Migraine is a neurovascular disorder characterized by recurrent episodes of moderate to severe headache, often unilateral, and accompanied by nausea, photophobia, and phonophobia¹. It affects approximately 12–15% of the global population, with a higher prevalence in females². Preventive pharmacotherapy is recommended for patients with frequent, long-lasting, or debilitating migraine attacks that interfere with daily functioning³.

Propranolol, a non-selective beta-adrenergic blocker, is among the most widely used agents for migraine prophylaxis. It is believed to exert its effect by stabilizing vascular tone and inhibiting cortical spreading depression⁴. Amitriptyline, a tricyclic antidepressant, is also commonly prescribed for migraine prevention due to its ability to modulate serotonergic and noradrenergic pathways⁵.

Despite their efficacy, both drugs are associated with distinct side-effect profiles. Propranolol may cause hypotension, bradycardia, fatigue, and depression, especially in elderly or cardiovascularly compromised patients⁶. Amitriptyline, on the other hand, may result in sedation, dry mouth, constipation, weight gain, and cardiac arrhythmias⁷.

Head-to-head comparisons of these agents are limited in literature. Most studies focus on efficacy, but the long-term tolerability and safety of these medications warrant systematic evaluation, particularly in primary care and neurology outpatient settings⁸. The choice of prophylactic agent is often individualized based on patient comorbidities, tolerability, and patient preferences⁹.

This study aims to compare the safety profiles of propranolol and amitriptyline in patients undergoing prophylactic treatment for migraine. By identifying and analyzing adverse drug reactions associated with both medications, this study seeks to aid clinicians in making evidence-based choices tailored to patient profiles¹⁰.

This was a prospective, randomized, open-label, comparative study conducted at a tertiary care center over a period of 6 months.

Sample Size:

A total of 100 patients diagnosed with migraine without aura as per the International Headache Society (IHS) criteria were enrolled.

Inclusion Criteria:

• Age 18–55 years
• Diagnosed with migraine without aura
• Minimum 4 migraine episodes/month
• Provided written informed consent

Exclusion Criteria:

• History of cardiovascular disorders (e.g., heart block, ischemic heart disease)
• Psychiatric illness or use of antidepressants
• Pregnancy or lactation
• Chronic renal or hepatic disease
• Hypersensitivity to propranolol or amitriptyline

Randomization and Intervention:

Patients were randomly allocated into two groups (n=50 each) using computer-generated sequences.

• Group A (Propranolol): 40–80 mg/day in divided doses
• Group B (Amitriptyline): 10–25 mg/day at bedtime

Follow-up and Assessment:

Participants were evaluated at baseline and at 4, 8, and 12 weeks. Adverse drug reactions (ADRs) were documented using the WHO-UMC causality assessment scale. Blood pressure, heart rate, ECG, and laboratory parameters (liver and renal function tests) were monitored at each visit.

Outcome Measures:

• Primary: Incidence and severity of ADRs
• Secondary: Dropout due to intolerance, vital parameter derangements

Statistical Analysis:

Data were analyzed using SPSS version 20.0. Categorical variables were analyzed using the Chi-square test. Continuous data were analyzed using Student’s t-test. A p-value <0.05 was considered statistically significant.

Table 1: Baseline Demographics

Table 2: Reduction in Migraine Frequency

In table 2, Both drugs demonstrate significant and comparable efficacy in reducing migraine frequency after 12 weeks: Propranolol: 6.5 → 2.1 attacks/month (Reduction of 4.4) Amitriptyline: 6.3 → 2.3 attacks/month (Reduction of 4.0). The final frequencies (2.1 vs 2.3) are very similar.

Table 3: Common ADRs Observed

In table 3, Propranolol: Higher rates of Fatigue (26% vs 12%), Dizziness (18% vs 10%), and Bradycardia (14% vs 0%). Lower rates of Dry Mouth (6%) and Weight Gain (2%). Amitriptyline: Significantly higher rates of Dry Mouth (34% vs 6%) and Weight Gain (28% vs 2%). Lower rates of Fatigue, Dizziness, and no Bradycardia.

Table 4: Dropout Rate Due to ADRs

Table 5: Changes in Vital Parameters

In table 5, Propranolol caused a statistically significant reduction in BP (126/82 → 118/76, p=0.03), consistent with its beta-blocker action. Amitriptyline had minimal, non-significant effect (124/80 → 122/78, p=0.45). This is a key differentiating factor: Propranolol lowers BP, Amitriptyline does not.

Table 6: Sedation Score (VAS)

In table 6, Confirms significantly higher sedation scores for Amitriptyline at both Week 4 (4.9 vs 2.1) and Week 12 (4.4 vs 1.9), aligning with its known sedative effects.

This comparative study evaluated the safety of two established prophylactic agents—propranolol and amitriptyline—in migraine patients. While both drugs significantly reduced the frequency of migraine attacks, their side-effect profiles showed distinct patterns.

Propranolol, a beta-blocker, has been reported to be effective in migraine prevention by reducing sympathetic activity and stabilizing vascular tone¹¹. In our study, propranolol demonstrated significant efficacy but was associated with cardiovascular ADRs such as bradycardia and hypotension, aligning with previous findings by Freitag et al.¹². These side effects, though not life-threatening, led to a few dropouts.

On the other hand, amitriptyline, a tricyclic antidepressant, has long been used for migraine prophylaxis, particularly beneficial in patients with coexisting depression or sleep disturbances¹³. Our study observed that amitriptyline led to more anticholinergic effects including dry mouth, sedation, and weight gain. These results corroborate the findings of Jackson et al. and Couch et al.¹⁴,¹⁵, who noted similar adverse reactions in migraine patients.

Interestingly, the dropout rate due to adverse effects was higher in the amitriptyline group, suggesting that despite its efficacy, tolerability may be a limiting factor in long-term use. Additionally, sedation scores remained significantly higher in the amitriptyline group, highlighting its central nervous depressant effects. These findings are consistent with earlier randomized controlled trials conducted by Lipton et al. and Bulloch et al.¹⁶,¹⁷.

While both agents demonstrated comparable efficacy, the selection should be guided by patient-specific factors. For instance, propranolol may be avoided in asthmatics or patients with baseline bradycardia, whereas amitriptyline should be used cautiously in those prone to sedation or metabolic side effects.

Both propranolol and amitriptyline are effective for migraine prophylaxis. However, their safety profiles differ significantly. Propranolol is associated with cardiovascular side effects, while amitriptyline causes more central and anticholinergic adverse effects. Individualized treatment selection based on comorbidities and patient tolerance is essential for optimal outcomes

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