Genetic Predictors of Analgesic Efficacy of Propranolol for Treating Postoperative Pain

NCT02511483 | Terminated Phase 2

• 1 other identifier: 15-169-MUHC
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

Brief Summary

This study is a randomized, double-blind, placebo controlled clinical trial. The main purpose of this study is to determine if postsurgical pain ratings are improved with treatment with oral Propranolol, and if the effectiveness of treatment can be modified by the presence or absence of SNPs (Single Nucleotide Polymorphism) associated with Cathecol-O-MethylTransferase (COMT) and mu-opioid receptor (MOR1) activity. The treatment period will last for three days and the observation period will last for six months. Effectiveness of treatment will be assessed by means of morphine consumption through quantitative evaluation of IV-PCA (Patient Controlled Analgesia) morphine as primary outcome measure.

Conditions

Postoperative Pain

Keywords

COMT; Beta-blocker; Hemicolectomy

Outcome Measures

Primary Outcomes (1)

• Total morphine delivered by IV-PCA

  Day II Post-op

Secondary Outcomes (7)

• Pressure Pain Threshold by digital pressure algometer

  Pre-op visit, Day I Post-op, Day II Post-op, four weeks Post-op

• Hyperalgesia test by von Frey hair

  Pre-op visit, Day I Post-op, Day II Post-op, four weeks Post-op

• Pain measured by the Numerical pain Rating Scale

  Pre-op visit, one evaluation during the first 8 Post-op hours, Day I Post-op, Day II Post-op, 4 weeks Post-op, 3 month Post-op, 6 months Post-op

• Somatization, depression and anxiety by SCL-90-R subscales

  Pre-op visit

• Sleep quality by PSQI

  Pre-op visit, 4 weeks Post-op, 3 months Post-op, 6 months Post-op

Other Outcomes (1)

• COMT-haplotypes by blood sampling genotyping

  Pre-op, Day III Post-op, 4 weeks Post-op

Study Arms (2)

IV-PCA morphine + Placebo PO

PLACEBO COMPARATOR

Pain control after surgery will be performed through IV-PCA morphine. Placebo will be administered with the same schedule of Propranolol in the experimental arm. Parallel evaluation of Quantitative Sensory Testing (QST), Psychometric assessment and COMT-haplotypes will be included along the trial.

Drug: IV-PCA morphine; Drug: Placebo PO; Procedure: Quantitative Sensory Testing (QST); Other: Psychometric assessment; Genetic: COMT-haplotypes

IV-PCA morphine + Propranolol PO

EXPERIMENTAL

The morning of the surgery a dose of Propranolol 20 mg PO will be administered. After surgery pain control will be performed with IV-PCA morphine; in addition a second dose of Propranolol 20 mg PO will be administered . During the first and second postoperative day Propranolol 30 mg PO (BID) will be administered. Parallel assessment of Quantitative Sensory Testing (QST), Psychometric assessment and COMT-haplotypes will be included along the trial.

Drug: Propranolol PO; Drug: IV-PCA morphine; Procedure: Quantitative Sensory Testing (QST); Other: Psychometric assessment; Genetic: COMT-haplotypes

Interventions

Propranolol PO DRUG

20 mg PO BID Day of Surgery, 30 mg PO BID Day I and Day II post-op.

Also known as: CAS No 525-66-6, DINs: 00740675, 00496480

IV-PCA morphine + Propranolol PO

IV-PCA morphine DRUG

Morphine delivered via IV-PCA pump for 48 hours after surgery with standard program: bolus 1 mg, lock out 7 minutes, no background infusion.

Also known as: Patient controlled Analgesia with intravenous morphine

IV-PCA morphine + Placebo PO; IV-PCA morphine + Propranolol PO

Placebo PO DRUG

Placebo tablets administered with the same schedule of Propranolol tablets

Also known as: tablet containing microcrystalline cellulose

IV-PCA morphine + Placebo PO

Quantitative Sensory Testing (QST) PROCEDURE

Assessment of PPT (Pressure Pain Threshold) by pressure algometer and assessment of the post-op area of hyperalgesia by von Frey hair no. 16.

Also known as: Pressure Pain Threshold and Hyperalgesia test

IV-PCA morphine + Placebo PO; IV-PCA morphine + Propranolol PO

Psychometric assessment OTHER

Questionnaires assessing for sleep quality (PSQI: Pittsburgh Sleep Quality Index), pain quality (sfMGPQ-Short Form-McGill Pain Questionnaire), somatization-depression-anxiety (SCL-90-R: Symptom Checklist 90 Revised), evolution of post-operative chronic pain (PQRS: Post-operative Quality of Recovery Scale)

Also known as: PSQI, sfMGPQ, SCL-90-R, PQRS

IV-PCA morphine + Placebo PO; IV-PCA morphine + Propranolol PO

COMT-haplotypes GENETIC

Assessing of High Pain Sensitivity (HPS), Average Pain Sensitivity (APS) and Low Pain Sensitivity (LPS) haplotypes for COMT by genotyping peripheral blood samples.

Also known as: HPS, APS, LPS

IV-PCA morphine + Placebo PO; IV-PCA morphine + Propranolol PO

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Elective laparoscopic hemicolectomy surgery.
• Self-reported Caucasians.
• ASA (American Society of Anesthesiologists) physical status of I or II.
• Agrees to provide signed and dated informed consent form.
• Willingness to agree with the Biobanking policy.

You may not qualify if:

• Uncontrolled medical or psychiatric conditions.
• Severe mental impairment.
• History of major depressive disorder, psychotic disorder or schizophrenia, and/or manic episodes within the past year.
• Active alcoholism within the past 6 months.
• Psychoactive recreational drug abuse within the past 6 months including MDMA, Ketamine, hallucinogens such as LSD and/or sympathomimetics such as Cocaine.
• Inability to comprehend pain assessment.
• Pregnancy and/or breast-feeding.
• Known hypersensitivity to Beta Blockers or Opioids.
• Currently taking Propranolol.
• Currently taking other hypotensive treatments.
• Currently taking Opioids.
• Patients with asthma or reactive airway disease.
• Patients with cardiac arrhythmia, coronary artery disease, congestive heart failure.
• Patients with renal failure or dialysis.
• Patients with liver insufficiency.

Sponsors & Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre: lead

Study Sites (2)

Montreal General Hospital

Montreal, Quebec, H3G 1A4, Canada

Location

Royal Victoria Hospital

Montreal, Quebec, H4A 3J1, Canada

Location

Related Publications (9)

• Orrey DC, Halawa OI, Bortsov AV, Shupp JW, Jones SW, Haith LR, Hoskins JM, Jordan MH, Bangdiwala SI, Roane BR, Platts-Mills TF, Holmes JH, Hwang J, Cairns BA, McLean SA. Results of a pilot multicenter genotype-based randomized placebo-controlled trial of propranolol to reduce pain after major thermal burn injury. Clin J Pain. 2015 Jan;31(1):21-9. doi: 10.1097/AJP.0000000000000086.

  PMID: 25084070 BACKGROUND

• Tchivileva IE, Lim PF, Smith SB, Slade GD, Diatchenko L, McLean SA, Maixner W. Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics. 2010 Apr;20(4):239-48. doi: 10.1097/FPC.0b013e328337f9ab.

  PMID: 20216107 BACKGROUND

• Zaugg M, Tagliente T, Lucchinetti E, Jacobs E, Krol M, Bodian C, Reich DL, Silverstein JH. Beneficial effects from beta-adrenergic blockade in elderly patients undergoing noncardiac surgery. Anesthesiology. 1999 Dec;91(6):1674-86. doi: 10.1097/00000542-199912000-00020.

  PMID: 10598610 BACKGROUND

• Schweinhardt P, Abulhasan YB, Koeva V, Balderi T, Kim DJ, Alhujairi M, Carli F. Effects of intravenous propranolol on heat pain sensitivity in healthy men. Eur J Pain. 2013 May;17(5):704-13. doi: 10.1002/j.1532-2149.2012.00231.x. Epub 2012 Oct 16.

  PMID: 23070986 BACKGROUND

• Pranevicius M, Pranevicius O. Non-opioid anesthesia with esmolol avoids opioid-induced hyperalgesia and reduces fentanyl requirement after laparoscopy. Anesth Analg. 2009 Mar;108(3):1048. doi: 10.1213/ane.0b013e3181938f3f. No abstract available.

  PMID: 19224829 BACKGROUND

• Chia YY, Chan MH, Ko NH, Liu K. Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy. Br J Anaesth. 2004 Dec;93(6):799-805. doi: 10.1093/bja/aeh268. Epub 2004 Sep 17.

  PMID: 15377583 BACKGROUND

• Chen YW, Chu CC, Chen YC, Hung CH, Wang JJ. Propranolol elicits cutaneous analgesia against skin nociceptive stimuli in rats. Neurosci Lett. 2012 Aug 30;524(2):129-32. doi: 10.1016/j.neulet.2012.07.036. Epub 2012 Jul 26.

  PMID: 22842397 BACKGROUND

• Zhang F, Tong J, Hu J, Zhang H, Ouyang W, Huang D, Tang Q, Liao Q. COMT gene haplotypes are closely associated with postoperative fentanyl dose in patients. Anesth Analg. 2015 Apr;120(4):933-40. doi: 10.1213/ANE.0000000000000563.

  PMID: 25532715 BACKGROUND

• Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1;14(1):135-43. doi: 10.1093/hmg/ddi013. Epub 2004 Nov 10.

  PMID: 15537663 BACKGROUND

MeSH Terms

Conditions

Pain, Postoperative

Interventions

Propranolol; Analgesia, Patient-Controlled; Lipopolysaccharides

Condition Hierarchy (Ancestors)

Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Pain; Neurologic Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Analgesia; Anesthesia and Analgesia; Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens; Biological Factors; Endotoxins; Bacterial Toxins; Toxins, Biological

Study Officials

• Luda Diatchenko, Professor

  Anesthesia Department McGill University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Anesthesia

Study Record Dates

• First Submitted: July 23, 2015
• First Posted: July 30, 2015
• Study Start: May 18, 2015
• Primary Completion: November 12, 2016
• Study Completion: November 12, 2016
• Last Updated: September 28, 2021

Record last verified: 2021-09

Locations

CA (2)