Contingent negative variation and efficacy of beta-blocking agents in migraine

Thirty-three patients with common migraine underwent contingent negative variation (CNV) recordings before receiving prophylactic beta-blocker treatment with either metoprolol (27 patients) or propranolol (6 patients) at mean daily dosages of 110 mg and 122 mg, respectively. After 3 months the therapeutic efficacy of the beta-blocker was assessed in each patient by means of a global severity score and compared with the initial CNV recordings. The mean clinical improvement was 62%. A significant positive correlation was found between CNV amplitude before prophylaxis and the clinical response to beta-blockers: patients with higher CNV tended to respond better to therapy. Eight of 10 patients with a CNV amplitude higher than -25 microV had a more than 50% reduction of the severity score--that is, a good or excellent response to the beta-blocking agent--whereas only 2 of 9 patients with an amplitude lower than -20 microV had a good response.     

Interaction between oral verapamil and beta-blockers during submaximal exercise: relevance of ancillary properties

The interaction between verapamil and beta-blockers may involve negative chronotropic, inotropic, and dromotropic effects. Three randomized, double-blind, crossover trials evaluated standardized submaximal exercise hemodynamics after oral verapamil (120 mg) and beta-blocker, alone and in combination, in groups of eight healthy men. The beta-blockers were propranolol (80 mg), metoprolol (100 mg), and pindolol (5 mg). During submaximal exercise, each beta-blocker produced similar reductions in heart rate. Likewise, each verapamil and beta-blocker combination caused greater decreases in heart rate and prolongation of PR interval than did either drug alone. Only the verapamil and propranolol combination produced greater reduction of systolic blood pressure and prolongation of rate-adjusted PR interval. All verapamil and beta-blocker combinations caused frequent adverse events, predominantly exercise fatigue and resting first-degree heart block. Although the verapamil and metoprolol or pindolol combinations produced lesser negative dromotropic or inotropic effects compared with verapamil and propranolol, coadministration of verapamil and any beta-blocker should be performed cautiously.     

Prophylactic treatment of classical and non-classical migraine with metoprolol—a comparison with placebo

A double-blind investigation with parallel groups was carried out in three Danish neurological clinics to evaluate the effect of metoprolol (Beloc, Betaloc, Seloken) versus placebo in migraine patients. 71 patients were included; 62 completed the study. The following parameters were used in the evaluation: frequency of headache attacks, days with migraine, severity score (days X intensity), and the consumption of pain-relieving tablets. The results of the study show that metoprolol 200 mg in Durules (a controlled release formulation) once daily is more effective regarding all evaluated parameters than placebo and that metoprolol is well tolerated.     

Platelet P1, P4-Di (adenosine-51) tetraphosphate (AP4A) in migraine patients before and during beta-adrenoceptor blockade

P1,P4-Di(adenosine-51) tetraphosphate (AP4A) is a metabolically inactive nucleotide which can be released from platelet dense granules. This study was designed firstly, to investigate whether platelet content of AP4A was decreased in patients with classical migraine and secondly, whether the content of AP4A was changed by beta-adrenoceptor blockade. No significant difference in platelet dense granule content of AP4A, was observed between 10 migraine patients and 10 normal controls. Both metoprolol, a beta 1-selective blocker and propranolol, a non-selective beta-blocker significantly decreased the migraine attack rate. However, while propranolol significantly reduced the platelet content of AP4A, metoprolol did not. Therefore, the present data suggest that platelet dense granule release, as estimated by the content of AP4A is not of major importance in migraine.     

Comparative Efficacy of Nadolol and Propranolol in the Management of Migraine

SYNOPSIS
A multicenter randomized double-blind study was conducted on 140 patients with classic and/or common migraine who received either nadolol (80 mg or 160 mg OD) or propranolol (80 mg bid). Admission into the 12-week active treatment period required at least 3 attacks per month during a placebo lead-in period. Abortive headache therapy was allowed at the patients' discretion, each keeping a diary of migraine attacks and use of medications. Clinical assessments were performed monthly.
Data from 42 patients were excluded from the evaluation of efficacy, mainly because of non-adherence to protocol requirements. Drug efficacy evaluation in the remaining 98 patients was based on 4 separate migraine indices: frequency of attacks, intensity of attacks, days of pain, and need for relief medication, with success being defined as a reduction in an index of at least 50% relative to baseline. A successful response in at least I index was found in 48% of patients on nadolol 80 mg (p=NS vs propranolol 160 mg) and in 69% of the patients on nadolol 160 mg compared with 54% on propranolol 160 mg (p<0.05). Success in all 4 indices was found in 21% of patients on nadolol 80 mg (p=NS vs propranolol 160 mg) and in 41% of patients on 160 mg nadolol as compared to 15% on propranolol 160 mg (p<0.05).
Adverse reactions required discontinuation from therapy in 2 of 48 patients on nadolol 80 mg (4.1%), 2 of 47 patients on nadolol 160 mg (4.3%), and 4 of 44 patients on propranolol 160 mg (9.1%).
This study indicates that, in the prophylaxis of migraine, 80 mg of nadolol administered once daily is equivalent in efficacy and safety to propranolol 80 mg administered twice daily. Furthermore, nadolol given as a single daily dose of 160 mg is superior to an equal total daily dose of propranolol administered twice daily.     

Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis

The aim of the present study was to ascertain, on the basis of single case statistics and time-series analysis, responder and non-responder rates for metoprolol, propranolol and nifedipine in migraine prophylaxis. In addition, an attempt was made to identify the dose relationship for the various drugs on headache parameters. In a double-blind dose-finding study, 58 patients were treated in five consecutive dosage steps each lasting 1-3 months. All patients kept a headache diary before, during and after treatment. Serum drug levels were also determined. The data were assessed by time-series analysis, as well as by multiple regression and analysis of variance. A significant improvement was noted in 54.4% of patients with migraine during treatment with metoprolol. The study did not confirm the high success rates in migraine prophylaxis of nifedipine and propranolol quoted in the literature. Administration of nifedipine led to an increase in migraine attacks in 71% of the patients. Nifedipine was of no value in the prophylaxis of migraine. Only 32% of patients showed a reduction in frequency of migraine attacks during administration of propranolol. The analysis of variance failed to show any significant difference between the responder rates for metoprolol and propranolol. Higher doses of propranolol and metoprolol were more effective. Multiple regression analysis explained a considerable part of variance for propranolol (but not for metoprolol) as a result of reduced intake of ergotamine preparations and analgesics. It can therefore be concluded that part of the prophylactic effect of propranolol is attributable to a reduction in the use of migraine medication.     

Flunarizine Versus Metoprolol in Migraine Prophylaxis: A Double-Blind, Randomized Parallel Group Study of Efficacy and Tolerability

The prophylactic effect of flunarizine and metoprolol was studied in a multi-center randomized, double-blind trial of 149 patients with migraine with or without aura. After a 4-week placebo run-in period, patients were randomly allocated to treatment with flunarizine 10 mg daily or metoprolol 200 mg daily for 16 weeks (parallel group design). Both drugs reduced the number of migraine days per month by 37% (95% confidence interval 21-53%) compared with the placebo run-in period. All efficacy parameters were significantly reduced by both drugs and no significant difference was found between the two drugs at any time of the treatment period. However, calculation of the 95% confidence limits showed that each drug may have a superiority of more than 100% on a single main effect parameter. The most common adverse experiences were day-time sedation (both drugs) and weight gain (flunarizine). Depression was the most serious side-effect occurring in 8% on flunarizine and 3% on metoprolol. We conclude that both drugs are effective in the prevention of migraine attacks but a higher number of dropouts occurred on flunarizine because of depression or weight gain.     

Comparison of four beta-blockers as assessed by 24-hour ECG recording

beta-Blockers are used as if they were equivalent. With ECG recordings in 42 patients we investigated the effect on sinus heart rate of four beta-blockers given at three successive daily doses. Heart rate was dose-dependently decreased by all drugs except acebutolol, the effect of which decreased at a higher dosage. The maximal effects of metoprolol, nadolol, and propranolol were similar but the drugs differed in potency (dosage producing 50% of maximal effect, calculated from the dose-effect relationships; nadolol, 0.3 mg/day; metoprolol, 120 mg/day; propranolol, 47 mg/day). Similar relationships were found with drug plasma concentrations (concentration producing 50% of maximal effect: nadolol, 3.5 ng/ml; metoprolol, 21 ng/ml; propranolol, 36 ng/ml) and with supine or upright heart rates and blood pressures. However, the drugs were not equivalent: In addition to its greater potency, nadolol differed from propranolol and metoprolol in the slope of its dose-response curve. We conclude that beta-blockers can be compared by ECG recordings and that nadolol is different from the other beta-blockers without intrinsic sympathomimetic activity.     

Long Acting Propranolol in the Prophylaxis of Migraine. Comparison of the Daily Doses of 80 mg and 160 mg

SYNOPSIS
The efficacy of long acting propranolol in a dosage of 80 mg once daily in comparison to 160 mg once daily was assessed in the prophylactic treatment of migraine in a double-blind cross-over trial. 48 patients with classic or common migraine were included in the investigation, 6 patients withdrew, but only one because of side-effects. A four week run-in placebo period preceded the drug treatments, the duration of drug treatments was 12 weeks and there was a wash-out placebo period of 4 weeks between the treatments.
The two long acting propranolol doses, 80 mg and 160 mg once daily seemed to be equally effective. There was no difference in the antimigraineous effect. Long acting propranolol decreased both the frequency and severity of migraine attacks. Side-effects reported during the trial were mild, both doses were well tolerated. The treatment compliance during the once daily treatment was very good.     

Metoprolol v. clonidine in the prophylactic treatment of migraine

In a double-blind, cross-over trial, the migraine prophylactic effect of the beta 1-adrenoceptor antagonist metoprolol was compared with that of clonidine. The dosage of metoprolol was 50 mg b.i.d. and of clonidine 50 micrograms b.i.d. Thirty-one patients were included; twenty-three completed the entire study. Six patients withdrew during clonidine treatment, one during metoprolol treatment and one during the wash-out period (placebo). Metoprolol had a significantly better migraine prophylactic effect than clonidine regarding such parameters as the attack frequency, the number of migraine days and the sum of intensity score. Compared to baseline (placebo), metoprolol decreased these parameters, while clonidine did not. Metoprolol, but not clonidine, also reduced the acute consumption of analgesics. No differences were found as regards side effects.     

Comparison of propranolol LA 80 mg and propranolol LA 160 mg in migraine prophylaxis: a placebo controlled study

Thirty patients with severe classical and common migraine participated in a double-blind placebo-con-trolled cross-over study of migraine prophylaxis with propranolol LA (long-acting) 80 mg once daily, or propranolol LA 160 mg once daily or placebo. Each treatment was given for two months. There were no significant differences between the three treatment periods in headache frequency, headache severity, nausea frequency or severity. There was a non-significant trend for reduced duration of headache with the two doses of propranolol. The possible reasons for this negative effect are discussed. The safety of propranolol and its lack of serious side effects were demonstrated.     

Effectiveness and tolerability of acupuncture compared with metoprolol in migraine prophylaxis

OBJECTIVES: In a randomized controlled multicenter trial extending over 24 weeks, we investigated whether acupuncture is as effective and safe as metoprolol in the prophylactic treatment of migraine under conditions similar to routine care. METHODS: One hundred fourteen migraine patients could be randomized to treatment over 12 weeks either with acupuncture (8 to 15 sessions) or metoprolol (100 to 200 mg daily). Main outcome measure was the difference in the number of migraine days between baseline and the weeks 9 to 12 after randomization (derived from a headache diary). RESULTS: Two of 59 patients randomized to acupuncture withdrew prematurely from the study compared to 18 of 55 randomized to metoprolol. The number of migraine days decreased by 2.5 +/- 2.9 days (baseline 5.8 +/- 2.5 days) in the acupuncture group compared to 2.2 +/- 2.7 days (baseline 5.8 +/- 2.9 days) in the metoprolol group (P= .721). The proportion of responders (reduction of migraine attacks by > or =50%) was 61% for acupuncture and 49% for metoprolol. Both physicians and patients reported fewer adverse effects in the acupuncture group. CONCLUSIONS: Due to missing the recruitment target (480 patients) and the high drop-out in the metoprolol group the results must be interpreted with caution. Still, they suggest that acupuncture might be an effective and safe treatment option for patients unwilling or unable to use drug prophylaxis.     

Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment?

OBJECTIVE: To evaluate the efficacy of oral treatment with nebivolol and metoprolol in the prophylaxis of migraine attacks. BACKGROUND: Beta-blockers such as propranolol and metoprolol are known to be effective in preventing migraine attacks. Following earlier observations of successful use of nebivolol in a few hypertensive patients with concomitant migraine, we conducted a prospective study to ascertain whether nebivolol would be effective and better tolerated, in a methodologically strict, randomized and double-blind setting. DESIGN AND METHODS: Randomized, double-blind study in 30 patients with confirmed migraine diagnosis, a minimum 1-year history, onset prior to 50 years of age, written records of attacks for the previous 3 months, and minimum 2 attacks per month. Primary endpoint was frequency of attacks (prevention of migraine attacks) in the final 4 weeks of a 14-week treatment on full dose of metoprolol and nebivolol. Secondary endpoints were time to therapeutic effect, duration of attacks, intensity of headache, consumption of analgesics, evaluation of accompanying symptoms, migraine disability assessment, clinical global impression, quality of life, and responder rates. The statistical analysis was prospectively planned and conducted for all randomized patients. RESULTS: Both metoprolol and nebivolol where similarly effective regarding the main endpoint (prevention of migraine attacks) as well as the secondary ones, and both had a fast onset of action, typically within 4 weeks from starting therapy, with responder rates increasing relatively little over time after the first 4 weeks. Use of acute pain medication decreased on both drugs, as well as accompanying symptoms. Both patients' and physicians' evaluations of disability and disease status were similarly favorable to the 2 treatments. Regarding safety, nebivolol was considerably better tolerated than metoprolol in terms of all reported events, treatment-related events, and event severity. CONCLUSIONS: Our results suggest that nebivolol is as effective as metoprolol in the prophylaxis of migraine attacks, with the advantages of being better tolerated and not requiring up-titration to achieve therapeutic levels. Further and larger trials should be conducted on nebivolol in the prevention of migraine attacks as it may provide an improvement in current migraine prophylaxis with beta-blockers.     

Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily

This was a phase-IV double-blind equivalence trial designed to assess the efficacy and tolerability of two doses of flunarizine (10 mg o.d.=FLU 10 mg and 5 mg o.d.=FLU 5 mg) in the prophylaxis of migraine, in comparison with slow-release propranolol (160 mg o.d.). A total of 808 subjects were treated in a treatment period of 16 weeks. 142 subjects discontinued the trial prematurely, mainly because of adverse events (n=58). The mean attack frequency in the double-blind period was 2.0 for the FLU 5 mg group, 1.9 for the FLU 10 mg group, and 1.9 for the propranolol group. The mean attack frequency in the last 28 days of the double-blind period was 1.8 for FLU 5 mg, 1.6 for FLU 10 mg, and 1.7 for propranolol. Both flunarizine groups were at least as effective as propranolol (P<0.001 in one-sided test). The percentage of responders (defined as subjects for whom attack frequency decreased by at least 50% compared to run-in) in the last 28 days of the double-blind period was 46% (118/259) for FLU 5 mg, 53% (141/264) for FLU 10 mg, and 48% (125/258) for propranolol. Statistical analysis showed that FLU 10 mg is at least as effective as propranolol (P<0.001) and showed a trend for noninferiority of FLU5 and propranolol (P=0.053). No statistically significant differences between the treatment groups were found for any of the secondary parameters. Overall, 190 subjects reported one or more adverse events during the run-in phase: 54 (20.5%) in the FLU 5 mg group, 76 (27.7%) in the FLU 10 mg group and 60 (22.3%) in the propranolol group. The results of this equivalence trial show that 10 mg flunarizine daily with a drug-free weekend is at least as effective as 160 mg propranolol in the prophylaxis of migraine for all evaluated parameters (one-sided equivalence tests) after 16 weeks of treatment. In addition, 5 mg flunarizine proves to be at least as effective as 160 mg propranolol when looking at the mean attack frequency for both the whole double-blind period and the last 28 days of treatment. However, in the analysis of responders, 160 mg propranolol seems to be slightly better than 5 mg flunarizine. In addition, no significant differences between the three treatments were found with regard to safety: all three treatments were generally well-tolerated and safe.     

A comparative study of oral acetylsalicyclic acid and metoprolol for the prophylactic treatment of migraine. A randomized, controlled, double-blind, parallel group phase III study

This study was a multinational, multicentre, double-blind, active controlled phase III trial designed to investigate efficacy and safety of 300 mg acetylsalicyclic acid (ASA) (n = 135) vs. 200 mg metoprolol (n = 135) in the prophylaxis of migraine. In total 270 (51 male and 219 female) patients, aged 18-65 years, suffering between two and six migraine attacks per month were recruited. The main objective was to show equivalence with respect to efficacy, defined as a 50% reduction in the rate of migraine attacks. A run-in phase was carried out with placebo for 4 weeks, followed by a 16-week drug phase. In both treatment groups the median frequency of migraine attacks improved during the study period, from three to two in the ASA group and from three to one in the metoprolol group; 45.2% of all metoprolol patients were responders compared with 29.6% with ASA. Medication-related adverse events were less frequent in the ASA group (37) than in the metoprolol group (73). The findings from this trial show that metoprolol is superior to ASA for migraine prophylaxis but has more side-effects. Acetylsalicylic acid is better tolerated than metoprolol. Using a strict responder criterion ASA showed a responder rate comparable with the placebo rate in the literature.     

The effect of propranolol on glyceryltrinitrate-induced headache and arterial response

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 microg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.     

Central cholinergic challenging of migraine by testing second-generation anticholinesterase drugs

The antinociceptive activity of donepezil, a novel cholinesterase inhibitor, was investigated in the mouse hot plate test. Donepezil (5 to 10 mg kg(-1) i.p.) induced a dose-dependent antinociception that reached its maximum effect 15 minutes after injection. Donepezil antinociception was prevented by the antimuscarinic drug scopolamine. At analgesic doses, donepezil did not alter gross animal behavior. These results indicate that donepezil is endowed by muscarinic antinociceptive properties, suggesting this compound as a potential therapeutic approach for the treatment of painful pathologies. Therefore, we investigated donepezil's effect in migraine. Donepezil (5 mg per os, evening assumption) was effective as a prophylatic agent in patients suffering from migraine with or without aura by reducing the number of hours with pain, the number of attacks, and the severity of the pain attack. The efficacy of donepezil was compared with that of the beta-blocker propranolol (40 mg bid per os), showing higher activity. Response rates of a large-sized open study devoid of entry criteria regarding migraine subtypes suggest the drug as an excellent prophylactic compound for migraine in general practice. Clinical results also indicate that the activation of the cholinergic system can represent a novel prophylactic approach to migraine.     

Propranolol in the Management of Recurrent Migraine: A Meta-analytic Review

We used meta-analytic statistical techniques to synthesize findings from studies that evaluated propranolol HCI for the prevention of recurrent migraine (2,403 treated patients). The modal migraine sufferer treated in these studies was a female, about 37 years of age, who suffered from common (rather than classical) migraines and reported a 17-year history of problem migraines. The modal treatment was 160 mg. propranolol per day. Meta-analysis revealed that, on average, propranolol yielded a 44% reduction in migraine activity when daily headache recordings were used to assess treatment outcome, and a 65% reduction in migraine activity when less conservative measures (e.g., clinical ratings of improvement, global patient reports) were used. Meta-analysis thus revealed substantial support for short-term effectiveness of propranolol. However, little information was available concerning the long-term effectiveness of propranolol.     

Effects of cimetidine and ranitidine on steady-state propranolol kinetics and dynamics

The influence of cimetidine (1000 mg daily, one day oral pretreatment) and ranitidine (300 mg daily by mouth, 1 and 6 days pretreatment) on steady-state propranolol (160 mg sustained-release capsule, once daily) plasma levels (Psss) and dynamic beta-blocker effects was assessed by bicycle ergometer exercise and isoproterenol sensitivity test in five normal subjects. During the 3 hr of the dynamic tests Psss were elevated from 25% to 67% by cimetidine, whereas Pss was unchanged by ranitidine. The estimated hepatic blood flow (EHBF) as calculated from indocyanine green (ICG) plasma clearance was only slightly reduced by 15 +/- 23% (mean +/- SD, n = 4) after one oral dose of 150 mg ranitidine and showed substantial intersubject variability. Dynamic parameters, like propranolol-induced heart rate and blood pressure changes under physical exercise or during the isoproterenol sensitivity test, were not influenced by ranitidine or cimetidine. Since our study was performed on normal subjects with relatively low propranolol doses these results do not rule out the risk of severe reinforcement of beta-adrenergic receptor blocking effects if propranolol and cimetidine are taken together by patients.     

Migraine Is Not a Platelet Disorder

SYNOPSIS
The platelet theory of migraine causation predicts that drugs inhibiting platelet activation will be effective in migraine prevention, but the literature indicates that this is only partly the case. Conversely, therapy achieving clinical benefit should be associated with reduced platelet activity. To test this concept, the β-adrenergic blockers propranolol (non-selective), metoprolol (β₁-selective) and Li-32468 (β₂-selective) were used in migraine therapy with assessments of platelet aggregation and release, plasma thromboxane A₂ (measured as thromboxane B₂) and clinical response.
Between propranolol and Li-32468, there was lack of correlation of clinical with platelet effects. Propranolol and metoprolol, whose established efficacy in migraine prophylaxis was reflected here, actually had opposite effects on platelet activity, which was increased with the former and inhibited by the latter. Yet both drugs gave elevated thromboxane B₂ levels.
In view of this complete dissociation between drug effects on platelets of migraineurs and symptoms of migraine, the platelet theory of migraine causation is untenable.