Effects of Pregabalin on Post-cesarean Pain
Condition: Uncomplicated Singleton Pregnancies
Study type: Interventional
Phase: Phase 1

Summary: 
      Post-cesarean pain management is essential for early mobilization of the mother so that she
      becomes able to care of her newborn. There choices for postoperative analgesia include
      spinal, systemic, or both opioids, non-steroidal anti-inflammatory drugs (NSAIDs), local
      anesthetic infiltrations of the wound, or transverse abdominis plane blocks, which are
      determined by drug availability, regional and individual preferences, resource limitations
      and financial considerations. The use of opioids is associated with adverse effects such as
      nausea, pruritus, sedation, and occasionally respiratory depression.

      Pregabalin is an anticonvulsant drug structurally related to the inhibitory neurotransmitter
      gamma amino butyric acid, that exerts its action by binding to the α-2-δ subunit of the
      voltage-dependent calcium channel. It reduces the release of the excitatory neurotransmitters
      and inhibits the hyperalgesia and central sensitization.

      A recent meta-analysis demonstrated that pregabalin reduce the postoperative 24 hours
      cumulative opioid consumption and opioid-related adverse effects namely, vomiting and visual
      disturbances after surgery. Compared with the use of pregabalin doses lower than 300 mg, the
      use of doses higher than 300 mg even reduced opioid consumption by 35%.

      It is not known if pregabalin is excreted in human milk. There is a case report on the
      extensive excretion of pregabalin in breast milk, but with low measured concentrations in
      infant as a consequence of maternal exposure during breast feeding. Food and Drug
      Administration recommends to discontinue nursing or to discontinue pregabalin in nursing
      mothers. Pre-delivery single exposure to pregabalin is expected to be safe for the newborns.

      Up to the authors' best knowledge, this is the first clinical study on the efficacy and
      safety of the administration of pregabalin before cesarean delivery.

      We hypothesis that the preoperative administration of a single dose of pregabalin will
      improve the quality of postoperative analgesia after cesarean delivery.

      This placebo-controlled study aims to compare the effects of preoperative administrations of
      single oral doses of pregabalin 150 mg and 300 mg on the postoperative pain scores,
      cumulative patient controlled morphine consumptions, neonatal Apgar and neurologic and
      adaptive capacity scores (NACS), and maternal and neonatal adverse effects in parturients
      scheduled to elective Cesarean delivery under spinal anesthesia.
    

Detailed description: 
      An independent investigator who will not be involved in the study will instruct the patients
      preoperatively about the use of patient controlled analgesia and visual analogue scale to
      assess the severity of postoperative pain (0 mm for no pain and100 mm for worst imaginable
      pain).

      Anaesthetic management will be standardized. Oral ranitidine 150 mg and metoclopramide 10 mg
      will be given the night before and on the morning of surgery, with 0.3 mol/L sodium citrate
      30 mL given 15 min before induction.

      Ninety minutes before surgery, subjects will be allocated randomly into three groups by
      drawing sequentially numbered sealed opaque envelopes containing a software-generated
      randomization code to the placebo (n = 45), pregabalin 150 mg (n = 45) and the pregabalin 300
      mg (n = 45) groups. The placebo and pregabalin capsules look identical and will be prepared
      by a local pharmacy. An anaesthesiologist not otherwise involved in the study and who will be
      blinded to treatment regimen will provide perioperative care. An independent investigator
      will collect perioperative data. All staff in the operating room will be unaware of patient
      allocation group.

      Maternal monitoring will include electrocardiography, non-invasive blood pressure, and pulse
      oximetry. Left uterine displacement will be maintained.

      Spinal anesthesia will be performed in all cases in sitting position at L3-L4 or L4-L5 spaces
      with hyperbaric bupivacaine 0.5% (12.5 mg) and fentanyl 20 µg. After the umbilical cord is
      clamped, a 10 IU infusion of oxytocin in 500 mL of lactated Ringer's solution will be
      infused.

      A paediatrician blinded to study group allocation will record Apgar scores at 1 and 5 min,
      umbilical cord blood gas analysis and NACS at 15 min, 2h, 24 and 48 h after delivery. NACS
      gives a maximum of 40 with a score >35 denoting vigor.The percentage of infants scoring <35
      will be determined.

      Postoperative analgesic regime will be standardized in all patients with 12-hourly
      intramuscular diclofenac 75 mg started immediately at the end of surgery and morphine via
      patient-controlled analgesia (PCA): 1 mg bolus with an 8 minutes lockout. Postoperative
      nausea or vomiting will be treated with intravenous metoclopramide 10 mg as required.

      Statistical analysis:

      Based on a previous study,7 the mean postoperative cumulative morphine consumption at 24 h
      after caesarean delivery was 38 mg with a standard deviation of 14 mg. An a priori power
      analysis indicated that 45 subjects were required in each group to detect a 25% reduction in
      the cumulative morphine consumption at 24 h after caesarean delivery, that was assumed to
      have a clinically significant effect, with a type-I error of 0.0167 (0.05/3 possible
      comparisons) and a power of 90%. Additional patients (10%) were included for a final sample
      size of 150 patients to account for patient dropout during the course of the study.
    

Intervention name(s): Placebo; Pregabalin 300 mg group; Pregabalin 150 mg group
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Ninety minutes before surgery, the parturients receive two identical placebo capsules; Ninety minutes before surgery, the parturients receive two capsules of pregabalin 150 mg; Ninety minutes before surgery, the parturients receive one capsule of pregabalin 150 mg and one placebo capsule
Intervention MeSH terms: Pregabalin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: caesarean delivery; spinal anesthesia; pregabalin; postoperative pain; morphine