Opioids use with inpatients (Proceedings)

Opioids are commonly used in veterinary medicine for their analgesic, sedative, and anti-diarrheal 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 a range of effects, from immunostimulation to immunosuppression. Studies in humans have demonstrated that withholding opioids in painful patients that are immunocompromised results in worsened immune function.

Mu opioid agonists (morphine, hydromorphone, fentanyl) result in dose-dependent analgesia with larger doses eliciting a greater effect. Mu opioids are effective in treating mild to severe pain. In contrast the partial mu agonist buprenorphine and kappa agonists (butorphanol, nalbuphine) have a ceiling effect, in which a sub-maximum level of analgesia is achieved and additional doses do not result in increased analgesic effects. Partial agonists are effective in treating mild to moderate pain.

Respiratory Effects

Mu opioid agonists produce a dose-dependent respiratory depression in animals while partial mu agonists and kappa agonists produce sub-maximum respiratory depression. In contrast to humans, the respiratory depressant effects of opioids in healthy animals administered clinically recommended doses produce minimal respiratory depression. Doses as high as 50 to 100 times the clinically recommended doses of morphine 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 which can potentially worsen cerebral edema.

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. The efficacy of tramadol in dogs as an antitussive is expected to be less than other species as the active metabolite is not produced in consistent or high concentrations.

Cardiovascular Effects

Clinically recommended dosages of opioids have minimal effects on the cardiovascular system in animals. The effects of IV morphine at clinically recommended doses 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, including blood pressure, 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. 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. Opioids affect the thermoregulatory center in the hypothalamus in dogs which results in a decrease in body temperature due to the increased panting. It is not uncommon for dogs to become hypothermic when administered opioids. In cats, the opposite effect is occasionally seen, in which the body temperature increases, and may occur more frequently with hydromorphone.

Emesis

Opioids (primarily morphine, hydromorphone) 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 antiemetics on the emetic center in the brain. Butorphanol (0.2 - 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. Fentanyl also has demonstrated antiemetic effects. Chronic administration of opioids may result in GI stasis and ileus with vomiting resulting from decreased GIT motility.

Specific Opioids

      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 0.6-1 hours. The current dose recommended in dogs is 0.1 mg/kg q 2-4 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 2-6 hours. Hydromorphone has been associated with sporadic hyperthermia in cats.

      Fentanyl

Fentanyl is a mu opioid agonist available as an injectable solution and transdermal patches. Injectable fentanyl can be administered as an IV bolus or constant rate infusion or as a subcutaneous injection. Fentanyl solution is acidic and burns on subcutaneous administration, but adding 8.4% sodium bicarbonate at a rate of 1 mL sodium bicarbonate to 20 mL fentanyl increases the pH resulting in well tolerated injections and apparently unaltered drug absorption. A dose of 15 microgram (mcg) per kg SC resulted in a rapid onset of sedation and panting with fentanyl plasma concentrations exceeding 1 ng/mL (plasma concentration associated with efficacy in humans) for at least 2 hours post injection. The current recommended dosages of fentanyl for injection are 5-10 mcg/kg IV q 2 h and 10-15 mcg/kg SC q 2-4 h in dogs and cats. The infusion rates of fentanyl are 3-5 mcg/kg/hr in dogs and 1-3 mcg/kg/hr in cats.

Fentanyl transdermal patches are available for use in dogs and cats. Transdermal fentanyl produces more variable plasma concentrations and subsequently effects compared to constant rate IV infusions. Fentanyl patches are relatively well tolerated in dogs, but sedation and lack of efficacy can occur due to variable drug absorption. Other opioid mediated effects such as constipation, panting, and dysphoria can occur. Fentanyl patches can present a risk to clients and must be dispensed cautiously. Fentanyl patches have been intentionally abused by humans and accidental drug exposure has also been reported with death occurring in some overdoses.

Studies have demonstrated that dogs can become dependent on opioids within 5-7 days of continuous administration. Therefore opioid dependence may occur after as few as 2 patches administered (6 days) to dogs. Withdrawal symptoms such as aggression, vomiting, pacing, tremors, vocalization and agitation can occur if a partial agonist (buprenorphine), agonist / antagonist (butorphanol) or antagonist is administered.

      Buprenorphine

Buprenorphine is a partial mu agonist which is 25-50 times more potent than morphine, and is 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 estimated to be 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 4-12 h. Buprenorphine is well absorbed from the buccal mucosa of cats, but not in dogs. Buprenorphine has a poor oral (PO) bioavailability in both dogs and cats. Cats tolerate oral transmucosal (OTM) administration of buprenorphine well, but if the dose is swallowed minimal effect will occur due to poor oral bioavailability. The dose in cats is 0.01-0.02 mg/kg q 4-12 hr OTM, IV, IM, SC.

      Nalbuphine

Nalbuphine is a mu antagonist and kappa agonist opioid. Nalbuphine is currently not a DEA scheduled drug, therefore is not subject to extensive record keeping and tracking. The clinical effects of nalbuphine after administration are similar to morphine (panting, sedation, and potentially vomiting), but the level of analgesia is only expected to be sufficient for mild to moderate pain (similar to butorphanol). Nalbuphine is recommended at a 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.

Disclaimer: The information is accurate to the best of the author's knowledge. However recommendations change as new data become available and errors are possible. The author recommends double checking the accuracy of all information including dosages.