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Chapter: Clinical Anesthesiology: Clinical Pharmacology: Analgesic Agents

Analgesic Agents: Opioids

Opioids bind to specific receptors located through-out the central nervous system and other tissues.

Analgesic Agents

Regardless of how expertly surgical and anesthetic procedures are performed, appropriate prescrip-tion of analgesic drugs, especially opioids and cyclooxygenase (COX) inhibitors, can make the difference between a satisfied and an unsatisfied postoperative patient. Studies have shown that out-comes can be improved when analgesia is provided in a “multimodal” format (typically emphasizing COX inhibitors and local anesthetic techniques while minimizing opioid use) as one part of a well-defined and well-organized plan for postoperative care .



Mechanisms of Action

Opioids bind to specific receptors located through-out the central nervous system and other tissues. Four major opioid receptor types have been identi-fied ( Table 10–1): mu (µ, with subtypes µ1 and µ2), kappa (κ), delta (δ), and sigma (σ). All opioid recep-tors couple to G proteins; binding of an agonist to an opioid receptor causes membrane hyperpolariza-tion. Acute opioid effects are mediated by inhibition of adenylyl cyclase (reductions in intracellular cyclic

adenosine monophosphate concentrations) and activation of phospholipase C. Opioids inhibit volt-age-gated calcium channels and activate inwardly rectifying potassium channels. Opioid effects vary based on the duration of exposure, and opioid toler-ance leads to changes in opioid responses.

Although opioids provide some degree of seda-tion and (in many species) can produce general anesthesia when given in large doses, they are prin-cipally used to provide analgesia. The properties of specific opioids depend on which receptor is bound (and in the case of spinal and epidural administra-tion 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 pentazocine) have less efficacy than so-called full agonists (eg, fentanyl) and under some circumstances will antagonize the actions of full agonists.

The opioid drugs mimic endogenous com-pounds. Endorphins, enkephalins, and dynorphins are endogenous peptides that bind to opioid recep-tors. These three families of opioid peptides differ in their amino acid sequences, anatomic distributions, and receptor affinities.

Opioid receptor activation inhibits the pre-synaptic release and postsynaptic response to excitatory neurotransmitters (eg, acetylcholine, substance P) from nociceptive neurons. The cel-lular mechanism for this action was described at the beginning. Transmission of pain impulses can be selectively modified at the level of the dorsal horn of the spinal cord with intrathe-cal or epidural administration of opioids. Opioid receptors also respond to systemically adminis-tered 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 opi-oids exert their greatest effect within the central nervous system, opiate receptors have also been identified on somatic and sympathetic peripheral nerves. Certain opioid side effects (eg, depression of gastrointestinal motility) are the result of opi-oid binding to receptors in peripheral tissues (eg, the wall of the gastrointestinal tract), and there are now selective antagonists for opioid actions out-side the central nervous system (alvimopan and oral naltrexone). The distribution of opioid recep-tors on axons of primary sensory nerves and the clinical importance of these receptors (if present) remains speculative, despite the persisting prac-tice of compounding of opioids in local anesthetic solutions applied to peripheral nerves.

Structure–Activity Relationships

Opioid receptor binding is a property shared by a chemically diverse group of compounds. Nonethe-less, there are common structural characteristics, which are shown in Figure 10–1. As is true for most classes of drugs, small molecular changes can convert an agonist into an antagonist. The levorotatory iso-mers are generally more potent than the dextrorota-tory opioid isomers.


A. Absorption

Rapid and complete absorption follows the intra-muscular injection of hydromorphone, morphine, or meperidine, with peak plasma levels usually reached after 20–60 min. Oral transmucosal fentanyl citrate absorption (fentanyl “lollipop”) provides rapid onset of analgesia and sedation in patients who are not good candidates for conventional oral, intravenous, or intramuscular dosing of opioids. The low molecular weight and high lipid solu-bility 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 concentra-tions of fentanyl reach a plateau within 14–24 h of application (with peak levels occurring after a lon-ger delay in elderly than in younger patients) and remain constant for up to 72 h. Continued absorp-tion from the dermal reservoir accounts for persist-ing measurable serum levels many hours after patch removal. Fentanyl patches are most often used for outpatient management of chronic pain and are par-ticularly appropriate for patients who require con-tinuous opioid dosing but cannot take the much less expensive, but equally efficacious, oral agents such as methadone.

A wide variety of opioids are effective by oral administration, including oxycodone, hydrocodone (most often in combination with acetaminophen), codeine, tramadol, morphine, hydromorphone, and methadone. These agents are much used for outpa-tient pain management.

Fentanyl is often administered in small doses (10–25 mcg) with local anesthetics for spinal anes-thesia, 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 12–18 hours of analgesia after intrathecal administration. Morphine and hydromorphone are commonly included in local anesthetic solutions infused for postoperative epidural analgesia. Extended-release epidural morphine (DepoDur) is administered as a single epidural dose (5–15 mg), the effects of which persist for 48 h.

B. Distribution

Table 10–2 summarizes the physical characteris-tics that determine distribution and tissue binding of opioid analgesics. After intravenous administra-tion, the distribution half-lives of all of the opioids are fairly rapid (5–20 min). The low fat solubility of morphine slows passage across the blood–brain bar-rier, 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 administeredin small doses. Interestingly, alfentanil has a morerapid 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 adminis-tered dose) available for binding in the brain.

Signifi cant 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 redistribu-tion (of drug from effect sites) terminate the clini-cal effects of all opioids. After smaller doses of the lipid-soluble drugs (eg, fentanyl or sufentanil), redistribution alone is the driver for reducing blood concentrations, whereas after larger doses biotrans-formation 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 is context sensi-tive; in other words, the half-time depends on thetotal dose of drug and duration of exposure .

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, conjugated in the liver, or both. Because of the high hepatic extraction ratio of opioids, their clearance depends on liver blood flow. The small Vdof alfentanil contributes to a short eliminationhalf-life (1.5 h). 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 metab-olite associated with seizure activity, particularly after very large meperidine doses. The end products of fentanyl, sufentanil, and alfentanil are inactive. Norfentanyl, the metabolite of fentanyl, can be mea-sured in urine long after the native compound is no longer detectable in blood to determine chronic fen-tanyl ingestion. This has its greatest importance in diagnosing fentanyl abuse.

Codeine is a prodrug that becomes active after it is metabolized by CYP to morphine. Trama-dol similarly must be metabolized by CYP to O-desmethyltramadol to be active. Oxycodone ismetabolized by CYP to series of active compounds that are less potent than the parent one.

The ester structure of remifentanil makes it sus-ceptible to hydrolysis (in a manner similar to esmo-lol) by nonspecific esterases in red blood cells and tissue (see Figure 10–1), yielding a terminal elimi-nation 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 context-sensitive half-time of remifentanil remains approximately 3 min regardless of the dose or duration of infusion. In its lack of accumulation remifentanil differs from other currently available opioids. Hepatic dysfunc-tion requires no adjustment in remifentanil dos-ing. Finally, patients with pseudocholinesterase deficiency have a normal response to remifentanil (as also appears true for esmolol).

D. Excretion

The end products of morphine and meperidine bio-transformation are eliminated by the kidneys, with less than 10% undergoing biliary excretion. Because 5–10% of morphine is excreted unchanged in the urine, kidney failure prolongs morphine duration of action. The accumulation of morphine metab-olites (morphine 3-glucuronide and morphine6-glucuronide) in patients with kidney failure has been associated with prolonged narcosis and venti-latory depression. In fact, morphine 6-glucuronide is a more potent and longer-lasting opioid agonist than morphine. As previously noted, normeperi-dine at increased concentrations may produce sei-zures; these are not reversed by naloxone. Renal dysfunction increases the likelihood of toxic effectsfrom normeperidine accumulation. However, both morphine and meperidine have been used safely and successfully in patients with kidney failure. Metabolites of sufentanil are excreted in urine and bile. The main metabolite of remifentanil is elimi-nated in urine, is several thousand times less potent than its parent compound, and thus is unlikely to produce any clinical opioid effects.

Eects on Organ Systems

A. Cardiovascular

In general, opioids have few direct effects on the heart. Meperidine tends to increase heart rate (it is structur-ally similar to atropine and was originally synthe-sized 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 meperi-dine (and only then at very large doses), the opioids do not depress cardiac contractility provided they are administered alone (which is almost never the circum-stance in surgical anesthetic settings). Nonetheless, arterial blood pressure often falls as a result of bra-dycardia, venodilation, and decreased sympathetic reflexes, sometimes requiring vasopressor support. These effects are more pronounced when opioids are administered in combination with benzodiazepines, in which case drugs such as sufentanil and fentanyl can be associated with reduced cardiac output. Bolus doses of meperidine, hydromorphone, and morphine evoke histamine release in some individuals that can lead to profound drops in systemic vascular resistance and arterial blood pressure. The potential hazards of histamine release can be minimized in susceptible patients by infusing opioids slowly or by pretreatment with H1 and H2 antagonists, or both. The end effects of histamine release can be reversed by infusion of intra-venous fluid and vasopressors.

Intraoperative hypertension during large-dose opioid anesthesia or nitrous oxide–opioid anesthesia is common. Such hypertension is oftenattributed to inadequate anesthetic depth, thus it is conventionally treated by the addition of other anes-thetic agents (benzodiazepines, propofol, or potent inhaled agents). If depth of anesthesia is adequate and hypertension persists, vasodilators or other antihypertensives may be used. The inherent cardiacstability provided by opioids is greatly diminished in actual practice when other anesthetic drugs, includ-ing nitrous oxide, benzodiazepines, propofol, or volatile agents, are typically added. The end result of polypharmacy can include myocardial depression.

B. Respiratory

Opioids depress ventilation, particularly respiratory rate. Thus, monitoring of respiratory rate provides a convenient, simple way of detecting early respiratory depression in patients receiving opioid analgesia. Opioids increase the partial pressure of carbon diox-ide (Paco2) and blunt the response to a CO2 chal-lenge, 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 prevent ade-quate bag-and-mask ventilation. This centrally

mediated muscle contraction is effectively treated with neuromuscular blocking agents. This problem is rarely seen now that large-dose opioid anesthesia is less often used in cardiovascular anesthesia prac-tice. Opioids can effectively blunt the bronchocon-strictive response to airway stimulation such as occurs during tracheal intubation.

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 barbiturates, pro-pofol, or benzodiazepines. These effects will occur during maintenance of normocarbia by artificial ventilation; however, 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 com-bined with hypotension, the resulting fall in cerebral perfusion pressure could be deleterious to patients with abnormal intracranial pressure–volume rela-tionships. Nevertheless, the important clinical message is that any trivial opioid-induced increase in intracranial pressure would likely be much less important than the much more likely large increases in intracranial pressure associated with intubation that might be observed in an inadequately anesthe-tized patient (from whom opioids were withheld). Opioids usually have almost no effects on the elec-troencephalogram (EEG), although large doses are associated with slow δ-wave activity. There are curi-ous sporadic case reports that large doses of fentanyl may rarely cause seizure 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. Prolonged oral dosing of opioids or infusion of large doses of remi-fentanil during general anesthesia can produce the phenomenon of opioid-induced tolerance. Repeated dosing of opioids will reliably produce tolerance, a phenomenon in which 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 whichpatients become more sensitive to painful stimuli. Infusion of large doses of (in particular) remifent-anil during general anesthesia can produce acute tolerance, in which much larger than usual doses of opioids will be required for postoperative analgesia. Relatively large doses of opioids are required to ren-der patients unconscious (Table 10–3). Regardless of the dose, however, opioids will not reliably pro-duce amnesia. Parenteral opioids have been the mainstay of pain control for more than a century. The relatively recent use of opioids in epidural and intrathecal spaces has revolutionized acute and chronic pain management.

Unique among the commonly used opioids, meperidine has minor local anesthetic qualities, par-ticularly 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 (nau-sea, 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 postanes-thetic 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 con-traction 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 receiv-ing 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 recent development of the peripheral opioid antagonists methylnaltrexone and alvimopan, and for their salutary effects in promoting motility in patients with opioid bowel syndrome, those receiv-ing chronic opioid treatment of cancer pain, and those receiving intravenous opioids after abdomi-nal surgery.

E. Endocrine

The neuroendocrine stress response to surgi-cal stimulation is measured in terms of thesecretion of specific hormones, including catechol-amines, antidiuretic hormone, and cortisol. Large doses of opioids (typically fentanyl or sufentanil) block the release of these hormones in response to surgery more completely than volatile anesthetics. Although much discussed, the actual clinical out-come benefit produced by attenuating the stress response, even in high-risk cardiac patients, remains speculative (and possibly nonexistent).

Drug Interactions

The combination of meperidine and monoamine oxidase inhibitors should be avoided as it may result in hypertension, hypotension, hyperpyrexia, coma, or respiratory arrest. The cause of this catastrophic interaction is incompletely understood. (The results of failure to appreciate this drug interaction in the celebrated Libby Zion case led to changes in work rules for house officers in the United States.)

Propofol, barbiturates, benzodiazepines, and other central nervous system depressants can have synergistic cardiovascular, respiratory, and sedative effects with opioids.

The biotransformation of alfentanil may be impaired following treatment with erythromy-cin, leading to prolonged sedation and respiratory depression.

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