Morphine is the prototype of opiate analgesics. Systemic effects of morphine are described above. One of the metabolites is morphine-6-glucuronide (M6G), which is active. The potency of other drugs is usually measured in comparison to morphine (i.e. ‘morphine equivalents’). Dosages for animals are listed in the range of 0.1–1.0 mg/kg every 4–6 hours, IM, SC, IV.
Methadone is a synthetic opioid currently used for analgesia and treatment of heroin addiction. Methadone interacts primarily with mu-opiate receptors, but also binds with variable affinity to N-methyl-D-aspartate (NMDA) and alpha-2 adrenergic receptors. The NMDA receptor effects may enhance the analgesic properties and decrease tolerance normally associated with repeated administration of opioids. The elimination rate in dogs is much faster than in people, with values in dogs ranging 1.75–4 hours following IV and SC administration.
Pethidine has one-third to one-sixth the potency of morphine, and is shorter acting (at 3–5 mg/kg its duration of action is less than 1 hour). With repeated use it may have fewer effects on the gastrointestinal tract than other opioids. The usual dose is 5–10 mg/kg for cats and 3–5 mg/kg for dogs, IM (SC in cats).
Fentanyl is a synthetic opiate with potent mu-opioid effects, without action on other receptors. Because the structure is distinct from opiate-derived drugs, some of the adverse effects attributed to morphine are not observed with fentanyl. Opioids are drugs that are derived purely from opium, whereas opiates have a similar structure but are not made from opium. Although it is 80–100 times more potent than morphine, fentanyl can be used safely when administered with care. The usually dose is 2–10 µg/kg IM, SC, IV or as an intravenous infusion. It is often used as a transdermal preparation.
Opioid Agonists/Antagonists and Partial Agonists
Opiate agonists/antagonists have effects that may differ qualitatively from those of pure opioid agonists such as morphine. Such differences may include less respiratory depression, fewer psychotic effects, fewer haemodynamic effects and less physical dependency. A ceiling on the analgesic effects (i.e. a limit to the analgesic efficacy of these drugs) distinguishes them from pure opioid agonists.
Butorphanol is a weak analgesic with a short duration. Butorphanol has mixed effects because it is a mu-antagonist, or a partial mu-agonist, but a kappa-agonist. It has opiate agonistic activity that is considered five times that of morphine. On the other hand, its antagonistic effects are weak and only one-fortieth of the antagonist effects of naloxone (some references suggest that it has no activity on the mu-receptor). Therefore, its agonist actions predominate. Butorphanol has been used as an antitussive and analgesic. It may have fewer gastrointestinal effects than pure opioid agonists but this has not been assessed in veterinary patients.
Butorphanol is used in dogs, horses, cats and some exotic animals. In dogs it has been used frequently for pre- and postoperative analgesia by injection at 0.2–0.8 mg/kg. Efficacy is limited to mild pain, however butorphanol may be useful as a part of a sedative combination for procedures such as radiography.
Buprenorphine is a partial mu-receptor agonist, with little effects on the kappa-receptor. It is 25–50 times more potent than morphine. It is available as a 300 µg/ml injection. In animals it is reported that the duration of analgesia is longer (e.g. 6–8 hours) than the duration of action of morphine, perhaps because it dissociates more slowly from receptors. Because of the higher affinity for the mu-receptor, higher doses of naloxone may be needed to reverse the effects of buprenorphine.
Although not a true opioid, tramadol will be discussed in this section. The exact mechanism of action for tramadol is uncertain; it is a complex drug whose metabolism and action in dogs and cats is still not fully understood. However, various possibilities exist: it has some mu-opioid receptor action, and may also inhibit the re-uptake of norepinephrine (NE) and serotonin (5HT). One of the isomers has greater effect on serotonin re-uptake and greater affinity for mu opiate receptors. The other isomer is more potent for inhibition of norepinephrine re-uptake and less active for inhibiting serotonin re-uptake. Taken together, the effects of tramadol may be explained through inhibition of serotonin re-uptake (similar to fluoxetine and other antidepressant drugs), action on alpha-2 receptors (similar to medetomidine and xylazine), and also action on mu-opioid receptors (similar to morphine). The metabolite (O-desmethyltramadol, also called M1) may have greater opioid effects than the parent drug (e.g. 200 times greater affinity for opioid receptor binding).
In emergency or critical patients, ketamine has minimal effects on cardiovascular function in all but severe shock cases. This is due to its ability to evoke sympathoadrenal responses which preserve cardiac output and blood pressure. In heart failure or unstable shock patients, ketamine has potent cardiovascular depressant effects. Ketamine also produces dose-dependent respiratory depression, characterised by decreased tidal volume, increased respiratory rate and apneustic breathing. This may be more frequent in those patients with cardiopulmonary instability. The combination of ketamine with diazepam or midazolam is useful for sedation or anaesthetic induction in the stable patient. Opioids may be added to this mixture to enhance analgesia. The author currently uses ketamine intravenous infusions for all surgical procedures.
Local anaesthesia is a valuable adjunct which may reduce parenteral drug requirement for sedation or chemical restraint. Commonly, local anaesthetics are used in infiltrative, epidural or regional intravenous applications. The most commonly used drugs in veterinary medicine are lidocaine (2%) and bupivacaine (0.5%). Both drugs have an excellent safety record and an acceptable duration of effect when used correctly. Bupivacaine has both a longer onset (15 minutes vs. 5 minutes) and duration (4 hours vs. 2 hours) of action when compared with lidocaine. For short-term procedures, lidocaine is acceptable and cost-effective. For continued pain management, bupivacaine is preferred.