An Isobolographic Study of Epidural Clonidine and Fentanyl After Cesarean Section

Abstract

Although the epidural administration of clonidine and fentanyl provides pain relief after surgery, the interaction between the two drugs has not been examined formally. This study used an isobolographic method to determine whether epidurally administered fentanyl and clonidine interact in an additive or synergistic manner. Ninety women with moderate to severe pain after elective cesarean section under epidural anesthesia were studied. Using a randomized, double-blind protocol, we assigned each patient to receive a single epidural injection of one of three doses of fentanyl, clonidine, or a fixed ratio combination. Pain relief, blood pressure (BP), heart rate (HR), and sedation were measured 15 min after injection. Each drug alone and in combination produced analgesia, as measured by pain relief scores, and reduced need for intravenous morphine. Although the effective dose producing analgesia in 50% of patients (ED50) for the mixture was only 52% of that predicted by an additive interaction, this did not differ significantly from additivity, likely due to large variability. Clonidine, alone or in combination with fentanyl, produced a minor reduction in BP, but did not affect HR or cause more sedation than fentanyl. Unlike studies in rodents, this clinical study did not demonstrate synergy between fentanyl and clonidine. This could reflect a true species difference or differences in methodologies used. Nonetheless, a reduced dose of fentanyl and clonidine can be combined for excellent analgesia.

Clonidine and Dexmedetomidine Produce Antinociceptive Synergy in Mouse Spinal Cord

“…There is an expectation that the dose reduction enabled by a synergistic interaction might reduce side effects. The utility of clonidine as a monotherapy 36–41 or combined with spinal opioids 42,43 and/or local anesthetics has been studied for decades 44,45 . Although the primary clinical use of dexmedetomidine has been as a sedative and anesthetic agent 46,47 , the combination of intrathecal dexmedetomidine with bupivacaine has recently been shown to be effective for analgesic control, comparing favorably with the combination of intrathecal clonidine and bupivacaine 48 .…”

The Delta-Opioid Receptor Is Sufficient, but Not Necessary, for Spinal Opioid-Adrenergic Analgesic Synergy

“…Compared with the analgesic effects of drugs acting independently, analgesic synergy arising from drug combinations is advantageous because it produces adequate analgesia at lower doses, which can potentially reduce side effects and tolerance (Walker et al, 2002). Pain management using opioid-a 2 AR agonist combinations reduces side effects associated with both a 2 AR and opioid treatments (Eisenach et al, 1994), and such combinations may also be effective in treating chronic pain conditions with reduced opioid sensitivity (Eisenach et al, 1995). In rodents, the opioid agonist morphine and the a 2 AR agonist clonidine synergize when coadministered at the spinal level, suggesting that beneficial opioid-adrenergic drug interactions occur at the spinal cord (Alguacil and Morales, 2004).…”

Postoperative pain management in obstetric anesthesia–new challenges and solutions

“…51,52 An epidural bolus administration of a combination of fentanyl and clonidine will reduce the analgesic dose of each component by approximately 60%. 53 Clonidine will also enhance and prolong the effect of local anesthesia intrathecally. 54,55 There is also evidence of additional analgesia when clonidine is added to local anesthesia in peripheral nerve blocks.…”