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A vision of the future for gastroparesis
Introduction
In gastroparesis, there is abnormal function of extrinsic vagal innervation, smooth muscle, enteric nervous system, or pacemakers in the stomach wall, specifically, the interstitial cells of Cajal (ICCs) or fibroblast-like cells that have receptors for platelet-derived growth factor α. The delay of gastric emptying in gastroparesis is associated with distal antral hypomotility, pylorospasm, or intestinal dysmotility. In general, antral hypomotility is usually present when there is pylorospasm . In patients with diabetes, delayed gastric emptying is associated with retinopathy and a number of complications of diabetes and, as shown originally by Kassander, with triopathy (retinopathy, neuropathy, nephropathy) . Nevertheless, in the modern era, with so many patients having type 2 diabetes rather than insulin-dependent and ketosis-prone type 1 diabetes, 39% of diabetic patients with gastroparesis in the NIH gastroparesis consortium database did not have any diabetic complications .
Another confounding factor in discussion of gastroparesis is the increased use of opioid medications for abdominal pain. Among 583 patients in the NIH gastroparesis consortium database, 41% were taking opioids which included 33% on potent morphine-like agents and the indication was abdominal pain for 61% of patients taking opioids. These patients have higher symptoms scores, greater levels of gastric retention, worse quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications compared with nonusers or those using weaker opioids (e.g., tramadol, tapentadol, codeine, or propoxyphene) . It has been proposed that such patients should be excluded from studies of pathophysiology, clinical characteristics, and outcomes of gastroparesis, and that such patients receive a therapeutic trial with a peripherally-active mu-opioid receptor antagonist to differentiate the relative contributions of the opioid and underlying disease to the gastroparesis . Given this controversy, opioid-induced gastroparesis will not be specifically addressed in this chapter.
There have been significant recent advances in understanding and treatment options for gastroparesis; however, many controversies exist and the field is rapidly changing. One of the inevitable challenges in the current and future management of gastroparesis is the broadening of the “definition” which includes symptomatically overlapping conditions that result from different pathophysiological mechanisms which are not always those associated with delayed gastric emptying. The other main pathophysiological mechanisms resulting in upper gastrointestinal symptoms mimicking those of gastroparesis are reduced gastric accommodation and increased gastroduodenal sensitivity; among almost 1300 patients (including 108 patients with diabetes) who underwent tests to evaluate both gastric emptying of solids and gastric accommodation using SPECT imaging, there were roughly equal proportions of patients with abnormal gastric emptying, abnormal gastric accommodation, both abnormal or neither abnormal ; the latter presumably reflecting gastroduodenal hypersensitivity.
New drugs targeting receptors with 5-HT 4 agonists, dopamine D 2/3 and NK 1 antagonists
Rationale
Disorders of gastric emptying can be identified with an optimal gastric emptying test, typically 4-hour measurement by scintigraphy, and can be targeted by drugs acting on traditional receptors including 5-HT 4 , dopamine D 2/3 , and NK 1 . Normal values and performance characteristics of the scintigraphic test have been published . Delayed gastric emptying is associated with nausea, vomiting, and bloating, but not with pain; moreover, there is a significant relationship between the acceleration of gastric emptying and the improvement in symptoms based on a meta-regression analysis which demonstrated that a change in gastric emptying t 1/2 of 20.4 minutes was associated with a 1 unit change in symptoms severity (based on standardized mean difference) .
There are several methods used to measure gastric accommodation, although most of the reports in the literature have used one of three methods: SPECT imaging , which unfortunately is not widely available; or an intragastric, infinitely compliant polyethylene balloon with tone measured by the intra-balloon volume as a barostat maintains constant pressure within the balloon; or intraluminal high resolution manometry . The latter two methods are predominantly used as research tests. In contrast, a nutrient drink test [with ingestion at constant rate until the maximum tolerated volume (MTV) is reached] may assess the overall functions of gastric accommodation and sensation . When the MTV of a nutrient drink is less than ~750 kilocalories, the MTV is linearly correlated with gastric accommodation measured by a barostat . Recent attempts to use two-dimensional imaging to estimate gastric accommodation require further validation .
Current state of evidence
Although it had not been approved or marketed for the indication of gastroparesis, there was evidence that the 5-HT 4 agonist, cisapride, accelerated gastric emptying and improved symptoms in patients with gastroparesis in short-term, placebo-controlled trials , as well as in long-term, open-label studies . Cisapride is a potent human ether-à-go-go-related gene (hERG) potassium channel inhibitor; it was taken off the market due to cardiovascular concerns (cardiac arrhythmias).
Since symptoms may result from diverse mechanisms, future treatment of gastroparesis symptoms should be based on identified pathophysiology. Potentially, effective pharmacological approaches are directed to the “traditional” pathways, specifically 5-HT 4 , dopamine D 2 and D 3 , and NK 1 receptors, or novel mechanisms (discussed in the next section).
5-HT 4 receptor agonists
In a randomized, placebo-controlled, cross-over study of 4 weeks duration with a 2-week washout, prucalopride improved symptom control as well as gastric emptying in 28 patients with idiopathic and 6 patients with diabetic gastroparesis . Similarly, velusetrag, was efficacious in the treatment of diabetic and idiopathic gastroparesis . Among “new generation” 5-HT 4 agonists, prucalopride, velusetrag, and naronapride are selective for 5-HT 4 receptors without hERG effects .
Results of the pharmacodynamics effects of a new specific 5-HT 4 receptor agonist, TAK-954 (TD-8954), are keenly awaited (NCT03281577). Velusetrag and TAK-954 had no significant effects on canine, porcine, and human coronary artery tone, human platelet aggregation, hERG potassium channel conductance, or off-target actions . TAK-954 had high affinity (pK(i)=9.4) for human recombinant 5-HT 4(c) receptors and selectivity (>2000-fold) over all other 5-HT and non-5-HT receptors, ion channels, enzymes, and transporters (n=78 tested) .
Targeting sensations with D 2 /D 3 and NK 1 antagonists
For increased gastric sensation, the dopamine D 2 / 3 antagonist, TAK-506, significantly increased the volume to fullness compared to baseline with 1 week of treatment . The NK 1 receptor antagonist, aprepitant, improved multiple symptoms of gastroparesis including nausea , and it has been shown to enhance gastric accommodation rather than affect gastric emptying in healthy controls . Similarly, tradipitant, a novel NK 1 receptor antagonist, improved nausea and other symptoms of gastroparesis in a 4-week, randomized, controlled trial .
What is needed for evidence-based clinical application?
Completion of phase III, pivotal, randomized, controlled trials in gastroparesis is required for all three classes of medications.
New drugs targeting a new mechanism: ghrelin receptor agonist
Rationale
Ghrelin is a 28-amino acid orexigenic hormone found mainly in the stomach. Administration of a pharmacological dose of ghrelin induced premature phase III of the migrating motor complex, increased proximal gastric tone through central and peripheral sites of action , and accelerated gastric emptying in some studies of patients with gastroparesis (reviewed in ref. ).
Relamorelin, a pentapeptide ghrelin receptor agonist, has potent prokinetic effects estimated to be 15- to 130-fold more potent than natural ghrelin . Relamorelin, 100 mg subcutaneous (s.c.), accelerated gastric emptying of solids in patients with prior documentation of delayed gastric emptying and either type 1 or type 2 diabetes mellitus , and it increased the frequency of distal antral contractions without inhibiting gastric accommodation or inducing satiation in healthy volunteers .
Current state of evidence
Relamorelin has proven clinical efficacy and safety in phase 2 A and 2B, randomized, controlled trials in patients with diabetic gastroparesis .
What is needed for evidence-based clinical application?
Completion of phase III, pivotal, randomized, controlled trials is required.
Modulation of M2 macrophages and oxidative stress
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