Clinical trial NCT02641301: Sustained-release Morphine Pharmacokinetics in Roux-en-Y Gastric Bypass Subjects
Official title: Study of the Concentrations of Long Acting Morphine After Oral Absorption in Subjects Who Underwent Gastric Bypass (OBEMO 2)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Bypass Complications
Keywords: obesity
Roux-en-Y-gastric bypass
pharmacokinetics
Pain
morphine
Lead sponsor: Hopital Lariboisière
Sponsor class: OTHER
First posted: 2015-12-29
Enrollment: 24
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: The purpose of this study is to determine whether sustained release morphine pharmacokinetics parameters in patients undergone roux-en-y gastric bypass (RYGB) differ from subjects who did not. Our hypothesis is that exposure is comparable. Indeed, in the Study OBEMO (Determinants of Oral Morphine Answer Among Obese Patients Before and After Gastric Bypass; NCT00943969) the investigators observed changes in pharmacokinetics parameters for immediate release morphine, probably due to an earlier absorption of the morphine, in agreement with the expected clinical effect of this formulation.

Detailed description: This is an open label study with two arms: patients undergone roux-en-y gastric bypass and volunteers who did not matched by sex, age and Body Mass Index (BMI). In the pharmacokinetic visit the subject takes an oral administration of sustained release morphine, 30 mg, then 11 samples are collected during 12 hours.

Eligibility criteria: Inclusion Criteria:

RYGB Group (n=12) :

* Subjects who undergone RYGB for at least 24 months
* Stable weight since almost one year (or weight loss below 10kg over the last year)

Control group (n=12) :

* Volunteers subjects, matched for age, sex, and Body mass index
* No history of bariatric surgery

Same characteristics

* Subjects volunteers for the study
* Age 20-65 years
* Written consent

Exclusion Criteria:

* Known allergy to morphine or naloxone
* Patients not affiliated to the french social security system
* Subjects yet recruited in a study with remuneration
* Abnormalities in liver function Prothrombin ratio \<70% and/ or aspartate transaminase \> 5 times the usual values and/ or alanine aminotransferase \>5 times the usual values and/ or in renal function (creatinine clearance Modification of Diet in Renal Disease (MDRD) \< 60ml/ min
* Respiratory insufficiency defined by an oximetry below 90%
* Pregnancy and breastfeeding
* Use of drugs contra-indicated or not advised with morphine:
* Agonists-antagonists opioids ( buprenorphine, nalbuphine, pentazocine ), naltrexone
* Alcohol intake \> 30g by day
* Cough medicine morphine-like ( dextromethorphan, noscapine, pholcodine )
* Codeine, ethylmorphine
* Other morphine agonist ( alfentanil, codeine, dextromoramide, dextropropoxyphene, dihydrocodeine, fentanyl, oxycodone, pethidin, phenoperidine, remifentanil, sufentanil, tramadol )
* Barbiturates, benzodiazepines
* Rifampicin

Primary outcomes:
measure: Morphine area under the curve (AUC0-inf) after its oral administration according to the morphine concentration.
timeFrame: During the study visit: morphine concentration at time hour 0,5 ; hour 1; hour 1,5 ; hour 2; hour2,5; hour3; hour 4; hour 5; hour 6; hour 8; hour 12 after its oral administration
Secondary outcomes:
measure: Area under ther curve [AUC] of morphine-3-glucuronide, morphine-6-glucuronide
timeFrame: During the study visit: concentration at time hour 0,5 ; hour 1; hour 1,5 ; hour 2; hour2,5; hour3; hour 4; hour 5; hour 6; hour 8; hour 12 after morphine oral administration
measure: Time of the maximum plasma concentration [Tmax] of morphine, morphine-3-glucuronide, morphine-6-glucuronide
timeFrame: During the study visit: concentrations at time hour 0,5 ; hour 1; hour 1,5 ; hour 2; hour2,5; hour3; hour 4; hour 5; hour 6; hour 8; hour 12 after morphine oral administration
measure: Observed clearance [Cl/F] of morphine, morphine-3-glucuronide, morphine-6-glucuronide
timeFrame: During the study visit: concentrations at time 0,5h; 1h; 1,5h; 2h; 2,5h; 3h; 4h; 5h; 6h; 8h; 12h after morphine oral administration
measure: Observed Volume of distribution [Vd / F] of morphine, morphine-3-glucuronide, morphine-6-glucuronide
timeFrame: During the study visit: concentrations at time hour 0,5 ; hour 1; hour 1,5 ; hour 2; hour2,5; hour3; hour 4; hour 5; hour 6; hour 8; hour 12 after morphine oral administration
measure: Plasma Half-Life [T1 /2] of morphine, morphine-3-glucuronide, morphine-6-glucuronide
timeFrame: During the study visit: concentrations at time hour 0,5 ; hour 1; hour 1,5 ; hour 2; hour2,5; hour3; hour 4; hour 5; hour 6; hour 8; hour 12 after morphine oral administration
measure: Maximum plasma concentration [Cmax] of morphine, morphine-3-glucuronide, morphine-6-glucuronide
timeFrame: During the study visit: concentrations at time hour 0,5 ; hour 1; hour 1,5 ; hour 2; hour2,5; hour3; hour 4; hour 5; hour 6; hour 8; hour 12 after morphine oral administration
Other outcomes:
Locations:
city: Paris
country: France
facility: Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisiere
city: Paris
country: France
facility: Hopital Pitie Salpetriere
Study officials:
affiliation: Hopital Lariboisiere
name: Jean-Francois JB Bergmann, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet. 2011 Feb 12;377(9765):557-67. doi: 10.1016/S0140-6736(10)62037-5. Epub 2011 Feb 3.
citation: Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD, Sullivan M, Wedel H; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004 Dec 23;351(26):2683-93. doi: 10.1056/NEJMoa035622.
citation: Padwal RS, Gabr RQ, Sharma AM, Langkaas LA, Birch DW, Karmali S, Brocks DR. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011 Jun;34(6):1295-300. doi: 10.2337/dc10-2140. Epub 2011 Apr 8.
citation: Skottheim IB, Stormark K, Christensen H, Jakobsen GS, Hjelmesaeth J, Jenssen T, Reubsaet JL, Sandbu R, Asberg A. Significantly altered systemic exposure to atorvastatin acid following gastric bypass surgery in morbidly obese patients. Clin Pharmacol Ther. 2009 Sep;86(3):311-8. doi: 10.1038/clpt.2009.82. Epub 2009 Jun 3.
citation: Hamad GG, Helsel JC, Perel JM, Kozak GM, McShea MC, Hughes C, Confer AL, Sit DK, McCloskey CA, Wisner KL. The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors. Am J Psychiatry. 2012 Mar;169(3):256-63. doi: 10.1176/appi.ajp.2011.11050719.
citation: Raebel MA, Newcomer SR, Reifler LM, Boudreau D, Elliott TE, DeBar L, Ahmed A, Pawloski PA, Fisher D, Donahoo WT, Bayliss EA. Chronic use of opioid medications before and after bariatric surgery. JAMA. 2013 Oct 2;310(13):1369-76. doi: 10.1001/jama.2013.278344.
citation: Hasselstrom J, Sawe J. Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet. 1993 Apr;24(4):344-54. doi: 10.2165/00003088-199324040-00007.
citation: Gourlay GK. Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine. Clin Pharmacokinet. 1998 Sep;35(3):173-90. doi: 10.2165/00003088-199835030-00002.
citation: Lloret-Linares C, Hirt D, Bardin C, Bouillot JL, Oppert JM, Poitou C, Chast F, Mouly S, Scherrmann JM, Bergmann JF, Decleves X. Effect of a Roux-en-Y gastric bypass on the pharmacokinetics of oral morphine using a population approach. Clin Pharmacokinet. 2014 Oct;53(10):919-30. doi: 10.1007/s40262-014-0163-0.
citation: Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg. 2013 Apr;23(4):427-36. doi: 10.1007/s11695-012-0864-0.
citation: Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes Rev. 2010 Jan;11(1):41-50. doi: 10.1111/j.1467-789X.2009.00614.x. Epub 2009 Jun 2.
citation: Skottheim IB, Jakobsen GS, Stormark K, Christensen H, Hjelmesaeth J, Jenssen T, Asberg A, Sandbu R. Significant increase in systemic exposure of atorvastatin after biliopancreatic diversion with duodenal switch. Clin Pharmacol Ther. 2010 Jun;87(6):699-705. doi: 10.1038/clpt.2010.32. Epub 2010 May 5.
citation: Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301-16. doi: 10.1146/annurev.med.080708.082713.
citation: Lotsch J, Weiss M, Ahne G, Kobal G, Geisslinger G. Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology. 1999 Apr;90(4):1026-38. doi: 10.1097/00000542-199904000-00016.
citation: Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther. 2003 Dec;74(6):543-54. doi: 10.1016/j.clpt.2003.08.011.