A nociceptive stimulus produces an unpleasant sensation. Pain is the coupling of the unpleasant sensation with conscious perception and eliciting an emotional response. There is debate on whether all animals have true emotional responses, and thus whether they can feel pain according to its definition, but there is no debate that nociception is present in animals. Nociceptive receptors are free nerve endings distributed throughout the body, which detect a nociceptive stimulus. Nociceptive stimuli are transmitted from peripheral nerves though the spinal cord to numerous areas within the central nervous system. Mechanical (pressure, fractures, stretching), temperature (hear or cold), and chemical (including endogenous substances such as inflammatory cytokines and changes in tissue pH) stimuli are all types of stimuli that produce pain. For the discussions in this chapter pain and nociception will be used synonymously.

Large strides have been made recently in the recognition and treatment of pain in animals. Numerous pharmacokinetic and pharmacodynamic studies have been performed in order to better gain our understanding of opioids in animals through laboratory and clinical studies. Treatment regimens used in humans cannot be easily extrapolated to animal species treated by veterinarians because of species differences in pain sensation, pharmacokinetic differences, efficacy, and adverse effects of opioids.

Opioids are considered the prototypical analgesic, antidiarrheal, and antitussive drugs by which other drugs are compared. Opium was first imported into the United States in 1840, primarily from the country of Turkey. It was widely used to treat a variety of maladies, including pain, diarrhea, and coughing. In the 1870s, because of widespread use after the Civil War, opiate use and addiction was a recognized problem. There are over 20 opiate alkaloids in opium and in the early 19th century, the chemist Sertürner isolated morphine, which he named after Morpheus, the Greek god of sleep and dreams. Heroin was also developed in the early 1900s by the same chemists at Bayer who developed aspirin. It was intended to be a safe and nonaddictive analgesic. There have been other attempts – none completely successful – during the next century to develop drugs as effective as the opiates, but without the abuse and addiction potential. The majority of opioids are now controlled by regulatory authorities.

Opioids produce a dose-dependent respiratory depression mediated via activation of the μ receptor. Respiratory depression is produced by a decreased response to increases in carbon dioxide partial pressures (PCO₂). The respiratory depressant effects of opioids are well tolerated in healthy animals even when supratherapeutic doses are administered. Concurrent anesthesia or other drugs that cause respiratory depression can increase the respiratory depressant effects of opioids (Hug et al., 1981). Respiratory depressant effects may be more problematic in animals with preexisting respiratory disease (asthma, bronchitis, cor pulmonale) or increased intracranial pressure. Neonatal animals (young, healthy, and pain free) tend to be more sensitive to the respiratory depressant effects of opioids, but opioids can still be safely administered to neonates.

Opioids cross the placenta and respiratory depressant and sedative effects on the fetus can occur and should be monitored and treated appropriately. Naloxone administered sublingual (or parenterally) to newborns will reverse deleterious opioid effects.

High doses of morphine and other opioids produce excitement. Very high doses can produce convulsions. Similarly, rapid IV administration of opioids can cause CNS excitation. In dogs, morphine, 180–200 mg/kg IV, produced grand mal seizures, and convulsive changes in electroencephalogram (EEG) tracings and excitement were seen in dogs administered morphine 20 mg/kg SC (Wikler and Altschul, 1950; de Castro et al., 1979). (Note that therapeutic doses rarely exceed 0.5–1 mg/kg.) Cats respond similarly to high doses of morphine where 20 mg/kg SC produced EEG tracings consistent with convulsive activity and generalized excitement (Tuttle and Elliot, 1969).

In veterinary medicine, there are great species differences with respect to excitement caused by opioids. Dogs typically become sedate, whereas cats, horses, and other large animal species are prone to excitement. The explanation for increased susceptibility to these effects in some animals is probably related to the distribution of opiate receptors in certain regions of the brain independent of the drug’s pharmacokinetics. The distribution of opiate receptors in brains of animals that are sedated from opioids (e.g., dogs) is greater than the animals that are more prone to excitement (horses). Alternatively, the excitement may be due to a release of excitatory neurotransmitters or decreased release of inhibitory neurotransmitters. Some anesthesiologists suggest that the reaction may be dopaminergic, adrenergic, or caused by decreased activity of the inhibitory neurotransmitters GABA or glycine (Werz and Macdonald, 1982). Release of acetylcholine also has been suggested as a cause of excitation (Mullin et al., 1973). In another study, it was suggested that excitement in animals may be caused by histamine release, but the doses of morphine exceeded clinically recommended doses in those studies. Morphine administration to dogs induced greater histamine release, and also more excitement compared to oxymorphone after administration of an equianalgesic dose, but the doses of morphine (2 mg/kg IV) were four times higher than recommended clinically (Robinson et al., 1988). When morphine was compared to hydromorphone in dogs (Guedes et al., 2007a), morphine caused a transient increase in plasma histamine and 1/5 dogs also exhibited neuroexcitatory behavior at 0.5 mg/kg IV. By contrast, hydromorphone did not cause increases in histamine but two dogs became excited after 0.1 mg/kg IV. These studies indicate histamine alone is not a cause of opioid-induced CNS excitation.

Most opioids have minimal effects on cardiac output in dogs, with clinically relevant doses resulting in changes ranging from slight increases to slight decreases, but methadone may produce more consistent decreases in cardiac output (Buckhold et al., 1977; Priano and Vatner, 1981; Copland et al., 1987; Maiante et al., 2009). Opioids produce bradycardia in dogs, but they usually compensate well to maintain cardiac output and treatment for the bradycardia is not routinely needed (Copland et al., 1992). Only if necessary should bradycardia can be reversed with an anticholinergic (e.g., atropine). Cardiac output is also maintained with opioids in horses and may be increased if excitatory effects occur (Muir et al., 1978; Robertson et al., 1981; Carregaro et al., 2006).

Opioids produce minimal vascular effects when administered to animals in clinically relevant doses (Barnhart et al., 2000; Pant et al., 1983; Hug et al., 1981; Kayaalp and Kaymakcalan, 1966; Priano and Vatner, 1981; Carregaro et al., 2006). Changes in mean arterial pressure range from minimal increases to minimal decreases (∼10% from baseline values). Increases in plasma histamine concentrations following morphine administration are often cited as producing hypotensive effects in dogs, but histamine release is short lived (Guedes et al., 2007a) and minimal effects on blood pressure are noted following IV morphine administration. The cardiovascular effects of opioids appear to be more pronounced in anesthetized animals due to interactions with the anesthetic and when supratherapeutic opioid are administered.

The effects of opioids on myocardial blood flow are variable with some studies demonstrating increases in blood flow where others show decreases, but these studies assessed supratherapeutic doses, ≥2 mg/kg (Pant et al., 1983; Vatner et al., 1975). This is in contrast to the consistent effects in humans, coronary vasodilation and increased myocardial perfusion.

Morphine’s effect on vascular tone has been used in the past as a treatment for acute cardiogenic pulmonary edema (Vismara et al., 1976). The benefits are attributed to splanchnic blood pooling, afterload reduction, or reduced breathing effort. Some investigators attributed the benefits to vasodilation caused by histamine release. This is considered a rather outdated use of morphine. Today we have potent diuretics and vasodilators to treat this condition.

Opioids produce an antitussive effect through a central inhibition of the cough center independent of their respiratory depressant effects (Chou and Wang, 1975). Both μ- and κ- receptor agonists have been documented to produce antitussive effects (Takahama and Shirasaki, 2007). The antitussive effect is more resistant to naloxone reversal than the analgesic effect of opioids (Chau et al., 1983). Morphine, codeine, butorphanol, and methadone have demonstrated antitussive effects in dogs or cats, and tramadol additionally in cats (Rosiere et al., 1956; Cavanagh et al., 1976; Nosal’ova et al., 1991). Hydrocodone has antitussive properties in rats and people, and is commonly used in dogs for this purpose although studies definitively demonstrating its efficacy in dogs and cats are lacking (Kasé et al., 1959; Hennies et al., 1988; Homsi et al., 2002).

Dextromethorphan, which does not affect opiate receptors, is used as an over-the-counter medication to treat coughing in people. It is believed to bind to high- and low-affinity sites in the brain that are distinct from opiate receptors (Grattan et al., 1995). A steric hindrance may prevent binding to the typical opiate receptors responsible for analgesic and other effects. In people, it is more effective in spontaneous naturally occurring cough than in experimental models (Capon et al., 1996). Dextromethorphan has been shown to be an effective antitussive in dogs after IV injection (ED₅₀ = 10.2 mg/kg IV), but the oral bioavailability is questionable (discussed more specifically later in Section Clinical Pharmacology, Antitussive) (Kasé et al., 1959; KuKanich and Papich, 2004a). Because it is believed that the parent drug, dextromethorphan, rather than a metabolite, is responsible for the antitussive effect (Capon et al., 1996), it is unlikely that oral administration will be effective as an antitussive in dogs.

Opioids produce a variety of effects on the urinary tract. μ-agonists increase the tone of urinary sphincters. Micturition is inhibited, which may result in urine retention and may be mediated by spinal as opposed to local mechanisms (Drenger et al., 1986, 1989).

Mu-receptor agonists decrease urine production. As discussed by Robertson et al. (2001), although it has been documented that morphine produces an antidiuretic effect and decrease in urine output, the exact mechanism is unclear. It is not known whether it is caused by a release of arginine vasopressin (AVP) (also known as antidiuretic hormone), or via some other mechanism. In contrast, κ opioid agonists produce a diuretic effect as a result of decreased AVP concentrations (Craft et al., 2000). For a drug such as morphine that acts as an agonist for both receptors, the net effect observed clinically is diuresis in most situations. This is complicated by the effect on the urinary bladder. Morphine increases the tone of the sphincter of the urinary bladder, making it more difficult for some animals to voluntarily urinate. Morphine also inhibits the urinary voiding reflex. As a result of these effects hospitalized animals should be monitored and interventions used to facilitate bladder emptying when necessary.

The effects of opioids on the immune system are complex. The immune system effects are likely related to the specific opioid administered, dose, and the duration of treatment. A complex interaction of the immune system, sympathetic nervous system, endocrine system (hypothalamic–pituitary–adrenal axis), and direct effects on leukocytes occur. Immunosuppressive and immuostimulant properties have been identified depending on the experimental conditions. Some painful patients may benefit from opiate effects on immune function (Page and Ben-Eliyahu, 1997). Extrapolations of the effects of opioids on the immune system from studies on human opioid abusers are likely inaccurate for veterinary patients because studies in humans are in the context of high dose administration, chronic use, and tolerance of human opioid abusers.

Although these traits are often associated with opioid use in humans, they have been well documented in animals. Tolerance and dependence can be demonstrated in animals, but opioids are seldom used for a long-enough period of time at large-enough dosages in veterinary patients for this issue to have clinical consequences. The NMDA receptor may play a role in opioid tolerance and dependence as treatment with NMDA antagonists attenuate withdrawal symptoms in experimental settings (Yeh et al., 2002). The consequence of tolerance is that drug dosages may need to be increased with chronic administration of opioids.

Opioids administered for a period as short as 5–7 days may result in dependence in dogs. In one study in dogs, constant rate infusion to dogs at a rate of 1–5 mg/kg/day produced physical dependence by day 8 (Yoshimura et al., 1993). Withdrawal signs can be elicited in dogs after dependence with injections of naloxone. Signs of withdrawal in dogs include nausea, aggression, vocalization, vomiting, hyperactivity, hyperthermia, tremors, and salivation. Withdrawal can also be elicited from administration of a μ antagonist or partial agonist such as butorphanol or buprenorphine in opioid-dependent dogs (Yoshimura et al., 1993).

Therefore, if an animal has been receiving continuous opioids drugs for longer than 5–7 days, withdrawal signs may occur after administration of an antagonist or partial agonist. However, clinical experience suggests that discontinuing the opioid rarely causes withdrawal signs for durations of administration less than a week. In contrast, withdrawal signs have occurred clinically when butorphanol (μ-antagonist) was administered to a dog after 1 week of morphine administration. Decreasing the dose of the μ agonist to wean a patient off an opioid or decrease opioid effects is a better strategy than switching to a partial agonist or antagonist.

Opioids are commonly used for analgesia and to relieve pain and anxiety from painful syndromes. Clinically, it is observed that there is great variability in response among patients, and between drugs. High variability has been recorded for pharmacokinetics in a species and analgesic responses varied by many fold in experimental studies. Therefore, careful observation and a willingness to adjust doses (or switch drugs) in individual patients is important to successful pain management.

Severe pain, often associated with trauma, should be treated with μ opioids agonists with high intrinsic activity (e.g., morphine, hydromorphone, fentanyl, methadone). Although some references have stated opioids should not be administered to painful animals in shock, there is no basis for this recommendation. Pain can contribute markedly to the adverse and life-threatening effects associated with shock and opioids often improve the hemodynamics and tissue perfusion of painful patients. As previously stated, the hypotensive effects of intravenous opioids (including morphine) are minimal when administered in clinically relevant doses, and concurrent supportive measures, such as fluid therapy, are essential to successful therapy in these patients. Mild to moderate pain (e.g., soft tissue surgery) has been managed with μ opioid agonists, partial agonists, mixed agonist–antagonists, or tramadol. The efficacy (and lack thereof) and variability of oral tramadol are discussed later.

Preemptive analgesia, dose administration prior surgical or a painful stimulus and continued into the postoperative period, provides more effective analgesia than holding off administration of opioids to the postoperative period in dogs (Lascelles et al., 1997). This is thought to occur by decreasing central sensitization (also known as the wind-up phenomenon).

Chronic and neuropathic pain appear to be less responsive to opioid analgesia. Higher doses of opioids in humans are needed for controlling neuropathic pain (Rowbotham et al., 2003). For neuropathic pain, it may be more effective to use a multimodal approach utilizing opioids in combination with other drug classes such as NMDA antagonists (e.g., ketamine), gabapentin, local anesthetics (e.g., lidocaine), or α-2 agonists (e.g., dexmedetomidine) appear to be more effective in refractory cases.

Butorphanol tablets (Torbutrol) are approved by the FDA for antitussive use in dogs. Hydrocodone is also routinely prescribed for its antitussive effects in dogs (see Chapter 48). Codeine exhibits poor bioavailability in dogs and may not be effective when administered orally. (Codeine has questionable antitussive properties in people as well (Takahama and Shirasaki, 2007).) Tramadol tablets have demonstrated effectiveness as an antitussive in experimental models in cats due to the formation of an opioid metabolite, but have yet to be evaluated clinically. All opioid agonists are expected to be effective antitussives when administered parenterally. As mentioned previously, oral dextromethorphan – a nonopiate that is a common ingredient in human over-the-counter cough medications – is probably not an effective antitussive in dogs because of the low oral bioavailability and lack of activity from metabolites.

As mentioned Section Opioid Pharmacodynamics, Cardiovascular Effects, routine use of morphine is no longer recommended in treatment of congestive heart failure in animals due to variable effects on coronary blood flow. Likewise, although used in the past as a treatment for acute cardiogenic pulmonary edema (Vismara et al., 1976), this is no longer a common use.

Opioids are effective antidiarrheal drugs as they decrease gastrointestinal secretions, decrease propulsive gastrointestinal contractions, and increase nonpropulsive segmental gastrointestinal contractions (see Chapter 46). Loperamide is the most commonly recommended opioid for the treatment of diarrhea because of reliable effects, availability over the counter (not a controlled substance), low cost, and safety profile. Loperamide is p-glycoprotein (p-gp) substrate and as a result is excluded from the CNS in normal animals. However, if concurrent p-gp inhibitors (e.g., cyclosporine, ketoconazole, spinosad) are coadministered or the animal is deficient in p-gp (some Collie dogs, Collie related breeds, and other herding breeds) than sedation, dysphoria, and other marked CNS opioid effects may be noted for prolonged periods of time, which may exceed 24 hours (Hugnet et al., 1996). Diphenoxylate in combination with atropine is also marketed as an antidiarrheal for humans, but is not used frequently in veterinary medicine as it has not demonstrated increased efficacy over loperamide. Diphenoxylate is a prescription drug, and is a schedule V controlled substance requiring special record keeping.

Opioids are commonly coadministered with sedatives, tranquilizers, and anesthetics. Additive or synergistic sedative and analgesic effects occur when opioids are used in combination with sedatives and anesthetics. Combinations of these drug classes result in decreased dosages of the individual drugs with the potential for decreased adverse effects. Additionally, preemptive analgesia increases the effectiveness of postoperative analgesics, decreasing opioid consumption, adverse effects, and cost. A more thorough review of sedation and anesthesia drug combinations is presented in Chapters 12 and 14.

Use of other opioids in food producing animals is permitted by the Animal Medicinal Drug Use Clarification Act (AMDUCA) if an adequate withdrawal interval can be determined. Therefore the Food Animal Residue Avoidance Databank (FARAD) or a reliable reference (Papich, 1996, 2016) should be consulted prior to opioid administration to food producing species in order to obtain the most current withdrawal interval recommendations.