In 1974 investigations began on a new class of compounds that produced vasoconstrictive effects via 5-HT receptors. The first compound successfully use in this way was 5-carboxamidotryptamine (5-CT). When applied to an isolated dog saphenous vein, 5-CT caused potent venoconstriction and induced significant hypotension in vivo. The next compound developed, AH25086 [(3–2-aminoethyl)-N-methyl-1-H-indole-5-acetamide], also constricted saphenous veins in dogs but had more 5-HT receptor selectivity. AH25086 was effective against acute migraine in human volunteers, but further research was stopped because it was deemed less suitable for development in humans, possibly owing to the fact that it was highly lipophobic and unsuitable for oral use.38,69 In 1984, sumatriptan was synthesized and its clinical success led to the rapid development of six other triptans currently including naratriptan, zolmitriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan (Fig. 51–2 and Table 51–5).
The triptans are all primarily 5-HT1B and 5-HT1D receptor agonists and have less activity at 5-HT1A and 5-HT1F receptors27 (Chap. 13). In the CNS, 5-HT1B receptors are located on cerebral vessels.32 Stimulation of these receptors results in cerebral vasoconstriction,15 reversing abnormal cerebral vasodilation. In contrast, the 5-HT1D receptors are located presynaptically on trigeminal neurons, and act as "autoreceptors" to decrease neurotransmitter release from central trigeminal nerve terminals.43 The triptans also inhibit dural neurogenic inflammation by preventing the release of vasodilating neuropeptides from peripheral trigeminal nerves.54,72 Peripherally, triptans cause vasoconstriction systemically through the 5-HT1B receptor.17,49
Sumatriptan has poor oral bioavailability but good subcutaneous bioavailability (96%), and is therefore preferentially given by this route. The newer triptans differ substantially from sumatriptan with regard to oral bioavailability, plasma half-life, time to maximum effect, and recurrence rate of headaches. All triptans are pharmacodynamically the same but pharmacokinetically different (see Table 51–5).
With appropriate therapeutic use, the common adverse effects associated with the triptans are minor and include nausea, vomiting, dyspepsia, flushing, and paresthesias.16,68 However, the most consequential adverse effects are chest pressure and vasoconstriction. Chest pressure symptoms are reported in up to 15% of sumatriptan users.9,62 Although triptans reduce coronary artery diameter by 10% to 15%, chest pressure symptoms are not believed to be secondary to cardiac ischemia. Alternate hypotheses for the chest pressure sensations include a generalized vasospastic disorder in migraineurs, esophageal spasm, bronchospasm, alterations of skeletal muscle energy metabolism, and central sensitization of pain pathways.18 Although the triptans show some degree of coronary artery constriction in vitro, recent studies demonstrate, and hence recommendations state, that there is no need for routine stress tests in low-risk patients prior to therapy with triptans.19,48,80
However, triptans can cause ischemia due to vasoconstriction. Therapeutic sumatriptan use is also associated with myocardial ischemia and or infarction, dysrhythmias, renal infarction, splenic infarction, and ischemic colitis.1,4,13,44,50,55,57,61 Cephalic vasoconstriction is the desired effect of sumatriptan, but there are reports of adverse neurologic events ranging from transient ischemic attacks to cerebral vascular events, hemorrhages, or infarctions.11,42,47,53 Extrapyramidal symptoms such as akathisia and dystonia may also occur.46 Spinal cord infarction is reported after therapeutic zolmitriptan use,82 and renal infarction is reported after therapeutic rizatriptan use.29 These complications have not been reported to date with the other triptans but are possible given their similar mechanisms of action.
Animal studies showed a wide margin of safety with oral sumatriptan. Subcutaneous administration of 2 g/kg of sumatriptan to rats was lethal. Death was preceded by erythema, inactivity, and tremor.39 Dogs survived 20 mg/kg and 100 mg/kg subcutaneous doses, but developed hind limb paralysis, erythema, tremor, salivation, and loss of vocalization.38 Reactions in other animals include seizures, inactivity, reduced respiratory rate, cyanosis, ptosis, ataxia, mydriasis, salivation, and lacrimation.39,75
Excessive triptan usage is associated with vascoconstrictive symptoms. A 43-year-old man who used 23 (25 mg) tablets of sumatriptan and 32 tablets of Midrin (a combination xenobiotic with isometheptene 65 mg, dichloraphenazone 100 mg, and acetaminophen 325 mg) over 7 days for headaches developed a left occipital infarction with a right hemianopsia. Digital subtraction angiography revealed segmental narrowing in multiple cerebral vessels. The hemianopsia and vessel findings resolved after cessation of the sumatriptan and Midrin and treatment with nicardipine.53 Two patients who received four times and 10 times the recommended dose of naratriptan developed severe hypertension.56 However, not all triptan overdosages result in toxicity. One 36-year-old man reportedly used 66 (6 mg) doses of sumatriptan subcutaneously over 4 weeks for his cluster headaches and had no adverse effects.78 The maximum recommended dosage of sumatriptan is 12 mg subcutaneously in a 24-hour period. Patients who took single doses of 100 to 150 mg of almotriptan did not have any adverse effects.2
In 2006, the FDA issued an alert, warning of an increased risk of serotonin syndrome with triptans used in combination with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors. The alert was based on 27 cases reported to the FDA Adverse Events Reporting System between 1998 and 2002. The cases involved triptan use in conjunction with SSRIs that were coded as serotonin syndrome or symptoms indicative of serotonin syndrome.73 A case series of serotonin syndrome from migraine medications described three cases of serotonin syndrome with sumatriptan use alone, sumatriptan with sertraline, and sumatriptan with methysergide, lithium, and sertraline.51 Other medications that might precipitate serotonin syndrome when used in conjunction with triptans include monoamine oxidase (MAO) inhibitors (see Chaps. 71 and 72).
Treatment of triptan-induced vasoconstriction is dependent on the route of exposure and the organ system affected. Decontamination is not feasible after subcutaneous exposures, but can be effective following overdose of oral preparations. Gastrointestinal (GI) decontamination should be performed with activated charcoal. Since vomiting is not as prominent with triptan exposure as with exposure to the ergot alkaloids, gastric emptying procedures such as orogastric lavage may be considered early, but only following massive ingestion. The oral forms of rizatriptan and zolmitriptan are formulated to dissolve on the tongue, limiting the effectiveness of gastrointestinal decontamination.
Triptan-induced vasoconstriction and ischemia should be reversed with a calcium channel blocker or intravenous vasodilators, such as sodium nitroprusside, nitroglycerin, or phentolamine.53 Cases of sumatriptan-associated myocardial ischemia were effectively treated with aspirin, heparin, and intravenous nitroglycerin.61 Thrombolytic therapy has not been investigated in this setting but should be instituted if clinically warranted.