Mode of Analgesic Action
Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAID) are presumed to exert their analgesic effects by inhibiting prostaglandin synthesis in the periphery; however, this probably is an oversimplified view of their action. In the periphery, various chemical mediators, such as serotonin, substance P, bradykinin, and histamine, are released in addition to prostaglandins in response to tissue injury, and the physiologic response to these chemicals is complex. These substances do not all produce pain when experimentally injected as individual substances. Instead, the combined effects of multiple chemicals are required before a pain response is produced. For example, when histamine, prostaglandin E2, or bradykinin is administered alone, pain does not result; when all the agents are given together, the combination produces intense pain. Therefore, prostaglandins probably induce hyperalgesia (excessive sensitivity to pain) in the local sensory nerve receptors when other chemical mediators exert their effects. The analgesic efficacy of an NSAID, however, does not correlate entirely with its capacity for prostaglandin inhibition in the periphery. Acetaminophen, which exhibits its analgesic action by inhibiting prostaglandin synthesis, also can produce analgesia at concentrations that do not inhibit peripheral cyclooxygenase activity and prostaglandin formation. Salicylates also can produce analgesia at concentrations that do not inhibit peripheral cyclooxygenase activity and prostaglandin formation. Therefore, the exact mechanism of NSAID analgesia has yet to be elucidated; however, the analgesic effect of NSAID is likely central in origin and involves substance-P receptors of the neurokinin-1 type and glutamate receptors of the NMDA type in addition to central prostaglandin inhibition. Because spinal administration of NSAIDs reduces the hyperalgesia evoked by spinal substance P and NMDA, the action of the NSAID appears to be independent of peripheral inflammation. NSAID actions through GABAergic pathways, arachidonic acid byproducts, and AMPA receptors also are being studied. Aspirin, the prototypical NSAID, has demonstrated synergistic activity with endogenous opioids at opioid receptors as well as enhancing serotonin's effects in the central nervous system.14,15
Opiates
Opiates can attach to one or more of five opioid receptors: the µ-, δ-, ε-, κ-, and σ-receptors. These receptors can be differentiated further into subtypes (e.g., µ1, µ2, δ1, δ2, κ1, κ2, and κ3). Animal models suggest that as many as seven subtypes of µ-receptors may exist, but it is not known how many of these can be found in humans. Stimulation of µ1-receptors may be responsible for the desired effects of supraspinal analgesia, and stimulation of µ2-receptors may lead to unwanted consequences such as respiratory depression, euphoria, constipation, and physical dependence. Some κ-receptors, as well as δ- and ε-receptors, also mediate analgesic response, although the role of ε-receptors is not fully understood. Autonomic stimulation, dysphoria, and hallucinations may be caused by σ-receptors. These are not considered true opioid receptors, but may interact with some opioid-like agents.
The effect of opiates on these receptor subtypes is gradually being discovered. Morphine can stimulate µ1-, µ2-, and κ-receptors, and perhaps this ability to stimulate multiple receptors accounts for morphine's mixed analgesic and side effect profile. Pure opiate antagonists (e.g., naloxone) occupy opiate receptors without eliciting a direct response and block the access of opiate agonists, such as morphine, to these receptors. As a result, pure narcotic antagonists block both the desired and undesired opiate effects. Pentazocine and butorphanol (both mixed agonist–antagonists) produce analgesia through stimulation of κ-receptors, but cause unwanted dysphoria and hallucinations through their effect on σ-receptors. Pentazocine and butorphanol also block access of morphine to µ-receptors, leading to withdrawal symptoms in individuals who are physically dependent on morphine or its analogs.
In the spinal cord, the highest concentration of opioid receptors is located around the C-fiber terminal zones in the lamina 1 of the dorsal horn and the substantia gelatinosa. The µ-opioid receptors constitute approximately 70% of the total receptor population; δ- and κ-receptors account for 24% and 6% of the population, respectively. µ-Receptors also are located in the afferent terminals. Because morphine has a 50 times higher affinity for the µ-receptor than for the δ- or κ-receptors, it is a very effective analgesic. The pharmacologic action of opioids depends on the availability of opioid receptors, and the cutting of peripheral nerves leads to degeneration and loss of opioid receptors in the nerve itself. As a result, postamputation pain often is not relieved by morphine or other opioids.
Opioids produce analgesia by three main mechanisms16:
- Presynaptically, opioids reduce the release of inflammatory transmitters (e.g., tachykinin, excitatory amino acids, and peptides) from the terminals of afferent C-fiber neurons after activation of opioid receptors.
- Opioids also can reduce the activity of output neurons, interneurons, and dendrites in the neuronal pathways by means of postsynaptic hyperpolarization.
- Opioids also inhibit neuronal activity via GABA and enkephalin neurons in the substantia gelatinosa.
Analgesic Adjunctive Agents
Analgesic medications often are prescribed concurrently with other drugs to enhance analgesia or to treat pain exacerbations. These adjunctive medications are most often used in the management of chronic pain, particularly when the dose of the primary analgesic has been optimized or when the underlying condition has progressed and is no longer adequately controlled by the primary analgesic agent. Other adjuvant agents may be added to analgesic therapy to reduce side effects, such as excessive sedation, nausea and vomiting, or constipation. The most common drug classes used as adjunctive analgesic agents are corticosteroids, anticonvulsants, heterocyclic antidepressants, α2-adrenergic agonists, NMDA receptor antagonists, local and oral anesthetics or antiarrhythmics, antihistamines and neuroleptics. Adjunct analgesic agents may be used as the primary analgesic agent in the treatment of neuropathic pain syndromes, where the usefulness of opioids is under debate. Neuropathic pain syndromes do not respond to NSAIDs.
Corticosteroids, such as dexamethasone, are useful in reducing pain associated with cerebral and spinal cord edema and in treating refractory neuropathic pain and bone pain, particularly metastatic bone pain. Corticosteroids may also provide other beneficial effects, such as mood elevation, antiemetic activity, and appetite stimulation.17
Antidepressants are commonly used to treat neuropathic pain (e.g., diabetic neuropathy, postherpetic neuralgia) and pain associated with insomnia or depression.18 They are used to treat fibromyalgia, a syndrome characterized by diffuse muscle and joint pain, which is thought to result from central dysregulation. Their analgesic effect is independent of their antidepressant effect. Postulated mechanisms of action involve blockade of norepinephrine reuptake, antagonism of histamine and muscarinic cholinergic receptors, α-adrenergic blockade, or suppression of C-fiber evoked activity in the spinal cord.19
Anticonvulsants; antiarrhythmics; α2-adrenergic antagonists; and the NMDA receptor antagonists, ketamine and dextromethorphan, also have been used to manage neuropathic pain with varying degrees of success. Antihistamines, such as hydroxyzine and promethazine, are often prescribed postoperatively to augment the analgesic effects of opioid agents. Hydroxyzine may provide minimal analgesia, whereas little evidence exists to confirm analgesic action for promethazine.20 The addition of phenothiazines and antihistamines may be useful in alleviating opioid-induced nausea and vomiting; however, these agents may potentiate orthostatic hypotension, respiratory depression, sedation, and extrapyramidal side effects.21 Use of these agents should not be a substitute for appropriate doses of opioid analgesics.
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