New and old approaches to treating acute peri-operative pain (Proceedings)
Because the entire CNS is heavily invested with opioid receptors that mediate central and spinal analgesia, the most effective class of analgesics is the pure agonist opioids, i.e. drugs such as morphine, hydromorphone, oxymorphone, etc. Exogenous administration of these drugs results in binding to endogenous receptors, thus mimicing the analgesic effects of the endogenous opiate system. Analgesia occurs from receptor activation in both the dorsal horn of the spinal cord and in the brain. A spectrum of opioid receptors have been identified within the CNS. The clinically important receptors are the mu, kappa, and delta opioid receptors. The mu receptor mediates central and spinal analgesia, as well as CNS sedation, bradycardia, respiratory depression, increased locomotor activity and euphoria or excitement. The kappa receptor mediates spinal analgesia and mild CNS sedation and respiratory depression. The delta receptor mediates excitement, mania, and dysphoric behavior.
The prototype opioid to which all others are compared with respect to receptor affinity is morphine. In addition to analgesia, all pure agonist opioids, such as morphine, can cause CNS sedation, respiratory depression, bradycardia, nausea and vomiting (although this is less common when the drugs are given to treat existing pain), GI ileus, and urinary retention. The extent of these side effects varies with species and with the individual. In certain species, such as cats and horses, excitement and increased locomotor activity are common, although this occurs less frequently or less dramatically when the drugs are given to treat preexisting pain. With all the opioid agonists, the degree of analgesia achieved, as well as the attendant side effects, are dose-related. Ideally, lower doses should be administered "pre-emptively" to provide intra- and post-operative analgesia and minimize side-effects. An important concept when using opioids in the perioperative period is that agonist opioids will decrease anesthetic requirement 40-50%. This means that a healthy dog or cat that has received an agonist opioid for premedication may only need the vaporizer set at ~ 1.0 – 1.5% (isoflurane) or 1.7 – 2.0% (sevoflurane).Morphine
Morphine can cause histamine release, particularly when higher doses are given intravenously as a bolus. Clinical signs of histamine release are vasodilation, flushing, facial swelling, hypotension, and urticaria. Very slow IV administration, if necessary, will minimize histamine release, but preferably this drug should be given intramuscularly or subcutaneously. It has been shown in humans that metabolites of morphine, specifically morphine-3-glucuronide and morphine-6-glucuronide, are responsible for much of the analgesic effect of this drug. Cats are unable to synthesize glucuronide metabolites. Clinical studies have verified that morphine is not a very useful analgesic in cats, likely due to the lack of glucuronide metabolite production. In dogs, morphine is a useful premedication (0.5 – 1.0 mg/kg), both by virture of its sedative effects and because it provides effective preemptive analgesia prior to surgery. The duration of action is approximately 6 hours, therefore a premedication dose of morphine may last long enough to cover analgesic needs into the post-operative period. For post-operative analgesia, morphine can be given IM 15 minutes before anticipated recovery. The animal thus recovers in a calm and pain-free fashion. There is some art to the administration of morphine prior to extubation. If a full dose is given IM while the animal is still anesthetized, then recovery will be slow. In my experience, if ¼ to ½ the normal dose of morphine is given (i.e. 0.25 –0.5 mg/kg) to a warm (i.e. rectal temperature must be ≥ 99° F) patient then recovery is not unduly prolonged and the animal is calm and comfortable at extubation.