Chapter 18: Opioids, Analgesia, and Pain Management

History. The first undisputed reference to opium is found in the writings of Theophrastus in the third century B.C. Arab physicians were well-versed in the uses of opium; Arab traders introduced the drug to the Orient, where it was employed mainly for the control of dysentery. By 1680, Sydenham was lauding opium: "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium."

Opium contains >20 distinct alkaloids. In 1806, Frederich Sertürner, a pharmacist's assistant, reported the isolation by crystallization of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. By the middle of the 19th century, the use of pure alkaloids in place of crude opium preparations began to spread throughout the medical world, an event that coincided with the development of the hypodermic syringe and hollow needle, permitting direct delivery of such water-soluble formulations "under the skin" into the body.

In addition to the remarkable beneficial effects of opioids, the side effects and addictive potential of these drugs also have been known for centuries. In the civil war in the U.S., the administration of "soldier's joy" often led to "soldier's disease," the opiate addiction brought about by medication of chronic pain states arising from war wounds. These problems stimulated a search for potent synthetic opioid analgesics free of addictive potential and other side effects. The early discovery of the synthetic product heroin by C.R. Alder Wright in 1874 was followed by its widespread utilization as a purportedly non-addictive cough suppressant and sedative. Unfortunately, heroin and all subsequent synthetic compounds that have been introduced into clinical use share the liabilities of classical opioids, including their addictive properties. However, this search for new opioid agonists led to the synthesis of opioid antagonists and compounds with mixed agonist–antagonist properties, which expanded therapeutic options and provided important tools for exploring mechanisms of opioid actions.

Until the early 1970s, the effects of morphine, heroin, and other opioids as anti-nociceptive and addictive agents, were well described, but mechanisms mediating the interaction of the opioid alkaloids with biological systems were unknown. In vivo and in vitro physiological studies investigating the pharmacology of opiate agonists, their antagonists, and cross-tolerance led to the hypothesis of three separate opioid receptors: mu (μ), kappa (κ), and delta (δ) (Martin et al., 1976). These results were paralleled by work showing multiple radioligand binding sites for opiates on brain cell membranes (Goldstein et al., 1971; Pert et al., 1973). The three-receptor hypothesis was confirmed by subsequent cloning, which indicated the existence of three main receptor types with an opioid pharmacology (Waldhoer et al., 2004). In 2000, the Committee on Receptor Nomenclature and Drug Classification of the International Union of Pharmacology adopted the terms MOP, DOP, and KOP receptors (mu opi oid peptide receptor, etc). In concert with identification of these opioid receptors, Kostelitz and associates (Hughes et al., 1975) identified an endogenous opiate-like factor that they called enkephalin ("from the head"). Soon afterward, two more classes of endogenous opioid peptides were isolated, the endorphins and dynorphins (Akil et al., 1984).

In the early work by Martin, a sigma (σ) receptor was identified and was thought to represent a site that accounted for the paradoxical excitatory effects of opiates; this site is now thought to be the phencyclidine binding site and is not strictly speaking an opiate receptor or an opiate site.

The POMC sequence contains a variety of non-opioid peptides including adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (αMSH), and β-lipotropin (β-LPH), all of which are generated by proteolytic cleavage of POMC. The major opioid peptide derived from further cleavage of β-lipotropin is the potent opioid agonist, β-endorphin. Although β-endorphin contains the sequence for met-enkephalin at its amino terminus, it is not converted to this peptide. The anatomical distribution of POMC-producing cells is relatively limited within the CNS, occurring mainly in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius. These neurons project widely to limbic and brainstem areas and to the spinal cord. POMC expression also occurs in the anterior and intermediate lobes of the pituitary and also are contained in pancreatic islet cells. Circulating β-endorphin derives primarily from the pituitary, from which it and other pituitary hormones are released (Chapter 38).

Proenkephalin contains multiple copies of met-enkephalin, as well as a single copy of leu-enkephalin. Proenkephalin peptides are present in areas of the CNS believed to be related to the processing of pain information (e.g., laminae I and II of the spinal cord, the spinal trigeminal nucleus, and the periaqueductal gray), to the modulation of affective behavior (e.g., amygdala, hippocampus, locus ceruleus, and the frontal cerebral cortex), to the modulation of motor control (e.g., caudate nucleus and globus pallidus), to the regulation of the autonomic nervous system (e.g., medulla oblongata), and to neuroendocrinological functions (e.g., median eminence). Although there are a few long enkephalinergic fiber tracts, these peptides are contained primarily in interneurons with short axons. The peptides from proenkephalin also are found in chromaffin cells of the adrenal medulla and in nerve plexuses and exocrine glands of the stomach and intestine. Circulating proenkephalin products are considered to be largely derived from these sites.

Prodynorphin contains three peptides of differing lengths that all begin with the leu-enkephalin sequence: dynorphin A, dynorphin B, and neoendorphin (Figure 18–1). The peptides derived from prodynorphin are distributed widely in neurons and to a lesser extent in astrocytes throughout the brain and spinal cord and are frequently found co-expressed with other opioid peptide precursors.

Nociceptin peptide is present in neurons widely distributed throughout brain (cortex, hippocampus, brainstem, and to a lesser degree, hypothalamus, thalamus, raphe nuclei, and periaqueductal gray matter) and spinal cord structures. It has been observed in neurons as well as astrocytes and neutrophils.

More recently, a family of peptides has been identified and named endomorphins, endomorphin-1 (Tyr–Pro–Trp–Phe–NH₂) and endomorphin-2 (Tyr–Pro–Phe–Phe–NH₂) (Zadina et al., 1997). By comparison with other opioid peptides, endomorphins have an atypical structure and display selectivity towards the μ opioid receptor (Fichna et al., 2007).

Several points should be stressed:

• Not all cells that make a given opioid pro-hormone 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 (Hook et al., 2008).

• Processing of these peptides is altered by physiological demands, leading to the release of a different mix of post-translationally 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 CSF arise from neuraxial systems and not from peripheral systems.

Following the cloning of the classical opioid receptors, the G-protein coupled 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 has an endogenous ligand, nociceptin/orphanin (FQ: N/OFQ) (Stevens, 2009). See Figure 18–2. Since this system does not display an opioid pharmacology (Fioravanti et al., 2008), it will not be discussed in detail in this chapter.

N/OFQ binding sites have been found to be largely in the CNS and to be densely distributed in cortical regions, ventral forebrain, hippocampus, brainstem, and spinal cord, as well as in a number of peripheral cells including basophils, endothelial cells, and macrophages.

Opiate Receptor Subtypes

The existence of three classes of opiate receptors (MOR, DOR, and KOR) is widely accepted. The opioid receptors appear early in vertebrate evolution, being already present with the appearance of jawed vertebrates. The human opiate receptors have been mapped to chromosome 1p355-33 (DOR), chromosome 8q11.23-21 (KOR), chromosome 6q25-26 (MOR), and chromosome 20q13.33 (NOR) (Dreborg et al., 2008). Low-stringency hybridization procedures have identified no opioid receptor types other than the cloned opioid receptors. Nevertheless, pharmacological studies have suggested the possible existence of at least two subtypes of each receptor. While cloning studies have not supported the existence of these subtypes as distinct classes, the modified specificity for opioid ligands may result from several underlying events.

Heterodimerization. In the membrane, opiate receptors can form both homo- and heterodimers. Dimerization can alter the pharmacological properties of the respective receptors. For example, DORs form heterodimers with both MORs and KORs. Thus, MOR-DOR and DOR-KOR heterodimers show less affinity for highly selective agonists, reduced agonist-induced receptor trafficking, and mutual synergy between receptor-selective agonists in binding to the respective agonists and also in the agonist-induced intracellular signaling (Gupta et al., 2006).

Alternative Splicing of Receptor RNA

Alternative splicing of receptor heteronuclear RNA (e.g., exon skipping and intron retention) is thought to play an important role in producing in vivo diversity within many members of the GPCR superfamily (Chapter 3). Splice variants exist within each of the three opioid receptor families, and this alternative splicing of receptor transcripts may be crucial for the diversity of opioid receptors. As an example, the human Oprm gene has at least two promoters, multiple exons, with many exons generating at least 11 splice variants that encode multiple morphine-binding isoforms, varying largely at their carboxy (intracellular) terminus. 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. Importantly, these splice variants have been found expressed in vivo (Pan, 2005).

Receptor Subtype Agonists/Antagonists

Studies on the presence and function of these receptors have depended upon the convergence between agonist/antagonist structure-activity studies and a variety of functional assays in biological and cloned receptor systems. Highly selective agonists have been developed that show specific affinity for the respective binding site and G-protein coupled reporter activation in cloned expression systems (e.g., DAMGO for MOR, DPDPE for DOR, and U-50,488, and U-69,593 for KOR) (Table 18–1). The study of the biological functions of opioid receptors in vivo has been aided by synthesis of selective antagonists. Among the most commonly used antagonists are cyclic analogs of somatostatin such as CTOP as a MOR antagonist, a derivative of naloxone called naltrindole as a DOR-receptor antagonist, and a bivalent derivative of naltrexone called nor-binaltorphimine (nor-BNI) as a KOR antagonist. These tools have made possible the characterization of the distribution of binding which, in conjunction with immunohistochemistry using antibodies derived from cloned receptors, has served to define the anatomical distribution of the receptors and the roles of the respective receptors in biological functions. Positron emission tomography (PET) has been used to characterize in vivo binding in brain with selective isotopically labeled ligands (Henriksen and Willoch, 2008). In vivo delivery of selective antagonists and agonists into specific brain regions has established the receptor types and anatomical distribution involved in mediating various opioid effects (see below).

Receptor Structure

Each receptor consists of an extracellular N-terminus, seven transmembrane helices, three extra- and intracellular loops, and an intracellular C-terminus characteristic of the GPCRs. The opioid receptors also possess two conserved cysteine residues in the first and second extracellular loops, which form a disulfide bridge.

Structural Correlates of Binding/Coupling Requirements for Opiate Ligands

Opiate Receptor Structures. Studies of chimeric receptors and site-directed mutagenesis of cloned receptors have provided definitive insights into structural determinants of opioid ligand–receptor interaction. Though there is significant complexity (Kane et al., 2006), several general principles define binding and selectivity. First, all opioid receptors display a binding pocket formed by TM₃-TM₇. Second, the pocket in the respective receptor is partially covered by the extracellular loops, which together with the extracellular termini of the TM segments, provide a gate conferring selectivity, allowing ligands, particularly peptides, to be differentially accessible to the different receptor types. Thus, alkaloids (e.g., morphine) bind in the core of the transmembrane portion of the receptor, whereas large peptidyl ligands bind at the extracellular loops. As noted, it is the extracellular loops that show the greatest structural diversity across receptors. Third, selectivity has been attributed to extracellular loops: first and third for the MOR, second for the KOR, and third for the DOR (Waldhoer et al., 2004). Alkaloid antagonists are thought to bind deeper into the pocket sterically hindering conformational changes leading to a functional antagonism.

Structure-Activity Relationships. Receptor selectivity by the various opiate agonists is commonly explained in terms of the "message-address" concept (Takemori and Portoghese, 1992). Thus, elements shared by all structures (reflecting agents that bind at all sites, such as naltrexone) represent the "message," while elements associated with a ligand binding at a specific receptor represent the structural "address." The common structural features constituting the message are:

• a protonated nitrogen

• a phenolic ring (that, with the protonated nitrogen, forms tyramine)

• a hydrophobic domain

To this "message" are added a variable "linker" region and the "address" that specifies opiate receptor selectivity (Figure 18–3). Refinements of this message-linker-address model have led to the synthesis of new compounds with the predicted specificity. For the KOR and DOR, elements constituting the address have been defined. Thus, for the KOR, a second basic hydrophobic group is implicated in forming a specific salt bridge; for the DOR, a hydrophobic group such as an indole forms the address. MOR ligands such as morphine lack a common chemical moiety and thus other elements are thought to contribute to ligand specificity at that receptor (Kane et al., 2006).

Opiate Receptor Coupling to Membrane Function

Agonist binding results in conformational changes in the GPCR, initiating the G protein activation/inactivation cycle (Chapter 3). The μ, δ, and κ receptors largely couple through pertussis toxin-sensitive, G_i/G_o proteins (but occasionally to G_s or G_z). Upon receptor activation, the G_i/G_o coupling results in a large number of intracellular events, including:

• Inhibition of adenylyl cyclase activity

• Reduced opening of voltage-gated Ca²⁺ channels

• Stimulation of K⁺ current though several channels including G protein-activated inwardly rectifying K⁺ channels (GIRKs)

• Activation of PKC and PLC_β

As with other GPCRs, the second intracellular loop is involved in the efficacy of G-protein activation while the third loop defines the α subunit that is activated (Gether, 2000).

Regulation of Opiate Receptor Disposition

Like other GPCRs, MOR and DORs can undergo rapid agonist-mediated internalization via a classic endocytic, β-arrestin-mediated pathway, whereas KORs do not internalize after prolonged agonist exposure (Chu et al., 1997). Internalization of the MOR and DORs apparently occurs via partially distinct endocytic pathways, suggesting receptor-specific interactions with different mediators of intracellular trafficking. These processes may be induced differentially as a function of the structure of the ligand. For example, certain agonists, such as etorphine and enkephalins, cause rapid internalization of the receptor, whereas morphine does not cause MOR internalization, even though it decreases adenylyl cyclase activity equally well. In addition, a truncated receptor with normal G-protein coupling recycles constitutively from the membrane to the cytosol (Segredo et al., 1997), suggesting that activation of signal transduction and internalization are controlled by distinct molecular mechanisms. These studies also support the hypothesis that different ligands induce different conformational changes in the receptor that result in divergent intracellular events, and they may provide an explanation for differences in the spectrum of effects of various opioids.

Functional Consequences of Acute and Chronic Opiate Receptor Activation

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

Desensitization. Acute agonist occupancy of the opiate receptors results in activation of the intracellular signaling outlined previously. In the face of a transient activation (minutes to hours), a phenomenon called acute tolerance or desensitization can be observed 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. Sustained administration of an opiate agonist (days to weeks) leads to progressive loss of drug effect. Here tolerance refers to a decrease in the apparent effectiveness of a drug with continuous or repeated agonist administration, and with the 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 phenomenon can be manifested at the level of the intracellular cascade (e.g., reduced inhibition of adenylyl cyclase) and at the organ system level (e.g., loss of sedative and analgesic effects).

This loss of effect with persistent exposure to an opiate agonist has several key properties:

• Changes in response are time-dependent, with changes occurring over short-term (minutes to hours, as with desensitization) and long-term intervals (weeks to months).

• Tolerance to drug effect is surmountable with higher doses of the opioid.

• Tolerance is reversible over time after termination of the drug.

• 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 (euphorogenic).

• 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).

The completeness of this cross-tolerance is not consistent and forms the basis for the switching between opioid drugs used in clinical therapy. This incomplete cross-tolerance has been hypothesized to reflect small but important differences in the receptors with which the different opiates of the same class bind (Pasternak, 2005).

Dependence. During the state of tolerance, the phenomenon of dependence is observed. 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). The withdrawal is manifested by the exaggerated appearance of enhanced signs of cellular activation. In the CNS, increased adenylyl cyclase, release of excitatory amino acids and cytokines, activation of microglia and astrocytes, and the initiation of apoptotic processes have been reported. Such indices of hyperexcitability are also noted in peripheral plexi such as are present in the GI tract and in autonomic ganglia (discussed later). 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) (Kreek et al., 1998). These phenomena are considered to be highly aversive and motivate the drug recipient to make robust efforts to avoid the withdrawal state. Consistent with the receptor selectivity of the effects, the withdrawal signs observed in an animal tolerant to a given opiate can be suppressed by application of another drug from the same class.

Addiction. Addiction is a behavioral pattern characterized by compulsive use of a drug and overwhelming involvement with its procurement and use. The positive, rewarding effects of opiates are considered to be the driving component for initiating the recreational use of opiates. This positive reward property in humans and animals is subject to the development of tolerance. Given the aversive nature of withdrawal symptoms, in the dependent organism, it is not surprising that avoidance and alleviation of withdrawal symptoms may become a primary motivation for compulsive drug taking (Kreek and Koob, 1998). When the drive to acquire the drug leads to drug-seeking behaviors that occur in spite of the physical, emotional, or societal damage suffered by the drug seeker, then the obsession or compulsion to acquire and use the drug is considered to reflect an addicted state. In animals, this may be manifest by willingness to tolerate very stressful conditions to acquire drug delivery. In humans, aberrant behaviors considered to be signs of addiction include prescription forgery, stealing drugs from others, and obtaining prescription drugs from nonmedical sources; these behaviors are considered indicators of an addiction disorder. Note that drug dependence is not synonymous with drug addiction. Any individual who is exposed for some period to opiates will display some degree of tolerance and should the drug be removed abruptly, there will be an expression of withdrawal signs, the severity of which will depend upon the dose and duration of drug exposure. Such a condition does not itself indicate an addicted state. Thus, tolerance and dependence are physiological responses seen in all patients but are not predictors of addiction (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 (Foley, 1993).

Mechanisms of Tolerance/Dependence-Withdrawal

The mechanisms underlying chronic tolerance and dependence/ withdrawal are controversial. Several types of events are considered to contribute.

Receptor Disposition. With chronic opiate exposure, the general consensus is that the loss of effect is not related to the density of membrane receptors. As noted, 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 (Koch et al., 2005; von Zastrow et al., 2003). These studies suggest that receptor desensitization and down-regulation are agonist specific. Other studies of GPCRs indicate that 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 (Krupnick and Benovic, 1998). 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. The lack of desensitization caused by morphine may result in prolonged receptor signaling, which even though less efficient than that observed with other agonists, would lead to further downstream cellular adaptations that increase tolerance development. The measurement of relative agonist signaling versus endocytosis (RAVE) for opioid agonists could be predictive of the potential for tolerance development (Waldhoer et al., 2004).

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 (Williams et al., 2001). Importantly, the chronic opioid effect initiates adaptive counterregulatory change. The best example of such cellular counterregulatory processes is the rebound increase in cellular cyclic AMP levels produced by "superactivation" of adenylyl cyclase and up-regulation of the amount of enzyme. Such superactivation leads to an induction of an excitatory state mediated by an increased cation current through activation of PKA. Terminal transmitter release is thus commonly enhanced during opioid withdrawal (Bailey and Connor, 2005).

System Level Counteradaptation. In the face of chronic opiate exposure, an evident loss of drug effect is noted. An important line of speculation is that the apparent loss of inhibitory effect 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. Similarly, in the face of chronic opiate exposure, opiate receptor occupancy will lead to the activation of PKC, which can phosphorylate and, accordingly, enhance the activation of local glutamate receptors of the N-methyl-D-aspartate (NMDA) type (Chapter 14). These receptors are known to 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 (Trujillo and Akil, 1991). These system level counteradaptation hypotheses may represent mechanisms that apply to specific systems (e.g., pain modulation) but not necessarily to others (e.g., sedation or miosis) (Christie, 2008).

Differential Tolerance Development and Fractional Occupancy Requirements. An interesting problem posed in explaining tolerance relates to the differential rates of tolerance development noted earlier. Why responses such as miosis show no tolerance over extended exposure (indeed, it is considered symptomatic in drug overdose of highly tolerant patients) while analgesia and sedation are more likely to show a reduction is not clear. One possibility is that tolerance represents a functional uncoupling of some fraction of the receptor population and that different physiological end points may require activation of different fractions of their coupled receptors to produce a given physiological effect. Accordingly, it would be consistent that receptors in the miosis pathways need to activate a small fraction of their receptors, relative to those systems mediating pain control to produce a significant physiological action (e.g., the systems mediating miosis have a greater functional receptor reserve).

Specificity of Analgesic Effects. The relief of pain by morphine-like opioids is selective in that other somatosensory modalities, such as light touch, proprioception, and the sense of moderate temperatures, are unaffected. Systematic psychophysical studies have shown that low doses of morphine produce reductions in the affective but not the perceived intensity of pain whereas higher (clinically effective) doses reduced both reported perceived intensity and the affective response otherwise evoked by acute experimental pain stimuli (Price et al., 1985). In general, 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. Any meaningful discussion of the action of analgesic agents must include the appreciation that all pain is not the same and that a number of variables contribute to the patient's pain report and therefore to the effect of the analgesic. Heuristically, one may think mechanistically of pain as several distinct sets of events, described in the next sections.

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 18–4) (Sorkin and Wallace, 1999). Examples of such states would be burn, post-incision, abrasion of the skin, inflammation of the joint, and musculoskeletal injury.

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 upon 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 dororsal horn reorganization, such that low-threshold afferent input carried by Aβ fibers evokes a pain state. This dorsal horn reorganization reflects changes in ongoing inhibition and in the excitability of dorsal horn projection neurons (Latremoliere and Woolf, 2009). 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 18–5). 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 (McQuay, 1988).

Sensory Versus Affective Dimensions. Information generated by a high intensity peripheral stimulus initiates activity in defined pathways that activate higher-order systems that reflect the aversive magnitude of the stimulus. This reflects the sensory-discriminative dimension of the pain experience (such as the ability to accurately estimate and characterize the pain state). Painful stimuli have the certain ability to generate strong emotional components that reflect a distinction between pain as a specific sensation subserved by distinct neurophysiological structures, and pain such as suffering (the original sensation plus the reactions evoked by the sensation; the affective motivational dimension) (Melzack and Casey, 1968). 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 (Yaksh, 1988).

Mechanisms of Opioid-Induced Analgesia. The analgesic actions of opiates after systemic delivery are believed to represent actions in the brain, spinal cord, and in some instances in the periphery.

Supraspinal Actions. The microinjection of opiates through chronically placed microinjection cannulae targeted at specific brain sites has shown that opiate agonists will, in a manner consistent with their respective activity at a MOR, block pain behavior after delivery into a number of highly circumscribed brain regions and that these analgesic effects are naloxone reversible. The best characterized of these sites is the mesencephalic periaqueductal gray (PAG) matter. Microinjections of morphine into this region will block nociceptive responses in every species examined from rodents to primates; 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 18–6. 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 5-HT at the level of the spinal dorsal horn. This release can attenuate dorsal horn excitability (Yaksh, 1997). 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 (the role of forebrain 5-HT and NE in mediating emotional tone is discussed in Chapter 15). In humans, it is not feasible to routinely access the site of action within the brain where opiates may act to alter nociceptive transmission as is done in preclinical models. However, intracerebroventricular opioids have been employed in humans for pain relief in cancer patients. Accordingly, it seems probable that the supraspinal site of opiate action in the human, as in other animal models, lies close to the ventricular lumen (Karavelis et al., 1996).

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 and the remainder are on local dorsal horn neurons. This finding is consistent with the presence of opioid receptor protein being synthesized in and transported from small dorsal root ganglion cells.

Confirmation of the presynaptic action is provided by the observation that spinal opiates reduce the release of primary afferent peptide transmitters such as substance P contained in small afferents (Yaksh et al., 1980). The presynaptic action corresponds to the ability of opiates to prevent the opening of voltage-sensitive Ca²⁺ 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. In humans, there is extensive literature indicating that a variety of opiates delivered spinally (intrathecally or epidurally) can induce a powerful analgesia that is reversed by low doses of systemic naloxone (Yaksh, 1997).

Peripheral Action. It has been a principal tenet of opiate action that these agents act "centrally." 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. Moreover, in studies examining normal animals, it can be demonstrated that the analgesic actions are limited if the agent does not readily penetrate the brain. Alternately, studies employing the 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 upon the exaggerated thresholds. This has been demonstrated for the response to mechanical stimulation applied to inflamed paw or inflamed knee joints. In the absence of inflammation, there is no local peripheral effect. This action is believed to be mediated by opiate receptors on the peripheral terminals of small primary afferents. Local opiates in the knee joint and in the skin can reduce the firing of spontaneously active afferents observed when these tissues are inflamed. Whether the effects are uniquely on the afferent terminal, whether the opiate acts upon inflammatory cells that release products that sensitize the nerve terminal, or both, is not known (Stein and Lang, 2009).

The mesolimbic dopamine system originates in the ventral segmental area (VTA) and projects to the nucleus accumbens (NAc) in the forebrain. Dopamine and glutamate projections from the VTA and prefrontal cortex (PFC), respectively, synapse on NAc GABAergic neurons. These cells project to the ventral pallidum (VP). In the NAc, ionotropic glutamate receptors activate, while dopamine D₂-like receptors inhibit GABAergic neurons. In general, interventions that suppress the NAc-VP GABA pathway leading to increased dopamine release are considered to be positively rewarding, supporting, for example, self-administration. Thus, dopamine delivered directly into the NAc, mimicking increased extracellular release, is powerfully reinforcing. Opiates increase DA release in the NAc, and catheterized animals will activate administration of opiates directly into their VTA and into the NAc, emphasizing the importance of that system in opiate reward. In the NAc, MORs are present postsynaptically on GABAergic neurons. The reinforcing effects of opiates in the VTA are thought to be mediated through inhibition of local GABAergic neuronal activity, which otherwise acts to inhibit DA outflow (Xi and Stein, 2002).

Mechanisms Underlying Respiratory Depression. Respiratory rate and tidal volume depend upon intrinsic rhythm generators located in the ventrolateral medulla. These systems generate a "respiratory" rhythm that is driven by afferent input reflecting the partial pressure of arterial O₂ as measured by chemosensors in the carotid and aortic bodies and CO₂ as measured by chemosensors in the brainstem. Morphine-like opioids depress respiration through MOR and DOR receptors in part by a direct depressant effect on rhythm generation, with changes in respiratory pattern and rate observed at lower doses than changes in tidal volume. A key property of opiate effects on respiration is the depression of the ventilatory response to increased CO₂. This effect is mediated by opiate depression of the excitability of brainstem chemosensory neurons. In addition to the effects on the CO₂ response, opiates will depress ventilation otherwise driven by hypoxia though an effect upon 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 (Pattinson, 2008). 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 (Lalley, 2008).

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 produces a decrease in 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 hours 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 their response to increased CO₂.

• COPD. Enhanced depression can also be noted in patients with chronic obstructive pulmonary disease (COPD) and sleep apnea secondary to diminished hypoxic drive.

• Relief of Pain. Because 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.

Sedation. Opiates can produce drowsiness and cognitive impairment. Such depression can augment respiratory impairment. These effects are most typically noted following initiation of opiate therapy or after dose incrementation. Importantly, these effects upon arousal resolve over a few days. As with respiratory depression, the degree of drug effect can be enhanced by a variety of predisposing patient factors including dementia, encephalopathies, or brain tumors as well as other depressant medications, including sleep aids, antihistamines, antidepressants, and anxiolytics (Cherny, 1996).

Different Opiates. Numerous studies have compared morphine and morphine-like opioids with respect to their ratios of analgesic to respiratory-depressant activities, and most have found that when equianalgesic doses are used, there is no significant difference. Maximal respiratory depression occurs within 5-10 minutes of intravenous administration of morphine or within 30-90 minutes of intramuscular or subcutaneous administration. Maximal respiratory depressant effects occur more rapidly with more lipid-soluble agents. After therapeutic doses, respiratory minute volume may be reduced for as long as 4-5 hours. Agents that have persistent kinetics, such as methadone, must be carefully monitored, particularly after dose incrementation.

Management of Opiate Depression. Life-threatening respiratory depression produced by any opiate agonist can be readily reversed by delivery of an opiate antagonist. Conversely, the ability to reverse the somnolent patient is considered to be indicative of an opiate-mediated effect. 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.

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. Importantly, these changes are reversible with removal of the opiate.

The mechanisms of the opiate regulation of gonadotrophin release may reflect a direct effect upon secreting pituicytes and an indirect action, through an effect on receptors present on hypothalamic neurons, to block release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH). This reduction of the releasing factors leads to reduced release of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and β-endorphin. This series of events leads to reduced circulating testosterone and cortisol. Secretion of thyrotropin is relatively unaffected.

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

Growth Hormone. Growth hormone (GH) is released in a pulsatile fashion from somatotrophs in the anterior pituitary. GH-releasing hormone (GHRH) neurons in the hypothalamic arcuate nucleus and inhibitory input from somatostatin (SST) cells in the periventricular nucleus regulate this. Although some opioids increase GH release, possibly by inhibiting SST release, acute morphine has little effect on plasma GH concentration (Bluet-Pajot et al., 2001).

Antidiuretic Hormone and Oxytocin. The effects of opiates on ADH and oxytocin release are complex. These hormones are synthesized in the perikarya of the magnocellular neurons in the parventricular and supraoptic nuclei of the hypothalamus and released from the posterior pituitary (Chapter 38). ADH (vasopressin) release can occur secondary to surgical stress, hypovolemia, hypotension, and low osmolarity, while oxytocin release typically is released with afferent stimuli related to the milk ejection pathway. KOR agonists inhibit the release of oxytocin and antidiuretic hormone (and cause prominent diuresis). In humans, the administration of MOR agonists has little effect or tends to produce antidiuretic effects. Morphine reduces oxytocin secretion in nursing women (Lindow et al., 1999). 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. Based on electrophysiology and localization of opiate receptors, these effects upon vasopressin and oxytocin release may reflect both a direct effect upon terminal secretion as well as indirect effects upon dopaminergic and noradrenergic modulatory projections into the parventricular and supraoptic hypothalamus (Gimpl and Fahrenholz, 2001).

Miosis. Illumination of the pupil activates a reflex arc, which through local circuitry in the Edinger Westphal nucleus, activates parasympathetic outflow through the ciliary ganglion to the pupil, producing constriction. MOR opiates induce pupillary constriction (miosis) in the awake state and block pupillary reflex dilation during anesthesia. The parasympathetic outflow is locally regulated by GABAergic interneurons. Opiates are believed to block the GABAergic interneuron-mediated inhibition (Larson, 2008). At high doses of agonists, the miosis is marked, and pinpoint pupils are pathognomonic; however, marked mydriasis will occur with the onset of asphyxia. While some tolerance to the miotic effect develops, addicts with high circulating concentrations of opioids continue to have constricted pupils. Therapeutic doses of morphine increase accommodative power and lower intraocular tension in normal and glaucomatous eyes.

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 (Young and da Silva, 2000) and occasionally seizure activity. While increased jaw and chest wall rigidity routinely occur at doses used for anesthesia induction, frank seizures and convulsions typically occur only at doses far in excess of those required to produce even profound analgesia. Myoclonus and seizures have been reported particularly in opioid tolerant patients on high doses of morphine-like opiates, including fentanyl, as encountered in hospice and terminal stages of pain therapy (Vella-Brincat and Macleod., 2007). However, seizures that are produced by some agents such as meperidine may occur at doses only moderately higher than those required for analgesia, especially in children, particularly with repeated delivery.

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 (McGinty, 1988).

• Direct stimulatory effects. Opiates may interact with receptors coupled through both inhibitory and stimulatory G-protein, with the inhibitory coupling but not the excitatory coupling showing tolerance with continued exposure (King et al., 2005).

• Actions mediated by non-opioid receptors. The metabolites of several opiates have been implicated in seizure activity, notably morphine-3-glucuronide (from morphine) and normeperidine (from meperidine) (Seifert and Kenendy, 2004; Smith, 2000).

A special case is the withdrawal syndrome from an opiate-dependent state in the adult and in the infant born to an opiate-dependent mother. Withdrawal in these circumstances, either by antagonists or abstinence, can lead to prominent EEG activation, tremor, and rigidity. Approaches to the management of such activation are controversial. Re-narcotization with a tapering dose and management of symptoms with anticonvulsants and anesthetics has been suggested (Farid et al., 2008). Anticonvulsant agents may not always be effective in suppressing opioid-induced seizures (Chapter 21).

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. There is no obligatory relationship between depression of respiration and depression of coughing, and effective antitussive agents are available that do not depress respiration (antitussives are discussed later in the chapter). Suppression of cough by such agents appears to involve receptors in the medulla that are less sensitive to naloxone (an opioid antagonist) than those responsible for analgesia (Chung and Pavord, 2008).

Cough is a protective reflex evoked by airway stimulation. It involves rapid expression of air against a transiently closed glottis. The reflex is complex, involving the central and peripheral nervous systems as well as the smooth muscle of the bronchial tree. Irritation of the bronchial mucosa causes bronchoconstriction, which in turn stimulates cough receptors (which probably represent a specialized type of stretch receptor) located in tracheobronchial passages. Afferent conduction from these receptors is via fibers in the vagus nerve; central components of the reflex probably include several mechanisms or centers that are distinct from the mechanisms involved in the regulation of respiration.

Nausea and vomiting are relatively uncommon in recumbent patients given therapeutic doses of morphine, but nausea occurs in ~40% and vomiting in 15% of ambulatory patients given 15 mg of the drug subcutaneously. This suggests that a vestibular component is also operative. Indeed, the nauseant and emetic effects of morphine are markedly enhanced by vestibular stimulation, and morphine and related synthetic analgesics produce an increase in vestibular sensitivity. A component of nausea is likely due to the gastric stasis that occurs postoperatively and that is exacerbated by analgesic doses of morphine (Greenwood-Van Meerveld, 2007). All clinically useful agonists produce some degree of nausea and vomiting. Careful, controlled clinical studies usually demonstrate that, in equianalgesic dosage, the incidence of such side effects is not significantly lower than that seen with morphine. Antagonists to the 5-HT3 receptor have supplanted phenothiazines and drugs used for motion sickness as the drugs of choice for the treatment of opioid-induced nausea and vomiting. Gastric prokinetic agents such as metoclopramide also are useful anti-nausea and anti-emetic drugs (Cameron et al., 2003); however, caution is warranted due to the propensity of metoclopramide to cause tardive dyskinesia (Chapter 46).

Effects on the myocardium are not significant in normal individuals. In patients with coronary artery disease but no acute medical problems, 8-15 mg morphine administered intravenously produces a decrease in O₂ consumption, left ventricular end-diastolic pressure, and cardiac work; effects on cardiac index usually are slight. In patients with acute myocardial infarction, the cardiovascular responses to morphine may be more variable than in normal subjects, and the magnitude of changes (e.g., the decrease in blood pressure) may be more pronounced (Roth et al., 1988). Anesthetic induction doses (described later) of the MOR result in a centrally mediated increase in vagal outflow to the heart, leading to an atropine-sensitive bradycardia.

Morphine may exert its well-known 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 and helping to relieve ischemia. It is not clear whether the analgesic properties of morphine in this situation are due to the reversal of acidosis that may stimulate local acid-sensing ion channels (McCleskey and Gold, 1999) or to a direct analgesic effect on nociceptive afferents from the heart.

When administered before experimental ischemia, 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 (Fryer et al., 2000). Some researchers suggest that opioids can be anti-arrhythmic and anti-fibrillatory during and after periods of ischemia (Fryer et al., 2000), although other data suggest that opioids can be arrhythmogenic (McIntosh et al., 1992).

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 because deaths after ordinary therapeutic doses have been reported. The concurrent use of certain phenothiazines may increase the risk of morphine-induced hypotension.

Cerebral circulation is not affected directly by therapeutic doses of opiates. However, opioid-induced respiratory depression and CO₂ retention can result in cerebral vasodilation and an increase in cerebrospinal fluid pressure. This pressure increase does not occur when PCO₂ is maintained at normal levels by artificial ventilation. Nevertheless, opioids produce changes in arousal that can obscure the clinical course of patients with head injuries.

Motor Tone. At therapeutic doses required for analgesia, opiates have little effect upon motor tone or function. However, high doses of opioids, as used for anesthetic induction, produce muscular rigidity in humans. Thus, rigidity of the chest wall and masseter severe enough to compromise respiration and intubation is not uncommon during anesthesia and routinely requires the use muscle relaxants.

Myoclonus, ranging from mild twitching to generalized spasm, is an occasional side-effect, which has been reported with all clinical opiate agonists; while it may be observed at lower therapeutic doses, it is particularly prevalent in hospice patients receiving high doses (Lyss et al., 1997). The increased muscle tone is certainly mediated by a central effect although the mechanisms of its effects are not clear. High doses of spinal opiates can increase motor tone, possibly through an inhibition of inhibitory interneurons in the ventral horn of the spinal cord. Alternately, intracranial delivery can initiate rigidity in animal models possible reflecting on increased extrapyramidal activity. As already indicated, both actions are reversed by opiate antagonists.

GI Tract. Opiates have important effects upon all aspects of GI function. It is estimated that 40-95% of patients treated with opioids develop constipation and that changes in bowel function can be demonstrated even with acute dosing (Benyamin et al., 2008). Opioid receptors are densely distributed in enteric neurons between the myenteric and submucosal plexi and on a variety of secretory cells. The more prominent expression of the action mediated by these receptors will be reviewed in the next sections. Importantly, the presence of opioids can obscure recognition of the diagnosis or clinical course in patients with acute abdominal conditions.

Esophagus. The esophageal sphincter is under control by brainstem reflexes that activate cholinergic motor neurons originating in the esophageal myenteric plexus. This system regulates passage of material from the esophagus to the stomach and prevents regurgitation; conversely, it allows relaxation in the act of emesis. Morphine inhibits lower esophageal sphincter relaxation induced by swallowing and by esophageal distension. This effect is believed to be centrally mediated, as peripherally restricted opiates such as loperamide do not alter esophageal sphincter tone (Sidhu and Triadafilopoulos, 2008).

Stomach. Movement of a meal though the stomach reflects the coordinated contractions of the antrum and the resting tone of the gastric reservoir. Relatively low doses of morphine result in an increase in tonic contracture of the antral musculature (secondary to an inhibition of local inhibitory neurons) and upper duodenum and reduced resting tone in the musculature of the gastric reservoir (secondary to inhibition of the motor neurons to the reservoir musculature), 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 hours, and the absorption of orally administered drugs is retarded. Morphine and other agonists usually decrease secretion of hydrochloric acid, although stimulation sometimes is evident. Activation of opioid receptors on parietal cells enhances secretion, but indirect effects, including increased secretion of somatostatin from the pancreas and reduced release of acetylcholine, appear to be dominant in most circumstances (Kromer, 1988).

Intestine. Morphine reduces propulsatile activity in the small and large intestine and diminishes intestinal secretions.

Propulsatile Activity. Opiate agonists suppress local neurogenic networks that provide a 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 nonpropulsatile. 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. These actions, combined with inattention to the normal sensory stimuli for defecation reflex owing to the central actions of the drug, contribute to morphine-induced constipation (Wood and Galligan, 2004).

The clinical relevance of the role of the peripheral opioid receptors in regulating GI motility after systemic opioids is supported by:

• The efficacy of peripherally limited opiate agonists such as loperamide as anti-diarrheals

• The ability of peripherally limited opiate antagonists such as methylnaltrexone to reverse the constipatory actions of systemic opiate agonists

Direct delivery of opioids into the cerebral ventricles or into the spinal intrathecal space could also inhibit GI propulsive activity as long as the extrinsic innervation to the bowel is intact. Although some tolerance develops to the effects of opioids on GI motility, patients who take opioids chronically remain constipated.

Intestinal Secretions. In the presence of intestinal hypersecretion that may be associated with diarrhea, morphine-like drugs inhibit the transfer of fluid and electrolytes into the lumen by naloxone-sensitive actions on the intestinal mucosa and within the CNS (Kromer, 1988). 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. Bile flow is regulated by the periodic contractions of the sphincter of Oddi, which is relaxed by inhibitory innervation. This inhibitory innervation is suppressed by opiates. After the subcutaneous injection of 10 mg morphine sulfate, the sphincter of Oddi constricts, and the pressure in the common bile duct may rise >10-fold within 15 minutes; this effect may persist for 2 hours or more. Fluid pressure also may increase in the gallbladder and produce symptoms that may vary from epigastric distress to typical biliary colic.

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. All opioids can cause biliary spasm. Atropine only partially prevents morphine-induced biliary spasm, but opioid antagonists prevent or relieve it. Papaverine, another alkaloid of the poppy that lacks opioid activity, produces smooth muscle relaxation and is used therapeutically for GI, urethral, and biliary colic and for other nonvisceral conditions (e.g., embolism and angina pectoris) accompanied by smooth muscle spasm.

Other Smooth Muscle

Ureter and Urinary Bladder. Voiding is a highly organized response initiated by afferents activated by bladder filling and spinobulbospinal reflex arcs, which lead to contraction of the bladder and a reflex relaxation of the external urinary sphincter (Fowler et al., 2008). Morphine inhibits the urinary voiding reflex and increases the tone of the external sphincter with a resultant increase in the volume of the bladder. In animal models, this effect is mediated by MOR and DOR agonists. Stimulation of either receptor type in the brain or in the spinal cord exerts similar actions on bladder motility (Dray and Nunan, 1987). 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, in humans, the inhibition of systemic opiate effects on micturition is reversed by peripherally restricted antagonists (Rosow et al., 2007).

Uterus. If the uterus has been made hyperactive by oxytocics, morphine tends to restore the tone, frequency, and amplitude of 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. Though controversial, it is not blocked by naloxone and thought not to be mediated by opioid receptors. Itching is readily seen with morphine and meperidine but to a much lesser extent with oxymorphone, methadone, fentanyl, or sufentanil. This pruritus is a common and potentially disabling complication of opioid use. It can be caused by systemic as well as intraspinal injections of therapeutic doses of opioids, but it appears to be more intense after epidural or intrathecal administration (Ballantyne et al., 1988). The spinal effect, which is reversible by naloxone, may reflect a disinhibition of itch-specific neurons that have been identified in the spinal dorsal horn (Schmelz, 2002).

Immune System. The effects of opioids on the immune system are complex. Opioids modulate immune function by direct effects on cells of the immune system and indirectly through centrally mediated neuronal mechanisms (Sharp and Yaksh, 1997). 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 hypothalamic-pituitary-adrenal (HPA) axis (Mellon and Bayer, 1998).

Direct effects on immune cells may involve unique, incompletely characterized variants of the classical neuronal opioid receptors, with MOR variants being most prominent (Sharp and Yaksh, 1997). Atypical receptors could account for the fact that it has been very difficult to demonstrate significant opioid binding on immune cells despite the observance of robust functional effects. In contrast, morphine-induced immune suppression largely is abolished in knockout mice lacking the receptor gene, suggesting that the receptor is a major target of morphine's actions on the immune system (Gaveriaux-Ruff et al., 1998). A proposed mechanism for the immune suppressive effects of morphine on neutrophils is through a nitric oxide–dependent inhibition of NF-kB activation (Welters et al., 2000). Others have proposed that the induction and activation of MAP kinase also may play a role (Chuang et al., 1997).

Overall, the effects of opioids appear to be modestly immunosuppressive, and increased susceptibility to infection and tumor spread have been observed. In some situations, immune effects appear more prominent with acute administration than with chronic administration, which could have important implications for the care of the critically ill (Sharp and Yaksh, 1997). In contrast, opioids have been shown to reverse pain-induced immunosuppression and increase tumor metastatic potential in animal models (Page and Ben-Eliyahu, 1997). Therefore, opioids may either inhibit or augment immune function depending on the context in which they are used. These studies also indicate that withholding opioids in the presence of pain in immunocompromised patients actually could worsen immune function. Taken together, these studies indicate that opioid-induced immune suppression may be clinically relevant both to the treatment of severe pain and in the susceptibility of opioid addicts to infection (e.g., human immunodeficiency virus (HIV) infection and tuberculosis). Different opioid agonists also may have unique immunomodulatory properties. Better understanding of these properties eventually should help to guide the rational use of opioids in patients with cancer or at risk for infection or immune compromise.

Temperature Regulation. Opioids alter the equilibrium point of the hypothalamic heat-regulatory mechanisms such that body temperature usually falls slightly. Systematic studies have shown that MOR agonists such as alfentanil and meperidine, acting in the CNS, will result in slightly increased thresholds for sweating and significantly lower the threshold temperatures for evoking vasoconstriction and shivering (Sessler, 2008). In precipitated withdrawal, elevated body temperatures are observed, an observation consistent with the report that chronic high dosage may increase body temperature (Martin, 1983).

Source and Composition of Opium

Because the synthesis of morphine is difficult, the drug still is obtained from opium or extracted from poppy straw. Opium is obtained from the unripe seed capsules of the poppy plant, Papaver somniferum. The milky juice is dried and powdered to make powdered opium, which contains a number of alkaloids. Only a few—morphine, codeine, and papaverine—have clinical utility. These alkaloids can be divided into two 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%).

Structure-Activity Relationship of the Morphine-Like Opioids. In addition to morphine, codeine, and the semisynthetic derivatives of the natural opium alkaloids, a number of other structurally distinct chemical classes of drugs have pharmacological actions similar to those of morphine. Clinically useful compounds include the morphinans, benzomorphans, methadones, phenylpiperidines, and propionanilides. Although the two-dimensional representations of these chemically diverse compounds appear to be quite different, molecular models show certain common characteristics, as indicated by the heavy lines in the structure of morphine shown in Figure 18–8. Among the important properties of the opioids that can be altered by structural modification are their affinities for various types of opioid receptors, their activities as agonists versus antagonists, their lipid solubilities, and their resistance to metabolic breakdown. For example, blockade of the phenolic hydroxyl at position 3, as in codeine and heroin, drastically reduces binding to receptors; these compounds are converted in vivo to the potent analgesics morphine and 6-acetyl morphine, respectively.

Absorption, Distribution, Metabolism, and Excretion

Absorption. In general, the opioids are modestly 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 though 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) (Neumann et al., 1982).

When morphine and most opioids are given intravenously, they act promptly. However, the more lipid-soluble compounds (e.g., fentanyl) act more rapidly than morphine after subcutaneous administration because of differences in the rates of absorption and entry into the CNS. 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 hours after the last dose, tissue concentrations are low.

The major pathway for the metabolism of morphine is conjugation with glucuronic acid. The two major metabolites formed are morphine-6-glucuronide and morphine-3-glucuronide. Small amounts of morphine-3,6-diglucuronide also may be formed. Although the 3- and 6-glucuronides are quite polar, both still can cross the blood-brain barrier to exert significant clinical effects (Christrup, 1997).

Morphine-6-glucuronide has pharmacological actions indistinguishable from those of morphine. Morphine-6-glucuronide given systemically is approximately twice as potent as morphine in animal models (Paul et al., 1989) and in humans (Osborne et al., 1988). With chronic administration, the 6-glucuronide accounts for a significant portion of morphine's analgesic actions (Osborne et al., 1988). Indeed, with chronic oral dosing, the blood levels of morphine-6-glucuronide typically exceed those of morphine. Given its greater MOR potency and its higher concentration, morphine-6-glucuronide may be responsible for most of morphine's analgesic activity in patients receiving chronic oral morphine. 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 t_1/2 of morphine is ~2 hours; the t_1/2 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 (Owen et al., 1983) and the general decline in renal function in the elderly.

Morphine-3-glucuronide, another important metabolite, has little affinity for opioid receptors but may contribute to excitatory effects of morphine (Smith, 2000). N-Demethylation of morphine to normorphine is a minor metabolic pathway in humans but is more prominent in rodents (Yeh et al., 1977). 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. Enterohepatic circulation of morphine and its glucuronides occurs, which accounts for the presence of small amounts of morphine in feces and urine for several days after the last dose.

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 t_1/2 of codeine in plasma is 2-4 hours.

CYP2D6 catalyzes the conversion of codeine to morphine. Well-characterized 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 (Eichelbaum and Evert, 1996). Other polymorphisms (e.g., the CYP2D6*2x2 genotype) can lead to ultra-rapid metabolism and thus increased sensitivity to codeine's effects due to higher than expected serum morphine levels in 4-5% of the US population and 16-28% of North Africans, Ethiopians, and Arabs (Eichelbaum and Evert, 1996). Other variations in metabolic efficiency among ethnic groups are apparent. For example, Chinese produce less morphine from codeine than do Caucasians and also are less sensitive to morphine's effects. The reduced sensitivity to morphine may be due to decreased production of morphine-6-glucuronide (Caraco et al., 1999). 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 (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.

A number of factors may alter a patient's sensitivity to opioid analgesics, including the integrity of the blood-brain barrier. For example, when morphine is administered to a newborn infant in weight-appropriate doses extrapolated from adults, unexpectedly profound effects (analgesia and respiratory depression) may be observed. This is due to the immaturity of the blood-brain barrier in neonates. As mentioned previously, 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. Changes in pharmacokinetic parameters only partially explain these observations. 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 because increased bioavailability after oral administration or cumulative effects may occur. 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 (Chan and Matzke, 1987). This metabolite also may accumulate during repeated administration of codeine to patients with impaired renal function. When repeated doses of meperidine are given to such patients, the accumulation of normeperidine may cause tremor and seizures. Similarly, the repeated administration of propoxyphene may lead to naloxone-insensitive cardiac toxicity caused by the accumulation of norpropoxyphene (Chan and Matzke, 1987).

Morphine and related opioids must be used cautiously in patients with compromised respiratory function (e.g., emphysema, kyphoscoliosis, severe obesity). In patients with cor pulmonale, death has occurred after therapeutic doses of morphine. Although many patients with such conditions seem to be functioning within normal limits, they are already using compensatory mechanisms, such as increased respiratory rate. Many have chronically elevated levels of plasma CO₂ and may be less sensitive to the stimulating actions of CO₂. The further imposition of the depressant effects of opioids can be disastrous. 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. While head injury per se does not constitute an absolute contraindication to the use of opioids, the possibility of exaggerated depression of respiration and the potential need to control ventilation of the patient must be considered. Finally, since opioids may produce mental clouding and side effects such as miosis and vomiting, which are important signs in following the clinical course of patients with head injuries, the advisability of their use must be weighed carefully against these risks.

Patients with reduced blood volume are considerably 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.

Aside from their ability to release histamine, opioid analgesics may evoke allergic phenomena, but a true allergic response is uncommon. The effects usually are manifested as urticaria and other types of skin rashes such as fixed eruptions; contact dermatitis in nurses and pharmaceutical workers also occurs. Wheals at the site of injection of morphine, codeine, and related drugs are likely secondary to histamine release. Anaphylactoid reactions have been reported after intravenous administration of codeine and morphine, but such reactions are rare. Such reactions may contribute to sudden death, episodes of pulmonary edema, and other complications that occur among addicts who use heroin intravenously (Chapter 24).

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 intravenous administration frequently produces a marked increase in heart rate.

Smooth Muscle. Meperidine has effects on certain smooth muscles qualitatively similar to those observed with other opioids. 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. Therapeutic doses given during active labor do not delay the birth process; in fact, the frequency, duration, and amplitude of uterine contraction sometimes may be increased (Zimmer et al., 1988). The drug does not interfere with normal postpartum contraction or involution of the uterus, and it does not increase the incidence of postpartum hemorrhage. See also "Therapeutic Uses" later in the chapter.

In humans, meperidine is hydrolyzed to meperidinic acid, which in turn is partially conjugated. Meperidine also is N-demethylated to normeperidine, which then may be hydrolyzed to normeperidinic acid and subsequently conjugated. The clinical significance of the formation of normeperidine is discussed later. Meperidine is metabolized chiefly in the liver, with a t_1/2 ≈3 hours. In patients with cirrhosis, the bioavailability of meperidine is increased to as much as 80%, and the t_1/2 of both meperidine and normeperidine are prolonged. Approximately 60% of meperidine in plasma is protein bound. Only a small amount of meperidine is excreted unchanged.

Untoward Effects, Precautions, and Contraindications. The pattern and overall incidence of untoward effects that follow the use of meperidine 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. As with other opioids, tolerance develops to some of these effects. The contraindications generally are the same as for other opioids. 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 t_1/2 of 15-20 hours, compared to 3 hours for meperidine. Since normeperidine is eliminated by the kidney and the liver, 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 hours or in doses >600 mg/day (see www.ahrq.gov).

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 most 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 5-HT, resulting in serotonergic overactivity (Stack et al., 1988). Conversely, the MAO inhibitor interaction with merperidine 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. Similarly, dextromethorphan (an analog of levorphanol used as a non-narcotic cough suppressant) also inhibits neuronal 5-HT uptake and must be avoided in these patients. In addition, tramadol and tapentadol (centrally acting synthetic opioid analgesics, described later) inhibit the uptake of norepinephrine and 5-HT and should not be used concomitantly with MAO inhibitors or selective serotonin reuptake inhibitors (SSRIs).

Chlorpromazine increases the respiratory-depressant effects of meperidine, as do tricyclic antidepressants; this is not true of 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; this is associated with an elevation of the concentration of normeperidine in plasma (Edwards et al., 1982). As with morphine, concomitant administration of amphetamine has been reported to enhance the analgesic effects of meperidine and its congeners while counteracting sedation.

Single doses of meperidine also appear to be effective in the treatment of postanesthetic shivering. Meperidine, 25-50 mg, is used frequently with antihistamines, corticosteroids, acetaminophen, or nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent or ameliorate infusion-related rigors and shaking chills that accompany the intravenous 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. The fraction of drug that is bound to protein is lower in the fetus; concentrations of free drug thus may be considerably higher than in the mother. Nevertheless, meperidine produces less respiratory depression in the newborn than does an equianalgesic dose of morphine or methadone (Fishburne, 1982).

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. Diarrhea refractory to maximal doses of diphenoxylate for 10 days is unlikely to be controlled by further therapy. Difenoxin, a metabolite of diphenoxylate, has actions similar to those of the parent compound. Like diphenoxylate, difenoxin is marketed in a fixed dose with atropine (motofen) for the management of diarrhea.

In human volunteers taking large doses of loperamide, concentrations of drug in plasma peak ~4 hours after ingestion; this long latency may be due to inhibition of GI motility and to enterohepatic circulation of the drug. The apparent elimination t_1/2 is 7-14 hours. 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 (Sadeque et al., 2000). Mice with deletions of one of the genes encoding the P-glycoprotein transporter have much higher brain levels and significant central effects after administration of loperamide (Schinkel et al., 1996). Inhibition of P-glycoprotein by many clinically used drugs, such as quinidine and verapamil, possibly could lead to enhanced central effects of loperamide.

In general, loperamide is unlikely to be abused parenterally because of its low solubility; large doses of loperamide given to human volunteers do not elicit pleasurable effects typical of opioids. The usual dosage is 4-8 mg/day; the daily dose should not exceed 16 mg.

Pharmacological Properties

CNS Effects. 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 non-depolarizing 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 receptor agonists, but the 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. As with morphine and meperidine, delayed respiratory depression also can be seen after the use of fentanyl or sufentanil, possibly owing to enterohepatic circulation. High doses of fentanyl can cause neuroexcitation and, rarely, seizure-like activity in humans (Bailey and Stanley, 1994). Fentanyl has minimal effects on intracranial pressure when ventilation is controlled and the arterial CO₂ concentration is not allowed to rise.

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. For this reason, high doses of fentanyl or sufentanil are commonly used as the primary anesthetic for patients undergoing cardiovascular surgery or for patients with poor cardiac function.

Absorption, Distribution, Metabolism, and Excretion. These agents are highly lipid soluble and rapidly cross the blood-brain barrier. This is reflected in the t_1/2 for equilibration between the plasma and cerebrospinal fluid of ~5 minutes for fentanyl and sufentanil. The levels in plasma and cerebrospinal fluid 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 t_1/2, 3-4 hours. 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 (Chapter 19). They are used commonly either intravenously, epidurally, or intrathecally. The analgesic effects of fentanyl and sufentanil are similar to those of morphine and other opioids. Fentanyl is ~100 times more potent than morphine, and sufentanil is ~1000 times more potent than morphine. The time to peak analgesic effect after intravenous administration of fentanyl and sufentanil (~5 minutes) is notably less than that for morphine and meperidine (~15 minutes). 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 (described later). Intravenous use of fentanyl and sufentanil for postoperative pain has been popular.

Epidural use of fentanyl and sufentanil for postoperative or labor analgesia has significant popularity. A combination of epidural opioids with local anesthetics permits reduction in the dosage of both components, minimizing the side effects of the local anesthetic (i.e., motor blockade) and the opioid (i.e., urinary retention, itching, and delayed respiratory depression in the case of morphine). An important caveat to their spinal use is that because of their rapid clearance, these agents at analgesic spinal doses can produce blood levels that are similar to those producing effects after systemic administration (Bernards, 2004).

The use of fentanyl and sufentanil in chronic pain treatment has become more widespread. The development of novel, minimally invasive routes of administration for fentanyl has facilitated the use of these compounds in chronic pain management. Transdermal patches (duragesic, others) that provide sustained release of fentanyl for 48-72 hours are available. However, factors promoting increased absorption (e.g., fever) can lead to relative overdosage and increased side effects (see "Routes of Analgesic Drug Administration" later in the chapter). Transbuccal absorption by the use of buccal tablets, soluble buccal film, and lollypop-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 though buccal absorption. Accordingly, there is little opportunity for overdosing by that route.

Absorption, Fate, and Excretion. Remifentanil has a more rapid onset of analgesic action than fentanyl or sufentanil. Analgesic effects occur within 1-1.5 minutes following intravenous administration. Peak respiratory depression after bolus doses of remifentanil occurs after 5 minutes (Patel and Spencer, 1996). Remifentanil is metabolized by plasma esterases, with a t_1/2 of 8-20 minutes (Burkle et al., 1996); thus, elimination is independent of hepatic metabolism or renal excretion. There is no prolongation of effect with repeated dosing or prolonged infusion. Age and weight can affect clearance of remifentanil, requiring that dosage be reduced in the elderly and based on lean body mass. However, neither of these conditions causes major changes in duration of effect. After 3- to 5-hour infusions of remifentanil, recovery of respiratory function can be seen within 3-5 minutes; full recovery from all effects of remifentanil is observed within 15 minutes (Glass et al., 1999). 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 intravenous infusion because its short duration of action makes bolus administration impractical. The titratability of remifentanil and its consistent, rapid offset make it ideally suited for short surgical procedures where rapid recovery is desirable. Remifentanil also has been used successfully for longer neurosurgical procedures, where rapid emergence from anesthesia may be important. However, in cases where 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.

Absorption, Distribution, Metabolism, and Excretion. Methadone is absorbed well from the GI tract and can be detected in plasma within 30 minutes of oral ingestion; it reaches peak concentrations at ~4 hours. After therapeutic doses, ~90% of methadone is bound to plasma proteins. Peak concentrations occur in brain within 1-2 hours of subcutaneous or intramuscular 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, the results of N-demethylation and cyclization to form pyrrolidines 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 t_1/2 of methadone is long, 15-40 hours.

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.

Side Effects, Toxicity, Drug Interactions, and Precautions. Side effects, toxicity, and conditions that alter sensitivity, as well as the treatment of acute intoxication, are similar to those described for morphine. During long-term administration, there may be excessive sweating, lymphocytosis, and increased concentrations of prolactin, albumin, and globulins in the plasma. 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. Serious cardiac arrhythmias, including torsades de pointes, have been observed during treatment with methadone.

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. In the U.S., prescribing methadone for abstinence syndrome and maintenance of heroin users is regulated by Federal Opioid Treatment Standards (42 CFR 8.12). The onset of analgesia occurs 10-20 minutes after parenteral administration and 30-60 minutes after oral medication. The average minimal effective analgesic concentration in blood is ~30 ng/mL (Gourlay et al., 1986). The typical oral dose is 2.5-10 mg repeated every 8-12 hours as needed depending on the severity of the pain and the response of the patient. Care must be taken when escalating the dosage because of the prolonged t_1/2 of the drug and its tendency to accumulate over a period of several days with repeated dosing. Iatrogenic overdoses have occurred during initiation of therapy and dosing titration with methadone because of too-rapid titration or the concomitant use of depressant drugs. The peak respiratory depressant effects of methadone typically occur later and persist longer than the peak analgesic effects 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 is not used widely as an antiperistaltic agent and should not be used in labor.

Despite its longer plasma t_1/2, 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. In contrast to morphine, methadone and many of its congeners retain a considerable degree of their effectiveness when given orally. In terms of total analgesic effects, methadone given orally is ~50% as effective as the same dose administered intramuscularly; however, the oral-parenteral potency ratio is considerably lower when peak analgesic effect is considered. In equianalgesic doses, the pattern and incidence of untoward effects caused by methadone and morphine are similar.

Because of its oral bioavailability and long t_1/2, 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 (Mattick et al., 2009). 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.

Pharmacological Actions. Although slightly less selective than morphine, propoxyphene binds primarily to μ opioid receptors and produces analgesia and other CNS effects that are similar to those seen with morphine-like opioids. It is likely that 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 would equal 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 (Beaver, 1988).

Absorption, Distribution, Metabolism, and Excretion. After oral administration, concentrations of propoxyphene in plasma reach their highest values at 1-2 hours. There is great variability between subjects in the rate of clearance and the plasma concentrations that are achieved. The average t_1/2 of propoxyphene in plasma after a single dose is 6-12 hours, which is longer than that of codeine. In humans, the major route of metabolism is N-demethylation to yield norpropoxyphene. The t_1/2 of norpropoxyphene is ~30 hours, and its accumulation with repeated doses may be responsible for some of the observed toxicity (Chan and Matzke, 1987).

Toxicity. Given orally, propoxyphene is approximately one-third as potent as orally administered codeine in depressing respiration. Moderately toxic doses usually produce CNS and respiratory depression, but with still larger doses the clinical picture may be complicated by convulsions in addition to respiratory depression. Delusions, hallucinations, confusion, cardiotoxicity, and pulmonary edema also have been noted. Respiratory-depressant effects are significantly enhanced when ethanol or sedative-hypnotics are ingested concurrently. Naloxone antagonizes the respiratory-depressant, convulsant, and some of the cardiotoxic effects of propoxyphene. A second aspect of propoxyphene toxicity is liver or renal toxicity that arises when the combination medication containing acetaminophen or acetylsalicylate, respectively, is employed in conjunction with intake of those medications separately, leading to a frank overdose of these adjuvants.

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 postaddicts. 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. In 2009, the European Medicines Agency completed a review of the safety and effectiveness of dextropropoxyphene-containing medicines and concluded that the benefits do not outweigh the risks and recommended a gradual withdrawal of marketing authorization throughout the EU (European Medicines Agency, 2009). The conclusion reached by the agency included an assessment that dextropropoxyphene-containing medicines are weak painkillers with a limited effectiveness in the treatment of pain and a narrow therapeutic index. Furthermore, the agency judged acetaminophen (paracetamol) containing combinations with dextropropoxyphene to be no more effective than acetaminophen alone. In the U.S., propoxyphene has been approved for mild to moderate pain since 1957. Recently the drug has been labeled with additional warnings related to the risk of rapidly fatal effects in the event of an overdose (FDA, 2009). Thus, in the U.S., propoxyphene should not be prescribed to patients who are suicidal or have a history of suicidal ideation. In addition, higher than expected serum levels of propoxyphene should be anticipated from the concommitant administration of strong CYP3A4 inhibitors such as ritonavir, ketoconazole, itraconazole, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil. Propoxphene alternatives should be considered for patients receiving a strong CYP3A4 inhibitor and others at risk for overdose, particularly those with preexisting heart disease.

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 norepinephrine and serotonin. 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.

Pharmacokinetics. 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. However, the primary O-demethylated metabolite of tramadol is two to four times as potent as the parent drug and may account for part of the analgesic effect. Tramadol is supplied as a racemic mixture, which is more effective than either enantiomer alone. The (+)-enantiomer binds to the receptor and inhibits serotonin uptake. The (–)-enantiomer inhibits norepinephrine uptake and stimulates α₂ adrenergic receptors (Lewis and Han, 1997). Tramadol undergoes extensive hepatic metabolism by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation with subsequent renal excretion. The rate of formation of the active metabolite is dependent on CYP2D6 and therefore is subject to both metabolic induction and inhibition. The elimination t_1/2 is 6 hours for tramadol and 7.5 hours for its active metabolite. Analgesia begins within an hour of oral dosing and peaks within 2-3 hours. The duration of analgesia is ~6 hours. The maximum recommended daily dose is 400 mg.

Side Effects and Adverse Effects. Common 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 (Duthie, 1998). Tramadol can cause seizures and possibly exacerbate seizures in patients with predisposing factors. While tramadol-induced analgesia is not entirely reversible by naloxone, tramadol-induced respiratory depression is reversed by naloxone. However, the use of naloxone increases the risk of seizure in patients exposed to tramadol. Misuse, diversion, physical dependence, abuse, addiction, and withdrawal have been reported in conjunction with the use of tramadol. Tramadol has been shown to reinitiate physical dependence in some patients who have previously been dependent on other opioids, thus it should be avoided in patients with a history of addiction. Precipitation of withdrawal necessitates that tramadol be tapered prior to discontinuation. Tramadol should not be used in patients taking MAO inhibitors (Lewis and Han, 1997), SSRIs, or other drugs that lower the seizure threshold (described earlier).

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. Like tramadol, it should not be used concurrently with agents that enhance monamine activity or lower the seizure threshold, such as MAO inhibitors and SSRIs. The major pathway of tapentadol metabolism is conjugation with glucuronic acid; ~70% of the dose is excreted in urine in the conjugated form.

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 opioid receptors. Higher doses of pentazocine (60-90 mg) elicit dysphoric and psychotomimetic effects. The mechanisms responsible for these side effects are not known but might involve activation of supraspinal receptors because it has been suggested that these untoward 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 opioid receptors. 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 (Bailey and Stanley, 1994).

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. After oral ingestion, naloxone is destroyed rapidly by the liver. An oral dose of ~50 mg pentazocine results in analgesia equivalent to that produced by 60 mg of orally administered codeine.

Pharmacological Actions and Side Effects. An intramuscular 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 as well as no futher 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 (Roth et al., 1988); nevertheless, morphine is generally considered a first-line agent for use during acute cardiac events to relieve chest pain and anxiety. The GI effects of nalbuphine probably are similar to those of pentazocine. 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 t_1/2 of 2-3 hours. Nalbuphine is 20-25% as potent when administered orally as when given intramuscularly. No oral dosage forms are commercially available in the U.S.

Tolerance and Physical Dependence. In subjects dependent on low doses of morphine (60 mg/day), nalbuphine precipitates an abstinence syndrome. Prolonged administration of nalbuphine can produce physical dependence. The withdrawal syndrome is similar in intensity to that seen with pentazocine. The potential for abuse of parenteral nalbuphine in subjects not dependent on receptor agonists probably is similar to that for parenteral 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 hours; 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 (Gear et al., 1999).

Therapeutic Use. In general, butorphanol tartrate (stadol, others) is considered to be best suited 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 hours. A nasal formulation is available and has proven to be effective in pain relief, including migraine pain. This formulation may be particularly useful for patients with severe headaches who are unresponsive to other forms of treatment.

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 onset, peak, and duration of action are similar to those that follow the administration of morphine. The plasma t_1/2 of butorphanol is ~3 hours. 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 (Popio et al., 1978).

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.

Pharmacological Actions and Side Effects. 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 (Wallenstein et al., 1986). Although variable, the duration of analgesia usually is longer than that of morphine. Some of the subjective and respiratory-depressant effects are unequivocally slower in onset and last longer than those of morphine. For example, peak miosis occurs ~6 hours after intramuscular injection, whereas maximal respiratory depression is observed at ~3 hours.

Because buprenorphine is a partial MOR agonist, it may cause symptoms of abstinence in patients who have been receiving 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 (Boysen and Hertel, 1988). Although respiratory depression has not been a major problem, it is not clear whether there is a ceiling for this effect (as seen with nalbuphine and pentazocine). 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. This suggests that buprenorphine dissociates very slowly from opioid receptors. The t_1/2 for dissociation from the receptor is 166 minutes for buprenorphine, as opposed to 7 minutes for fentanyl (Boas and Villiger, 1985). 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.

Buprenorphine is relatively well absorbed by most routes. Administered sublingually, the drug (0.4-0.8 mg) produces satisfactory analgesia in postoperative patients. Concentrations in blood peak within 5 minutes of intramuscular injection and within 1-2 hours of oral or sublingual administration. While the plasma t_1/2 in plasma is ~3 hours, this value bears little relationship to the rate of disappearance of effects (discussed earlier). Both N-dealkylated and conjugated metabolites are detected in the urine, but most of the drug is excreted unchanged in the feces. About 96% of the circulating drug is bound to protein.

Physical Dependence. When buprenorphine is discontinued, a withdrawal syndrome develops that is delayed in onset for 2-14 days; this consists of typical but generally not very severe morphine-like withdrawal signs and symptoms, and it persists for 1-2 weeks (Fudala et al., 1989).

Therapeutic Uses. Buprenorphine (buprenex) injection is indicated for use as an analgesic. In the U.S., use of the oral formulations of buprenorphine (subutex) and buprenorphine in fixed-dose combination with naloxone (suboxone) is limited to the treatment of opioid dependence by the Drug Addiction Treatment Act (DATA) of 2000 [21 U.S.C. 823(g)]. This act created an opportunity for clinicians with special training to be exempted from the requirement to obtain a special DEA license when using buprenorphine to treat opioid addicts. The usual intramuscular or intravenous dose for analgesia is 0.3 mg given every 6 hours. Buprenorphine is metabolized to norbuprenorphine by CYP3A4. Thus, care should be taken in treating patients who also are taking known inhibitors of CYP3A4 (e.g., azole antifungals, macrolide antibiotics, and HIV protease inhibitors), as well as drugs that induce CYP3A4 activity (e.g., certain anticonvulsants and rifampin).

Buprenorphine for the treatment of opioid addiction is initiated with sublingual drug, followed by maintenance therapy with a fixed-dose combination formulation of buprenorphine and naloxone. The partial agonist properties of buprenorphine limit its utility in the treatment of addicts who require high maintenance doses of opioids (Kreek et al., 2002).

Chemistry. Relatively minor changes in the structure of an opioid can convert a drug that is primarily an agonist into one with antagonistic actions at one or more types of opioid receptors. The most common such substitution is that of a larger moiety (e.g., an allyl or methylcyclopropyl group) for the N-methyl group that is typical of the MOR agonists. Such substitutions transform morphine to nalorphine, levorphanol to levallorphan, and oxymorphone to naloxone (NARCAN, others) or naltrexone (revia, vivitrol, others) (Figure 18–8). 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 (Martin, 1983). Nalmefene (no longer marketed in the U.S.) is a relatively pure MOR antagonist that is more potent than naloxone (Dixon et al., 1986). A number of other non-peptide antagonists have been developed that are relatively selective for individual types of opioid receptors. These include cyprodime and β funaltrexamine, for MOR; naltrindole for DOR; and norbinaltorphimine for KOR (Portoghese, 1989), though these agents are not in clinical use.

The majority of the agents noted above 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).

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 (Drolet et al., 2001). In the face of a variety of physical (pain) or psychological stressors, an increased release of a variety of opioid peptides occurs. Many stressors will activate central circuits. Changes in circulating levels of endorphins in plasma are often cited in events such as runner's high, yet such peripheral changes have little significance to central systems, given the minimal ability of these peptides to penetrate the blood-brain barrier.

Pain. Opiate antagonism in humans is associated with variable effects ranging from no effect to a mild hyperalgesia and even hypoalgesia as measured in a variety of well-controlled experimental pain paradigms (France et al., 2007). A number of studies have, however, suggested that agents such as naloxone appear to attenuate the analgesic effects of placebo medications and acupuncture (Benedetti and Amanzio, 1997).

Stress. Even at high doses of different antagonists, normal subjects typically show modest changes in blood pressure or heart rate. In laboratory animals, the administration of naloxone will reverse or attenuate the hypotension associated with shock of diverse origins, including that caused by anaphylaxis, endotoxin, hypovolemia, and injury to the spinal cord; opioid agonists aggravate these conditions (Amir, 1988; Faden, 1988).

Affect. High doses of naltrexone appeared to cause mild dysphoria in one study but little or no subjective effects in others (Gonzalez and Brogden, 1988).

Endocrine Effects. Endogenous opioid peptides participate in the regulation of pituitary secretion apparently by exerting tonic inhibitory effects on the release of certain hypothalamic hormones (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. Antagonists do not consistently alter basal or stress-induced concentrations of prolactin in plasma in men; paradoxically, naloxone stimulates the release of prolactin in women. Opioid antagonists augment the increases in plasma concentrations of cortisol and catecholamines that normally accompany stress or exercise.

Endogenous opioid peptides probably have some role in the regulation of feeding or energy metabolism: in laboratory models, opioid antagonists increase energy expenditure, interrupt hibernation in appropriate species, induce weight loss, and prevent stress-induced overeating and obesity. These observations have led to the experimental use of opioid antagonists in the treatment of human obesity, especially that associated with stress-induced eating disorders. 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 (Atkinson, 1987).

Even after prolonged administration of high doses of the antagonist alone, discontinuation of naloxone is not followed by any recognizable withdrawal syndrome, and the withdrawal of naltrexone, another relatively pure antagonist, produces very few signs and symptoms. However, 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 (Yoburn et al., 1988). Naltrexone and naloxone have no known potential for abuse.

Compared with naloxone, naltrexone retains much more of its efficacy by the oral route, and its duration of action approaches 24 hours after moderate oral doses. Peak concentrations in plasma are reached within 1-2 hours and then decline with an apparent t_1/2 of ~3 hours; this value does not change with long-term use. Naltrexone is metabolized to 6-naltrexol, which is a weaker antagonist but has a longer t_1/2, ~13 hours. Naltrexone is much more potent than naloxone, and l00 mg oral doses given to patients addicted to opioids produce concentrations in tissues sufficient to block the euphorigenic effects of 25-mg intravenous doses of heroin for 48 hours (Gonzalez and Brogden, 1988). Methylnaltrexone is handled similarly to naltrexone. It is converted to methyl-6-naltrexol isomers and is largely eliminated primarily as the unchanged drug with significant active renal secretion. The terminal disposition t_1/2 of methylnaltrexone is ~8 hours.

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 this agent 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 used cautiously because it also can precipitate withdrawal in dependent subjects and cause undesirable cardiovascular side effects. By carefully titrating the dose of naloxone, it usually is possible to rapidly antagonize the respiratory-depressant actions without eliciting a fully expressed withdrawal syndrome. 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 intravenous or intramuscular 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) and have been approved by the FDA for that use. With distribution restricted to the periphery, these agents do not alter central opioid agonist actions. Worrisome reports of GI perforation in this setting are under review by FDA. Other strategies for the management of opioid-induced constipation are described in Chapter 46.

Management of Abuse Syndromes. There is considerable interest in the use of opiate antagonists such as naltrexone as an adjuvant in treating a variety of non-opioid dependency syndromes such as alcoholism (Chapters 23 and 24), where an opiate antagonist decreases the chance of relapse (Anton, 2008). Interestingly, patients with a single nucleotide polymorphism (SNP) in the MOR gene have significantly lower relapse rates to alcoholism when treated with naltrexone (Haile et al., 2008). Naltrexone is FDA-approved for treatment of alcoholism.

Trauma. The potential utility of opiate antagonists in the treatment of shock, stroke, spinal cord and brain trauma, and other disorders that may involve mobilization of endogenous opioid peptides has been reported; but opioid antagonists have failed to demonstrate neuroprotective benefits and their study in trauma has been largely abandoned (Hawryluk et al., 2008).

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. Compared with codeine, dextromethorphan produces fewer subjective and GI side effects (Matthys et al., 1983). In therapeutic dosages, the drug does not inhibit ciliary activity, and its antitussive effects persist for 5-6 hours. Its toxicity is low, but extremely high doses may produce CNS depression.

Sites that bind dextromethorphan with high affinity have been identified in membranes from various regions of the brain (Craviso et al., 1983). 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 (Elliott et al., 1994). Thus, the mechanism by which dextromethorphan exerts its antitussive effect still is not clear.

The average adult dosage of dextromethorphan hydrobromide is 10-30 mg three to six 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.

Two other antitussives not currently recognized as generally safe and effective (GRAS/E) by the FDA, carbetapentane (pentoxyverine) and caramiphen, are known to bind avidly to the dextromethorphan binding sites; codeine, levopropoxyphene, and other antitussive opioids (as well as naloxone) do not bind. Although noscapine (discussed later) enhances the affinity of dextromethorphan, it appears to interact with distinct binding sites (Karlsson et al., 1988). The relationship of these binding sites to antitussive actions is not known; however, these observations, coupled with the ability of naloxone to antagonize the antitussive effects of codeine but not those of dextromethorphan, indicate that cough suppression can be achieved by a number of different mechanisms.

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 because the substitution at the 3-position is not removed by metabolism. Pholcodine is at least as effective as codeine as an antitussive; it has a long t_1/2 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 three times daily; doses as high as 600 mg daily have been used safely.

Though they have important therapeutic uses, epidural and intrathecal opioids have their own dose-dependent side effects, such as pruritis, 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 hours after a bolus dose. While the risk of delayed respiratory depression is reduced with more lipophilic opioids, it is not eliminated. Extreme vigilance and appropriate monitoring are required for all opioid-naïve patients receiving intraspinal narcotics. 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 (Shnider and Levinson, 1987). Many opioids and other adjuvants are commonly used for neuraxial administration in adults and children; however, the majority of agents employed have not undergone appropriate preclinical safety evaluation and approval for these clinical indications; thus, such uses are "off-label". Thus, at this time, those agents approved for spinal delivery are certain preservative-free formulations of morphine sulfate (duramorph, depodur, others) and sufentanil (sufenta). It is important to remember that 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 and safety by another route (e.g., PO, IV) may not translate to safety after spinal delivery (Yaksh and Allen, 2004).

Patients on chronic spinal opioid therapy are less likely to experience respiratory depression. Selected patients who fail conservative therapies for chronic pain may receive intraspinal opioids chronically through an implanted programmable pump.

Analogous to the relationship between systemic opioids and NSAIDs, intraspinal narcotics often are combined with other agents that include local anesthetics, N-type Ca²⁺ channel blockers (e.g., ziconotide), α₂ adrenergic agonists, and GABA_B agonists. This permits synergy between drugs with different mechanisms allowing the use of lower concentrations of both agents, minimizing side-effects and the opioid-induced complications (Wallace and Yaksh, 2000).

Local Drug Action

Opioid receptors on peripheral sensory nerves respond to locally applied opioids during inflammation (Stein, 1993). Peripheral analgesia permits the use of lower doses, applied locally, than those necessary to achieve a systemic effect. The pain relief generated by this route of delivery is limited but the technique has been demonstrated to have some efficacy in postoperative pain (Stein, 1993). Development of such compounds and expansion of clinical applications of this technique are active areas of research.

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 minutes. In the U.S., only morphine and hydromorphone are available in rectal suppository formulations.

Inhalation

Opioids can be delivered by nebulizer. However, this delivery method is rarely used due to erratic absorption from the lung and highly variable therapeutic effect.

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) have been approved for the treatment of cancer pain; in this setting, transmucosal fentanyl relieves pain within 15 minutes, and patients easily can titrate the appropriate dose. A buccal fentanyl "film" is FDA-approved for the treatment of cancer pain (onsolis). The film is applied to the buccal mucosa and slowly dissolves releasing the fentanyl to cross the mucosa into the bloodstream. A New Drug Application has been filed with the FDA for a sublingual tablet (abstral, formerly rapinyl). Transmucosal fentanyl also has been studied as a premedicant for children; however, this technique has been largely abandoned owing to undesirable side effects such as respiratory depression, sedation, nausea, vomiting, and pruritus.

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 minutes of delivery (Kress et al., 2009).

Transdermal and Iontophoretic 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. Unlike other transdermal systems (i.e., transdermal scopolamine), anatomic position of the patch does not affect absorption. However, fever and external heat sources (heating pads, hot baths) can increase absorption of fentanyl and potentially lead to an overdose (Rose et al., 1993). This modality is well suited for cancer pain treatment because of its ease of use, prolonged duration of action, and stable blood levels (Portenoy et al., 1993). It may take up to 12 hours to develop analgesia and up to 16 hours to observe full clinical effect. Plasma levels stabilize after two sequential patch applications, and the kinetics do not appear to change with repeated applications (Portenoy et al., 1993). However, there may be a great deal of variability in plasma levels after a given dose. The plasma t_1/2 after patch removal is ~17 hours. 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.

Iontophoresis is the transport of soluble ions through the skin by using a mild electric current. This technique has been employed with morphine (Ashburn et al., 1992). Unlike transdermal opioids, a drug reservoir does not build up in the skin, thus limiting the duration of both desired and undesired effects. Patient-controlled iontophoretic transdermal fentanyl systems have been developed, but none is currently marketed.

Pain Intensity. Increased pain intensity may require titrating doses to produce acceptable analgesia with tolerable side effects.

Type of Pain State. Systems underlying a pain state may be broadly categorized as being mediated by events secondary to injury and inflammation and by injury to the sensory afferent or nervous system. Neuropathic conditions may be less efficaciously managed by opiates than pain secondary to tissue injury and inflammation. Such pain states are more efficiently managed by combination treatment modalities.

Acuity and Chronicity of Pain. The pain state in any given clinical condition is not typically constant and will vary over time. In chronic pain states, the daily course of the pain may fluctuate, e.g., being greater in the morning hours or upon awakening. Arthritic states display flares that are associated with an exacerbated pain condition. Changes in the magnitude of pain occur during the daily routine resulting in "breakthrough pain" during episodic events such as dressing changes (incident pain). These examples emphasize the need for individualized management of increased or decreased pain levels with baseline analgesic dosing supplemented with the use of short-acting "rescue" medications as required. In the face of ongoing severe pain, analgesics should be dosed in continuous or "around-the-clock" fashion rather than on an as-needed basis. This provides more consistent analgesic levels and avoids unnecessary suffering (Vashi et al., 2005).

Opioid Tolerance. Chronic exposure to one opiate agonist typically leads to a reduction in the efficacy of other opiate agonists. The degree of tolerance can be remarkable. For example, 10 mg of an oral opioid (such as morphine) is considered a high dose for a treatment-naïve individual whereas 100 mg IV may produce only minor sedation in severely tolerant individual.

Patient Physical State and Genetic Variables. Codeine, hydrocodone, and oxycodone are weak analgesic prodrugs that are metabolized into the much more effective analgesic drugs morphine, hydromorphone, and oxymorphone, respectively, by CYP2D6 (Supernaw, 2001). The analgesic properties of morphine, hydromorphone, oxymorphone, propoxyphene, and fentanyl are largely due to their direct influence on opioid receptors and do not require additional metabolism, although the first metabolite of propoxyphene, norpropoxyphene, is also an effective analgesic with a very long t_1/2. CYP2D6 activity is genetically diminished in 7% of whites, 3% of blacks, and 1% of Asians (Eichelbaum and Gross, 1990); rendering oxycodone, hydrocodone, and codeine relatively ineffective analgesics in these "poor metabolizers" and potentially toxic for "ultra-rapid" metabolizers.

The activity of CYP2D6 is inhibited by selective serotonin reuptake inhibitors, including fluoxetine, fluvoxamine, paroxetine, sertraline, and bupropion, medications that are commonly administered to pain patients. The CYP2D6 inhibition resulting from these interacting medications may render opioids less effective as analgesics in some patients. Whereas diminished activity of the CYP2D6 isoenzyme will lead to less efficacy of prodrug opioids, the opposite occurs with methadone. Although methadone is primarily metabolized through the CYP3A4 isoenzyme, genetic polymorphisms involving deficiencies in the CYP2C9, CYP2CI9, and CYP2D6 isoenzymes may lead to surprisingly high methadone plasma concentrations resulting in overdose.

Opioids are highly protein bound and factors such as plasma pH may dramatically change binding. In addition, α₁-acid glycoprotein (AAG) is an acute-phase reactant protein that is elevated in cancer patients and has a high affinity for basic drugs such as methadone and meperidine. Morphine and meperidine should be avoided in patients with renal impairment since morphine-6-glucuronide (a metabolite of morphine) and normeperidine (a metabolite of meperidine) are excreted by the kidney and will accumulate and lead to toxicity. Other states that may increase the risk of adverse effects of the opioids include chronic obstructive pulmonary disease, sleep apnea, dementia, benign prostratic hypertrophy, unstable gait, and pretreatment constipation.

Routes of Administration Available. The aim in chronic pain states is to prefer to employ the least invasive routes of drug administration, which include oral, buccal, or transdermal delivery. IV routes are more useful in perioperative in-hospital pain management and during end-of-life care. Patients with chronic pain states where side effects from systemic drug exposure are intolerable and are candidates for spinal drug delivery; however, this may require surgery for indwellng catheterization and pump placement.

Dose Selection/Titration. The conservative approach to the initiation of chronic opioid therapy suggests starting with low doses that may be incremented on the basis of the pharmacokinetics of the drug. In chronic pain states, the aim would be the use of long-acting medications to permit once or twice daily dosing (e.g., controlled release formulations or methadone). Such agents reach steady-state slowly. Rapid incrementation is to be avoided and rescue medication should be made available for breakthrough pain during initial dosing titration.

Opiate Rotation. Opioid rotation is the practice of changing to a different opioid when the patient either fails to achieve benefit or side effects are reached before analgesia is sufficient. In a retrospective review, it was found that the first opioid prescribed was effective for 36% of patients, was stopped because of side effects in 30%, and was stopped for ineffectiveness in 34% (Quang-Cantagrel et al., 2000). Of the remaining patients, the second opioid prescribed after the failure of the first was effective in 31%, the third in 40%, the fourth in 56%, and the fifth in 14%. Thus, if it is necessary to change the opioid prescription because of intolerable side effects or ineffectiveness, the cumulative percentage of efficacy increases with each new opioid tested. Failure or intolerance of one opioid cannot necessarily predict the patient's response or acceptance to another. Practically, opioid rotation involves incrementing the dose of a given opioid, e.g. morphine, to one limited by side-effect and insufficient analgesia. At this point an alternate opioid medication at an equieffective dose may be substituted for the first medication. Agents typically involved in such rotation sequences are various oral opioids such as morphine, methadone, dilaudid, and oxycodone and the fentanyl patch systems. Care must be taken to titrate the doses and monitor the patient closely during such drug transitions.

Combination Therapy. In general, the use of combinations of drugs with the same pharmacological kinetic profile is not warranted (e.g., morphine plus methadone). Nor if the drugs have overlapping targets and opposing effects (e.g., combining a MOR agonist with an agent having mixed agonist/antagonist properties). On the other hand, 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, it is routinely recommended that opioids be combined with other analgesic agents, such as NSAIDs or acetaminophen. In this way, one can take advantage of the analgesic effects produced by the adjuvant and minimize the dose requirement of the opioid. In some situations, NSAIDs can provide analgesia equal to that produced by 60 mg codeine. The analgesic synergism between opioids and aspirin-like drugs is discussed below and in Chapter 34. 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. Different classes of drug may have distinguishable efficacy in different models of pain processing (Table 18–8).

The "opioid-sparing" strategy is the backbone of the "analgesic ladder" for pain management proposed by the World Health Organization. Weaker opioids can be supplanted by stronger opioids in cases of moderate and severe pain. Antidepressants such as duloxetine and amitriptyline are used in the treatment of chronic neuropathic pain but have limited intrinsic analgesic actions in acute pain. However, antidepressants may enhance morphine-induced analgesia (Levine et al., 1986).

Dyspnea

Morphine is used to alleviate the dyspnea of acute left ventricular failure and pulmonary edema, and the response to intravenous 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 (Hoffman and Reynolds, 1987). 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 (Johnson et al., 1983). 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 opioids as the primary anesthetic agent, it is important to use 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.

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. As respiratory exchange decreases, blood pressure, at first likely to be near normal, will fall progressively. 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. Noncardiogenic pulmonary edema is seen commonly with opioid poisoning. It probably is not due to contaminants or to anaphylactic reactions, and it has been observed after toxic doses of morphine, methadone, propoxyphene, and pure heroin.

The triad of coma, pinpoint pupils, and depressed respiration strongly suggests opioid poisoning. The finding of needle marks suggestive of addiction further supports the diagnosis. Mixed poisonings, however, are not uncommon. Examination of the urine and gastric contents for drugs may aid in diagnosis, but the results usually become available too late to influence treatment.

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 hours, and fatalities have occurred as a result of premature discontinuation of naloxone. In cases of overdoses of these drugs, a continuous infusion of naloxone should be considered. Toxicity owing to overdose of pentazocine and other opioids with mixed actions may require higher doses of naloxone.