Association Between Clinical Effect of Morphine With PCA After Surgery and Pharmacogenetics (PCA-Gene)

• ClinicalTrials.gov Identifier: NCT01233752
• Recruitment Status: Completed
• First Posted: November 3, 2010
• Last Update Posted: July 19, 2013
• Sponsor: IRCCS Policlinico S. Matteo
• Information provided by (Responsible Party): Massimo Allegri, IRCCS Policlinico S. Matteo

Tracking Information

• First Submitted Date: November 2, 2010
• First Posted Date: November 3, 2010
• Last Update Posted Date: July 19, 2013
• Study Start Date: July 2010
• Actual Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2010)

Assessment of the medium morphine dose (mg/kg/die)in the two groups homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene; group B: both homozygous and heterozygous patients for the less frequent allele [ Time Frame: first 24 h after surgery ]

Valutation of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 2, 2010)

• Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure [ Time Frame: during 24 h postsurgery ]
  Frequency of the variants at the loci OPRM1, COMT, UGTs, ESR1, both in patients with NRS ≤4 and in those having NRS >4 at least once during 24 hours.
• Detection of the medium morphine dose [ Time Frame: First 24 h after surgery ]
  Detection of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 though the first 48 hours after surgery.
• Pharmacokinetics of morphine with PCA after surgery [ Time Frame: 48 h after surgery ]
  Pharmacokinetic study of both morphine and its principal active and/or toxic metabolites (M3G and M6G).
• Variants frequency at loci OPRM1, COMT, UGTs, ESR1 [ Time Frame: Within 48h after surgery ]
  Variants frequency at loci OPRM1, COMT, UGTs, ESR1 in the patients with Cmax and AUC of both morphine and M3G-M6G metabolites >2 standard deviations higher than expected population curve ("outliers").
• Detection of the possible side effects. [ Time Frame: 72 h postopratively ]
• Detection of the association between M3G/M6G ratio and polymorphisms of UGTs (and possible side effects). [ Time Frame: within 72 h postoperatively ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Association Between Clinical Effect of Morphine With PCA After Surgery and Pharmacogenetics
• Official Title: Association Between Clinical Effect of Morphine in Patients With PCA After Major Surgery and Pharmacogenetics: Prospective Observational Clinical Study.
• Brief Summary: Identification of the genetic polymorphisms that could be correlated either with a better clinical response or with a major predisposition of patients to develop tolerance and/or side effects to the treatment with morphine.

Detailed Description

Valuation of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%).

In order to avoid the bias related to alterations in metabolism, patients with Cmax and AUC of morphine (and metabolites M6G and M3G) >2 standard deviation higher than expected population curve ("outliers") will be excluded for the primary purpose.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

genes OPRM1, COMT, UGTs, ESR1

• Sampling Method: Probability Sample
• Study Population: Pazients scheduled for major abdominal or urological surgery with postoperative pain control by PCA morphine administration

Condition

• Anesthesia
• Surgery

Intervention

Drug: morphine chlorhydrate

The drug will be administrated by a bolus 45 minutes before the end of the surgery, with the following modalities: bolus with morphine chlorhydrate 0.15 mg/kg ± 20%. Also acetaminophene 1g and ketoprofen 160 mg (ketorolac 30mg) will be administrated during the operation.

At the exit of the operative compartment patients will have an electronic pump (PCA) for 48h with morphine chlorhydrate to be used in boluses by 1 mg with a lock out of 5 mins, max dose 20 mg in 4 hours.

Moreover, ketoprofen will be prescribed 160 mg x 2 per day (ketorolac 30mg x 2) (in case of allergy acetaminophene 1g x 3 daily).

Postoperative analgesic treatment is lasting 48h for each patient (between starting of the PCA infusion (T0) and the following 48h).

Other Name: morfina cloridrato

Study Groups/Cohorts

• Group A
  Homozygous patients,using PCA administration with morphine chlorhydrate for postoperative analgesia, for the more frequent allele of the polymorphism A118G of OPRM1 gene
  Intervention: Drug: morphine chlorhydrate
• Group B
  Both homozygous and heterozygous patients,using PCA administration with morphine chlorhydrate for postoperative analgesia, for the less frequent allele of the polymorphism A118G of OPRM1 gene
  Intervention: Drug: morphine chlorhydrate

Publications *

• Cattaneo S, Ingelmo P, Scudeller L, Gregori M, Bugada D, Baciarello M, Marchesini M, Alberio G, Normanno M, Jotti GS, Meschi T, Fanelli G, Massimo A. Sex differences in the daily rhythmicity of morphine consumption after major abdominal surgery. J Opioid Manag. 2017 Mar/Apr;13(2):85-94. doi: 10.5055/jom.2017.0372.
• De Gregori M, Diatchenko L, Ingelmo PM, Napolioni V, Klepstad P, Belfer I, Molinaro V, Garbin G, Ranzani GN, Alberio G, Normanno M, Lovisari F, Somaini M, Govoni S, Mura E, Bugada D, Niebel T, Zorzetto M, De Gregori S, Molinaro M, Fanelli G, Allegri M. Human Genetic Variability Contributes to Postoperative Morphine Consumption. J Pain. 2016 May;17(5):628-36. doi: 10.1016/j.jpain.2016.02.003. Epub 2016 Feb 21.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 18, 2013): 224
• Original Estimated Enrollment (submitted: November 2, 2010): 0
• Actual Study Completion Date: July 2013
• Actual Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Males and females over 18 years, under 75 years, scheduled for postoperative pain control by PCA morphine administration
• HIV negative
• Classification American Society of Anesthesiologists (ASA) I: without systemic disease
• Classification ASA II or III (mild systemic disease or severe systemic disease that limits the activity without invalidity).
• Undergoing abdominal and urologic major surgery (neither urgent nor emergency surgery)
• Signed informed consent

Exclusion criteria:

• Usual assumption of analgesic opioids
• Cognitive alterations nor mental retardation
• Severe hepatic/renal insufficiency (cholinesterase <3000 mU/ml, total bilirubinaemia <2 mg/dl and creatininaemia <1.2 mg/dl)
• Inpatients in intensive therapy, either with sedation and/or mechanic ventilation.
• Allergies to morphine and derivates

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT01233752
• Other Study ID Numbers: PT-SM-07-PCA-Gene
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Massimo Allegri, IRCCS Policlinico S. Matteo
• Study Sponsor: IRCCS Policlinico S. Matteo
• Collaborators: Not Provided

Investigators

• Principal Investigator: Massimo Allegri, MD; IRCCS Policlinico San Matteo

• PRS Account: IRCCS Policlinico S. Matteo
• Verification Date: July 2013