Opioids for acute and chronic pain management (Proceedings)

Patient stress is probably a contributing factor in some cases of adverse patient outcome. Stress during induction of anesthesia can increase circulating catecholamine concentration predisposing the heart to arrhythmias. Additionally, stress or anxiety can lead to increased doses of anesthetic agents resulting in excessive anesthetic depth once the patient is anesthetized. Premedication with a tranquilizer or sedative will help reduce anxiety and stress during the perioperative period.

Use of analgesics prior to surgery (preemptive analgesia) may also be beneficial. Opioids are commonly incorporated into premedication protocols to facilitate sedation and analgesia. When opioids are used, anesthetic drug associated respiratory depression may be enhanced, but adequate patient monitoring will facilitate early detection of significant respiratory depression and allow appropriate management

Pain Management

Acute clinical pain typically arises from soft tissue trauma or inflammation, with the most common example being postoperative surgical pain. Though it does not serve a protective function in the sense that physiologic pain does, acute pain does play a biologically adaptive role by facilitating tissue repair and healing. This is achieved by hyper-sensitizing the injured area (primary hyperalgesia) as well as the surrounding tissues (secondary hyperalgesia) to all types of stimuli, such that contact with any external stimulus is avoided and the reparative process can proceed undisturbed. This realization is not, however, a license to allow patients to suffer needlessly in the postoperative period or upon presentation in the emergency room. By having an appreciation of the underlying functional basis of such pain the practitioner is able to initiate appropriate pain management strategies while taking steps to optimize wound healing.

Pain Physiology

An important conceptual breakthrough in understanding pain physiology is the recognition that pain following most types of noxious stimulation is usually protective and quite distinct from pain resulting from overt damage to tissues or nerves. It plays an integral adaptive role as part of the body's normal defense mechanisms, warning of contact with potentially damaging environmental insults and initiating behavioral and reflex avoidance strategies. It is also often referred to as nociceptive pain because it is only elicited when intense noxious stimuli threaten to injure tissue. It is characterized by a high stimulus threshold, is well localized and transient, and demonstrates a stimulus-response relationship similar to the other somatosensations. This protective mechanism is facilitated by a highly specialized network of nociceptors and primary sensory neurons which encode the intensity, duration and quality of noxious stimuli and, by virtue of their topographically organized projections to the spinal cord, its location.

Nociception

The physiologic component of pain is termed nociception, which is comprised of the processes of transduction, transmission and modulation of neural signals generated in response to an external noxious stimulus. It is a physiologic process that, when carried to completion, results in the conscious perception of pain. In its simplest form the pain pathway can be considered as a three neuron chain, with the first order neuron originating in the periphery and projecting to the spinal cord, the second order neuron ascending the spinal cord, and the third order neuron projecting to the cerebral cortex. On a more complex level, the pathway involves a network of branches and communications with other sensory neurons and descending inhibitory neurons from the midbrain that modulate afferent transmission of painful stimuli.

Descending Modulation of Pain

The descending modulatory system has been described as having four tiers. The final, and perhaps most important, site involved in the descending modulation of nociceptive information is at the level of the spinal cord. Just as dorsal horn processing is vital to the integration of ascending noxious input, its role in anti-nociception is equally crucial. Dense concentrations of GABA, glycine, serotonin, norepinephrine and the endogenous opioid peptides (enkephalins, endorphins and dynorphins) have been identified in dorsal horn neurons, and all produce inhibitory effects on nociceptive transmission. Specifically, the spinal opioid system fine-tunes descending control mechanisms by acting both presynaptically, as well as postsynaptically. Communication among dorsal horn neurons involves complex interactions, and it is now apparent that a single neuron may be influenced by many neurotransmitters, that each neurotransmitter may have numerous actions in a given region, and that multiple neurotransmitters may exist within a single neuron. Simply stated on a more global level, nociceptive processing is a three-neuron chain with dual input at each level. Discriminative and affective aspects of pain are transmitted in related, and yet distinct ascending pathways, with modifications made by both segmental and descending modulatory systems.

Management of Surgical Pain

Most clinical pain syndromes associated with surgery are complex and often involve more than one type of pain. It can be very difficult to predict the mechanisms mediating pain associated with multiple types of tissue and neuronal damage. Acute and chronic pain states may occur simultaneously. An animal with osteosarcoma may present with classic symptoms of chronic inflammatory pain and hypersensitivity, while surgery to amputate the affected limb will generate pain sensation typical of acute tissue injury. Amputation following a traumatic event may also initiate neuropathic pain associated with large nerve transection. It should not be surprising that a single drug administered at a "standard" dose would not be an effective strategy for managing all types of pain associated with surgical treatment. The clinical objective following surgery should be to minimize debilitating pathologic pain while maintaining the protective, adaptive aspects associated with physiologic pain.

One of the strategies used to achieve this objective is the concept of preemptive analgesia. The plasticity of the nervous system in response to noxious input has been well established. Initiating treatment prior to, or as early as possible after, acute insult is believed to inhibit peripheral and central sensitization processes. A second strategy involves combining drugs and techniques to achieve beneficial additive or synergistic analgesic effects (multimodal or balanced analgesia), and a third is to incorporate regional nerve blocks whenever possible prior to surgical insult of tissue. With this approach, lower anesthetic doses can be used thereby reducing potential undesirable side effects during the perioperative period.

Analgesic Agents

Opioids are a diverse group of natural and synthetic drugs used extensively in the management of post-operative pain in man and animals. Use in the surgical patient is becoming more widespread with the development of novel delivery systems such as the transdermal patch. The traditional view that a given drug always behaves as either an agonist or an antagonist at a particular receptor is a gross over-simplification, and recent studies have demonstrated that a number of variables appear to contribute to the effectiveness of various opioids in the clinical setting. Dosage, species, and stimulus intensity, character and duration can all alter the overall analgesic effect of an opioid. Opioids dampen peripheral and central afferent nociceptive transmission and thus, are extremely effective in treating acute inflammatory pain associated with recent surgical trauma. They are not, however, equally efficacious in managing all types of pain. Neuropathic pain syndromes are often characterized by a poor or short-lived response to opioid therapy.

Morphine

Morphine is the prototypical opioid drug. Morphine is a full agonist at mu, delta, and kappa receptors. It also may have agonistic properties at other receptors at extremely high doses. Morphine administration results in analgesia, constipation, urinary retention, and respiratory depression. Clinically significant respiratory depression occurs at clinically used doses in humans and some primates, but in most veterinary species it doesn't result in dangerous respiratory depression unless given at very high doses or in patients with certain types of CNS or pulmonary disease. Morphine is a useful analgesic in dogs, cats, horses, and rats. Morphine is also a reasonable antitussive but is not commonly used for this effect because of addiction potential.

Morphine is well known for causing nausea and vomiting (in those species capable of vomiting). The incidence of vomiting is influenced by co-administration of drugs and usually limited to the first 15 minutes following injection. Morphine is usually given IM or SC but can be given IV if diluted and given slowly. When given IV it can cause histamine release and circulatory shock, but this is rare if administered correctly. Morphine can cause urinary retention and constipation. This doesn't occur in all patients, but can be uncomfortable when it does. Morphine alters gastroinestinal motility resulting in initial defecation followed by inhibited progressive motility.

Hydromorphone

Hydromorphone is a full mu agonist used in human and veterinary medicine. Clinically it is used very much like morphine. Hydromorphone can cause vomiting, but the incidence is lower than morphine. Hydromorphone is much less expensive than oxymorphone and lasts about as long as morphine. It can be administered IV, IM, and SC.

Hydromorphone has been associated with the development of hyperthermia in cats. This appears to be a central alteration in thermoregulation and usually is mild (e.g. 103-104 degrees) however; it may reach critical levels in rare patients and body temperature should be monitored. While most commonly associated with hydromorphone, hyperthermia may be seen with almost any of the mu receptor agonists.

Fentanyl

Fentanyl is a highly lipid soluble, short acting, full mu agonist opioid analgesic. It is useful for intraoperative and postoperative analgesia. Fentanyl has duration of action of about 30 min to 2 hours. It is usually administered by a continuous intravenous infusion or by repeated intravenous boluses because of its short duration of action. Fentanyl is also available in a transdermal patch that is specifically designed for human use. The patch releases a constant amount of fentanyl per hour. The fentanyl is subsequently absorbed across the skin and taken up systemically. The patch is designed for human skin and body temperature. Its use in animals has been associated with huge variations in plasma drug concentrations. Patch adherence and skin preparation are also problems in veterinary patients.

Buprenorphine

Buprenorphine is a partial mu agonist. It is relatively lipid soluble and has a high affinity for the mu receptor. Buprenorphine has a slow onset but a very long duration of action (about 6 to 12 hours). It is used for postoperative pain control in patients with mild to moderate pain intensity.

Butorphanol

Butorphanol is a mu receptor antagonist and a kappa receptor agonist and it was believed it would have some useful analgesic properties without the abuse potential. It is approved for use as an antitussive in dogs and an analgesic in cats and horses. It is not labeled as an analgesic in dogs. Some studies have examined its use as an analgesic in dogs with mixed results. Butorphanol demonstrates a "ceiling effect" to its anlagesic action and cannot create the profound analgesic state that other opioids can. Its analgesic action is believed by most to be reasonable for mild types of pain but not suitable for moderate to severe pain. Because of the "ceiling effect" at mu receptors, butorphanol has not been associated with the profound respiratory depression observed with mu agonsists. Butorphanol is not commonly associated with vomiting and constipation. Butorphanol is used by some as an antiemetic at doses greater than those used for analgesia. Its antiemetic action appears to be most useful before administration of chemotherapuetic agents to dogs.

Nalbuphine

Nalbuphine is classified as agonist-antagonists and are clinically similar to butorphanol. Nalbuphine is used more commonly in human medicine than butorphanol. Some anesthesiologists use nalbuphine for antagonism of mu agonists since reversal is not associated with complete loss of analgesia.

Tramadol

Tramadol is a an opioid receptor agonist that has opioid and non-opioid mechanisms of action. It appears the administration of naloxone can antagonize some of the analgesia produced by Tramadol, but the administration of an alpha-2 antagonist is also required to block most of the analgesia. This is a desirable combination of mechanisms since alpha-2 agonists and opioids have additive or synergic analgesic actions. Tramadol also appears to inhibit the reuptake of norepinephrine and serotonin. Tramadol works well in humans, but doesn't appear to work in dogs and cats. Metabolism is required to produce active metabolites responsible for the non-opioid mechanisms. Species differences in liver metabolism result in variable non-opioid analgesia.

Naltrexone and Naloxone

Naltrexone and naloxone are opioid receptor antagonists. They will block the actions of all mu and kappa agonists. Naltrexone has reasonable oral bioavailability and is usually dispensed to addicts to keep them from taking heroin. Naloxone use is usually reserved for emergency situations such as overdose or profound respiratory depression. Naloxone is given intravenously and has a duration of action of about 2 hours. Repeated administration is required when antagonizing long acting opioids such as methadone or buprenorphine.