PCA Ketamine-Morphine VS PCA Morphine as Post-Operative Analgesia in Colorectal Surgery.
Condition: Ketamine; Morphine
Study type: Interventional
Phase: Phase 4

Summary: 
      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 postoperative 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 the pre-anaesthetic clinic (PAC). Those who
      consented will be taught to use the 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.
    

Detailed description: 
      INTRODUCTION

      Patient-controlled analgesia (PCA) has been an established efficient and safe technique for
      providing postoperative analgesia [1-3]. It is a delivery system with which patients
      self-administer predetermined doses of analgesic medication to relieve their pain [1]. A
      reviewed meta-analysis conducted by McNicol et al (2015) provided evidence that PCA opioids
      provide superior analgesia in comparison to conventional intravenous opioids analgesia [2].
      PCA has been associated with better pain relief and patient satisfaction with less
      postoperative complications and side effects [1-3].

      Despite years of advances in pain management, opioids have been the mainstay for the
      treatment of postoperative pain particularly in moderate to severe pain [1-3]. A variety of
      opioids have been used for PCA, namely morphine, fentanyl, pethidine and oxycodone. Of all
      the opioids, morphine is the most studied drug and remained the drug of choice for PCA
      including in Malaysian hospitals' settings [1,4]. However, it is also associated with known
      side effects such as respiratory depression, sedation, nausea and vomiting, pruritus,
      constipation and urinary retention [2,4]. 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 [5, 6].

      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 [5-7]. Ketamine at
      sub-anaesthetic dose (0.2-0.5 mg/kg) produces intense analgesia [5-9]. The analgesic effects
      of ketamine are primarily due to its activity in the thalamic and limbic systems which are
      responsible for interpretation of painful signals and modulation of pain [9]. Activation of
      NMDA receptors located at the dorsal horns, by excitatory neurotransmitters particularly
      glutamate, induced by peripheral nociceptive stimuli results in hyperexcitability of the
      dorsal root neurones, which is the pathophysiology of acute pain. It has also been reported
      that μ receptor activation by opioids leads to a sustained increase in glutamate synaptic
      effectiveness at the level of NMDA receptors [8]. The combination of ketamine, a
      non-competitive antagonist at the NMDA receptor with morphine hence will have a synergistic
      effect and this may allow a reduction in doses of both drugs and potentially reduce the side
      effects related to both [8-18].

      Since its development in 1962, various studies have been conducted to prove the efficacy of
      ketamine as postoperative analgesia and as an opioid-sparing agent [7]. A review by Laskowski
      et al. (2010) described IV ketamine improved the quality of pain control, in addition to
      decreased opioid consumption with particular benefits observed in painful procedures,
      including upper abdominal, thoracic, and major orthopaedic surgeries [7]. Carstensen et al.
      (2010) 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 including sedation, nausea,
      vomiting, pruritus, urinary retention and desaturation in the morphine group [10]. In
      comparison to opioids, ketamine's lack of respiratory depressant effects also favours its use
      as an opioid adjunct in patients with airway and respiratory compromise, such as morbid
      obesity and post-thoracotomy patients [7,10-13].

      The main concern and limitation with regard to ketamine use is its psychomimetic side
      effects, particularly hallucinations and delirium. However, most studies suggested that the
      incidence of psychomimetic side effects is minimal with a subanaesthetic dose of ketamine.
      Both Subramaniam et al. (2004) and Carstensen et al. (2010) found no significance increased
      in CNS and psychomimetic side effects in patients receiving ketamine as compared to morphine
      alone [8,11]. While Mathews et al. (2012) reported an incidence of hallucination/vivid dreams
      requiring the intervention of 2.9%, and an incidence requiring no intervention of 3.3% in a
      prospective cohort study of 1026 patients receiving PCA ketamine-morphine post-operatively in
      a variety of surgical settings [12]. The optimum dose for ketamine in combination with
      morphine is also another issue being addressed in most studies, as various studies used
      different doses and combinations of ketamine with morphine. A study conducted by Sveticic et
      al. (2003) analysed 12 different combinations of ketamine and morphine in PCA and their
      correlation with reduction in pain score and incidence of side effects following spine and
      hip surgery. The study recommended a combination of morphine with ketamine in a ratio of 1:1
      as the best ratio [18].

      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 Hospital Sultanah Aminah Johor Bahru. The use of PCA ketamine however, has been
      practised in selective postoperative abdominal surgery patients in our Intensive Care Unit
      (ICU) setting, owing to the fact that ketamine is superior to opioids in reducing the risk of
      postoperative ileus and nausea and vomiting which may already be exacerbated by the patient's
      underlying illnesses. The PCA ketamine regime used in our ICU is 1mg/ml bolus with a lock-out
      period of 5 minutes and background infusion of 1mg/hour, which is, as per our experience,
      well tolerated in most patients. Therefore, hopefully, the results gained from this study
      will help us to understand better about PCA ketamine-morphine and its effectiveness in our
      local population, in the hope that we can provide better care and postoperative pain
      management for our patients in the future.

      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
      consent were obtained. 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 postoperative management of the patients. The drugs
      were labelled as study drugs with the study number. The patients, nurses who cared for the
      patients, the anaesthetist who performed the anaesthesia 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 anaesthesia 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 hours post-operation, the patient's overall satisfaction score was assessed using a 1 to 5
      Likert scale (1 - very unsatisfied, 2 - unsatisfied, 3 - neutral, 4 - satisfied and 5 - very
      satisfied). If patients experience hallucinations or delirium, the 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 the Power and Sample Size Calculations program. The α
      value is set at 0.05 and the power of study at 90%. The sample size is calculated using a
      t-test. The calculation is derived from the mean pain score and standard deviation as quoted
      in Javery et al. [12].

      Requested output: Sample size

      Independent:

      Alpha = 0.05; power = 0.9; δ = 1.5; SD 1.67 The case sample size for the t-test = 27 Total
      sample: 27 x 2 plus 10% drop-out rate = 60 Sample = 30 per study group

      All data were analyzed using the SPSS (Statistical Package for The Social Sciences) software.
      The chi-square test or Fisher exact test was used when appropriate to calculate any
      significant differences for categorical variables. An 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 the
      Chi-square test. A p-value of less than 0.05 was considered statistically significant.
    

Intervention name(s): Ketamine-Morphine; Morphine
Intervention type(s): Drug; Drug
Intervention description(s): PCA ketamine (Ketamine HCl, Pfizer Inc., US) 0.5 mg plus morphine 0.5 mg ml-1 (ratio 1:1); PCA morphine (Pfizer Inc., US) 1 mg ml-1
Other intervention name(s): Ketamine Hydrochloric, Pfizer Inc., US; Morphine Pfizer Inc., US; Morphine Pfizer Inc., US
Intervention MeSH terms: Ketamine; Morphine
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.
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Colorectal surgery; patient-controlled analgesia; postoperative pain management