenac (78% of attacks), the patient ingested the second tablet of test medication. The number of attacks aborted within 2 h of the first drug intake and before any escape medication was the main judgement parameter. The treatment was considered as a success if the measure on the visual analogue scale was less than 10 mm 2 h after the first drug intake, or if the attack duration was reported as less than 2 h by the patient, with no escape medication during these 2 h. Whenever an attack was resolved within 2 h, and relapsed within 24 h, it was considered as a treatment failure. Using these criteria, 51 attacks out of the 186 treated with diclofenac aborted in 2 h (27%) and 35 out of the 187 treated with placebo (19%). In the cross-over analysis, 27 patients out of 91 (30%) had more aborted attacks in 2 h with diclofenac than placebo, 13 out of 91 patients (14%) being in the opposite situation (Table 3 and Fig. 1), which shows significant treatment effect (p < 0.05). These results

3 CEPHALALGIA 11 (1991) Oral diclofenac in migraine attacks 61 Table 2. Patient characteristics at inclusion. Group I Group II Total (n = 53) (n = 51) (n = 104) Female/male 41/12 39/12 80/24 Age (years) t 37.5 ± ± ± 11.1 Duration of migraine (years)t 18.7 ± ± ± 11.8 Frequency of attacks/month Total t 4.9 ± ± ± 1.9 Attacks on wakening t 0.8 ± ± ± 0.9 Prophylactic drug treatment 19/53 (36%) 23/51 (45%) 42/104 (40%) Unilateral pain 46/53 (87%) 46/51 (90%) 92/104 (88%) Pulsatility 49/53 (92%) 45/51 (88%) 94/104 (90%) Nausea and/or vomiting 45/53 (85%) 46/50 (92%) 91/103 (88%) Photo and/or phonophobia 41/51 (80%) 42/48 (88%) 83/99 (84%) Familial history of migraine 42/52 (81%) 37/50 (74%) 79/102 (77%) t Mean ± SD Four successive attacks treated in the following order: Group I: Diclofenac - diclofenac - placebo - placebo. Group II: Placebo placebo - diclofenac - diclofenac. No significant difference between the two groups was found on any criterion. Table 3. Main judgement parameter: number of attacks aborted in 2 h. D I Number of Placebo aborted attacks in 2 h Total C L 0 F E N A C Total In this table, patients are classified according to the number of attacks aborted in 2 h with each drug. They have the same results in the diagonal, better results with diclofenac under the diagonal and better results with placebo above the diagonal. were confirmed by the complementary analysis on the 83 patients who treated four attacks with a treatment effect still significant at the 5% level. Results varied greatly between centres, particularly with placebo where the proportion of aborted attacks in 2 h ranged from 7% to 29%. With diclofenac, the success rate ranged from 25% to 39%, with the exception of one centre where no treated attack aborted in 2 h. The intensity of headache evaluated on visual analogue scales was reduced from 52.1 mm (SO 24.0) before treatment to 45.6 mm (27.6) after 2 h for diclofenac and from 53.0 mm (25.5) to 50.5 mm (27.6) for placebo. The difference of 5 mm in favour of diclofenac 2 h after the first drug intake did not reach statistical significance (p = 0.17). Escape medication was taken in 54% of the attacks treated with diclofenac and 66% of those treated with placebo. In the cross-over analysis, 32% of the patients took escape medication less often for diclofenac than for placebo and 11% were in the opposite situation (Fig. 1), which is significant in favour of diclofenac (p < 0.01). The protocol authorized any escape medication with the exclusion of non-steroidal anti-inflammatory drugs (including aspirin). Despite this, salicylates represented 26% of all escape medications, probably because it was the usual treatment. Although it has an impact on criteria such as duration of the attack, it does not interfere with the main parameter: number of attacks aborted in 2 h, i.e. before escape medication. The duration of the attack was on average shorter by 2 h after diclofenac than after placebo, but the difference was not statistically significant in the cross-over analysis (p = 0.08). No statistical difference was found between diclofenac and placebo for the presence of nausea or vomiting which occurred in 40% of the attacks and was shown equally for diclofenac and placebo (Fig. 1). The overall efficacy of the treatment was recorded for each attack by the patient and by the physician on a four points verbal scale (0 = nil, 1 = moderate, 2 = good, 3 = excellent). Diclofenac was scored 0.90 (SO 0.78) by the patient and 1.03 (0.88) by the physician, and placebo 0.62 (0.68) and 0.66 (0.76) respectively. Both evaluations were significantly in favour of diclofenac (p < 0.005) in the cross-over analysis. Safety Safety was evaluated by the physician for the 382 treated attacks. At least one side effect was reported during 26 attacks out of 191 treated with diclofenac (13.6%), and during 18 attacks out of 191 treated with placebo (9.4%) ct test, p = 0.20). Thirty-six symptoms were reported with diclofenac and 23 with placebo, gastrointestinal complaints representing almost half of the symptoms in each group.

4 62 H Massiou et al. CEPHALALGIA 11 (1991) "it of patients * * 32 D>P D=P P>D ABORTED ATTACKS IN 2 HOURS Fig. 1. Proportion of patients in the cross-over analysis according to their compared response between diclofenac (0) and placebo (P). 0> P: Better results under diclofenac than under placebo; 0 = P: Same results under diclofenac and placebo; P > 0: Better results under placebo than under diclofenac; * : p < 0.05 for treatment effect in the cross-over analysis. Three patients dropped out after one or two attacks treated with diclofenac because of nausea and vomiting (1 case), or diarrhoea and abdominal pain (2 cases). In most instances, however, it was difficult to distinguish between a gastrointestinal side effect induced by the drug and the usual accompanying symptoms of migraine. Discussion This study demonstrates that oral diclofenac, administered at an initial dose of 50 mg, with an additional 50 mg if needed, is a well tolerated and effective treatment of migraine attacks. The main parameter of efficacy: the number of attacks aborted within 2 h of drug intake, is now recommended by the International Headache Society, because it is clinically relevant, Simple and not affected by escape medication (16). The latter is of particular relevance since our study indicates that when an escape medication was used, little attention was paid to the specifications of the protocol. Tfelt-Hansen and Olesen (14) stressed that this parameter is a severe one, with low discriminative power. This is confirmed by the rather low percentage of successes observed on this criterion in our trial, the difference between diclofenac and placebo being, however, statistically significant. No previous controlled trial of non-steroidal anti-inflammatory drugs has used this parameter, so any comparison between these studies and ours is impossible. In this trial, diclofenac was significantly more effective than placebo as regards this main criterion and other parameters such as the need for escape medication and the global evaluation of medication. For two other parameters, the intensity of headache after 2 h and the attack duration, a trend towards better results with diclofenac was observed, but statistical significance was not reached. The duration of an attack is a complicated parameter, as it is influenced not only by the test drug but also by the use of escape medication. Headache intensity was recorded in this trial with visual analogue scales on a self-assessment card; investigators reported that some patients forgot to fill in these scales, or did not exactly understand their meaning; it is then possible that the lack of statistical significance is due to unreliable answers of some patients. If such visual scales are used in further studies, they will have to be accompanied by a more precise explanation written on the patient's case report form. Our results indicate that oral diclofenac is worth trying in the treatment of migraine attacks. However, the oral route is not always the best, because of nausea, vomiting and slow gastric emptying accompanying migraine attacks; it might therefore be interesting to test diclofenac suppositories in this indication.

5 CEPHALALGIA 11 (1991) Oral diclofenac in migraine attacks 63 Acknowledgements.-Participating investigators: M. G. Bousser (Hop. Saint-Antoine, Paris), B. Mihout (Rouen), A. Pradalier (Hop. Rothschild, Paris), C Loisy (Vichy), A. Rascol (Hop. Purpan, Toulouse), A. Guillard (Hop. Tenon, Paris), P. Henry (Hop. Pellegrin-Tripode, Bordeaux). References 1. Andersson PG, Hinge HH, Johansen 0, Andersen C, Lademann A, Gotzche PC Double-blind study of naproxen vs placebo in the treatment of acute migraine attack. Cephalalgia 1989;9: Awidi AS. Efficacy of flurbiprofen in the treatment of acute migraine attacks: a double-blind cross-over study. Curr Ther Res 1982;32: Carasso RL, Peled 0, Yehuda S. Flufenamic acid in menstrual migraine. Int J Neurosci 1985;27: Hakkarainen H, Vapaatalo H, Gothoni G, Parantainen J. Tolfenamic acid is as effective as ergotamine during migraine attacks. Lancet 1979;2: Johnson ES, Ratcliffe OM, Wilkinson M. Naproxen sodium in the treatment of migraine. Cephalalgia 1985;5: Kinnunen E, Erkinjuntti T, Farkkila M, Palomaki H, Porras I, Teirmaa H, Freudenthal Y, Andersson P. Placebo controlled double-blind trial of pirprofen and an ergotamine tartrate compound in migraine attacks. Cephalalgia 1988;8: Nestvold K, Kloster R, Partinen M, Sulkava R. Treatment of acute migraine attack: naproxen and placebo compared. Cephalalgia 1985;5: Sacks W. The use of isopyrine-phenylbutazone compound in migraine. SA Med J 1980;58: Sargent JD, Baumel B, Peters K, Diamond S, Saper JR, Eisner LS, Solbach P. Aborting a migraine attack: naproxen sodium v. ergotamine plus caffeine. Headache 1988;28: Tfelt-Hansen P, Olesen J. Effervescent metoclopramide and aspirin (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind study. Cephalalgia 1984; 4: Tokola RA, Kangasniemi P, Neuvonen PI, Tokola 0. Tolfenamic acid, metoclopramide, caffeine and their combinations in the treatment of migraine attacks. Cephalalgia 1984;4: Del Bene E, Poggioni M, Garagiola U, Maresca V. Intramuscular treatment of migraine attacks using diclofenac sodium: a cross-over clinical trial. J Int Med Res 1987;15: Pradalier A, Clapin A, Dry J. Non-steroid anti-inflammatory drugs in the treatment and long-term prevention of migraine attacks. Headache 1988;28: Tfelt-Hansen P, Olesen J. Methodological aspects of drug trials in migraine. Neuroepidemiology 1985;4: Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979;8: Bousser MG, Baron JC The clinician's view on end points. Neuroepidemiology 1987;6:228-33