xml: <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/NCT06021717</url>
    </required_header>
    <id_info>
      <org_study_id>JEP-2018-092</org_study_id>
      <nct_id>NCT06021717</nct_id>
    </id_info>
    <brief_title>PCA Ketamine-Morphine VS PCA Morphine as Post-Operative Analgesia in Colorectal Surgery</brief_title>
    <official_title>PCA Ketamine-Morphine Versus PCA Morphine as Post-Operative Analgesia in Colorectal Surgery</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Universiti Kebangsaan Malaysia Medical Centre</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Universiti Kebangsaan Malaysia Medical Centre</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 goal of this clinical trial is to compare the effectiveness of PCA ketamine-morphine&#xD;
        versus conventional PCA morphine in postoperative patients undergoing elective laparotomy&#xD;
        colorectal surgery under general anaesthesia. The specific objectives are:&#xD;
  &#xD;
          1. To compare the post-operative analgesic requirement with PCA ketamine-morphine in&#xD;
             comparison with PCA morphine.&#xD;
  &#xD;
          2. To compare the postoperative pain scores between PCA ketamine-morphine and PCA morphine.&#xD;
  &#xD;
          3. To assess patients' overall satisfaction with PCA ketamine-morphine in comparison with&#xD;
             PCA morphine.&#xD;
  &#xD;
          4. To study the incidence of side effects of PCA ketamine-morphine in comparison with PCA&#xD;
             morphine.&#xD;
  &#xD;
        Participants will be screened and recruited at pre-anaesthetic clinic (PAC). Those who&#xD;
        consented will be taught to use PCA machine and the potential side effects of the study&#xD;
        drugs. They will be randomly allocated into either Group A or Group B by computer generated&#xD;
        randomization a day before planned surgery.&#xD;
  &#xD;
        Researchers will compare Group A and Group B to see post-operative pain scores, patients'&#xD;
        overall satisfaction and any incidence of side effects.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        INTRODUCTION&#xD;
  &#xD;
        Patient-controlled analgesia (PCA) is an established, efficient and safe technique for&#xD;
        providing postoperative analgesia and has been associated with better pain relief and patient&#xD;
        satisfaction with less postoperative complications and side effects [1]. Despite years of&#xD;
        advances in pain management, opioids have been the mainstay for treatment of postoperative&#xD;
        pain particularly in moderate to severe pain. Of all opioids, morphine is the most studied&#xD;
        drug and remains the drug of choice for PCA, especially in Malaysian hospitals. However,&#xD;
        morphine usage is also associated with known side effects such as sedation, nausea and&#xD;
        vomiting, pruritus, urinary retention and respiratory depression [2]. A review of 32 studies&#xD;
        involving opioids-based PCA-22 of which were PCA morphine-reported an incidence of 19%&#xD;
        nausea, 18.1% vomiting, 30.9 % of nausea and/or vomiting, 25.7% sedation, 17.9% urinary&#xD;
        retention, 17.9% pruritus and 15.2% hypoxia and 1.6% respiratory depression that may be&#xD;
        life-threatening associated with PCA opioids use [3, 4]. The concept of multimodal analgesia&#xD;
        hence was introduced to reduce opioid-related side effects. Adjuvants such as acetaminophen&#xD;
        and non-steroidal anti-inflammatory drugs are commonly used nowadays in combination with&#xD;
        opioids as opioid-sparing agents to reduce opioid usage [5].&#xD;
  &#xD;
        Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has undergone a recent resurgence of&#xD;
        interest among acute care providers as an adjunct in acute pain management [6, 7]. Ketamine&#xD;
        at a sub-anesthetic dose (0.2-0.5 mg kg-1) produces intense analgesia [5, 8]. Since its&#xD;
        development in 1962, various studies have been conducted to prove the efficacy of ketamine as&#xD;
        post-operative analgesia and as an opioid-sparing agent [8-10]. A review by Laskowski and&#xD;
        colleagues described that IV ketamine improved the quality of pain control, in addition to&#xD;
        decreased opioid consumption with the particular benefit being observed in painful&#xD;
        procedures, such as upper abdominal, thoracic, and major orthopedic surgeries [11]. While&#xD;
        Carstensen and co-workers in a qualitative review comparing PCA ketamine-morphine with PCA&#xD;
        morphine alone also described the superior efficacy of ketamine-morphine in providing pain&#xD;
        control with a significantly higher incidence of opioid-related side effects in the morphine&#xD;
        group [12]. In comparison to opioids, ketamine's lack of respiratory depressant effects also&#xD;
        favors its use as an opioid adjunct in patients with airway and respiratory compromise,&#xD;
        especially in morbid obesity and post-thoracotomy patients [13, 14].&#xD;
  &#xD;
        Despite the potential efficacy with published evidence of PCA ketamine-morphine in&#xD;
        postoperative pain management, its use is not well established in most Malaysian hospitals&#xD;
        including the current study site. Hence, the aim of this study was to evaluate the&#xD;
        effectiveness of PCA ketamine-morphine in comparison to conventional PCA morphine alone as&#xD;
        postoperative analgesia in colorectal surgery patients in the current study site.&#xD;
  &#xD;
        METHODS&#xD;
  &#xD;
        This prospective double-blind randomized controlled trial was conducted in Hospital Sultanah&#xD;
        Aminah Johor Bahru from February to October 2018 after obtaining ethics approval from the&#xD;
        local and institutional ethics committee (NMRR-17-1863-37291 &amp; JEP-2018-092). Sixty elective&#xD;
        American Society of Anaesthesiologists (ASA) I or II patients scheduled for lower midline&#xD;
        laparotomy colorectal surgery aged between 18-70 years old were recruited and informed&#xD;
        consents were obtained. Patients with a known allergy to morphine or ketamine, uncontrolled&#xD;
        hypertension, past history of chronic pain on regular analgesics, psychiatric illness on&#xD;
        psychiatric drugs, BMI more than 35 and creatine clearance less than 30 were excluded from&#xD;
        the study. All patients who consented were taught the usage of a PCA machine and the&#xD;
        potential side effects of ketamine and morphine preoperatively. They were randomly allocated&#xD;
        into either Group A or Group B by computer-generated randomization a day before planned&#xD;
        surgery.&#xD;
  &#xD;
        Group A received PCA ketamine (Ketamine HCl, Pfizer Inc., US) 0.5 mg plus morphine 0.5 mg&#xD;
        ml-1 (ratio 1:1) while Group B received PCA morphine (Pfizer Inc., US) 1 mg ml-1 as&#xD;
        postoperative analgesia. There was no baseline infusion and the lock-out period was set to 5&#xD;
        minutes. The study drugs were prepared one day before the surgery by the pharmacist who was&#xD;
        not involved in the intraoperative and post-=operative management of the patients. The drugs&#xD;
        were labelled as study drugs with the study number. The patients, nurses who cared for the&#xD;
        patients, the anesthetist who performed the anesthesia and the investigators who gathered the&#xD;
        data were blinded to patients' group allocation.&#xD;
  &#xD;
        All patients had standard monitoring of blood pressure, electrocardiogram (ECG), oxygen&#xD;
        saturation and end-tidal carbon dioxide (CO2). They were pre-oxygenated with 100% oxygen for&#xD;
        2-3 minutes. The induction of general anesthesia was standardized to intravenous (IV)&#xD;
        fentanyl (Cephalon Inc., US) 2 mcg kg-1, IV propofol (Diprivan, Pfizer Inc., US) 2 mg kg-1&#xD;
        and IV rocuronium (US) 0.6 mg kg-1 and intubation with the appropriate size of the&#xD;
        endotracheal tube. Anesthesia was maintained with desflurane (Suprane, Novartis AG,&#xD;
        Switzerland) in a mixture of 50% of oxygen and 50% of air, and titrated to achieve a minimum&#xD;
        alveolar concentration (MAC) of 1.0. All patients received IV dexamethasone (US) 8 mg after&#xD;
        induction and IV morphine 0.1 mg kg-1 as intraoperative analgesia. Boluses of IV fentanyl 25&#xD;
        mcg were given if extra analgesia was required and recorded. IV ondansetron (US) 4 mg was&#xD;
        given upon initiation of skin closure. The skin incision site was infiltrated with 0.25%&#xD;
        Bupivacaine (US) 10-20 ml during skin closure. The standard dose of IV neostigmine and IV&#xD;
        atropine was used to reverse residual neuromuscular blockade at the end of surgery.&#xD;
  &#xD;
        At the recovery bay, pain score was assessed using the Numerical Rating Scale (NRS), by which&#xD;
        patients scored their pain intensity between number 0 to 10, with 0 being no pain at all and&#xD;
        10 being the worst pain imaginable. If the pain score was &gt; 4 at rest, IV morphine boluses&#xD;
        were given and titrated according to the pre-set morphine protocol until the pain score was ≤&#xD;
        4. PCA machine with the study drug(s) was commenced once the pain score was ≤ 4 at rest.&#xD;
  &#xD;
        Patients were assessed 30 minutes after the commencement of PCA, at 6 hourly intervals for&#xD;
        the first 24 hours and subsequently at 12 hourly intervals for the next 24 hours&#xD;
        post-operatively by the Acute Pain Service (APS) team. They were solely on PCA as&#xD;
        post-operative analgesia as the patients were kept nil by mouth for the first 48 hours&#xD;
        postoperatively. All patients were assessed for pain score, sedation score, respiratory rate&#xD;
        and other side effects of morphine and ketamine including nausea and vomiting, pruritus,&#xD;
        dizziness and hallucinations. If the pain score was &gt; 4 at rest during the assessment, 2 ml&#xD;
        of PCA drug was given as boluses and titrated every 10 minutes to achieve a pain score ≤ 4.&#xD;
  &#xD;
        Cumulative morphine consumption was also recorded. Sedation was assessed using Pasero&#xD;
        Opioid-Induced Sedation Scale (POSS) (S - sleep, easy to arouse, 1 - awake and alert, 2 -&#xD;
        slightly drowsy, easy to arouse, 3 - frequently drowsy, arousable, drift to sleep during the&#xD;
        conversation, 4 - somnolent, minimal or no response to verbal or physical stimulation).&#xD;
        Treatment for nausea, vomiting and pruritus was given as deemed appropriate and recorded. At&#xD;
        48-hour post-operation, the patient's overall satisfaction score was assessed using 1 to 5&#xD;
        Likert scale (1 - very unsatisfied, 2 - unsatisfied, 3 - neutral, 4 - satisfied and 5 - very&#xD;
        satisfied). If patients experience hallucinations or delirium, PCA bolus dose was reduced by&#xD;
        0.2 ml and the symptoms were reassessed after 1 hour. If symptoms persist, the PCA bolus dose&#xD;
        was reduced further by 0.2 ml every hour until symptoms disappear and PCA subsequently&#xD;
        continued at the reduced dose.&#xD;
  &#xD;
        Patients with complicated surgeries in which they became haemodynamically unstable and&#xD;
        required post-operative ICU admission, developed anaphylaxis after commencement of study&#xD;
        drugs, developed persistent delirium or hallucination after reduction of PCA bolus dose and&#xD;
        pain was uncontrollable with the reduced dose or those who refused to continue with the study&#xD;
        for any reasons were withdrawn from the study and given other means of analgesia as&#xD;
        appropriate by the acute pain service (APS) team.&#xD;
  &#xD;
        The sample size was calculated using 'Power and Sample Size Calculations' program. The sample&#xD;
        size was estimated using t-test calculation as derived from mean pain score and standard&#xD;
        deviation as quoted in a study by Javery and colleagues [15]. The α value was set at 0.05 and&#xD;
        power of study at 90% and standard deviation at 1.67, whereby it was estimated that 27&#xD;
        patients were required for each group. Anticipating a 10% drop-out rate, 30 patients were&#xD;
        eventually recruited in each group, resulting in 60 patients for the whole study.&#xD;
  &#xD;
        All data were analyzed using the SPSS (Statistical Package for The Social Sciences) software.&#xD;
        Chi-square test or Fisher exact test was used when appropriate to calculate any significant&#xD;
        differences for categorical variables. Independent t-test or Mann Whitney U test was used as&#xD;
        appropriate to determine any significant differences for continuous variables. The incidence&#xD;
        of side effects between the two groups was compared using Chi-square test. A P value of less&#xD;
        than 0.05 was considered statistically significant.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Completed</overall_status>
    <start_date type="Actual">April 5, 2018</start_date>
    <completion_date type="Actual">April 4, 2019</completion_date>
    <primary_completion_date type="Actual">April 4, 2019</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>
      <intervention_model_description>Participants were randomly allocated into either Group A or Group B by computer-generated randomization a day before planned surgery.&#xD;
  Group A will receive PCA ketamine-morphine 0.5 mg/ml in 1:1 ratio while group B will receive PCA morphine 1mg/ml,</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Triple (Participant, Care Provider, Investigator)</masking>
      <masking_description>The patients, nurses who cared for the patients, the anesthetist who performed the anesthesia and the investigators who gathered the data were blinded to patients' group allocation.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>PCA drugs demanded and delivered</measure>
      <time_frame>30 minutes after commencement of PCA until 48 hours</time_frame>
      <description>Total PCA drugs demanded and delivered</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Pain score</measure>
      <time_frame>30 minutes after commencement of PCA until 48 hours</time_frame>
      <description>Pain score at rest and on movement with NRS&#xD;
  Numerical Rating Scale (NRS) for pain score assessment A numerical pain assessment tool from 0 to 10, where 0 denotes no pain, 5 denotes moderate pain and 10 denotes worst possible pain.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Incidence of side effects</measure>
      <time_frame>30 minutes after commencement of PCA until 48 hours</time_frame>
      <description>Opiod related side effects : nausea and vomiting, pruritus, dizziness, respiratory depression and treatment on PRN basis if indicated&#xD;
  Ketamine related side effects : delirium, hallucinations, hypertension, tachycardia</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Patients' overall satisfaction</measure>
      <time_frame>At 48 hours post oeprative</time_frame>
      <description>Assessment of patients' overall satisfaction with a 5-points scales at 48 hours.&#xD;
  A 5-point scale from 1 to 5, where:&#xD;
  = very unsatisfied&#xD;
  = unsatisfied&#xD;
  = neutral&#xD;
  = satisfied&#xD;
  = very satisfied</description>
    </primary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Actual">60</enrollment>
    <condition>Ketamine</condition>
    <condition>Morphine</condition>
    <arm_group>
      <arm_group_label>Group A</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>PCA ketamine (Ketamine HCl, Pfizer Inc., US) 0.5 mg plus morphine 0.5 mg ml-1 (ratio 1:1) as postoperative analgesia.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Group B</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>PCA morphine (Pfizer Inc., US) 1 mg ml-1 as postoperative analgesia.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Ketamine-Morphine</intervention_name>
      <description>PCA ketamine (Ketamine HCl, Pfizer Inc., US) 0.5 mg plus morphine 0.5 mg ml-1 (ratio 1:1)</description>
      <arm_group_label>Group A</arm_group_label>
      <other_name>Ketamine Hydrochloric, Pfizer Inc., US</other_name>
      <other_name>Morphine Pfizer Inc., US</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Morphine</intervention_name>
      <description>PCA morphine (Pfizer Inc., US) 1 mg ml-1</description>
      <arm_group_label>Group B</arm_group_label>
      <other_name>Morphine Pfizer Inc., US</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Elective American Society of Anaesthesiologists (ASA) I or II patients scheduled for&#xD;
               lower midline laparotomy colorectal surgery aged between 18-70 years old&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients with a known allergy to morphine or ketamine, uncontrolled hypertension, past&#xD;
               history of chronic pain on regular analgesics, psychiatric illness on psychiatric&#xD;
               drugs, BMI more than 35 and creatine clearance less than 30.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>70 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Chian Yong Liu, MMed (Anaes)</last_name>
      <role>Principal Investigator</role>
      <affiliation>Universiti Kebangsaan Malaysia Medical Centre</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>Universiti Kebangsaan Malaysia Medical Centre</name>
        <address>
          <city>Kuala Lumpur</city>
          <state>Wilayah Persekutuan</state>
          <zip>56000</zip>
          <country>Malaysia</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Malaysia</country>
    </location_countries>
    <reference>
      <citation>Pouldar TM, Maher DP, Betz AW, Wiegers JJ, Friedman JA, Zaidi SS, Rejali A, Tran HP, Yumul R, Louy C. Adverse Effects Associated with Patient-Controlled Analgesia with Ketamine Combined with Opioids and Ketamine Infusion with PCA Bolus in Postoperative Spine Patients: A Retrospective Review. J Pain Res. 2022 Oct 10;15:3127-3135. doi: 10.2147/JPR.S358770. eCollection 2022.</citation>
      <PMID>36247824</PMID>
    </reference>
    <reference>
      <citation>Ragazzoni L, Kwizera A, Caviglia M, Bodas M, Franc JM, Ssemmanda H, Ripoll-Gallardo A, Della-Corte F, Alenyo-Ngabirano A. Intra-operative low-dose ketamine does not reduce the cost of post-operative pain management after surgery: a randomized controlled trial in a low-income country. Afr Health Sci. 2019 Dec;19(4):3127-3135. doi: 10.4314/ahs.v19i4.35.</citation>
      <PMID>32127889</PMID>
    </reference>
    <reference>
      <citation>Viderman D, Tapinova K, Nabidollayeva F, Tankacheev R, Abdildin YG. Intravenous versus Epidural Routes of Patient-Controlled Analgesia in Abdominal Surgery: Systematic Review with Meta-Analysis. J Clin Med. 2022 May 5;11(9):2579. doi: 10.3390/jcm11092579.</citation>
      <PMID>35566705</PMID>
    </reference>
    <reference>
      <citation>Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand. 2001 Aug;45(7):795-804. doi: 10.1034/j.1399-6576.2001.045007795.x.</citation>
      <PMID>11472277</PMID>
    </reference>
    <reference>
      <citation>Argoff CE. Recent management advances in acute postoperative pain. Pain Pract. 2014 Jun;14(5):477-87. doi: 10.1111/papr.12108. Epub 2013 Aug 15.</citation>
      <PMID>23945010</PMID>
    </reference>
    <reference>
      <citation>Hansen KB, Yi F, Perszyk RE, Furukawa H, Wollmuth LP, Gibb AJ, Traynelis SF. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol. 2018 Aug 6;150(8):1081-1105. doi: 10.1085/jgp.201812032. Epub 2018 Jul 23.</citation>
      <PMID>30037851</PMID>
    </reference>
    <reference>
      <citation>Simonini A, Brogi E, Cascella M, Vittori A. Advantages of ketamine in pediatric anesthesia. Open Med (Wars). 2022 Jul 6;17(1):1134-1147. doi: 10.1515/med-2022-0509. eCollection 2022.</citation>
      <PMID>35859796</PMID>
    </reference>
    <reference>
      <citation>Brinck ECV, Virtanen T, Makela S, Soini V, Hynninen VV, Mulo J, Savolainen U, Rantakokko J, Maisniemi K, Liukas A, Olkkola KT, Kontinen V, Tarkkila P, Peltoniemi M, Saari TI. S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: A randomized, double-blind, placebo-controlled clinical trial. PLoS One. 2021 Jun 7;16(6):e0252626. doi: 10.1371/journal.pone.0252626. eCollection 2021.</citation>
      <PMID>34097713</PMID>
    </reference>
    <reference>
      <citation>Zhou L, Yang H, Hai Y, Cheng Y. Perioperative Low-Dose Ketamine for Postoperative Pain Management in Spine Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Res Manag. 2022 Mar 31;2022:1507097. doi: 10.1155/2022/1507097. eCollection 2022.</citation>
      <PMID>35401887</PMID>
    </reference>
    <reference>
      <citation>Wang L, Johnston B, Kaushal A, Cheng D, Zhu F, Martin J. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials. Can J Anaesth. 2016 Mar;63(3):311-25. doi: 10.1007/s12630-015-0551-4. Epub 2015 Dec 10.</citation>
      <PMID>26659198</PMID>
    </reference>
    <reference>
      <citation>Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011 Oct;58(10):911-23. doi: 10.1007/s12630-011-9560-0. Epub 2011 Jul 20.</citation>
      <PMID>21773855</PMID>
    </reference>
    <reference>
      <citation>Carstensen M, Moller AM. Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: a qualitative review of randomized trials. Br J Anaesth. 2010 Apr;104(4):401-6. doi: 10.1093/bja/aeq041. Epub 2010 Mar 5.</citation>
      <PMID>20207747</PMID>
    </reference>
    <reference>
      <citation>Ghanavatian S, James DL, Sadolf JS. The role of short-term, low dose intravenous ketamine infusion in Calciphylaxis. CEN Case Rep. 2021 Aug;10(3):422-425. doi: 10.1007/s13730-020-00557-8. Epub 2021 Feb 19.</citation>
      <PMID>33606191</PMID>
    </reference>
    <reference>
      <citation>Mathews TJ, Churchhouse AM, Housden T, Dunning J. Does adding ketamine to morphine patient-controlled analgesia safely improve post-thoracotomy pain? Interact Cardiovasc Thorac Surg. 2012 Feb;14(2):194-9. doi: 10.1093/icvts/ivr081. Epub 2011 Nov 28.</citation>
      <PMID>22159259</PMID>
    </reference>
    <reference>
      <citation>Javery KB, Ussery TW, Steger HG, Colclough GW. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth. 1996 Mar;43(3):212-5. doi: 10.1007/BF03011736.</citation>
      <PMID>8829857</PMID>
    </reference>
    <verification_date>May 2023</verification_date>
    <study_first_submitted>August 27, 2023</study_first_submitted>
    <study_first_submitted_qc>August 27, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 1, 2023</study_first_posted>
    <last_update_submitted>August 27, 2023</last_update_submitted>
    <last_update_submitted_qc>August 27, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 1, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Colorectal surgery</keyword>
    <keyword>patient-controlled analgesia</keyword>
    <keyword>postoperative pain management</keyword>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Ketamine</mesh_term>
      <mesh_term>Morphine</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06021717
  org study id: JEP-2018-092
  nct id: NCT06021717
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  The goal of this clinical trial is to compare the effectiveness of PCA ketamine-morphine
        versus conventional PCA morphine in postoperative patients undergoing elective laparotomy
        colorectal surgery under general anaesthesia. The specific objectives are:
  
          1. To compare the post-operative analgesic requirement with PCA ketamine-morphine in
             comparison with PCA morphine.
  
          2. To compare the postoperative pain scores between PCA ketamine-morphine and PCA morphine.
  
          3. To assess patients' overall satisfaction with PCA ketamine-morphine in comparison with
             PCA morphine.
  
          4. To study the incidence of side effects of PCA ketamine-morphine in comparison with PCA
             morphine.
  
        Participants will be screened and recruited at pre-anaesthetic clinic (PAC). Those who
        consented will be taught to use PCA machine and the potential side effects of the study
        drugs. They will be randomly allocated into either Group A or Group B by computer generated
        randomization a day before planned surgery.
  
        Researchers will compare Group A and Group B to see post-operative pain scores, patients'
        overall satisfaction and any incidence of side effects.
  INTRODUCTION
  
        Patient-controlled analgesia (PCA) is an established, efficient and safe technique for
        providing postoperative analgesia and has been associated with better pain relief and patient
        satisfaction with less postoperative complications and side effects [1]. Despite years of
        advances in pain management, opioids have been the mainstay for treatment of postoperative
        pain particularly in moderate to severe pain. Of all opioids, morphine is the most studied
        drug and remains the drug of choice for PCA, especially in Malaysian hospitals. However,
        morphine usage is also associated with known side effects such as sedation, nausea and
        vomiting, pruritus, urinary retention and respiratory depression [2]. A review of 32 studies
        involving opioids-based PCA-22 of which were PCA morphine-reported an incidence of 19%
        nausea, 18.1% vomiting, 30.9 % of nausea and/or vomiting, 25.7% sedation, 17.9% urinary
        retention, 17.9% pruritus and 15.2% hypoxia and 1.6% respiratory depression that may be
        life-threatening associated with PCA opioids use [3, 4]. The concept of multimodal analgesia
        hence was introduced to reduce opioid-related side effects. Adjuvants such as acetaminophen
        and non-steroidal anti-inflammatory drugs are commonly used nowadays in combination with
        opioids as opioid-sparing agents to reduce opioid usage [5].
  
        Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has undergone a recent resurgence of
        interest among acute care providers as an adjunct in acute pain management [6, 7]. Ketamine
        at a sub-anesthetic dose (0.2-0.5 mg kg-1) produces intense analgesia [5, 8]. Since its
        development in 1962, various studies have been conducted to prove the efficacy of ketamine as
        post-operative analgesia and as an opioid-sparing agent [8-10]. A review by Laskowski and
        colleagues described that IV ketamine improved the quality of pain control, in addition to
        decreased opioid consumption with the particular benefit being observed in painful
        procedures, such as upper abdominal, thoracic, and major orthopedic surgeries [11]. While
        Carstensen and co-workers in a qualitative review comparing PCA ketamine-morphine with PCA
        morphine alone also described the superior efficacy of ketamine-morphine in providing pain
        control with a significantly higher incidence of opioid-related side effects in the morphine
        group [12]. In comparison to opioids, ketamine's lack of respiratory depressant effects also
        favors its use as an opioid adjunct in patients with airway and respiratory compromise,
        especially in morbid obesity and post-thoracotomy patients [13, 14].
  
        Despite the potential efficacy with published evidence of PCA ketamine-morphine in
        postoperative pain management, its use is not well established in most Malaysian hospitals
        including the current study site. Hence, the aim of this study was to evaluate the
        effectiveness of PCA ketamine-morphine in comparison to conventional PCA morphine alone as
        postoperative analgesia in colorectal surgery patients in the current study site.
  
        METHODS
  
        This prospective double-blind randomized controlled trial was conducted in Hospital Sultanah
        Aminah Johor Bahru from February to October 2018 after obtaining ethics approval from the
        local and institutional ethics committee (NMRR-17-1863-37291 & JEP-2018-092). Sixty elective
        American Society of Anaesthesiologists (ASA) I or II patients scheduled for lower midline
        laparotomy colorectal surgery aged between 18-70 years old were recruited and informed
        consents were obtained. Patients with a known allergy to morphine or ketamine, uncontrolled
        hypertension, past history of chronic pain on regular analgesics, psychiatric illness on
        psychiatric drugs, BMI more than 35 and creatine clearance less than 30 were excluded from
        the study. All patients who consented were taught the usage of a PCA machine and the
        potential side effects of ketamine and morphine preoperatively. They were randomly allocated
        into either Group A or Group B by computer-generated randomization a day before planned
        surgery.
  
        Group A received PCA ketamine (Ketamine HCl, Pfizer Inc., US) 0.5 mg plus morphine 0.5 mg
        ml-1 (ratio 1:1) while Group B received PCA morphine (Pfizer Inc., US) 1 mg ml-1 as
        postoperative analgesia. There was no baseline infusion and the lock-out period was set to 5
        minutes. The study drugs were prepared one day before the surgery by the pharmacist who was
        not involved in the intraoperative and post-=operative management of the patients. The drugs
        were labelled as study drugs with the study number. The patients, nurses who cared for the
        patients, the anesthetist who performed the anesthesia and the investigators who gathered the
        data were blinded to patients' group allocation.
  
        All patients had standard monitoring of blood pressure, electrocardiogram (ECG), oxygen
        saturation and end-tidal carbon dioxide (CO2). They were pre-oxygenated with 100% oxygen for
        2-3 minutes. The induction of general anesthesia was standardized to intravenous (IV)
        fentanyl (Cephalon Inc., US) 2 mcg kg-1, IV propofol (Diprivan, Pfizer Inc., US) 2 mg kg-1
        and IV rocuronium (US) 0.6 mg kg-1 and intubation with the appropriate size of the
        endotracheal tube. Anesthesia was maintained with desflurane (Suprane, Novartis AG,
        Switzerland) in a mixture of 50% of oxygen and 50% of air, and titrated to achieve a minimum
        alveolar concentration (MAC) of 1.0. All patients received IV dexamethasone (US) 8 mg after
        induction and IV morphine 0.1 mg kg-1 as intraoperative analgesia. Boluses of IV fentanyl 25
        mcg were given if extra analgesia was required and recorded. IV ondansetron (US) 4 mg was
        given upon initiation of skin closure. The skin incision site was infiltrated with 0.25%
        Bupivacaine (US) 10-20 ml during skin closure. The standard dose of IV neostigmine and IV
        atropine was used to reverse residual neuromuscular blockade at the end of surgery.
  
        At the recovery bay, pain score was assessed using the Numerical Rating Scale (NRS), by which
        patients scored their pain intensity between number 0 to 10, with 0 being no pain at all and
        10 being the worst pain imaginable. If the pain score was > 4 at rest, IV morphine boluses
        were given and titrated according to the pre-set morphine protocol until the pain score was ≤
        4. PCA machine with the study drug(s) was commenced once the pain score was ≤ 4 at rest.
  
        Patients were assessed 30 minutes after the commencement of PCA, at 6 hourly intervals for
        the first 24 hours and subsequently at 12 hourly intervals for the next 24 hours
        post-operatively by the Acute Pain Service (APS) team. They were solely on PCA as
        post-operative analgesia as the patients were kept nil by mouth for the first 48 hours
        postoperatively. All patients were assessed for pain score, sedation score, respiratory rate
        and other side effects of morphine and ketamine including nausea and vomiting, pruritus,
        dizziness and hallucinations. If the pain score was > 4 at rest during the assessment, 2 ml
        of PCA drug was given as boluses and titrated every 10 minutes to achieve a pain score ≤ 4.
  
        Cumulative morphine consumption was also recorded. Sedation was assessed using Pasero
        Opioid-Induced Sedation Scale (POSS) (S - sleep, easy to arouse, 1 - awake and alert, 2 -
        slightly drowsy, easy to arouse, 3 - frequently drowsy, arousable, drift to sleep during the
        conversation, 4 - somnolent, minimal or no response to verbal or physical stimulation).
        Treatment for nausea, vomiting and pruritus was given as deemed appropriate and recorded. At
        48-hour post-operation, the patient's overall satisfaction score was assessed using 1 to 5
        Likert scale (1 - very unsatisfied, 2 - unsatisfied, 3 - neutral, 4 - satisfied and 5 - very
        satisfied). If patients experience hallucinations or delirium, PCA bolus dose was reduced by
        0.2 ml and the symptoms were reassessed after 1 hour. If symptoms persist, the PCA bolus dose
        was reduced further by 0.2 ml every hour until symptoms disappear and PCA subsequently
        continued at the reduced dose.
  
        Patients with complicated surgeries in which they became haemodynamically unstable and
        required post-operative ICU admission, developed anaphylaxis after commencement of study
        drugs, developed persistent delirium or hallucination after reduction of PCA bolus dose and
        pain was uncontrollable with the reduced dose or those who refused to continue with the study
        for any reasons were withdrawn from the study and given other means of analgesia as
        appropriate by the acute pain service (APS) team.
  
        The sample size was calculated using 'Power and Sample Size Calculations' program. The sample
        size was estimated using t-test calculation as derived from mean pain score and standard
        deviation as quoted in a study by Javery and colleagues [15]. The α value was set at 0.05 and
        power of study at 90% and standard deviation at 1.67, whereby it was estimated that 27
        patients were required for each group. Anticipating a 10% drop-out rate, 30 patients were
        eventually recruited in each group, resulting in 60 patients for the whole study.
  
        All data were analyzed using the SPSS (Statistical Package for The Social Sciences) software.
        Chi-square test or Fisher exact test was used when appropriate to calculate any significant
        differences for categorical variables. Independent t-test or Mann Whitney U test was used as
        appropriate to determine any significant differences for continuous variables. The incidence
        of side effects between the two groups was compared using Chi-square test. A P value of less
        than 0.05 was considered statistically significant.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Participants were randomly allocated into either Group A or Group B by computer-generated randomization a day before planned surgery.
  Group A will receive PCA ketamine-morphine 0.5 mg/ml in 1:1 ratio while group B will receive PCA morphine 1mg/ml,
  primary purpose: Treatment
  masking: Triple (Participant, Care Provider, Investigator)
  masking description: The patients, nurses who cared for the patients, the anesthetist who performed the anesthesia and the investigators who gathered the data were blinded to patients' group allocation.
  measure: PCA drugs demanded and delivered
  time frame: 30 minutes after commencement of PCA until 48 hours
  description: Total PCA drugs demanded and delivered
  measure: Pain score
  time frame: 30 minutes after commencement of PCA until 48 hours
  description: Pain score at rest and on movement with NRS
  Numerical Rating Scale (NRS) for pain score assessment A numerical pain assessment tool from 0 to 10, where 0 denotes no pain, 5 denotes moderate pain and 10 denotes worst possible pain.
  measure: Incidence of side effects
  time frame: 30 minutes after commencement of PCA until 48 hours
  description: Opiod related side effects : nausea and vomiting, pruritus, dizziness, respiratory depression and treatment on PRN basis if indicated
  Ketamine related side effects : delirium, hallucinations, hypertension, tachycardia
  measure: Patients' overall satisfaction
  time frame: At 48 hours post oeprative
  description: Assessment of patients' overall satisfaction with a 5-points scales at 48 hours.
  A 5-point scale from 1 to 5, where:
  = very unsatisfied
  = unsatisfied
  = neutral
  = satisfied
  = very satisfied
  arm group label: Group A
  arm group type: Experimental
  description: PCA ketamine (Ketamine HCl, Pfizer Inc., US) 0.5 mg plus morphine 0.5 mg ml-1 (ratio 1:1) as postoperative analgesia.
  arm group label: Group B
  arm group type: Active Comparator
  description: PCA morphine (Pfizer Inc., US) 1 mg ml-1 as postoperative analgesia.
  intervention type: Drug
  intervention name: Ketamine-Morphine
  description: PCA ketamine (Ketamine HCl, Pfizer Inc., US) 0.5 mg plus morphine 0.5 mg ml-1 (ratio 1:1)
  arm group label: Group A
  other name: Ketamine Hydrochloric, Pfizer Inc., US
  other name: Morphine Pfizer Inc., US
  intervention type: Drug
  intervention name: Morphine
  description: PCA morphine (Pfizer Inc., US) 1 mg ml-1
  arm group label: Group B
  other name: Morphine Pfizer Inc., US
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 70 Years
  healthy volunteers: No
  last name: Chian Yong Liu, MMed (Anaes)
  role: Principal Investigator
  affiliation: Universiti Kebangsaan Malaysia Medical Centre
  facility: 
  country: Malaysia
  citation: Pouldar TM, Maher DP, Betz AW, Wiegers JJ, Friedman JA, Zaidi SS, Rejali A, Tran HP, Yumul R, Louy C. Adverse Effects Associated with Patient-Controlled Analgesia with Ketamine Combined with Opioids and Ketamine Infusion with PCA Bolus in Postoperative Spine Patients: A Retrospective Review. J Pain Res. 2022 Oct 10;15:3127-3135. doi: 10.2147/JPR.S358770. eCollection 2022.
  PMID: 36247824
  citation: Ragazzoni L, Kwizera A, Caviglia M, Bodas M, Franc JM, Ssemmanda H, Ripoll-Gallardo A, Della-Corte F, Alenyo-Ngabirano A. Intra-operative low-dose ketamine does not reduce the cost of post-operative pain management after surgery: a randomized controlled trial in a low-income country. Afr Health Sci. 2019 Dec;19(4):3127-3135. doi: 10.4314/ahs.v19i4.35.
  PMID: 32127889
  citation: Viderman D, Tapinova K, Nabidollayeva F, Tankacheev R, Abdildin YG. Intravenous versus Epidural Routes of Patient-Controlled Analgesia in Abdominal Surgery: Systematic Review with Meta-Analysis. J Clin Med. 2022 May 5;11(9):2579. doi: 10.3390/jcm11092579.
  PMID: 35566705
  citation: Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand. 2001 Aug;45(7):795-804. doi: 10.1034/j.1399-6576.2001.045007795.x.
  PMID: 11472277
  citation: Argoff CE. Recent management advances in acute postoperative pain. Pain Pract. 2014 Jun;14(5):477-87. doi: 10.1111/papr.12108. Epub 2013 Aug 15.
  PMID: 23945010
  citation: Hansen KB, Yi F, Perszyk RE, Furukawa H, Wollmuth LP, Gibb AJ, Traynelis SF. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol. 2018 Aug 6;150(8):1081-1105. doi: 10.1085/jgp.201812032. Epub 2018 Jul 23.
  PMID: 30037851
  citation: Simonini A, Brogi E, Cascella M, Vittori A. Advantages of ketamine in pediatric anesthesia. Open Med (Wars). 2022 Jul 6;17(1):1134-1147. doi: 10.1515/med-2022-0509. eCollection 2022.
  PMID: 35859796
  citation: Brinck ECV, Virtanen T, Makela S, Soini V, Hynninen VV, Mulo J, Savolainen U, Rantakokko J, Maisniemi K, Liukas A, Olkkola KT, Kontinen V, Tarkkila P, Peltoniemi M, Saari TI. S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: A randomized, double-blind, placebo-controlled clinical trial. PLoS One. 2021 Jun 7;16(6):e0252626. doi: 10.1371/journal.pone.0252626. eCollection 2021.
  PMID: 34097713
  citation: Zhou L, Yang H, Hai Y, Cheng Y. Perioperative Low-Dose Ketamine for Postoperative Pain Management in Spine Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Res Manag. 2022 Mar 31;2022:1507097. doi: 10.1155/2022/1507097. eCollection 2022.
  PMID: 35401887
  citation: Wang L, Johnston B, Kaushal A, Cheng D, Zhu F, Martin J. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials. Can J Anaesth. 2016 Mar;63(3):311-25. doi: 10.1007/s12630-015-0551-4. Epub 2015 Dec 10.
  PMID: 26659198
  citation: Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011 Oct;58(10):911-23. doi: 10.1007/s12630-011-9560-0. Epub 2011 Jul 20.
  PMID: 21773855
  citation: Carstensen M, Moller AM. Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: a qualitative review of randomized trials. Br J Anaesth. 2010 Apr;104(4):401-6. doi: 10.1093/bja/aeq041. Epub 2010 Mar 5.
  PMID: 20207747
  citation: Ghanavatian S, James DL, Sadolf JS. The role of short-term, low dose intravenous ketamine infusion in Calciphylaxis. CEN Case Rep. 2021 Aug;10(3):422-425. doi: 10.1007/s13730-020-00557-8. Epub 2021 Feb 19.
  PMID: 33606191
  citation: Mathews TJ, Churchhouse AM, Housden T, Dunning J. Does adding ketamine to morphine patient-controlled analgesia safely improve post-thoracotomy pain? Interact Cardiovasc Thorac Surg. 2012 Feb;14(2):194-9. doi: 10.1093/icvts/ivr081. Epub 2011 Nov 28.
  PMID: 22159259
  citation: Javery KB, Ussery TW, Steger HG, Colclough GW. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth. 1996 Mar;43(3):212-5. doi: 10.1007/BF03011736.
  PMID: 8829857
  responsible party type: Sponsor
  mesh term: Ketamine
  mesh term: Morphine
  sharing ipd: No