<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/NCT01719705</url>
  </required_header>
  <id_info>
    <org_study_id>R/60</org_study_id>
    <nct_id>NCT01719705</nct_id>
  </id_info>
  <brief_title>Effects of Pregabalin on Post-cesarean Pain</brief_title>
  <official_title>Efficacy of Preoperative Pregabalin on the Post-caesarean Pain; a Dose-response Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mansoura University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mansoura University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Post-cesarean pain management is essential for early mobilization of the mother so that she&#xD;
      becomes able to care of her newborn. There choices for postoperative analgesia include&#xD;
      spinal, systemic, or both opioids, non-steroidal anti-inflammatory drugs (NSAIDs), local&#xD;
      anesthetic infiltrations of the wound, or transverse abdominis plane blocks, which are&#xD;
      determined by drug availability, regional and individual preferences, resource limitations&#xD;
      and financial considerations. The use of opioids is associated with adverse effects such as&#xD;
      nausea, pruritus, sedation, and occasionally respiratory depression.&#xD;
&#xD;
      Pregabalin is an anticonvulsant drug structurally related to the inhibitory neurotransmitter&#xD;
      gamma amino butyric acid, that exerts its action by binding to the α-2-δ subunit of the&#xD;
      voltage-dependent calcium channel. It reduces the release of the excitatory neurotransmitters&#xD;
      and inhibits the hyperalgesia and central sensitization.&#xD;
&#xD;
      A recent meta-analysis demonstrated that pregabalin reduce the postoperative 24 hours&#xD;
      cumulative opioid consumption and opioid-related adverse effects namely, vomiting and visual&#xD;
      disturbances after surgery. Compared with the use of pregabalin doses lower than 300 mg, the&#xD;
      use of doses higher than 300 mg even reduced opioid consumption by 35%.&#xD;
&#xD;
      It is not known if pregabalin is excreted in human milk. There is a case report on the&#xD;
      extensive excretion of pregabalin in breast milk, but with low measured concentrations in&#xD;
      infant as a consequence of maternal exposure during breast feeding. Food and Drug&#xD;
      Administration recommends to discontinue nursing or to discontinue pregabalin in nursing&#xD;
      mothers. Pre-delivery single exposure to pregabalin is expected to be safe for the newborns.&#xD;
&#xD;
      Up to the authors' best knowledge, this is the first clinical study on the efficacy and&#xD;
      safety of the administration of pregabalin before cesarean delivery.&#xD;
&#xD;
      We hypothesis that the preoperative administration of a single dose of pregabalin will&#xD;
      improve the quality of postoperative analgesia after cesarean delivery.&#xD;
&#xD;
      This placebo-controlled study aims to compare the effects of preoperative administrations of&#xD;
      single oral doses of pregabalin 150 mg and 300 mg on the postoperative pain scores,&#xD;
      cumulative patient controlled morphine consumptions, neonatal Apgar and neurologic and&#xD;
      adaptive capacity scores (NACS), and maternal and neonatal adverse effects in parturients&#xD;
      scheduled to elective Cesarean delivery under spinal anesthesia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      An independent investigator who will not be involved in the study will instruct the patients&#xD;
      preoperatively about the use of patient controlled analgesia and visual analogue scale to&#xD;
      assess the severity of postoperative pain (0 mm for no pain and100 mm for worst imaginable&#xD;
      pain).&#xD;
&#xD;
      Anaesthetic management will be standardized. Oral ranitidine 150 mg and metoclopramide 10 mg&#xD;
      will be given the night before and on the morning of surgery, with 0.3 mol/L sodium citrate&#xD;
      30 mL given 15 min before induction.&#xD;
&#xD;
      Ninety minutes before surgery, subjects will be allocated randomly into three groups by&#xD;
      drawing sequentially numbered sealed opaque envelopes containing a software-generated&#xD;
      randomization code to the placebo (n = 45), pregabalin 150 mg (n = 45) and the pregabalin 300&#xD;
      mg (n = 45) groups. The placebo and pregabalin capsules look identical and will be prepared&#xD;
      by a local pharmacy. An anaesthesiologist not otherwise involved in the study and who will be&#xD;
      blinded to treatment regimen will provide perioperative care. An independent investigator&#xD;
      will collect perioperative data. All staff in the operating room will be unaware of patient&#xD;
      allocation group.&#xD;
&#xD;
      Maternal monitoring will include electrocardiography, non-invasive blood pressure, and pulse&#xD;
      oximetry. Left uterine displacement will be maintained.&#xD;
&#xD;
      Spinal anesthesia will be performed in all cases in sitting position at L3-L4 or L4-L5 spaces&#xD;
      with hyperbaric bupivacaine 0.5% (12.5 mg) and fentanyl 20 µg. After the umbilical cord is&#xD;
      clamped, a 10 IU infusion of oxytocin in 500 mL of lactated Ringer's solution will be&#xD;
      infused.&#xD;
&#xD;
      A paediatrician blinded to study group allocation will record Apgar scores at 1 and 5 min,&#xD;
      umbilical cord blood gas analysis and NACS at 15 min, 2h, 24 and 48 h after delivery. NACS&#xD;
      gives a maximum of 40 with a score &gt;35 denoting vigor.The percentage of infants scoring &lt;35&#xD;
      will be determined.&#xD;
&#xD;
      Postoperative analgesic regime will be standardized in all patients with 12-hourly&#xD;
      intramuscular diclofenac 75 mg started immediately at the end of surgery and morphine via&#xD;
      patient-controlled analgesia (PCA): 1 mg bolus with an 8 minutes lockout. Postoperative&#xD;
      nausea or vomiting will be treated with intravenous metoclopramide 10 mg as required.&#xD;
&#xD;
      Statistical analysis:&#xD;
&#xD;
      Based on a previous study,7 the mean postoperative cumulative morphine consumption at 24 h&#xD;
      after caesarean delivery was 38 mg with a standard deviation of 14 mg. An a priori power&#xD;
      analysis indicated that 45 subjects were required in each group to detect a 25% reduction in&#xD;
      the cumulative morphine consumption at 24 h after caesarean delivery, that was assumed to&#xD;
      have a clinically significant effect, with a type-I error of 0.0167 (0.05/3 possible&#xD;
      comparisons) and a power of 90%. Additional patients (10%) were included for a final sample&#xD;
      size of 150 patients to account for patient dropout during the course of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">June 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</primary_completion_date>
  <phase>Phase 1</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>cumulative patient controlled morphine consumptions</measure>
    <time_frame>24 hours after delivery</time_frame>
    <description>cumulative patient controlled morphine consumptions 24 hours after delivery</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>postoperative pain scores</measure>
    <time_frame>1, 4, 6, 12, 24 and 48 hours after delivery</time_frame>
    <description>visual analogue scale to assess the severity of postoperative pain (0 mm for no pain and100 mm for worst imaginable pain) at rest and on movement</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>neonatal Apgar scores</measure>
    <time_frame>1 and 5 min aftr delivery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurologic and adaptive capacity scores</measure>
    <time_frame>at 15 min, 2h, 24 and 48 h after delivery</time_frame>
    <description>NACS gives a maximum of 40 with a score &gt;35 denoting vigor.The percentage of infants scoring &lt;35 will be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal sedation</measure>
    <time_frame>every two hours after delivery, for 48 hours after delivery</time_frame>
    <description>sedation (0, alert; 1, somnolent easy to arouse; 2, somnolent difficult to arouse or asleep; 3, not arousable)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal nausea and vomiting</measure>
    <time_frame>at 24 hours after delivery</time_frame>
    <description>nausea and vomiting (0: no nausea; 1: nausea no vomiting; 2: nausea and vomiting),</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Adverse effects</measure>
    <time_frame>24 hours after delivery</time_frame>
    <description>difficulties in lactation, pruritus, dry mouth, flatulence, hypoglycaemia, dizziness, somnolence, ataxia, vertigo, confusion, incoordination, tremor, dyspnoea, blurred or abnormal vision</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">135</enrollment>
  <condition>Uncomplicated Singleton Pregnancies</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>receive two identical placebo capsules</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pregabalin 150 mg group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>one capsule of pregabalin 150 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pregabalin 300 mg group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>two capsules of pregabalin 150 mg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Ninety minutes before surgery, the parturients receive two identical placebo capsules</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pregabalin 300 mg group</intervention_name>
    <description>Ninety minutes before surgery, the parturients receive two capsules of pregabalin 150 mg</description>
    <arm_group_label>Pregabalin 300 mg group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pregabalin 150 mg group</intervention_name>
    <description>Ninety minutes before surgery, the parturients receive one capsule of pregabalin 150 mg and one placebo capsule</description>
    <arm_group_label>Pregabalin 150 mg group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  spinal anesthesia&#xD;
&#xD;
          -  elective cesarean delivery&#xD;
&#xD;
          -  breech presentation&#xD;
&#xD;
          -  cephalopelvic disproportion&#xD;
&#xD;
          -  previous caesarean delivery&#xD;
&#xD;
          -  American Society of Anesthesiologists class I and II&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  communication barriers&#xD;
&#xD;
          -  cardiovascular diseases&#xD;
&#xD;
          -  renal diseases&#xD;
&#xD;
          -  hepatic diseases&#xD;
&#xD;
          -  endocrinal diseases&#xD;
&#xD;
          -  neuropsychiatric diseases&#xD;
&#xD;
          -  morbid obesity&#xD;
&#xD;
          -  diabetes mellitus&#xD;
&#xD;
          -  anaemia&#xD;
&#xD;
          -  bleeding disorders&#xD;
&#xD;
          -  prolonged P-R interval&#xD;
&#xD;
          -  hypersensitivity to pregabalin&#xD;
&#xD;
          -  receiving pregabalin&#xD;
&#xD;
          -  receiving anticonvulsants&#xD;
&#xD;
          -  receiving antidepressants&#xD;
&#xD;
          -  receiving antipsychotics&#xD;
&#xD;
          -  alcohol or drug abuse&#xD;
&#xD;
          -  Opiates abuse&#xD;
&#xD;
          -  benzodiazepines during the last week&#xD;
&#xD;
          -  pregnancy-induced hypertension&#xD;
&#xD;
          -  evidence of intrauterine growth restriction&#xD;
&#xD;
          -  fetal compromise&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>38 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Samah A El Kenany, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Anethesiology Dept, College of Medicine, Mansoura University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mohamed R El Tahan, M.D.</last_name>
    <role>Study Chair</role>
    <affiliation>Mansoura University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>College of Medicine, Mansoura University</name>
      <address>
        <city>Mansoura</city>
        <state>DK</state>
        <zip>050</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mansoura University Hospitals</name>
      <address>
        <city>Mansoura</city>
        <state>DK</state>
        <zip>050</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>July 2015</verification_date>
  <study_first_submitted>October 28, 2012</study_first_submitted>
  <study_first_submitted_qc>October 30, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 1, 2012</study_first_posted>
  <last_update_submitted>July 29, 2015</last_update_submitted>
  <last_update_submitted_qc>July 29, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 31, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mansoura University</investigator_affiliation>
    <investigator_full_name>Mohamed R El Tahan</investigator_full_name>
    <investigator_title>Associate Professor of Anesthesiology &amp; SICU</investigator_title>
  </responsible_party>
  <keyword>caesarean delivery</keyword>
  <keyword>spinal anesthesia</keyword>
  <keyword>pregabalin</keyword>
  <keyword>postoperative pain</keyword>
  <keyword>morphine</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pregabalin</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01719705
org study id: R/60
nct id: NCT01719705
lead sponsor: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: cumulative patient controlled morphine consumptions
time frame: 24 hours after delivery
description: cumulative patient controlled morphine consumptions 24 hours after delivery
measure: postoperative pain scores
time frame: 1, 4, 6, 12, 24 and 48 hours after delivery
description: visual analogue scale to assess the severity of postoperative pain (0 mm for no pain and100 mm for worst imaginable pain) at rest and on movement
measure: neonatal Apgar scores
time frame: 1 and 5 min aftr delivery
measure: Neurologic and adaptive capacity scores
time frame: at 15 min, 2h, 24 and 48 h after delivery
description: NACS gives a maximum of 40 with a score >35 denoting vigor.The percentage of infants scoring <35 will be determined.
measure: Maternal sedation
time frame: every two hours after delivery, for 48 hours after delivery
description: sedation (0, alert; 1, somnolent easy to arouse; 2, somnolent difficult to arouse or asleep; 3, not arousable)
measure: Maternal nausea and vomiting
time frame: at 24 hours after delivery
description: nausea and vomiting (0: no nausea; 1: nausea no vomiting; 2: nausea and vomiting),
measure: Adverse effects
time frame: 24 hours after delivery
description: difficulties in lactation, pruritus, dry mouth, flatulence, hypoglycaemia, dizziness, somnolence, ataxia, vertigo, confusion, incoordination, tremor, dyspnoea, blurred or abnormal vision
arm group label: Placebo
arm group type: Placebo Comparator
description: receive two identical placebo capsules
arm group label: Pregabalin 150 mg group
arm group type: Active Comparator
description: one capsule of pregabalin 150 mg
arm group label: Pregabalin 300 mg group
arm group type: Active Comparator
description: two capsules of pregabalin 150 mg
intervention type: Drug
intervention name: Placebo
description: Ninety minutes before surgery, the parturients receive two identical placebo capsules
arm group label: Placebo
intervention type: Drug
intervention name: Pregabalin 300 mg group
description: Ninety minutes before surgery, the parturients receive two capsules of pregabalin 150 mg
arm group label: Pregabalin 300 mg group
intervention type: Drug
intervention name: Pregabalin 150 mg group
description: Ninety minutes before surgery, the parturients receive one capsule of pregabalin 150 mg and one placebo capsule
arm group label: Pregabalin 150 mg group
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 38 Years
healthy volunteers: No
last name: Samah A El Kenany, MD
role: Principal Investigator
affiliation: Anethesiology Dept, College of Medicine, Mansoura University
last name: Mohamed R El Tahan, M.D.
role: Study Chair
affiliation: Mansoura University
facility: 
facility: 
country: Egypt
responsible party type: Principal Investigator
investigator affiliation: Mansoura University
investigator full name: Mohamed R El Tahan
investigator title: Associate Professor of Anesthesiology & SICU
mesh term: Pregabalin