Conflict of Interest Statement: Dr. Pierce is employed by NuPathe Inc.
Address all correspondence to M. Pierce, NuPathe Inc., Conshohocken, PA 19428, USA.
The objective of this paper is to review evidence showing that migraine patients who are nauseated before using oral triptans tend to have a poor treatment response, as well as to establish a framework for further investigation of the association between response to oral medications and pretreatment nausea among migraineurs.
Synthesis and Conclusion
In patients with migraine, pretreatment nausea predicts a poor response to oral triptans. This finding may be inherent in the oral route of delivery of medication, as pretreatment nausea is associated with gastric stasis, which can impair absorption of oral medications and reduce therapeutic efficacy. In addition, oral triptans contribute to the development of nausea among migraine patients who are nausea free before they treat, perhaps because oral tablet use triggers or exacerbates nausea in the same manner as eating or drinking among patients who are nauseated or vulnerable to nausea. Importantly, these observations are derived from a small evidence base and post-hoc analyses or, in the case of treatment-emergent nausea, adverse event reports. Further assessment of the relationships between nausea and oral triptans is necessary before drawing firm conclusions. Should these observations be validated, the use of oral triptans in migraine attacks with nausea or in patients prone to nausea should be reevaluated. Novel routes of administration for triptans allow patients to receive the benefits of migraine-specific therapy even when oral therapy is suboptimal.
Nausea, a cardinal feature of migraine, has been shown to influence the outcome of acute treatment by causing patients to delay or avoid taking oral medications. Other research has extended this finding, revealing issues specific to oral triptans that may affect the management of migraine attacks in patients with nausea. First, the presence of pretreatment nausea predicts poor response to oral triptans[2, 3] even when patients take their medication as directed. Second, data support the possibility that oral triptans contribute to development of nausea among migraineurs who are nausea free before they treat.4-8 Taken together, these observations may have far-reaching implications for the acute treatment of migraineurs whose attacks are accompanied by nausea. This paper summarizes the main findings from these studies and establishes a framework for further investigation of these observations.
Response to Oral Triptans in Patients With Nausea at Baseline
The impact of nausea at pretreatment baseline (among several other variables) on response to oral triptans has been evaluated in 2 large clinical trial databases.[2, 3] In both databases, the presence of nausea at baseline was among the strongest of several predictors of inability to achieve pain relief or pain-free response in clinical trials of oral triptans.
Data from the Sumatriptan Naratriptan Aggregate Patient database, which contains data from 128 clinical trials that included 28,407 migraine sufferers treating approximately 130,000 migraine attacks, were analyzed to identify determinants of response to sumatriptan tablets. Twenty-four possible univariate predictors of headache response were assessed using recursive partitioning and logistic regression techniques with data from 3706 patients who took 100 mg sumatriptan tablets or placebo in double-blind studies. Nausea at baseline was one of 7 strong negative predictors of headache relief 2 hours after dosing with sumatriptan tablets. Other negative predictors of headache relief 2 hours postdose were baseline pain severity, baseline disability, baseline vomiting, baseline pulsating pain, onset during waking hours, and baseline photophobia/phonophobia. Nausea at baseline was one of 9 strong negative predictors of pain-free response 2 hours after dosing with 100 mg sumatriptan tablets. Other negative predictors of pain-free response 2 hours postdose were baseline pain severity, baseline disability, baseline pulsating pain, baseline vomiting, baseline photophobia/phonophobia, aura associated with the attack, age <34 years, and unilateral pain. Variables that did not significantly predict clinical response to oral sumatriptan included sex; for women, whether the patient was menopausal, used oral contraceptives, or was capable of bearing children; race; body mass index; continent and country of residence; day of the week of onset of the headache; whether baseline pain was aggravated by activity; setting for first dose of medication (in doctor's office or at home); length of time between onset of headache and dosing with medication; and time of day of onset of headache.
First-attack data from 10 randomized, double-blind, placebo-controlled migraine trials (n = 8473) were used to identify predictors of nonresponse to 100 mg sumatriptan tablets or eletriptan tablets 20, 40, or 80 mg. In multivariate regression analyses, 3 of the strongest and most significant baseline predictors of failure to achieve pain-free response 2 hours postdose were identified: severe headache pain, presence of photophobia/phonophobia, and presence of nausea.
The reason for the association of baseline nausea with poor response to oral triptans is not known. Possibly, nausea is a marker for particularly severe migraine that is treatment resistant – although observations of the natural course of untreated migraine attacks show that nausea and severe headache pain can occur independently of each other within attacks. Alternatively, nausea may constitute a marker for migraine-associated gastric stasis, which can impair absorption of triptan tablets – a topic further discussed elsewhere in this supplement. Nausea-associated impairment of absorption could underlie the poor response to oral triptans in patients with pretreatment nausea. Studies comparing the efficacy of oral triptan tablets with that of non-oral forms whose absorption is not impacted by gastric function would shed light on this possibility. The basis of the association of nausea with poor response to oral triptans warrants further assessment.
Triptans and Treatment-Emergent Nausea
Nausea is a defining feature of migraine. Although not present during every migraine attack in all patients, nausea is pervasive: among the 6448 respondents with episodic migraine and nausea symptom data in the American Migraine Prevalence and Prevention (AMPP) study, approximately half (49.5%) reported high-frequency nausea (defined as nausea at least half the time) with headache. Some evidence suggests that, besides being a feature of migraine, nausea may be a side effect of oral triptans. In clinical trials of oral triptans, nausea is often among the most common treatment-emergent drug-related adverse events.[5, 13] Moreover, in oral triptan clinical trials,6-8 but not in migraine trials of sumatriptan subcutaneous injection, nausea is often the most common adverse event of any cause reported more frequently with active treatment than with placebo. These observations are consistent with the possibility that oral triptans cause or exacerbate nausea; however, the degree to which the nausea is attributable to oral triptan therapy vs the ongoing migraine attack itself is difficult to determine. One strategy to further investigate this possibility is to compare treatment-emergent nausea in a placebo-controlled trial of an oral triptan only in those patients who achieve freedom from pain at 2 hours. In this type of comparison, nausea is unlikely to be a residual or emergent symptom of the migraine attack, but rather is likely to be due to the drug administered.
While post-treatment nausea is likely a result of the ongoing migraine attack in many cases, it would not be surprising if, consistent with investigators' categorization of nausea as a drug-related adverse event,[5, 13] oral tablets taken by patients for a migraine attack contribute to development of nausea. The threshold for development of nausea during a migraine attack is likely low in many patients. Among such patients, eating, drinking, and use of oral medications could trigger nausea in patients without nausea at pretreatment baseline or could exacerbate it in patients with baseline nausea. The possibility that the oral route of delivery of triptans accounts for the triggering or exacerbation of nausea is supported by the observation that, while nausea is often reported as an adverse event more often with triptan tablets than with placebo,6-8 it is not reported as an adverse event more often in migraine with sumatriptan subcutaneous injection than placebo.
The phenomenon of treatment-emergent nausea with oral triptans has not been fully characterized nor has its potential causes been assessed. Results of the only investigation to date to assess treatment-emergent nausea with triptans have been inconclusive. In this post-hoc analysis of clinical trial data from patients with no nausea at pretreatment baseline, nausea was reported as a symptom (rather than an adverse event) over the 2-hour postdose period significantly more often with 100 mg sumatriptan tablets than with placebo ( Figure). However, this pattern of results was not observed with other oral triptans. Systematic elucidation of treatment-emergent nausea is warranted given its impact on the patient and the course of treatment of migraine. Should treatment-emergent nausea prove to be caused by use of oral triptans, then use of non-oral formulations with less or no nausea-triggering or -exacerbating capability should be considered. In designing studies to investigate treatment-emergent nausea, the possibility that oral triptans could induce nausea in some patients and relieve it in others should be borne in mind. In the event that oral triptans induce nausea in some patients and relieve it in others, the impact of oral triptans on nausea could be obscured in a study employing a between-subjects design. A within-subjects design would be the most appropriate means of assessing the impact of oral triptan therapy on treatment-emergent nausea.
Summary and Conclusions
The data reviewed in this paper may have important clinical implications. If pretreatment nausea predicts poor response to oral triptans, and oral triptans are associated with iatrogenic nausea, then the use of oral triptans in migraine attacks with nausea or in patients prone to nausea should be reevaluated, and alternative routes of triptan administration should be considered. Because these observations are derived from a small evidence base, additional research is needed to explain the relationship between nausea and oral triptans and to refine the treatment approach to migraineurs whose attacks include nausea as a prominent feature.
The author acknowledges Jane Saiers, PhD (The WriteMedicine, Inc.), for assistance with writing the manuscript. Dr. Saiers' work was funded by NuPathe Inc.