Abstract
Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.
Highlights
Morphine is the mainstay of cancer pain and postoperative analgesic management, but its side effects can limit dosage and reduce quality of life (Bowdle 1998; Chaney 1995; McNicol et al, 2003)
The present study revealed for the first time that systemically administered donepezil, an acetylcholinesterase inhibitor, partially restores morphine-induced respiratory depression and morphineinduced deterioration of phrenic nerve apnea threshold in anesthetized rabbit
This study suggests that donepezil at 100 μg/kg inhibits about 30% of the acetylcholinesterase activity and donepezil at 250 μg/kg inhibits about 55% of the activity in living monkeys (Shiraishi et al, 2005)
Summary
Morphine is the mainstay of cancer pain and postoperative analgesic management, but its side effects can limit dosage and reduce quality of life (Bowdle 1998; Chaney 1995; McNicol et al, 2003). Numerous articles have proposed various candidates as antagonistic drugs for opiate-induced respiratory depression (Weinstock et al, 1980; Weinstock et al, 1981; Weinstock et al, 1982; Snir-Mor et al 1983; Willette et al, 1987; Elmalem et al, 1991; Berkenbosch et al, 1994; Ballanyi et al, 1997; Owen et al, 2000; Manzke et al, 2003; Lalley, 2004; 2005). None of these have been applied to clinical practice far because most
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