Intrathecal Morphine Analgesia vs. Continuous Epidural Analgesia vs. Systemic Analgesia in Colorectal Surgery. (KOLORIT)

Comparison of Intrathecal Morphine, Epidural Bupivacaine With Sufentanil and Systemic Patient Controlled Analgesia With Morphine for Analgesia After Colorectal Surgery: Prospective Randomised Study.

The purpose of this study is to determine which postoperative analgesia is optimal after colorectal surgery. The investigators will compare intrathecal morphine, continuous epidural analgesia and standard systemic analgesia. All patients will have the possibility to administer themselves intravenous morphine as needed.

Study Overview

• Status: Completed
• Conditions: Epidural Analgesia; Morphine; Analgesia, Patient-Controlled; Anesthesia; Spinal; Surgery, Colorectal; Intravenous Drug Delivery Systems
• Intervention / Treatment: Drug: Morphine intrathecal; Drug: Morphine intravenous; Drug: Bupivacaine + Sufentanil epidural

Detailed Description

Introduction

Colorectal surgery is a frequent operation with expected strong post-operative pain. Thoracic epidural analgesia is a preferred method by many authors, but it is not without risks. As patients in our hospital usually stay at a surgical ICU for 24 hours only and epidural infusion of opioids is prohibited at standard wards according to our hospital standards, it seems to be too demanding method. Systemic analgesia with strong opioids is usually an alternative, but high doses of opioids are known to cause side effects. The last possibility is a single-shot intrathecal injection of morphine which demonstrated long-lasting analgesia after various procedures. The main advantage is easy technique, absence of catheters and low cost. There are not enough studies to decide which method is the most convenient. The purpose of this prospective randomized open clinical study is to determine which postoperative analgesia is optimal after colorectal surgery. The investigators will compare intrathecal morphine, continuous epidural analgesia and compare both methods to standard systemic analgesia. All patients will have the possibility to administer themselves intravenous morphine as needed.

Hypotheses

1. Intrathecal morphine is non-inferior to continuous epidural analgesia
2. ] Intrathecal morphine will decrease the need for i.v. systemic patient controlled analgesia (PCA) with morphine

Aims of the study

Primary aims

1. To demonstrate non-inferiority of analgesia with intrathecal morphine 0.3mg compared to continuous epidural analgesia with 8 ml/hour of mixture of bupivacaine 0.125% and sufentanil 0,4ug/ml. Non-inferiority is defined as consumption of PCA morphine during 24 and 72 hours not higher than 10% compared to control group.
2. To demonstrate significantly lower consumption (at least 10%) of PCA morphine in patients with intrathecal morphine 0.3 mg compared to systemic analgesia with PCA morphine only.

Secondary aims

1. To demonstrate similar or lower side effects of intrathecal morphine compared to epidural or systemic analgesia. The investigators will record number of patients with respiratory rate <8/min, SpO2<90%, changes of blood pressure and pulse rate > 30% above base level before surgery, episodes of postoperative nausea and vomiting
2. To demonstrate the same or shorter interval since surgery to the first bowel movement confirmed by auscultation and interval to the first flatus.
3. To demonstrate the same or lower pain intensity in patients with intrathecal morphine compared to other two groups. The effect will be measured by area below visual analogue scale (0 - 10) pain intensity after 24 and 72 hours

Duration of the study: Three days

Method

Design: Study will be performed as prospective randomized open clinical study

Setting: Surgical ICU

Inclusion criteria: Patients with elective colorectal surgery (left or right hemicolectomy, subtotal colectomy, resection of sigmoid, rectal or cecum)

Exclusion criteria: Known allergy to any of drugs used, coagulopathy, sepsis, cognitive dysfunction and/or inability to understand instruction. Pregnancy (is assessed as a part of pre-operative examination). Abuse of drugs or administration of morphine therapy 5 or less days before surgery. Idiopathic bowel disease.

Anesthesia: General anesthesia will be performed in all groups using propofol for induction and rocuronium for intubation and muscle relaxation. Patients will be ventilated to normocapnia by oxygen + air + desflurane mixture. Sufentanil 5 - 10 mcg will be administered if needed. Paracetamol 1 g i.v. will be administered approximately 30 min before the end of anesthesia and ondansetron 4 mg i.v. will be administered 10 min. before the end of anesthesia. At the end of anesthesia patients will be administered atropine and neostigmine to obtain TOF ration >90%.

Standard postoperative analgesia: All patients will be administered paracetamol 1g i.v. every 6 h for next 72 hours and can use PCA morphine, bolus dose 1 mg, lock-out interval 5 min. for 3 days at surgical ICU.

Monitoring: Except of standard anesthesia and ICU monitoring (ECG, pulse oximetry and non-invasive blood pressure) pain intensity (VAS 0 - 10) and side effects (see above) will be recorded.

Power analysis: Total number of patients to demonstrate primary aims is 75 divided in ratio 1:2:2; n=15 in systemic analgesia group (PCA) and n=30 in each group with epidural and intrathecal analgesia. Standard tests will be used to analyse results. P value < 0.05 will be considered significant.

Interventions:

1. Systemic analgesia: Patients will be administered standard general anesthesia. After surgery, bolus doses of morphine 2 mg will be administered until level of pain will be < 4 (VAS 0 - 10). Analgesia will be continued by PCA device using morphine, bolus dose 1 mg, lock-out interval 5 min. for 3 days at surgical ICU.
2. Epidural analgesia: An epidural catheter will be inserted before induction of anesthesia in a sitting position between T9 and T10 - T12 and L1 vertebrae. A test dose of 4 ml 0.5 bupivacaine will be administered to rule out intravascular injection or subarachnoid or subdural block. Standard general anesthesia will be performed. Thirty minutes before the end of the surgery, patients will be administered a bolus of a mixture of bupivacaine 0.5% (3 ml) + sufentanil 10 mcg (2 ml) + NS 5 ml followed by a continuous infusion of a mixture containing in 1 ml bupivacaine 0.125% and sufentanil 0.4 mcg at 8 ml/h. At the same time patients will have the possibility to use PCA device with morphine, bolus dose 1 mg, lock-out interval 5 min for 3 days at a surgical ICU. Epidural infusion will be stopped 24 hours after surgery.
3. Intrathecal analgesia: An intrathecal administration of preservative-free morphine 0.3 mg in 3 ml NS prepared in sterile ampoules by a hospital pharmacy will be performed before induction of anesthesia in a sitting position between L2 and L3 - L4/L5 vertebrae. Standard general anesthesia will be performed. After surgery, the patients will have the possibility to use PCA device with morphine, bolus dose 1 mg, lock-out interval 5 min for 3 days at a surgical ICU.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czechia
  • Praha, Czechia, 100 00
    • University Hospital Královské Vinohrady

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with elective colorectal surgery (left or right hemicolectomy, subtotal colectomy, resection of sigmoid, rectal or cecum)

Exclusion Criteria:

• Known allergy to any of drugs used, coagulopathy, sepsis, cognitive dysfunction and/or inability to understand instruction.
• Pregnancy (is assessed as a part of pre-operative examination).
• Abuse of drugs or morphine therapy before surgery.
• Idiopathic bowel disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Morphine intrathecal; An intrathecal administration of preservative-free morphine 0.3 mg in 3 ml NS prepared in a sterile ampoules by a hospital pharmacy will be performed before induction of anaesthesia in a sitting position between L2 and L3 - L4/L5 vertebrae. Standard general anaesthesia will be performed. After surgery, the patients will have the possibility to use PCA device with morphine, bolus dose 1 mg, lock-out interval 5 min for 3 days at a surgical ICU.	Drug: Morphine intrathecal; Administration of intrathecal injection of 0.3 mg preservative-free morphine in 3 ml NS; Other Names: Morphine spinal; Drug: Morphine intravenous; Patiernt-controlled i.v. analgesia with morphine; Other Names: Morphine and patient controlled analgesia
Active Comparator: Bupivacaine + Sufentanil epidural; An epidural catheter will be inserted before induction of anaesthesia in a sitting position between T9 and T10 - T12 and L1 vertebrae. A test dose of 4 ml 0.5 bupivacaine will be administered to rule out intravascular injection or subarachnoid or subdural block. Standard general anaesthesia will be performed. Thirty minutes before the end of the surgery, patients will be administered a bolus of a mixture of bupivacaine 0.5% (3 ml) + sufentanil 10 mcg (2 ml) + NS 5 ml followed by a continuous infusion of a mixture containing in 1 ml bupivacaine 0,125% and sufentanil 0,4 mcg at 8 ml/h. At the same time patients will have the possibility to use PCA device with morphine, bolus dose 1 mg, lock-out interval 5 min for 3 days at a surgical ICU.	Drug: Morphine intravenous; Patiernt-controlled i.v. analgesia with morphine; Other Names: Morphine and patient controlled analgesia; Drug: Bupivacaine + Sufentanil epidural; Continuous epidural infusion of a mixture containing in 1 ml bupivacaine 0,125% and sufentanil 0,4 mcg at 8 ml/h.; Other Names: Epidural analgesia with bupivacaine and sufentanil
Active Comparator: Morphine intravenous; Patients will be administered standard general anaesthesia. After surgery, bolus doses of morphine 2 mg will be administered until level of pain will be < 4 (VAS 0 - 10). Analgesia will be continued by PCA device using morphine, bolus dose 1 mg, lock-out interval 5 min. for 3 days at surgical ICU.	Drug: Morphine intravenous; Patiernt-controlled i.v. analgesia with morphine; Other Names: Morphine and patient controlled analgesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-inferiority of analgesia with intrathecal morphine 0.3mg compared with epidural mixture bupivacaine 0.125% and sufentanil 0,4ug/ml.	Non-interiority is defined as difference in morphine consumption during patient-controlled analgesia no more than 10%	Within the first 3 days after surgery
Better analgesia after intrathecal morphine compared to systemic analgesia with morphine	Lower consumption of PCA morphine in patients with intrathecal morphine compared to systemic analgesia with PCA morphine only.	Within the first 3 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Side effects of intrathecal morphine compared to epidural or systemic analgesia	Number of patients with respiratory rate <8/min, SpO2<90%, changes of blood pressure and pulse rate > 30% above base level before surgery, episodes of postoperative nausea and vomiting, interval since surgery to the first bowel movement confirmed by auscultation and interval to the first flatus.	Within the first 3 days after surgery
Pain intensity	Area below visual analogue scale (0 - 10) pain intensity after 72 hours	Within the first 3 days after surgery

Collaborators and Investigators

• Sponsor: Charles University, Czech Republic
• Investigators: Principal Investigator: Jiri Malek, M.D., 3rd Medical Faculty, Charles University and University Hiospital Kralovske Vinohrady

Publications and helpful links

General Publications

• Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000 Dec 16;321(7275):1493. doi: 10.1136/bmj.321.7275.1493.
• Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KS; MASTER Anaethesia Trial Study Group. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet. 2002 Apr 13;359(9314):1276-82. doi: 10.1016/S0140-6736(02)08266-1.
• Meylan N, Elia N, Lysakowski C, Tramer MR. Benefit and risk of intrathecal morphine without local anaesthetic in patients undergoing major surgery: meta-analysis of randomized trials. Br J Anaesth. 2009 Feb;102(2):156-67. doi: 10.1093/bja/aen368.
• De Pietri L, Siniscalchi A, Reggiani A, Masetti M, Begliomini B, Gazzi M, Gerunda GE, Pasetto A. The use of intrathecal morphine for postoperative pain relief after liver resection: a comparison with epidural analgesia. Anesth Analg. 2006 Apr;102(4):1157-63. doi: 10.1213/01.ane.0000198567.85040.ce.
• Devys JM, Mora A, Plaud B, Jayr C, Laplanche A, Raynard B, Lasser P, Debaene B. Intrathecal + PCA morphine improves analgesia during the first 24 hr after major abdominal surgery compared to PCA alone. Can J Anaesth. 2003 Apr;50(4):355-61. doi: 10.1007/BF03021032. English, French.
• Beaussier M, Weickmans H, Parc Y, Delpierre E, Camus Y, Funck-Brentano C, Schiffer E, Delva E, Lienhart A. Postoperative analgesia and recovery course after major colorectal surgery in elderly patients: a randomized comparison between intrathecal morphine and intravenous PCA morphine. Reg Anesth Pain Med. 2006 Nov-Dec;31(6):531-8. doi: 10.1016/j.rapm.2006.06.250.
• Sakowska M, Docherty E, Linscott D, Connor S. A change in practice from epidural to intrathecal morphine analgesia for hepato-pancreato-biliary surgery. World J Surg. 2009 Sep;33(9):1802-8. doi: 10.1007/s00268-009-0131-2.
• Virlos I, Clements D, Beynon J, Ratnalikar V, Khot U. Short-term outcomes with intrathecal versus epidural analgesia in laparoscopic colorectal surgery. Br J Surg. 2010 Sep;97(9):1401-6. doi: 10.1002/bjs.7127.
• Levy BF, Scott MJ, Fawcett W, Fry C, Rockall TA. Randomized clinical trial of epidural, spinal or patient-controlled analgesia for patients undergoing laparoscopic colorectal surgery. Br J Surg. 2011 Aug;98(8):1068-78. doi: 10.1002/bjs.7545. Epub 2011 May 17.
• Werawatganon T, Charuluxananan S. WITHDRAWN: Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database Syst Rev. 2013 Mar 28;(3):CD004088. doi: 10.1002/14651858.CD004088.pub3.
• Manion SC, Brennan TJ. Thoracic epidural analgesia and acute pain management. Anesthesiology. 2011 Jul;115(1):181-8. doi: 10.1097/ALN.0b013e318220847c. No abstract available.
• Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990-1999. Anesthesiology. 2004 Oct;101(4):950-9. doi: 10.1097/00000542-200410000-00021.
• Holte K, Kehlet H. Epidural analgesia and risk of anastomotic leakage. Reg Anesth Pain Med. 2001 Mar-Apr;26(2):111-7. doi: 10.1053/rapm.2001.21241.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2017
• Primary Completion (Actual): December 14, 2018
• Study Completion (Actual): December 17, 2018

Study Registration Dates

• First Submitted: December 28, 2016
• First Submitted That Met QC Criteria: December 30, 2016
• First Posted (Estimate): January 2, 2017

Study Record Updates

• Last Update Posted (Actual): January 31, 2019
• Last Update Submitted That Met QC Criteria: January 29, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Agnosia; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Anesthetics, Local; Bupivacaine; Morphine; Sufentanil; Dsuvia
• Other Study ID Numbers: KOLORIT1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No