The greek god "Morpheus" was the namesake for morphine. Morpheus was the god of dreams.
The greek god "Morpheus" was the namesake for morphine. Morpheus was the god of dreams. The chemist Serturner was the first to publish the isolation of morphine from the opium poppy, and named this new chemical after Morpheus, presumably because he recognized that it caused somnolence. Prior to the chemical isolation of morphine, opium had been well-established to induce analgesia, as well as euphoria and sedation, which lead to its popularity as a recreational habit in certain cultures. The term "opioid" refers to any drug derived from opium, or with chemical structure similar to drugs derived from opium. "Narcotic" refers to any drug, of any class, that induces a somnolent-like state (aka narcosis), and does not specifically infer any analgesic properties.
The most well accepted and relevant opioid receptors are mu, kappa, and delta. They are members of the transmembrane G-protein coupled superfamily of receptors found within the CNS and other parts of the body. Opioid receptors of all 3 types have been identified in the spinal cord dorsal horn (laminae II and III), in the medulla, hippocampus, thalamus, raphe nucleus, all areas of the cerebral cortex, and in the periphery including joint synovial membranes, pleural membranes, etc. It has also been shown that opioid receptors can be newly synthesized and expressed in tissues at the onset of inflammation, which renders potential therapeutic benefits to local application of opioids in peripheral tissues. The relative percentage of opioid receptor types and their distribution varies between species and few of the common veterinary species have been studied. In the adult human brain, the relative percentage of mu, kappa, and delta receptors is approximately evenly divided, with 29% of cortical receptors being mu, 34% being kappa, and 37% being delta. The relative distribution of receptor types in various species may be one explanation for the different behavioral or analgesic effects elicited by opioids with different agonist or antagonist activities. For example, in birds it is well established that analgesia is superior with butorphanol compared with morphine. Because butorphanol is a kappa agonist and mu antagonist, one could speculate that birds have a higher proportion of kappa receptors in the areas of their CNS that process information about pain.
A drug that binds the receptor and causes a conformational change resulting in ion flux and intracellular changes is referred to as an agonist. A drug that binds a receptor but causes no conformational change and simply blocks the receptor from binding by other drugs is referred to as an antagonist.
Drugs that are agonists at the mu receptor result in spinal and supraspinal (CNS) analgesia, sedation in some species (primates, dogs, exotics), euphoria, bradycardia, mild respiratory depression (except primates), ileus, constipation, nausea, vomition, urinary retention. Kappa agonist drugs result in mild supraspinal analgesia, mild sedation. Delta agonist drugs cause dysphoria and agitation. Thus a pure agonist drug such as morphine will have effects at all 3 receptors and the clinical result is therefore predictable. Opioids are also classified with respect to their relative receptor affinity, with morphine being the gold standard to which all others are compared. By definition, morphine has a receptor affinity = 1. If an opioid has a receptor affinity = 10 (e.g. oxymorphone), this simply means that it takes 1/10th the number of molecules to elicit the same result, not that the drug is "better" or more analgesic, just more potent. This is why morphine is typically dosed at 1.0 mg/kg and oxymorphone at 0.1 mg/kg.
As with any drug, there will be individual variability in opioid effects and analgesia. This may be due to differences in the intensity of pain perceived between individuals or the difference in pain tolerance in a given individual. It also may be due to differing bioavailability of the drug depending on the patient. For example, a geriatric patient generally has a lower volume of distribution; therefore a given dose of drug in mg/kg will result in higher plasma concentrations. A second example is the species-specific bioavailability of oral morphine (MS Contin). In dogs there is a huge 1st pass effect, such that therapeutic concentrations of morphine are rarely achieved, whereas in people this 1st pass effect does not occur and therefore MS Contin is analgesic in people. There may also be differences in metabolism and clearance of the drug depending on the species or an individual animal's renal and hepatic function. For example, in cats morphine is probably not broken down into its glucuronide metabolites, resulting in longer circulating half-lives of the parent drug. Finally, in people at least, there are genetic differences in opioid responsiveness: for example morphine induced respiratory depression is greatest in the Native American Indian, followed by Caucasians, followed by Asians. These genetic differences have not been studied in veterinary medicine, but many have observed that Northern Breeds of dogs (Husky, Malamute) become very vocal and dysphoric after high doses of opioids and seem to do "better" when low doses are used, combined with sedation.
Most opioids administered by the oral route undergo significant 1st pass metabolism in the dog. Parenterally administered opioids are metabolized in the liver, with active or inactive metabolites being excreted renally. Hepatic extraction of opioids is proportional to hepatic blood flow, so under anesthesia if cardiac output is decreased and hepatic blood flow decreases, the duration of effect of the administered opioid may be more prolonged. Lipid solubility of the opioid determines its rate of uptake into the CNS and spinal cord and hence determines onset of action; for example, fentanyl is highly lipid soluble and the onset time to effect after IV administration is 1-2 minutes.
The agonist opioids in common clinical practice include: morphine, hydromorphone, oxymorphone, meperidine, methadone, fentanyl, and remifentanyl. These drugs all provide the effects predictable from mu receptor activation, but most importantly are the gold standard for analgesia and should be a component of therapy before, during, and after any major surgical event, including ovariohysterectomy, declaws, and castration. All of these drugs cause the undesirable (sometimes desirable) side effects noted for mu, kappa, and delta receptor activation, so I will focus on the differences between their individual use.
Morphine can cause histamine release, particularly when higher doses are given intravenously as a bolus. Clinical signs of histamine release are vasodilation, flushing, facial swelling, hypotension, and urticaria. Very slow IV administration, if necessary, will minimize histamine release, but preferably this drug should be given intramuscularly or subcutaneously. It has been shown in humans that metabolites of morphine, specifically morphine-3-glucuronide and morphine-6-glucuronide, are responsible for much of the analgesic effect of this drug. Cats are unable to synthesize glucuronide metabolites. Clinical studies have verified that morphine is not a very useful analgesic in cats, likely due to the lack of glucuronide metabolite production. Of the agonist opioids, morphine is the most likely to cause nausea and vomition and the least likely to cause panting. It is one of the least expensive opioids and the longest lasting (4-6 hours), so it is an economical choice for dogs.
Both of these drugs are effective in dogs as well as cats. Both drugs are less likely to induce vomition than morphine and both drugs can safely be given IV due to their lack of histamine-releasing properties. Panting is more common with oxymorphone and hydromorphone than with morphine. Hydromorphone, but not oxymorphone, has been documented to cause dramatic post-operative hyperthermia in cats (temperatures reaching 107° F). This is most often a problem when the cat has become cold during surgery and then homeostatic mechanisms to rewarm seem to overshoot normothermia. Personal impression is that cats sedate a little better with oxymorphone, particularly when it is combined with low doses of acepromazine or midazolam.
This is a short acting agonist opioid that has many similar properties to morphine, i.e. histamine release, nausea. Clinical impression is that it does not cause as much sedation as morphine in dogs. Because meperidine's duration is ~ 1 hour it is not a very useful opioid for perioperative analgesia, but may be useful for mild sedation for diagnostic procedures.
This drug is a racemic mix for R and S isomers, and only the R isomer is active at the mu receptor. It does not appear to have as much intrinsic euphoric or analgesic activity as the other mu agonists, but it also has some pharmacological properties that make it an interesting analgesic. Methadone is an NMDA antagonist, so it may be useful in preventing or treating wind up pain in chronic pain states. Its long duration and lack of dramatic sedation make it a reasonable choice for moderately painful procedures as well. In people there is a high incidence of inter-individual bioavailability and half-live, so this should be considered as a possibility in veterinary patients as well when using this drug for analgesia.
The (+) isomer of tramadol is a weak mu agonist, as is the metabolite 0-desmethyltramadol. Tramadol is currently very popular for use in chronic pain states, but in the U.S. only the oral formulation is available. Injectable tramadol has been shown to have moderate analgesic efficacy in cats after ovariohysterectomy. Tramadol also has activity as a serotonin reuptake inhibitor and norepinephrine reuptake inhibitor in the CNS, so these 2 mechanisms may contribute to an analgesic effect.
These 2 opioid agonists have a very short duration of effect and are extremely useful as an IV constant rate infusion (CRI), for administration both during and after surgery. Fentanyl undergoes hepatic metabolism and long CRI's (days) will cause accumulation of fentanyl. This drug is also taken up in the lung, so this mechanism contributes to waning fentanyl levels when a CRI is stopped. The fentanyl patch is popular for post-operative pain, but it is important to remember that it takes up to 24 hours to reach therapeutic levels after placement in dogs, and 12 hours in cats, and that individual serum levels can vary dramatically between patients. The use of remifentanyl is very much like fentanyl, but the onset and offset time is almost immediate, as this drug is highly lipid soluble and is metabolized by plasma esterases and undergoes no hepatic metabolism. Therefore, remifentanyl is useful for patients with hepatic insufficiency, but care should be exercised in bolusing the drug or turning it off, as the resultant effects (sudden increased depth or sudden absence of analgesia, respectively) can be dramatic.
Butorphanol, Nalbuphine, and Buprenorphine
Butorphanol is a mixed agonist-antagonist opioid, with agonist activity at kappa receptors and antagonist activity at mu and delta receptors. This drug is not as effective an analgesic as the pure agonist opioids, but it is associated with fewer side effects. Butorphanol is less likely to cause CNS excitement, respiratory depression, or sedation. Clinical impression, however, is that butorphanol is only moderately effective in treating major pain, and should be reserved for simple procedures involving minimal tissue trauma. Butorphanol CRI's can be useful for treatment of refractory nausea at doses of 0.1 – 0.2 mg/kg/hour. Because of butorphanol's antagonist activity at the mu receptor, it will also reverse the clinical effects of agonist opioids, including analgesia.
Nalbuphine is similar to butorphanol and is a mixed agonist-antagonist drug with agonist effects at the kappa receptor. In people nalbuphine has been shown to decrease pain thresholds in males, but not in females. In a recent study at the UW, we found that nalbuphine was worse than saline in treating corneal pain in male dogs. The results of this study will soon be published, but more evidence is needed to document whether nalbuphine has any place in analgesic therapy.
Buprenorphine is a "partial agonist" opioid with high affinity for the mu receptor but moderate intrinsic activity. Thus, buprenorphine has moderate analgesic potency and a long duration of action (8 – 12 hours). It is only mildly sedative in dogs and cats but appears to provide acceptable post-operative analgesia for low-grade pain. In cats and ferrets, but not in dogs, buprenorphine is absorbed transmucosally as well. This is because the pKa of buprenorphine is close to the pH of saliva in the mouth of a cat and ferret and the non-ionized portion of drug is well absorbed across mucosal membranes. This route will not be effective in dogs.