New developments in opioids: old drugs and some future directions (Proceedings)

Opioids are commonly used in veterinary medicine for their analgesic, sedative, and anti-diarrhea properties. Opioids are also effective antitussive agents and in appropriate doses opioids can provide anxiolytic effects. The analgesic effects of opioids are mediated primarily through activity in the central nervous system (CNS) including the spinal cord and brain. Effects on the gastrointestinal tract (GIT) are primarily local effects and include decreased propulsive contractions, increased segmental contractions, and decreased fluid secretions. Local analgesic effects can also be obtained by direct injection into the synovium. Leukocytes, which have opiate receptors, are also affected by opioids eliciting multiple effects ranging from immunostimulation to immunosuppression. Studies in humans have demonstrated that withholding opioids in painful patients that are immunocompromised result in worsened immune function.

Mu opioid agonists (morphine, hydromorphone, fentanyl) result in dose-dependant analgesia with larger doses eliciting a greater effect. In contrast mu the partial agonist buprenorphine and kappa agonists (butorphanol, nalbuphine) have a ceiling effect, in which a submaximal level of analgesia is achieved and additional doses do not result in increased analgesic effects.

Respiratory effects

Mu opioid agonists produce a dose-dependant respiratory depression in animals while partial mu agonists and kappa agonists produce submaximal respiratory depression. In contrast to humans, the respiratory depressant effects of opioids in healthy animals clinically recommended doses produce minimal respiratory depression. Doses as high as 50 to 100 times the clinically recommended doses resulted in severe respiratory depression, but not death in animals. However animals with underlying respiratory disease (bronchitis, asthma, pleural effusion, cor pulmonale, etc.) are at in increased risk for respiratory adverse effects. Animals with head trauma are at an increased risk of cerebral edema when administered opioids as the opioids decrease the animal's response to increasing carbon dioxide levels.

Antitussive effects

Opioids also have antitussive effects which are independent of the respiratory depressant effects. Mu opioid agonists (morphine, hydrocodone, codeine, et al), buprenorphine, and kappa agonists (butorphanol) are effective antitussive agents. Tramadol also has antitussive effects in experimental models, but its effectiveness has not been investigated clinically.

Cardiovascular effects

Clinically recommended dosages of opioids have minimal effects on the cardiovascular system in animals. The effects of IV morphine on the blood pressure of dogs have been variable ranging from mild decreases to mild increases. Histamine concentrations increase following IV morphine injection, but the clinical relevance appears to be minimal as changes in cardiovascular parameters are minimal. In contrast to humans, dogs administered morphine (at higher than recommended doses) had increased coronary vascular resistance and decreased coronary blood flow. Therefore, routine administration of morphine for the treatment of congestive heart failure is not recommended. The opioids result in minimal effects on cardiac output, however decreased heart rate is routinely observed in dogs. Morphine also exerts protective effects towards ventricular tachycardia.

Thermoregulation

Panting commonly occurs in dogs after administration of opioids. Morphine affects the thermoregulatory center in the hypothalamus in dogs which results in a decrease in body temperature. In cats, the opposite effect is occasionally seen, in which the body temperature increases, and may occur more frequently with hydromorphone.

Emesis

Opioids can result in emesis following administration to dogs and cats that is thought to be primarily due to stimulation of the chemoreceptor trigger zone (CRTZ). Conversely, some opioids act as antiemetic on the emetic center in the brain. Butorphanol (0.4 mg/kg IV, IM, SC) has been used as an antiemetic in dogs and cats receiving chemotherapy in which the vomiting is not controlled with standard antiemetic drugs.

Hydrocodone

Hydrocodone is mu opioid agonist most commonly used in veterinary medicine as an antitussive; however it is routinely used in humans as an analgesic. Hydrocodone is metabolized to hydromorphone, an active metabolite which is also a mu agonist. Recent studies in dogs suggest that hydrocodone is metabolized to hydromorphone in dogs with hydromorphone concentrations persisting to at least 8 hours after 0.5 mg/kg hydrocodone bitartrate PO. The analgesic effects of hydrocodone have not been determined in dogs. Hydrocodone tablets containing 10 mg hydrocodone bitartrate and 300 mg acetaminophen can be quartered with relatively good precision, therefore a dose of ¼ tablet per 11# of body weight to dogs q 8-12 hours PO can be administered. Hydrocodone is inexpensive, but is subject to abuse. Therefore it may be best not to stock hydrocodone in the clinic, but script it out to a local pharmacy to decrease liability potential. Do not administer the combination product to cats as the acetaminophen is toxic to cats.

Hydromorphone

Hydromorphone is a mu agonist opioid with similar effects and adverse effects as morphine. Hydromorphone has been used in both dogs and cats. Recent studies in dogs indicate it is rapidly eliminated with an elimination half-life of 0.6 hours. The current dose recommended in dogs is 0.1 mg/kg q 2 hours or as a constant rate infusion at 0.03 mg/kg/hr. Pharmacokinetic studies have been conducted in cats with hydromorphone being rapidly eliminated (elimination half-life 1.6 hours). The dose recommended for use in cats is 0.1 mg/kg q 2-4 hours. Hydromorphone has been associated with occasional hyperthermia in cats.

Buprenorphine

Buprenorphine is a partial mu agonist which is 25-50 times more potent than morphine, and is only effective for mild to moderate pain. Buprenorphine may be more effective for chronic pain as compared to morphine, although definitive results are lacking. Buprenorphine has a wide margin of safety with doses 100 times the recommended doses being non-lethal. Despite the long half-life of buprenorphine in dogs, experimental models have indicated the duration of effect is approximately 3 hours after administration of 0.02 mg/kg and longer than 3 hours after 0.04 mg/kg SC. A lag from time of administration to peak effect is about an hour following SC administration; in comparison the peak effect of IV morphine occurs at about 45 minutes in dogs. However it is important to note that an analgesic effect does occur prior to reaching the peak effect. The buprenorphine dose in dogs is 0.02-0.04 mg/kg IV, IM, SC q 4-6 h. Buprenorphine is well absorbed from the buccal mucosa of cats, but has a poor oral (PO) bioavailability in both dogs and cats. The bioavailability of buprenorphine from oral transmucosal administration in dogs is low, but the oral bioavailability is only 3-6%. Cats tolerate oral transmucosal (OTM) administration of buprenorphine well, but if the dose is swallowed no effect will occur due to the poor bioavailability. The dose in cats is 0.01-0.02 mg/kg q 4-8 hr OTM, IV, IM, SC.

Nalbuphine

Nalbuphine is a mu antagonist and kappa agonist opioid. Nalbuphine is currently not an FDA scheduled drug, therefore is not subject to extensive record keeping and tracking. The clinical effects of nalbuphine after administration are similar to morphine, but the level of analgesia is only expected to be sufficient for mild to moderate pain (similar to butorphanol). Nalbuphine is cost-effective with a recommended dose of 0.1-0.25 mg/kg IV, IM, SC q 2-4 hours for cats and 0.25-1 mg/kg IV, IM, SC q 2 – 4 hours for dogs.

Tramadol

Although tramadol is technically not an opioid, it is usually discussed with the opioids. The mechanism of action of tramadol is complex with tramadol eliciting effects as a serotonin and norepinephrine reuptake inhibitor. Tramadol is metabolized to an active metabolite which has effects as a mu opioid agonist and as a serotonin and norepinephrine reuptake inhibitor. Tramadol is very bitter tasting, therefore broken tablets are difficult to administer to dogs and cats.

Experimental models have demonstrated tramadol is an effective antitussive agent. Little data is available on the effectiveness of tramadol as an analgesic in dogs or cats. Potential adverse effects (serotonin syndrome) can occur if tramadol is combined with other serotonin reuptake inhibitors such as tricyclic antidepressants (clomipramine, amitriptyline), fluoxetine (Reconcile, Prozac), paroxetine (Paxil), mirtazapine (Remeron), selegiline, duloxetine, and venlafaxine. Serotonin syndrome can result in tremors, seizures, hypertension, hyperthermia, and in severe cases death. Concurrent administration of ondansetron (Zofran), a 5HT3 antagonist as an antiemetic may decrease the analgesic effectiveness of tramadol. Adverse effects of tramadol are typically mild and can include sedation, vomiting, and dysphoria. Tramadol may provoke seizures in animals prone to seizures or may decrease the effectiveness of anticonvulsants, therefore should be used when the benefits outweigh the risks in these patients. Intoxication of tramadol typically results in seizures which diazepam has been effective in treating. Some unchanged tramadol is excreted in the urine which may indicate diuresis may increase the elimination of tramadol, although this has not been demonstrated.

There is little data available on tramadol use in dogs and cats, but it is widely used. Tramadol is rapidly eliminated from dogs after oral administration. Recent studies are suggestive the bioavailability of tramadol in dogs is lower than originally determined and the dose of tramadol needs to be increased with dosages from 5 - 10 mg/kg PO q 8-12 hours in dogs to maintain similar plasma drug concentrations as those in humans. Recent data in cats suggest that it is variably absorbed after oral administration with large amounts of the active metabolite produced. Adverse effects in cats were similar to other opioids and included miosis, salivation, and some mild dysphoria after administration of 4 mg/kg PO. The current recommended dose in cats is 1-2 mg/kg PO q 12h although this dose has not been extensively evaluated for efficacy or safety.