Intrathecal Midazolam, Fentanyl and Nalbuphine as Adjuvants to Bupivacaine in Spinal Anesthesia for Cesarean Section

Intrathecal Midazolam is a Comparable Alternative to Fentanyl and Nalbuphine as Adjuvant to Bupivacaine in Spinal Anesthesia for Elective Cesarean Section; a Randomized Controlled Double-blind Trial

The main limitations of spinal anesthesia are its short duration of action and do not provide prolonged postoperative analgesia when it is performed only with local anesthetics. Adding adjuvants drugs to intrathecal local anesthetics improves quality and duration of spinal blockade, and prolongs postoperative analgesia. It is also possible to reduce dose of local anesthetics, as well as total amount of systemic postoperative analgesics.

Study Overview

• Status: Completed
• Conditions: Pain, Acute
• Intervention / Treatment: Drug: Bupivacaine; Drug: Fentanyl; Drug: Nalbuphine; Drug: Midazolam

Detailed Description

Several spinal adjuvants have been used to improve spinal anesthesia quality and to prolong postsurgical analgesia; Intrathecal opioids are the most commonly utilized. Intrathecal opioids cause analgesia by binding to opioid receptors in the dorsal horn of the spinal cord. They prolong the duration of analgesia and allow early ambulation of patients.

Fentanyl, a short-acting lipophilic opioid, is known to augment the quality of subarachnoid block in many studies. However, worrisome adverse effects such as pruritus, urinary retention, post-operative vomiting, and respiratory depression limit the use of opioids.

Nalbuphine is a synthetic opioid with mixed agonist antagonist effect. It binds to both mu- and kappa receptors; binding of nalbuphine to mu receptors competitively displaces other mu-agonists from these receptors without any agonist activity, therefore decreasing the side effects on mu agonist (nausea, vomiting, respiratory depression, urinary retention, pruritis, and prolonged sedation). While when binding to kappa receptors, nalbuphine has agonist effect (analgesic effect) through the kappa receptors distributed in the brain and spinal cord. There have been no documented studies of nalbuphine neurotoxicity.

Midazolam is a short acting benzodiazepine with anxiolytic, sedative, anticonvulsant and muscle relaxant effects, influencing GABA receptor and influence on neurons by entering chloride into them. It is water soluble in its acid formulation but is highly lipid soluble in vivo. It has been reported to have a spinally mediated anti-nociceptive effect. Previous studies have shown that intrathecal administration of midazolam added to bupivacaine improves the duration and quality of spinal anesthesia.

This study is carried out to evaluate and compare the effects of intrathecal midazolam (2 mg), fentanyl (25 micrograms) and nalbuphine (800 micrograms) as additives to intrathecal hyperbaric bupivacaine (0.5 %) with regards to: onset and duration of sensory block, onset and duration of motor block, duration of effective analgesia postoperative, side effects associated with the drug.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Egypt
  • Qalubia
    • Banhā, Qalubia, Egypt, 13511
      • Samar Rafik Amin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. ASA physical status I and ASA II
2. Age from 18-40 years
3. Scheduled to undergo elective cesarean section under spinal anesthesia.

Exclusion Criteria:

1. ASA physical status III or IV patients.
2. Patients refuse spinal anesthesia.
3. Patients physically dependent on narcotics or benzodiazepine.
4. Patients with history of drug allergy to one of used adjuvants.
5. Patients with gross spinal abnormality, localized skin sepsis, hemorrhagic diathesis or neurological involvement/ diseases and any contraindication for spine.
6. Patients who are unable to communicate.
7. Morbid obesity.
8. Failure of spinal blockade.
9. Complicated pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Bupivacaine; patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine (12.5 mg) plus 0.5 ml sterile water.	Drug: Bupivacaine; patients will be put in the sitting position and lean forward. After sterilization, Dural puncture will be performed at L4-L5 interspace or L3-L4 with a 25 gauge Quincke spinal needle. patients will receive the local anesthetic dose of 0.5% heavy bupivacaine (12.5 mg) and 0.5 ml of sterile water will be added.
EXPERIMENTAL: Fentanyl; patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine (12.5 mg) plus 0.5 ml fentanyl (25µg).	Drug: Fentanyl; patients will be put in the sitting position and lean forward. After sterilization, Dural puncture will be performed at L4-L5 interspace or L3-L4 with a 25 gauge Quincke spinal needle. patients will receive the local anesthetic dose of 0.5% heavy bupivacaine (12.5 mg) and 0.5 ml of fentanyl (25µg) will be added.
EXPERIMENTAL: Nalbuphine; patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine (12.5 mg) plus 0.8 mg nalbuphine hydrochloride in 0.5 ml sterile water.	Drug: Nalbuphine; patients will be put in the sitting position and lean forward. After sterilization, Dural puncture will be performed at L4-L5 interspace or L3-L4 with a 25 gauge Quincke spinal needle. patients will receive the local anesthetic dose of 0.5% heavy bupivacaine (12.5 mg) and 0.8 mg nalbuphine hydrochloride in 0.5 ml sterile water will be added.
EXPERIMENTAL: Midazolam; patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine (12.5 mg) plus 2mg of midazolam in 0.5 ml sterile water.	Drug: Midazolam; patients will be put in the sitting position and lean forward. After sterilization, Dural puncture will be performed at L4-L5 interspace or L3-L4 with a 25 gauge Quincke spinal needle. patients will receive the local anesthetic dose of 0.5% heavy bupivacaine (12.5 mg) and 0.4 ml of midazolam (2mg) + 0.1 ml of sterile water will be added.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of effective analgesia	it is the time interval from the subarachnoid block to the first analgesic intervention (VAS >3)	24 hours postoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The onset of sensory block:	it is the time from end of intrathecal injection to absence of pain at T5 dermatome.	2 minutes for ten minutes, every 5 minutes for the next 20 minutes after intrathecal injection
Duration of complete sensory block:	it is the time interval from the subarachnoid block to the first sensation of pain (VAS >0).	12 hours postoperative
Onset of complete motor blockade	it is the time per minutes from intrathecal injection until Bromage scale to be 3.	every 2 minutes for 10 minutes after intrathecal injection
Duration of motor block:	it is the time per minutes from intrathecal injection until Bromage score 0.	6 hours postoperative
Total dose of analgesic consumption	if VAS pain score >3, intravenous 30 mg keterolac will be administered and can be repeated after 6 h if needed. If the mother was still complaining of pain or the VAS is still greater than 3 after 20 min from ketorolac injection, she will be given intravenous pethidine in a dose of 0.5 mg/kg.	24 hours postoperative
Maternal adverse effects	All mothers will be monitored for the associated adverse effects such as postoperative nausea and vomiting (PONV), sedation, pruritus, hypotension, bradycardia, shivering, and respiratory depression.	24 hours postoperative

Collaborators and Investigators

• Sponsor: Benha University

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 20, 2021
• Primary Completion (ACTUAL): January 14, 2022
• Study Completion (ACTUAL): February 24, 2022

Study Registration Dates

• First Submitted: June 14, 2021
• First Submitted That Met QC Criteria: June 14, 2021
• First Posted (ACTUAL): June 18, 2021

Study Record Updates

• Last Update Posted (ACTUAL): April 5, 2022
• Last Update Submitted That Met QC Criteria: March 24, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anesthetics, Local; Fentanyl; Midazolam; Bupivacaine; Nalbuphine
• Other Study ID Numbers: RC6-5-2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No