Association Between Clinical Effect of Morphine With PCA After Surgery and Pharmacogenetics

Study Overview
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Brief Summary
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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
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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.

Official Title
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Association Between Clinical Effect of Morphine in Patients With PCA After Major Surgery and Pharmacogenetics: Prospective Observational Clinical Study.

Conditions
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Anesthesia, Surgery

Intervention / Treatment
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* Drug: morphine chlorhydrate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group A<br>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<br>* 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).<br>* Other names: morfina cloridrato;|
| Group B<br>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<br>* 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).<br>* Other names: morfina cloridrato;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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%). | first 24 h after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure | 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. | during 24 h postsurgery | 
| Detection of the medium morphine dose | Detection of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 though the first 48 hours after surgery. | First 24 h after surgery | 
| Pharmacokinetics of morphine with PCA after surgery | Pharmacokinetic study of both morphine and its principal active and/or toxic metabolites (M3G and M6G). | 48 h after surgery | 
| Variants frequency at loci OPRM1, COMT, UGTs, ESR1 | 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). | Within 48h after surgery | 
| Detection of the possible side effects. |  | 72 h postopratively | 
| Detection of the association between M3G/M6G ratio and polymorphisms of UGTs (and possible side effects). |  | within 72 h postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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systemic morphine analgesia, pharmacogenetics, pharmacokinetics