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Michael Camilleri,1 Martin Hale,2 Bart Morlion,3 Jan Tack,4 Lynn Webster,5 James Wild6 1Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA; 2Gold Coast Research, LLC, Plantation, FL, USA; 3Leuven Center for Algology and Pain Management, University Hospital Leuven, University of Leuven, Leuven, Belgium; 4Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium; 5PRA Health Sciences, Salt Lake City, UT, USA; 6Upstate Clinical Research Associates, Williamsville, NY, USACorrespondence: Michael CamilleriClinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, 200 First St. S.W., Charlton Building, Rm. 8-110, Rochester, MN, 55905, USATel +1 507-266-2305Fax +1 507-538-5820Email camilleri.michael@mayo.eduObjective: Opioid-induced constipation is among the most common side effects associated with opioid use in patients with chronic non-cancer pain, and it can have a significant negative impact on health-related quality of life (QOL). This analysis evaluated the effect of naldemedine 0.2 mg on patient-reported outcomes in three phase 3 clinical studies.Methods: COMPOSE-1 and COMPOSE-2 were identical randomized, double-blind, placebo-controlled, parallel-group studies of 12 weeks’ duration, allowing data to be integrated (n=1095). COMPOSE-3 was similar in design, but of 52 weeks’ duration (n=1241). Patients were adults with chronic non-cancer pain who had been treated with opioid analgesics for ≥ 3 months and experiencing opioid-induced constipation. Patient-reported outcomes included Patient Assessment of Constipation Symptoms (PAC-SYM; 12 questions assessed on a 5-point Likert scale), PAC-QOL (28 questions assessed on a 5-point Likert scale), and Subject Global Satisfaction (measured on a 7-point Likert scale). The proportion of patients achieving a ≥ 1.5 improvement in PAC-SYM and PAC-QOL was calculated. The correlation between change in PAC-SYM and PAC-QOL scores and frequency of bowel movements was also explored.Results: The proportion of PAC-SYM and PAC-QOL responders was significantly higher for naldemedine than for placebo at all assessed time points in COMPOSE-1/COMPOSE-2 (p< 0.005 for both) and COMPOSE-3 (p< 0.005 and p< 0.0001, respectively). There was a statistically significant correlation between improvement in PAC-SYM/PAC-QOL and frequency of bowel movements at all time points (p≤ 0.0002). The majority of patients treated with naldemedine reported markedly or moderately improved satisfaction with constipation and abdominal symptoms on the Subject Global Satisfaction questionnaire.Discussion: Naldemedine treatment was associated with a rapid and sustained clinically relevant improvement in patient-reported outcomes, indicating improvement in opioid-induced constipation-related symptoms and QOL.ClinicalTrials.gov Registration: NCT01965158, NCT01993940, NCT01965652.Keywords: gastrointestinal tract, minimal clinically important difference, mu opioid receptor, patient satisfaction, quality of life

Lynn R Webster,1 Michael Camilleri,2 Andrew Finn3 1PRA Health Sciences, Salt Lake City, UT, 2Mayo Clinic Rochester, MN, 3BioDelivery Sciences, Inc., Raleigh, NC, USA Abstract: Buprenorphine and buprenorphine–naloxone fixed combinations are effective for managing patients with opioid dependence, but constipation is one of the most common side effects. Evidence indicates that the rate of constipation is lower when patients are switched from sublingual buprenorphine–naloxone tablets or films to a bilayered bioerodible mucoadhesive buccal film formulation, and while the bilayered buccal film promotes unidirectional drug flow across the buccal mucosa, the mechanism for the reduced constipation is unclear. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered buprenorphine may expose patients to higher concentrations of norbuprenorphine than buprenorphine, while chronic dosing of the buccal formulation results in higher buprenorphine concentrations than norbuprenorphine. Because norbuprenorphine is a potent full agonist at mu-opioid receptors, the differences in norbuprenorphine exposure may explain the observed differences in treatment-emergent constipation between the sublingual formulation and the buccal film formulation of buprenorphine–naloxone. To facilitate the understanding and management of opioid-dependent patients at risk of developing opioid-induced constipation, the clinical profiles of these formulations of buprenorphine and buprenorphine-naloxone are summarized, and the incidence of treatment-emergent constipation in clinical trials is reviewed. These data are used to propose a potential role for exposure to norbuprenorphine, an active metabolite of buprenorphine, in the pathophysiology of opioid-induced constipation. Keywords: opioid, safety, buccal, sublingual, dependence, maintenance

Matheni Sathananthan,1 Sayeed Ikramuddin,2 James M Swain,3,6 Meera Shah,1 Francesca Piccinini,4 Chiara Dalla Man,4 Claudio Cobelli,4 Robert A Rizza,1 Michael Camilleri,5 Adrian Vella1 1Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA; 2Division of General Surgery, University of Minnesota, Minneapolis, MN, USA; 3Division of General Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA; 4Department of Information Engineering, University of Padua, Padua, Italy; 5Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA; 6Scottsdale Healthcare Bariatric Center, Scottsdale, AZ, USA Purpose: Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans. Patients and methods: We utilized a randomized, cross-over study design where participants were studied after 2 weeks of activation or inactivation of vagal nerve blockade (VNB). Seven obese subjects with impaired fasting glucose previously enrolled in a long-term study to examine the effect of VNB on weight took part. We used a standardized triple-tracer mixed meal to enable measurement of the rate of meal appearance, endogenous glucose production, and glucose disappearance. The 550 kcal meal was also labeled with 111In-diethylene triamine pentaacetic acid (DTPA) to measure gastrointestinal transit. Insulin action and ß-cell responsivity indices were estimated using the minimal model. Results: Integrated glucose, insulin, and glucagon concentrations did not differ between study days. This was also reflected in a lack of effect on β-cell responsivity and insulin action. Furthermore, fasting and postprandial endogenous glucose production, integrated meal appearance, and glucose disposal did not differ in the presence or absence of VNB. Similarly, gastric emptying and colonic transit were unchanged by VNB. Conclusion: In this pilot study in nondiabetic humans, electrical vagal blockade had no acute effects on glucose metabolism, insulin secretion and action, or gastric emptying. It remains to be determined if more pronounced effects would be observed in diabetic subjects. Keywords: vagotomy, insulin secretion, insulin action, endogenous glucose production