Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II
Neuropharmacology

chapter 18
Opioids, Analgesia, and Pain Management

Pain is a component of virtually all clinical pathologies, and management of pain is a primary clinical imperative. Opioids are a mainstay of pain treatment, but depending upon the pain state, therapy may involve NSAIDs, anticonvulsants, or antidepressants.

The term opiate refers to compounds structurally related to products found in opium derived from the resin of the opium poppy, Papaver somniferum. Opiates include the natural plant alkaloids, such as morphine, codeine, thebaine, and many semisynthetic derivatives. An opioid is any agent that has the functional and pharmacological properties of an opiate. Endogenous opioids are naturally occurring ligands for opioid receptors found in animals. The term endorphin is used synonymously with endogenous opioid peptides but also refers to a specific endogenous opioid, β-endorphin. Although the termnarcotic originally referred to any drug that induced narcosis or sleep, the word has become associated with opioids and is often used in a legal context to refer to substances with abuse or addictive potential.

ENDOGENOUS OPIOID PEPTIDES

Several distinct families of endogenous opioids peptides have been identified: principally the enkephalins, endorphins, and dynorphins (Table 18–1). These families have several common properties:

Table 18–2

Endogenous Opioid Peptides

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• Each derives from a distinct precursor protein, pre-pro-opiomelanocortin (pre-POMC), preproenkephalin, and preprodynorphin, respectively, encoded by a corresponding gene.

• Each precursor is subject to complex cleavages by distinct trypsin-like enzymes, and to a variety of posttranslational modifications resulting in the synthesis of multiple peptides, some of which are active.

• Most opioid peptides with activity at a receptor share the common amino-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu) followed by various C-terminal extensions yielding peptides of 5-31 residues; the endomorphins, with different terminal sequences, are exceptions.

The opioid peptide precursors are a protean family (Figure 18–1). The major opioid peptide derived from POMC is the potent opioid agonist, β-endorphin. The POMC sequence also is processed into a variety of nonopioid peptides including adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (α-MSH), and β-lipotropin (β-LPH). Although β-endorphin contains the sequence for met-enkephalin at its amino terminus, it is not converted to this peptide. Proenkephalin contains multiple copies of met-enkephalin, as well as a single copy of leu-enkephalin. Prodynorphin contains 3 peptides of differing lengths that all begin with the leu-enkephalin sequence: dynorphin A, dynorphin B, and neoendorphin. Nociceptin peptide or orphanin FQ (now termed N/OFQ) shares structural similarity with dynorphin A.

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Figure 18–1 Peptide precursors. (Reproduced with permission from Akil H, Owens C, Gustein H, et al. Endogenous opioids: Overview and current issues. Drug Alcohol Depend, 1998;51:127-140. Copyright © Elsevier.)

Endomorphins belong to a novel family of peptides that include: endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). Endomorphins have an atypical structure and display selectivity towards the μ opioid receptor. Several points should be stressed:

• Not all cells that make a given opioid prohormone precursor store and release the same mixture of opioid peptides; this results from differential processing secondary to variations in the cellular complement of peptidases that produce and degrade the active opioid fragments.

• Processing of these peptides is altered by physiological demands, leading to the release of a different mix of posttranslationally derived peptides by a given cell under different conditions.

• Opioid peptides are found in plasma and reflect release from secretory systems such as the pituitary and the adrenals that do not reflect neuraxial release. Conversely, levels of these peptides in brain/spinal cord and in cerebrospinal fluid (CSF) arise from neuraxial systems and not from peripheral systems.

OPIOID RECEPTORS

The 3 opioid receptors—μ, δ, and κ (MOR, DOR, and KOR)—belong to the rhodopsin family of GPCRs (see Chapter 3) and share extensive sequence homologies (55-58%). Highly selective agonists have been developed that show specific affinity for the respective binding site (e.g., DAMGO for μ, DPDPE for δ, and U-50,488, and U-69,593 for κ) (Table 18–2). Commonly used antagonists (Table 18–3) include cyclic analogs of somatostatin such as CTOP as a μ receptor antagonist, a derivative of naloxone called naltrindole as a δ receptor antagonist, and a bivalent derivative of naltrexone called nor-binaltorphimine (nor-BNI) as a κ-receptor antagonist.

Table 18–2

Opioid Agonists

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Table 18–3

Opioid Antagonists

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In the membrane, opiate receptors can form both homo- and heterodimers. Dimerization can alter the pharmacological properties of the respective receptors. Splice variants exist within each of the 3 opioid receptor families, and this alternative splicing of receptor transcripts may be crucial for the diversity of opioid receptors. Given the functional importance of the intracellular components of the GPCRs, it is not surprising that significant differences exist for the receptor isoforms in terms of agonist-induced G protein activation and receptor internalization.

An opiate receptor-like protein (ORL1 or NOP) was cloned based on its structural homology (48-49% identity) to other members of the opioid receptor family; it is G-protein coupled, has an endogenous ligand (nociception/orphanin, FQ: N/OFQ), but does not display an opioid pharmacology.

OPIATE RECEPTOR SIGNALING

The μ, δ, and κ receptors couple through pertussis toxin-sensitive, Gi/Go proteins (but occasionally to Gs or Gz). Upon receptor activation, the Gi/Go coupling results in a large number of intracellular events, including:

• Inhibition of adenylyl cyclase activity

• Reduced opening of voltage-gated Ca2+ channels (reduces neurotransmitter release from presynaptic terminals)

• Stimulation of K+ current through several channels including G protein-activated inwardly rectifying K+ channels (GIRKs) (hyperpolarizes and inhibits postsynaptic neurons)

• Activation of PKC and PLCβ

FUNCTIONAL CONSEQUENCES OF ACUTE AND CHRONIC OPIATE RECEPTOR ACTIVATION

The loss of effect with exposure to opiates occurs over short- and long-term intervals.

INTERNALIZATION. μ and δ receptors can undergo rapid agonist-mediated internalization via a classic endocytic, β-arrestin-mediated pathway, whereas κ receptors do not internalize after prolonged agonist exposure. Internalization of the μ and δ receptors may be induced differentially as a function of the structure of the ligand.

DESENSITIZATION. In the face of a transient activation (minutes to hours), acute tolerance or desensitization occurs that is specific for that receptor and disappears with a time course parallel to the clearance of the agonist. Short-term desensitization probably involves phosphorylation of the receptors resulting in an uncoupling of the receptor from its G-protein and/or internalization of the receptor.

TOLERANCE. Here tolerance refers to a decrease in the apparent effectiveness of a drug with continuous or repeated agonist administration (days to weeks), that, following removal of the agonist, disappears over several weeks. This tolerance is reflected by a reduction in the maximum achievable effect or a right shift in the dose-effect curve. This loss of effect with persistent exposure to an opiate agonist has several key properties:

• Different physiological responses develop tolerance at different rates. Thus, at the organ system level, some end points show little or no tolerance development (pupillary miosis), some show moderate tolerance (constipation, emesis, analgesia, sedation), and some show rapid tolerance (euphorigenic).

• In general, opiate agonists of a given class will typically show a reduced response in a system rendered tolerant to another agent of that class (e.g., cross-tolerance between the μ agonists, such as morphine and fentanyl). This cross-tolerance is not consistent or complete, thereby forming the basis for the switching between opioid drugs in clinical therapy.

DEPENDENCE. Dependence represents a state of adaptation manifested by receptor/drug class-specific withdrawal syndrome produced by cessation of drug exposure (e.g., by drug abstinence) or administration of an antagonist (e.g., naloxone). At the organ system level, withdrawal is manifested by significant somatomotor and autonomic outflow (reflected by agitation, hyperalgesia, hyperthermia, hypertension, diarrhea, pupillary dilation, and release of virtually all pituitary and adrenomedullary hormones) and by affective symptoms (dysphoria, anxiety, and depression).

ADDICTION. Addiction is a behavioral pattern characterized by compulsive use of a drug. The positive, rewarding effects of opiates are considered to be the driving component for initiating the recreational use of opiates. This positive reward property is subject to the development of tolerance. Given the aversive nature of withdrawal symptoms, avoidance and alleviation of withdrawal symptoms may become a primary motivation for compulsive drug taking. Drug dependence is not synonymous with drug addiction. Tolerance and dependence are physiological responses seen in all patients but are not predictors of addiction (see Chapter 24). For example, cancer pain often requires prolonged treatment with high doses of opioids, leading to tolerance and dependence. Yet abuse in this setting is considered to be unusual.

MECHANISMS OF TOLERANCE/DEPENDENCE-WITHDRAWAL. The mechanisms underlying chronic tolerance and dependence/withdrawal are controversial. Several types of events may to contribute.

Receptor Disposition. Acute desensitization or receptor internalization may play a role in the initiation of chronic tolerance but is not sufficient to explain persistent changes observed with chronic exposure. Thus, morphine, unlike other μ agonists, does not promote μ receptor internalization or receptor phosphorylation and desensitization. Receptor desensitization and downregulation are agonist specific. Endocytosis and sequestration of receptors do not invariably lead to receptor degradation but can also result in receptor dephosphorylation and recycling to the surface of the cell. Accordingly, opioid tolerance may not be related to receptor desensitization but rather to a lack of desensitization. Agonists that rapidly internalize opioid receptors also would rapidly desensitize signaling, but this desensitization would be at least partially reset by recycling of “reactivated” opioid receptors.

Adaptation of Intracellular Signaling Mechanisms in the Opioid Receptor-Bearing Neurons. Coupling of MOR to cellular effectors, such as inhibition of adenylyl cyclase, activation of inwardly rectifying K+ channels, inhibition of Ca2+ currents, and inhibition of terminal release of transmitters demonstrates functional uncoupling of receptor occupancy from effector function. Importantly, the chronic opioid effect initiates adaptive counter-regulatory change. The best example of such cellular counter-regulatory processes is the rebound increase in cellular cyclic AMP levels produced by “superactivation” of adenylyl cyclase and upregulation of the amount of enzyme.

System Level Counter-Adaptation. With chronic opiate exposure, there is a loss of drug effect; this may reflect an enhanced excitability of the regulated link. Thus, tolerance to the analgesic action of chronically administered μ opiates may result in an activation of bulbospinal pathways that increases the excitability of spinal dorsal horn pain transmission linkages. With chronic opiate exposure, opiate receptor occupancy will lead to the activation of PKC, which can phosphorylate and, accordingly, enhance the activation of local NMDA glutamate receptors (see Chapter 14). These receptors mediate a facilitated state leading to enhanced spinal pain processing. Blocking of these receptors can at least partially attenuate the loss of analgesic efficacy with continued opiate exposure. These system level counter-adaptation hypotheses represent mechanisms that may apply to specific systems (e.g., pain modulation) but not necessarily to others (e.g., sedation or miosis).

EFFECTS OF CLINICALLY USED OPIOIDS

Opiates, depending on their receptor specificities, produce a variety of effects consistent with the role played by the organ systems with which the receptors are associated. Although the primary clinical use of opioids is for their pain-relieving properties, opioids produce a host of other effects. This is not surprising in view of the wide distribution of opioid receptors in the brain and the periphery.

ANALGESIA. Morphine-like drugs produce analgesia, drowsiness, and euphoria (changes in mood, and mental clouding). When therapeutic doses of morphine are given to patients with pain, they report the pain to be less intense or entirely gone. In addition to relief of distress, some patients may experience euphoria. Analgesia often occurs without loss of consciousness, though drowsiness commonly occurs. Morphine at these doses does not have anticonvulsant activity and usually does not cause slurred speech, emotional lability, or significant motor uncoordination. When morphine in an analgesic dose is given to normal, pain-free individuals, the patients may report the drug experience to be frankly unpleasant. There may be drowsiness, difficulty in mentation, apathy, and lessened physical activity. As the dose is increased, the subjective, analgesic, and toxic effects, including respiratory depression, become more pronounced. The relief of pain by morphine-like opioids is selective in that other sensory modalities, such as light touch, proprioception, and the sense of moderate temperatures, are unaffected. Low doses of morphine produce reductions in the affective but not the perceived intensity of pain. Continuous dull pain (as generated by tissue injury and inflammation) is relieved more effectively than sharp intermittent (incident) pain, such as that associated with the movement of an inflamed joint, but with sufficient amounts of opioid it is possible to relieve even the severe piercing pain associated with acute renal or biliary colic.

PAIN STATES AND MECHANISMS UNDERLYING DIFFERENT PAIN STATES

Acute Nociception. Acute activation of small high-threshold sensory afferents (Aδ and C fibers) generates transient input into the spinal cord, which in turn leads to activation of neurons that project contralaterally to the thalamus and thence to the somatosensory cortex. A parallel spinofugal projection is to the medial thalamus and from there to the anterior cingulate cortex, part of the limbic system. The output produced by acutely activating this ascending system is sufficient to evoke pain reports. Examples of such stimuli include a hot coffee cup, a needle stick, or an incision.

Tissue Injury. Following tissue injury or local inflammation (e.g., local skin burn, toothache, rheumatoid joint), an ongoing pain state arises that is characterized by burning, throbbing, or aching and an abnormal pain response (hyperalgesia) and can be evoked by otherwise innocuous or mildly aversive stimuli (tepid bathwater on a sunburn; moderate extension of an injured joint). This pain typically reflects the effects of active factors (such as prostaglandins, bradykinin, cytokines, and H+ ions, among many mediators) released into the injury site, which have the ability to activate the terminal of small high-threshold afferents (Aδ and C fibers) and to reduce the stimulus intensity required to activate these sensory afferents (peripheral sensitization). In addition, the ongoing afferent traffic initiated by the injury leads to the activation of spinal facilitatory cascades, yielding a greater output to the brain for any given input. This facilitation is thought to underlie the hyperalgesic states. Such tissue injury-evoked pain is often referred to as “nociceptive” pain (Figure 18–2). Examples of such states would be burn, post-incision, abrasion of the skin, inflammation of the joint, and musculoskeletal injury.

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Figure 18–2 Mechanisms of tissue injury-evoked nociception.

Nerve Injury. Injury to the peripheral nerve yields complex anatomical and biochemical changes in the nerve and spinal cord that induce spontaneous dysesthesias (shooting, burning pain) and allodynia (light touch hurts). This nerve injury pain state may not depend on the activation of small afferents, but may be initiated by low-threshold sensory afferents (e.g., Aβ fibers). Such nerve injuries result in the development of ectopic activity arising from neuromas formed by nerve injury and the dorsal root ganglia of the injured axons as well as a dorsal horn reorganization, such that low-threshold afferent input carried by Aβ fibers evokes a pain state. Examples of such nerve injury-inducing events include nerve trauma or compression (carpal tunnel syndrome), chemotherapy (as for cancer), diabetes, and in the post-herpetic state (shingles). These pain states are said to be neuropathic (Figure 18–3). Many clinical pain syndromes, such as found in cancer, typically represent a combination of these inflammatory and neuropathic mechanisms. Although nociceptive pain usually is responsive to opioid analgesics, neuropathic pain is typically considered to respond less well to opioid analgesics.

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Figure 18–3 Mechanisms of nerve injury-evoked nociception.

Sensory Versus Affective Dimensions. When pain does not evoke its usual responses (anxiety, fear, panic, and suffering), a patient’s ability to tolerate the pain may be markedly increased, even when the capacity to perceive the sensation is relatively unaltered. It is clear, however, that alteration of the emotional reaction to painful stimuli is not the sole mechanism of analgesia. Thus, intrathecal administration of opioids can produce profound segmental analgesia without causing significant alteration of motor or sensory function or subjective effects.

MECHANISMS OF OPIOID-INDUCED ANALGESIA. The analgesic actions of opiates after systemic delivery represent actions in the brain, spinal cord, and in some instances in the periphery.

Supraspinal Actions. Microinjections of morphine into the mesencephalic periaqueductal gray (PAG) matter region will block nociceptive responses; naloxone will reverse these effects. Several mechanisms exist whereby opiates with an action limited to the PAG may act to alter nociceptive transmission. These are summarized in Figure 18–4. MOR agonists block release of the inhibitory transmitter GABA from tonically active PAG systems that regulate activity in projections to the medulla. PAG projections to the medulla activate medullospinal release of NE and 5HT at the level of the spinal dorsal horn. This release can attenuate dorsal horn excitability. Interestingly, this PAG organization can also serve to increase excitability of dorsal raphe and locus coeruleus from which ascending serotonergic and noradrenergic projections to the limbic forebrain originate.

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Figure 18–4 Mechanisms of opiate action in producing analgesia. Top left: Schematic of organization of opiate action in the periaqueductal gray. Top right: Opiate-sensitive pathways in PAG μ-opiate actions block the release of GABA from tonically active systems that other-wise regulate the projections to the medulla (1) leading to an activation of PAG outflow resulting in activation of forebrain (2) and spinal (3) monoamine receptors that regulate spinal cord projections (4), which provide sensory input to higher centers and mood. Bottom left: Schematic of primary afferent synapse with second-order dorsal horn spinal neuron, showing pre- and postsynaptic opiate receptors coupled to Ca2+ and K+ channels, respectively. Opiate-receptor binding is highly expressed in the superficial spinal dorsal horn (substantia gelatinosa). These receptors are located pre-synaptically on the terminals of small primary afferents (C fibers) and postsynaptically on second-order neurons. Presynaptically, activation of MOR blocks the opening of the voltage-sensitive Ca2+ channel, which otherwise initiates transmitter release. Postsynaptically, MOR activation enhances opening of K+ channels, leading to hyperpolarization. Thus, an opiate agonist acting at these sites jointly serves to attenuate the afferent-evoked excitation of the second-order neuron.

Spinal Opiate Action. A local action of opiates in the spinal cord will selectively depress the discharge of spinal dorsal horn neurons evoked by small (high-threshold) but not large (low-threshold) afferent nerve fibers. Intrathecal administration of opioids in animals ranging from mouse to human will reliably attenuate the response of the organism to a variety of somatic and visceral stimuli that otherwise evoke pain states. Specific opiate binding and receptor protein are limited for the most part to the substantia gelatinosa of the superficial dorsal horn, the region in which small, high-threshold sensory afferents show their principal termination. A significant proportion of these opiate receptors are associated with small peptidergic primary afferent C fibers; the remainder are on local dorsal horn neurons.

Spinal opiates reduce the release of primary afferent peptide transmitters such as substance P contained in small afferents. The presynaptic action corresponds to the ability of opiates to prevent the opening of voltage-sensitive Ca+ channels, thereby preventing transmitter release. A postsynaptic action is demonstrated by the ability of opiates to block excitation of dorsal horn neurons directly evoked by glutamate, reflecting a direct activation of dorsal horn projection neurons. The activation of K+ channels in these postsynaptic neurons, leading to hyperpolarization, is consistent with a direct postsynaptic inhibition. The joint capacity of spinal opiates to reduce the release of excitatory neurotransmitters from C fibers and to decrease the excitability of dorsal horn neurons is believed to account for the powerful and selective effect of opiates on spinal nociceptive processing. A variety of opiates delivered spinally (intrathecally or epidurally) can induce a powerful analgesia that is reversed by low doses of systemic naloxone.

Peripheral Action. Direct application of opiates to a peripheral nerve can, in fact, produce a local anesthetic-like action at high concentrations, but this is not naloxone reversible and is believed to reflect a “nonspecific” action. Conversely, direct injection of these agents into peripheral sites have demonstrated that under conditions of inflammation, where there is an increased terminal sensitivity leading to an exaggerated pain response (e.g., hyperalgesia), the local action of opiates can exert a normalizing effect on the exaggerated thresholds. Whether the effects are uniquely on the afferent terminal, whether the opiate acts on inflammatory cells that release products that sensitize the nerve terminal, or both, is not known.

MOOD ALTERATIONS AND REWARDING PROPERTIES. The mechanisms by which opioids produce euphoria, tranquility, and other alterations of mood (including rewarding properties) are complex and not entirely clear. Neural systems that mediate opioid reinforcement overlap with, but are distinct from, those involved in physical dependence and analgesia. Behavioral and pharmacological data point to a pivotal role of the mesocorticolimbic dopamine system that projects to the nucleus accumbens (NAc) in drug-induced reward and motivation (Figure 18–5).

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Figure 18–5 Schematic pathways underlying rewarding properties of opiates. Upper panel: This sagittal section of rat brain shows DA and GABA inputs from the ventral tegmental area (VTA) and prefrontal cortex (PFC), respectively, into the nucleus accumbens (NAc). Lower panel: Neurons are labeled with their primary neurotransmitters. At a cellular level, MOR agonists reduce excitability and transmitter release at the sites indicated by inhibiting Ca2+ influx and enhancing K+ current (see Figure 18–4). Thus, opiate-induced inhibition in the VTA on GABA-ergic interneurons or in the NAc reduce GABA-mediated inhibition and increase outflow from the ventral pallidum (VP), which appears to correlate with a positive reinforcing state (enhanced reward).

RESPIRATION. Although effects on respiration are readily demonstrated, clinically significant respiratory depression rarely occurs with standard analgesic doses in the absence of other contributing variables (discussed in the next sections). It should be stressed, however, that respiratory depression represents the primary cause of morbidity secondary to opiate therapy. In humans, death from opiate poisoning is nearly always due to respiratory arrest or obstruction. Opiates depress all phases of respiratory activity (rate, minute volume, and tidal exchange) and produce irregular and aperiodic breathing. The diminished respiratory volume is due primarily to a slower rate of breathing; with toxic amounts of opioids, the rate may fall to 3-4 breaths/min. Thus, opioids must be used with caution in patients with asthma, chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, preexisting respiratory depression, hypoxia, or hypercapnia to avoid apnea due to a decrease in respiratory drive coinciding with an increased airway resistance. Although respiratory depression is not considered to be a favorable therapeutic effect of opiates, their ability to suppress respiratory drive is used to therapeutic advantage to treat dyspnea resulting, e.g., in patients with COPD, where air hunger leads to extreme agitation, discomfort, and gasping; similarly, opiates find use in patients who require artificial ventilation.

Morphine-like opioids depress respiration through μ receptors and δ receptors in part by a direct depressant effect on rhythm generation. A key property of opiate effects on respiration is the depression of the ventilatory response to increased CO2. Opiates also will depress ventilation otherwise driven by hypoxia through an effect on carotid and aortic body chemosensors. Importantly, with opiates, hypoxic stimulation of chemoreceptors still may be effective when opioids have decreased the responsiveness to CO2, and inhalation of O2 may remove the residual drive resulting from the elevated PO2 and produce apnea. In addition to the effect upon respiratory rhythm and chemosensitivity, opiates can have mechanical effects on airway function by increasing chest wall rigidity and diminishing upper airway patency.

FACTORS EXACERBATING OPIATE-INDUCED RESPIRATORY DEPRESSION. A number of factors are recognized as increasing the risk of opiate-related respiratory depression even at therapeutic doses:

• Other medications. The combination of opiates with other depressant medications, such as general anesthetics, tranquilizers, alcohol, or sedative-hypnotics, produces additive depression of respiratory activity.

• Sleep. Natural sleep decreases the sensitivity of the medullary center to CO2, and the depressant effects of morphine and sleep are at least additive. Obstructive sleep apnea is considered to be an important risk factor for increasing the likelihood of fatal respiratory depression.

• Age. Newborns can show significant respiratory depression and desaturation; and this may be evident in lower Apgar scores if opioids are administered parenterally to women within 2-4 h of delivery because of transplacental passage of opioids. Elderly patients are at greater risk of depression because of reduced lung elasticity, chest wall stiffening, and decreased vital capacity.

• Disease. Opiates may cause a greater depressant action in patients with chronic cardiopulmonary or renal diseases because they can manifest a desensitization of the response to increased CO2.

• COPD. Enhanced depression can also be noted in patients with COPD and sleep apnea secondary to diminished hypoxic drive (although morphine can relieve gasping in late-stage COPD by this mechanism).

• Relief of Pain. Pain stimulates respiration; removal of the painful condition (as with the analgesia resulting from the therapeutic use of the opiate) will reduce the ventilatory drive and lead to apparent respiratory depression.

Respiratory depression produced by any opiate agonist can be readily reversed by delivery of an opiate antagonist. Opiate antagonist reversal in the somnolent patient is considered to be indicative of an opiate-mediated somnolence. It is important to remember that most opiate antagonists have a relatively short duration of action as compared to an agonist such as morphine or methadone and fatal “re-narcotization” can occur if vigilance is not exercised.

NEUROENDOCRINE EFFECTS. The regulation of the release of hormones and factors from the pituitary is under complex regulation by opiate receptors in the hypothalamic-pituitary-adrenal (HPA) axis. Broadly considered, morphine-like opioids block the release of a large number of HPA hormones.

Sex Hormones. In males, acute opiate therapy reduces plasma cortisol, testosterone, and gonadotrophins. Inhibition of adrenal function is reflected by reduced cortisol production and reduced adrenal androgens (dehydroepiandrosterone, DHEA). In females, morphine will additionally result in lower LH and FSH release. In both males and females, chronic therapy can result in endocrinopathies, including hypogonadotrophic hypogonadism. In men, this may result in decreased libido and, with extended exposure, reduced secondary sex characteristics. In women these exposures are associated with menstrual cycle irregularities. These changes are reversible with removal of the opiate.

Prolactin. Prolactin release from the anterior pituitary is under inhibitory control by DA released from neurons of the arcuate nucleus. MOR agonists act presynaptically on these DA-releasing terminals to inhibit DA release and thereby increase plasma prolactin.

Antidiuretic Hormone and Oxytocin. KOR agonists inhibit the release of oxytocin and antidiuretic hormone (and cause prominent diuresis). It should be noted that agents such as morphine may yield a hypotension secondary to histamine release and this would, by itself, promote ADH release.

MIOSIS. MOR agonists induce pupillary constriction (miosis) in the awake state and block pupillary reflex dilation during anesthesia. The parasympathetic outflow is locally regulated by GABA-ergic interneurons. Opiates are believed to block the GABA-ergic interneuron-mediated inhibition.

OTHER EFFECTS

SEIZURES AND CONVULSIONS. In older children and adults, moderately higher doses of opiates produce EEG slowing. In the newborn, morphine has been shown to produce epileptiform activity and occasionally seizure activity. Several mechanisms are most certainly involved in these excitatory actions:

• Inhibition of inhibitory interneurons. Morphine-like drugs excite certain groups of neurons, especially hippocampal pyramidal cells, probably from inhibition of the release of GABA by interneurons.

• Direct stimulatory effects.

• Actions mediated by non-opioid receptors. The metabolites of several opiates (morphine-3-glucuronide, normeperidine) have been implicated in seizure activity.

COUGH. Morphine and related opioids depress the cough reflex at least in part by a direct effect on a cough center in the medulla and this can be achieved without altering the protective glottal function. Cough is a protective reflex evoked by airway stimulation. It involves rapid expression of air against a transiently closed glottis.

NAUSEANT AND EMETIC EFFECTS. Nausea and vomiting produced by morphine-like drugs are side effects caused by direct stimulation of the chemoreceptor trigger zone for emesis in the area postrema of the medulla.

CARDIOVASCULAR SYSTEM. In the supine patient, therapeutic doses of morphine-like opioids have no major effect on blood pressure or cardiac rate and rhythm. Such doses can, however, produce peripheral vasodilation, reduced peripheral resistance, and an inhibition of baroreceptor reflexes. Thus, when supine patients assume the head-up position, orthostatic hypotension and fainting may occur. The peripheral arteriolar and venous dilation produced by morphine involves several mechanisms:

• Morphine induces release of histamine from mast cells, leading to vasodilation; this effect is reversed by naloxone but only partially blocked by H1 antagonists

• Morphine blunts reflex vasoconstriction caused by increased PCO2

Morphine may exert its therapeutic effect in the treatment of angina pectoris and acute myocardial infarction by decreasing preload, inotropy, and chronotropy, thus favorably altering determinants of myocardial O2 consumption. Morphine has been shown to produce cardioprotective effects. Morphine can mimic the phenomenon of ischemic preconditioning, where a short ischemic episode paradoxically protects the heart against further ischemia. This effect appears to be mediated through receptors signaling through a mitochondrial ATP-sensitive K+ channel in cardiac myocytes; the effect also is produced by other GPCRs signaling through Gi. Morphine-like opioids should be used with caution in patients who have decreased blood volume because these agents can aggravate hypovolemic shock. Morphine should be used with great care in patients with cor pulmonale; deaths after ordinary therapeutic doses have been reported. Concurrent use of certain phenothiazines may increase the risk of morphine-induced hypotension.

MOTOR TONE. High doses of opioids, as used for anesthetic induction, produce muscular rigidity. Myoclonus, ranging from mild twitching to generalized spasm, is an occasional side effect, which has been reported with all clinical opiate agonists; it is particularly prevalent in patients receiving high doses. Increase motor tone and rigidity are reversed by opiate antagonists.

GI TRACT. Between 40% and 95% of patients treated with opioids develop constipation and changes in bowel function. Opioid receptors are densely distributed in enteric neurons between the myenteric and submucosal plexi and on a variety of secretory cells.

Esophagus. Morphine inhibits lower esophageal sphincter relaxation induced by swallowing and by esophageal distension; the effect is believed to be centrally mediated.

Stomach. Morphine increases in tonic contracture of the antral musculature and upper duodenum and reduces resting tone in the musculature of the gastric reservoir, thereby prolonging gastric emptying time and increasing the likelihood of esophageal reflux. Passage of the gastric contents through the duodenum may be delayed by as much as 12 h, and the absorption of orally administered drugs is retarded. Morphine and other agonists usually decrease secretion of hydrochloric acid.

Intestine. Morphine reduces propulsatile activity in the small and large intestine and diminishes intestinal secretions. Opiate agonists suppress rhythmic inhibition of muscle tone leading to concurrent increases in basal tone in the circular muscle of the small and large intestine. This results in enhanced high-amplitude phasic contractions, which are nonpropulsive. The upper part of the small intestine, particularly the duodenum, is affected more than the ileum. A period of relative atony may follow the hypertonicity. The reduced rate of passage of the intestinal contents, along with reduced intestinal secretion, leads to increased water absorption, increasing viscosity of the bowel contents, and constipation. The tone of the anal sphincter is augmented greatly, and reflex relaxation in response to rectal distension is reduced. Patients who take opioids chronically remain constipated. Intestinal secretion arises from activation of enterocytes by local cholinergic submucosal plexus secretomotor neurons. Opioids act though μ/δ receptors on these secretomotor neurons to inhibit their excitatory output to the enterocytes and thereby reduce intestinal secretion.

Biliary Tract. Morphine constricts the sphincter of Oddi, and the pressure in the common bile duct may rise >10-fold within 15 min. Fluid pressure also may increase in the gallbladder and produce symptoms that may vary from epigastric distress to typical biliary colic. All opioids can cause biliary spasm. Some patients with biliary colic experience exacerbation rather than relief of pain when given opioids. Spasm of the sphincter of Oddi probably is responsible for elevations of plasma amylase and lipase that occur sometimes after morphine administration.

OTHER SMOOTH MUSCLE

Ureter and Urinary Bladder. Morphine inhibits the urinary voiding reflex and increases the tone of the external sphincter with a resultant increase in the volume of the bladder. Tolerance develops to these effects of opioids on the bladder. Clinically, opiate-mediated inhibition of micturition can be of such clinical severity that catheterization sometimes is required after therapeutic doses of morphine, particularly with spinal drug administration. Importantly, the inhibition of systemic opiate effects on micturition is reversed by peripherally restricted antagonists.

Uterus. Morphine may prolong labor. If the uterus has been made hyperactive by oxytocics, morphine tends to restore the contractions to normal.

SKIN. Therapeutic doses of morphine cause dilation of cutaneous blood vessels. The skin of the face, neck, and upper thorax frequently becomes flushed. These changes may be due in part to the release of histamine and may be responsible for the sweating and some of the pruritus that commonly follow the systemic administration of morphine (described later). Histamine release probably accounts for the urticaria commonly seen at the site of injection. Itching is readily seen with morphine and meperidine but to a much lesser extent with oxymorphone, methadone, fentanyl, or sufentanil. This pruritus can be caused by systemic as well as intraspinal injections of opioids, but it is more intense after epidural or intrathecal administration.

IMMUNE SYSTEM. Opioids modulate immune function by direct effects on cells of the immune system and indirectly through centrally mediated neuronal mechanisms. The acute central immunomodulatory effects of opioids may be mediated by activation of the sympathetic nervous system; the chronic effects of opioids may involve modulation of the HPA axis. Direct effects on immune cells may involve unique variants of the classical neuronal opioid receptors, with μ receptor variants being most prominent. A proposed mechanism for the immune suppressive effects of morphine on neutrophils is through NO–dependent inhibition of NF-kB activation. Activation of MAP kinase also may play a role.

TEMPERATURE REGULATION. Opioids alter the equilibrium point of the hypothalamic heat-regulatory mechanisms such that body temperature usually falls slightly. Agonists at the μ receptor (e.g., alfentanil and meperidine), acting in the CNS, result in slightly increased thresholds for sweating and significantly lower the threshold temperatures for evoking vasoconstriction and shivering.

FUNCTIONAL OPIOID DRUG TYPES

Most of the clinically used opioid agonists presented in Table 18–4 are relatively selective for MOR. They produce analgesia, affect mood and rewarding behavior, and alter respiratory, cardiovascular, GI, and neuroendocrine function. KOR agonists, with few exceptions (e.g., butorphanol), are not typically employed for long-term therapy as they may produce dysphoric and psychotomimetic effects. DOR agonists have not found clinical utility, and NOP agonists lack analgesic effects. Opiates that are relatively receptor selective at lower doses will interact with additional receptor types when given at high doses, especially as doses are escalated to overcome tolerance.

Table 18–4

Dosing Data for Clinically Employed Opioid Analgesics

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The mixed agonist–antagonist agents frequently interact with more than 1 receptor class at usual clinical doses. A “ceiling effect” limiting the amount of analgesia attainable often is seen with these drugs, such as buprenorphine, which is approved for the treatment of opioid dependence. Some mixed agonist–antagonist drugs, such as pentazocine and nalorphine (not available in the U.S.), can precipitate withdrawal in opioid-tolerant patients. For these reasons, except for the sanctioned use of buprenorphine to manage opioid addiction, the clinical use of mixed agonist–antagonist drugs is generally limited.

The dosing guidelines and duration of action for the numerous drugs that are part of opioid therapy are summarized in Table 18–4.

MORPHINE AND STRUCTURALLY RELATED AGONISTS

MORPHINE. Morphine remains the standard against which new analgesics are measured.

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Morphine is obtained from opium or extracted from poppy straw. Powdered opium contains a number of alkaloids; only a few—morphine, codeine, and papaverine—have clinical utility. These alkaloids are divided into 2 distinct chemical classes, phenanthrenes and benzylisoquinolines. The principal phenanthrenes are morphine (10% of opium), codeine (0.5%), and thebaine (0.2%). The principal benzylisoquinolines are papaverine (1%) (a smooth muscle relaxant) and noscapine (6%). Many semisynthetic derivatives are made by relatively simple modifications of morphine or thebaine.

Absorption. Opioids are absorbed from the GI tract; absorption through the rectal mucosa is adequate and a few agents (e.g., morphine, hydromorphone) are available in suppositories. The more lipophilic opioids are absorbed readily through the nasal or buccal mucosa. Those with the greatest lipid solubility also can be absorbed transdermally. Opioids, particularly morphine, have been widely used for spinal delivery to produce analgesia through a spinal action. These agents display useful transdural movement adequate to permit their use epidurally.

With most opioids, including morphine, the effect of a given dose is less after oral than after parenteral administration because of variable but significant first-pass metabolism in the liver. For example, the bioavailability of oral preparations of morphine is only ~25%. The shape of the time-effect curve also varies with the route of administration, so the duration of action often is somewhat longer with the oral route. If adjustment is made for variability of first-pass metabolism and clearance, adequate relief of pain can be achieved with oral administration of morphine. Satisfactory analgesia in cancer patients is associated with a very broad range of steady-state concentrations of morphine in plasma (16-364 ng/mL). When morphine and most opioids are given intravenously, they act promptly. Compared with more lipid-soluble opioids such as codeine, heroin, and methadone, morphine crosses the blood-brain barrier at a considerably lower rate.

Distribution and Metabolism. About one-third of morphine in the plasma is protein-bound after a therapeutic dose. Morphine itself does not persist in tissues, and 24 h after the last dose, tissue concentrations are low. The major pathway for the metabolism of morphine is conjugation with glucuronic acid. The 2 major metabolites formed are morphine-6-glucuronide and morphine-3-glucuronide. Morphine-6-glucuronide has pharmacological actions indistinguishable from those of morphine. With chronic administration, the 6-glucuronide accounts for a significant portion of morphine’s analgesic actions. Morphine-6-glucuronide is excreted by the kidney. In renal failure, the levels of morphine-6-glucuronide can accumulate, perhaps explaining morphine’s potency and long duration in patients with compromised renal function. In adults, the t1/2 of morphine is ~2 h; the t1/2 of morphine-6-glucuronide is somewhat longer. Children achieve adult renal function values by 6 months of age. In elderly patients, lower doses of morphine are recommended based on a smaller volume of distribution and the general decline in renal function. Morphine-3-glucuronide has little affinity for opioid receptors but may contribute to excitatory effects of morphine. N-Dealkylation also is important in the metabolism of some congeners of morphine.

Excretion. Morphine is eliminated by glomerular filtration, primarily as morphine-3-glucuronide; 90% of the total excretion takes place during the first day. Very little morphine is excreted unchanged.

CODEINE. In contrast to morphine, codeine is ~60% as effective orally as parenterally as an analgesic and as a respiratory depressant. Codeine analogs such as levorphanol, oxycodone, and methadone have a high ratio of oral-to-parenteral potency. The greater oral efficacy of these drugs reflects lower first-pass metabolism in the liver. Once absorbed, codeine is metabolized by the liver, and its metabolites are excreted chiefly as inactive forms in the urine. A small fraction (~10%) of administered codeine is O-demethylated to morphine, and free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, codeine’s antitussive actions may involve distinct receptors that bind codeine itself, and codeine is commonly employed for the management of cough. The t1/2 of codeine in plasma is 2-4 h.

CYP2D6 catalyzes the conversion of codeine to morphine. Genetic polymorphisms in CYP2D6 lead to the inability to convert codeine to morphine, thus making codeine ineffective as an analgesic for ~10% of the Caucasian population. Other polymorphisms (e.g., the CYP2D6*2×2 genotype) can lead to ultrarapid metabolism and thus increased sensitivity to codeine’s effects due to higher than expected serum morphine levels. Thus, it is important to consider the possibility of metabolic enzyme polymorphism in any patient who experiences toxicity or does not receive adequate analgesia from codeine or other opioid prodrugs (e.g., hydrocodone and oxycodone).

HEROIN. Heroin (diacetylmorphine) is rapidly hydrolyzed to 6-monoacetylmorphine (6-MAM), which in turn is hydrolyzed to morphine. Heroin and 6-MAM are more lipid soluble than morphine and enter the brain more readily. Evidence suggests that morphine and 6-MAM are responsible for the pharmacological actions of heroin. Heroin is excreted mainly in the urine largely as free and conjugated morphine.

UNTOWARD EFFECTS AND PRECAUTIONS

Morphine and related opioids produce a wide spectrum of unwanted effects, including respiratory depression, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, increased pressure in the biliary tract, urinary retention, and hypotension. Rarely, a patient may develop delirium. Increased sensitivity to pain after analgesia has worn off and between-dose withdrawal also may occur.

A number of factors may alter a patient’s sensitivity to opioid analgesics, including the integrity of the blood-brain barrier. Morphine is hydrophilic, so proportionately less morphine normally crosses into the CNS than with more lipophilic opioids. In neonates or when the blood-brain barrier is compromised, lipophilic opioids may give more predictable clinical results than morphine. In adults, the duration of the analgesia produced by morphine increases progressively with age; however, the degree of analgesia that is obtained with a given dose changes little. The patient with severe pain may tolerate larger doses of morphine. However, as the pain subsides, the patient may exhibit sedation and even respiratory depression as the stimulatory effects of pain are diminished.

All opioid analgesics are metabolized by the liver and should be used with caution in patients with hepatic disease. Renal disease also significantly alters the pharmacokinetics of morphine, codeine, dihydrocodeine, meperidine, and propoxyphene. Although single doses of morphine are well tolerated, the active metabolite, morphine-6-glucuronide, may accumulate with continued dosing, and symptoms of opioid overdose may result. This metabolite also may accumulate during repeated administration of codeine to patients with impaired renal function.

Morphine and related opioids must be used cautiously in patients with compromised respiratory function (e.g., emphysema, kyphoscoliosis, severe obesity). The respiratory-depressant effects of opioids and the related capacity to elevate intracranial pressure must be considered in the presence of head injury or an already elevated intracranial pressure. Patients with reduced blood volume are more susceptible to the vasodilating effects of morphine and related drugs, and these agents must be used cautiously in patients with hypotension from any cause.

Morphine causes histamine release, which can cause bronchoconstriction and vasodilation. Morphine has the potential to precipitate or exacerbate asthmatic attacks and should be avoided in patients with a history of asthma. Other receptor agonists associated with a lower incidence of histamine release, such as the fentanyl derivatives, may be better choices for such patients. Opioid analgesics may evoke allergic phenomena, the effects usually are manifested as urticaria and other types of skin rashes.

LEVORPHANOL

Levorphanol (LEVO-DROMORAN) is the principal available opioid agonist of the morphinan series.

The D-isomer (dextrorphan) is devoid of analgesic action but has inhibitory effects at NMDA receptors. It has affinity at the MOR, KOR, and DORs and is available for intravenous (IV), intramuscular (IM), and oral administration. The pharmacological effects of levorphanol closely parallel those of morphine. However, clinical reports suggest that it may produce less nausea and vomiting. Levorphanol is metabolized less rapidly than morphine and has a t1/2 of 12-16 h; repeated administration at short intervals may thus lead to accumulation of the drug in plasma.

MEPERIDINE, DIPHENOXYLATE, LOPERAMIDE

These agents are MOR agonists with principal pharmacological effects on the CNS and neural elements in the bowel.

MEPERIDINE

Meperidine is predominantly an MOR agonist that produces a pattern of effects similar but not identical to those already described for morphine.

CNS Actions. Meperidine is a potent MOR agonist yielding strong analgesic actions. Meperidine causes pupillary constriction, increases the sensitivity of the labyrinthine apparatus, and has effects on the secretion of pituitary hormones similar to those of morphine. Meperidine sometimes causes CNS excitation, characterized by tremors, muscle twitches, and seizures; these effects are due largely to accumulation of a metabolite, normeperidine. Meperidine has well-known local anesthetic properties, particularly noted after epidural administration. As with morphine, respiratory depression is responsible for an accumulation of CO2, which in turn leads to cerebrovascular dilation, increased cerebral blood flow, and elevation of cerebrospinal fluid pressure.

Cardiovascular System. The effects of meperidine on the cardiovascular system generally resemble those of morphine, including the ability to release histamine following parenteral administration. Intramuscular administration of meperidine does not affect heart rate significantly, but IV administration frequently produces a marked increase in heart rate.

Smooth Muscle, GI Tract. Meperidine does not cause as much constipation as does morphine, even when given over prolonged periods of time; this may be related to its greater ability to enter the CNS, thereby producing analgesia at lower systemic concentrations. As with other opioids, clinical doses of meperidine slow gastric emptying sufficiently to delay absorption of other drugs significantly. The uterus of a nonpregnant woman usually is mildly stimulated by meperidine. Administered before an oxytocic, meperidine does not exert any antagonistic effect.

ADME. Meperidine is absorbed by all routes of administration. The peak plasma concentration usually occurs at ~45 min, but the range is wide. After oral administration, only ~50% of the drug escapes first-pass metabolism to enter the circulation, and peak concentrations in plasma usually are observed in 1-2 h. Meperidine is metabolized chiefly in the liver, with a t1/2 ~3 h. In patients with cirrhosis, the bioavailability of meperidine (the N-demethyl metabolite) is increased to as much as 80%, and the t1/2 of both meperidine and normeperidine are prolonged. Only a small amount of meperidine is excreted unchanged.

UNTOWARD EFFECTS, PRECAUTIONS, AND CONTRAINDICATIONS. The overall incidence of untoward effects are similar to those observed after equianalgesic doses of morphine, except that constipation and urinary retention may be less common. Patients who experience nausea and vomiting with morphine may not do so with meperidine; the converse also may be true. In patients or addicts who are tolerant to the depressant effects of meperidine, large doses repeated at short intervals may produce an excitatory syndrome including hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions. These excitatory symptoms are due to the accumulation of normeperidine, which has a t1/2 of 15-20 h, compared to 3 h for meperidine. Decreased renal or hepatic function increases the likelihood of toxicity. As a result of these properties, meperidine is not recommended for the treatment of chronic pain because of concerns over metabolite toxicity. It should not be used for longer than 48 h or in doses >600 mg/day.

INTERACTIONS WITH OTHER DRUGS. Severe reactions may follow the administration of meperidine to patients being treated with MAO inhibitors. Two basic types of interactions can be observed. The more prominent is an excitatory reaction (“serotonin syndrome”) with delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma, and death. This reaction may be due to the ability of meperidine to block neuronal reuptake of 5HT, resulting in serotonergic overactivity. Conversely, the MAO inhibitor interaction with meperidine may resemble acute narcotic overdose owing to the inhibition of hepatic CYPs. Therefore, meperidine and its congeners are contraindicated in patients taking MAO inhibitors or within 14 days after discontinuation of an MAO inhibitor. Dextromethorphan (an analog of levorphanol used as a nonnarcotic cough suppressant) also inhibits neuronal 5HT uptake and must be avoided in these patients.

Chlorpromazine increases the respiratory-depressant effects of meperidine, as do tricyclic antidepressants (but not diazepam). Concurrent administration of drugs such as promethazine or chlorpromazine also may greatly enhance meperidine-induced sedation without slowing clearance of the drug. Treatment with phenobarbital or phenytoin increases systemic clearance and decreases oral bioavailability of meperidine. As with morphine, concomitant administration of amphetamine has been reported to enhance the analgesic effects of meperidine and its congeners while counteracting sedation.

THERAPEUTIC USES. The major use of meperidine is for analgesia. The analgesic effects of meperidine are detectable ~15 min after oral administration, peak in 1-2 h, and subside gradually. The onset of analgesic effect is faster (within 10 min) after subcutaneous or IM administration, and the effect reaches a peak in ~1 h, corresponding closely to peak concentrations in plasma. In clinical use, the duration of effective analgesia is ~1.5-3 h. In general, 75-100 mg meperidine hydrochloride (pethidine, DEMEROL, others) given parenterally is approximately equivalent to 10 mg morphine. In terms of total analgesic effect, meperidine is about one-third as effective when given orally as when administered parenterally.

Single doses of meperidine can be effective in the treatment of postanesthetic shivering. Meperidine, 25-50 mg, is used frequently with antihistamines, corticosteroids, acetaminophen, or NSAIDs to prevent or ameliorate infusion-related rigors and shaking chills that accompany the IV administration of agents such as amphotericin B, aldesleukin (interleukin-2), trastuzumab, and alemtuzumab. Meperidine crosses the placental barrier and even in reasonable analgesic doses causes a significant increase in the percentage of babies who show delayed respiration, decreased respiratory minute volume, or decreased O2 saturation or who require resuscitation. Fetal and maternal respiratory depression induced by meperidine can be treated with naloxone.

DIPHENOXYLATE

Diphenoxylate is a meperidine congener that has a definite constipating effect in humans. Its only approved use is in the treatment of diarrhea (see Chapter 46). Diphenoxylate is unusual in that even its salts are virtually insoluble in aqueous solution, thus reducing the probability of abuse by the parenteral route. Diphenoxylate hydrochloride is available only in combination with atropine sulfate (LOMOTIL, others). The recommended daily dosage of diphenoxylate for the treatment of diarrhea in adults is 20 mg in divided doses. Difenoxin a metabolite of diphenoxylate, is marketed in a fixed dose with atropine (MOTOFEN) for the management of diarrhea.

LOPERAMIDE

Loperamide (IMODIUM, others), like diphenoxylate, is a piperidine derivative. It slows GI motility by effects on the circular and longitudinal muscles of the intestine. Part of its antidiarrheal effect may be due to a reduction of GI secretion. In controlling chronic diarrhea, loperamide is as effective as diphenoxylate and little tolerance develops to its constipating effect. Concentrations of drug in plasma peak ~4 h after ingestion. The apparent elimination t1/2 is 7-14 h. Loperamide is poorly absorbed after oral administration and, in addition, apparently does not penetrate well into the brain due to the exporting activity of P-glycoprotein, which is widely expressed in the brain endothelium. The usual dosage is 4-8 mg/day; the daily dose should not exceed 16 mg.

FENTANYL AND CONGENERS

FENTANYL

Fentanyl is a synthetic opioid related to the phenylpiperidines. The actions of fentanyl and its congeners, sufentanil, remifentanil, and alfentanil, are similar to those of other MOR agonists. Fentanyl and sufentanil are very important drugs in anesthetic practice because of their relatively short time to peak analgesic effect, rapid termination of effect after small bolus doses, and cardiovascular safety and their capacity to significantly reduce the dosing requirement for the volatile agents (see Chapter 19). In addition to a role in anesthesia, fentanyl also is used in the management of severe pain states.

PHARMACOLOGICAL PROPERTIES

CNS. Fentanyl and its congeners are all extremely potent analgesics and typically exhibit a very short duration of action when given parenterally. As with other opioids, nausea, vomiting, and itching can be observed. Muscle rigidity, while possible after all narcotics, appears to be more common after the high doses used in anesthetic induction. Rigidity can be treated with depolarizing or nondepolarizing neuromuscular blocking agents while controlling the patient’s ventilation. Care must be taken to make sure that the patient is not simply immobilized but aware. Respiratory depression is similar to that observed with other MOR agonists, but onset is more rapid. As with analgesia, respiratory depression after small doses is of shorter duration than with morphine but of similar duration after large doses or long infusions. Delayed respiratory depression also can be seen after the use of fentanyl or sufentanil, possibly owing to enterohepatic circulation.

Cardiovascular System. Fentanyl and its derivatives decrease heart rate and mildly decrease blood pressure. However, these drugs do not release histamine and direct depressant effects on the myocardium are minimal.

ADME. These agents are highly lipid soluble and rapidly cross the blood-brain barrier. This is reflected in the t1/2 for equilibration between the plasma and CSF of ~5 min for fentanyl and sufentanil. The levels in plasma and CSF decline rapidly owing to redistribution of fentanyl from highly perfused tissue groups to other tissues, such as muscle and fat. As saturation of less well-perfused tissue occurs, the duration of effect of fentanyl and sufentanil approaches the length of their elimination t1/2, 3-4 h. Fentanyl and sufentanil undergo hepatic metabolism and renal excretion. With the use of higher doses or prolonged infusions, the drugs accumulate, these clearance mechanisms become progressively saturated, and fentanyl and sufentanil become longer acting.

THERAPEUTIC USES. Fentanyl citrate (SUBLIMAZE, others) and sufentanil citrate (SUFENTA, others) have widespread popularity as anesthetic adjuvants (see Chapter 19), administered intravenously, epidurally, or intrathecally. Fentanyl is ~100 times more potent than morphine; sufentanil is ~1000 times more potent than morphine. The time to peak analgesic effect after IV administration of fentanyl and sufentanil (~5 min) is notably less than that for morphine and meperidine (~15 min). Recovery from analgesic effects also occurs more quickly. However, with larger doses or prolonged infusions, the effects of these drugs become more lasting, with durations of action becoming similar to those of longer-acting opioids.

The use of fentanyl and sufentanil in chronic pain treatment has become more widespread. Transdermal patches (DURAGESIC, others) that provide sustained release of fentanyl for 48-72 h are available. However, factors promoting increased absorption (e.g., fever) can lead to relative overdosage and increased side effects. Transbuccal absorption by the use of buccal tablets, and lollipop-like lozenges permits rapid absorption and has found use in the management of acute incident pain (FENTORA, ACTIQ, ONSOLIS, others) and for the relief of breakthrough cancer pain. As fentanyl is poorly absorbed in the GI tract, the optimal absorption is through buccal absorption. Epidural use of fentanyl and sufentanil for postoperative or labor analgesia is popular. A combination of epidural opioids with local anesthetics permits reduction in the dosage of both components.

REMIFENTANIL

The pharmacological properties of remifentanil are similar to those of fentanyl and sufentanil. Remifentanil produces similar incidences of nausea, vomiting, and dose-dependent muscle rigidity.

ADME. Remifentanil has a more rapid onset of analgesic action than fentanyl or sufentanil. Analgesic effects occur within 1-1.5 min following IV administration. Peak respiratory depression after bolus doses of remifentanil occurs after 5 min. Remifentanil is metabolized by plasma esterases, with a t1/2 of 8-20 min; thus, elimination is independent of hepatic metabolism or renal excretion. Age and weight can affect clearance of remifentanil. After 3- to 5-h infusions of remifentanil, recovery of respiratory function can be seen within 3-5 min; full recovery from all effects of remifentanil is observed within 15 min. The primary metabolite, remifentanil acid, has 0.05-0.025% of the potency of the parent compound, and is excreted renally.

THERAPEUTIC USES. Remifentanil hydrochloride (ULTIVA) is useful for short, painful procedures that require intense analgesia and blunting of stress responses; the drug is routinely given by continuous IV infusion because its short duration of action. When postprocedural analgesia is required, remifentanil alone is a poor choice. In this situation, either a longer-acting opioid or another analgesic modality should be combined with remifentanil for prolonged analgesia, or another opioid should be used. Remifentanil is not used intraspinally because of its formulation with glycine, an inhibitory transmitter in the spinal dorsal horn.

METHADONE AND PROPOXYPHENE

METHADONE

Methadone is a long-acting MOR agonist with pharmacological properties qualitatively similar to those of morphine. The analgesic activity of methadone, a racemate, is almost entirely the result of its content of L-methadone, which is 8-50 times more potent than the D-isomer. D-methadone also lacks significant respiratory depressant action and addiction liability but possesses antitussive activity.

MAJOR EFFECTS; SIDE EFFECTS. The outstanding properties of methadone are its analgesic activity, its efficacy by the oral route, its extended duration of action in suppressing withdrawal symptoms in physically dependent individuals, and its tendency to show persistent effects with repeated administration. Miotic and respiratory-depressant effects can be detected for >24 h after a single dose; on repeated administration, marked sedation is seen in some patients. Effects on cough, bowel motility, biliary tone, and the secretion of pituitary hormones are qualitatively similar to those of morphine. Side effects are similar to those described for morphine. Rifampin and phenytoin accelerate the metabolism of methadone and can precipitate withdrawal symptoms. Unlike other opioids, methadone is associated with the prolonged QT syndrome and is additive with agents known to prolong the QT interval.

ADME. Methadone is absorbed well from the GI tract and can be detected in plasma within 30 min of oral ingestion; it reaches peak concentrations at ~4 h. Peak concentrations occur in brain within 1-2 h of subcutaneous or IM administration, and this correlates well with the intensity and duration of analgesia. Methadone also can be absorbed from the buccal mucosa. Methadone undergoes extensive biotransformation in the liver. The major metabolites, pyrrolidine and pyrroline, are excreted in the urine and the bile along with small amounts of unchanged drug. The amount of methadone excreted in the urine is increased when the urine is acidified. The t1/2 of methadone is long, 15-40 h. Methadone appears to be firmly bound to protein in various tissues, including brain. After repeated administration, there is gradual accumulation in tissues. When administration is discontinued, low concentrations are maintained in plasma by slow release from extravascular binding sites; this process probably accounts for the relatively mild but protracted withdrawal syndrome.

THERAPEUTIC USES. The primary uses of methadone hydrochloride (DOLOPHINE, others) are relief of chronic pain, treatment of opioid abstinence syndromes, and treatment of heroin users. The onset of analgesia occurs 10-20 min after parenteral administration and 30-60 min after oral medication. The typical oral dose is 2.5-10 mg repeated every 8-12 h as needed depending on the severity of the pain and the response of the patient. Care must be taken when increasing the dosage because of the prolonged t1/2 of the drug and its tendency to accumulate over a period of several days with repeated dosing. The peak respiratory depressant effects of methadone typically occur later and persist longer than peak analgesia, so it is necessary to exercise vigilance and strongly caution patients against self-medicating with CNS depressants, particularly during treatment initiation and dose titration. Methadone should not be used in labor. Despite its longer plasma t1/2, the duration of the analgesic action of single doses is essentially the same as that of morphine. With repeated use, cumulative effects are seen, so either lower dosages or longer intervals between doses become possible.

Because of its oral bioavailability and long t1/2, methadone has been widely implemented as a replacement modality to treat heroin dependence. Methadone, like other opiates, will produce tolerance and dependence. Thus, addicts who receive daily subcutaneous or oral therapy develop partial tolerance to the nauseant, anorectic, miotic, sedative, respiratory-depressant, and cardiovascular effects of methadone. Many former heroin users treated with oral methadone show virtually no overt behavioral effects. Development of physical dependence during the long-term administration of methadone can be demonstrated following abrupt drug withdrawal or by administration of an opioid antagonist. Likewise, subcutaneous administration of methadone to former opioid addicts produces euphoria equal in duration to that caused by morphine, and its overall abuse potential is comparable with that of morphine.

PROPOXYPHENE

Propoxyphene is structurally related to methadone. Its analgesic effect resides in the D-isomer. However, L-propoxyphene seems to have some antitussive activity.

PHARMACOLOGICAL ACTIONS. Although slightly less selective than morphine, propoxyphene binds primarily to MOR and produces analgesia and other CNS effects that are similar to those seen with morphine-like opioids. At equianalgesic doses, the incidence of side effects such as nausea, anorexia, constipation, abdominal pain, and drowsiness are similar to those of codeine. As an analgesic, propoxyphene is about one-half to two-thirds as potent as codeine given orally. A dose of 90-120 mg of propoxyphene hydrochloride administered orally provides the analgesic effects of 60 mg of codeine, a dose that usually produces about as much analgesia as 600 mg aspirin. Combinations of propoxyphene and aspirin, like combinations of codeine and aspirin, afford a higher level of analgesia than does either agent given alone. Given orally, propoxyphene is approximately one-third as potent as orally administered codeine in depressing respiration. Larage toxic doses may produce convulsions in addition to respiratory depression. Naloxone antagonizes the respiratory-depressant, convulsant, and some of the cardiotoxic effects of propoxyphene.

ADME. After oral administration, peak plasma concentrations occur at 1-2 h. There is great variability between subjects in the rate of clearance. The average t1/2 of propoxyphene in plasma after a single dose is 6-12 h, which is longer than that of codeine. In humans, the major route of metabolism is N-demethylation to yield norpropoxyphene. The t1/2 of norpropoxyphene is ~30 h; it may accumulate with repeated doses and cause some toxicity.

Higher than expected serum levels of propoxyphene will occur from the concomitant administration of strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil). Propoxyphene alternatives should be considered for patients receiving a strong CYP3A4 inhibitor and others at risk for overdose, particularly those with preexisting heart disease.

TOLERANCE AND DEPENDENCE. Very large doses (800 mg propoxyphene hydrochloride [DARVON, others] or 1200 mg of the napsylate [DARVON-N] per day) reduce the intensity of the morphine withdrawal syndrome somewhat less effectively than do 1500 mg doses of codeine. Maximal tolerated doses are equivalent to daily doses of 20-25 mg morphine given subcutaneously. The use of higher doses of propoxyphene is accompanied by untoward effects including toxic psychoses. Very large doses produce some respiratory depression in morphine-tolerant addicts, suggesting that cross-tolerance between propoxyphene and morphine is incomplete. Abrupt discontinuation of chronically administered propoxyphene hydrochloride (up to 800 mg/day given for almost 2 months) results in mild abstinence phenomena, and large oral doses (300-600 mg) produce subjective effects that are considered pleasurable by post-addicts. The drug is quite irritating when administered either intravenously or subcutaneously, so abuse by these routes results in severe damage to veins and soft tissues.

THERAPEUTIC USES. The European Medicines Agency has concluded that the benefits of dextropropoxyphene do not outweigh the risks, that dextropropoxyphene-containing medicines are weak painkillers with a narrow therapeutic index and limited effectiveness in the treatment of pain, and that acetaminophen-containing combinations with dextropropoxyphene are no more effective than acetaminophen alone. Consequently, the Agency has recommended a gradual withdrawal of marketing authorization throughout the E.U. In the U.S., the FDA has asked companies to voluntarily remove propoxyphene-containing products from the market due to concerns related to cardiotoxic effects of the drug at therapeutic doses.

OTHER OPIOID AGONISTS

TRAMADOL. Tramadol (ULTRAM) is a synthetic codeine analog that is a weak MOR agonist. Part of its analgesic effect is produced by inhibition of uptake of NE and 5HT. In the treatment of mild to moderate pain, tramadol is as effective as morphine or meperidine. However, for the treatment of severe or chronic pain, tramadol is less effective. Tramadol is as effective as meperidine in the treatment of labor pain and may cause less neonatal respiratory depression.

ADME. Tramadol is 68% bioavailable after a single oral dose and 100% available when administered intramuscularly. Its affinity for the μ-opioid receptor is only 1/6000 that of morphine. The primary O-demethylated metabolite of tramadol is 2-4 times more potent than the parent drug and may account for part of the analgesic effect. Tramadol is supplied as a racemate that is more effective than either enantiomer alone. The (+)-enantiomer binds to the receptor and inhibits 5HT uptake. The (–)-enantiomer inhibits NE uptake and stimulates α2 adrenergic receptors. Tramadol undergoes extensive hepatic metabolism by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation with subsequent renal excretion. The elimination t1/2 is 6 h for tramadol and 7.5 h for its active metabolite. Analgesia begins within an hour of oral dosing and peaks within 2-3 h. The duration of analgesia is ~6 h. The maximum recommended daily dose is 400 mg.

Side Effects; Adverse Effects. Side effects of tramadol include nausea, vomiting, dizziness, dry mouth, sedation, and headache. Respiratory depression appears to be less than with equianalgesic doses of morphine, and the degree of constipation is less than that seen after equivalent doses of codeine. Tramadol can cause seizures and possibly exacerbate seizures in patients with predisposing factors. Tramadol-induced respiratory depression is reversed by naloxone. Precipitation of withdrawal necessitates that tramadol be tapered prior to discontinuation. Tramadol should not be used in patients taking MAO inhibitors, SSRIs, or other drugs that lower the seizure threshold.

TAPENTADOL. Tapentadol (NUCYNTA) is structurally and mechanistically similar to tramadol. It displays a mild opioid activity and possesses monoamine reuptake inhibitor activity. It is considered similar to tramadol in activity, efficacy, and side-effect profile.

OPIOID AGONISTS/ANTAGONISTS AND PARTIAL AGONISTS

Drugs such as nalbuphine and butorphanol are competitive MOR antagonists but exert their analgesic actions by acting as agonists at KOR receptors. Pentazocine qualitatively resembles these drugs, but it may be a weaker MOR receptor antagonist or partial agonist while retaining its KOR agonist activity. Buprenorphine, however, is a partial agonist at MOR. The stimulus for the development of mixed agonist–antagonist drugs was a desire for analgesics with less respiratory depression and addictive potential. However, the clinical use of these compounds is limited by undesirable side effects and limited analgesic effects.

PENTAZOCINE

Pentazocine was synthesized as part of a deliberate effort to develop an effective analgesic with little or no abuse potential. It has agonistic actions and weak opioid antagonistic activity.

PHARMACOLOGICAL ACTIONS AND SIDE EFFECTS. The pattern of CNS effects produced by pentazocine generally is similar to that of the morphine-like opioids, including analgesia, sedation, and respiratory depression. The analgesic effects of pentazocine are due to agonistic actions at KOR. Higher doses of pentazocine (60-90 mg) elicit dysphoric and psychotomimetic effects; these effects may be reversible by naloxone. The cardiovascular responses to pentazocine differ from those seen with typical receptor agonists, in that high doses cause an increase in blood pressure and heart rate. Pentazocine acts as a weak antagonist or partial agonist at MOR. Pentazocine does not antagonize the respiratory depression produced by morphine. However, when given to patients dependent on morphine or other MOR agonists, pentazocine may precipitate withdrawal. Ceiling effects for analgesia and respiratory depression are observed at doses above 50-100 mg of pentazocine.

THERAPEUTIC USES. Pentazocine lactate (TALWIN) injection is indicated for the relief of moderate to severe pain and is also used as a preoperative medication and as a supplement to anesthesia. Pentazocine tablets for oral use are only available in fixed-dose combinations with acetaminophen (TALACEN, others) or naloxone (TALWIN NX). Combination of pentazocine with naloxone reduces the potential misuse of tablets as a source of injectable pentazocine by producing undesirable effects in subjects dependent on opioids. An oral dose of ~50 mg pentazocine results in analgesia equivalent to that produced by 60 mg of codeine orally.

NALBUPHINE

Nalbuphine is a KOR agonist-MOR antagonist opioid with effects that qualitatively resemble those of pentazocine; however, nalbuphine produces fewer dysphoric side effects than pentazocine.

PHARMACOLOGICAL ACTIONS AND SIDE EFFECTS. An IM dose of 10 mg nalbuphine is equianalgesic to 10 mg morphine, with similar onset and duration of analgesic and subjective effects. Nalbuphine depresses respiration as much as do equianalgesic doses of morphine; however, nalbuphine exhibits a ceiling effect such that increases in dosage beyond 30 mg produce no further respiratory depression or analgesia. In contrast to pentazocine and butorphanol, 10 mg nalbuphine given to patients with stable coronary artery disease does not produce an increase in cardiac index, pulmonary arterial pressure, or cardiac work, and systemic blood pressure is not significantly altered; these indices also are relatively stable when nalbuphine is given to patients with acute myocardial infarction. Nalbuphine produces few side effects at doses of 10 mg or less; sedation, sweating, and headache are the most common. At much higher doses (70 mg), psychotomimetic side effects (e.g., dysphoria, racing thoughts, and distortions of body image) can occur. Nalbuphine is metabolized in the liver and has a plasma t1/2 of 2-3 h. Nalbuphine is 20-25% as potent when administered orally as when given intramuscularly. Prolonged administration of nalbuphine can produce physical dependence. The withdrawal syndrome is similar in intensity to that seen with pentazocine.

THERAPEUTIC USE. Nalbuphine hydrochloride (NUBAIN, others) is used to produce analgesia. Because it is an agonist–antagonist, administration to patients who have been receiving morphine-like opioids may create difficulties unless a brief drug-free interval is interposed. The usual adult dose is 10 mg parenterally every 3-6 h; this may be increased to 20 mg in nontolerant individuals. A caveat: Agents that act through the KOR have been reported to be relatively more effective in women than in men.

BUTORPHANOL

Butorphanol is a morphinan congener with a profile of actions similar to those of pentazocine and nalbuphine: KOR agonist and MOR antagonist.

PHARMACOLOGICAL ACTIONS AND SIDE EFFECTS. In postoperative patients, a parenteral dose of 2-3 mg butorphanol produces analgesia and respiratory depression approximately equal to that produced by 10 mg morphine or 80-100 mg meperidine. The plasma t1/2 of butorphanol is ~3 h. Like pentazocine, analgesic doses of butorphanol produce an increase in pulmonary arterial pressure and in the work of the heart; systemic arterial pressure is slightly decreased. The major side effects of butorphanol are drowsiness, weakness, sweating, feelings of floating, and nausea. While the incidence of psychotomimetic side effects is lower than that with equianalgesic doses of pentazocine, they are qualitatively similar. Nasal administration is associated with drowsiness and dizziness. Physical dependence can occur.

THERAPEUTIC USE. Butorphanol tartrate (STADOL, others) is used for the relief of acute pain (e.g., postoperative), and because of its potential for antagonizing MOR agonists should not be used in combination. Because of its side effects on the heart, it is less useful than morphine or meperidine in patients with congestive heart failure or myocardial infarction. The usual dose is 1-4 mg of the tartrate given intramuscularly, or 0.5-2 mg given intravenously, every 3-4 h. A nasal formulation is available and has proven to be effective in pain relief, including migraine pain.

BUPRENORPHINE

Buprenorphine is a highly lipophilic MOR agonist, 25-50 times more potent than morphine. It is a partial MOR agonist (e.g., has limited intrinsic activity) and accordingly can display antagonism when used in conjunction with a full agonist.

PHARMACOLOGICAL ACTIONS. Buprenorphine produces analgesia and other CNS effects that are qualitatively similar to those of morphine. About 0.4 mg buprenorphine is equianalgesic with 10 mg morphine given intramuscularly. Some of the subjective and respiratory-depressant effects are unequivocally slower in onset and last longer than those of morphine. Buprenorphine is a partial MOR agonist; thus, it may cause symptoms of abstinence in patients who have been receiving μ receptor agonists for several weeks. It antagonizes the respiratory depression produced by anesthetic doses of fentanyl about as well as naloxone without completely reversing opioid pain relief. The respiratory depression and other effects of buprenorphine can be prevented by prior administration of naloxone, but they are not readily reversed by high doses of naloxone once the effects have been produced, probably due to slow dissociation of buprenorphine from opioid receptors. The t1/2 for dissociation from the receptor is 166 min for buprenorphine, as opposed to 7 min for fentanyl. Therefore, plasma levels of buprenorphine may not parallel clinical effects. Cardiovascular and other side effects (e.g., sedation, nausea, vomiting, dizziness, sweating, and headache) appear to be similar to those of morphine-like opioids.

Administered sublingually, buprenorphine (0.4-0.8 mg) produces satisfactory analgesia in postoperative patients. Concentrations in blood peak within 5 min of IM injection and within 1-2 h of oral or sublingual administration. While the plasma t1/2 in plasma is ~3 h, this value bears little relationship to the rate of disappearance of effects. Both N-dealkylated and conjugated metabolites are detected in the urine, but most of the drug is excreted unchanged in the feces. When buprenorphine is discontinued, a withdrawal syndrome develops that is delayed in onset for 2-14 days and persists for 1-2 weeks.

THERAPEUTIC USES. Buprenorphine (BUPRENEX) injection is indicated for use as an analgesic. Oral formulations of buprenorphine (SUBUTEX) and buprenorphine in fixed-dose combination with naloxone (SUBOXONE) are used for treatment of opioid dependence. The usual IM or IV dose for analgesia is 0.3 mg given every 6 h. Buprenorphine is metabolized to norbuprenorphine by CYP3A4 and should not be taken with known inhibitors of CYP3A4 (e.g., azole antifungals, macrolide antibiotics, and HIV protease inhibitors), or drugs that induce CYP3A4 activity (e.g., certain anticonvulsants and rifampin).

OPIOID ANTAGONISTS

A variety of agents bind competitively to 1 or more of the opioid receptors, display little or no intrinsic activity, and robustly antagonize the effects of receptor agonists.

Relatively minor changes in the structure of an opioid can convert a drug that is primarily an agonist into 1 with antagonistic actions at 1 or more types of opioid receptors. Simple substitutions transform morphine to nalorphine, levorphanol to levallorphan, and oxymorphone to naloxone (NARCAN, others) or naltrexone (REVIA, VIVITROL, others). In some cases, congeners are produced that are competitive antagonists at MOR but that also have agonistic actions at KORs; nalorphine and levallorphan have such properties. Other congeners, especially naloxone and naltrexone, appear to be devoid of agonistic actions and interact with all types of opioid receptors, albeit with somewhat different affinities. Nalmefene (not marketed in the U.S.) is a relatively pure MOR antagonist that is more potent than naloxone. The majority of these agents are relatively lipid soluble and have excellent CNS bioavailability after systemic delivery. A recognition that there was a need for antagonism limited to peripheral sites led to the development of agents that have poor CNS bioavailability such as methylnaltrexone (RELISTOR).

PHARMACOLOGICAL PROPERTIES

Opioid antagonists have obvious therapeutic utility in the treatment of opioid overdose. Under ordinary circumstances, these opioid antagonists produce few effects in the absence of an exogenous agonist. However, under certain conditions (e.g., shock), when the endogenous opioid systems are activated, the administration of an opioid antagonist alone may have visible consequences.

EFFECTS IN THE ABSENCE OF OPIOID AGONISTS. Subcutaneous doses of naloxone up to 12 mg produce no discernible effects in humans, and 24 mg causes only slight drowsiness. Naltrexone also is a relatively pure antagonist but with higher oral efficacy and a longer duration of action. The effects of opiate receptor antagonists are usually both subtle and limited. Most likely this reflects the low levels of tonic activity and organizational complexity of the opioid systems in various physiologic systems. Opiate antagonism in humans is associated with variable effects ranging from no effect to a mild hyperalgesia. A number of studies have, however, suggested that agents such as naloxone appear to attenuate the analgesic effects of placebo medications and acupuncture.

Endogenous opioid peptides participate in the regulation of pituitary secretion apparently by exerting tonic inhibitory effects on the release of certain hypothalamic hormones (see Chapter 38). Thus, the administration of naloxone or naltrexone increases the secretion of gonadotropin-releasing hormone and corticotropin-releasing hormone and elevates the plasma concentrations of LH, FSH, and ACTH, as well as the steroid hormones produced by their target organs. Naloxone stimulates the release of prolactin in women. Endogenous opioid peptides probably have some role in the regulation of feeding or energy metabolism; however, naltrexone does not accelerate weight loss in very obese subjects, even though short-term administration of opioid antagonists reduces food intake in lean and obese individuals. Long-term administration of antagonists increases the density of opioid receptors in the brain and causes a temporary exaggeration of responses to the subsequent administration of opioid agonists.

EFFECTS IN THE PRESENCE OF OPIOID AGONISTS

Antagonistic Effects. Small doses (0.4-0.8 mg) of naloxone given intramuscularly or intravenously prevent or promptly reverse the effects of receptor agonists. In patients with respiratory depression, an increase in respiratory rate is seen within 1-2 min. Sedative effects are reversed, and blood pressure, if depressed, returns to normal. Higher doses of naloxone are required to antagonize the respiratory-depressant effects of buprenorphine; 1 mg naloxone intravenously completely blocks the effects of 25 mg heroin. Naloxone reverses the psychotomimetic and dysphoric effects of agonist–antagonist agents such as pentazocine, but much higher doses (10-15 mg) are required. The duration of antagonistic effects depends on the dose but usually is 1-4 h. Antagonism of opioid effects by naloxone often is accompanied by an “overshoot” phenomenon. For example, respiratory rate depressed by opioids transiently becomes higher than that before the period of depression. Rebound release of catecholamines may cause hypertension, tachycardia, and ventricular arrhythmias. Pulmonary edema also has been reported.

Effects in Opioid-Dependent Patients. In subjects who are dependent on morphine-like opioids, small subcutaneous doses of naloxone (0.5 mg) precipitate a moderate to severe withdrawal syndrome that is very similar to that seen after abrupt withdrawal of opioids, except that the syndrome appears within minutes of administration and subsides in ~2 h. The severity and duration of the syndrome are related to the dose of the antagonist and to the degree and type of dependence. Naloxone produces overshoot phenomena suggestive of early acute physical dependence 6-24 h after a single dose of a μ agonist.

ADME

Although absorbed readily from the GI tract, naloxone is almost completely metabolized by the liver before reaching the systemic circulation and thus must be administered parenterally. The t1/2 of naloxone is ~1 h, but its clinically effective duration of action can be even less. Compared with naloxone, naltrexone has more efficacy by the oral route, and its duration of action approaches 24 h after moderate oral doses. Peak concentrations in plasma are reached within 1-2 h and then decline with an apparent t1/2 of ~3 h. Naltrexone is metabolized to 6-naltrexol, which is a weaker antagonist with longer t1/2, ~13 h. Naltrexone is much more potent than naloxone, and 100-mg oral doses given to patients addicted to opioids produce concentrations in tissues sufficient to block the euphorigenic effects of 25-mg IV doses of heroin for 48 h. Methylnaltrexone is similar to naltrexone; it is converted to methyl-6-naltrexol isomers and eliminated primarily as the unchanged drug with active renal secretion. The t1/2 of methylnaltrexone is ~8 h.

THERAPEUTIC USES

TREATMENT OF OPIOID OVERDOSAGE. Opioid antagonists, particularly naloxone, have an established use in the treatment of opioid-induced toxicity, especially respiratory depression. Its specificity is such that reversal by naloxone is virtually diagnostic for the contribution of an opiate to the depression. Naloxone acts rapidly to reverse the respiratory depression associated with high doses of opioids. It should be titrated cautiously because it also can precipitate withdrawal in dependent subjects and cause undesirable cardiovascular side effects. The duration of action of naloxone is relatively short, and it often must be given repeatedly or by continuous infusion. Opioid antagonists also have been employed effectively to decrease neonatal respiratory depression secondary to the IV or IM administration of opioids to the mother. In the neonate, the initial dose is 10 μg/kg given intravenously, intramuscularly, or subcutaneously.

MANAGEMENT OF CONSTIPATION. The peripherally limited antagonists such as methylnaltrexone have a very important role in the management of the constipation and the reduced GI motility present in the patient undergoing chronic opioid therapy (as for chronic pain or methadone maintenance). Other strategies for the management of opioid-induced constipation are described in Chapter 46.

MANAGEMENT OF ABUSE SYNDROMES. There is interest in the use of opiate antagonists such as naltrexone as an adjuvant in treating a variety of nonopioid dependency syndromes such as alcoholism (see Chapters 23 and 24), where an opiate antagonist decreases the chance of relapse. Interestingly, patients with a single nucleotide polymorphism (SNP) in the MOR gene have significantly lower relapse rates to alcoholism when treated with naltrexone. Naltrexone is FDA-approved for treatment of alcoholism.

CENTRALLY ACTIVE ANTITUSSIVES

Cough is a useful physiological mechanism that serves to clear the respiratory passages of foreign material and excess secretions. It should not be suppressed indiscriminately. There are, however, situations in which cough does not serve any useful purpose but may, instead, annoy the patient, prevent rest and sleep, or hinder adherence to otherwise beneficial medication regimens (e.g., angiotensin-converting enzyme [ACE] inhibitor-induced cough). In such situations, the physician should try to substitute a drug with a different side-effect profile (e.g., an AT1 antagonist in place of an ACE inhibitor) or add an antitussive agent that will reduce the frequency or intensity of the coughing. A number of drugs reduce cough as a result of their central actions, including opioid analgesics (codeine, hydrocodone, and dihydrocodeine are most commonly used). Cough suppression often occurs with lower doses of opioids than those needed for analgesia. A 10- or 20-mg oral dose of codeine, although ineffective for analgesia, produces a demonstrable antitussive effect, and higher doses produce even more suppression of chronic cough. A few other antitussive agents are noted below.

DEXTROMETHORPHAN

Dextromethorphan (D-3-methoxy-N-methylmorphinan) is the D-isomer of the codeine analog methorphan; however, unlike the L-isomer, it has no analgesic or addictive properties and does not act through opioid receptors. The drug acts centrally to elevate the threshold for coughing. Its effectiveness in patients with pathological cough has been demonstrated in controlled studies; its potency is nearly equal to that of codeine, but dextromethorphan produces fewer subjective and GI side effects. In therapeutic dosages, the drug does not inhibit ciliary activity, and its antitussive effects persist for 5-6 h. Its toxicity is low, but extremely high doses may produce CNS depression. The average adult dosage of dextromethorphan hydrobromide is 10-30 mg 3-6 times daily, not to exceed 120 mg daily. The drug is marketed for over-the-counter sale in liquids, syrups, capsules, soluble strips, lozenges, and freezer pops or in combinations with antihistamines, bronchodilators, expectorants, and decongestants. An extended-release dextromethorphan suspension (DELSYM) is approved for twice-daily administration.

Although dextromethorphan is known to function as an NMDA receptor antagonist, the dextromethorphan binding sites are not limited to the known distribution of NMDA receptors. Thus, the mechanism by which dextromethorphan exerts its antitussive effect still is not clear.

OTHER ANTITUSSIVES. Pholcodine [3-O-(2-morpholinoethyl) morphine] is used clinically in many countries outside the U.S. Although structurally related to the opioids, pholcodine has no opioid-like actions. Pholcodine is at least as effective as codeine as an antitussive; it has a long t1/2 and can be given once or twice daily.

Benzonatate (TESSALON, others) is a long-chain polyglycol derivative chemically related to procaine and believed to exert its antitussive action on stretch or cough receptors in the lung, as well as by a central mechanism. It is available in oral capsules and the dosage is 100 mg 3 times daily; doses as high as 600 mg daily have been used safely.

ROUTES OF ANALGESIC DRUG ADMINISTRATION

In addition to the traditional oral and parenteral formulations for opioids, many other methods of administration have been developed in an effort to improve therapeutic efficacy while minimizing side effects.

PATIENT-CONTROLLED ANALGESIA (PCA). With this modality, the patient has limited control of the dosing of opioid from an infusion pump programmed within tightly mandated parameters. PCA can be used for IV, epidural, or intrathecal administration of opioids. This technique avoids delays inherent in administration by a caregiver and generally permits better alignment between pain control and individual differences in pain perception and responsiveness to opioids.

SPINAL DELIVERY. Administration of opioids into the epidural or intrathecal space provides more direct access to the first pain-processing synapse in the dorsal horn of the spinal cord. This permits the use of doses substantially lower than those required for oral or parenteral administration (Table 18–5).

Table 18–5

Epidural or Intrathecal Opioids for the Treatment of Acute (Bolus) or Chronic (Infusion) Pain

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Epidural and intrathecal opioids have their own dose-dependent side effects, such as pruritus, nausea, vomiting, respiratory depression, and urinary retention. Hydrophilic opioids such as morphine (DURAMORPH, others) have a longer residence times in the cerebrospinal fluid; as a consequence, after intrathecal or epidural morphine, delayed respiratory depression can be observed for as long as 24 h after a bolus dose. The risk of delayed respiratory depression is reduced with more lipophilic opioids. Use of intraspinal opioids in the opioid-naïve patient is reserved for postoperative pain control in an inpatient monitored setting. Epidural administration of opioids has become popular in the management of postoperative pain and for providing analgesia during labor and delivery. Lower systemic opioid levels are achieved with epidural opioids, leading to less placental transfer and less potential for respiratory depression of the newborn. Agents approved for spinal delivery are certain preservative-free formulations of morphine sulfate (DURAMORPH, DEPODUR, others) and sufentanil (SUFENTA). The spinal route of delivery represents a novel environment wherein the neuraxis may be exposed to exceedingly high concentrations of an agent for an extended period of time; safety by another route (e.g., PO, IV) may not translate to safety after spinal delivery.

Intraspinal narcotics often are combined with other agents that include local anesthetics, N-type Ca+ channel blockers (e.g., ziconotide), α2 adrenergic agonists, and GABAB agonists. The synergy between drugs with different mechanisms allows the use of lower concentrations of both agents, minimizing side effects and opioid-induced complications.

RECTAL ADMINISTRATION. This route is an alternative for patients with difficulty swallowing or other oral pathology and who prefer a less invasive route than parenteral administration. This route is not well tolerated by most children. Onset of action is within 10 min. In the U.S., only morphine and hydromorphone are available in rectal suppository formulations.

ORAL TRANSMUCOSAL ADMINISTRATION. Opioids can be absorbed through the oral mucosa more rapidly than through the stomach. Bioavailability is greater owing to avoidance of first-pass metabolism, and lipophilic opioids are absorbed better by this route than are hydrophilic compounds such as morphine. A transmucosal delivery system that suspends fentanyl in a dissolvable sugar-based lollipop (ACTIQ, others) or rapidly dissolving buccal tablet (FENTORA) and a buccal fentanyl “film” are FDA-approved for the treatment of cancer pain (ONSOLIS).

TRANSNASAL ADMINISTRATION. Butorphanol, a KOR agonist/MOR antagonist, has been employed intranasally. A transnasal pectin-based fentanyl spray is currently in clinical trials for the treatment of cancer-related pain. Administration is well tolerated and pain relief occurs within 10 min of delivery.

TRANSDERMAL ADMINISTRATION. Transdermal fentanyl patches are approved for use in sustained pain. The opioid permeates the skin, and a “depot” is established in the stratum corneum layer. However, fever and external heat sources (heating pads, hot baths) can increase absorption of fentanyl and potentially lead to an overdose. This modality is well suited for cancer pain treatment because of its ease of use, prolonged duration of action, and stable blood levels. There may be great variability in plasma levels after a given dose. The plasma t1/2 after patch removal is ~17 h. Thus, if excessive sedation or respiratory depression is experienced, antagonist infusions may need to be maintained for an extended period. Dermatological side effects from the patches, such as rash and itching, usually are mild. Opiate-addicted patients have been known to chew the patches and receive an overdose.

THERAPEUTIC CONSIDERATIONS

Management of pain is an important element in any therapeutic intervention. Failure to adequately manage pain can have important negative consequences on physiological function such as autonomic hyperreactivity (increased blood pressure, heart rate, suppression of gastrointestinal motility, reduced secretions), reduced mobility leading to deconditioning, muscle wasting, joint stiffening, and decalcification, and can contribute to deleterious changes in the psychological state (depression, helplessness syndromes, anxiety). By many hospital accrediting organizations, and by law in many states, appropriate pain assessment and adequate pain management are considered to be standard of care, with pain being considered the “fifth vital sign.”

GUIDELINES FOR OPIATE DOSING

The World Health Organization provides a 3-step ladder as a guide to treat both cancer pain and chronic noncancer pain (Table 18–6). The 3-step ladder encourages the use of more conservative therapies before initiating opioid therapy. Weaker opioids can be supplanted by stronger opioids in cases of moderate and severe pain. Antidepressants such as duloxetine and amitriptyline that are used in the treatment of chronic neuropathic pain have limited intrinsic analgesic actions in acute pain; however, antidepressants may enhance morphine-induced analgesia. In the presence of severe pain, the opioids should be considered sooner rather than later.

Table 18–6

World Health Organization Analgesic Laddera

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Numerous societies and agencies have published guidelines for the use of strong opioids in treating pain. While slightly different in particulars, all guidelines to date share the criteria of Table 18–7. Methadone dosing is considered separately in Table 18–8.

Table 18–7

Guidelines for the Use of Opioids to Treat Chronic Pain

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Table 18–8

Oral Morphine to Methadone Conversion Guidelines

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Suggestions for the oral and parenteral dosing of commonly used opioids (see Table 18–2) are only guidelines. They are typically constructed with the use of these agents in the management of acute (e.g., postoperative) pain in opioid-naïve patients. A number of factors will contribute to the dosing requirement (described in subsequent sections).

VARIABLES MODIFYING THE THERAPEUTIC RESPONSE TO OPIATES

There is substantial individual variability in responses to opioids. A standard IM dose of 10 mg morphine sulfate will relieve severe pain adequately in only 2 of 3 patients. The minimal effective analgesic concentration for opioids, such as morphine, meperidine (pethidine), alfentanil, and sufentanil, varies among patients by factors of 5-10.

The 12th edition of the parent text covers a variety of issues that can affect patient response to opiates, including physical condition of the patient, disease, intensity of pain, type of pain, acuity and chronicity of pain, opioid tolerance, pharmacokinetic variables, and genetic factors. These factors will affect the choice of agent and mode of delivery. Other considerations include opioid rotation (changing to a different opioid when the patient fails to achieve benefit or side effects become limiting before analgesia is sufficient), and combination therapy.

Certain opiate combinations are useful. For example, in a chronic pain state with periodic incident or breakthrough pain, the patient might receive a slow-release formulation of morphine for baseline pain relief and the acute incident pain may be managed with a rapid-onset/short-lasting formulation such as buccal fentanyl. For inflammatory or nociceptive pain, opioids may be usefully combined with other analgesic agents, such as NSAIDs or acetaminophen (Table 18–9). In some situations, NSAIDs can provide analgesia equal to that produced by 60 mg codeine. In the case of neuropathic pain, other drug classes may be useful in combination with the opiate. For example, antidepressants that block amine reuptake, such as amitriptyline or duloxetine, and anticonvulsants such as gabapentin, may enhance the analgesic effect and may be synergistic in some pain states.

Table 18–9

Summary of Drug Target and Site of Action of Common Drug Classes and Relative Efficacy by Pain State

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NONANALGESIC THERAPEUTIC USES OF OPIOIDS

DYSPNEA. Morphine is used to alleviate the dyspnea of acute left ventricular failure and pulmonary edema, and the response to IV morphine may be dramatic. The mechanism underlying this relief is not clear. It may involve an alteration of the patient’s reaction to impaired respiratory function and an indirect reduction of the work of the heart owing to reduced fear and apprehension. However, it is more probable that the major benefit is due to cardiovascular effects, such as decreased peripheral resistance and an increased capacity of the peripheral and splanchnic vascular compartments. Nitroglycerin, which also causes vasodilation, may be superior to morphine in this condition. In patients with normal blood gases but severe breathlessness owing to chronic obstruction of airflow (“pink puffers”), dihydrocodeine, 15 mg orally before exercise, reduces the feeling of breathlessness and increases exercise tolerance. Nonetheless, opioids generally are contraindicated in pulmonary edema unless severe pain also is present.

ANESTHETIC ADJUVANTS. High doses of opioids, notably fentanyl and sufentanil, are widely used as the primary anesthetic agents in many surgical procedures. They have powerful “MAC-sparing” effects, e.g., they reduce the concentrations of volatile anesthetic otherwise required to produce an adequate anesthetic depth. Although respiration is so depressed that physical assistance is required, patients can retain consciousness. Therefore, when using an opioid as the primary anesthetic agent, use it in conjunction with an agent that results in unconsciousness and produces amnesia such as the benzodiazepines or low concentrations of volatile anesthetics. High doses of opiate also result in prominent rigidity of the chest wall and masseters requiring concurrent treatment with muscle relaxants to permit intubations and ventilation.

TREATMENT OF ACUTE OPIOID TOXICITY

Acute opioid toxicity may result from clinical overdosage, accidental overdosage, or attempts at suicide. Occasionally, a delayed type of toxicity may occur from the injection of an opioid into chilled skin areas or in patients with low blood pressure and shock. The drug is not fully absorbed, and therefore, a subsequent dose may be given. When normal circulation is restored, an excessive amount may be absorbed suddenly. In nontolerant individuals, serious toxicity with methadone may follow the oral ingestion of 40-60 mg. In the case of morphine, a normal, pain-free adult is not likely to die after oral doses <120 mg or to have serious toxicity with <30 mg parenterally.

SYMPTOMS AND DIAGNOSIS. The patient who has taken an overdose of an opioid usually is stuporous or, if a large overdose has been taken, may be in a profound coma. The respiratory rate will be very low, or the patient may be apneic, and cyanosis may be present. If adequate oxygenation is restored early, the blood pressure will improve; if hypoxia persists untreated, there may be capillary damage, and measures to combat shock may be required. The pupils will be symmetrical and pinpoint in size; however, if hypoxia is severe, they may be dilated. Urine formation is depressed. Body temperature falls, and the skin becomes cold and clammy. The skeletal muscles are flaccid, the jaw is relaxed, and the tongue may fall back and block the airway. Frank convulsions occasionally may be noted in infants and children. When death occurs, it is nearly always from respiratory failure. Even if respiration is restored, death still may occur as a result of complications that develop during the period of coma, such as pneumonia or shock.

TREATMENT. The first step is to establish a patent airway and ventilate the patient. Opioid antagonists can produce dramatic reversal of the severe respiratory depression, and the antagonist naloxone is the treatment of choice. However, care should be taken to avoid precipitating withdrawal in dependent patients, who may be extremely sensitive to antagonists. The safest approach is to dilute the standard naloxone dose (0.4 mg) and slowly administer it intravenously, monitoring arousal and respiratory function. With care, it usually is possible to reverse the respiratory depression without precipitating a major withdrawal syndrome. If no response is seen with the first dose, additional doses can be given. Patients should be observed for rebound increases in sympathetic nervous system activity, which may result in cardiac arrhythmias and pulmonary edema. For reversing opioid poisoning in children, the initial dose of naloxone is 0.01 mg/kg. If no effect is seen after a total dose of 10 mg, one can reasonably question the accuracy of the diagnosis. Pulmonary edema sometimes associated with opioid overdosage may be countered by positive-pressure respiration. Tonic-clonic seizures, occasionally seen as part of the toxic syndrome with meperidine, propoxyphene, and tramadol, are ameliorated by treatment with naloxone.

The presence of general CNS depressants does not prevent the salutary effect of naloxone, and in cases of mixed intoxications, the situation will be improved largely owing to antagonism of the respiratory-depressant effects of the opioid (however, some evidence indicates that naloxone and naltrexone also may antagonize some of the depressant actions of sedative-hypnotics). One need not attempt to restore the patient to full consciousness. The duration of action of the available antagonists is shorter than that of many opioids; hence patients can slip back into coma. This is particularly important when the overdosage is due to methadone. The depressant effects of these drugs may persist for 24-72 h, and fatalities have occurred as a result of premature discontinuation of naloxone. In cases of overdoses of these drugs, a continuous infusion of nalox-one should be considered. Toxicity owing to overdose of pentazocine and other opioids with mixed actions may require higher doses of naloxone.