In clinical practice opioids are used in many aspects of patient management. They are used to provide sedation, parenteral and regional analgesia for acute and chronic conditions, and to induce and/or maintain anesthesia. They may be used alone or in combination with other drugs and may be administered by various routes (percutaneous, per os [PO], subcutaneous [SQ], intramuscular [IM], intravenous [IV], by IV infusion, intra-articular, epidural and peri-neural). The selection of the appropriate opioid and technique is dependent on drug availability, patient and owner compliance and other circumstances. The following section will highlight the key clinical applications of opioids. When not included in the text, dosing information is provided in Table 1.

OPIOIDS USED FOR PREMEDICATION AND/OR TREATMENT OF PERI-PROCEDURAL PAIN

Opioids are commonly used for premedication and perioperative analgesia. Morphine continues to be the prototypical mu (µ) opioid agonist and is a safe, effective analgesic for most small animal patients. It is efficacious for mild to severe pain and has the added benefit of being a good sedative for dogs. In comparison with other commonly used µ opioid agonists, morphine has a longer duration of action and is less expensive. Side effects in dogs are generally dose and route of administration dependent and include respiratory depression, bradycardia, vomiting, defecation, dysphoria and histamine related vasodilation and hypotension. Oxymorphone and hydromorphone are equally effective analgesics, but they have a shorter duration of action. They are also associated with a lower incidence of gastrointestinal side effects and do not cause histamine release following intravenous administration. Methadone is another opioid agonist that has been used with good results in dogs and cats. However its availability has been limited due to other circumstances within the U.S.. Meperidine and fentanyl are both short acting opioids that may be used when short term (30 minutes to 1 hour) analgesia is desirable. They are generally less sedating than the previously mentioned opioids when administered via the SQ or IM routes. While fentanyl has a high degree of cardiovascular safety, meperidine has the potential to cause histamine release (and associated hypotension) especially when administered intravenously.

Buprenorphine is a unique drug in that it is classified as a partial µ agonist. Unlike the aforementioned drugs that have a high potential for human abuse and are therefore federally strictly regulated, buprenorphine has fewer government restrictions on its use in the U.S. compared to other µ opioids. Its efficacy as an analgesic for small animal patients continues to be studied with promising results following both intravenous and buccal mucosal administration in cats. Butorphanol, a kappa (kappa ) agonist and µ antagonist drug is less effective than morphine or oxymorphone for moderate to severe pain and has a short to intermediate duration of action. While its efficacy as a sedative seems to vary, it is thought to cause less respiratory depression and dysphoria when compared to the µ opioid agonists. It is a federally regulated substance in the U.S..

OPIOIDS USED FOR INDUCTION AND MAINTENANCE OF ANESTHESIA

Due to the large margin of cardiovascular safety, opioids are frequently used for induction of anesthesia and/or as part of a balanced anesthetic technique in hemodynamically compromised patients. Use of opioids for induction of anesthesia is reserved primarily for dogs due to the potential for significant arousal in cats with high dose IV administration. Fentanyl, oxymorphone and hydromorphone or the opioids that do not release histamine when administered IV are best suited for use as induction agents. The time from IV drug administration to intubation is shorter with fentanyl than with oxymorphone or hydromorphone. This combined with the reduced cost of fentanyl has favored the use of this drug in our clinical practice. The concurrent use of a benzodiazepine is suggested as a means of improving muscle relaxation and providing suitable intubation conditions. As animals frequently maintain sensitivity to environmental noise following induction with an opioid, a quiet environment is highly recommended when using this technique. In the absence of pre-treatment with an anticholinergic, bradycardia is frequently observed. Significant respiratory depression is also common necessitating mechanical ventilation in many of these animals.

While any of the mentioned opioids may be used as part of a balanced anesthetic technique, drugs with a shorter effective plasma half-life (e.g., fentanyl, alfentanil and remifentanil) are best suited for use in this manner. Fentanyl has been shown to be efficacious for reducing the dose requirement for inhaled anesthetics during administration via constant IV infusion in both dogs and cats. Further, cardiovascular function is better maintained with a combination of opioid and inhaled anesthetic (providing bradycardia is treated) when compared to the higher dose of inhaled anesthetic alone. Respiratory depression is observed and may require intervention to prevent clinically significant respiratory acidosis. To facilitate a return of respiratory function in the recovery period, the infusion rate should be lowered or the infusion discontinued during the last 20-30 minutes of the procedure.

INTRAVENOUS OPIOIDS FOR POST OPERATIVE PAIN

Many of the aforementioned opioids may be administered for analgesia by IV infusion in the postoperative period. Morphine (0.05-0.2 mg/kg/hour, IV), fentanyl (1-5 µg/kg/hour) or hydromorphone (0.01-0.1 mg/kg/hour) are all used in this manner. The lower end of the dose range generally forms the starting point in cats, while dogs initially receive doses in the mid range. Patients on constant rate infusions should be regularly observed for both efficacy of the treatment and potential side effects including bradycardia, sedation, respiratory depression and dysphoria.

REGIONAL USE OF OPIOIDS

Epidural and intra-articular opioids are being widely used for treatment of pain. While many drugs have been administered either by single or repeated dose, or by constant infusion via an epidural catheter, preservative free morphine (0.1 mg/kg) is most commonly used in our practice. The calculated dose is reduced by one-half to two-thirds if cerebrospinal fluid is observed in the needle. While the response especially during the intra-operative period varies between patients, they appear to be more comfortable and many are more willing to ambulate early in the post-operative period. Retention of urine is a frequently observed side effect and it is recommended that the patients' bladder be evaluated and evacuated as needed following epidural morphine administration. While a clear dosing and administration protocol has not been established for intra-articular opioids, there is evidence for the presence of opioid receptors in the joint. In general the dose administered is limited by the size of the joint; preservative free morphine is most commonly used.

OPIOIDS USED FOR TREATMENT OF CHRONIC PAIN

While non-steroidal anti-inflammatory drugs are frequently used to treat osteoarthritis-associated pain, chronic cancer pain is more commonly treated with opioids. Cancer pain is defined as pain that is the result of primary tumor growth, metastatic disease, or the toxic effects of chemotherapy and radiation. Neuropathic pain (another form of chronic pain) may also be associated with cancer.

Oral use of opioids. Oral morphine is administered at a starting dose of 1 mg/kg PO, QID in dogs and 0.5 mg/kg PO, QID in cats. Sustained release morphine may be administered two to three times a day. The bioavailability of oral morphine is approximately 20% in dogs, therefore it is likely that the dose will need to be increased over time. The dose of morphine is started low in order to minimize the frequency of side effects. Some animals respond to oral morphine with a return to more normal activity as their pain subsides. It is also possible that an animal will become excessively sedate, in which case the dose will need to be reduced. Other animals may become agitated and vocal. Here again the opioid dose could be reduced or a tranquilizer such as acepromazine or diazepam may be added to decrease the excitatory response. It may take several days to optimize the dosing schedule, i.e., maximize patient comfort while minimizing side effects. Over time, the dose of morphine may need to be increased if the disease process continues, the animal becomes tolerant to morphine, or both.

Butorphanol, an opioid agonist-antagonist, may also be administered orally for the treatment of chronic pain. The utility of oral butorphanol in dogs is limited by the short duration of action and decreased efficacy compared to morphine. In contrast, the clinical impression is that cats with mild to moderate pain frequently respond well to oral butorphanol. Butorphanol is dosed empirically at a dose of 0.5 to 4 mg/kg, PO, TID to QID. As with morphine, the dose is started low and incrementally increased.

Robertson et al (personal communication) at the University of Florida have recently evaluated analgesic activity of buprenorphine in cats using a thermal threshold testing model. A dose of 20 µg/kg was administered orally in syrup. Analgesic benefits were noted within 30 minutes of administration and were shown to last for at least 6 hours following administration. Clinically a dose of 10-20 µg/kg may be used in this manner and re-dosed at 6-12 hour intervals.

Transdermal administration of opioids. A transdermal administration system has been developed for the continuous delivery of fentanyl (fentanyl patch: Duragesic, Janssen Pharmaceutica). The transdermal system is designed to maintain effective plasma concentrations of fentanyl, thereby promoting continuous analgesia over approximately 72 hours after the initial 6-24 hour loading period. The patch is applied to a section of skin that has been clipped of hair (not shaved) and gently cleaned. The optimum dosing schedule has not been established for the dog and cat and as a result the analgesic benefit to individual patients is somewhat inconsistent. Effective target plasma concentrations generally considered in the range of 1-2 ng/ml. The patch is available in four sizes, delivering 25, 50, 75, or 100 µg/hour. Empirically, small dogs (< 10 kg) receive a 25 µg patch, medium dogs (10 to 29 kg) receive a 50 µg patch, and large dogs (>30 kg) receive a 75 µg patch. Cats and very small dogs may receive a 25 µg patch that has been partially taped over to decrease the amount of fentanyl absorption. Regardless of the dose administered, the animal must be monitored for side effects typical of the opioids, particularly respiratory depression. It is generally recommended that owners return their animal for patch changes and so that proper disposal of the patch occurs. As with other opioids concern for public health safety is essential.

Table 1. Clinically Useful Dosages Of Selected Opioids For Dogs And Cats