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.

Gastrointestinal effects

Emesis and nausea result from opioid effects on the chemoreceptor trigger zone (CRTZ) and may also stimulate central dopamine receptors in the vomiting center. Interestingly, repeated use of opioids may have an antiemetic effect. Additionally, the emetic effects of opioids are lessened in painful patients, possibly due to the presence of high circulating concentrations of endogenous opiates.

Gastrointestinal ileus is a result of central and peripheral opioid receptor stimulation. Stimulation of µ receptors in the submucosal plexus, myenteric plexus and longitudinal muscle of the ileum results in inhibition of intestinal acetylcholine and Substance P. This leads to delayed gastric emptying, decreased secretion, decreased propulsive motility and increased pyloric sphincter tone. In contrast to emesis, this effect is often not seen with the first dose, but is present with subsequent doses. The end result is constipation, which is often considered an adverse effect, but has also been used therapeutically for the treatment of diarrhea.

Urinary effects

Opioids, particularly µ agonists, cause increased tone of urinary sphincters, which may result in urine retention. They can also cause decreased urine production, possibly through release of antidiuretic hormone. Stimulation of κ opioid receptors, on the other hand, produce a diuretic effect via decreases in antidiuretic hormone.

Immunomodulation

Immunostimulant and immunosuppressive effects of opioids have been demonstrated under experimental conditions. Presently, the effects are poorly understood. There is likely a complex interaction between the opioid receptors and the immune system, sympathetic nervous system and the endocrine system that produces these effects. A direct effect on leukocytes may also occur. The clinical significance of this is unknown in veterinary medicine, but withholding opioids in immunocompromised humans can result in a worsening of immune function.

Tolerance and dependence

Tolerance may occur with opioid administration in animals as it does in humans. Tolerance results in the need for increasing doses to produce a similar analgesic response with chronic dosing. Physical dependence in dogs may occur after as little as 5-7 days, resulting in signs of withdrawal after administration has stopped or with the administration of an opioid antagonist or partial agonist. These signs include nausea, aggression, vocalization, vomiting, hyperactivity, hyperthermia, tremors and salivation. Decreasing the dose and weaning the patient off the medication is recommended if opioids have been used for longer than 5-7 days.

Pharmacokinetics and routes of administration

In general, the opioid analgesics have a short half-life, a high clearance, a large volume of distribution, and a low oral bioavailability. This results in short-lived effects and requires frequent dosing for most drugs in this category. Parenteral administration is often recommended, and due to the short half-life, constant rate infusions may be necessary to maintain a prolonged analgesic effect. Many drugs in this class are subject to a high first-pass effect with oral administration and are cleared by the liver prior to reaching the systemic circulation. Tramadol and hydrocodone are the only drugs that have adequate oral bioavailability. Sublingual administration has been used as a way to circumvent the first-pass effects and this is a commonly used route of administration for buprenorphine, particularly in cats. Transdermal absorption can also be accomplished with some drugs, mainly fentanyl, which is commercially available in transdermal patches which have become quite popular for treating pain in a variety species. Epidural administration of opioids has been used to deliver high concentrations to spinal opioid receptors. In general, this decreases the risk of adverse effects such as sedation and dysphorias, but may still result in urine retention and constipation. For the more lipophilic drugs, such as fentanyl and buprenorphine, epidural administration results in rapid distribution to the plasma, and minimal benefits over systemic administration.

Opioid antagonists

Opioid antagonist drugs are used for the reversal of severe respiratory depression in patients administered inappropriate doses of opioids, or in newborns that are born from pregnant animals receiving opioids. Repeat dosing may be required, as the effects of the reversal agents may be shorter-lived than those of the agonists. Antagonists should not be used in severely painful animals, as they can result in an acute exacerbation of pain, cardiovascular shock and even death. Naloxone, naltrexone and nalmefene are opioid antagonist drugs that can be used in veterinary medicine. Butorphanol is a κ receptor agonist, but also has µ receptor antagonist properties, and is therefore sometimes used to reverse µ agonists, such as morphine.

Drug interactions

Drug-drug interactions can occur when opioids are administered together, depending on their effects on the different receptors. For example, co-administration of morphine, a pure µ agonist with butorphanol, a κ agonist and a µ antagonist, may result in partial reversal of the analgesic, respiratory depressive and sedative effects from the morphine. This interaction may therefore be clinically useful in some patients. The most frequent drug-drug interaction seen is the additive sedative effects when opioids are combined with other tranquilizers. In humans, severe reactions can occur with co-administration of MAO inhibitors and meperidine, but this has not been reported in veterinary species. Tramadol should not be co-administered with other serotonin agonists.

Table 1. Specific opioid drugs.