Opioids and NSAIDs for perioperative 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. Non-steroidal anti-inflammatory drugs are commonly being administered during the perioperative period. Debate exists as to when to administer the drugs (preoperatively vs. postoperatively). Since intraoperative hypotension is always possible, the author prefers to administer NSAIDs during or after surgery once adequate perfusion pressures have been assured during anesthesia. While data exists to support the safe use of preoperative NSAIDs in healthy patients undergoing relatively short periods of anesthesia, if the approach of reducing risk during anesthesia is taken, it is rational to wait until surgery is nearing completion before administering NSAIDs.

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) (Table 1), and a third is to incorporate regional nerve blocks whenever possible prior to surgical insult of tissue (Table 2). 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.

Local anesthetics act either by blocking sodium channels that prevent nerve impulse transmission and nociceptor excitation, or by inhibiting modulatory nociceptive processing when administered centrally. In addition to their well-known topical, local and regional effects, recent studies have documented the efficacy of low dose intravenous lidocaine infusions in the management of hyperalgesia and neuropathic pain states induced by trauma or surgical procedure.

Non-steroidal anti-inflammatory drugs continue to be the mainstay of chronic pain management in both human and veterinary patients. Recent development of more selective agents has generated considerable interest in their use for intra- and postoperative pain as well. Traditionally, it has been believed that the analgesic effects of NSAIDs are related to their ability to inhibit cyclooxygenase activity and prevent prostaglandin synthesis and peripheral nociceptor sensitization. However, there is considerable evidence that at least some NSAIDs have a central spinal site of action, and may act synergistically with other analgesic compounds.

Alpha 2 adrenergic agonists bind to alpha 2 receptors located in the dorsal horn of the spinal cord, modulating the release of substance P, calcitonin gene-related peptide and various other neurotransmitters involved in rostral transmission of nociceptive information. Opioids likely exert their analgesic action through similar modulatory pathways and co-administration may result in additive or synergistic drug interactions. In humans alpha 2 agonists are often used as "rescue therapy" when opioid tolerance has developed. Use in surgical patients should be reserved for patients that have been stabilized with normal cardiopulmonary function.

Nonpharmacologic therapy

In addition to drug intervention, there are a number of nonpharmacologic methods being employed to supplement analgesia. The importance of good nursing care in animals recovering from surgery cannot be overemphasized. Techniques such as physiotherapy, chiropractic or massage therapy may help to alleviate pain following trauma, and may facilitate an earlier return of function.

Table 1. Sedative analgesic combinations for MINOR surgical and diagnostic procedures

§ Medetomidine doses are µg/kg (note in table).

‡ Induction of general anesthesia can be accomplished with minimal doses of Propofol, Thiopental, or Ketamine following initial exam or diagnostic procedure.

* Anticholinergics are routinely co-administered with these regimens when continuing to general anesthesia (glycopyrrolate 0.01 mg/kg IM).

• In old animals sedated with an opioid, or opioid and phenothiazine combinations induction to anesthesia is often possible with low IV doses of benzodiazepine.

Table 2. Regional anesthesia techniques

§ Inhalant anesthetic dose requirements are usually significantly reduced. Appropriate monitoring including end-tidal CO2, pulse oximetry, and arterial blood pressure should be used to monitor respiratory and cardiovascular depression.