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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Massimo Allegri, IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier:
NCT01233752
First received: November 2, 2010
Last updated: July 18, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention
Anesthesia
Surgery
Drug: morphine chlorhydrate

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Association Between Clinical Effect of Morphine in Patients With PCA After Major Surgery and Pharmacogenetics: Prospective Observational Clinical Study.

Resource links provided by NLM:


Further study details as provided by IRCCS Policlinico S. Matteo:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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%).


Secondary Outcome Measures:
  • Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure [ Time Frame: during 24 h postsurgery ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
  • Detection of the association between M3G/M6G ratio and polymorphisms of UGTs (and possible side effects). [ Time Frame: within 72 h postoperatively ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

genes OPRM1, COMT, UGTs, ESR1


Enrollment: 224
Study Start Date: July 2010
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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
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
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
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Pazients scheduled for major abdominal or urological surgery with postoperative pain control by PCA morphine administration

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01233752

Locations
Italy
Azienda Ospedaliera San Gerardo
Monza, Italy, 20052
Fondazione IRCCS Policlinico San Matteo
Pavia, Italy, 27100
Sponsors and Collaborators
IRCCS Policlinico S. Matteo
Investigators
Principal Investigator: Massimo Allegri, MD IRCCS Policlinico San Matteo
  More Information

No publications provided

Responsible Party: Massimo Allegri, MD, IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier: NCT01233752     History of Changes
Other Study ID Numbers: PT-SM-07-PCA-Gene
Study First Received: November 2, 2010
Last Updated: July 18, 2013
Health Authority: Italy: Ministry of Health

Keywords provided by IRCCS Policlinico S. Matteo:
systemic morphine analgesia
pharmacogenetics
pharmacokinetics

Additional relevant MeSH terms:
Morphine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 16, 2014