Effect of Granisetron on Morphine Induced Pruritus in Cesarean Section
Condition: Pruritus
MeSH terms: Pruritus
Study type: Interventional
Phase: Phase 2

Summary: 
      Neuraxial anesthesia, which includes epidural anesthesia and intrathecal anesthesia, is a
      frequent anesthetic approach for caesarean delivery and other lower abdominal and lower limb
      anesthetic procedures. The addition of neuraxial morphine to local anesthetics provides an
      effective and prolonged postoperative analgesia. Neuraxial administration of morphine which
      is considered as a gold standard for analgesia has been associated with a frequent incidence
      of pruritus and postoperative nausea and vomiting.

      The incidence of neuraxial opioid induced pruritus varies widely from 30% - 60% after
      orthopedic surgery with intrathecal morphine injection and from 60% - 100% in pregnant women
      after neuraxial opioid administration. Parturients appear to be the most susceptible to
      neuraxial opioid-induced pruritus which probably might be due to the interaction of estrogens
      with opioid receptors.

      Although the exact mechanism of neuraxial opioid induced pruritus is unclear, the postulated
      mechanisms include the presence of an "itch center" in the central nervous system (CNS),
      medullary dorsal horn activation, antagonism of inhibitory transmitters, modulation of
      5-hydroxytryptamine subtype 3 (5-HT3) or serotonergic pathways and the involvement of
      prostaglandins.

      There is dense concentration of opioid receptors and 5-HT3 receptors in the dorsal part of
      the spinal cord and the nucleus of the spinal tract of the trigeminal nerve in the medulla.
      Activation of these receptors by neuraxial opioid administration or by circulating estrogen
      in parturients results in neuraxial opioid induced pruritus which is usually localized to the
      face, neck, or upper thorax. Nalbuphine, propofol and ondansetron have been used effectively
      in the treatment of pruritus associated with neuraxial morphine in surgical patients.

      Granisetron is a potent and highly selective 5-HT3 receptor antagonist that has little or no
      affinity for other 5-HT receptors, or dopaminergic, adrenergic, benzodiazepine, histaminic,
      or opioid receptors. Its onset of action is 1-3 min, peak plasma level 30 min, plasma
      half-life is 4-6 h and duration of action up to 24 h. Its longer duration of action than that
      of ondansetron may coincide with the peak incidence of pruritus after intrathecal morphine
      (6-9 h). In contrast, other 5-HT3-receptor antagonists have affinities for various
      receptor-binding sites. For example, ondansetron has detectable binding to 5-HT1B, 5-HT1C,
      α1-adrenergic, and μ-opioid receptor sites. Although not proven, the binding of these agents
      to additional receptor subtypes other than their target receptor may underlie the inferior
      adverse event profile seen with ondansetron compared with granisetron.
    

Detailed description: 
      The study will be carried on 40 parturients scheduled for elective cesarean section (CS)
      under intrathecal anesthesia. They will be randomly allocated into two equal groups of 20
      parturients each:

      Group A: (placebo group) will receive 200 ug morphine sulphate will be injected intrathecally
      & 2 mL of normal saline 0.9%.

      Group B: (treatment group) will receive 200 ug morphine sulphate will be injected
      intrathecally & 2 mL of 2 mg granisetron IV injection.

      Preoperative assessment:

      The day prior to surgery, all patients will undergo preanesthetic checkup including detailed
      history, thorough general, physical, systemic examination and weight of the patient. They
      will be kept NOP (nil per mouth) 6-8 hours for solids and 2 hours for water and clear fluids.

      Preparation of the patients:

      Written consent, coagulation profile, emergency resuscitation equipments including airway
      devices, advanced cardiac life support drugs. Parturients will be educated regarding the
      visual analogue scale (VAS).

      Parturients in the holding area:

      The patients will be positioned in the supine position, with uterine displacement to the left
      lateral side.

        -  Baseline monitoring readings of the maternal vital signs including Heart rate (HR),
           noninvasive systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial
           pressure (MAP), arterial oxygen saturation (SpO2) and respiratory rate (RR).

        -  Then IV cannula 18 G will be inserted into forearm vein and normal saline 0.9% solution
           15 ml/kg will be infused for all women participating in the study over 20-30 minutes as
           a preload.

        -  The study drugs will be given 30 min before administration of intrathecal anesthesia.

        -  All patients will be premedicated with ranitidine 50 mg IV and then they will be
           transferred to the operating room.

      Parturient in the operating room:

      The previous monitoring data will be recorded again for the second time. Then subarachnoid
      block will be carried out under complete aseptic condition in the sitting position with the
      table in the horizontal level using 25 G pencil point spinal needle. Intrathecal block will
      be performed at the level of L 3-4 or L 4-5 vertebral interspaces; 12.5 mg (2.5 ml) of
      hyperbaric bupivacaine 0.5% and 200 ug morphine sulphate will be injected intrathecally at a
      rate of 1 ml/15 second after obtaining free flow of CSF. Immediately after end of injection
      of the drugs intrathecally, the parturient will be placed in the supine position with left
      lateral uterine displacement by putting a wedge under right hip (15ﹾ left-tilted supine
      position). All patients will receive supplemental oxygen 4 L/min via facemask until delivery
      of the baby. Sensory block will be assessed using loss of sensation in response to cold
      sensation (using ice cube). Surgery will start when the maximum height of sensory block
      reaches T6 or higher. Motor blockade will be assessed by modified Bromage scale (1 = unable
      to move feet or knees; 2 = able to move feet only; 3 = just able to move knees; 4 = full
      flexion of knees; 5 = no detectable weakness of hip flexion while supine; 6 = able to perform
      partial knee bend).

      A third monitoring reading of the vital data will be taken immediately, 5 min and 10 min
      after spinal block and before the surgical operation (CS) starts.

      Intraoperative assessment:

        -  After subarachnoid block parturients will be monitored for HR, NIBP, SpO2 and RR every 5
           min till the end of the surgery. All parturients will be continuously monitored
           intraoperatively for any episodes of hypotension or bradycardia. Hypotension: defined as
           more than 20% decrease in maternal systolic blood pressure from the baseline. It will be
           treated with IV crystalloid fluid bolus and/or 3 mg IV ephedrine boluses when needed.
           Bradycardia defined as maternal heart rate < 60 beats/min. If occurred, it will be
           treated with IV atropine sulphate 0.5mg.

        -  After delivery of the baby, IV oxytocin 5 U will be administered slowly followed by an
           oxytocin infusion 0.03 U/mL at a rate of 200 mL/hr.

      Study outcomes:

      Primary outcome:

      Incidence of pruritus during the first postoperative 24 hours.

      Secondary outcomes:

        1. Onset time of pruritus

        2. Duration, location of pruritus and severity of pruritus according to the pruritus
           grading score The pruritus grading system (PGS) score for each patient is based on:
           distribution, frequency, severity of itch and quality of sleep.

           Pruritus Grading System

           Each patient's itch grade is calculated as the sum of the individual scores as:

             -  Distribution:Solitary site 1, Multiple sites 2, Generalized 3

             -  Frequency: Episodic 1, Frequent 3, Continuous 5

             -  Severity: Rubbing 1, Scratching 1, Localized excoriations 3, Generalized
                excoriations 5

             -  Sleep disturbance: Rare 0, Occasional 2, Frequent 4,Totally restless 6

           Mild grade: if total score is between 0 and 5.

           Moderate grade: if total score is between 6 and 11.

           Severe grade: if total score is between 12 and 19.

           The onset of pruritus will be assessed and recorded every 15 min for 4 hours along with
           the complaint by the patient. Pruritus scores will then be evaluated at 4, 8 and 24
           hours post-surgery. For patients with pruritus who request treatment, antihistamines
           such as pheniramine maleate and μ-opioid receptor antagonists such as naloxone will be
           used depending upon the severity assessed by the clinician, if required.

        3. Postoperative pain assessment, by a blinded Post-Anesthesia Care Unit (PACU) nurse using
           VAS at 6, 12, 18 and 24 hours after intrathecal morphine injection. Visual analog scale
           (Fig. 1) is a validated approach to pain measurement (Wood, 2004). The most common VAS
           consists of a 10-cm line with one end labeled "no pain" and the other end labeled "worst
           pain imaginable." The patient marks the line at the point that best describes the pain
           intensity. The length of the line to the patient's mark is measured and recorded in
           millimeters. The main theoretical advantage of the VAS is that it does not limit pain to
           10 discrete levels of intensity, permitting a more detailed rating of pain.

           Rescue analgesia will be given in the form of perfalgan (paracetamol) 1 gm/ 6 h (max 4
           gm per day) IV infusion and/or pethidine (meperidine) 1 mg/ kg IM when VAS is greater
           than 4.

        4. Perioperative adverse events will be recorded, including nausea, vomiting (treated with
           10 mg IV metoclopramide), intraoperative shortness of breath and respiratory depression
           (RR < 8 breaths/ min), and postoperative headache in the first 24 hours postoperatively.

        5. Participants' satisfaction after end of the delivery: 1) not satisfied or 2) satisfied
           and willing to take the same medication and procedure in the future when indicated.

      Serum serotonin measurment:

      Two blood samples (2 mL each) will be withdrawn from each parturient. One sample will be
      withdrawn in the holding area before preload infusion and granisetron injection (basal
      reading for serum serotonin) and the other one will be withdrawn 6 hours after intrathecal
      morphine injection in both groups. Repeated freezing and thawing of the samples should be
      avoided. Hemolytic and especially lipemic serum samples should not be used with this assay.
      Storage: up to 6 hours at 2 - 8ºC; for longer periods (up to 6 months) at - 20 ºC.

      Intended use and principle of the test: Enzyme Immunoassay for the quantitative determination
      of serotonin in serum. In the first step, serotonin is quantitatively acylated. The
      subsequent competitive ELISA kit uses the microtiter plate format. The antigen is bound to
      the solid phase of the microtiter plate. The acylated standards, controls and samples and the
      solid phase bound analyte compete for a fixed number of antiserum binding sites. After the
      system is in equilibrium, free antigen and free antigen-antiserum complexes are removed by
      washing. The antibody bound to the solid phase is detected by an anti-rabbit IgG-peroxidase
      conjugate using TMB as a substrate. The reaction is monitored at 450 nm.

      Quantification of unknown samples is achieved by comparing their absorbance with a reference
      curve prepared with known standard concentrations. Expected reference values in serum: Males:
      80 - 450 ng/ml and females: 40 - 400 ng/ml
    

Intervention name(s): Morphine Sulfate; Placebo; Granisetron
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 200 ug morphine sulphate will be injected intrathecally; 2 mL of normal saline 0.9% IV injection; 2 mL of 2 mg granisetron IV injection
Other intervention name(s): Normal saline 0.9%; Kytril, Sancuso
Intervention MeSH terms: Morphine; Granisetron
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: comparison of the effect of intravenous granisetron with the effect of using placebo on morphine induced pruritus in parturients undergoing elective cesarean section under spinal anesthesia.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Granisetron; Serum Serotonin; Morphine