Trigeminovascular effects of propranolol in men and women, role for sex steroids

Abstract

Objective Assess whether propranolol modulates the trigeminovascular system in both men and women. Methods We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to T max ) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2–1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double‐blind, placebo‐controlled cross‐over study, including healthy males ( n = 10) and females on contraceptives ( n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20–39 years old). Results Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin‐induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients. Interpretation Propranolol (80 mg) inhibits capsaicin‐induced increases in dermal blood flow in a sex‐dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system.

Characterization of trigeminal C‐fiber reactivity through capsaicin‐induced release of calcitonin gene‐related peptide

“…Another limitation is the inclusion of patients who take migraine preventatives. In the case of beta‐blockers, DBF seems indeed to be influenced 38 . We performed a sensitivity analysis with these participants under beta‐blockers and did not see any different results.…”

“…In the case of beta-blockers, DBF seems indeed to be influenced. 38 We performed a sensitivity analysis with these participants under beta-blockers and did not see any different results. However, this should be considered in further studies.…”

Mode and site of action of therapies targeting CGRP signaling

“…Although the key mechanisms and sites of action for medications used in migraine prevention remain unclear, it seems that almost all affect the trigeminal CGRP system indirectly [ 116 , 117 ]. They inhibit CGRP release and consequently reverse sensitization in chronic migraine [ 116 , 118 ].…”

“…Propranolol is a non-selective β-adrenoceptor antagonist also frequently used to prevent migraine attacks. However, it has been shown that it has agonist effects on prejunctional 5-HT 1D and 5-HT 1F receptors in trigeminal fibers through which can inhibit the release of CGRP from these fibers that innervate the forehead skin and dura mater [ 117 ]. Interestingly, a single point mutation in the seventh transmembrane domain of the 5-HT 1 receptor increases 100–1000 fold the affinity of β-adrenoreceptor antagonists for the 5-HT 1D/1F receptors [ 127 ].…”

Health equity, care access and quality in headache – part 2

“…Alternatives to antiepileptics include beta-blockers, antidepressants, and OnabotulinumtoxinA. In the case of beta-blockers, propranolol is considered a safe option during pregnancy and breastfeeding; however, it is important to consider that propranolol efficacy has been shown to vary depending on the hormonal status of patients [ 83 ], and when taken in the third trimester, it should be stopped a few days before delivery since there is an increased risk of respiratory depression, neonatal bradycardia, and hypoglycemia [ 73 , 74 , 84 ]. Tricyclic antidepressants like amitriptyline can also be an alternative, but they should be taken with caution since their intake during the third trimester could result in neonatal withdrawal symptoms.…”