Analgesics in practice: opioids and nontraditional medications (Proceedings)

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Analgesics in practice: opioids and nontraditional medications (Proceedings)


Opioids are classically used for analgesia in cases of moderate to severe pain. They can have other uses and effects, however. Sedation, calming/euphoria, and chemical restraint can all be achieved through opioid use in animals. Additionally, they can be used to inhibit gastrointestinal motility in cases of diarrhea, inhibit cough (antitussive effects), and to increase locomotor activity (horses). However, these effects can also be considered the side effects, and may limit their use in certain cases.

Mechanism of action

Opioids exert an effect by binding to receptors which activate G-coupled proteins, resulting in inhibition of adenylyl cyclase, and activate receptor linked K+ ion channels while simultaneously inhibiting voltage gated Ca2+ channels. This results in hyperpolarization of nerves and decreases neurotransmitters such as acetylcholine, substance P, dopamine, and norepinephrine. Opioid receptors are present in peripheral tissues, including the joint capsule and eye, in the dorsal horn of the spinal cord, and in high density in the brain. There are at least three opioid receptors that have been classified, the µ, κ, and δ receptors. The receptor types activated by individual drugs will determine the therapeutic and adverse effects associated with use.

The µ receptors are associated with the greatest degree of analgesia, and can be used for sedation as well as an appetite stimulant. However, µ receptors are also associated with the most adverse effects. Respiratory depression, ileus, nausea/vomiting, and CNS excitement are some of the more clinically important adverse effects of µ receptor stimulation. Lesser effects include decreased biliary secretion, antidiuresis and decreased urine voiding reflexes, decreased uterine contractions, miosis/mydriasis and immunomodulation. Pure µ opioid agonists include morphine, fentanyl, hydromorphone, oxymorphone. They are useful for moderate to severe pain and have a dose-dependent effect. As dose increases, so does the analgesic effect. Buprenorphine is a partial µ opioid agonist and can be used for moderate pain, with fewer respiratory side effects than the pure µ opioid agonists. However, because it is a partial agonist, there can be a ceiling effect which limits its use in severe pain.

The κ receptors are also considered analgesic, and can be used for sedation and appetite stimulation. Other effects associated with κ receptors include ileus, diuresis and miosis/mydriasis. Butorphanol is a κ receptor agonist that is useful in veterinary medicine because it provides good analgesia, with less respiratory depression effects.

The δ receptors are associated with analgesia, increased appetite, and immunomodulation. The only drug used in veterinary medicine that has a significant δ receptor effect is etorphine, a very potent opioid used for capture and sedation of zoo and wild animals.

Adverse effects and side effects

Respiratory depression

Dose-dependent respiratory depression is produced through activation of the µ opioid receptor. Activation of this receptor causes a decreased response to increased partial pressure of CO2. In normal, healthy animals, these effects are clinically insignificant. The use of µ receptors agonists in animals with pre-existing respiratory disease or increased intracranial pressure may result in hypoventilation and adverse effects, therefore use in these patients is contraindicated. Opioids do cross the blood-placental barrier and can cause respiratory depression in the fetus.

Cns excitement

Excitation and/or convulsions can be seen with opioid administration. Cats and horses are particularly sensitive to the CNS excitement effects of opioids, although the effects can be produced at high doses in many species, including dogs. This may be explained by differences in receptor distribution in the CNS. The mechanism of CNS excitement is not fully understood, however common theories include release of excitatory neurotransmitters, decreased activity of the inhibitory neurotransmitter GABA, release of acetylcholine or release of histamine.

Cardiovascular effects

The µ agonists can cause cardiovascular changes in animals that vary according to species. There is an increase in cardiac output in some species (horses), but a decrease in others (dogs). The decreased cardiac outputin dogs is accompanied by bradycardia, although the effects on stroke volume are minimal. Therefore these drugs can be used in cardiovascularly unstable patients with proper monitoring. Changes in blood pressure are minimal in animals.

Antitussive effects

Opioids cause central inhibition of the cough center, resulting in antitussive effects that are independent of the respiratory depressant effects. Activation of µ and κ receptors will produce this effect. Morphine, butorphanol, methadone and tramadol have all been demonstrated to cause depressed cough reflexes in dogs or cats.