17 Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis University of Georgia, Athens, GA, USA Opioids and opioid antagonists are a heterogenic group of pharmaceuticals, included in this textbook due to the clinical use of some drugs for particular mental conditions. Narcotic antagonists can be effective in the treatment of stereotypies and compulsive disorders in nonhuman animals. One possibility is that stress, such as an overstimulating or understimulating environment, causes an animal to initiate stereotypic behavior. Carrying out the stereotypic behavior then causes the release of endogenous endorphins, which reinforce the behavior. Narcotic antagonists would block this release of the endogenous endorphins, thereby blocking the reinforcement. This would result in the animal discontinuing the behavior. However, studies confirming this theory are lacking in veterinary medicine. An alternative hypothesis is that opioids are directly involved in the initiation of the stereotypic behavior. The narcotic antagonists then block the opioids, thereby preventing their inducing stereotypic behavior. This hypothesis is supported by the rapid clinical response that occurs when opioid antagonists are administered. Opioids do enhance amphetamine‐induced stereotypic behavior, and naloxone blocks this enhancement. While both morphine (0.1–0.5 mg kg−1) and oxymorphone (0.125–0.50 mg kg−1) have been reported as alleviating the crying of separation distress in puppies, they also decreased motor activity, indicating sedation (Panksepp et al. 1978). Timid beagle/telomian hybrids have also been treated with morphine at 0.25 mg kg−1. While they did show some improvement with the combination of morphine and behavior modification, they also became less socially solicitous than placebo‐treated dogs, possibly as a consequence of the sedative effects (Panksepp et al. 1983). Morphine has also been shown to decrease a variety of aggression types in laboratory animals (Gianutsos and Lal 1978). Nevertheless, these medications are not recommended for these or other problems, which are best treated with safer medications that can be used in the long term in association with behavior therapy. Indications of opiate antagonists include stereotypic behavior, obsessive‐compulsive disorder, including lick granulomas and tail‐chasing in dogs, and self‐mutilation and cribbing in horses. Opiate antagonists have been found to be beneficial in the treatment of some forms of self‐injurious behavior in humans as well as nonhuman animals (Richardson and Zaleski 1983; Herman et al. 1987; Smith and Pittelkow 1989; Sandman et al. 1990). Gastrointestinal effects, especially diarrhea, may occur with the use of opioid antagonists. While opioid antagonists have shown substantial promise in the treatment of stereotypic behaviors in multiple species, their use is not yet widespread for a number of reasons. Some can only be given parenterally and all are expensive. Also, opioid antagonists may be more effective in the early phases of obsessive‐compulsive disorder, though this phenomenon has not been studied across all species and all manifestations of compulsive behaviors. Nevertheless, dramatic results in some cases make them a class of drugs that should be considered in the treatment of any stereotypic behavior, especially if the patient’s safety is at stake. Diprenorphine, which is not reviewed below, has been used in the treatment of cribbing in horses (Dodman et al. 1987). Cribbing is a behavior that occurs in horses kept in confinement. During cribbing, the horse grabs a horizontal object with its teeth, bites down hard, and flexes its neck. It may or may not swallow air as it does this. Diprenorphine was twice administered to a horse with a problem with cribbing behavior, once at 0.02 mg kg−1 and the second time at 0.03 mg kg−1 intramuscularly (IM). In both cases, after a latency period of 30 minutes, injection of diprenorphine resulted in almost total discontinuation of cribbing for periods of 3–5.5 hours. Animal doses are given in Table 17.1. Table 17.1 Doses of various opiate antagonists inhibitors for dogs, cats, horses, and parrots. Source: Brown et al. (1987a); Turner (1993); Overall (1997); Nurnberg et al. (1997). All doses for naltrexone are oral. Nalmefene reverses and prevents the effects of opioids, including respiratory depression, sedation, and hypotension. It has a longer duration of action than naloxone. It is equally bioavailable if given by intravenous, intramuscular, or subcutaneous routes. Peak levels are reached within minutes if it is given intravenously. However, there is a delay to maximum plasma concentration if it is given subcutaneously (about 1.5 hours in humans) or intramuscularly (about 2.3 hours in humans). If nalmefene is given parenterally, it blocks 80% of brain opioid receptors within five minutes (Baker Norton Pharmaceuticals, Inc. 1997). Nalmefene is primarily metabolized by glucuronide conjugation, which occurs in the liver, after which the metabolites are excreted in the urine. Less than 5% of the urinary excretion is the parent compound. Fecal excretion accounts for only 17% of a nalmefene dose (Baker Norton Pharmaceuticals 1997). The pharmacokinetics of nalmefene have been studied in three mixed‐breed dogs given 0.5–0.9 mg kg−1 IV. Elimination half‐life was 120–218 minutes (Dodman et al. 1988b). In the horse, nalmefene has a half‐life of three to five hours following intramuscular injection of 1 mg kg−1. With intravenous injection the half‐life is only 50 minutes. After oral administration of 2 mg kg−1, no intact nalmefene is detectable in the plasma. High levels of nalmefene glucuronide appear rapidly after oral administration and are detectable for up to 16 hours. In this species, therefore, nalmefene must be administered parenterally, as it has poor oral bioavailability with extensive first‐pass metabolism (Dixon et al. 1992). Nalmefene is used in humans for reversal of the effects of opioid medications. It has also been used to treat pathological gambling (Grant et al. 2006). Nalmefene is contraindicated in patients with a known history of intolerance to the medication. In humans with hepatic or renal disease, there is a decrease in plasma clearance (Baker Norton Pharmaceuticals 1997). Side effects have not been reported in non‐addicted animals given clinically relevant doses. Administration of up to 1200 mg m−2 day−1 to rats has not resulted in any decrease in fertility, reproductive performance or offspring survival. Giving up to 2400 mg m−2 day−1 orally to rats or up to 96 mg m−2 day−1 intravenously to rabbits did not result in any harm to the fetuses. Administration of up to 205 mg m−2 day−1 in rat pups did not cause any adverse events (Baker Norton Pharmaceuticals 1997). Nalmefene has been administered to humans after administration of benzodiazepines with no adverse interactions (Baker Norton Pharmaceuticals 1997). Dodman et al. (1988b) studied the use of various narcotic antagonists for the treatment of stereotypic self‐licking, self‐chewing, and scratching in nine dogs. Nalmefene was injected subcutaneously (SC) at a dose of 1–4 mg kg−1 after a baseline rate of self‐licking, self‐chewing, and scratching was measured. During the 90‐minute period following the injection, the amount of time spent in these behaviors was significantly reduced in six of the nine dogs. The problem behaviors were completely suppressed for 75 minutes in two dogs. No side effects were reported. Dodman et al. (1987) treated five crib‐biting horses with nalmefene across 20 trials by a variety of routes, specifically intramuscularly (IM), subcutaneously, intravenously via continuous infusion and via a sustained release implant. Doses for the IM and SC injections ranged from 0.08 to 0.1 mg kg−1. A single injection resulted in discontinuation of cribbing for 2.75–13 hours. The sustained release preparations resulted in a substantial decrease in cribbing for a minimum of two days. Dodman et al. (1988a) reported a case study of a 500‐kg Arabian stallion with a four‐year history of self‐mutilation, specifically biting the flank and pectoral region. The stallion was treated, on successive days, with doses of 0.2 mg kg−1, 0.4 mg kg−1, 0.8 mg kg−1, and 1.6 mg kg−1 given IM as a single dose. There was a dose‐specific decrease in acts of self‐mutilation or attempted self‐mutilation during the four hours following the injection, with a 94% decrease at the highest dose. While this result seems promising, the authors report that, in preliminary pharmacokinetic studies, horses excrete nalmefene rapidly and the bioavailability of nalmefene given to horses is low. Naloxone is a pure opioid antagonist. As such, it prevents or reverses the effects of opioids, such as respiratory depression, hypotension, and sedation. Product literature for humans states that in the absence of opioids or opioid agonists, it exhibits essentially no pharmacological activity. However, it is precisely because of its efficacy in some animals exhibiting stereotypic behavior that it is used in clinical behavioral medicine (as opposed to veterinary behavior). It does not produce dependence or tolerance. The mechanism of action is not fully understood, but it appears to act by competing with opioids for receptor sites (Endo Pharmaceuticals 2001). Naloxone undergoes glucuronide conjugation in the liver and is excreted in the urine. In human adults, the serum half‐life is 30–81 minutes (Endo Pharmaceuticals 2001). In humans, naloxone is used for reversal of opioid depression, including respiratory depression. It is also used as an adjunctive agent in the management of septic shock, in which situation it facilitates the raising of blood pressure (Endo Pharmaceuticals 2001). Naloxone is contraindicated in patients with a known sensitivity to it. It should be used with caution in patients with preexisting cardiac disease (Endo Pharmaceuticals 2001). Some decrease in activity has been observed in cats (see below). Studies of reproduction in mice and rats given high doses of naloxone have not resulted in any impairment of reproduction or teratogenicity (Endo Pharmaceuticals 2001).
Opioids and Opioid Antagonists
Action
Overview of Indications
Contraindications, Side Effects, and Adverse Events
Clinical Guidelines
Opiate antagonist
Cat
Dog
Parrot
Horse
Naltrexone
25–50 mg cat−1 q24h
1–2.2 mg kg−1 q12–24 h
1.5 mg kg−1 q12h
0.7 mg kg−1 q24h
Naloxone
0.01 mg kg−1 SC as a test dose
Pentazocine
2.5 mg kg−1 q12h
Specific Medications
I. Nalmefene
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
Other Information
Effects Documented in Nonhuman Animals
Dogs
Horses
II. Naloxone HCl
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
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