Opioids (Proceedings)

Even in the modern day, opioids remain the cornerstone of analgesia. Aesop's fables gave rise to the saying that "Familiarity breeds contempt"; these drugs are often underappreciated because of their long history as analgesics. Opioids may not be "novel" but they are critical to pain relief and a strategy that our patients benefit from. Opioids are have a high margin of safety and efficacy, and are reversible should the need arise. This lecture will review pertinent information about opioids, and case examples where the use of opioids is beneficial.

The poppy plant, from which opium (and thus morphine) is derived, was known to have analgesic properties as far back as 5000 BC. However, morphine (the "prototype" opioid) was not actually isolated until the early 1800s—which was the same time an interest in general anesthesia was rising, to facilitate the practice of surgery. However, it was not until the late 1980s when Wall proposed the benefit of adding analgesia to reduce pain before the painful or noxious sensation began. Indeed, evidence suggests that pain in the early postoperative period is a predictor of long-term pain (Katz et al. 1996). After much investigation, it is believed that it is the processing of pain at the level of the spinal cord that heavily contributes to the long-term response of the body. Opioids, which work at the dorsal horn of the spinal cord as well as supraspinally, can modulate this pain transmission (although unlike local anesthetics they cannot prevent it). In addition to analgesia, opioids can contribute to sedation, a reduction in anesthetic drugs necessary, and cardiovascular stability of patients who are receiving opioids prior to anesthesia.

Because the effects of opioids are related to the receptor the opioid targets, a brief review of opioid receptors is warranted. Our primary target is the OP3 or μ receptor, as this receptor is primarily responsible for the analgesic effects of opioids. Drugs that target this receptor include fentanyl, hydromorphone, meperidine, methadone, morphine, remifentanil, and tramadol. Drugs that target the μ receptor have a perfect efficacy and are all as potent, and potentially quite a bit more potent, than morphine. Buprenorphine, which works at the μ receptor, is more potent but less efficacious than morphine. Some opioids also target the OP2 or κ receptors (butrophanol, pentazocine, nalbuphine). While these drugs may be more potent than morphine, they are not as efficacious as morphine. In the cat, there is some evidence that butrophanol may provide acceptable analgesia of longer duration than in the dog for procedures that are not highly invasive. The last receptor class is OP1, or the d receptor, which dose not appear to have much to offer in regards to acute analgesia. However, there may be benefits for chronic pain (Gaveriaux-Ruff et al. 2011).

In addition to opioids providing analgesia alone, there is a growing body of research suggesting that opioids, when combined with other analgesics, may provide even better analgesia than when administered alone (multimodal analgesia). For example, recent work by Slingsby suggests that in a research model, cats given a combination of 10 mcg/kg buprenorphine with 20 mcg/kg of dexmedetomidine had better analgesia than if either drug were administered alone—with analgesia that was earlier in onset and with a longer duration (Slingsby, Murrell and Taylor 2010). A similar synergism has been demonstrated in veterinary species between non-steroidal anti-inflammatory drugs (NSAIDs) and opioids.

Various routes of administration can balance an analgesic plan. Most opioids are systemically administered (intramuscularly or intravenously). However, opioids are easily incorporated into constant rate infusions (CRIs). First, one must select a rate they would like to administer the opioid. If there is no published data readily available on the dosage to deliver per hour, a rate can be safely estimated if the duration of the drug is known, and the range of the dose is divided by the drug duration. For example, hydromorphone is expected to last approximately 4 hours, with a typical dose ranging from 0.05mg/kg to 0.2 mg/kg. Therefore, a CRI of hydromorphone would range from 0.0125 o 0.05 mg/kg per hour. Many practices may not have specialized equipment with which to administer this range of drug. An alternative is to administer this drug with the patient's fluids, if pre-cautions are taken to avoid bolusing those fluids to the patient. For example, let us consider a 50 kg dog receiving a liter of fluid in the post-operative period. We could select a fluid rate and add the appropriate number of milligrams to the liter. If 2.2 ml/kg/hr were selected, the total fluids required equals 110 mls/hr, and therefore a liter bag of fluids would last for about 9 hours. If we selected a mid range for the hydromorphone CRI (0.025mg/kg/hr), we would need a total of 1.25mg of hydromorphone per hour. Therefore, we could add 9 hours worth of hydromorphone to a one-liter bag (11.25 mg).

Opioids are also used as part of epidural analgesia. The benefit of administering an epidural opioid as opposed to systemic opioid administration is the increased duration of action without the side effects of a systemically administered opioid. In order to reap this benefit, the opioid selected should remain in the epidural space with a long enough duration to provide post-operative analgesia. Opioid drugs that are hydrophilic, as opposed to lipophilic, in nature can reasonably achieve this, with the classic opioid exhibiting this property being morphine. A successfully placed morphine epidural may last 16-24 hours, providing the patient with maximum analgesic benefits but minimal systemic side effects. Another key characteristic of drugs for administration into the epidural space is availability in a form without preservatives. Morphine comes in a preservative free formulation, but other opioids may require special compounding.

Is there benefit to administering per os? Buprenorphine can be administered buccally for oral transmucosal (OTM) absorption, resulting in almost 100% bioavailability after OTM administration in the cat. The cat is unique in that that have a more alkaline mouth that may enhance absorption of this drug. Small studies in the dog demonstrate there may be clinical analgesia present in the canine receiving OTM buprenorphine, but pharmacokinetic data suggests that the bioavailability is less than half of what is seen in the cat (Abbo et al. 2008). Buprenorphine may not be the only opioid that is suitable for OTM administration in the cat; methadone has shown promise as well.

Two drugs that would be convenient for oral administration, given their ready availability, are codeine and oral morphine. However, these drugs are less than ideal clinically. Codeine is only 4% bioavailable, making it difficult to believe claims that it provides adequate analgesia. Oral morphine has extremely variable individual patient responses, but generally low plasma concentrations, also limiting its clinical utility.

Tramadol, an opioid that works weakly at the m opioid receptor as well as has serotonin and norepinephrine reuptake inhibitor properties, is gaining popularity in veterinary medicine as a send home analgesic. It has good oral bioavailability in cats; plasma levels of its active metabolite O-desmethyl-tramadol were low in dogs, but yet analgesia was still considered adequate. The half-life of tramadol is longer in cats than dogs, so dosing intervals can be extended in the feline. There appears to be a synergistic action of tramadol with NSAIDs, suggesting that these combination may provide adequate send home analgesia after procedures considered outpatient.

In summary, there is still evidence in our modern world that opioids provide a solid cornerstone of analgesia with which to build our pain management plan upon. Their safety profile, versatility and reversibility make this drugs a vital part of veterinary practice.

References

Abbo, L. A., J. C. Ko, L. K. Maxwell, R. E. Galinsky, D. E. Moody, B. M. Johnson & W. B. Fang (2008) Pharmacokinetics of buprenorphine following intravenous and oral transmucosal administration in dogs. Vet Ther, 9, 83-93.

Gaveriaux-Ruff, C., C. Nozaki, X. Nadal, X. C. Hever, R. Weibel, A. Matifas, D. Reiss, D. Filliol, M. A. Nassar, J. N. Wood, R. Maldonado & B. L. Kieffer (2011) Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain, 152, 1238-48.

Katz, J., M. Jackson, B. Kavanah & A. Sandler (1996) Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain, 12, 50-55.

Slingsby, L. S., J. C. Murrell & P. M. Taylor (2010) Combination of dexmedetomidine with buprenorphine enhances the antinociceptive effect to a thermal stimulus in the cat compared with either agent alone. Vet Anaesth Analg, 37, 162-70.