New Developments In The Treatment Of Gastroparesis.pdf

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ScienceDirect New developments in the treatment of gastroparesis and functional dyspepsia Jan Tack1 and Michael Camilleri2 Functional dyspepsia (FD) and gastroparesis are frequent causes of upper gastrointestinal symptoms such as postprandial fullness, early satiation, epigastric pain or burning, upper abdominal bloating, bothersome belching, nausea and vomiting. The underlying pathophysiological mechanisms are heterogeneous and involved mechanisms such as abnormal gastric motility (accommodation, emptying), visceral hypersensitivity, low grade mucosal inflammation and cellular changes in enteric nerves, muscle or interstitial cells of Cajal. Patient-reported outcomes for evaluating treatment efficacy in these conditions were recently developed and validated. Prokinetic agents, which enhance gastric motility, are used for treating both gastroparesis and FD. In FD, besides acid suppressive therapy and Helicobacter pylori eradication, neuromodulators and drugs that enhance gastric accommodation can be applied. In gastroparesis, anti-emetics may also provide symptom relief. Novel approaches under evaluation in these conditions are the fundus relaxing agents acotiamide and buspirone and the antidepressant mirtazapine in FD. For gastroparesis, recently studied agents include the prokinetic ghrelin agonist relamorelin, the prokinetic serotonergic agents velusetrag and prucalopride, the antiemetic aprepitant and per-endoscopic pyloric myotomy procedures.

Addresses 1 TARGID, University Hospital, Leuven, Belgium 2 Mayo Clinic, Rochester, MN, USA

bothersome belching, nausea and vomiting, and routine diagnostic work-up for underlying structural or metabolic disease, such as endoscopy, blood tests and radiological examination often fail to identify a cause for the symptoms. Functional dyspepsia (FD) is considered a heterogeneous condition: postprandial distress syndrome (PDS), characterized by meal-related symptoms such as postprandial fullness and early satiation, and epigastric pain syndrome (EPS), characterized by meal-unrelated symptoms such as epigastric pain or burning [1,2]. In patients with persisting symptoms, assessment of motility is often the next step, most commonly measurement of gastric emptying. When this is delayed, the patient is considered as having gastroparesis, a syndrome characterized by upper gastrointestinal symptoms including nausea or vomiting, and delayed gastric emptying in the absence of mechanical obstruction [3,4]. Gastroparesis occurs in several clinical settings, particularly as a complication of diabetes mellitus, upper gastrointestinal surgery, neurological disease, collagen vascular disorders, viral infections, drugs, etc. In the majority of cases no underlying cause is found and gastroparesis is termed idiopathic [3,4]. This review summarizes current pathophysiological concepts and recent progress in the treatment of functional dyspepsia and gastroparesis.

Corresponding author: Tack, Jan ([email protected])

Current Opinion in Pharmacology 2018, 43:111–117

Pathophysiological concepts: disordered motility, visceral hypersensitivity and mucosal alterations

This review comes from a themed issue on Gastrointestinal

Pathophysiological mechanisms in FD

Edited by Giovanni Sarnelli and Jan Tack

The pathophysiology of FD is most likely heterogeneous, with different underlying mechanisms contributing to somewhat more specific diverse symptom patterns [1,2] (Figure 1). Impaired gastric accommodation to a meal, delayed gastric emptying and hypersensitivity to gastric distention are the mechanisms classically implicated in PDS [5]. Impaired gastric accommodation to a meal is present in up to 50% of FD patients, is associated with early satiation and weight loss, and may result in redistribution of the meal to the distal stomach and more rapid gastric emptying [5,6]. Visceral hypersensitivity is present in approximately one third of FD patients and is associated with higher intensity ratings of all epigastric symptoms, including pain [5,7]. Visceral hypersensitivity is supported by functional brain imaging studies or lack of anti-nociceptive in response to gastric signals and by comorbid psychosocial disorders such as anxiety, depression

https://doi.org/10.1016/j.coph.2018.08.015 1471-4892/ã 2018 Published by Elsevier Ltd.

Introduction Functional and motility disorders of the stomach are commonly encountered in gastroenterology clinical practice [1,2]. Patients present with upper gastrointestinal symptoms such as postprandial fullness, early satiation, epigastric pain or burning, upper abdominal bloating, www.sciencedirect.com

Current Opinion in Pharmacology 2018, 43:111–117

112 Gastrointestinal

Figure 1

1

2 Anti-emetics 7 1. 2.

Neuromodulators

3. 4. 5. 6. 7.

Fundus relaxants 3

Anxiety, depression, somatization Central mechanisms of visceral hypersensitivity Peripheral mechanisms of hypersensitivity to gastric distention Impaired gastric accommodation Delayed gastric emptying Low-grade duodenal inflammation Nausea/vomiting center

Gastroprokinetics 4 Endoscopic myotomy

5 6

Current Opinion in Pharmacology

Pathophysiological mechanisms serving as (potential) therapeutic targets in functional dyspepsia and gastroparesis.

and somatization [8,9,10]. Delayed gastric emptying occurs in up to one third of FD patients and, in some series, has been associated with postprandial fullness, nausea and vomiting [4,5,11]. More recently, impaired duodenal mucosal integrity, with low-grade mucosal inflammation characterized by eosinophils and mast cells, has been reported as a putative pathophysiological mechanism in FD [1,5,12,13], conceivably associated with changes in upper gastrointestinal microbiota [14,15]. Mechanisms in gastroparesis Cellular mechanisms

Several studies have documented loss of interstitial cells of Cajal (ICC) and fibrosis of the muscular layers in severe cases of diabetic gastroparesis [16,17]. Similar findings have been reported in idiopathic gastroparesis patients, but inflammatory cell infiltration around myenteric neurons and neuronal loss have also been implicated [16,17]. The triggers leading to ICC or neuronal loss are incompletely understood. Animal models of type 1 diabetes have implicated a phenotypical switch from anti-inflammatory or alternatively activated M2 macrophages to pro-inflammatory M1 or classically activated macrophages [18]. While some human observations are consistent with such a mechanism [19], other data from patients with idiopathic gastroparesis do not support the reduction in ICCs or M2 macrophages, and in contrast provided evidence of reduced electrically-coupled fibroblast like cells that are positive for PDGFRa with no reduction in M2 macrophages [20]. Current Opinion in Pharmacology 2018, 43:111–117

Pathophysiology

In diabetic and idiopathic gastroparesis, the correlation of symptoms with the delay in gastric emptying is the subject of continuing debate, with recent analysis showing the best correlations are found in studies that use optimally measured gastric emptying for at least 3 hours by scintigraphy or breath test [21]. Similar to FD, mechanisms such as impaired accommodation and visceral hypersensitivity also contribute in patients with gastroparesis [22,23].

Diagnostic considerations in patients with upper GI symptoms Gastroparesis may result from iatrogenic causes, including bariatric and other gastric surgery and, more commonly, from medications. The two most relevant drug classes are all opioids and anti-diabetic medications such as pramlintide and GLP-1 agonists (e.g. exenatide and liraglutide), but not dipeptidyl peptidase IV inhibitors such as vildagliptin and sitagliptin. After excluding obstruction or significant mucosal diseases, getting the right diagnosis for the patient’s symptoms is an essential first step, especially because classical symptoms of gastroparesis may result from impaired gastric accommodation. Among 1287 patients presenting to a tertiary care center with upper gastrointestinal symptoms, there was an approximately equal proportion (25%) with delayed gastric emptying, impaired gastric accommodation, a combination of both, or absence of both [6]. This is consistent with a broader spectrum of gastric neuromuscular dysfunctions that may present with www.sciencedirect.com

Treatment of gastroparesis and functional dyspepsia Tack and Camilleri 113

prominent symptoms such as early satiety and postprandial fullness. This reflects the overlap of ‘gastroparesis’ with functional dyspepsia.

become available, the focus in the past years has been on gastroparesis (see below) not FD. Drugs that enhance accommodation

Impaired gastric accommodation may be recognized with validated methods where available (SPECT and MRI), or with screening tests such as the size of the proximal stomach on the gastric scintigraphy scan taken immediately after radiolabeled meal ingestion, or by means of a water load or nutrient drink test [24–29].

Endpoints for clinical trials Functional dyspepsia

To date, there is a paucity of validated patient-reported outcome (PRO) measures to evaluate treatment efficacy in FD. The Leuven Postprandial Distress Scale for PDS was validated in 2016 [30]. The content validity and psychometric performance of a new PRO, the Functional Dyspepsia Symptom Diary, was recently reported [31]. Next validation steps, including test–retest reliability, sensitivity to change and determination of the minimal clinically important difference are needed to establish this diary as a PRO for FD studies.

Impaired accommodation is the most commonly documented motor abnormality in FD. The anxiolytic 5HT1A agonist buspirone was tested in 17 patients: there were improved FD symptoms with enhancement of gastric accommodation without effects on anxiety to explain symptomatic benefit. PDS symptoms and especially early satiation benefitted most from buspirone 10 mg t.i.d. treatment [37]. A multi-center 4-week study of tandospirone, another 5-HT1A agonist, in 144 FD patients demonstrated alleviation of epigastric pain and discomfort, independent of changes in anxiety and depression levels [38].

There is substantial progress validating PROs for gastroparesis. With recent psychometric validation and responsiveness of two PROs in gastroparesis: the American Neurogastroenterology and Motility Society (ANMS) Gastroparesis Cardinal Symptom Index (GCSI) daily diary and the Diabetic Gastroparesis Symptom Severity Diary; these are used in ongoing clinical trials presented to regulatory authorities [32,33].

Acotiamide is a mixed presynaptic muscarinic auto-receptor inhibitor and a cholinesterase inhibitor, that enhanced both gastric contractility and accommodation in preclinical models [38]. In extensive phase 2 studies in Europe, Japan and the U.S.A., PDS symptoms were the most responsive symptoms with 100 mg t.i.d. the optimal dose [39]. A 4-week phase 3 study in FD patients in Japan showed superiority of acotiamide over placebo for PDS symptoms (early satiation, postprandial fullness, upper abdominal bloating); acotiamide was well tolerated [40] and safe in a one-year open label study in 207 FD patients [41]. Mechanistic placebo-controlled studies, including an and a scintigraphy study in 50 FD patients, showed that acotiamide enhances gastric accommodation (in ultrasound study in 34 FD patients) and gastric emptying (by scintigraphy in 50 FD patients) [42,43].

Treatment approaches

Neuromodulators

Functional dyspepsia Current therapeutic approaches

In a study conducted in patients with functional dyspepsia, amitriptyline (tricyclic antidepressant) improved symptoms in patients who did not have delayed gastric emptying, and it modestly improved sleep quality. The typical doses is 25 mg/day [44,45]. Nortryptiline was not superior to placebo for relief of symptoms in gastroparesis [46].

Gastroparesis

Guidelines recommend eradication in patients with upper GI symptoms and negative endoscopy who are Helicobacter pylori infected, although the therapeutic effect is limited in size and delayed [34]. Acid suppression using PPI therapy is the traditional first-line therapy in FD, although this may be most effective for EPS and overlapping GERD [34,35]. Meta-analysis confirms efficacy of prokinetics as a group, but very few agents are widely available and the design and quality of studies are extremely heterogeneous [34]. Domperidone is available in many countries outside the United States of America, and while there is low-quality evidence of efficacy, the drug has been associated with QT prolongation [34]. Other prokinetics, available in selected countries include clebopride, cinitapride, mosapride, tegaserod and itopride. The evidence for their efficacy is often limited or lacking and there may be risk for adverse events such as pseudo-parkinsonism with drugs that have dopamine antagonistic effects in the brain, such as clebopride or cinitapride [36]. Although newer prokinetics have www.sciencedirect.com

In a systematic review and meta-analysis, psychotropics provide superior benefit to placebo in FD, particularly tricyclic antidepressants and older antipsychotics (like sulpiride and levosulpiride, which also have dopamine2 antagonistic properties) [44]. The largest neuromodulator trial included 292 FD patients randomized to 8 weeks treatment with placebo, amitriptyline or escitalopram. Escitalopram showed no benefit while amitriptyline improved symptoms only in the subgroup with epigastric pain (EPS-like subgroup) or those with normal gastric emptying [46]. It modestly improved sleep quality [47]. The treatment response to amitriptyline was not influenced by genetic variants in the GNb3 (825C>T) or the serotonin reuptake transporter (5-HTT LPR genetic Current Opinion in Pharmacology 2018, 43:111–117

114 Gastrointestinal

variants) genes, and the therapeutic effect was not explained by effects on gastric motility, nutrient volume tolerance or psychosocial co-morbidity [47–49]. Mirtazapine, an antidepressant with activity on diverse neurotransmitter receptors, was efficacious in nondepressed and non-anxious FD patients with major weight loss [50]. In addition to increased body weight, mirtazapine improved overall symptoms, early satiation nausea, and nutrient volume tolerance. In a mechanistic healthy volunteers study, mirtazapine did not significantly affect gastric sensorimotor functions suggesting a predominantly central mode of action [51]. Targeting gut microbiota in FD

Probiotic containing products are popular as self-management or prescribed treatment for bowel symptoms, and there are now early data on upper GI symptoms. In a 4week controlled study, 100 healthy Japanese adults with upper gastrointestinal symptoms were randomized to daily ingestion of a fermented milk with or without Bifidobacterium bifidum YIT10347. The intervention did not alter gastric emptying rate but improved postprandial discomfort and epigastric pain, but also bowel symptoms such as diarrhea and flatulence, making it unclear whether symptomatic benefit can be attributed to the upper gastrointestinal effects [52]. Another study from Japan randomized FD patients to 12 weeks treatment with Lactobacillus gasseri OLL2716 or placebo, with a tendency of better symptom improvement and a higher rate of symptom elimination (17 versus 35%, p = 0.048) in the active group [53]. In a study from Hong Kong, H. pylori negative FD patients were randomized to rifaximin 400 mg or placebo t.i.d. for 2 weeks and followed up for 8 weeks. Rifaximin was well tolerated and superior to placebo in providing adequate relief (78% versus 52%, P = 0.02). Most responsive symptoms seemed to be belching and postprandial fullness/bloating [54]. The mechanism and site of action of rifaximin in this indication remain to be established. Gastroparesis Prokinetics

Both ghrelin and motilin enhance gastric emptying rate, and agonists at the respective receptors have been developed for treatment of gastroparesis [55]. Relamorelin, an injectable ghrelin receptor agonist (10 ug s.c. once or twice daily), was evaluated in a placebo-controlled phase 2 study in 204 patients with diabetic gastroparesis (88% type 2). In a pre-specified analysis in patients with active vomiting (n = 119), twice-daily relamorelin significantly enhanced gastric emptying and improved symptoms of vomiting, nausea, abdominal pain, bloating, and early satiety compared to placebo [56]. Relamorelin (10, 30 or 100 ug s.c. twice daily), was evaluated in a2b study in 393 patients with diabetic Current Opinion in Pharmacology 2018, 43:111–117

gastroparesis and active vomiting symptoms (90% type 2DM). Relamorelin significantly improved symptoms of nausea, abdominal pain, postprandial fullness, and bloating over placebo, and also enhanced gastric emptying. Elevated glycemia occurred dose-dependently in 15% of patients treated with relamorelin [57]. In placebo-controlled, double-blind, randomized mechanistic studies in healthy volunteers, relamorelin 30 ug s.c. significantly enhanced the frequency of normal amplitude antral contractions, without reducing gastric volumes and nutrient volume tolerance [58] suggesting the gastroprokinetic effect is unlikely to interfere with gastric accommodation. Relamorelin is currently being tested in phase 3 trials in diabetic gastroparesis. Prucalopride (1–2 mg/day), a 5-HT4 receptor agonist, is approved in most countries (other than USA) for the treatment of chronic constipation [59]. The drug accelerates gastric emptying and was shown in a preliminary report to enhance gastric emptying and to relieve symptoms in 28 patients with idiopathic gastroparesis [60]. Velusetrag, another 5-HT4 receptor agonist, showed symptom improvement and enhanced gastric emptying at 5 mg dose in a 3-dose phase 2b study compared to placebo in 232 patients with idiopathic or diabetic gastroparesis [61]. Anti-emetics

Aprepitant, a selective neurokinin-1 receptor antagonist used in the treatment of chemotherapy induced nausea and vomiting, was evaluated in a 4-week placebo-controlled study in 126 patients with chronic nausea and vomiting caused by ‘gastroparesis-like syndrome’ [62]. All patients had at least moderate symptoms of chronic nausea and vomiting; other characteristics of the patient cohort were delayed gastric emptying in 57%, diabetes in 29% and narcotic use in 8%. Aprepitant had no significant effect over placebo on the primary outcome variable, reduction in nausea with at least 25 mm on a 100 mm VAS scale (46 versus 40%). However, aprepitant showed significant improvement in overall, nausea and vomiting symptom severity measured by the GCSI, but also was associated with more frequent adverse events. Baseline clinical characteristics did not affect the response. Separately, effects of aprepitant on gastric sensorimotor function were evaluated in a placebo-controlled study in 24 healthy subjects. Aprepitant did not alter gastric emptying, but increased gastric volumes and gastric accommodation and tended to increase gastric nutrient volume tolerance [63]. In 33 gastroparesis patients seen in an emergency department with vomiting, patients were randomized to standard treatment with or without haloperidol 5 mg i.v. Those treated with haloperidol had significantly lower scores for pain and nausea one hour after administration, www.sciencedirect.com

Treatment of gastroparesis and functional dyspepsia Tack and Camilleri 115

and no adverse events were reported [64]. Prolonged usage of haloperidol or related drugs, such as chlorpromazine, needs to be evaluated. Metoclopramide use is associated with a black box warning due to induction of extrapyramidal symptoms. In a multi-center 4-week placebo-controlled trial, a new formulation of metoclopramide as nasal spray 10 mg t.i.d. was studied in 285 diabetic patients (82.5% type 2 DM) with gastroparesis-like symptoms. Female patients had significantly greater symptom relief (measured by GCSI) to metoclopramide than placebo nasal spray [65]. Metoclopramide was generally well tolerated, although dysgeusia, headache and dizziness occurred more frequently than with placebo. As this trial did not require delayed gastric emptying in history or at baseline, it remains unclear whether the patients had gastroparesis, and further studies with the nasal spray formulation need to appraise risks of extrapyramidal and other CNS adverse events.

(acotiamide, relamorelin), anti-emetics, psychotropics including tricyclic agents for pain and therapies targeting the pylorus. Jan Tack is supported by a Methusalem grant from Leuven University.

Conflict of interest statement Jan Tack has given Scientific advice to AlfaWassermann, Allergan, Christian Hansen, Danone, Gru¨nenthal, Ironwood, Neutec, Shire, Takeda, Theravance, Tsumura, Zealand and Zeria pharmaceuticals and has served on the Speaker bureau for Abbott, Allergan, Janssen, Shire, Takeda and Zeria Michael Camilleri has given advice to Allergan and Takeda, with no personal remuneration, and has received research support from Allergan/Rhythm and from Takeda.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as  of special interest  of outstanding interest

Gastric electrical stimulation

A systematic review and meta-analysis evaluated 13 cohort series supporting evidence of benefit but 5 controlled trials failed to show benefit. In addition, metaregression analysis showed a strong correlation between baseline symptom severity scores and magnitude of improvement, suggesting regression to the mean was a major contributor to the perceived benefit [66].

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Summary Research on FD and gastroparesis continues to explore pathophysiological mechanisms and novel treatment approaches. In FD, the research focus has shifted to the potential of loss of mucosal integrity, low-grade inflammation and potentially changes in microbiota in the duodenum as emerging areas of interest. In gastroparesis, the role of macrophages in the loss of interstitial cells of Cajal as a mechanism of disease is an ongoing hot topic. We anticipate continued advances in novel treatment approaches including new prokinetic agents www.sciencedirect.com

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Current Opinion in Pharmacology 2018, 43:111–117