Pain, 42 (1990) l-13

Elsevier PAIN 01623

Clinical Section

Pharmacological versus non-pharmacological prophylaxis of recurrent migraine headache: a meta-analytic review of clinical trials Kenneth A. Holroyd a and Donald B. Penzien b aDepartment

of Psychology and Institute of Health and Behavioral Sciences, Ohio Universi[y, Athens, OH 45701-2979 (U.S.A.), and b Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 392164505 (U.S.A.)

(Received 4 October 1989, accepted 16 February 1990)

In order to generate information about the relative effectiveness of the most widely used pharmacological and SununerY non-pharmacological interventions for the prophylaxis of recurrent migraine (i.e., propranolol HCl and combined relaxation/ thermal biofeedback tray), me~-~~y~s was used to integrate results from 25 clinical trials evaluating the effectiveness of propranolol and 35 clinical trials evaluating the effectiveness of relaxation/biofeedback training (2445 patients, coflectively). Meta-analysis revealed substantial, but very similar improvements have been obtained with propranolol and with relaxation/ biofeedback training. When daily recordings have been used to assess treatment outcome, both propranolol and relaxation/biofeedback have yielded a 43% reduction in migraine headache activity in the average patient. When improvements have been assessed using other outcome measures (e.g., physician/therapist ratings), improvements observed with each treatment have been about 20% greater. In both cases, improvements observed with propranolol and r~~ation/biof~back have been significantly larger than improvement observed with placebo medication (14% reduction) or in untreated patients (no reduction). Meta-analysis tlms revealed substantial empirical support for the effectiveness of both propranolol and relaxation/biofeedback training, but revealed no support for the contention that the two treatments differ in effectiveness. These results suggest that greater attention should be paid to determining the relative costs and benefits of widely used pharmacological and non-pharmacological treatments. Key words: Migraine; Propranolol; Relaxation training; Biofeedback training; Phrophylaxis; Meta-analysis

Introduction

In the last two decades, both pharmacological and non-pha~acolo~c~ ~te~entions for the prevention of recurrent migraine have come into

Correspondence to: Dr. K.A. Holroyd, Department of Psychology, Institute of Health and Behavioral Sciences, Ohio University, Athens, OH 45701-2979, U.S.A. 0304-3959/90/$03.50

widespread clinical use. The most widely used pharmacological treatment, and the ‘gold standard’ against which new pharmacological agents are evaluated, is propranolol. The initial observation that migraines abated with the administration of propranolol was made fortuitously during a study evaluating this medication for the management of angina 1191. Several double-blind clinical trials subsequently confirmed that propr~olol produces significantly larger reductions in mi-

0 1990 Elsevier Science Publishers B.V. (Biomedical Division)

2

graine headache activity than are observed either in untreated patients or with placebo [25,27]. C’urrently, propranolol is widely advocated as the treatment of choice for the prophylaxis of migraine [9,70,21]. For some time it was assumed that the effectiveness of propranolol in preventing migraine resulted from its beta-adrenergic blocking properties; however, this assumption has been challenged in recent years [14]. At present, the mechanism whereby propranolol prevents migraine episodes remains unclear [20,21]. The most widely used non-pharmacological treatment for recurrent migraine is probably the combination of relaxation and thermal biofeedback training. The initial observation that migraines abated following the acquisition of the handwarming response was made fortuitously during basic research investigating the learned control of peripheral vascular activity [22]. In both clinical application and in research, thermal biofeedback training is typically administered in conjunction with relaxation training. Research has verified that this combination of thermal biofeedback and relaxation training produces clinically and statistically significant reductions in migraine headache activity [3]. Additional evidence also suggests that this combination treatment may yield somewhat better outcomes than either treatment element administered alone [4,16]. Until recently, it was thought that improvements in migraine following thermal biofeedback training resulted from patients ‘learning to turn off excessive sympathetic outflow’ [22, p. 4191 because it was assumed that digital vasodilation during volitional handwarming resulted solely from decreased sympathetic (alpha-adrenergic) activity. However, this assumption recently has been challenged [8,11]. At present, the mechanism whereby this non-pharmacological treatment produces improvement in migraine remains unclear. Despite the fact that both relaxation/ biofeedback training and propranolol have been intensively investigated and are widely used in clinical settings, little is known about the relative effectiveness of these 2 treatment modalities. The 3 studies that have directly compared the effectiveness of these 2 treatments have reached conflicting conclusions [15,18,24]. When dropouts are taken

into account, the findings 01’ Sovak et al. 1341 tend to favor relaxation/ biofeedback training. In contrast, Mathew’s [lS] findings strongly favor propranolol, and Penzien et al.‘s [ 181 findings suggest that similar results are achieved with these 2 treatment modalities. In the absence of convergent evidence from clinical trials that directly compare the effectiveness of propranolol and relaxation/biofeedback training, indirect methods of comparing the results achieved with these 2 treatments may yield valuable information [12]. In particular, metaanalysis permits the quantitative comparison of improvements in migraine that have been reported with propranolol and with relaxation/ biofeedback training in the large. but separate literatures evaluating these treatments. The primary goals of the present review were: (a) to quantitatively compare results reported with propranolol and with relaxation/ biofeedback training in the treatment of migraine, and (b) to compare the improvements reported with these 2 active treatments to improvements reported with placebo medication and observed in untreated migraine sufferers. A secondary goal was to examine the relationship between the type of outcome measure that is used to assess treatment outcome and improvements in migraine reported with propranolol and with relaxation/biofeedback training. Evidence from studies evaluating nonpharmacological treatments suggests that daily recordings of headache yield more conservative estimates of improvement than do more global patient or therapist ratings [6.16,17]. It is yet to be determined whether results observed with pharmacological treatment are similarly influenced by the type of outcome measure that is used to assess treatment outcome.

Methods Selection of studies With minor modifications, we used both the criteria for including studies and the outcome measures used in earlier meta-analyses of the headache treatment literature [4,5,13]. For a study to be included in the meta-analysis, the following

3

minimal information was required: (a) identification of patients as adult migraine sufferers (some samples combined migraine and mixed headache sufferers), (b) a description of an appropriate treatment (propranolol or relaxation/ biofeedback training) or control (placebo or no treatment) condition, (c) at least 5 patients in the same treatment or control condition, and (d) a description of the dependent measure(s) that could be used to derive a headache improvement score (see below). Seventy-three studies reporting usable data for 60 treatment groups (hereafter referred to as trials) [7] and 37 control groups met the above criteria for inclusion in the meta-analysis. Studies were located through the following literature search methods: (a) Final computer searches of the Medline, Medlars II, and Psycinfo data bases were executed during June, 1989. (b) The most recent volumes of more than 20 journals that publish relevant articles also were searched during June, 1989. (c) The reference section of each article located via the above search was examined, along with the reference sections of numerous journal articles and book chapters on the topic of headache. (d) Published abstracts were used when necessary information was contained in the abstract or could be obtained by contacting the authors.

Improvement score The preferred measure of headache activity for

analysis was the headache index (a composite score which takes both intensity and duration into account). When no headache index score was reported, a composite headache index score was formed by taking an average of the available measures (e.g., frequency, duration, intensity) *. Per-

* To determine the relationship between our calculated index scores and authors’ reported index scores, we calculated a Pearson correlation coefficient between these two scores for a sample of 10 studies where both measures were available. The analysis yielded an r of 0.86 (P < 0.01) suggesting that the reported and calculated index scores were quite similar.

cent improvement in headache using the following formula:

was calculated

% improvement =

pretreatment-treatment headache index x loo, pretreatment headache index

The treatment headache index was assessed following the completion of relaxation/biofeedback training or following the final propranolol dose adjustment (if the latter was indicated). Improvement scores for placebo and no treatment conditions were calculated in a parallel manner. When available, data from patients’ daily headache recordings were used to calculate improvement scores. When daily headache recording data were not available, a more global estimate of improvement was used (i.e., physician/ therapist ratings of headache activity, or percentage of patients deemed significantly improved at posttreatment). However, the type of outcome measure used (percent improvement score derived from daily headache recording vs. more global measure of headache improvement) was coded so we could determine whether reported results have varied as a function of type of outcome measure. Treatment and control conditions Propranolol. To be included in the propranolol

condition, a study must have evaluated the use of propranolol specifically for the treatment of migraine headache. The study report must have permitted the calculation of the improvement observed with propranolol relative to a baseline when neither prophylactic medication nor placebo were administered. Thus, studies that permitted only the calculation of the improvement in headache activity relative to a placebo baseline were not included. Relaxation /biofeedback training. To be included in this condition, patients must have been treated with a combination of thermal biofeedback (feedback of the skin temperature of the hand) and relaxation training. Relaxation training referred to the use of any of several relaxation training procedures including progressive muscle relaxation training [2], training in elicitation of the relaxation response [l], or autogenic training [23].

4

Thermal biofeedback training and relaxation could be administered either concurrently or in succession. PIuceho. To be included in the placebo condition, patients must have been administered placebo on the same schedule as the active prophylactic medication being evaluated, but they must not have been informed whether they were taking placebo or active prophylactic medication. The study report must have permitted the calculation of the improvement observed with placebo relative to a baseline when no prophylactic medication was administered. In order to obtain an adequate number of placebo improvement scores for analysis, placebo improvement scores were obtained not only from studies evaluating propranolol, but also from studies evaluating other prophylactic migraine medications (e.g., calcium channel blockers). No attempt was made, however, to locate all existing studies evaluating all prophylactic medications that may have included a placebo condition. No treatment control. To be included in this condition, patients must have been administered neither placebo nor active treatment for their headaches, but they must have been evaluated in the same manner as patients receiving active treatment (e.g., by completing daily recordings of headache activity). Other study variables Characteristics of the patient sample, propranolol or relaxation/ biofeedback treatments, and study research designs also were coded. This information was obtained primarily to allow us to characterize the propranolol and relaxation/ biofeedback treatment literatures. Our ability to examine relations~ps between study characteristics and reported study results was limited by the number of propranolol and relaxation/ biofeedback studies available for analysis and by the fact that information of interest was not reported in all available studies. The following variables could be coded in at least 50% of propranolol or relaxation/ biofeed-

back studies in the meta-analysis *: (a) Number of patients: number of patients completing each treatment or control procedure. (b) Gender: percentage of males in the patient sample. (c) Age: the mean age was obtained for each treatment group; when data were not available for a treatment group, the mean age for the study sample was substituted. id) Type of outcome measure: percentage reduction in headache activity calculated from patient daily headache recordings was distinguished from other outcome measures. (e) Dropout rate: percentage of patients who failed to complete treatment. (f) ~jgra~ne diagnosis: percentage of patients with a diagnosis of classic migraine * *. In addition, variables of specific relevance to either propranolol or relaxation/biofeedback treatment were coded. For propranolol, the following variables could be coded: (a) Propra~oloi dose: the final propranolol dose (mg/day); in studies where dose varied across patients, the mean dose was encoded. (b) Dropout rate due to drug side effects: percentage of patients reported as failing to complete treatment because of propranolol side effects. (c) Blind to drug condition: whether double-, single- or unblind conditions were maintained concerning the medications administered. For relaxation/ biofeedback studies, the following variables could be coded: (a) Number of relaxation ,/ biofeedback sessions. (b) Transfer training: whether procedures were used to facilitate transfer of relaxation/hand warming skills from the treatment setting to the every-day environment was incorporated into treatment.

* Other information of potential interest (e.g., chronicrty of headache disorder) was not reported in a sufficient number of studies to provide reliable information. ** Classic migraine was ~stin~ished from common migraine in at least 50% of propranoloi studies but less than 50% of relaxation/biofeedback studies.

5

TABLE

I

CHARACTERISTICS

OF TREATMENT

GROUPS

Mean

SD.

Range

Gender (5%male) Propranolol Relaxation/biofeedback

22.8 15.6

14.0 13.8

oo-

50 40

21 26

Mean age (years) Propranolol Relaxation/biofeedback

37.1 37.7

3.8 5.0

2727-

42 49

17 21

Number of clients b Propranolol Relaxation/biofeedback

28.6 20.5

16.7 15.5

8-787 5-154

22 34

Dropout ( W) Propranolol Relaxation/biofeedback

18.0 14.3

12.6 9.9

0o-

21 22

Characteristic

of group

No. of clinical trials a

36 35

a Number of groups for which data were available out of 25 propranolol groups and 35 behavioral groups. b Four outliers (n = 154-787) were excluded from calculation of the mean and standard deviation.

Results Characteristics of studies Patient samples. Patient sample characteristics that could be coded for at least 50% of available propranolol and at least 50% of available relaxation/ biofeedback treatment groups are presented in Table I. It can be seen that patient samples have been predominantly female with a mean age in the late thirties, and dropout rates reported with both treatments have been less than 20%. Propranolol trials and relaxation/ biofeedback training trials did not differ significantly on any of the variables in Table 1. Overall, patient samples used in these two literatures appeared quite similar, at least as could be determined from the information that has been reported in published studies. Research designs. The modal clinical trial of propranolol was designed to compare the effectiveness of propranolol and an alternate pharmacological treatment or treatments (56% of studies). Approximately one-half of the propranolol studies employed crossover designs (52%). Clinical trials

of propranolol were, for the most part, doubleblind (65% double-blind, 9% single-blind). The modal clinical trial of relaxation/biofeedback training was designed to compare the effectiveness of relaxation/ biofeedback and alternate non-pharmacological treatment or treatments (48% of studies); most studies (63% of studies) employed between-group comparison designs. Neither the patient nor the therapist were blind with respect to the content of the behavioral treatment that was administered in these studies. Daily headache recordings (as opposed to physician/ therapist judgments or more global, retrospective patient reports) were used to evaluate treatment outcome in about one-half of the studies evaluating propranolol (48%) and in about two-thirds of the studies evaluating relaxation/ biofeedback training (63%). Treatment procedures. In trials of propranolol, the daily propranolol dose ranged from 80 to 300 mg, with a modal dose of 160 mg (33% of studies) and a mean dose of 153.0 mg. In the average treatment group, 5.4% of patients (or about onethird of total dropouts) were specifically identified as dropping out because of drug side effects. Medically adverse side effects (e.g., severe orthostatic hypertension) were reported infrequently, however, being reported in only 17% of studies and in only 2.3% of the total sample of treated patients. Relaxation/ biofeedback training was administered in 2-24 treatment sessions. Ten training sessions were administered in the average clinical trial, with 57% of studies administering between 8 and 12 treatment sessions. Some effort was made to encourage transfer of skills learned during training to everyday situations in virtually all studies (94%). Information about therapists was provided in only a few studies (31%), but in this minority of studies, most therapists (82%) were doctoral candidates or had earned a doctorate in psychology. Treatment outcome The distribution of the 97 improvement scores was symmetrical and unimodal. A KolmogorovSmirnov one sample goodness of fit test yielded a z score of 0.64; P > 0.81, indicating that the dis-

6 TABLE

II

AVERAGE MIGRAINE CONTROL

PERCENTAGE HEADACHE FOR GROUPS

IMPROVEMENT ALL TREATMENT

IN AND

Note: Relaxation/biofeedback refers to the combination of relaxation training and thermal biofeedback training, Propran. refers to propanolol, Placebo refers to placebo control condition, and Untreated refers to headache monitoring control condition. Treatment

conditions

Relaxation/ biofeedback

Propran.

Average group % improvement a

55.1

55.1

Average subject % improvement b.c Range of scores (W) S.D. No. of groups

56.4 55.2 11 to 93 26 to 84 20.3 17.0 35 25

Placebo

12.2

Untreated

1.1

14.3 3.2 -23 to 32 -30 to 33 15.2 17.7 20 17

a Average percent improvement in headache activity across trials. b Average percent improvement in headache activity per patient (i.e., weighted by sample size). ’ One outlier (n = 787) was excluded from calculation of the average subject improvement scores.

tribution in improvement scores did not differ significantly from the normal distribution. Bartlett-Box F test also indicated that the variances associated with the 5 treatment conditions were homogeneous, F = 0.72; P > 0.54. Table II presents mean reductions in headache activity reported with relaxation/ biofeedback training, with propranolol, and with placebo, as well as the mean improvement observed in untreated patients. Both the mean improvement exhibited in the average trial and sample size adjusted improvement scores are presented. The sample size adjusted means provide the more clinically interpretable of the two measures because they provide information about the response of the average patient to treatment. It can be seen in Table II that both relaxation/ biofeedback training and propranolol have yielded greater than a 50% reduction in headache activity in the average patient. In contrast, untreated patients have shown virtually no improvement in

and patients administered headache activity, placebo have shown only small reductions in headache activity (about 14%) *. Improvements reported with propranolol and with relaxation/ biofeedback thus have been about 4 times larger than improvements that have been reported with placebo. One-way ANOVA confirmed that there were significant differences in the mean improvement scores associated with the treatment and control conditions, F (3, 93) = 54.9, P < 0.001. Post-hoc tests (Tukey’s HSD) further revealed that relaxation/ biofeedback training and propranolol each yielded significantly greater reductions in headache activity than has been reported either with placebo or in untreated patients (at least P < 0.05) but the 2 active treatments did not differ from one another in effectiveness. Improvements reported with placebo did not differ significantly from improvements observed in untreated patients. Influence of outcome measures. Results reported in studies that used daily headache recording differed noticeably from results reported in studies using other outcome measures (e.g., physician ratings of improvement, patient global reports of improvement). Improvements in headache activity were about 20% smaller with both propranolol (44.1% vs. 65.2%) and relaxation/biofeedback (47.3% vs. 68.2%) when improvement was assessed with daily headache recordings than when assessed with other measures. A 2 (type of outcome measure) X 2 (treatment condition) ANOVA confirmed this observation, revealing a significant main effect for type of outcome measure, F (1, 56) = 24.2, P < 0.001; the interaction term was not significant. Because daily recordings probably provide a more accurate (and certainly a more conservative) measure of improvement than more global ratings

* Clinical trials that reported improvements with propranolol relative to a placebo baseline were not included in this meta-analysis because results reported in this form are not directly comparable to results reported in studies evaluating relaxation/biofeedback training. However, results from those studies (n = 28) are consistent with results presented in Table II. Thus. propranolol yielded a 35.3% reduction in headache activity beyond that observed with placebo.

7

TABLE

III

AVERAGE PERCENTAGE IMPROVEMENT IN MIGRAINE HEADACHE FOR TREATMENT AND CONTROL GROUPS USING DAILY HEADACHE RECORDS AS OUTCOME MEASURES Note: Rel~ation/biof~back refers to the combination of relaxation training and thermal biofeedback training, Propran. refers to propranolol, Placebo refers to placebo control condition, and Untreated refers to headache monitoring control condition. Treatment

conditions

Relaxation/ biofeedback

Propran.

Average group % improvement ’

41.3

44.1

Average subject % improvement ’

43.3

43.7

Range of scores (W) 11 to 87 26 to 65 S.D. 19.6 13.6 No. of groups 22 12 * Average percent improvement trials. ’ Average percent improvement tient (i.e., weighted by sample

TABLE

Untreated

11.9

0.2

14.3

2.1

- 23 to 32 - 30 to 33 17.2 17.9 15 15

in headache in headache size).

activity activity

across per pa-

IV

CORRELATES Characteristic

OF IMPROVEMENT of group

Type of outcome data b Year of report Number of clients ’ Dropout rate (Se) Gender (W male) Mean age (years) Blind to drug condition d Dropout due to side effects (I%) Migraine diagnosis ’ (S classic) Propranolol dose (mg/day) a b ’ d ’

Placebo

of improvement or reports of headache activity, the best estimates of treatment effects can be obtained from studies that employed daily recording measures to assess treatment outcome. Therefore, the analyses presented above comparing improvement scores across the 4 treatment and control conditions were repeated using only data from studies that used daily headache recordings to assess treatment outcome. Table III presents mean reductions in headache activity for the various treatment and control conditions from studies that used daily headache recordings to assess treatment outcome. It can be seen that the estimates of treatment efficacy presented in Table III are more conservative than those presented in Table II. One-way ANOVA conducted on improvement scores from studies that used daily recordings to assess treatment outcome still confirmed that there were significant differences in the mean improvement scores associated with the treatment and control conditions, F (3, 64) = 29.4, P -C 0.001. Tukey’s HSD tests again indicated that relaxation/ biofeedback training and propranolol each

IN MIGRAINE Propranolol

HEADACHE

AT END OF TREATMENT

studies

Behavioral

studies

r

No. of trials a

Signif.

r

No. of trials a

Signif.

0.63 - 0.10 -0.10 - 0.20 0.31 - 0.09 -0.39 -0.13 - 0.09 0.33

25 25 25 21 21 17 23 18 17 18

P c 0.001 ns “S ns ns ns PiO.06

0.50 - 0.40 0.14 0.17 -0.11 0.18

35 35 34 22 26 21

P i 0.002 P < 0.02 ns ns ns ns

tlS

ns ns

Number of clinical trials for which data were available out of 25 propranolol trials and 35 behavioral Daily headache measures assigned lower code. Four outliers (n = 154-787) were excluded from analysis of the sample size data. Double-blind design assigned higher code. This variable could not be coded in a sufficient number of behavioral studies to permit analysis.

trials.

8 produced significantly larger reductions in headache activity than have been reported with placebo or in untreated patients (at least P -cO.OS), but that relaxation/biofeedback and propranolol did not differ from one another in effectiveness. Reductions in headache activity observed with placebo also did not differ significantly from those observed in untreated patients. When only data from daily headache recordings are used to assess treatment outcome, conclusions about the relative effectiveness of relaxation/ biofeedback training and propranolol thus remain unchanged. However, estimates of the effectiveness of the two treatments are somewhat reduced. Other variables and treatment effects Correlations between selected study variables and improvements reported with propranolol and with relaxation/biofeedback are reported in Table IV. Correlations were calculated only for variables that could be coded for approximately twothirds or more of either propranolol or relaxation/ biofeedback studies. Nevertheless, these correlations must be interpreted cautiously because they are based on a small number of observations. Consistent with results reported above, improvements reported with both propranolol and relaxation/biofeedback training were significantly correlated with the type of outcome measure used. In both literatures, type of outcome measure accounted for at least 25% of the variance in reported improvement scores across studies. No other variables were significantly correlated with propranolol improvement scores, although there was a trend for studies that used double-blind procedures to report somewhat smaller improvements with propranolol than studies that did not use double-blind procedures. In the relaxation/ biofeedback literature, the only variable (other than type of outcome measure) that was correlated with reported improvement was the year study results were published or presented. Earlier studies reported somewhat greater improvement with relaxation/ biofeedback training than more recent studies. Backward multiple regression analysis revealed that when both type of outcome measure and year of study were considered conjointly as predictor variables, only

type of outcome measure remained in the regression equation, B = 20.8, t = 3.34, P < 0.01. Thus, in both treatment literatures, type of outcome measure appeared to be the primary study characteristic that was predictive of study outcome. However, a relatively small number of studies provided information on all variables, so the possibility that other study characteristics among those assessed here or among those that could not be encoded from available studies also are predictive of study outcome cannot be ruled out. Discussion In the last 2 decades, the effectiveness of either propranolol or the combination of relaxation and thermal biofeedback training for the prophylaxis of recurrent migraine has been evaluated in more than 100 studies. Despite this large body of research, relatively little information is available concerning the comparative effectiveness of these 2 widely used treatments because both treatments rarely have been evaluated in the same study. In order to obtain information about the relative effectiveness of these 2 treatments, meta-analysis was used to integrate results from studies evaluating either treatment. Results from 25 studies evaluating the effectiveness of propranolol and results from 35 studies evaluating the effectiveness of relaxation/biofeedback training (2445 patients, collectively) were analyzed to compare the relative effectiveness of these 2 treatment modalities. Meta-analysis revealed that very similar improvements in migraine have been observed with propranolol and with relaxation/ biofeedback training. In studies using patient daily recordings of headache activity, approximately a 45% reduction in migraine headache activity has been observed in the average patient treated with propranolol or with relaxation/ biofeedback training. In studies using less conservative outcome measures, reductions in migraine headache activity observed with both treatments have been about 20% larger. The clinically significant improvements in migraine that have been observed with both propranolol and with relaxation/ biofeedback training have contrasted sharply with results that have been observed in migraine sufferers adminis-

9

tered placebo or in untreated migraine sufferers. Only small and statistically non-significant improvements in migraine headache activity have been observed with placebo, and virtually no improvement has been observed in untreated patients who simply recorded their headache activity. Thus, meta-analysis revealed substantial empirical support for the effectiveness of both propranolol and relaxation/biofeedback training but revealed no empirical support for the contention that these 2 treatments differ in effectiveness. Two of the 3 studies that have directly compared the effectiveness of propranolol and relaxation/biofeedback training have yielded results that are consistent with and quite similar to the results of the present meta-analysis (Table III). Both Penzien et al. [18] and Sovak et al. [24] found propranolol and relaxation/biofeedback training to be similarly effective for the prophylaxis of recurrent migraine (although Sovak et al. found a significantly higher dropout rate with propranolol than with relaxation/ biofeedback training). Penzien et al. found a 42% reduction in migraine headache activity with propranolol and a 39% reduction with relaxation/ biofeedback training; Sovak et al. did not report mean reductions in headache activity but reported that 45% of migraine sufferers treated with propranolol and 54% of migraine sufferers treated with relaxation/ biofeedback training showed at least a 50% reduction in headache activity. The present meta-analysis and the studies of Penzien et al. and Sovak et al. thus yield quite similar estimates of effectiveness of these 2 treatments and lead to similar conclusions concerning their relative effectiveness. Results from the Penzien et al. and Sovak et al. studies and from the present meta-analysis contrast sharply with results reported by Mathew [15], who found substantially larger reductions in migraine headache activity with propranolol than with relaxation/biofeedback training. Relative to results reported in studies included in this metaanalysis (Table III), Mathew reported substantially better results with propranolol (62% vs. 44% improvement) and slightly poorer results with relaxation/biofeedback training (35% vs. 43%). In fact, 75% of the trials in this meta-analysis (18 of 24) using similar outcome measures have reported

smaller improvements with propranolol and 88% of the trials (30 of 34) have reported larger improvements with relaxation/ biofeedback training than were reported by Mathew. This suggests that Mathew’s results may overestimate the improvement typically observed with propranolol while underestimating the improvement typically observed with relaxation/ biofeedback training. If propranolol and relaxation/ biofeedback training are, in fact, equally effective for the prophylaxis of recurrent migraine, this very equivalence of outcomes suggests other questions that deserve attention. Among these are the following: (a) Do propranolol and relaxation/ biofeedback training yield similar long-term as well as short-term results? (b) Can the combination of propranolol and relaxation/ biofeedback training yield better results than either treatment separately? (c) Are certain subgroups of patients more likely to respond to either propranolol or relaxation/ biofeedback training? (d) Do propranolol and relaxation/ biofeedback training yield similar improvements in quality of life (e.g., reductions in migraine-related disability, iatrogenic effects of treatment) as well as similar reductions in migraine headache activity? Clinical trials that directly compare the effectiveness of these 2 treatment modalities (and possibly their combination) will be necessary to provide answers to the above questions. To date, such studies only rarely have been conducted, probably because different groups of investigators with different professional affiliations have tended to evaluate pharmacological and non-pharmacological treatments. Answers to the above questions may depend on the ability and inclination of researchers who have focused exclusively on either the evaluation of pharmacological or nonpharmacological treatments to join efforts for collaborative studies that compare benefits and costs of these 2 treatment modalities. Meta-analysis also revealed that outcomes observed with propranolol and with relaxation/ biofeedback training have varied with the type of measure that was used to assess treatment outcome. Reported improvements have been significantly smaller when reductions in migraine were

calculated from patient daily headache recordings than when more global measures (e.g.. patient reports or physician/ therapist ratings) have been used to assess treatment outcome. This relationship has been observed previously in studies evaluating non-pharmacological treatments, both when treatment outcomes in a single sample of patients have been assessed simultaneously by means of both global patient reports and by daily recordings [6,17], and when treatment outcomes reported in studies using different outcome measures are compared via meta-analysis [16]. Results from the present meta-analysis add to these findings by confirming that a similar relationship holds in clinical trials of pharmacological treatments. This finding highlights the value of daily headache recordings in clinical trials respective of whether pharmacological or non-pharmacological treatments are being evaluated. In fact, where the use of daily headache recordings is not feasible, study results probably should be qualified by acknowledgment that other, more global outcome measures probably overestimate the magnitude of treatment effects relative to daily recordings. In summary, a synthesis of results from studies that have evaluated either propranolol or relaxation/ biofeedback training for the prophylaxis of recurrent migraine revealed that both treatments have produced substantial reductions in headache activity which differed significantly from those observed in untreated migraine sufferers or migraine sufferers administered placebo. Metaanalysis thus revealed substantial support for the effectiveness of both propranolol and relaxation/ biofeedback training, but revealed no evidence that would indicate these 2 treatments differ in effectiveness. These results suggest that greater attention needs to be paid to determining the relative costs and benefits of the primary pharmacological and non-pharmacological treatments, both when these treatments are administered individually and when administered in combination.

then. and Michael Wagner for their assistance in reviewing studies included in this review. This work was supported (in part) by Grant No. 1 MO1 RR02303 from the General Clinical Research Centers Program. Division of Research Resources, National Institutes of Health.

References

9

10 1I

12

13

14

Acknowledgements

15

The authors would like to thank Dr. Jeffrey E. Holm, Dr. Karl G. Hursey, Dr. Hans-Ulrich Witt-

I6

Benson, H.. The Relaxation Response, William Morrow and Co.. New York, 1975. Bernstein. D.A. and Borkovec. T.D., Progressive Relaxation Training: a Manual for the Helping Professions, Research Press, Champaign, IL, 1973. Blanchard, E.B. and Andrasik, F.. Biofeedback treatment of vascular headache. In: J.P. Hatch and J.D. Rugh (Eds.). Biofeedback: Studies in Clinical Efficacy. Plenum Press, New York, 1987, pp. l-79. Blanchard, E.B. and Andrasik, F.. Psychological assessment and treatment of headache: recent developments and emerging issues, J. Consult. Clin Psychol.. 50 (1982) 859 897. Blanchard, E.B., Andrasik, F.. Ahles, T.A., Tedera, S.J. and O’Keefe, D., Migraine and tension headache: a meta-analytic review, Behav. Ther., 11 (1980) 6133631. Blanchard, E.B.. Andrasik, F.. Neff, D.F., Jurish, S.E. and O’Keefe, D.. Social validation of the headache diary, Behav. Ther., 12 (1981) 711-715. Christensen, H., Hadzi-Pavlovic. D., Andrews, G. and Mattick. R., Behavior therapy and tricyclic medication in the treatment of obsessive-compulsive disorder: a quantitative review, J. Consult, Clin. Psychol., 55 (1987) 701.-711. Cohen. R. and Coffman. J.. Beta-adrenergic vasodilator mechanism in the finger, Circ. Res., 49 (1981) 1233146. Diamond, S. and Dalessio, D.J., The Practicing Physician‘\ Approach to Headache, 4th edn., Williams and Wilkins. Baltimore, MD, 1986. Doogan. D.P.. Prophylaxis of migraine with beta-blockers. Practitioner, 227 (1983) 44-444 Freedman. R.R., Sabharwal. S.C. and Ianni, P.. Nonneural beta-adrenergic vasodilating mechanism in temperature biofeedback, Psychosom. Med., 50 (1988) 394-401. Gerzberg, Z.B. and Horwitz, R.I., Resolving conflicting clinical trials: guidelines for meta-analysis. J. Clin. Epidemiol., 41 (1988) 503-509. Holroyd, K.A. and Penzien, D.B.. Client variables and the behavioral treatment of recurrent tension headache: .I meta-analytic review, J. Behav. Med., 9 (1986) 515-536. Koch-Weser, J., Non-beta-blocking properties of propranolol, New Engl. J. Med., 293 (1975) 988-989. Mathew, N.T., Prophylaxis of migraine and mixed headache: a randomized controlled study, Headache, 21 (1981) 105-109. Penzien. D.B.. Holroyd, K.A.. Hursey, K.G.. Holm. J.E.

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and Wittchen, H.U., Behavioral treatment of recurrent migraine: a meta-analysis of over five-dozen group outcome studies. Paper presented at the meeting of the Association for Advancement of Behavior Therapy, Houston, TX, 1985. Penzien, D.B., Holm, J.E., Holroyd, K.A., Hursey, K.G. and Harkabus, L., Interrelationships among daily and global self-report measures of headache. Paper presented at the meeting of the Association for Advancement of Behavior Therapy, Chicago, IL, 1986. Penzien, D.B., Johnson, C.A, Carpenter, D.E., Prather, R.C., Beckham, J.C., Porzelius, J., Campos, P.E., Perkins, T.S., Krug, L., Pbert, L., Payne, T.J. and Holroyd, K., Home-based behavioral treatment vs. propranolol for recurrent migraine: preliminary findings. Paper presented at the meeting of the Society of Behavioral Medicine, San Francisco, CA, 1989. Rabkin, R., Stables, D.P., Levin, N.W. and Suzman, M.M., The prophylactic value of propranolol in angina pectoris, Am. J. Cardiol., 18 (1986) 370-380. Raskin, N.H., Headache, Churchill Livingstone, New York, 1988. Saper, J.R. (Ed.), Headache Disorders: Current Concepts and Treatment Strategies, John Wright/PSG, Littleton, MA, 1983. Sargent, J.D., Walters, E.D. and Green, E.E., Psychosomatic self-regulation of migraine headaches, Sem. Psychiat., 5 (1973) 415-428. Schultz, J. and Luthe, W., Autogenic Training: a Psychophysiologic Approach in Psychotherapy, Vol. 1, Grune and Stratton, New York, 1969. Sovak, M., Kunzel, M., Stembach, R. and Dalessio, D.J., Mechanism of the biofeedback therapy of migraine: volitional manipulation of the psychophysiological background, Headache, 21 (1981) 89-92. Standnes, B., The prophylactic effect of timolol versus propranolol and placebo in common migraine: beta-blockers in migraine, Cephalalgia, 2 (1982) 165-170. Stensrud, P. and Sjaastad, O., Short-term clinical trial of propranolol in racemic form (Inderal), o-propranolol and placebo in migraine, Acta Neurol. Stand., 53 (1986) 229232.

27 Tfelt-Hansen, P., Standnes, B., Kangasneimi, P., Hakkarainen, H. and Olesen, J., Timolol and propranolol for common migraine prophylaxis, Acta Neurol. Stand., 69 (1984) l-8.

Appendix A References

of studies included in the meta-analysis

1 Albers, G.W., Simon, L.T., Hamik, A. and Peroutka, S.J., Nifedipine versus propranolol for the initial prophylaxis of migraine, Headache, 29 (1989) 214-217. 2 Andersson, P.G. and Petersen, E.N., Propranolol and

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femoxetine, a 5 HT-uptake inhibitor, in migraine prophylaxis, Acta Neurol. Stand., 64 (1989) 280-288. Andreychuk, T. and Skriver, C., Hypnosis and biofeedback in the treatment of migraine headache, Int. J. Clin. Exp. Hypn., 23 (1975) 172-183. Baldrati, A., Cortelli, P., Prccaccianti, G., Gamberini, G., D’Alessandro, R., Baruzzi, A. and Sacquegna, T., Propranolol and acetylsalicylic acid in migraine prophylaxis, Acta Neurol. Stand., 67 (1983) 181-186. Barrios, F.X., Social skills training and psychosomatic disorders. In: D.P. Rathjen and J.P. Foreyt (Eds.), Social Competence: Interventions for Children and Adults, Pergamon Press, New York, 1980, pp. 271-301. Behan, P.O. and Reid, M., Propranolol in the treatment of migraine, Practitioner, 224 (1980) 201-204. Bild, R. and Adams, H.E., Modification of migraine headaches by cephalic blood volume pulse and EMG biofeedback, J. Consult. Clin. Psychol., 48 (1980) 51-57. Billings, R.F., Thomas, M.R., Rapp, MS., Reyes, E. and Leith, M., Differential efficacy of biofeedback in headache, Headache, 24 (1984) 211-215. Blanchard, E.B., Andrasik, F., Appelbaum, K.A., Evans, D.D., Jurish, S.E., Teders, S.J., Rodichok, L.D. and Barron, K.D., The efficacy and cost-effectiveness of minimal-therapist-contact, non-drug treatments of chronic migraine and tension headache, Headache, 25 (1985) 214-220. Blanchard, E.B., Appelbaum, K.A., Radnitz, C.L., Morrill, B., Michultka, D., Kirsch, C., Guarnieri, P., Hillhouse, J., Evans, D.D., Jaccard, J. and Barron, K.D., A controlled evaluation of thermal biofeedback and thermal biofeedback with cognitive therapy in the treatment of vascular headache, J. Consult. Clin. Psychol., 58 (1990) 216-224. Blanchard, E.B., Theobald, D.E., Williamson, D.A., Silver, B.V. and Brown, D.A., Temperature biofeedback in the treatment of migraine headache, Arch. Gen. Psychiat., 35 (1978) 581-588.

12 Borgesen, SE., Nielsen, J.L. and Moller, C.E., Prophylactic treatment of migraine with propranolol, Acta Neurol. Stand., 50 (1974) 651-656. 13 Camey, P. and Fitzsimmons, G., Psychophysiological stress, biofeedback, and migraine therapy, Biofeedback SelfRegul., 7 (1982) 591 (abstr.). 14 Cortelli, P., Sacquegna, T., Albani, F., Baldrati, A., D’Alessandro, R., Baruzzi, A. and Lugaresi, E., Propranolol plasma levels and relief of migraine: relationship between plasma propranolol and 4-hydroxypropranolol concentrations and clinical effects, Arch. Neurol., 42 (1985) 46-48. 15 Daly, E.J., Donn, P.A., Galliher, M.J. and Zimmerman, J.S., Biofeedback applications to migraine and tension headaches: A double-blinded outcome study, Biofeedback Self-Regul., 8 (1983) 135-152. 16 Fahrion, S.L., Autogenic biofeedback treatment for migraine, Mayo Clin. Proc., 52 (1977) 776-784. 17 Ford, M.R., Stroebel, CF., Strong, P. and Szarek, B.L., Quieting response training: long-term evaluation of a clinical biofeedback practice, Biofeedback Self-Regul., 8 (1983) 265-278.

12 18 Forssman, B., Henriksson, K., Johannsson, V., Lindvall, L. and Lundin, H., Propranolol for migraine prophylaxis. Headache, 16 (1976) 238-245. 19 Frenken, C. and Nuijten, S., Fhmarizine. a new preventive approach to migraine: a double-blind comparison with placebo, Clin. Neurol. Neurosurg., 86 (1984) 17-20. 20 Gallagher, M.R. and Warner, J.G.. Patient motivation in the treatment of migraine: a non-medicinal study. Headache, 24 (1984) 269-271. 21 Gauthier, J., Doyon, J., Lacroix, R. and Drolet, M., Blood volume pulse biofeedback in the treatment of migraine headache: a controlled evaluation, Biofeedback Self-Regul.. 8 (1983) 427-442. 22 Gauthier, J., Lacroix, R.. Cote, A.. Doyon. J. and Drolet. M., Biofeedback control of migraine headaches: a comparison of two approaches, Biofeedback Self-Regul.. 10 (1985) 139-759. 23 Gelmers, H.J., Nimodipine, a new calcium antagonist, in the prophylactic treatment of migraine, Headache. 23 (1983) 106-109. 24 Heaton, G., Biofeedback in headache management: an evaluation of 56 patients. J. Indiana State Med. Ass., 72 (1979) 198-199. 25 Holdorff, B., Sinn, M. and Roth, G., Propranolol in der migrane Prophylaxe (Propranolol in the prophylaxis of migraine), Med. Klin., 72 (1977) 1115-1118. 26 Holroyd, K.A., Holm, J.E., Hursey, K.G., Penzien, D.B.. Cordingley, G.E., Theofanous, A.G., Richardson, SC. and Tobin, D.L., Recurrent vascular headache: home-based behavioral treatment vs. abortive pharmacological treatment. J. Consult. Clin. Psychol., 56 (1988) 218-223. 21 Johnson. R.H., Homabrook, R.W. and Lambie, D.G.. Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neural. Stand.. 73 (1986) 490-492. 28 Julien, J., Vallat, J.-M., Lagueny, A. and Darriet, M.D., Le traitement prophylactique des migraines par le propranolol (Prophylactic treatment of migraine with propranolol). Nouv. Presse Med., 5 (1976) 653. P., Andersen, A.R., Andersson. P.G.. Gilhus, 29 Kangasniemi, N.E., Hedman, C., Hultgren. M., Vilming, S. and Olesen, .I.. Classic migraine: effective prophylaxis with metoprolol, Cephalalgia, 7 (1987) 231-238. P.J., Nyrke. T., Lang, A.H. and Petersen. E., 30 Kangasniemi, Femoxetine, a new 5-HT uptake inhibitor, and propranolol in the prophylactic treatment of migraine. Acta Neurol. Stand.. 68 (1983) 262-267. K., Propranolol (Inderal) and 31 Kass, B. and Nestvold, clonidine (Catapressan) in the prophylactic treatment of migraine: a comparative trial, Acta Neurol. Stand., 61 (1988) 351-356. D. and Roberts, A.H., Skin temperature bio32 Kewman, feedback and migraine headaches: a double-blind study, Biofeedback Self-Regul., 5 (1980) 327-345. 33 Klimek, A., Niewodniczy, A., Pozniak-Patewicz. W.R. and Rydzewckui, W.. Propranol w leczeniu migreny i pokrewnych bolow glowy (Propranolol in the treatment of migraine and related headaches), Pol. Tyg. Lek.. 33 (1978) 1109-1111.

34 Klimek, A. and Niewodniczy, A., Propranolol in the treatment of migraines. Zh. Nevropatol. Psikhiat., 82 (1982) 75 -78. 35 Knapp, T.W.. Migrane. Beltz Verlag, Weinheim, 1983. 36 Lake, A., Rainey, J. and Papsdorf, J.D., Biofeedback and rational-emotive therapy in the management of migraine headache, J. Appl. Behav. Anal., 12 (1979) 127 -140. 31 Lake, A.E. and Pingel, J.D., Positive and negative side effects related to biofeedback-assisted relaxation training for headaches, Headache, 24 (1984) 166 (abstr.). 38 Largen, J.W., Mathew. R.J.. Dobbins, K. and Claghorn. J.L., Specific and non-specific effects of skin temperature control in migraine management, Headache, 21 (1981) 36. 44. 39 Largen, J.W. and Mathew, R.J.. Cerebral blood flow and headache activity in normal volunteers and migraineurs trained in skin-temperature self-regulation. In: R.J. Mathew (Ed.), Treatment of Migraine: Pharmacological and Biofeedback Considerations, Spectrum. New York. 1981, pp. 91-126. 40 Leblond, G., Gauthier, J. and Drolet, M., Le role de la retroaction biologique de type thermique et de la relaxation dans le soulagement de la migraine (The role of thermal biofeedback and relaxation in the relief of migraine), Techno]. ThCr. Comportement. 9 (1985) 27-45. 41 Lindegaard, K.F.. Ovrelid, L. and Sjaastad, O., Naproxen in the prevention of migraine attacks: a double-blind placebo-controlled cross-over study, Headache. 20 (1980) 96-98. 42 Machado, H.P. and Gomez. A.M.L., The effectiveness of psychophysiological techniques in the treatment of migraine headaches, Biofeedback Self-Regul., 10 (1985) 105 (abstr.). J.R.. Propranolol 43 Malvea. B.P., Gwon, N. and Graham, prophylaxis of migraine, Headache, 12 (1973) 163-167. 44 Masel, B.E., Chesson, A.L., Peters, B.H., Levin, H.S. and Alperin, J.B., Platelet antagonists in migraine prophylaxis: a clinical trial using aspirin and dipyridamole, Headache, 20 (1980) 13-18. N.T., Prophylaxis of migraine and mixed 45 Mathew, headache: a randomized controlled study, Headache. 21 (1981) 105-109. D.W. and Kohlenberg, R.J., Self-help treat46 McDonald, ment of migraine headache: an outcome study. Paper presented at the meeting of the American Psychological Association, Toronto. 1984. S. and Franklin. M.A., Biofeed41 Medina, J.L., Diamond. back therapy for migraine, Headache, 16 (1976) 115-11X. G.. Manafi. T., Logothetra, J. and 48 Mentenopolous. Bostantzopoulou, S., Flunarizine in the prevention of classical migraine: a placebo controlled evaluation, Cephalalgia. 2 (1985) 135-140. A. and lannone, A., Autogenic 49 Mitch, P.S., McGrady. feedback training in migraine: a treatment report, Headache, 15 (1976) 267-270. 50 Mitchell, K.R. and Mitchell, D.M., Migraine: an exploratory treatment application of programmed behaviour therapy techniques, J. Psychosom. Res., 15 (1971) 1377157. 51 Mitchell, K.R. and White. R.G.. Behavioral self-manage-

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ment: an application to the problem of migraine headache, Behav. Ther., 8 (1977) 213-221. Mondrup, K. and Msller, C.E., Prophylactic treatment of migraine with clonidine: a controlled clinical trial, Acta Neurol. Scand., 56 (1977) 405-412. Nair, K.G., A pilot study of the value of propranolol in migraine, J. Postgrad. Med., 21 (1974) 111-113. Nappi, G., Sandrini, G., Savoini, G., Cavallini, A., deRysky, C. and Micieli, G., Comparative efficacy of cyclandelate versus fhmarizine in the prophylactic treatment of migraine, Drugs, 33, Suppl. 2 (1987) 103-109. Penzien, D.B., Ray, S.E., Holm, J.E., Brown, T.A., Allen, K.A., Fitterling, J.M., Beckham, J.C and Terre, L., Homebased behavioral and cognitive-behavioral treatment of recurrent headache: preliminary findings. Paper presented at the meeting of the Society of Behavioral Medicine, Boston,

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