Why Triptan Treatment Can Fail: Focus on Gastrointestinal Manifestations of Migraine
- Conflict of Interest: Consultant for NuPathe, speaker's bureau for Allergan, MAP, Nautilus and Zogenix, royalty with Oxford University Press and Springer, grants with Allergan and NuPathe.
Address all correspondence to L.C. Newman, The Headache Institute at Roosevelt Hospital Center, 425 W. 59th Street, Suite 4A, New York, NY 10019, USA.
Results of randomized, double-blind, controlled studies establish the efficacy of triptans in the acute treatment of migraine, but triptan benefits demonstrated in clinical trials have not consistently been realized in clinical practice. This paper explores the contribution of gastrointestinal manifestations of migraine – namely nausea (with or without vomiting) and gastroparesis – to triptan treatment failure.
Migraine-related nausea and vomiting and migraine-associated gastroparesis appear to be prevalent and highly impactful and have been characterized as being among the greatest challenges affecting migraine care today. These gastrointestinal signs and symptoms have not been satisfactorily taken into account in the management of migraine, which is dominated by the use of oral therapies. Oral triptans are not the optimal therapy in the presence of migraine-related nausea because nausea predicts poor response to oral triptans and because nausea can cause patients to delay oral treatment, which can further compromise therapeutic efficacy. Oral triptans are not the optimal therapy in the presence of migraine-associated gastroparesis because these agents rely on gastric motility and gastrointestinal absorption and may be ineffective or slowly or inconsistently effective in the presence of gastroparesis. Health care providers need to work with their patients to address the still-all-too-frequent problem of treatment failure in migraine. First, health care providers need to have greater appreciation of the importance of nausea, vomiting, and gastroparesis as factors affecting migraine prognosis and treatment success. Second, health care providers need to systematically assess migraine patients for gastrointestinal signs and symptoms. Finally, patients and health care providers need to be willing to practice customized migraine care, in which patients tailor the treatment and formulation to the characteristics and context of the individual migraine episode.
American Migraine Prevalence and Prevention
Sumatriptan Naratriptan Aggregate Patient
Triptans for Migraine
For the acute treatment of migraine, several triptans are available including sumatriptan, naratriptan, rizatriptan, zolmitriptan, frovatriptan, eletriptan, and almotriptan.1-4 All triptans are available as oral tablets, or, some also as orally disintegrating tablets, and some of the triptans are also available in additional formulations including intranasal and subcutaneous forms. The availability of multiple triptans and multiple formulations facilitates the tailoring of therapy to individual patients' needs.
Results of randomized, double-blind, controlled studies establish the efficacy of triptans in the acute treatment of migraine. However, triptan benefits demonstrated in clinical trials have not consistently been realized in clinical practice. Results of real-world studies demonstrate high rates of patient dissatisfaction with current migraine therapy.[7, 8] In one recent study, for example, 42% of 183 migraineurs at 3 headache centers were dissatisfied with the degree of relief provided by their acute migraine medication – a triptan oral tablet for the majority of patients – and 37% were dissatisfied with the speed of relief. Dissatisfaction with treatment is linked to a high rate of discontinuation of the triptans and may be the cause of the low triptan utilization and high turnover in clinical practice.
The reasons for treatment failure in migraine often relate to incomplete or incorrect diagnosis; missing and therefore failing to address important exacerbating factors; inadequate pharmacotherapy; inadequate nonpharmacologic treatment; and other factors such as the patient's unrealistic expectations, failure to account for the influence of comorbid conditions, and the need for inpatient treatment ( Box). These reasons, which have been comprehensively reviewed elsewhere, also apply specifically to failure of triptan treatment. This paper explores the contribution of gastrointestinal manifestations of migraine – namely nausea (with or without vomiting) and gastroparesis – to triptan treatment failure. Gastrointestinal manifestations of migraine have been characterized as being among the greatest challenges affecting migraine care today.
Box 1. Possible Reasons for Treatment Failure in Migraine. From Lipton et al
- The diagnosis is incomplete or incorrect
- A secondary headache disorder goes undiagnosed
- A primary headache disorder is misdiagnosed
- The number of headache disorders is not clear
- Important exacerbating factors have been missed
- Acute headache medication or caffeine overuse
- Hormonal triggers
- Dietary or lifestyle triggers
- Psychosocial factors
- Other medications
- Pharmacotherapy has been inadequate
- Ineffective drug
- Excessive initial doses
- Inadequate final doses
- Inadequate duration of treatment
- Combination therapy required
- Poor absorption
- Nonpharmacologic treatment has been inadequate
- Physical medicine
- Cognitive behavioral therapy
- Other factors
- Unrealistic expectations
- Comorbid and concomitant conditions
- Inpatient treatment required
The Importance of Gastrointestinal Symptoms and Signs in Migraine
The failure to account for the heterogeneity of migraine in setting treatment strategies may help to explain the high rates of dissatisfaction with triptans and their low utilization and high turnover in clinical practice. The features of migraine attacks and the contexts in which migraine attacks occur vary from attack to attack as well as from patient to patient. Current treatment strategies, which are dominated by the use of oral forms of migraine medication, do not address this heterogeneity. While the oral tablet can be effective for many types of migraine attacks a patient can experience, it is not the optimum treatment for every migraine or every patient. Migraine attacks associated with gastrointestinal symptoms and signs, in particular, are not best treated by oral medications.
Nausea in Migraine
The majority of migraineurs (≥73%) have experienced nausea (with or without vomiting) during migraine episodes, and most experience nausea during most of their migraine episodes.[13, 14] Among the 6448 respondents with episodic migraine and nausea symptom data in the 2009 American Migraine Prevalence and Prevention (AMPP) survey, approximately half (49.5%) reported high-frequency nausea (ie, ≥half the time) with headache. Patients with high-frequency nausea compared with those with no/rare nausea were significantly more likely (P ≤ .05) to experience other headache symptoms frequently; to be disabled or on medical leave; to have higher grades of disability; to have greater headache severity and impact; to be dissatisfied with medication; and to report higher levels of agreement that headache medications interfered with ability to work and to perform other activities. The authors of that study concluded that high-frequency migraine-associated nausea is prevalent and likely contributes to causing migraine-associated disability and impact. They identified nausea as a marker for severe, debilitating migraine and suggested that effective management of nausea could reduce the burden of headache among those with episodic migraine.
The presence of nausea predicts poor response to oral triptans. In a study using the Sumatriptan Naratriptan Aggregate Patient database, 24 possible univariate predictors of headache response (ie, headache relief or pain-free response) were assessed in 3706 patients who received sumatriptan tablets 100 mg or placebo in double-blind studies. Nausea was one of 7 significant predictors of failure to experience headache relief 2 hours postdose and one of 9 significant predictors of failure to experience pain-free response 2 hours postdose. Similarly, in an analysis of data from 10 randomized, double-blind, placebo-controlled eletriptan migraine trials (n = 8473), the strongest baseline predictors of failure to achieve pain-free response 2 hours postdose were presence of nausea, severe headache pain, and presence of photophobia/phonophobia.
The reason that nausea predicts poor response to triptans has not been determined. Possibly, as suggested by the AMPP study authors, nausea is a marker for severe, debilitating migraine. Nausea can also be associated with poor response because it influences patients' medication-taking behavior. Migraine-associated nausea can cause patients to delay or avoid taking oral medication, with a resultant reduction or loss of therapeutic efficacy; vomiting can render oral medications ineffective in the event medication is expelled. In a 2010 National Headache Foundation survey of 500 US migraineurs, 66% reported that nausea and/or vomiting accompany their migraines. Among the patients who took prescription oral medication (n = 271), approximately 4 in 10 indicated that they had delayed or avoided taking medication because of migraine-associated nausea or vomiting. Delayed administration of triptan tablets has therapeutic consequences: for example, almotriptan demonstrated significantly better efficacy when administered early in the migraine episode when pain is still mild.
Gastroparesis in Migraine
Like nausea and vomiting, migraine-associated gastroparesis can affect therapeutic efficacy. (Gastroparesis associated with migraine is discussed from a gastroenterologist's perspective elsewhere in this supplement.) Several studies have demonstrated an association between the presence of migraine headache and delayed gastric emptying.21-23 Gastric emptying appears to be slowed in migraineurs outside of an attack relative to gastric emptying in individuals without migraine. Research using gastric scintigraphy demonstrates that there was a significant delay in migraineurs compared with nonmigrainous controls. Furthermore, migraineurs had a 78% to 80% slower rate of gastric emptying both ictally and interictally. The slow rate of gastric emptying in migraineurs can retard drug absorption[21, 22] with resultant compromise of therapeutic efficacy.
Delay in gastric emptying is associated with nausea in migraine. In 64 control patients without migraine and 46 migraine patients not experiencing a migraine attack, gastric emptying times were within the predicted normal range (although they were higher in migraineurs outside an attack than in nonmigraineur control patients [T 10.1 vs 8.7 minutes]). Gastric emptying times in 14 migraineurs during 20 attacks were delayed during severe or moderate attacks. Among these patients, gastric emptying rate was significantly correlated with the intensity of headache, nausea, and photophobia. Gastric stasis may cause the nausea that occurs with some migraine attacks.
Gastrointestinal Signs and Symptoms in Migraine: Therapeutic Implications
Migraine-related nausea and vomiting and migraine-associated gastroparesis appear to be prevalent and highly impactful. These gastrointestinal signs and symptoms have not been satisfactorily taken into account in the management of migraine, which is dominated by the use of oral therapies. Oral triptans are not the optimal therapy in the presence of migraine-related nausea because nausea predicts poor response to oral triptans and because nausea can cause patients to delay treatment, which can further compromise therapeutic efficacy. Oral triptans may not be the optimal therapy in the presence of migraine-associated gastroparesis because these agents rely on gastric motility and gastrointestinal absorption and may be ineffective or slowly or inconsistently effective in the presence of gastroparesis. Similarly, nasal spray preparations are not wholly absorbed in the nasal passages. Sprays often enter the nasal pharynx and are swallowed, so they, too, depend in part on gastrointestinal absorption.
Most of the therapeutic challenges presented by gastrointestinal signs and symptoms of migraine relate to the impact of these signs and symptoms on drug delivery. Nausea delays drug delivery by causing patients to delay taking oral medications. Gastroparesis delays drug delivery via an impact on drug absorption. Vomiting prevents drug delivery through expulsion of medication. Nonoral drug delivery routes that negate or minimize the impact of gastrointestinal signs and symptoms should be useful in overcoming these challenges. The choice of nonoral drug delivery routes should be customized to the individual patient and migraine attack. Strengths and limitations of triptan delivery systems are listed in the Table. Sumatriptan injection is rapidly effective but appears to have a greater side effect burden than other triptan formulations – probably because the injection produces higher maximal concentrations than the other forms. Moreover, many patients dislike using injections. Triptan nasal sprays, besides relying in part on gastrointestinal absorption, have a bitter taste, which can be particularly adverse for patients experiencing nausea and/or vomiting. The bitter or bad taste can lead the patient to delay or avoid treatment.
Table 1. Strengths and Limitations of Currently Available Triptan Delivery Systems. Modified From Rapoport et al
- Rapid onset of relief
- Rapid, consistent, high plasma concentrations
- Robust efficacy
- Bypasses gastric stasis problems
- Bypasses hepatic first-pass metabolism
- Uncomfortable/painful delivery
- Administration not discreet
- Increased triptan adverse effects
- Injection-site irritation
- Increase in all adverse effects
- May exacerbate nausea and vomiting because of injection delivery and rapid rise in plasma and brain concentrations (tingling, flushing)
|Nasal spray|| |
- Rapid onset of relief
- Robust efficacy
- Partially bypasses gastric stasis problems
- Partially bypasses hepatic first-pass metabolism
- Unpleasant and/or strange taste
- Not a familiar delivery approach
- Administration not discreet
- May exacerbate nausea because of taste
- Partially dependent on small bowel absorption as some drug is swallowed
- Possible local nasal irritation or stuffiness
|Oral tablets|| |
- Often preferred
- Requires liquid
- May exacerbate nausea
- Dependent on gastrointestinal absorption
- Lower bioavailability caused by hepatic first-pass metabolism
|Orally disintegrating tablets|| |
- Moderately familiar
- Does not require liquid
- May exacerbate nausea because of taste
- Dependent on gastrointestinal absorption
- Bioavailability influenced by hepatic first-pass metabolism
Health care providers need to work with their patients to address the still-all-too-frequent problem of treatment failure in migraine. First, health care providers need to have greater appreciation of the importance of nausea, vomiting, and gastroparesis as factors affecting migraine prognosis and treatment success. Second, health care providers need to systematically assess migraine patients for gastrointestinal signs and symptoms. Finally, patients and health care providers need to be willing to practice customized migraine care, in which patients tailor the treatment and formulation to the characteristics and context of the individual migraine episode. Support for the viability of formulation-based, customized care comes from studies conducted in clinical practice, where patients given the flexibility to choose among triptan formulations to manage their migraines did not restrict themselves to one formulation but instead chose a formulation best suited to the characteristics of the individual migraine episode.[26, 27]
The author acknowledges Jane Saiers, PhD (The WriteMedicine, Inc.), for assistance with writing the manuscript. Dr. Saiers' work was funded by NuPathe Inc.