Donald C. Sawyer

Dose-response of intravenous butorphanol to increase visceral nociceptive threshold in dogs.

Abstract This study was designed to determine the effective analgesic dose of butorphanol administered intravenously to obtund visceral nociception, as well as to determine duration of this effect. Additionally, cardiovascular changes and sedative effects were defined. Eight healthy dogs were each given five doses of butorphanol (0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg) plus a sterile water placebo intravenously in a randomized blinded format. Antinociception was assessed using an inflatable Silastic balloon inserted into the colon. Blood pressures and pulse rates were measured with a noninvasive monitor. The greatest efficacy and longest duration of antinociception were produced by 0.4 mg/kg of butorphanol, with a duration of 38 ± 9 min. Arterial blood pressure and pulse rate did not vary at antinociceptive doses. Mild sedation was observed at all doses, which generally lasted longer than the antinociceptive effects. These data suggest that butorphanol can be given alone intravenously to provide visceral antinociception lasting 30–45 min without significant side effects.

Pain control in small-animal patients

Abstract An understanding of receptors and mechanisms involved in pain and suffering is essential in selecting proper methods of treatment. Detection of pain, knowing types of pain, and understanding reasons why presurgical administration of analgesic drugs (pre-emptive analgesia) is essential to relief of pain and distress. Animals feel pain to the same extent as humans and they have a wide variation in tolerance to pain stimuli as well. Animals may express pain or discomfort in two ways. Excessive activity or relative lethargy are both overt reflections of a painful state. Expressions of pain may be exhibited by moaning, groaning, crying, whimpering, looking at the painful area, licking or biting or simply a decrease in activity. Pain may be categorized as minor, moderate, or severe. Pain may be superficial, somatic (muscle and skin), or visceral or combinations. Moderate and severe pain always require treatment and visceral pain is usually more intense than somatic pain. Opiate receptors are the normal sites of action of several endogenous substances. There are three major types of opioid receptors designated as mu, kappa and sigma. Opioids and opioid antagonists have different affinities for different receptors. Agonist analgesics such as morphine, meperidine, fentanyl, and oxymorphone exert their effects by attaching to the mu receptors. A relatively pure antagonist, naloxone, will displace another compound on these receptors but exert little or no effect. The mixed drugs, agonist–antagonists or partial agonists, may be used as analgesics if no opioid compound has been used, or as antagonists to reverse the effects of an opioid on the mu receptor while at the same time not competing with the effects on the k receptor that is, preserving the analgesia provided by that receptor. Some of the mixed drugs are better agonists wile others are better antagonists. Animals recovering from surgery are often surprised and confused because they hurt and therefore sedation along with analgesia preanesthesia is often desirable and necessary for proper treatment of postsurgical pain. Therefore, giving an analgesic before surgery will be advantageous. The second choice is to give analgesics after surgery, but before recovery from anesthesia.

Kappa antinociceptive activity of spiradoline in the cold-water tail-flick assay in rats.

Spiradoline (U62066E) a racemic mixture of the two enantiomers U63639(+) and U63640(-), appears to have kappa opioid receptor activity, but the contribution of each enantiomer toward this activity is still in question. To determine the activity of each enantiomer in comparison to the racemic mixture, the three forms were tested in the cold-water tail-flick (CWTF) assay in male Sprague-Dawley rats. Antinociception by spiradoline was completely antagonized by naloxone 0.50 mg/kg, a dose five times that required to antagonize antinociception by fentanyl in this same assay. In a second series of tests, fentanyl-induced antinociception was markedly reduced, while spiradoline-induced antinociception was essentially unchanged. in methadone-tolerant animals. Of the enantiomers, only U63640 produced antinociception, whereas U63639 failed to affect the nociceptive response. Additionally, spiradoline failed to produce antinociception in animals pretreated with norbinaltorphimine (kappa receptor specific), but antinociception was not affected in animals pretreated with beta-funaltrexamine (mu receptor specific). These results show that spiradoline is a full antinociceptive agonist in the CWTF assay and that the effects of the drug are mediated through kappa opioid receptors.

Oxymorphone-induced analgesia and colonic motility measured in colorectal distension

Changes in colonic motility in rats following intravenous (IV) oxymorphone (0.1 mg/kg), atropine (0.1 mg/kg), or saline were monitored to determine whether opioid-induced changes in colonic motility affect antinociceptive measurements when using colorectal distension (CRD) as a nociceptive assay. Polygraph recordings of colonic pressures, contraction frequencies, and the pressure-volume relationship of the stimulus showed that oxymorphone produced a transient increase in contraction frequencies when compared to atropine- and saline-treated rats. The transient increase in contraction frequency caused by oxymorphone declined to baseline levels at 30 min after administration, the time at which the nociceptive threshold for CRD was tested. Neither oxymorphone nor atropine changed baseline pressures or the pressure-volume curve for the balloon stimulus. Antinociceptive results from CRD at 30 min posttreatment showed that only oxymorphone produced significant antinociception. We conclude that oxymorphone does not produce changes in colonic motility that complicate antinociceptive measurements in CRD and that CRD is an effective means of testing opioid-induced visceral antinociception.