Chapter 10 Analgesics PDF

 CHAPTER 10 Analgesic Agents KEY CONCEPTS The accumulation of morphine metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in patients...

 CHAPTER 10 Analgesic Agents KEY CONCEPTS The accumulation of morphine metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in patients with kidney failure has been associated with narcosis and ventilatory depression. Rapid administration of larger doses of opioids (particularly fentanyl, sufentanil, remifentanil, and alfentanil) can induce chest wall rigidity severe enough to make ventilation with bag and mask nearly impossible. Prolonged dosing of opioids can produce “opioid-induced hyperalgesia,” in which patients become more sensitive to painful stimuli. Infusion of large doses of (in particular) remifentanil during general anesthesia can produce acute tolerance, in which much larger than usual doses of opioids are required for postoperative analgesia. The neuroendocrine stress response to surgery is measured in terms of the secretion of specific hormones, including catecholamines, antidiuretic hormone, and cortisol. Large doses of opioids inhibit the release of these hormones in response to surgery more completely than volatile anesthetics. Aspirin is unique in that it irreversibly inhibits COX-1 by acetylating a serine residue in the enzyme. The irreversible nature of its inhibition underlies the nearly 1-week persistence of its clinical effects (eg, inhibition of platelet aggregation to normal) after drug discontinuation. Regardless of how expertly surgical and anesthetic procedures are performed, appropriate use of analgesic drugs such as local anesthetics, opioids, ketamine, gabapentinoids, acetaminophen, and cyclooxygenase (COX) inhibitors can make the difference between a satisfied and an unsatisfied postoperative patient. Moreover, studies have shown that outcomes can be improved when analgesia is provided in a “multimodal” format (typically minimizing opioid use) as one part of a well-organized plan for enhanced recovery after surgery (ERAS; see Chapter 48). OPIOIDS Mechanisms of Action Opioids bind to specific receptors located throughout the central nervous system and other tissues. Four major opioid receptor types have been identified (Table 10–1): mu (μ, with subtypes μ1 and μ2), kappa (κ), delta (δ), and sigma (σ). All opioid receptors couple to G proteins; binding of an agonist to an opioid receptor causes membrane hyperpolarization. Acute opioid effects are mediated by inhibition of adenylyl cyclase (reductions in intracellular cyclic adenosine monophosphate concentrations) and activation of phospholipase C. Opioids inhibit voltage-gated calcium channels and activate inwardly rectifying potassium channels. Opioid effects vary based on the duration of exposure, and opioid tolerance leads to changes in opioid responses. TABLE 10–1 Classification of opioid receptors.1  Although opioids provide some degree of sedation and in some species can produce general anesthesia when given in large doses, they are principally used to provide analgesia. The clinical actions of opioids depend on which receptor is bound (and in the case of spinal and epidural administration of opioids, the location in the neuraxis where the receptor is located) and the binding affinity of the drug. Agonist–antagonists (eg, nalbuphine, nalorphine, butorphanol, and buprenorphine) have less efficacy than full agonists (eg, fentanyl or morphine), and under some circumstances agonist–antagonists will antagonize the actions of full agonists. Pure opioid antagonists (eg, naloxone or naltrexone) are discussed in Chapter 17. Opioid compounds mimic endorphins, enkephalins, and dynorphins, endogenous peptides that bind to opioid receptors. Opioid receptor activation inhibits the presynaptic release and postsynaptic response to excitatory neurotransmitters (eg, acetylcholine, substance P) released by nociceptive neurons. Transmission of pain impulses can be selectively modified at the level of the dorsal horn of the spinal cord with intrathecal or epidural administration of opioids. Opioid receptors also respond to systemically administered opioids. Modulation through a descending inhibitory pathway from the periaqueductal gray matter to the dorsal horn of the spinal cord may also play a role in opioid analgesia. Although opioids exert their greatest effect within the central nervous system, opioid receptors have also been identified on somatic and sympathetic peripheral nerves. Certain opioid side effects (eg, constipation) are the result of opioid binding to receptors in peripheral tissues (eg, the gastrointestinal tract), and there are now selective antagonists for opioid actions outside the central nervous system (alvimopan and methylnaltrexone). The clinical importance of opioid receptors on primary sensory nerves (if present) remains speculative, despite the persisting practice of compounding of opioids in local anesthetic solutions applied to peripheral nerves. Structure–Activity Relationships A chemically diverse group of compounds bind opioid receptors. These agents have common structural characteristics, which are shown in Figure 10–1. Small molecular changes convert an agonist into an antagonist. The levorotatory opioid isomers are generally more potent than the dextrorotatory isomers. FIGURE 10–1 Opioid agonists and antagonists share part of their chemical structure, which is outlined in cyan. Pharmacokinetics A. Absorption Rapid and complete absorption follows intramuscular or subcutaneous injection of hydromorphone, morphine, or meperidine, with peak plasma levels usually reached after 20–60 min. A wide variety of opioids are effective by oral administration, including oxycodone, hydrocodone, codeine, tramadol, morphine, hydromorphone, and methadone. Oral transmucosal fentanyl citrate absorption (fentanyl “lollipop”) provides rapid onset of analgesia and sedation in patients who are not good candidates for oral, intravenous, or intramuscular dosing of opioids. The low molecular weight and high lipid solubility of fentanyl also favor transdermal absorption (the transdermal fentanyl “patch”). The amount of fentanyl absorbed per unit of time depends on the surface area of skin covered by the patch and also on local skin conditions (eg, blood flow). The time required to establish a reservoir of drug in the upper dermis delays by several hours the achievement of effective blood concentrations. Serum concentrations of fentanyl reach a plateau by 14 to 24 h of application (with greater delays in elderly than in younger patients) and remain constant for up to 72 h. Continued absorption from the dermal reservoir accounts for persisting fentanyl serum levels many hours after patch removal. Fentanyl patches are most often used for outpatient management of chronic pain and should be reserved for patients who require continuous opioid dosing but cannot use the much less expensive, but equally efficacious and long-acting oral agents. Fentanyl is often administered in small doses (10–25 mcg) intrathecally with local anesthetics for spinal anesthesia, and adds to the analgesia when included with local anesthetics in epidural infusions. Morphine in doses between 0.1 and 0.5 mg and hydromorphone in doses between 0.05 and 0.2 mg provide 12 to 18 h of analgesia after intrathecal administration. Morphine and hydromorphone are commonly included in local anesthetic solutions infused for postoperative epidural analgesia. B. Distribution Table 10–2 summarizes the physical characteristics that determine distribution and tissue binding of opioid analgesics. After intravenous administration, the distribution half-lives of the opioids are short (5–20 min). The low lipid solubility of morphine delays its passage across the blood–brain barrier, however, so that its onset of action is slow and its duration of action is prolonged. This contrasts with the increased lipid solubility of fentanyl and sufentanil, which are associated with a faster onset and shorter duration of action when administered in small doses. Interestingly, alfentanil has a more rapid onset of action and shorter duration of action than fentanyl following a bolus injection, even though it is less lipid soluble than fentanyl. The high nonionized fraction of alfentanil at physiological pH and its small volume of distribution (Vd) increase the amount of drug (as a percentage of the administered dose) available for binding in the brain. TABLE 10–2 Physical characteristics of opioids that determine distribution.1 Significant amounts of lipid-soluble opioids can be retained by the lungs (first-pass uptake); as systemic concentrations fall they will return to the bloodstream. The amount of pulmonary uptake is reduced by prior accumulation of other drugs, increased by a history of tobacco use, and decreased by concurrent inhalation anesthetic administration. Unbinding of opioid receptors and redistribution (of drug from effect sites) terminate the clinical effects of all opioids. After smaller doses of the lipid-soluble drugs (eg, fentanyl or sufentanil), redistribution alone is paramount for reducing blood concentrations, whereas after larger doses biotransformation becomes an important driver in reducing plasma levels below those that have clinical effects. Thus, the time required for fentanyl or sufentanil concentrations to decrease by half (the “half- time”) is context sensitive; in other words, the context-sensitive half-time increases as the total dose of drug or duration of exposure, or both, increase (see Chapter 7). C. Biotransformation With the exception of remifentanil, all opioids depend primarily on the liver for biotransformation and are metabolized by the cytochrome P (CYP) system, are conjugated in the liver, or both. Because of the high hepatic extraction ratio of opioids, their clearance depends on liver blood flow. Morphine and hydromorphone undergo conjugation with glucuronic acid to form, in the former case, morphine 3-glucuronide and morphine 6-glucuronide, and in the latter case, hydromorphone 3-glucuronide. Meperidine is N-demethylated to normeperidine, an active metabolite associated with seizure activity, particularly with very large meperidine doses. The end products of fentanyl, sufentanil, and alfentanil are inactive. Norfentanyl, the metabolite of fentanyl, can be measured in urine long after the native compound is no longer detectable in blood to determine chronic fentanyl ingestion. This has its greatest importance in diagnosing fentanyl abuse. Codeine is a prodrug that becomes active after it is metabolized by CYP2D6 to morphine. Ultrarapid metabolizers of this drug (with genetic variants of CYP2D6) are subject to greater drug effects and side effects; slow metabolizers (including genetic variants and those exposed to inhibitors of CYP2D6 such as fluoxetine and bupropion) experience reduced efficacy of codeine. Tramadol similarly must be metabolized by CYP to O-desmethyltramadol to be active. Hydrocodone is metabolized by CYP2D6 to hydromorphone (a more potent compound) and by CYP3A4 to norhydrocodone (a less potent compound). Oxycodone is metabolized by CYP2D6 and other enzymes to series of active compounds that are less potent than the parent one. The ester structure of remifentanil makes it susceptible to hydrolysis (in a manner similar to esmolol) by nonspecific esterases in red blood cells and tissue (see Figure 10–1), yielding a terminal elimination half-life of less than 10 min. Remifentanil biotransformation is rapid and the duration of a remifentanil infusion has little effect on wake-up time (Figure 10–2). The half-time of remifentanil remains approximately 3 min regardless of the dose or duration of infusion. In its lack of accumulation (and lack of context sensitivity) remifentanil differs from other currently available opioids. Hepatic dysfunction requires no adjustment in remifentanil dosing. Finally, patients with pseudocholinesterase deficiency have a normal response to remifentanil (as also appears true for esmolol). FIGURE 10–2 In contrast to other opioids, the time necessary to achieve a 50% decrease in the plasma concentration of remifentanil (its half-time) is very short and is not influenced by the duration of the infusion (it is not context sensitive). (Reproduced with permission from Egan TD. The pharmacokinetics of the new short-acting opioid remifentanil [GI87084B] in healthy adult male volunteers. Anesthesiology. 1993 Nov;79(5):881–892.) D. Excretion The end products of morphine and meperidine biotransformation are eliminated by the kidneys, with less than 10% undergoing biliary excretion. Because 5% to 10% of morphine is excreted unchanged in the urine, kidney failure prolongs morphine duration of action. The accumulation of morphine metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in patients with kidney failure has been associated with prolonged narcosis and ventilatory depression. In fact, morphine 6-glucuronide is a more potent and longer-lasting opioid agonist than morphine. As previously noted, normeperidine at increased concentrations may produce seizures; these are not reversed by naloxone. Renal dysfunction increases the likelihood of toxic effects from normeperidine accumulation. However, both morphine and meperidine have been used safely in patients with kidney failure. Metabolites of sufentanil are excreted in urine and bile. The main metabolite of remifentanil is several thousand times less potent than its parent compound and is unlikely to produce any clinical opioid effects. It is renally excreted. If it accumulates due to renal failure, it doesnt cause problems because its metabolites are safe? Effects on Organ Systems A. Cardiovascular In general, opioids have minimal direct effects on the heart. Meperidine tends to increase heart rate (it is structurally similar to atropine and was originally synthesized as an atropine replacement), whereas larger doses of morphine, fentanyl, sufentanil, remifentanil, and alfentanil are associated with a vagus nerve–mediated bradycardia. With the exception of meperidine (and only then at very large doses), the opioids do not depress cardiac contractility provided they are administered alone (which is almost never the case in surgical anesthetic settings). Nonetheless, arterial blood pressure often falls as a result of opioid- induced bradycardia, venodilation, and decreased sympathetic reflexes. The inherent cardiac stability provided by opioids is greatly diminished in practice when other anesthetic drugs, including benzodiazepines, propofol, or volatile agents are added. For example, sufentanil and fentanyl can be associated with reduced cardiac output when administered in combination with benzodiazepines. Bolus doses of meperidine, hydromorphone, and morphine evoke varying amounts of histamine release that can lead to profound drops in systemic vascular resistance and arterial blood pressure. The potential hazards of histamine release can be minimized by infusing opioids slowly or by pretreatment with H1 and H2 antagonists. Histamine side effects can be treated by infusion of intravenous fluid and vasopressors. Intraoperative hypertension during opioid-based intravenous or nitrous oxide– opioid anesthesia is common. Such hypertension is often attributed to inadequate anesthetic depth; thus it is conventionally treated by the addition of other anesthetic agents (benzodiazepines, propofol, or potent inhaled agents). When depth of anesthesia is adequate we recommend treating hypertension with antihypertensives rather than with additional anesthetics. B. Respiratory Opioids depress ventilation, particularly respiratory rate. Thus, respiratory rate and end-tidal CO2 tension (in contrast to arterial oxygen saturation) provide simple metrics for the early detection of respiratory depression in patients receiving opioid analgesia. Opioids increase the partial pressure of carbon dioxide (PaCO2) and blunt the response to a CO2 challenge, resulting in a shift of the CO2 response curve downward and to the right (Figure 10–3). These effects result from opioid binding to neurons in the respiratory centers of the brainstem. The apneic threshold—the greatest Paco2 at which a patient remains apneic —rises, and hypoxic drive is decreased. Morphine and meperidine can cause histamine-induced bronchospasm in susceptible patients. Rapid administration of larger doses of opioids (particularly fentanyl, sufentanil, remifentanil, and alfentanil) can induce chest wall rigidity severe enough to make ventilation with bag and mask nearly impossible. This centrally mediated muscle contraction is effectively treated with neuromuscular blocking agents. This problem is rarely seen now that large-dose opioid anesthesia is no longer a mainstay of cardiovascular anesthesia practice. Opioids can blunt the bronchoconstrictive response to airway stimulation such as occurs during tracheal intubation. FIGURE 10–3 Opioids depress ventilation. This is graphically displayed by a shift of the CO2 curve downward and to the right. C. Cerebral The effects of opioids on cerebral perfusion and intracranial pressure must be separated from any effects of opioids on PaCO2. In general, opioids reduce cerebral oxygen consumption, cerebral blood flow, cerebral blood volume, and intracranial pressure, but to a much lesser extent than propofol, benzodiazepines, or barbiturates, provided normocarbia is maintained by artificial ventilation. There are some reports of mild—but transient and almost certainly unimportant —increases in cerebral artery blood flow velocity and intracranial pressure following opioid boluses in patients with brain tumors or head trauma. If combined with hypotension, the resulting fall in cerebral perfusion pressure could be deleterious to patients with abnormal intracranial pressure–volume relationships. Nevertheless, the important clinical message is that any trivial opioid-induced increase in intracranial pressure would be much less important than the predictably large increases in intracranial pressure associated with intubation of an inadequately anesthetized patient (from whom opioids were withheld). Opioids usually have almost no effects on the electroencephalogram (EEG), although large doses are associated with slow δ-wave activity. There are case reports that large doses of fentanyl may rarely cause seizure-like activity; however, some of these apparent seizures have been retrospectively diagnosed as severe opioid-induced muscle rigidity. EEG activation and seizures have been associated with the meperidine metabolite normeperidine, as previously noted. Stimulation of the medullary chemoreceptor trigger zone is responsible for opioid-induced nausea and vomiting. Curiously, nausea and vomiting are more common following smaller (analgesic) than very large (anesthetic) doses of opioids. Repeated dosing of opioids (eg, prolonged oral dosing) will reliably produce tolerance, a phenomenon in which progressively larger doses are required to produce the same response. This is not the same as physical dependence or addiction, which may also be associated with repeated opioid administration. Prolonged dosing of opioids can also produce “opioid-induced hyperalgesia,” in which patients become more sensitive to painful stimuli. Infusion of large doses of (in particular) remifentanil during general anesthesia can produce acute tolerance, in which much larger than usual doses of opioids will be required for immediate, postoperative analgesia. Relatively large doses of opioids are required to render patients unconscious (Table 10–3). However, even at very large doses opioids will not reliably produce amnesia. The use of opioids in epidural and intrathecal spaces has revolutionized acute and chronic pain management (see Chapters 47 and 48). what is considered a large dose of remifentanyl? TABLE 10–3 Uses and doses of common opioids.  Unique among the commonly used opioids, meperidine has minor local anesthetic qualities, particularly when administered into the subarachnoid space. Meperidine’s clinical use as a local anesthetic has been limited by its relatively low potency and propensity to cause typical opioid side effects (nausea, sedation, and pruritus) at the doses required to induce local anesthesia. Intravenous meperidine (10–25 mg) is more effective than morphine or fentanyl for decreasing shivering in the postanesthetic care unit and meperidine appears to be the best agent for this indication. D. Gastrointestinal Opioids slow gastrointestinal motility by binding to opioid receptors in the gut and reducing peristalsis. Biliary colic may result from opioid-induced contraction of the sphincter of Oddi. Biliary spasm, which can mimic a common bile duct stone on cholangiography, is reversed with the opioid antagonist naloxone or glucagon. Patients receiving long-term opioid therapy (eg, for cancer pain) usually become tolerant to many of the side effects but rarely to constipation. This is the basis for the development of the peripheral opioid antagonists methylnaltrexone, alvimopan, naloxegol, and naldemedine, which promote gastrointestinal motility in patients with varying indications, such as treatment of opioid bowel syndrome, side effects from opioid treatment of noncancer pain, or reduction of ileus in those receiving intravenous opioids after abdominal surgery. E. Endocrine The neuroendocrine stress response to surgery is measured in terms of the secretion of specific hormones, including catecholamines, antidiuretic hormone, and cortisol. Large doses of fentanyl or sufentanil inhibit the release of these hormones in response to surgery more completely than volatile anesthetics. The actual clinical outcome benefit produced by attenuating the stress response with opioids, even in high-risk cardiac patients, remains speculative (and we suspect nonexistent), whereas the many drawbacks of excessive doses of opioids are readily apparent. Other Effects A. Cancer Reoccurrence Retrospective studies have associated general anesthesia (including opioids) with an increased risk of cancer reoccurrence after surgery as compared to techniques that emphasize opioid-sparing regional anesthetic techniques for analgesia. Ongoing clinical trials will likely clarify whether general anesthesia, opioids, both, or neither influence outcomes after cancer surgery. B. Substance Abuse There is a well-publicized epidemic of opioid abuse in western democracies, particularly in the United States. Although it comprises less than 5% of the world’s population, the United States consumes 80% of the world’s prescription opioids (and nearly all of the world’s supply of hydrocodone)! Large numbers of patients admit to using prescribed opioids in a recreational fashion, and drug overdosage (most often from prescribed drugs) is the leading cause of accidental death in the United States. Many opioid addicts can trace their addiction to opioids prescribed by a physician for acute or chronic pain. There are many causes of this terrible problem, including excessive and misleading marketing of opioids to physicians, unwise prescribing practices by physicians, inappropriate and misleading assertions by “thought leaders” (many with ties to the pharmaceutical industry) regarding opioids, and well-intended but poorly thought out recommendations for assessment and treatment of pain by certifying agencies. In response the U.S. Centers for Disease Control and Prevention and many other agencies have released guidelines for responsible prescribing of opioids. Drug Interactions The combination of meperidine and monoamine oxidase inhibitors may result in hemodynamic instability, hyperpyrexia, coma, respiratory arrest, or death. The cause of this catastrophic interaction is incompletely understood. (The failure to appreciate this drug interaction in the controversial Libby Zion case led to changes in work hour rules for house officers in the United States.) Propofol, barbiturates, benzodiazepines, inhaled anesthetics, and other central nervous system depressants can have synergistic cardiovascular, respiratory, and sedative effects with opioids. The clearance of alfentanil may be impaired and the elimination half-life prolonged following treatment with erythromycin. CYCLOOXYGENASE INHIBITORS Mechanisms of Action Many over-the-counter nonsteroidal antiinflammatory agents (NSAIDs) work through inhibition of cyclooxygenase (COX), the key step in prostaglandin synthesis. COX catalyzes the production of prostaglandin H1 from arachidonic acid. The two forms of the enzyme, COX-1 and COX-2, have differing distribution in tissue. COX-1 receptors are widely distributed throughout the body, including the gut and platelets. COX-2 is produced in response to inflammation. COX-1 and COX-2 enzymes differ further in the size of their binding sites: the COX-2 site can accommodate larger molecules that are restricted from binding at the COX-1 site. This distinction is in part responsible for selective COX-2 inhibition. Agents that inhibit COX nonselectively (eg, aspirin) will control fever, inflammation, pain, and thrombosis. COX-2 selective agents (eg, celecoxib, etoricoxib) can be used perioperatively without concerns about platelet inhibition or gastrointestinal upset. Curiously, while COX-1 inhibition decreases thrombosis, selective COX-2 inhibition increases the risk of heart attack, thrombosis, and stroke. Acetaminophen inhibits COX in the brain without binding to the active site of the enzyme (as is true for NSAIDs) to produce its antipyretic activities. Acetaminophen analgesia may result from modulation of the endogenous cannabinoid vanilloid receptor systems in the brain, but the actual mechanism of action remains speculative. Acetaminophen has no major effects on COX outside the brain. Aspirin, the first of the NSAIDs, formerly was used as an antipyretic and analgesic. Now it is used almost exclusively for prevention of thrombosis in susceptible individuals or for acute myocardial infarction. Aspirin is unique in that it irreversibly inhibits COX-1 by acetylating a serine residue in the enzyme, resulting in a nearly 1-week persistence of its clinical effects (eg, inhibition of platelet aggregation) after drug discontinuation. COX inhibitors are most often administered orally. Acetaminophen, ibuprofen, diclofenac, and ketorolac are available for intravenous administration. Unfortunately, intravenous acetaminophen has an acquisition cost several orders of magnitude greater than oral acetaminophen; therefore its use is tightly restricted in many medical centers. “Multimodal” analgesia typically includes the use of acetaminophen, COX inhibitors, possibly a gabapentinoid, regional or local anesthesia techniques, and other approaches aimed at improving the analgesia while reducing the requirement for opioids in postoperative patients. Multimodal analgesia protocols are best used as part of an enhanced recovery after surgery (ERAS) protocol, a topic that is extensively considered in Chapter 48. Structure–Activity Relationships The COX enzyme is inhibited by an unusually diverse group of compounds that can be grouped into salicylic acids (eg, aspirin), acetic acid derivatives (eg, ketorolac), propionic acid derivatives (eg, ibuprofen), heterocyclics (eg, celecoxib), and others. Thus, a conventional discussion of structure to potency (and other factors) is not useful for these chemicals, other than to note that the heterocyclics tend to be the compounds with the greatest selectivity for the COX-2 rather than COX-1 form of the enzyme. Pharmacokinetics A. Absorption COX inhibitors when taken orally will typically achieve their peak blood concentrations in less than 3 h. Some COX inhibitors are formulated for topical application (eg, as a gel to be applied over joints or as liquid drops to be instilled on the eye). Ketorolac has been widely used as part of a local anesthetic “cocktail” to be injected around the surgical site and joint after arthroplasty. B. Distribution In blood, COX inhibitors are highly bound by plasma proteins, chiefly albumin. Their lipid solubility allows them to readily permeate the blood–brain barrier to produce a central analgesia and antipyresis, and to penetrate joint spaces to produce (with the exception of acetaminophen) an antiinflammatory effect. C. Biotransformation Most COX inhibitors undergo hepatic biotransformation. Acetaminophen at increased doses yields sufficiently large concentrations of N-acetyl-p- benzoquinone imine to produce hepatic failure. D. Excretion Nearly all COX inhibitors are excreted in urine after biotransformation. Effects on Organ Systems A. Cardiovascular COX inhibitors do not act directly on the cardiovascular system. Any cardiovascular effects result from the actions of these agents on coagulation. Prostaglandins maintain the patency of the ductus arteriosus; thus COX inhibitors have been administered to neonates to promote closure of a persistently patent ductus arteriosus and prostaglandins have been infused to maintain patency of the ductus in neonates awaiting surgery for ductal- dependent congenital cardiac lesions. B. Respiratory At appropriate clinical doses, none of the COX inhibitors have effects on respiration or lung function. Aspirin overdosage has very complex effects on acid–base balance and respiration. C. Gastrointestinal The classic complication of COX-1 inhibition is gastrointestinal upset. In its most extreme form this can cause upper gastrointestinal bleeding. Both complications result from direct actions of the drug, in the former case, on protective effects of prostaglandins in the mucosa, and in the latter case, on the combination of mucosal effects and inhibition of platelet aggregation. Acetaminophen toxicity is a common cause of fulminant hepatic failure and need for hepatic transplantation in western societies; it has replaced viral hepatitis as the most common cause of acute hepatic failure. D. Renal There is good evidence that NSAIDs, especially selective COX-2 inhibitors, adversely affect renal function in certain patients. Therefore, NSAIDs are generally avoided in patients with reduced creatinine clearance and in others who are dependent upon renal prostaglandin release for vasodilation to avoid hemodynamically mediated acute kidney injury (eg, patients with hypovolemia, heart failure, cirrhosis, diabetic nephropathy, or hypercalcemia). GABAPENTIN & PREGABALIN Gabapentin was introduced as an antiepileptic agent but was serendipitously discovered to have analgesic properties. It found its earliest applications in the treatment of chronic neuropathic pain and is now licensed for postherpetic neuralgia. It and the closely related compound pregabalin are also widely prescribed for diabetic neuropathy. These agents form part of many multimodal postoperative pain protocols, particularly after total joint arthroplasty. There is no evidence that one agent is predictably more efficacious than the other. Although these agents have been shown to bind to voltage-gated calcium channels and N-methyl-D-aspartate (NMDA) receptors, their exact mechanism of action remains speculative. Despite the structural similarities these agents have to γ-aminobutyric acid (GABA) their clinical effects do not appear to arise from binding to GABA receptors. When used for treatment of chronic pain these agents are generally started at relatively small doses and increased incrementally until side effects of dizziness or sedation appear. An adequate trial of gabapentin can require as much a month to achieve the optimal dosage. Determining the optimal dosage of the more potent pregabalin generally requires less time. When used as part of a multimodal postoperative pain protocol these agents are generally prescribed in a standard dose that is maintained for the several days during which the protocol runs its course. SUGGESTED READINGS Angst MS. Intraoperative use of remifentanil for TIVA: Postoperative pain, acute tolerance, and opioid-induced hyperalgesia. J Cardiothorac Vasc Anesth. 2015;29(suppl 1):S16. Brunton LL, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018: chaps 18, 34. Food and Drug Administration. Acetaminophen overdose and liver injury—