Although prokinetic agents typically are used for gastroparesis, antiemetic, analgesic, and neuromodulatory medications may help manage nausea, vomiting, pain, or discomfort. Antiemetic benefits are supported by few case reports. An open series reported symptom reductions with transdermal granisetron in gastroparesis. Opiates are not advocated in gastroparesis because they worsen nausea and delay emptying. Neuromodulators have theoretical utility, but the tricyclic agent nortriptyline showed no benefits over placebo in an idiopathic gastroparesis study raising doubts about this strategy. Neurologic and cardiac toxicities of these medications are recognized. Additional controlled study is warranted to define antiemetic, analgesic, and neuromodulator usefulness in gastroparesis.
Key points
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A recent series reported reduced nausea and vomiting caused by open-label transdermal granisetron, a 5-hydroxytryptamine-3 (5-HT 3 ) receptor antagonist, in patients with gastroparesis.
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Opiate analgesics are often taken for pain control; however, caution should be exercised because these agents worsen nausea and vomiting and further delay gastric emptying.
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As with antiemetics, support for use of neuromodulatory agents was restricted to individual cases; however, the largely negative findings from a multicenter, randomized, placebo-controlled trial of the tricyclic antidepressant nortriptyline in patients with idiopathic gastroparesis raise doubts about the effectiveness of neuromodulators in this condition.
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Postulated benefits of antiemetic and neuromodulatory therapies must be weighed against adverse outcomes during gastroparesis treatment, which recently have stressed neurologic and cardiac toxicities of these drugs.
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Placebo-controlled trials must be conducted to characterize the usefulness of these drug classes in managing gastroparesis symptoms.
Introduction
Gastroparesis presents with a range of symptoms referable to the upper gut including nausea, vomiting, early satiety, postprandial fullness, bloating, distention, and upper abdominal pain or discomfort. Although increased gastric retention is mandated for diagnosis, gastroparesis symptom severity correlates poorly with the degree of gastric emptying delay. In a large gastroparesis cohort comprising both diabetic and idiopathic patients from the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Consortium, gastric retention measured at 2 and 4 hours showed no relation to overall or individual symptom intensities among 319 patients with delayed emptying and 106 with normal emptying. Likewise in functional dyspepsia, emptying parameters show no correlation or are only weakly associated with fullness but not nausea, pain, or bloating. One investigation calculated that only 10% of the variance in dyspeptic symptoms relates to gastric emptying rates. Other physiologic defects are proposed to contribute to symptom development. In studies in which combined gastric emptying and barostat testing was performed in dyspeptic patients, delayed gastric emptying correlated with nausea, vomiting, and postprandial fullness, whereas impaired gastric fundic accommodation associated with epigastric pain, early satiety, and weight loss. In a different report, the prevalence of hypersensitivity to gastric distention was greatest (44%) among patients who rated abdominal pain as their predominant symptom.
Because of the importance of delayed emptying in diagnosing gastroparesis, the main focus of treating this condition has been on prokinetic agents that promote gastric evacuation. However, in gastroparesis and functional dyspepsia, metoclopramide and domperidone reduce symptoms over the long term even when there is diminution of initial prokinetic effects with time. Many benefits of these agents may therefore stem from antiemetic effects in the central nervous system. Furthermore, agents with only prokinetic treatments without central antiemetic effects (erythromycin, pyloric botulinum toxin) may be less effective than therapies with combined prokinetic and antiemetic action. One systematic review calculated benefits in only 43% of patients with gastroparesis receiving erythromycin.
These investigations raise the possibility that pharmaceuticals with actions unrelated to gastrokinesis may be beneficial for some gastroparesis manifestations. Medications with only antiemetic mechanisms of action would theoretically be effective with prominent vomiting (and nausea). In contrast, central analgesics or drugs targeting other sensorimotor defects, such as enhanced sensitivity or impaired accommodation, might be useful for discomfort or pain.
Introduction
Gastroparesis presents with a range of symptoms referable to the upper gut including nausea, vomiting, early satiety, postprandial fullness, bloating, distention, and upper abdominal pain or discomfort. Although increased gastric retention is mandated for diagnosis, gastroparesis symptom severity correlates poorly with the degree of gastric emptying delay. In a large gastroparesis cohort comprising both diabetic and idiopathic patients from the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Consortium, gastric retention measured at 2 and 4 hours showed no relation to overall or individual symptom intensities among 319 patients with delayed emptying and 106 with normal emptying. Likewise in functional dyspepsia, emptying parameters show no correlation or are only weakly associated with fullness but not nausea, pain, or bloating. One investigation calculated that only 10% of the variance in dyspeptic symptoms relates to gastric emptying rates. Other physiologic defects are proposed to contribute to symptom development. In studies in which combined gastric emptying and barostat testing was performed in dyspeptic patients, delayed gastric emptying correlated with nausea, vomiting, and postprandial fullness, whereas impaired gastric fundic accommodation associated with epigastric pain, early satiety, and weight loss. In a different report, the prevalence of hypersensitivity to gastric distention was greatest (44%) among patients who rated abdominal pain as their predominant symptom.
Because of the importance of delayed emptying in diagnosing gastroparesis, the main focus of treating this condition has been on prokinetic agents that promote gastric evacuation. However, in gastroparesis and functional dyspepsia, metoclopramide and domperidone reduce symptoms over the long term even when there is diminution of initial prokinetic effects with time. Many benefits of these agents may therefore stem from antiemetic effects in the central nervous system. Furthermore, agents with only prokinetic treatments without central antiemetic effects (erythromycin, pyloric botulinum toxin) may be less effective than therapies with combined prokinetic and antiemetic action. One systematic review calculated benefits in only 43% of patients with gastroparesis receiving erythromycin.
These investigations raise the possibility that pharmaceuticals with actions unrelated to gastrokinesis may be beneficial for some gastroparesis manifestations. Medications with only antiemetic mechanisms of action would theoretically be effective with prominent vomiting (and nausea). In contrast, central analgesics or drugs targeting other sensorimotor defects, such as enhanced sensitivity or impaired accommodation, might be useful for discomfort or pain.
Management goals
Given the disconnect between symptoms and gastric emptying, it is reasonable to propose that the primary goal of treating gastroparesis should focus on symptom reductions rather than stimulation of gastric emptying. Pharmacologic agents in diverse drug classes are available that decrease nausea, vomiting, and abdominal pain by acting as antiemetics, analgesics, or modulators of enteric neuronal function. These medications represent the sole forms of treatment of some individuals or may complement gastric prokinetic drugs in others. Little controlled investigation has been performed to define benefits of these agents in gastroparesis. Thus, use of these medications is based on pathophysiologic plausibility and expert opinion.
Pharmacologic strategies
The benefits of antiemetic, analgesic, and neuromodulatory medications in gastroparesis are unproved and may be modest in scope. Because of these limitations, decisions on any gastroparesis therapies rely on defining and assessing the severity of symptoms that represent the target of treatment. Introduction of validated surveys to measure numerical symptom intensity represents an advance in quantifying gastroparesis severity. The Gastroparesis Cardinal Symptom Index (GCSI) comprises 9 questions in 3 domains (nausea/vomiting, fullness/early satiety, bloating/distention) rated from 0 (no symptoms) to 5 (very severe) and shows good test-retest reliability and treatment response. The GCSI–Daily Diary adds a pain/discomfort domain to this survey and is administered daily. In comprehensive evaluations of a large patient cohort from the Gastroparesis Consortium followed for 48 weeks, overall GCSI scores decreased only by an average of 0.3 points while subjects were under the care of clinicians with expertise in managing this condition. Subjects with predominant nausea and/or vomiting more often improved than those with predominant upper abdominal pain. Future controlled investigations of novel therapies will determine whether medications targeting nausea and vomiting are more effective than those that are designed to reduce other gastroparesis symptoms.
Antiemetic Agents
Nausea is the most prevalent gastroparesis symptom, being experienced by 90% to 95% of patients, whereas 55% to 80% report vomiting. Nausea and/or vomiting represent the predominant symptoms, prompting specialist referral of 44% of patients ( Table 1 ). In a single-center study, nausea scores averaged 3.4 (on a scale from 0 to 5) over 8 hours daily in patients with both diabetic and idiopathic gastroparesis. Mean daily vomiting frequencies ranged from 3.5 with idiopathic disease to 7.3 for diabetics with gastroparesis. Vomiting with gastroparesis often occurs 30 to 120 minutes after eating. The vomitus may contain partially digested food residue from meals ingested days before.
| Predominant Symptom Subscale | Predominant Symptom | Individual Symptom (N) | Individual Symptom (%) | Symptom Subscale (N) | Symptom Subscale (%) |
|---|---|---|---|---|---|
| Abdominal pain/discomfort | Upper abdominal pain | 27 | 7 | 81 | 21 |
| Abdominal pain location not specified | 42 | 11 | |||
| Lower abdominal pain | 6 | 2 | |||
| Upper abdominal discomfort | 2 | 0.5 | |||
| Abdominal discomfort location not specified | 2 | 0.5 | |||
| Lower abdominal discomfort | 2 | 0.5 | |||
| Nausea/vomiting | Nausea | 135 | 34 | 172 | 44 |
| Vomiting | 36 | 9 | |||
| Retching | 1 | 0.3 | |||
| Postprandial fullness/early satiety | Stomach fullness | 26 | 7 | 47 | 12 |
| Not able to finish normal-sized meal | 8 | 2 | |||
| Feeling excessively full after meals | 8 | 2 | |||
| Loss of appetite | 5 | 1 | |||
| Bloating/distention | Bloating | 26 | 7 | 27 | 7 |
| Stomach or belly visibly larger | 1 | 0.3 | |||
| Esophageal symptoms | Heartburn during the day | 1 | 0.3 | 32 | 8 |
| Heartburn, did not specify day vs when lying down | 5 | 1 | |||
| Feeling of discomfort inside chest during day | 1 | 0.3 | |||
| Feeling of discomfort inside chest, did not specify day vs lying down | 4 | 1 | |||
| Regurgitation or reflux during day | 4 | 1 | |||
| Regurgitation or reflux lying down | 3 | 1 | |||
| Regurgitation or reflux, did not specify day vs lying down | 12 | 3 | |||
| Bitter, acid, or sour taste in mouth | 2 | 0.5 | |||
| Bowel habit abnormalities | Constipation | 18 | 5 | 33 | 8 |
| Diarrhea | 15 | 4 | |||
| Miscellaneous | No symptom specified | 1 | 0.3 | 1 | 0.3 |
Because of the prevalence and severity of nausea and vomiting in gastroparesis, antiemetic agents commonly are prescribed. In data on 416 patients from the Gastroparesis Consortium, antiemetics were used similarly with idiopathic disease (61%) and gastroparesis from type 1 (70%) and type 2 (66%) diabetes. However, symptom improvements are not different between gastroparetics who take versus do not take antiemetic drugs over 48 weeks of care. Although not specifically investigated, this suggests that antiemetics provide no more than modest benefits to gastroparetics referred to centers specializing in motility disorders.
Antiemetic drugs acting on several receptor subtypes have been developed for clinical conditions with nausea and vomiting ( Table 2 ). Histamine H 1 antagonists (eg, promethazine, meclizine, dimenhydrinate) are useful for vomiting in conditions with activation of the vestibular system (motion sickness, labyrinthitis), uremia, and postoperative settings. Side effects of antihistamines include sedation and mouth dryness. Nonsedating newer antihistamines (astemizole, cetirizine, fexofenadine) are less effective antiemetics. Muscarinic M 1 antagonists given orally or as transdermal patches (scopolamine) also are best characterized in labyrinthine conditions, including motion sickness, and can elicit side effects including sedation, dryness of the eyes and mouth, constipation, urinary retention, and headaches. Dopamine D 2 antagonists in the phenothiazine (eg, prochlorperazine) and butyrophenone (eg, droperidol, haloperidol) classes exert beneficial effects with vomiting from acute gastroenteritis, medication and cancer chemotherapy, radiation therapy, and surgery. Therapy with dopamine antagonists may cause sleep disturbances, mood changes, anxiety, and movement disorders, and gynecomastia, galactorrhea, or menstrual irregularities from drug-induced hyperprolactinemia. Some agents with antidopaminergic activity also evoke antihistaminic and antimuscarinic side effects. Serotonin 5-hydroxytryptamine-3 (5-HT 3 ) antagonists (eg, ondansetron, granisetron, dolasetron, palonosetron) can be swallowed, dissolved within the mouth, administered intravenously, or applied transdermally. 5-HT 3 antagonists are effective for prophylaxis of emesis and postoperative vomiting induced by chemotherapy and radiotherapy but also have been used for bulimia nervosa, emesis caused by hepatic or renal disease, and nausea with human immunodeficiency virus infection. In contrast, 5-HT 3 antagonists offer only limited benefits to prevent nausea instead of vomiting. 5-HT 3 antagonist use is complicated by constipation, headaches, increased liver chemistries, and cardiac rhythm disturbances secondary to QTc interval prolongation. Neurokinin -1 receptor subtype (NK 1 ) antagonists show potent antiemetic effects for chemotherapy-induced nausea and vomiting, postoperative nausea and vomiting, and motion sickness given orally (aprepitant) or intravenously (fosaprepitant). Unlike 5-HT 3 antagonists, NK 1 antagonists are effective at reducing nausea as well as vomiting. Side effects of these agents include bowel habit changes, anorexia, and singultus. Cannabinoid-1 receptor subtype (CB1) agonists (eg, dronabinol) are approved for preventing chemotherapy-induced vomiting but side effects include sedation, euphoria, impaired cognition, and rarely syncope and hallucinations in the elderly. A cannabinoid hyperemesis syndrome mimicking cyclic vomiting syndrome occurs with long-standing use of large amounts of cannabis, but this condition has not been reported with prescription agents like dronabinol.
| Medication Class | Examples | Published Data in Gastroparesis |
|---|---|---|
| Histamine H 1 antagonist | Dimenhydrinate Meclizine Promethazine | None |
| Muscarinic (cholinergic) M 1 antagonist | Scopolamine | None |
| Dopamine D 2 antagonist | Prochlorperazine Trimethobenzamide | 1 case report (thiethylperazine) |
| Serotonin 5-HT 3 antagonist | Ondansetron Granisetron Dolasetron | 1 case report (intraperitoneal ondansetron) 1 case series (36 patients, granisetron) |
| Neurokinin NK 1 antagonist | Aprepitant | 2 case reports |
| Cannabinoid CB 1 agonist | Dronabinol | None |
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