Intrathecal Morphine Analgesia vs. Continuous Epidural Analgesia vs. Systemic Analgesia in Colorectal Surgery.

Study Overview
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Brief Summary
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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.

Detailed Description
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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 Intrathecal morphine is non-inferior to continuous epidural analgesia ] Intrathecal morphine will decrease the need for i.v. systemic patient controlled analgesia (PCA) with morphine Aims of the study Primary aims 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. 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 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 To demonstrate the same or shorter interval since surgery to the first bowel movement confirmed by auscultation and interval to the first flatus. 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: 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. 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. 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.

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

Conditions
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Analgesia, Patient-Controlled, Epidural Analgesia, Anesthesia; Spinal, Morphine, Surgery, Colorectal, Intravenous Drug Delivery Systems

Intervention / Treatment
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* Drug: Morphine intrathecal
* Drug: Bupivacaine + Sufentanil epidural
* Drug: Morphine intravenous


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Morphine intrathecal<br>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<br>* Administration of intrathecal injection of 0.3 mg preservative-free morphine in 3 ml NS<br>* Other names: Morphine spinal;Drug: Morphine intravenous<br>* Patiernt-controlled i.v. analgesia with morphine<br>* Other names: Morphine and patient controlled analgesia;|
| Active Comparator: Bupivacaine + Sufentanil epidural<br>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: Bupivacaine + Sufentanil epidural<br>* Continuous epidural infusion of a mixture containing in 1 ml bupivacaine 0,125% and sufentanil 0,4 mcg at 8 ml/h.<br>* Other names: Epidural analgesia with bupivacaine and sufentanil;Drug: Morphine intravenous<br>* Patiernt-controlled i.v. analgesia with morphine<br>* Other names: Morphine and patient controlled analgesia;|
| Active Comparator: Morphine intravenous<br>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<br>* Patiernt-controlled i.v. analgesia with morphine<br>* Other names: Morphine and patient controlled analgesia;|

What is the study measuring?
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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 |