<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03007121</url>
  </required_header>
  <id_info>
    <org_study_id>KOLORIT1</org_study_id>
    <nct_id>NCT03007121</nct_id>
  </id_info>
  <brief_title>Intrathecal Morphine Analgesia vs. Continuous Epidural Analgesia vs. Systemic Analgesia in Colorectal Surgery.</brief_title>
  <acronym>KOLORIT</acronym>
  <official_title>Comparison of Intrathecal Morphine, Epidural Bupivacaine With Sufentanil and Systemic Patient Controlled Analgesia With Morphine for Analgesia After Colorectal Surgery: Prospective Randomised Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Charles University, Czech Republic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Charles University, Czech Republic</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine which postoperative analgesia is optimal after&#xD;
      colorectal surgery. The investigators will compare intrathecal morphine, continuous epidural&#xD;
      analgesia and standard systemic analgesia. All patients will have the possibility to&#xD;
      administer themselves intravenous morphine as needed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction&#xD;
&#xD;
      Colorectal surgery is a frequent operation with expected strong post-operative pain. Thoracic&#xD;
      epidural analgesia is a preferred method by many authors, but it is not without risks. As&#xD;
      patients in our hospital usually stay at a surgical ICU for 24 hours only and epidural&#xD;
      infusion of opioids is prohibited at standard wards according to our hospital standards, it&#xD;
      seems to be too demanding method. Systemic analgesia with strong opioids is usually an&#xD;
      alternative, but high doses of opioids are known to cause side effects. The last possibility&#xD;
      is a single-shot intrathecal injection of morphine which demonstrated long-lasting analgesia&#xD;
      after various procedures. The main advantage is easy technique, absence of catheters and low&#xD;
      cost. There are not enough studies to decide which method is the most convenient. The purpose&#xD;
      of this prospective randomized open clinical study is to determine which postoperative&#xD;
      analgesia is optimal after colorectal surgery. The investigators will compare intrathecal&#xD;
      morphine, continuous epidural analgesia and compare both methods to standard systemic&#xD;
      analgesia. All patients will have the possibility to administer themselves intravenous&#xD;
      morphine as needed.&#xD;
&#xD;
      Hypotheses&#xD;
&#xD;
        1. Intrathecal morphine is non-inferior to continuous epidural analgesia&#xD;
&#xD;
        2. ] Intrathecal morphine will decrease the need for i.v. systemic patient controlled&#xD;
           analgesia (PCA) with morphine&#xD;
&#xD;
      Aims of the study&#xD;
&#xD;
      Primary aims&#xD;
&#xD;
        1. To demonstrate non-inferiority of analgesia with intrathecal morphine 0.3mg compared to&#xD;
           continuous epidural analgesia with 8 ml/hour of mixture of bupivacaine 0.125% and&#xD;
           sufentanil 0,4ug/ml. Non-inferiority is defined as consumption of PCA morphine during 24&#xD;
           and 72 hours not higher than 10% compared to control group.&#xD;
&#xD;
        2. To demonstrate significantly lower consumption (at least 10%) of PCA morphine in&#xD;
           patients with intrathecal morphine 0.3 mg compared to systemic analgesia with PCA&#xD;
           morphine only.&#xD;
&#xD;
      Secondary aims&#xD;
&#xD;
        1. To demonstrate similar or lower side effects of intrathecal morphine compared to&#xD;
           epidural or systemic analgesia. The investigators will record number of patients with&#xD;
           respiratory rate &lt;8/min, SpO2&lt;90%, changes of blood pressure and pulse rate &gt; 30% above&#xD;
           base level before surgery, episodes of postoperative nausea and vomiting&#xD;
&#xD;
        2. To demonstrate the same or shorter interval since surgery to the first bowel movement&#xD;
           confirmed by auscultation and interval to the first flatus.&#xD;
&#xD;
        3. To demonstrate the same or lower pain intensity in patients with intrathecal morphine&#xD;
           compared to other two groups. The effect will be measured by area below visual analogue&#xD;
           scale (0 - 10) pain intensity after 24 and 72 hours&#xD;
&#xD;
      Duration of the study: Three days&#xD;
&#xD;
      Method&#xD;
&#xD;
      Design: Study will be performed as prospective randomized open clinical study&#xD;
&#xD;
      Setting: Surgical ICU&#xD;
&#xD;
      Inclusion criteria: Patients with elective colorectal surgery (left or right hemicolectomy,&#xD;
      subtotal colectomy, resection of sigmoid, rectal or cecum)&#xD;
&#xD;
      Exclusion criteria: Known allergy to any of drugs used, coagulopathy, sepsis, cognitive&#xD;
      dysfunction and/or inability to understand instruction. Pregnancy (is assessed as a part of&#xD;
      pre-operative examination). Abuse of drugs or administration of morphine therapy 5 or less&#xD;
      days before surgery. Idiopathic bowel disease.&#xD;
&#xD;
      Anesthesia: General anesthesia will be performed in all groups using propofol for induction&#xD;
      and rocuronium for intubation and muscle relaxation. Patients will be ventilated to&#xD;
      normocapnia by oxygen + air + desflurane mixture. Sufentanil 5 - 10 mcg will be administered&#xD;
      if needed. Paracetamol 1 g i.v. will be administered approximately 30 min before the end of&#xD;
      anesthesia and ondansetron 4 mg i.v. will be administered 10 min. before the end of&#xD;
      anesthesia. At the end of anesthesia patients will be administered atropine and neostigmine&#xD;
      to obtain TOF ration &gt;90%.&#xD;
&#xD;
      Standard postoperative analgesia: All patients will be administered paracetamol 1g i.v. every&#xD;
      6 h for next 72 hours and can use PCA morphine, bolus dose 1 mg, lock-out interval 5 min. for&#xD;
      3 days at surgical ICU.&#xD;
&#xD;
      Monitoring: Except of standard anesthesia and ICU monitoring (ECG, pulse oximetry and&#xD;
      non-invasive blood pressure) pain intensity (VAS 0 - 10) and side effects (see above) will be&#xD;
      recorded.&#xD;
&#xD;
      Power analysis: Total number of patients to demonstrate primary aims is 75 divided in ratio&#xD;
      1:2:2; n=15 in systemic analgesia group (PCA) and n=30 in each group with epidural and&#xD;
      intrathecal analgesia. Standard tests will be used to analyse results. P value &lt; 0.05 will be&#xD;
      considered significant.&#xD;
&#xD;
      Interventions:&#xD;
&#xD;
        1. Systemic analgesia: Patients will be administered standard general anesthesia. After&#xD;
           surgery, bolus doses of morphine 2 mg will be administered until level of pain will be &lt;&#xD;
           4 (VAS 0 - 10). Analgesia will be continued by PCA device using morphine, bolus dose 1&#xD;
           mg, lock-out interval 5 min. for 3 days at surgical ICU.&#xD;
&#xD;
        2. Epidural analgesia: An epidural catheter will be inserted before induction of anesthesia&#xD;
           in a sitting position between T9 and T10 - T12 and L1 vertebrae. A test dose of 4 ml 0.5&#xD;
           bupivacaine will be administered to rule out intravascular injection or subarachnoid or&#xD;
           subdural block. Standard general anesthesia will be performed. Thirty minutes before the&#xD;
           end of the surgery, patients will be administered a bolus of a mixture of bupivacaine&#xD;
           0.5% (3 ml) + sufentanil 10 mcg (2 ml) + NS 5 ml followed by a continuous infusion of a&#xD;
           mixture containing in 1 ml bupivacaine 0.125% and sufentanil 0.4 mcg at 8 ml/h. At the&#xD;
           same time patients will have the possibility to use PCA device with morphine, bolus dose&#xD;
           1 mg, lock-out interval 5 min for 3 days at a surgical ICU. Epidural infusion will be&#xD;
           stopped 24 hours after surgery.&#xD;
&#xD;
        3. Intrathecal analgesia: An intrathecal administration of preservative-free morphine 0.3&#xD;
           mg in 3 ml NS prepared in sterile ampoules by a hospital pharmacy will be performed&#xD;
           before induction of anesthesia in a sitting position between L2 and L3 - L4/L5&#xD;
           vertebrae. Standard general anesthesia will be performed. After surgery, the patients&#xD;
           will have the possibility to use PCA device with morphine, bolus dose 1 mg, lock-out&#xD;
           interval 5 min for 3 days at a surgical ICU.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 10, 2017</start_date>
  <completion_date type="Actual">December 17, 2018</completion_date>
  <primary_completion_date type="Actual">December 14, 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Non-inferiority of analgesia with intrathecal morphine 0.3mg compared with epidural mixture bupivacaine 0.125% and sufentanil 0,4ug/ml.</measure>
    <time_frame>Within the first 3 days after surgery</time_frame>
    <description>Non-interiority is defined as difference in morphine consumption during patient-controlled analgesia no more than 10%</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Better analgesia after intrathecal morphine compared to systemic analgesia with morphine</measure>
    <time_frame>Within the first 3 days after surgery</time_frame>
    <description>Lower consumption of PCA morphine in patients with intrathecal morphine compared to systemic analgesia with PCA morphine only.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Side effects of intrathecal morphine compared to epidural or systemic analgesia</measure>
    <time_frame>Within the first 3 days after surgery</time_frame>
    <description>Number of patients with respiratory rate &lt;8/min, SpO2&lt;90%, changes of blood pressure and pulse rate &gt; 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain intensity</measure>
    <time_frame>Within the first 3 days after surgery</time_frame>
    <description>Area below visual analogue scale (0 - 10) pain intensity after 72 hours</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">75</enrollment>
  <condition>Analgesia, Patient-Controlled</condition>
  <condition>Epidural Analgesia</condition>
  <condition>Anesthesia; Spinal</condition>
  <condition>Morphine</condition>
  <condition>Surgery, Colorectal</condition>
  <condition>Intravenous Drug Delivery Systems</condition>
  <arm_group>
    <arm_group_label>Morphine intrathecal</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bupivacaine + Sufentanil epidural</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Morphine intravenous</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will be administered standard general anaesthesia. After surgery, bolus doses of morphine 2 mg will be administered until level of pain will be &lt; 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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Morphine intrathecal</intervention_name>
    <description>Administration of intrathecal injection of 0.3 mg preservative-free morphine in 3 ml NS</description>
    <arm_group_label>Morphine intrathecal</arm_group_label>
    <other_name>Morphine spinal</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupivacaine + Sufentanil epidural</intervention_name>
    <description>Continuous epidural infusion of a mixture containing in 1 ml bupivacaine 0,125% and sufentanil 0,4 mcg at 8 ml/h.</description>
    <arm_group_label>Bupivacaine + Sufentanil epidural</arm_group_label>
    <other_name>Epidural analgesia with bupivacaine and sufentanil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Morphine intravenous</intervention_name>
    <description>Patiernt-controlled i.v. analgesia with morphine</description>
    <arm_group_label>Bupivacaine + Sufentanil epidural</arm_group_label>
    <arm_group_label>Morphine intrathecal</arm_group_label>
    <arm_group_label>Morphine intravenous</arm_group_label>
    <other_name>Morphine and patient controlled analgesia</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with elective colorectal surgery (left or right hemicolectomy, subtotal&#xD;
             colectomy, resection of sigmoid, rectal or cecum)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergy to any of drugs used, coagulopathy, sepsis, cognitive dysfunction and/or&#xD;
             inability to understand instruction.&#xD;
&#xD;
          -  Pregnancy (is assessed as a part of pre-operative examination).&#xD;
&#xD;
          -  Abuse of drugs or morphine therapy before surgery.&#xD;
&#xD;
          -  Idiopathic bowel disease.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jiri Malek, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>3rd Medical Faculty, Charles University and University Hiospital Kralovske Vinohrady</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Kralovske Vinohrady</name>
      <address>
        <city>Praha</city>
        <zip>100 00</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Czechia</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>12670812</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>17138196</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>19548026</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20603849</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21590762</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>23543529</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11118174</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11965272</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21606825</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>15448529</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>19151046</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>16551916</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11251133</PMID>
  </reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <last_update_submitted>January 29, 2019</last_update_submitted>
  <last_update_submitted_qc>January 29, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 31, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Charles University, Czech Republic</investigator_affiliation>
    <investigator_full_name>Jiri Malek</investigator_full_name>
    <investigator_title>Assoc. Prof. MD, Ph.D.</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Agnosia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sufentanil</mesh_term>
    <mesh_term>Morphine</mesh_term>
    <mesh_term>Dsuvia</mesh_term>
    <mesh_term>Bupivacaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03007121
org study id: KOLORIT1
nct id: NCT03007121
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Non-inferiority of analgesia with intrathecal morphine 0.3mg compared with epidural mixture bupivacaine 0.125% and sufentanil 0,4ug/ml.
time frame: Within the first 3 days after surgery
description: Non-interiority is defined as difference in morphine consumption during patient-controlled analgesia no more than 10%
measure: Better analgesia after intrathecal morphine compared to systemic analgesia with morphine
time frame: Within the first 3 days after surgery
description: Lower consumption of PCA morphine in patients with intrathecal morphine compared to systemic analgesia with PCA morphine only.
measure: Side effects of intrathecal morphine compared to epidural or systemic analgesia
time frame: Within the first 3 days after surgery
description: 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.
measure: Pain intensity
time frame: Within the first 3 days after surgery
description: Area below visual analogue scale (0 - 10) pain intensity after 72 hours
arm group label: Morphine intrathecal
arm group type: Experimental
description: 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.
arm group label: Bupivacaine + Sufentanil epidural
arm group type: Active Comparator
description: 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.
arm group label: Morphine intravenous
arm group type: Active Comparator
description: 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.
intervention type: Drug
intervention name: Morphine intrathecal
description: Administration of intrathecal injection of 0.3 mg preservative-free morphine in 3 ml NS
arm group label: Morphine intrathecal
other name: Morphine spinal
intervention type: Drug
intervention name: Bupivacaine + Sufentanil epidural
description: Continuous epidural infusion of a mixture containing in 1 ml bupivacaine 0,125% and sufentanil 0,4 mcg at 8 ml/h.
arm group label: Bupivacaine + Sufentanil epidural
other name: Epidural analgesia with bupivacaine and sufentanil
intervention type: Drug
intervention name: Morphine intravenous
description: Patiernt-controlled i.v. analgesia with morphine
arm group label: Bupivacaine + Sufentanil epidural
arm group label: Morphine intrathecal
arm group label: Morphine intravenous
other name: Morphine and patient controlled analgesia
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jiri Malek, M.D.
role: Principal Investigator
affiliation: 3rd Medical Faculty, Charles University and University Hiospital Kralovske Vinohrady
facility: 
country: Czechia
citation: 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.
PMID: 12670812
citation: 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.
PMID: 17138196
citation: 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.
PMID: 19548026
citation: 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.
PMID: 20603849
citation: 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.
PMID: 21590762
citation: 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.
PMID: 23543529
citation: 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.
PMID: 11118174
citation: 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.
PMID: 11965272
citation: 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.
PMID: 21606825
citation: 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.
PMID: 15448529
citation: 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.
PMID: 19151046
citation: 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.
PMID: 16551916
citation: 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.
PMID: 11251133
responsible party type: Principal Investigator
investigator affiliation: Charles University, Czech Republic
investigator full name: Jiri Malek
investigator title: Assoc. Prof. MD, Ph.D.
mesh term: Agnosia
mesh term: Sufentanil
mesh term: Morphine
mesh term: Dsuvia
mesh term: Bupivacaine
sharing ipd: No