Halawi, Houssam

Abstract Background Nausea, vomiting, and constipation ( OIC ) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu‐opiate opioid receptor antagonist. Aim To compare the effects on pan‐gut transit of treatment with codeine, naloxegol, or combination in healthy volunteers. Methods We conducted a randomized, double‐blind, placebo‐controlled, single‐center, parallel‐group study in 72 healthy opioid‐naïve adults, randomized to: codeine (30 mg q.i.d.), naloxegol (25 mg daily), codeine and naloxegol, or matching placebo. During 3 days of treatment, we measured gastric emptying ( GE ) T 1/2 , colonic filling at 6 hours ( CF 6), colonic geometric center at 24 and 48 hours, and ascending colon emptying ( ACE ) T 1/2 . Key Results Participants were 59.7% women, median BMI 25.0 kg/m 2 , and median age 33.8 years. Codeine significantly retarded GE T 1/2, CF 6, overall colonic transit, and ACE T 1/2 . There was significant difference ( P = .026) in GE T 1/2 between codeine (144.0 min [ IQR 110.5‐238.6]) and naloxegol (95.5 min [89.1‐135.4]). There was a significant overall group difference in CF 6 ( P = .023), with significant difference ( P = .019) between codeine (11.0% [0.0‐45.0]) and naloxegol (51% [18.8‐76.2]). However, no significant differences were found between codeine‐treated participants concomitantly receiving placebo or naloxegol. Conclusions and Inferences Short‐term administration of naloxegol (25 mg) in healthy, opioid‐naïve volunteers does not reverse the retardation of gastric, small bowel, or colonic transit induced by acute administration of codeine. Further studies with naloxegol at higher dose are warranted to assess the ability to reverse the retardation of transit caused by acute administration of codeine in opioid‐naïve subjects.

AbstractBackgroundOpioid‐induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu‐opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid‐naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid‐naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.MethodsA PubMed search of μ‐opioid antagonists to counter μ‐opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.Key ResultsThe approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid‐naïve subjects. Trials investigating the required dose of alvimopan showed 0.5‐1 mg dose was efficacious in treating OIC; a 10‐fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid‐naïve subjects compared to chronic opioid users. Opioid‐naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.Conclusions & InferencesOpioid‐naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ‐opioid antagonist effect.

Aprepitant, an NK1 receptor antagonist, is approved for the treatment of chemotherapy-induced or postoperative emesis by blocking NK1 receptors in the brain stem vomiting center. The effects of NK1 receptors on gastric functions and postprandial symptoms in humans are unclear; a single, crossover study did not show a significant effect of aprepitant on gastrointestinal transit. Our aim was to compare, in a randomized, double-blind, placebo-controlled, parallel-group study (12 healthy volunteers per group), the effects of aprepitant vs. placebo on gastric emptying of solids (by scintigraphy) with a 320-kcal meal, gastric volumes (GVs; fasting and accommodation by single photon emission-computed tomography ), satiation [maximum tolerated volume (MTV)], and symptoms after a dyspeptogenic meal of Ensure. Aprepitant (125 mg on day 1, followed by 80 mg on days 2–5) or placebo, one tablet daily, was administered for 5 consecutive days. Statistical analysis was by unpaired rank sum test, adjusted for sex difference and body mass index. To assess treatment effects on symptoms, we incorporated MTV in the model. Aprepitant increased fasting, postprandial, and accommodation GV and tended to increase volume to fullness and MTV by ~200 kcal. However, aprepitant increased aggregate symptoms, nausea, and pain scores after ingestion the MTV of Ensure. There was no significant effect of aprepitant on gastric half-emptying time of solids. We conclude that NK1 receptors are involved in the control of GV and in determining postprandial satiation and symptoms. Further studies of the pharmacodynamics and therapeutic role of NK1 receptor antagonists in patients with gastroparesis and dyspepsia are warranted. NEW & NOTEWORTHY Aprepitant increases fasting, postprandial, and accommodation gastric volumes. Aprepitant increases volume to fullness and maximum tolerated volume during a nutrient drink test. NK1 receptors are involved in the control of gastric volume and in determining postprandial satiation and symptoms.

The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m 2 ): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV) by using Ensure nutrient drink test (30 ml/min) and symptoms 30 min after MTV. Relationships between GE or GA with satiety, satiation, and symptoms were analyzed using Spearman rank ( r s ) and Pearson ( R) linear correlation coefficients. We found a higher VTF during satiation test correlated with a higher calorie intake at ad libitum buffet meal ( r s = 0.535, P < 0.001). There was a significant inverse correlation between gastric half-emptying time (GE T 1/2 ) and VTF ( r s = −0.317, P < 0.001) and the calorie intake at buffet meal ( r s = −0.329, P < 0.001), and an inverse correlation between GE Tlag and GE25% emptied with VTF ( r s = −0.273, P < 0.001 and r s = −0.248, P < 0.001, respectively). GE T 1/2 was significantly associated with satiation (MTV, R = −0.234, P < 0.0001), nausea ( R = 0.145, P = 0.023), pain ( R = 0.149, P = 0.012), and higher aggregate symptom score ( R = 0.132, P = 0.026). There was no significant correlation between GA and satiation, satiety, postprandial symptoms, or GE. We concluded that GE of solids, rather than GA, is associated with postprandial symptoms, satiation, and satiety in healthy participants. NEW & NOTEWORTHY A higher volume to comfortable fullness postprandially correlated with a higher calorie intake at ad libitum buffet meal. Gastric emptying of solids is correlated to satiation (volume to fullness and maximum tolerated volume) and satiety (the calorie intake at buffet meal) and symptoms of nausea, pain, and aggregate symptom score after a fully satiating meal. There was no significant correlation between gastric accommodation and either satiation or satiety indices, postprandial symptoms, or gastric emptying.

Several chemical and molecular factors in the intestine are reported to be altered and to have a potentially significant role in irritable bowel syndrome (IBS), particularly in IBS with diarrhea. These include bile acids; short-chain fatty acids; mucosal barrier proteins; mast cell products such as histamine, proteases, and tryptase; enteroendocrine cell products; and mucosal mRNAs, proteins, and microRNAs. This article reviews the current knowledge and unanswered questions in the pathobiology of the chemical and molecular factors in IBS. Evidence continues to point to significant roles in pathogenesis of these chemical and molecular mechanisms, which may therefore constitute potential targets for future research and therapy. However, it is still necessary to address the interaction between these factors in the gut and to appraise how they may influence hypervigilance in the central nervous system in patients with IBS.