Triptans were developed to more specifically target 5-HT_1B/D receptor mechanisms recognized to be key to the antimigraine mechanism of ergot alkaloids. They are vasoconstrictive, through an effect on serotonin (5-HT)_1B receptors, and suppress release of neuropeptides through 5-HT_1D receptors, which are located on cerebrovascular endothelium and dural afferent fibers, respectively. These actions reduce neurogenic inflammation and dural afferent sensitization. Lasmiditan is a newly approved agonist of the 5-HT_1F receptor. Activation of this receptor decreases neuronal excitability in the migraine headache pain pathway presumably by a central effect, as this drug does not appear to exert the typical peripheral effects of triptans, such as vasoconstriction (Goadsby and Classey, 2003).

In animals, 5-HT levels in the dorsal raphe nucleus are modulated estrogen, through a combination of estrogen-related increased tryptophan hydroxylase levels, and decreased reuptake (Gupta et al., 2011; Aggarwal et al., 2012). As estrogen levels drop, 5-HT levels in the brain decline. Further, estrogen has been found to attenuate 5-HT induced vasoconstriction (Gupta et al., 2011). In ovariectomized female rats, the expression of 5HT_1B receptors in the trigeminal ganglion is reduced by about one-third (Aggarwal et al., 2012). Estrogen treatment of ovariectomized female rats restores the level of 5HT_1B receptor expression to that seen in normally cycling rats (Aggarwal et al., 2012). Injection of sumatriptan is known to induce localized mechanical sensitivity, in a sexually dimorphic manner, with female rats showing sensitivity at lower sumatriptan concentrations than males (Araldi et al., 2017). This effect appears to be mediated by estrogen, as gonadectomy attenuates and estrogen treatment enhances it (Araldi et al., 2017). Somewhat surprisingly, in female rats, sumatriptan induced mechanical sensitivity is mediated through 5-HT_1D receptors, whereas in male rats, it is mediated through 5-HT_1B receptors.

It has been reported that oral administration of frovatriptan 2.5 mg produces peak and area under the curve plasma concentrations that are about twice as high in women as in men due to an apparent lower bioavailability in men (Jhee et al., 2001; Elkind et al., 2004; Negro et al., 2011). Frovatriptan, perhaps due to its long half-life, has a lower rate of headache recurrence than other triptans at 24 h post-administration, but also suffers from a lowered headache relief rating at 2 h (Jhee et al., 2001; Negro et al., 2011). Importantly, naratriptan, rizatriptan, and zolmitriptan also show similar, although less dramatic, sex-related differences in peak and area under the curve plasma concentrations (Ferrari et al., 2011). It is not clear what, if any, relationship exists between the efficacy of these agents in migraine and the plasma concentration achieved (Ferrari et al., 2011; Vetvik and Macgregor, 2017). However, in comparison trials of frovatriptan versus rizatriptan, zolmitriptan, or almotriptan, all produced relatively similar efficacy to ameliorate or eliminate migraine headache, which was not different when men and women were compared (Franconi et al., 2014). A recent meta-analysis did, however, find an increased risk for women to have headache reoccurrence 24 and 48 h after triptan treatment, and concluded that this was not explained by a different initial response to these abortive drugs (van Casteren et al., 2019). This same meta-analysis found that women also have a higher risk of adverse events than men when treated with triptans (van Casteren et al., 2019). Most studies of triptans for migraine have a much smaller number of men than of women and thus response efficacy stratified by sex is not often reported (Vetvik and Macgregor, 2017). This was also the case in the study of Franconi et al. (2014) where the female to male ratio was more than 4:1, and thus it is unclear if this confound prevented the identification of sex-related differences in triptan efficacy (Franconi et al., 2014). Thus, one cannot exclude the possibility that low numbers of men in these studies precluded an identification of an actual sex-related difference in efficacy.

Non-steroidal anti-inflammatory drugs act by inhibition of the enzyme cyclooxygenase, which converts arachidonic acid to prostaglandins, of which prostaglandin E, F_2α, and I (prostacyclin) are thought to contribute to headache pain, in part by sensitizing afferent fibers and altering the excitability of trigeminovascular neurons (Dong et al., 2009). Paracetamol is a non-specific mild analgesic used by some migraineurs. Its mechanism of action with regard to migraine is uncertain. In a human experimental pain study that examined the effectiveness of ibuprofen 800 mg on electrically evoked ear lobe pain tolerance in healthy men and women, only men showed a significant analgesic response (Walker and Carmody, 1998). The only sex-related difference in pharmacokinetic (PK) parameters was the weight-adjusted volume of distribution, which was twice as high in women. No relationship between plasma ibuprofen concentration and analgesia in men was identified, suggesting that the slightly higher concentrations of ibuprofen found in men were not likely the explanation for this sex-related difference. Subsequent research by the same group found that expectation of analgesia in men was the likely reason for the difference in ibuprofen efficacy in this model (Butcher and Carmody, 2012). The absorption of ketoprofen is more rapid in men than in women, with men achieving higher maximum concentrations in the plasma (Lorier et al., 2016; Magallanes et al., 2016); however, this NSAID is not as commonly used for acute migraine treatment. Not all NSAIDs show a sex-related difference in their PK. Diclofenac potassium oral solution, which is used as an abortive for migraine headache, has not been shown to have a different disposition in men compared with women (Chen et al., 2015). Ketorolac, an NSAID, which is available in injectable form, has been shown to be effective as a migraine abortive agent (Rao et al., 2016). There is no clinical evidence that ketorolac has a sex-related difference in its efficacy (Friedman et al., 2015). However, in an animal model of masticatory muscle pain, peripheral application of ketorolac was found to exert a significantly greater effect in female rats (Cairns et al., 2012). The relevance of this finding to the actions of ketorolac as a migraine abortive is uncertain, but at least theoretically, this suggests that certain NSAIDs may work better in one sex than in another.

Orally ingested ASA is absorbed more quickly in women than in men, but is also hydrolyzed (de-acetylated) and cleared more rapidly from the plasma of women, which may explain a decreased efficacy of ASA as an antithrombolytic in female migraineurs (Buchanan et al., 1983; Jesurum et al., 2012). However, in a retrospective study of 61 migraine patients, no sex-related difference in the efficacy of ASA to ameliorate migraine headache was found, although the authors speculated that plasma concentrations of intact ASA might be predictive of response (Ross-Lee et al., 1983). A study of a combination of paracetamol, ASA, and caffeine (Excedrin) in men and women migraineurs showed a trend toward higher headache pain relief as the percentage of men in the study group was increased (Silberstein et al., 1999). When the study population included 25% men, headache was relieved in 65%, whereas when the study population had only 17% men, headache relief was reduced to only 56% at 2 h post-administration (Lipton et al., 1998). In a study of women alone, Excedrin ameliorated or eliminated migraine in 58% of women at 2 h post dose (Silberstein et al., 1999). Assuming that the efficacy in the study of women alone is representative of the effectiveness of Excedrin, a simple calculation based on the population with the highest percentage of men in the Lipton et al. study can be used to estimate efficacy in men. This calculation suggests that the efficacy of this therapy in men would have been around 86% to produce the overall rate reported in the combined studies. There is some evidence that men are more likely to use ASA for migraine than women, and this might be explained, in part, by an increased efficacy of ASA in men, however, to date, no research has investigated if such a difference exists.

The gepants, e.g., rimegepant, are small molecule CGRP receptor antagonists, which have shown some promise as abortives in migraine headache treatment (Croop et al., 2019). Antagonism at this receptor attenuates neurogenic inflammation and is effective in aborting migraine headache (Edvinsson et al., 2018). Evidence, discussed below, suggests that CGRP receptor antagonists could exhibit sex-related differences in their efficacy. In the most recent, placebo controlled study, 85% of migraine patients enrolled were women, and no assessment of sex-related differences in drug efficacy was reported (Croop et al., 2019).

In healthy humans, plasma CGRP levels are higher in woman than in men (Valdemarsson et al., 1990). There appears to be a greater expression of the CGRP receptors by trigeminal ganglion neurons in male than in female rats, but a higher baseline expression of CGRP in the brainstem of female rats (Stucky et al., 2011). Estrogen does not appear to alter the expression of CGRP in some animal studies, but in others increased its expression (Gupta et al., 2011; Aggarwal et al., 2012). Application of CGRP to the dura of male and female rats resulted in lower facial mechanical withdrawal thresholds in female rats for 72 h, but not in male rats (Avona et al., 2019). Furthermore, dural application of CGRP in female, but not male rats caused nociceptive priming, which was evident up to 14 days post-administration (Avona et al., 2019). Application of CGRP to the dura of male rats does not excite or mechanically sensitize dural afferent fibers, but does increase dural blood flow (Levy et al., 2005). Results from experiments to examine the effect of CGRP on dural afferent fiber response characteristics in female rats have not been reported. However, while CGRP mediates increased blood flow, it does not appear to contribute to the mechanical sensitization of temporalis muscle nociceptors by intramuscular injection of glutamate in female rats, which suggests that CGRP may not directly affect trigeminal nociceptors in either sex (Gazerani et al., 2010). Treatment of ovariectomized rats with estrogen raises CGRP plasma levels and increases CGRP expression in arterioles (Gupta et al., 2011). This is in line with findings that plasma levels of CGRP are higher in women than in men, and increased by estrogen containing birth control pills (Gupta et al., 2011).

Ketamine is an antagonist at nicotinic, muscarinic and the N-methyl-D-aspartate (NMDA) glutamate receptor subtypes. It is a centrally acting analgesic, although it may also exert some of its antimigraine effects by inhibition of neurogenic inflammation, as trigeminal afferent fibers express a subtype of the NMDA receptor (Wang et al., 2012). It is not clear whether ketamine is effective in migraine, although studies with intranasal ketamine suggest that it may reduce headache-related pain (Afridi et al., 2013; Etchison et al., 2018; Benish et al., 2019).

Trigeminal nociceptors in both animals and humans express NR_2B subunit containing NMDA receptors, with a greater expression in females than in males (Wong et al., 2014). The expression of peripheral NMDA receptors by nociceptors in the trigeminal system is modulated by estrogenic tone and NMDA-evoked afferent discharge is also greater in female rats (Dong et al., 2007). In healthy human subjects, injection of glutamate into the masseter muscle results in pain that can be attenuated by co-administration of ketamine. A higher concentration of co-administered ketamine is required to attenuate this muscle pain in women, which is consistent with the greater expression of NMDA receptors by masticatory muscle nociceptors in women (Cairns et al., 2003; Castrillon et al., 2007, 2012). Theoretically, ketamine might be more effective as an analgesic/abortive in men.

Opioids are occasionally used as abortives and act on three receptor subtypes to exert analgesic effects. These receptors are found throughout the central nervous system and may be expressed by a subgroup of trigeminal primary afferent fibers. Activation of these receptors decreases neurotransmitter release (pre-synaptic inhibition) and neuronal excitability (post-synaptic inhibition). There is some evidence that morphine produces greater analgesia in women and is more likely to be prescribed for women with migraine (Niesters et al., 2010; Connelly et al., 2019).