Comparison of Propranolol, Flunarizine and Their Combination in Preventing Migraine in Adults in a Tertiary Care Hospital in Bangladesh: An Open-label Parallel-arm Randomized Controlled Trial

Migraine is a highly prevalent neurological disorder, and in Bangladesh it accounts for approximately 25% of all headache disorders, predominantly affecting individuals aged 15-34 years and imposing a substantial socioeconomic burden through lost work hours and reduced productivity. Propranolol (a non-selective beta-blocker) and flunarizine (a calcium channel blocker) are both established first-line agents for migraine prophylaxis, but head-to-head comparative data in the Bangladeshi population are scarce, and evidence on their combined use remains limited. Prior trials comparing the two agents have produced mixed results, with some favoring flunarizine, others favoring propranolol, and others showing no significant difference. A subset of patients (30-40%) fail to respond adequately to monotherapy, and combination therapy targeting both beta-adrenergic and calcium-channel mechanisms has shown promise in earlier small trials without a clear increase in adverse events.

This study is an open-label, parallel-arm randomized controlled trial conducted in the inpatient and outpatient departments of Neurology and Medicine at Chittagong Medical College Hospital (CMCH), Chattogram, Bangladesh, over a planned duration of 18 months (12-week intervention period per participant, with follow-up at 6 and 12 weeks).

A total of 177 adult patients with episodic migraine (diagnosed per ICHD-3 criteria) will be enrolled using consecutive sampling and randomly allocated via software-generated block randomization (block size of six) with allocation concealment using sealed opaque envelopes, to one of three parallel groups (59 participants per group):

Group 1 (Propranolol): Started at 40 mg daily, increased to 80 mg daily after 7 days.

Group 2 (Flunarizine): Started at 5 mg daily, increased to 10 mg daily after 7 days.

Group 3 (Combination): Propranolol 40 mg plus flunarizine 5 mg daily initially; after 7 days, propranolol maintained at 40 mg while flunarizine is increased to 10 mg daily.

Acute attacks during the study may be managed with naproxen (NSAID) as first-line and zolmitriptan (triptan) if naproxen is ineffective.

At baseline, participants undergo a comprehensive evaluation including demographic data, general and systemic examination, baseline laboratory testing (ECG, RBS, SGPT, SGOT, serum creatinine), migraine history (frequency, duration, severity), MIDAS (Migraine Disability Assessment) score using a Bengali-translated version adopted with author permission, and headache severity (Numeric Rating Scale) and duration. Participants maintain a daily headache diary throughout the study.

Follow-up visits occur at 6 and 12 weeks, during which the headache diary is reviewed, adverse effects are recorded, treatment adherence is assessed by self-report and pill counting [(pills dispensed - pills returned) / pills expected to be taken × 100, with ≥80% considered adherent], MIDAS score is re-assessed at study end, headache severity/duration are reassessed, and Patient Global Evaluation (1-4 Likert scale) is recorded. Vital signs (pulse, blood pressure) and BMI are recorded at each visit. Participants experiencing intolerable adverse effects may be withdrawn and offered alternative treatment.

The primary outcome is the reduction in number of monthly migraine days from baseline to 12 weeks, analyzed using ANCOVA adjusting for baseline values and potential confounders (age, gender, baseline headache frequency), with Bonferroni-corrected pairwise comparisons between the three groups. Secondary analyses include repeated-measures ANOVA for headache severity (NRS), Wilcoxon signed-rank or paired t-tests for MIDAS score change, and Chi-square/Fisher's exact tests for responder rate (≥50% reduction in monthly migraine days at week 12) and adverse effect frequency. Exploratory subgroup analyses by age (<40 vs ≥40 years) and gender will be conducted using ANCOVA or logistic regression as appropriate. Both intention-to-treat and per-protocol analyses will be performed, with missing data handled via ITT principles and multiple imputation if needed. Effect sizes (Cohen's d, partial eta squared) and 95% confidence intervals will be reported for all point estimates. Analyses will be performed using SPSS version 27.0 or later, with statistical significance set at p < 0.05.

Informed consent will be obtained from all participants prior to enrollment. Detailed information about the study's objectives, procedures, potential risks, benefits, and the voluntary nature of participation will be provided in a written format. Participants will be given ample opportunity to ask questions and will be informed that they may withdraw from the study at any time without consequence.

Confidentiality will be maintained at all stages of the study. All participant data will be anonymized using a unique identifier, and personal identifying information will be stored securely. Data will be analyzed and reported in aggregate form to protect participant anonymity. Only authorized personnel will have access to the study data.

A Data Safety and Monitoring Committee (DSMC) will ensure participant safety and the ethical conduct of the trial. The DSMC will periodically review safety data, adverse events, serious adverse events, protocol deviations, dropout patterns, and overall trial progress. If any participant experiences intolerable side effects or other health concerns, appropriate medical intervention will be provided, and the participant will be withdrawn from the study if necessary. Any serious adverse events will be reported to the DSMC and ethics committee in accordance with ethical guidelines.

Finally, the ethical principle of beneficence will be upheld by ensuring that the potential benefits of participation outweigh any risks. The study will aim to improve the management of migraines, leading to better patient outcomes and a more efficient healthcare system, particularly in underserved regions.