Opioid Use and Potency Are Associated With Clinical Features, Quality of Life, and Use of Resources in Patients With Gastroparesis

Hasler, William L.; Wilson, Laura; Nguyen, Linda Anh B.; Snape, William J.; Abell, Thomas L.; Koch, Kenneth L.; McCallum, Richard W.; Pasricha, Pankaj J.; Sarosiek, Irene; Farrugia, Gianrico; Grover, Madhusudan; Lee, Linda A.; Miriel, Laura; Tonascia, James; Hamilton, Frank A.; Parkman, Henry P.; Clarke, John O.; Kim, Yale; Ullah, Nighat; DeVole, Nata; Greene, Mary; Lee, Candice; Ponsetto, Courtney; Shetler, Katerina; Kantor, Steven; Lytes, Vanessa; Palit, Amiya; Simmons, Kellie; Hejazi, Reza; Roeser, Kathy; Vasquez, Denise; Vega, Natalia; Beatty, Karen; Hatter, Lisa; Howard, Ronna; Nowotny, Lindsay; Tang, Shou Ching; Amin, Om; Henry, Olivia; Kedar, Archana; McNair, Valerie; Pruett, Susanne; Smith, Margaret; Spree, Danielle C.; Castle, Michelle; Coleski, Radoslav; Wootten, Sophanara; Baxter, Lynn; Brown, Anya; Culler, Samantha; Hooker, Judy; Stuart, Paula; Bernard, Cheryl E.; Callés-Escandon, Jorge; Olmedo, José Javier Serrano; James, Steven; Torrance, Rebecca; Raaphorst, Rebekah Van; Belt, Patricia; Hallinan, Erin; Colvin, Ryan; Donithan, Michele; Green, Mika; Isaacson, Milana; Kim, Wana; May, Patrick; Sternberg, Alice L.; Natta, Mark Van; Vaughn, Ivana A.; Yates, Katherine P.

doi:10.1016/j.cgh.2018.10.013

Cited by 62 publications

(49 citation statements)

References 38 publications

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“…[62][63][64][65][66] Although the cause of gastroparesis is idiopathic in the majority of cases, 67 diabetes, post gastric surgery (eg, vagal nerve injury), various neurologic (eg, Parkinson's disease), endocrine, and eating disorders, as well as medications such as opioids and anticholinergics, are established causes. [61][62][63]68 Given the strong association of gastroparesis with nausea and emesis in humans, we further explored the abnormal gastric retention of food we observed in mice treated with PDE4 inhibitors under the premise that it may represent a useful correlate of nausea and emesis in humans and hence provide a tool to further delineate the role of individual PDE4s in mediating the established adverse effects of PDE4 inhibitors. All PDE inhibitors, Clonidine and Yohimbine were initially dissolved in DMSO, subsequently diluted into phosphatebuffered saline (PBS), pH 7.4, containing final concentrations of 5% DMSO and 5% Cremophor EL (Millipore Sigma, St. Louis, MO) and were applied by intraperitoneal injection (100 µL per 20 g body weight).…”

Section: Introductionmentioning

confidence: 99%

PAN‐selective inhibition of cAMP‐phosphodiesterase 4 (PDE4) induces gastroparesis in mice

et al. 2020

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Inhibitors of cAMP‐phosphodiesterase 4 (PDE4) exert a number of promising therapeutic benefits, but adverse effects, in particular emesis and nausea, have curbed their clinical utility. Here, we show that PAN‐selective inhibition of PDE4, but not inhibition of PDE3, causes a time‐ and dose‐dependent accumulation of chow in the stomachs of mice fed ad libitum without changing the animals' food intake or the weight of their intestines, suggesting that PDE4 inhibition impairs gastric emptying. Indeed, PDE4 inhibition induced gastric retention in an acute model of gastric motility that traces the passage of a food bolus through the stomach over a 30 minutes time period. In humans, abnormal gastric retention of food is known as gastroparesis, a syndrome predominated by nausea (>90% of cases) and vomiting (>80% of cases). We thus explored the abnormal gastric retention induced by PDE4 inhibition in mice under the premise that it may represent a useful correlate of emesis and nausea. Delayed gastric emptying was produced by structurally distinct PAN‐PDE4 inhibitors including Rolipram, Piclamilast, Roflumilast, and RS25344, suggesting that it is a class effect. PDE4 inhibitors induced gastric retention at similar or below doses commonly used to induce therapeutic benefits (e.g., 0.04 mg/kg Rolipram), thus mirroring the narrow therapeutic window of PDE4 inhibitors in humans. YM976, a PAN‐PDE4 inhibitor that does not efficiently cross the blood‐brain barrier, induced gastroparesis only at significantly higher doses (≥1 mg/kg). This suggests that PDE4 inhibition may act in part through effects on the autonomic nervous system regulation of gastric emptying and that PDE4 inhibitors that are not brain‐penetrant may have an improved safety profile. The PDE4 family comprises four subtypes, PDE4A, B, C, and D. Selective ablation of any of these subtypes in mice did not induce gastroparesis per se, nor did it protect from PAN‐PDE4 inhibitor‐induced gastroparesis, indicating that gastric retention may result from the concurrent inhibition of multiple PDE4s. Thus, potentially, any of the four PDE4 subtypes may be targeted individually for therapeutic benefits without inducing nausea or emesis. Acute gastric retention induced by PDE4 inhibition is alleviated by treatment with the widely used prokinetic Metoclopramide, suggesting a potential of this drug to alleviate the side effects of PDE4 inhibitors. Finally, given that the cause of gastroparesis remains largely idiopathic, our findings open the possibility that a physiologic or pathophysiologic downregulation of PDE4 activity/expression may be causative in a subset of patients.

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Section: Introductionmentioning

confidence: 99%

PAN‐selective inhibition of cAMP‐phosphodiesterase 4 (PDE4) induces gastroparesis in mice

et al. 2020

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“…Opioids may worsen gastric emptying, increase the risk of narcotic bowel syndrome, and potentially cause addiction, tolerance, and/or overdose . They also are associated with poor quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications compared with non‐use . Unfortunately, at least 31%‐50% of adults with GP are prescribed opioids for their abdominal pain …”

Section: Introductionmentioning

confidence: 99%

“…They also are associated with poor quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications compared with non‐use . Unfortunately, at least 31%‐50% of adults with GP are prescribed opioids for their abdominal pain …”

Section: Introductionmentioning

confidence: 99%

Childhood gastroparesis is a unique entity in need of further investigation

Febo‐Rodriguez

Chumpitazi

Shulman

2019

Neurogastroenterology Motil

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Background Despite increasing knowledge regarding gastroparesis (GP) in adults, little is known regarding the incidence, prevalence, and natural history of childhood GP. Exacerbating the knowledge gap in pediatric GP is both the lack of normative data for gastric emptying scintigraphy in children and lack of GP‐specific pediatric reported outcome measures. Purpose The aim of this article was to review the available literature on pediatric GP and identify similarities and differences with studies in adults. We performed a comprehensive search in MEDLINE and Google Scholar from inception to April 2019 for articles published in English using the following combination of keywords: gastroparesis, pediatric gastroparesis, outcomes, metoclopramide, erythromycin, domperidone, cisapride, and gastric neurostimulator. The limited available pediatric data, often retrospective, suggest marked differences between adult and pediatric GP in several aspects including etiology, concomitant co‐morbidities (eg, psychiatric disorders), clinical symptom presentation, diagnostic evaluation, response to therapies, and clinical outcome. Further research in pediatric GP is needed and holds the promise to further elucidate the mechanisms of this disorder in children and lead to pediatric‐focused therapies.

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“…3 Opioid-induced constipation, dysphagia, esophageal dysmotility, narcotic bowel syndrome, gastroparesis, nausea, vomiting, and delayed gastric emptying are direct side effects of opioid use associated with the abundant opioid receptors in the gastrointestinal tract. [4][5][6][7][8][9][10] Many side effects go unreported owing to inadequate provider knowledge/understanding and patient embarrassment. 11 These morbidities are accompanied by a 5-fold increase in fatal opioid overdoses between 1999 and 2016, totaling approximately 350,000 people; a staggering 115 deaths per day in the United States.…”

mentioning

confidence: 99%

“…Nonopioid alternatives, dose reduction, switching opioids, and modifying the route of administration Opioid-induced nausea and vomiting 5 Central and peripheral nerve effects; impacts 40% of patients using opioids to treat chronic pain Nonopioid alternatives, dose reduction, switching opioids, antiemetics, promotility agents (eg, metoclopramide) and modifying the route of administration Gastroparesis 9,25 Altered gastric motility, delayed emptying Although opioids adversely affect gastrointestinal motility, 30%-46% of patients with gastroparesis patients regularly use opioids Nonopioid alternatives, dose reduction, switching opioids, antiemetics, pro-motility agents (eg, metoclopramide) and modifying the route of administration. Opioid-induced constipation 7,8,11 Altered colon motility Opioid-induced constipation affects 81% of users, often leading to opioid dose modification or discontinuation…”

mentioning

confidence: 99%