Migraine and Gastroparesis From a Gastroenterologist's Perspective

Authors


  • Conflict of Interest: Consultant for NuPathe Inc, ProStraken, Inc, Evoke Pharma, GSK, Tranzyme Pharmaceuticals, Rhythm, Inc.

Address all correspondence to H.P. Parkman, GI Section – Parkinson Pavilion 8th Floor, Temple University School of Medicine, 3401 North Broad Street, Philadelphia, PA 19140, USA.

Abstract

Gastroparesis is a chronic stomach disorder manifested by delayed emptying of solids and liquids without evidence of mechanical obstruction. Evidence from pharmacokinetic and gastric motor studies conducted over the past 40 years shows that delayed gastric emptying often occurs in migraine. This paper provides a general overview of gastroparesis for the headache specialist, discusses the research on the association of gastroparesis and migraine, and considers the clinical implications of that association. The nature, causes, correlates, and consequences of gastric stasis in migraine are just beginning to be elucidated; much further study is warranted. The data available to date show that gastric stasis in migraine appears to be clinically important. Evidence from both pharmacokinetic studies and studies measuring gastric motor function suggests that gastric stasis may delay absorption of an orally administered drug, delay its peak serum concentrations, and delay its effectiveness. These results suggest that oral migraine medications, which rely on absorption from the gastrointestinal tract, may be affected in the presence of migraine-associated gastric stasis. Several non-oral formulations that do not rely on gastrointestinal absorption are available or in development for the treatment of migraine and symptoms of gastroparesis.

Abbreviations: 
AUC

area under the curve

Botox

botulinum toxin

Gastroparesis is a chronic stomach disorder manifested by delayed emptying of solids and liquids without evidence of mechanical obstruction.[1] Pharmacokinetic and gastric motor studies conducted over the past 40 years show that delayed gastric emptying can occur in patients with migraine.[1] This paper provides a general overview of gastroparesis for the headache specialist, discusses the research on the association of gastroparesis and migraine, and considers the clinical implications of that association.

Gastroparesis Overview

Incidence and Prevalence

The epidemiology of gastroparesis has not been systematically studied. In the United States, the condition appears to be common and to occur more often in women than men. Data from the Rochester Epidemiology Project, a database of linked medical records of residents of Olmsted County, Minnesota, show that the age-adjusted incidence of definite gastroparesis per 100,000 person-years for the years 1996 to 2006 was 9.8 for women and 2.4 for men[2] (definite gastroparesis was defined as diagnosis of delayed gastric emptying by standard scintigraphy and symptoms of nausea and/or vomiting, postprandial fullness, early satiety, bloating, or epigastric pain for more than 3 months). The age-adjusted prevalence of definite gastroparesis per 100,000 persons was 37.8 for women and 9.6 for men.

The prevalence of gastroparesis might be increasing. Data from the US Healthcare Cost and Utilization Project Nationwide Inpatient Sample, a nationally representative sample of 5 to 8 million hospitalizations per year, show that from 1995 to 2004, hospitalizations with gastroparesis as the primary diagnosis increased by 158% and those with gastroparesis as the secondary diagnosis increased by 136% compared with a 13% increase in all hospitalizations.[3] Of the 5 upper gastrointestinal conditions studied as primary diagnoses (ie, gastroparesis, gastroesophageal reflux disease, gastric ulcer, gastritis, non-specific nausea/vomiting), gastroparesis had the longest length of stay and the second highest total costs in 1995 and 2004. The increase in hospitalization rate for gastroparesis could reflect increasing prevalence and/or the effects of heightened awareness about and better identification of gastroparesis.[3]

Symptoms

Common symptoms of gastroparesis include nausea (>92% of patients), vomiting (84% of patients), and early satiety (60% of patients).[4] Other symptoms include postprandial fullness; postprandial abdominal distension; abdominal pain, which is often meal induced and nocturnal; and bloating.[5, 6] Symptoms can be persistent or can manifest as episodic flares.

Symptom profile can be established and symptom severity assessed with the Gastroparesis Cardinal Symptom Index, a subset of the Patient Assessment of Upper Gastrointestinal Symptoms.[7] The GCSI comprises 3 subscales (nausea and vomiting, postprandial fullness and early satiety, and bloating) that the patient scores with reference to the preceding 2 weeks.[7] A variant on the GCSI, the GCSI daily diary, can be used to record symptoms on a daily basis and may be more accurate in recording symptoms.[8]

Etiology

Major etiologies of gastroparesis are diabetic, post-surgical, and idiopathic.[1, 9, 10] Less common causes of gastroparesis include connective tissue disease, ischemia, cancer, neurologic disease such as Parkinson's, eating disorders, metabolic or endocrine conditions, medications such as anticholinergics or opiates, and critical illness.[9]

Gastroparesis is a relatively common complication of diabetes: delayed gastric emptying appears to occur in approximately one third to two thirds of patients with long-standing type 1 diabetes and approximately one third of patients with type 2 diabetes.[9] Diabetic gastroparesis, likely attributed to disease-associated damage to the vagus nerve, is frequently observed in association with other diabetic complications such as neuropathy, retinopathy, and nephropathy. Glucose can modify gastric emptying tests and symptoms; hyperglycemia can delay gastric emptying and worsen symptoms of gastroparesis, whereas hypoglycemia may accelerate gastric emptying.[11]

Post-surgical gastroparesis can occur with many types of operations but is most often observed after upper abdominal procedures due to injury to the vagus nerve.[1] Bariatric surgeries and pancreatic surgery have also been associated with gastroparesis.

Profiles of 243 patients with idiopathic gastroparesis enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry were recently characterized based on medical histories, symptoms questionnaires, and gastric emptying scintigraphy.[12] Patients' mean age was 41 years, and the majority (88%) were female. Approximately half of patients were overweight or obese (46%). Half (50%) had acute onset of symptoms. The most common presenting symptoms were nausea (34%), vomiting (19%), and abdominal pain (23%). Severe delay in gastric emptying (>35% retention at 4 hours) was present in 28% of patients. Severe delay in gastric emptying was associated with more severe symptoms of nausea and vomiting and loss of appetite compared with patients with mild or moderate delay. The percentages of patients with severe anxiety and severe depression were 36% and 18%, respectively; 86% met criteria for functional dyspepsia. The authors concluded that idiopathic gastroparesis is a heterogeneous syndrome that primarily affects young women and often affects overweight or obese individuals.

Pathophysiology

Gastric emptying is mediated by the autonomic nervous system, which regulates fundic accommodation, antral contraction, and pyloric relaxation.[1] These regional gastric motility changes with food ingestion are mediated through smooth muscle cells, which control stomach contractions; interstitial cells of Cajal, which regulate gastric pacemaker activity; and enteric neurons, which initiate smooth muscle cell activity.[1] The pathophysiology of gastroparesis has not been fully elucidated but appears to involve abnormalities in functioning of all 3 elements (autonomic nervous system, smooth muscle cells, enteric neurons). Histologic studies demonstrate defects in the morphology of enteric neurons, smooth muscle cells, and interstitial cells of Cajal and increased concentrations of inflammatory cells in gastric tissue.[1, 9, 10]

A minority of patients with idiopathic gastroparesis (19% in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry study noted earlier[12]) report an initial infectious prodrome such as gastroenteritis or respiratory infection. It has been suggested that idiopathic gastroparesis of acute onset with infectious prodrome could constitute postviral or viral injury to the neural innervation of the stomach or the interstitial cells of Cajal in the stomach.

Diagnosis

Differential diagnosis of gastroparesis entails excluding other possible causes including gastric outlet obstruction, peptic ulcer disease, neoplasm, small bowel obstruction, and inflammatory bowel disorder.[9] For evaluating gastric motor function, the standard test is gastric emptying scintigraphy, which uses a labeled isotope bound to solid food to image gastric motility.[9, 13] Examples of normal and delayed gastric emptying rates measured with gastric emptying scintigraphy after consumption of a low-fat egg-white sandwich meal with water are shown in the Figure.

Figure —.

Illustrations of normal and delayed gastric emptying rate (% gastric retention of meal) after a low-fat egg-white sandwich meal with water. Image courtesy of Drs. Henry Parkman and Alan Maurer.

Use of a wireless motility capsule to quantify luminal pH and pressure is an alternative to gastric emptying scintigraphy.[9] This test measures whole-gut transit – that is, gastric emptying, small bowel transit, and colonic transit. Gastric emptying is manifested by a significant, sustained increase in pH as the capsule passes from the acidic stomach to the alkaline small intestine.

Breath tests, another alternative to gastric emptying scintigraphy, measure radiolabeled CO2 in exhaled breath samples after duodenal processing of a consumed substrate.[9] Findings generally correlate well with results of gastric emptying scintigraphy. This test is used clinically in Europe, whereas in the United States, breath tests are most often employed in research studies and rarely used in the clinic.

While gastric motor testing is useful in diagnosing gastroparesis, it has drawbacks. First, gastric emptying rates measured by gastric motor testing generally correlate poorly with symptoms and quality-of-life impact of gastroparesis.[14, 15] This finding suggests that factors in addition to slow gastric emptying contribute to symptoms. Relatively high interindividual and intraindividual variability in gastric emptying rates measured with gastric motor testing constitutes another limitation of gastric motor testing.[9] The relative contributions to these variabilities of gastric motor testing methodology and biologic inconsistency in gastric emptying are not currently known.

Management

Management of gastroparesis is guided by the goals of correcting fluid, electrolyte, and nutritional deficiencies; identifying and treating the cause of delayed gastric emptying (eg, diabetes); and suppressing or eliminating symptoms.[1] Treatment approaches include dietary modification, medications to enhance gastric emptying or control emesis, surgical and endoscopic approaches, and psychological interventions.[9, 16] Many approaches have not been evaluated in placebo-controlled studies, and the relative usefulness of the various treatment options remains to be established.[9]

Dietary measures entail adjustment to meal composition and frequency.[1, 9] Eating small meals is recommended as patients often have early satiety, that is, feeling full when eating a normal size meal, In addition, larger meals may alter gastric emptying times.[17, 18] Consuming mainly liquids such as soups and stews can be useful as gastric emptying of liquids is often preserved in patients with gastroparesis.[1] Avoidance of fats and indigestible fibers is recommended because they delay gastric emptying.[1, 9] When small meals are used in the gastroparesis diet, more frequent meals, ∼4-5 meals per day, are often needed to maintain caloric intake.

Medications with gastric prokinetic properties, which are the mainstay of treatment for gastroparesis, include metoclopramide, erythromycin, and domperidone.[16, 19] Metoclopramide is the only medication licensed in the United States for the treatment of gastroparesis.[1] Anti-emetics include the phenothiazine derivatives (eg, prochlorperazine), the serotonin-3 receptor antagonists (eg, ondansetron), the dopamine receptor antagonists (eg, metoclopramide), the histamine receptor antagonists (eg, diphenhydramine), and benzodiazepines (eg, lorazepam).[1, 19]

Surgical and endoscopic approaches are considered in patients in whom drug therapy is ineffective and who cannot meet their nutritional requirements.[1] Endoscopic treatment entails injection of botulinum toxin (Botox; Allergan, Inc., Irvine, CA, USA) into the pyloric sphincter. Botox injections reduce pyloric muscle spasms that are thought to contribute to delayed gastric emptying. Although this may help in some patients, controlled clinical trials have not shown efficacy of this treatment.

Surgical treatments include placement of jejunostomy tubes and gastric electrical stimulation.[1] These options are typically considered only in patients with severe, refractory gastroparesis.

Migraine and Gastroparesis

Evidence suggests that migraine attacks are associated with delayed gastric emptying.[20] Nausea, a symptom of gastric stasis, is also a defining feature of migraine headaches. Episodic migraine, according to International Classification of Headache Disorders, 2nd edition criteria, is manifested by headache that is not attributed to another disorder and that lasts 4 to 72 hours (untreated or unsuccessfully treated) with at least 2 of the characteristics of (1) unilateral location; (2) pulsating quality; (3) moderate or severe pain intensity; and (4) aggravation by or causing avoidance of routine physical activity with (1) nausea and/or vomiting and/or (2) photophobia and phonophobia.[21] The nature of the relationship between gastric stasis and migraine-associated nausea is unknown. Gastric stasis has been hypothesized to be a reason for the nausea that occurs in headaches. Alternatively or in addition, acute nausea is thought to delay gastric emptying.[20]

The initial evidence for the association between migraine and gastroparesis came from studies assessing the pharmacokinetics of drugs used in the treatment of migraine.22-25 The results show that rates of absorption of migraine drugs are generally slower during migraine attacks than during migraine-free periods and in migraineurs during migraine attacks compared with nonmigraineurs. In addition, rate of absorption of migraine drugs could be enhanced by administration of metoclopramide, which facilitates gastric emptying.[23, 25]

For example, in a series of studies, salicylate absorption from effervescent aspirin tablets was reduced in migraine patients during a migraine attack relative to a migraine-free period and in migraine patients compared with nonmigrainous control individuals.[22] The reduced absorption had therapeutic consequences as patients in whom aspirin absorption was delayed took longer to respond to therapy and were more likely to need additional treatment than those in whom absorption was not delayed. Metoclopramide improved the rate of absorption of aspirin. In other research, absorption of orally administered tolfenamic acid was delayed during a migraine attack compared with a migraine-free period in 7 female patients with migraine[23] Pretreatment with rectally administered metoclopramide before migraine attacks enhanced absorption of orally administered tolfenamic acid. A similar effect of a migraine attack on absorption of orally administered acetaminophen has been documented.[24, 25]

Absorption of triptans, like the non-specific medications described earlier, might be affected during a migraine attack,[26] although some research has not demonstrated this effect.[27, 28] In an open, 2-period study, the oral absorption of zolmitriptan 10 mg was compared during a moderate or severe migraine attack vs a migraine-free period in 20 patients.[26] Zolmitriptan was less rapidly absorbed during a migraine attack compared with the migraine-free period. The median area under the curve (AUC) was 15.7 ng/mL/h lower during a migraine (median AUC: 18.4 ng/mL/h) compared with a migraine-free period (median AUC: 33.4 ng/mL/h), and the time to reach maximum plasma concentration was delayed. Plasma zolmitriptan concentrations were generally higher in those patients who responded to treatment.[26]

The indirect evidence of impaired gastric emptying in these pharmacokinetic studies is complemented by more recently obtained direct evidence of impaired gastric emptying measured by gastric emptying scintigraphy.[20, 29] Interestingly, the gastric emptying scintigraphy studies suggest that gastric stasis might occur interictally in migraine as well as during a migraine attack. In one study, gastric emptying scintigraphy using a standard meal was performed in migraine patients both during a migraine attack and interictally as well as in age- and sex-matched controls (n = 10 per group).[20] Among migraineurs, based on T1/2, most of the migraineurs met or nearly met the clinical diagnostic criteria for “gastroparesis” ictally (78%) and interictally (80%) using normative data at this institution the time to half emptying was delayed compared with normative data from the institution both during a migraine attack (by 78%) and during the interictal period (by 80%). Gastric stasis was less pronounced during a migraine attack (149.9 minutes) compared with an interictal period (188.8 minutes). Gastric emptying was significantly delayed in migraineurs (interictally) compared with nonmigrainous controls (migraine 188.8 minutes vs controls 111.8 minutes). In another study performed in 3 patients with migraine, gastric emptying measured with gastric emptying scintigraphy was delayed during a spontaneous migraine attack (124 minutes), a migraine attack induced by a visual trigger (182 minutes), and an interictal period (243 minutes) compared with normal values.[29] The authors suggested that the interictal abnormality in gastric emptying might be attributed to abnormal autonomic nervous system functioning in migraineurs compared with controls. The data from both of these studies should be interpreted in the context of the small sample sizes. While the phenomenon of gastric stasis during a migraine attack is well established in the pharmacokinetic and gastric motor studies, the possibility of interictal gastric stasis in migraine warrants further study in other patient populations and settings.

The degree of delay in gastric emptying measured by epigastric impedance correlated with the severity of migraine symptoms in 14 migraineurs studied during 20 migraine attacks.[30] Gastric emptying was delayed during moderate or severe attacks, and delays were significantly correlated with the intensity of headache, nausea, and photophobia. In contrast, gastric emptying measured by epigastric impedance fell within the predicted normal range in 64 nonmigraineur control patients and 46 migraine patients outside an attack. The results of this study should be interpreted in the context of its limitations, which include lack of information on use of concomitant medications that can affect gastric emptying, and the use of the as yet unvalidated technique of epigastric impedance. The findings warrant extension in studies using other methods to measure gastric motor function.

Conclusions

The nature, causes, correlates, and consequences of gastric stasis in migraine are just beginning to be elucidated; much further study is warranted. The data available to date show that gastric stasis in migraine appears to be clinically important because gastric stasis may delay absorption of an oral drug, delay its peak serum concentrations, and delay its effectiveness. These results suggest that oral migraine medications, which rely on absorption from the gastrointestinal tract, may be less effective to use in the context of migraine-associated gastric stasis. Several non-oral formulations that do not rely on gastrointestinal absorption are available or in development for the treatment of migraine. In the context of gastric stasis associated with migraine, the latter formulations should be considered in patient management.

Acknowledgments

This manuscript was taken, in part, from a lecture titled “Migraine Headaches and Gastroparesis from a Gastroenterologist's Perspective” given in May 2011 by Dr. Henry Parkman. The author acknowledges Jane Saiers, PhD (The WriteMedicine, Inc.), for assistance with editing the manuscript. Dr. Saiers' work was funded by NuPathe Inc.

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