Review: Analyzing Role of Propranolol in Migraine

Migraine is one of the most common causes of primary headaches. It is a disorder characterized by repetitive attacks of headache with moderate to severe intensity, frequently joined by photophobia, phonophobia, and nausea (1). With an estimated global prevalence going somewhere in the range of 8 and 18%, migraine headaches are quite common. It has now been laid out that migraines cause significant disability even during periods between attacks (2).

The way that repetitive episodes of migraine can be practically disabling and can debilitate one's quality of life, has made preventive therapy for all migraine patients a priority. Preventive therapy is not only pointed at diminishing the recurrence, seriousness, and time span of migraine attacks; rather it can go quite far in expanding responsiveness to acute migraine therapy, consequently improving the quality of life (3).

According to the International Headache Society (IHS)'s diagnostic rule, migraine includes having no less than 5 attacks that last 4–72 hours, that are unilateral, pulsating, moderate or severe in intensity, and bothered by or cause evasion of routine physical activity and are likewise followed by nausea and/or vomiting, photophobia or phonophobia (2).

Pathophysiology of migraine- The underlying pathophysiology of migraine is however only partly perceived to date, migraine attacks have been reliably connected with neuronal activation, attributable to cortical spreading activation (CSD) or a brainstem generator (3). Malfunctioning of brain areas and channels, which regulate the excitability of nociceptive brain circuits as well as central sensitization is assumed to play a role, the latter particularly in the transformation from episodic to chronic migraine (1).

Exploring the role of prophylactic therapy in migraine- Research has reported that prophylactic migraine treatment should be considered in patients with more than 3 migraine headaches per month or at least 8 headache days in one month, patients encountering severe debilitating headaches despite appropriate acute therapy and in certain migraine subtypes like hemiplegic migraine, basilar migraine, and migraine with prolonged aura (3).

Preventive prescription restrains CSD through various systems, such as blocking calcium and sodium channels, blocking gap junctions, and repressing matrix metalloproteinases (3). Among the currently used drugs for migraine prophylaxis and prevention, beta-blockers stand firm in an exceptionally encouraging situation.

Beta-blockers and their mechanism of action -Inhibition of β1-mediated effects are regarded to be the chief technique by which the beta blockers work (1). Propranolol, a non-selective beta-adrenergic receptor antagonist, was initially used for treating angina pectoris (4). Progressively, as the different probability of this medication was revealed attributable to its activity at numerous receptor locales and its capacity to exert central and peripheral impacts, its non-cardiovascular therapeutic efficacy was engaged upon.

Propranolol inhibits nitric oxide production by blocking inducible nitric oxide synthase (NOS). Propranolol also inhibits kainate-induced currents and is synergistic with N-methyl-D-aspartate blockers, which reduce neuronal activity and have membrane-stabilizing properties (1). In a double-blind randomized study, it was revealed that propranolol diminished VEP amplitude in migraine patients, inspiring a superior clinical response to the prophylactic treatment. In addition, propranolol lowered the neuronal firing rate of noradrenergic neurons of the locus coeruleus (1).

Studies supporting propranolol in migraine prophylaxis –

Rabkin et al. coincidentally tracked down the therapeutic impact of propranolol for migraine while researching its utilization in angina pectoris. From that point forward, a heap of studies has viewed propranolol as safe and powerful in overseeing migraine headaches (4).

1. Holroyd et al. conducted a meta-analysis to evaluate results from 53 such studies (N = 2403) that assessed the effect of propranolol on migraine headaches. Reduction in migraine activity was 44% (when daily headache recordings were used to assess efficacy) and 65% (when less conservative measures such as clinical ratings of improvement and global patient reports were used to assess efficacy) for propranolol and only 14% for placebo. (4)

2. A Cochrane review conducted by Linde and Rossnagel evaluated 58 clinical trials assessing efficacy and safety of propranolol compared to placebo and other drugs (including other beta-blockers, calcium antagonists, and several other drugs) in adults with migraine. The results showed propranolol to be more effective than placebo and as effective and safe as other drugs. (4)

3. He et al. conducted a network meta-analysis to compare various migraine prophylactic medications. The medication included topiramate, gabapentin, propranolol, amitriptyline, divalproex, and valproate. Of these six medications studied, propranolol demonstrated significantly fewer average migraine headache days compared to placebo. Further, propranolol was found to be safer and more tolerable. Thus, considering all the parameters together, propranolol was the most beneficial treatment for migraine. (4)

4. In a major meta-analysis with 38 trials comparing beta-blockers to placebo with a total of 2019 participants, researchers concluded that propranolol was superior in efficacy to placebo. They further highlighted that propranolol reduced headache by 50%, higher than the reduction rate found in the placebo group (1).

5. Shamliyan et al reviewed pharmacologic treatment for episodic migraine and reported that beta-blockers were effective; their outcome was a 50% reduction in headaches, an outcome recommended by the International Headache Society (IHS)as a secondary outcome (5).

6. An elaborate review by Jackson JL, consisting of 108 randomized controlled trials, 50 placebo-controlled, and 58 comparative effectiveness trials concluded that Propranolol is effective in reducing the burden of patients with episodic migraine headaches, lowering headaches from 5 to 3 headaches a month, leading to a substantial residual headache burden among sufferers. They further revealed that Propranolol reduces headaches by more than 50% as well as reduces the number of analgesic medication doses required. It also reduces the severity or duration of the headaches experienced. Propranolol and metoprolol exert similar effects and propranolol is as effective as flunarizine (5)

What do Guidelines say?

According to the 2012 AHS/AAN (American Academy of Neurology) Guidelines for Migraine Prevention in Adults, propranolol has been listed as a Level A medication i.e. medication that has proven effective and should be offered to patients who require migraine prophylaxis. It has also been documented as a "first line" drug for migraine(3). The European Federation of the Neurological Societies (EFNS) guideline has also recommended propranolol as a first-line treatment for the prevention of migraine(1). Monotherapy is usually preferred for migraine, as no critical advantages of utilizing more than one medication have been recognized(3).

Key pointers –

Migraine has emerged to be a growing health concern.

Tailoring prophylactic medication according to patient characteristics, comorbidities, and expected side effects is a good approach.

Among commonly used beta-blockers, propranolol has shown the most consistent potency in preventing as well as managing migraine episodes successfully. Acknowledging its superiority, it has made its way as a Level A drug in the Guidelines for Migraine Prevention in Adults.

Conclusion- With evidence highlighting that migraine remains underdiagnosed (6), it is time that legitimate diagnosis followed by adept pharmacotherapy be engaged upon. As a growing wealth of evidence backs the supremacy of propranolol in migraine prophylaxis, this drug has established an inflexible stance as first-line therapy. With studies emphasizing that one-third of migraine patients require preventive therapy(1) the need to explore the maximum capacity of propranolol in managing the equivalent cannot be more emphasized.

References

1. Sprenger, T., Viana, M., & Tassorelli, C. (2018). Current prophylactic medications for migraine and their potential mechanisms of action. Neurotherapeutics, 15(2), 313-323.

2. Jackson JL, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A, et al. (2015) A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PLoS ONE 10(7): e0130733. doi:10.1371/journal. pone.0130733

3. Kumar A, Kadian R. Migraine Prophylaxis. [Updated 2021 Oct 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507873/

4. Srinivasan A. V. (2019). Propranolol: A 50-Year Historical Perspective. Annals of Indian Academy of Neurology, 22(1), 21–26. https://doi.org/10.4103/aian.AIAN_201_18

5. Jackson JL, Kuriyama A, Kuwatsuka Y, Nickoloff S, Storch D, Jackson W, et al. (2019) Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis. PLoS ONE 14(3): e0212785. https://doi.org/10.1371/journal.pone.0212785

6. Teleanu, R. I., Vladacenco, O., Teleanu, D. M., & Epure, D. A. (2016). Treatment of Pediatric Migraine: a Review. Maedica, 11(2), 136–143.