Abstract
Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Index of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 +/- 4.8 %, 92.3% +/- 22.8 % of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.
Highlights
Opioid analgesics are among the most effective agents currently available for treating postoperative and chronic pain
We studied whether systemically administered donepezil, an acetylcholinesterase inhibitor, is effective in counteracting buprenorphineinduced respiratory depression in anesthetized rabbits
We found that donepezil alleviates buprenorphine-induced respiratory depression, without any effects on end-tidal CO2 (EtCO2) or systolic blood pressure
Summary
Opioid analgesics are among the most effective agents currently available for treating postoperative and chronic pain Apart from their analgesic actions, all opiates induce various side effects (Bowdle, 1998; Gan, 2006), of which respiratory depression is the most serious and potentially life-threatening (Bailey et al, 2000). Fentanyl and morphine, both μopioid agonists, are widely and frequently used for acute and chronic pain treatment (Trescot et al, 2008). In the present study, using anesthetized rabbits as a model, we have investigated whether donepezil can counteract buprenorphine-induced respiratory depression
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