Sustained-release Morphine Pharmacokinetics in Roux-en-Y Gastric Bypass Subjects

Bypass Complications Clinical Trial

— OBEMO2  

Official title:

Study of the Concentrations of Long Acting Morphine After Oral Absorption in Subjects Who Underwent Gastric Bypass (OBEMO 2)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02641301
• Other study ID #: OBEMO2
• Status: Active, not recruiting
• Phase: Phase 4
• First received: December 14, 2015
• Last updated: November 28, 2016
• Start date: December 2015
• Est. completion date: March 2017

Study information

• Verified date: November 2016
• Source: Hopital Lariboisière
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 24
• Est. completion date: March 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 20 Years to 65 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Bypass Complications

Intervention

Drug:
• Sustained release morphine sulfate, 30 mg
A single oral administration of a capsule of sustained release morphine sulfate, 30 mg, on one day.

Locations

Country	Name	City	State
France	Hopital Pitie Salpetriere	Paris
France	Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisiere	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Hopital Lariboisière

Country where clinical trial is conducted

France, 

References & Publications (15)

Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg. 2013 Apr;23(4):427-36. doi: 10.1007/s11695-012-0864-0. — View 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. — View Citation

Gourlay GK. Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine. Clin Pharmacokinet. 1998 Sep;35(3):173-90. Review. — View 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. — View Citation

Hasselström J, Säwe 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. — View 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. — View Citation

Lloret-Linares C, Hirt D, Bardin C, Bouillot JL, Oppert JM, Poitou C, Chast F, Mouly S, Scherrmann JM, Bergmann JF, Declèves 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. — View Citation

Lötsch 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. — View 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. Review. — View 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. — View 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. — View 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. Review. — View Citation

Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjöström 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. — View 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. — View 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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Morphine area under the curve (AUC0-inf) after its oral administration according to the morphine concentration.		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	No
Secondary	Area under ther curve [AUC] of morphine-3-glucuronide, morphine-6-glucuronide		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	No
Secondary	Time of the maximum plasma concentration [Tmax] of morphine, morphine-3-glucuronide, morphine-6-glucuronide		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	No
Secondary	Observed clearance [Cl/F] of morphine, morphine-3-glucuronide, morphine-6-glucuronide	Blood samples gathered from hour 0,5 to hour 12 and urine sample gathered from the start to the end of the study visit.	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	No
Secondary	Observed Volume of distribution [Vd / F] of morphine, morphine-3-glucuronide, morphine-6-glucuronide		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	No
Secondary	Plasma Half-Life [T1 /2] of morphine, morphine-3-glucuronide, morphine-6-glucuronide		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	No
Secondary	Maximum plasma concentration [Cmax] of morphine, morphine-3-glucuronide, morphine-6-glucuronide		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	No