Association Between Clinical Effect of Morphine With PCA After Surgery and Pharmacogenetics - Full Text View

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:

Drug Information available for: Morphine sulfate

U.S. FDA Resources

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

Estimated Enrollment:	100
Study Start Date:	July 2010
Estimated Study Completion Date:	July 2013
Estimated Primary Completion Date:	July 2013 (Final data collection date for primary outcome measure)

Groups/Cohorts	Assigned Interventions
Group A Homozygous patients 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 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

Groups/Cohorts

Assigned Interventions

Group A

Homozygous patients 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 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

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

Contacts

Contact: Massimo Allegri, MD

00390382 ext 502627

m.allegri@smatteo.pv.it

Locations

Italy
Azienda Ospedaliera San Gerardo	Recruiting
Monza, Italy, 20052
Contact: Pablo Ingelmo, MD
Contact: Giovanni Vitale, MD
Principal Investigator: Pablo Ingelmo, MD
Fondazione IRCCS Policlinico San Matteo	Recruiting
Pavia, Italy, 27100
Contact: Massimo Allegri, MD 00390382 ext 502627 m.allegri@smatteo.pv.it
Principal Investigator: Massimo Allegri, MD

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:	January 19, 2012
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
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Central Nervous System Depressants
Narcotics

ClinicalTrials.gov processed this record on June 17, 2013

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