Opioid Analgesics

Opioids have been the mainstay of pain treatment for thousands of years, and remain so today. Opioids exert their therapeutic effects by mimicking the action of endogenous opioid peptides at opioid receptors. Effects on both local neurons and intrinsic pain-modulating circuitry lead to analgesia, other therapeutic effects, and also to undesirable side effects. This chapter will provide the background necessary to understand the mechanisms of action and important pharmacological properties of clinically used opioids. First, the endogenous opioid system is discussed with a focus on the receptors and circuitry utilized by the opioids. A discussion of clinically used compounds follows, describing in detail their pharmacological properties and therapeutic uses. Routes of administration, pain treatment strategies, and current therapeutic guidelines also are presented. This information should provide a rational basis for understanding opioid actions, thereby reducing fear of opioid use and encouraging effective treatment of pain.

It is now well known that opioids such as heroin and morphine exert their effects by mimicking naturally occurring substances, termed endogenous opioid peptides or endorphins. Much now is known about the basic biology of the endogenous opioid system and its molecular and biochemical complexity, widespread anatomy, and diversity. The diverse functions of this system include the best-known sensory role, prominent in inhibiting responses to painful stimuli; a modulatory role in gastrointestinal, endocrine, and autonomic functions; an emotional role, evident in the powerful rewarding and addicting properties of opioids; and a cognitive role in the modulation of learning and memory. The endogenous opioid system is complex and subtle, with a great diversity in endogenous ligands (over a dozen), yet with only four major receptor types. This chapter presents key facts about the biochemical and functional nature of the opioid system. This information then is used to establish a basis for understanding the actions of clinically used opioid drugs and current strategies for pain treatment.

Terminology

The term opioid refers broadly to all compounds related to opium. The word opium is derived from opos, the Greek word for juice, the drug being derived from the juice of the opium poppy, Papaver somniferum. Opiates are drugs derived from opium, and include the natural products morphine, codeine, thebaine, and many semisynthetic congeners derived from them. Endogenous opioid peptides are the naturally occurring ligands for opioid receptors. The term endorphin is used synonymously with endogenous opioid peptides, but also refers to a specific endogenous opioid, -endorphin. The term narcotic was derived from the Greek word for stupor. At one time, the term referred to any drug that induced sleep, but then it became associated with opioids. It often is used in a legal context to refer to a variety of substances with abuse or addictive potential.

History

The first undisputed reference to opium is found in the writings of Theophrastus in the third century B.C. Arabian physicians were well versed in the uses of opium; Arabian traders introduced the drug to the Orient, where it was employed mainly for the control of dysenteries. During the Middle Ages, many of the uses of opium were appreciated. In 1680, Sydenham wrote: '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 more than 20 distinct alkaloids. In 1806, Sertrner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. The discovery of other alkaloids in opium quickly followedcodeine by Robiquet in 1832, and papaverine by Merck in 1848. By the middle of the nineteenth century, the use of pure alkaloids rather than crude opium preparations began to spread throughout the medical world.

In addition to the remarkable beneficial effects of opioids, the toxic side effects and addictive potential of these drugs also have been known for centuries. These problems stimulated a search for potent, synthetic opioid analgesics free of addictive potential and other side effects. Unfortunately, all of the synthetic compounds that have been introduced into clinical use share the liabilities of classical opioids. However, the 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 endogenous opioid system was totally unknown. The actions of morphine, heroin, and other opioids as antinociceptive and addictive agents, while well described, often were studied in the context of interactions with other neurotransmitter systems, such as monoaminergic and cholinergic. Some investigators suggested the existence of a specific opioid receptor because of the unique structural requirements of opiate ligands (Beckett and Casy, 1954), but the presence of an opiate-like system in the brain remained unproven. A particularly misleading observation was that the administration of the opioid antagonist naloxone to a normal animal produced little effect, although the drug was effective in reversing or preventing the effects of exogenous opiates. The first physiological evidence suggesting an endogenous opioid system was the demonstration that analgesia produced by electrical stimulation of certain brain regions was reversed by naloxone (Akil et al., 1972; Akil et al., 1976). Pharmacological evidence for an opiate receptor also was building. In 1973, investigators in three laboratories demonstrated opiate binding sites in the brain (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973). This was the first use of radioligand binding assays to demonstrate the presence of membrane-associated neurotransmitter receptors in the brain.

Stimulation-produced analgesia, its naloxone reversibility, and the discovery of opioid receptors strongly pointed to the existence of endogenous opioids. In 1975, Hughes and associates identified an endogenous, opiate-like factor that they called enkephalin (from the head) (Hughes et al., 1975). Soon after, two more classes of endogenous opioid peptides were isolated, the dynorphins and endorphins. Details of these discoveries and the unique properties of the opioid peptides have been reviewed previously (Akil et al., 1984).

Given the large number of endogenous ligands being discovered, it was not surprising that multiple classes of opioid receptors also were found. The concept of opioid-receptor multiplicity arose shortly after the initial demonstration of opiate binding sites. Based on results of in vivo studies in dogs, Martin and colleagues postulated the existence of multiple types of opiate receptors (Martin et al., 1976). Receptor-binding studies and subsequent cloning confirmed the existence of three main receptor types, , and . A fourth member of the opioid peptide receptor family, the nociceptin/orphanin FQ (N/OFQ) receptor, was cloned in 1994 (Bunzow et al., 1994; Mollereau et al., 1994). In addition to these four major classes, a number of subtypes have been proposed, such as epsilon, often based on bioassays from different species (Schulz et al., 1979); iota (Oka, 1980); lambda (Grevel and Sadee, 1983); and zeta (Zagon et al., 1989). In 2000, the Committee on Receptor Nomenclature and Drug Classification of the International Union of Pharmacology adopted the terms MOP, DOP, and KOP to indicate -, and -opioid peptide receptors, respectively. The original Greek letter designation is used in this and other chapters. The Committee also recommended the term NOP for the N/OFQ receptor.

Morphine and most other clinically used opioid agonists exert their effects through opioid receptors. These drugs affect a wide range of physiological systems. They produce analgesia, affect mood and rewarding behavior (see also Chapter 24: Drug Addiction and Drug Abuse), and alter respiratory, cardiovascular, gastrointestinal, and neuroendocrine function. -Opioid receptor agonists also are potent analgesics in animals, and in isolated cases have proved useful in human beings (Coombs et al., 1985). The main barrier to the clinical use of agonists is that most of the available agents are peptides and do not cross the bloodbrain barrier, thus requiring intraspinal administration. However, much effort currently is being devoted to the development of clinically useful agonists. -Selective agonists produce analgesia that has been shown in animals to be mediated primarily at spinal sites. Respiratory depression and miosis may be less severe with agonists. Instead of euphoria, -receptor agonists produce dysphoric and psychotomimetic effects (Pfeiffer et al., 1986). In neural circuitry mediating both reward and analgesia, and agonists have been shown to have antagonistic effects (see below).

Mixed agonist-antagonist compounds were developed for clinical use with the hope that they would have less addictive potential and less respiratory depression than morphine and related drugs. In practice, however, it has turned out that for the same degree of analgesia, the same intensity of side effects will occur. (American Pain Society, 1999). A 'ceiling effect,' limiting the amount of analgesia attainable, often is seen with these drugs. Some mixed agonist-antagonist drugs, such as pentazocine and nalorphine, can produce severe psychotomimetic effects that are not reversible with naloxone (suggesting that these undesirable side effects are not mediated through classical opioid receptors). Also, pentazocine and nalorphine can precipitate withdrawal in opioid-tolerant patients. For these reasons, the clinical use of these mixed agonist-antagonist drugs is limited.

Analgesia

In human beings, morphine-like drugs produce analgesia, drowsiness, changes in mood, and mental clouding. A significant feature of the analgesia is that it occurs without loss of consciousness. When therapeutic doses of morphine are given to patients with pain, they report that the pain is less intense, less discomforting, or entirely gone; drowsiness commonly occurs. In addition to relief of distress, some patients experience euphoria.

When morphine in the same dose is given to a normal, pain-free individual, the experience may be unpleasant. Nausea is common, and vomiting also may occur. There may be feelings of drowsiness, difficulty in mentation, apathy, and lessened physical activity. As the dose is increased, the subjective, analgesic, and toxic effects, including respiratory depression, become more pronounced. Morphine does not have anticonvulsant activity and usually does not cause slurred speech, emotional lability, or significant motor incoordination.

The relief of pain by morphine-like opioids is relatively selective, in that other sensory modalities are not affected. Patients frequently report that the pain is still present, but that they feel more comfortable (see section on Therapeutic Uses of Opioid Analgesics). Continuous, dull pain is relieved more effectively than sharp, intermittent pain, but with sufficient amounts of opioid it is possible to relieve even the severe pain associated with renal or biliary colic.

Any meaningful discussion of the action of analgesic agents must include some distinction between pain as a specific sensation, subserved by distinct neurophysiological structures, and pain as suffering (the original sensation plus the reactions evoked by the sensation). It is generally agreed that all types of painful experiences, whether produced experimentally or occurring clinically as a result of pathology, include both the original sensation and the reaction to that sensation. It also is important to distinguish between pain caused by stimulation of nociceptive receptors and transmitted over intact neural pathways (nociceptive pain) and pain that is caused by damage to neural structures, often involving neural supersensitivity (neuropathic pain). Although nociceptive pain usually is responsive to opioid analgesics, neuropathic pain typically responds poorly to opioid analgesics and may require higher doses of drug (McQuay, 1988).

In clinical situations, pain cannot be terminated at will, and the meaning of the sensation and the distress it engenders are markedly affected by the individual's previous experiences and current expectations. In experimentally produced pain, measurements of the effects of morphine on pain threshold have not always been consistent; some workers find that opioids reliably elevate the threshold, while many others do not obtain consistent changes. In contrast, moderate doses of morphine-like analgesics are effective in relieving clinical pain and increasing the capacity to tolerate experimentally induced pain. Not only is the sensation of pain altered by opioid analgesics, but the affective response is changed as well. This latter effect is best assessed by asking patients with clinical pain about the degree of relief produced by the drug administered. 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. Intrathecal administration of opioids can produce profound segmental analgesia without causing significant alteration of motor or sensory function or subjective effects (Yaksh, 1988).

Mechanisms and Sites of Opioid-Induced Analgesia

While cellular and molecular studies of opioid receptors are invaluable in understanding their function, it is critical to place them in their anatomical and physiological context to fully understand the opioid system. Pain control by opioids needs to be considered in the context of brain circuits modulating analgesia and the functions of the various receptor types in these circuits. Excellent reviews of this topic are available (Fields et al., 1991; Harris, 1996).

It has been well established that the analgesic effects of opioids arise from their ability to inhibit directly the ascending transmission of nociceptive information from the spinal cord dorsal horn and to activate pain control circuits that descend from the midbrain, via the rostral ventromedial medulla, to the spinal cord dorsal horn. Opioid peptides and their receptors are found throughout these descending pain control circuits (Mansour et al., 1995; Gutstein et al., 1998). -Opioid receptor mRNA and/or ligand binding is seen throughout the periaqueductal grey (PAG), pontine retricular formation, median raphe, nucleus raphe magnus, and adjacent gigantocellular reticular nucleus in the rostral ventromedial medulla (RVM) and spinal cord. Evaluation of discrepancies between levels of ligand binding and mRNA expression provides important insights into the mechanisms of -opioid receptor-mediated analgesia. For instance, the presence of significant -opioid receptor ligand binding in the superficial dorsal horn but scarcity of mRNA expression (Mansour et al., 1995) suggests that the majority of these spinal -receptor ligand binding sites are located presynaptically on the terminals of primary afferent nociceptors. This conclusion is consistent with the high levels of -opioid receptor mRNA observed in dorsal root ganglia (DRG). A similar mismatch between -receptor ligand binding and mRNA expression is seen in the dorsolateral PAG (a high level of binding and sparse mRNA) (Gutstein et al., 1998). -Opioid receptor mRNA and ligand binding have been demonstrated in the ventral and ventrolateral quadrants of the PAG, the pontine reticular formation, and the gigantocellular reticular nucleus, but only low levels are seen in the median raphe and nucleus raphe magnus. As with the -opioid receptor, there are significant numbers of -opioid receptor binding sites in the dorsal horn but no detectable mRNA expression, suggesting an important role for presynaptic actions of the -opioid receptor in spinal analgesia. -Opioid receptor mRNA and ligand binding are widespread throughout the PAG, pontine reticular formation, median raphe, nucleus raphe magnus and adjacent gigantocellular reticular nucleus. Again, -receptor ligand binding but minimal mRNA have been found in the dorsal horn. Although all three receptor mRNAs are found in the DRG, they are localized on different types of primary afferent cells. -Opioid receptor mRNA is present in medium and large diameter DRG cells, -opioid receptor mRNA in large diameter cells, and -opioid receptor mRNA in small and medium diameter cells (Mansour et al., 1995). This differential localization might be linked to functional differences in pain modulation.

The distribution of opioid receptors in descending pain control circuits indicates substantial overlap between and receptors. Receptors and receptors are most anatomically distinct from the -opioid receptor in the PAG, median raphe, and nucleus raphe magnus (Gutstein et al., 1998). A similar differentiation of and receptors from is seen in the thalamus, suggesting that interactions between the receptor and the receptor may be important for modulating nociceptive transmission from higher nociceptive centers as well as in the spinal cord dorsal horn. The actions of -receptor agonists are invariably analgesic, whereas those of -receptor agonists can be either analgesic or antianalgesic. Consistent with the anatomical overlap between the and receptors, the antianalgesic actions of the -receptor agonists appear to be mediated by functional antagonism of the actions of -receptor agonists. The receptor produces analgesia within descending pain control circuits, at least in part, by the removal of GABAergic inhibition of RVM-projecting neurons in the PAG and spinally projecting neurons in the RVM (Fields et al., 1991). The pain-modulating effects of the -receptor agonists in the brainstem appear to oppose those of -receptor agonists. Application of a -opioid agonist hyperpolarizes the same RVM neurons that are depolarized by a -opioid agonist, and microinjections of a -receptor agonist into the RVM antagonize the analgesia produced by microinjections of agonists into this region (Pan et al., 1997). This is the strongest evidence to date demonstrating that opioids can have antianalgesic as well as analgesic effects. This finding may explain behavioral evidence for a reduction in hyperalgesia that follows injections of naloxone under certain circumstances.

As mentioned above, there is significant opioid-receptor ligand binding, and little detectable receptor mRNA expression in the spinal cord dorsal horn, but high levels of opioid-receptor mRNA in DRG. This distribution might suggest that the actions of opioid-receptor agonists relevant to analgesia at the spinal level are predominantly presynaptic. At least one presynaptic mechanism with potential clinical significance is inhibition of spinal tachykinin signaling. It is well known that opioids decrease the pain-evoked release of tachykinins from primary afferent nociceptors (Jessell and Iversen, 1977; Yaksh et al., 1980). Recently, the significance of this effect has been questioned. Trafton et al. (1999) have demonstrated that at least 80% of tachykinin signaling in response to noxious stimulation remains intact after the intrathecal administration of large doses of opioids. These results suggest that, while opioid administration may reduce tachykinin release from primary afferent nociceptors, this reduction has little functional impact on the actions of tachykinins on postsynaptic pain-transmitting neurons. This implies that either tachykinins are not central to pain signaling and/or opioid-induced analgesia at the spinal level or that, contrary to the conclusions suggested by anatomical studies, presynaptic opioid actions may be of little analgesic significance.

Just as important insights have been made into mechanisms of opioid-induced analgesia at the brainstem and spinal levels, progress also has been made in understanding forebrain mechanisms. It is well known that the actions of opioids in bulbospinal pathways are critical to their analgesic efficacy. The precise role of forebrain actions of opioids and whether or not these actions are independent of those in bulbospinal pathways are less well defined. It is clear that opioid actions in the forebrain contribute to analgesia, because decerebration prevents analgesia when rats are tested for pain sensitivity using the formalin test (Matthies and Franklin, 1992), and microinjection of opioids into several forebrain regions are analgesic in this test (Manning et al., 1994). However, because these manipulations frequently do not change the analgesic efficacy of opioids in measures of acute phasic nociception, such as the tailflick test, a distinction has been made between forebrain-dependent mechanisms for morphine-induced analgesia in the presence of tissue injury and bulbospinal mechanisms for this analgesia in the absence of tissue injury. In an important series of experiments, Manning and Mayer (1995a; 1995b) have shown that this distinction is not absolute. Analgesia induced by systemic administration of morphine in both the tailflick and formalin tests was disrupted either by lesioning or reversibly inactivating the central nucleus of the amygdala, demonstrating that opioid actions in the forebrain contribute to analgesia in measures of tissue damage as well as acute, phasic nociception. The involvement of the amygdala in analgesia is intriguing, as the amygdala has been implicated in the environmental activation of pain control circuits, and it projects extensively to brainstem regions involved in descending pain control (Manning and Mayer, 1995a; 1995b).

Simultaneous administration of morphine at both spinal and supraspinal sites results in synergy in analgesic response, with a tenfold reduction in the total dose of morphine necessary to produce equivalent analgesia at either site alone. The mechanisms responsible for spinal/supraspinal synergy are readily distinguished from those involved with supraspinal analgesia (Pick et al., 1992a). In addition to the well-described spinal/supraspinal synergy, synergistic - and -agonist interactions also have been observed within the brainstem between the periaqueductal gray, locus coeruleus, and nucleus raphe magnus (Rossi et al., 1993).

Opioids also can produce analgesia when administered peripherally. Opioid receptors are present on peripheral nerves (Fields et al., 1980) and will respond to peripherally applied opioids and locally released endogenous opioid compounds when 'up-regulated' during inflammatory pain states (Stein et al., 1991; Stein, 1993). During inflammation, immune cells capable of releasing endogenous opioids are present near sensory nerves, and a perineural defect allows opioids access to the nerves (Stein, 1993; Stein, 1995). It appears that this also may occur in neuropathic pain models (Kayser et al., 1995), perhaps because of the presence of immune cells near damaged nerves (Monaco et al., 1992) and perineural defects extant in these conditions.

The Role of N/OFQ and Its Receptor in Pain Modulation

N/OFQ mRNA and peptide are present throughout descending pain control circuits. For instance, N/OFQ-containing neurons are present in the PAG, the median raphe, throughout the RVM, and in the superficial dorsal horn (Neal et al., 1999b). This distribution overlaps with that of opioid peptides, but the extent of colocalization remains unclear. N/OFQ-receptor ligand binding and mRNA are seen in the PAG, median raphe, and RVM (Neal et al., 1999a). Spinally, there is stronger N/OFQ-receptor mRNA expression in the ventral horn than in the dorsal horn, but higher levels of ligand binding in the dorsal horn. There also are high N/OFQ-receptor mRNA levels in the DRG.

Despite clear anatomical evidence for a role of the N/OFQ system in pain modulation, its function remains unclear. Targeted disruption of the N/OFQ receptor in mice had little effect on basal pain sensitivity in several measures, whereas targeted disruption of the N/OFQ precursor consistently elevated basal responses in the tailflick test, suggesting an important role for N/OFQ in regulating basal pain sensitivity (Nishi et al., 1997; Koster et al., 1999). Intratheca1 injections of N/OFQ have been shown to be analgesic (Yamamoto et al., 1997; Xu et al., 1996); however, supraspinal administration has produced either hyperalgesia, antiopioid effects, or a biphasic hyperalgesic/analgesic response (Rossi et al., 1996b, Rossi et al., 1997; Grisel et al., 1996). These conflicting findings may be explained in part by a study in which it was shown that N/OFQ inhibits both pain-facilitating and analgesia-facilitating neurons in the RVM (Pan et al., 2000). Activation of endogenous analgesic circuitry was blocked by administration of N/OFQ. If the animal was hyperalgesic, the enhanced pain sensitivity also was blocked by N/OFQ. Thus, the effects of N/OFQ on pain responses appear to depend on the preexisting state of pain in the animal.

Mood Alterations and Rewarding Properties

The mechanisms by which opioids produce euphoria, tranquility, and other alterations of mood (including rewarding properties) are not entirely clear. However, the neural systems that mediate opioid reinforcement are distinct from those involved in physical dependence and analgesia (Koob and Bloom, 1988). Behavioral and pharmacological evidence points to the role of dopaminergic pathways, particularly involving the nucleus accumbens (NAcc), in drug-induced reward. There is ample evidence for interactions between opioids and dopamine in mediating opioid-induced reward.

A full appreciation of mechanisms of drug-induced reward requires a more complete understanding of the NAcc and related structures at the anatomical level as well as a careful examination of the interface between the opioid system and dopamine receptors. The NAcc, portions of the olfactory tubercle, and the ventral and medial portions of the caudate-putamen constitute an area referred to as the ventral striatum (Heimer et al., 1982). The ventral striatum is implicated in motivation and affect (limbic functions), while the dorsal striatum is involved in sensorimotor and cognitive functions (Willner et al., 1991). Both the dorsal and ventral striatum are heterogeneous structures that can be subdivided into distinct compartments. In the middle and caudal third of the NAcc, the characteristic distribution of neuroactive substances results in two unique compartments termed the core and the shell (Zahm and Heimer, 1988; Heimer et al., 1991). It is important to note that other reward-relevant brain regions (e.g., the lateral hypothalamus and medial prefrontal cortex) implicated with a variety of abused drugs are connected reciprocally to the shell of the NAcc. Thus, the shell of the NAcc is the site that may be involved directly in the emotional and motivational aspects of drug-induced reward.

Prodynorphin- and proenkephalin-derived opioid peptides are expressed primarily in output neurons of the striatum and NAcc. All three opioid receptor types are present in the NAcc (Mansour et al., 1988) and are thought to mediate, at least in part, the motivational effects of opiate drugs. Selective - and -receptor agonists are rewarding when defined by place preference (Shippenberg et al., 1992) and intracranial self-administration (Devine and Wise, 1994) paradigms. Conversely, selective -receptor agonists produce aversive effects (Cooper, 1991; Shippenberg et al., 1992). Naloxone and selective antagonists also produce aversive effects (Cooper, 1991). Positive motivational effects of opioids are partially mediated by dopamine release at the level of the NAcc. Thus, -receptor activation in these circuits inhibits dopamine release (Mulder et al., 1991; Mulder and Schoffelmeer, 1993), while - and -receptor activation increases dopamine release (Chesselet et al., 1983; Devine et al., 1993). Distinctive cell clusters in the shell of the accumbens contain proenkephalin, prodynorphin, receptors, and receptors as well as dopamine receptors. These clusters possibly could be a region where the motivational properties of dopaminergic and opioid drugs are processed. The potential role of these structures and the neural circuits in which they are embedded in the rewarding effects of opioids will be of great interest.

The locus ceruleus (LC) contains both noradrenergic neurons and high concentrations of opioid receptors and is postulated to play a critical role in feelings of alarm, panic, fear, and anxiety. Neural activity in the LC is inhibited by both exogenous opioids and endogenous opioid-like peptides.

Other CNS Effects

While opioids are used clinically primarily for their pain-relieving properties, they produce a host of other effects. This is not surprising in view of the wide distribution of opioids and their receptors, both in the brain and in the periphery. A brief summary of some of these effects is presented below. High doses of opioids can produce muscular rigidity in human beings. Chest wall rigidity severe enough to compromise respiration is not uncommon during anesthesia with fentanyl, alfentanil, remifentanil, and sufentanil (see Monk et al., 1988). Opioids and endogenous peptides cause catalepsy, circling, and stereotypical behavior in rats and other animals.

Effects on the Hypothalamus

Opioids alter the equilibrium point of the hypothalamic heat-regulatory mechanisms, such that body temperature usually falls slightly. However, chronic high dosage may increase body temperature (see Martin, 1983).

Neuroendocrine Effects

Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and -endorphin; the last two peptides usually are released simultaneously from corticotropes in the pituitary. As a result of the decreased concentrations of pituitary trophic hormones, the concentrations of testosterone and cortisol in plasma decline. Secretion of thyrotropin is relatively unaffected.

The administration of agonists increases the concentration of prolactin in plasma, probably by reducing the dopaminergic inhibition of its secretion. Although some opioids enhance the secretion of growth hormone, the administration of morphine or -endorphin has little effect on the concentration of the hormone in plasma. With chronic administration, tolerance develops to the effects of morphine on hypothalamic releasing factors. Observations in patients maintained on methadone reflect this phenomenon; in women, menstrual cycles that had been disrupted by intermittent use of heroin return to normal; in men, circulating concentrations of LH and testosterone are usually within the normal range.

Although -receptor agonists inhibit the release of antidiuretic hormone and cause diuresis, the administration of -opioid agonists tends to produce antidiuretic effects in human beings. The effects of opioids on neuroendocrine function have been reviewed by (Howlett and Rees, 1986) and by (Grossman, 1988).

Miosis

Morphine and most and agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. Following toxic doses of agonists, the miosis is marked and pinpoint pupils are pathognomonic; however, marked mydriasis occurs when asphyxia intervenes. Some tolerance to the miotic effect develops, but addicts with high circulating concentrations of opioids continue to have constricted pupils. Therapeutic doses of morphine increase accommodative power and lower intraocular tension in both normal and glaucomatous eyes.

Convulsions

In animals, high doses of morphine and related opioids produce convulsions. Several mechanisms appear to be involved, and different types of opioids produce seizures with different characteristics. Morphine-like drugs excite certain groups of neurons, especially hippocampal pyramidal cells; these excitatory effects probably result from inhibition of the release of GABA by interneurons (see McGinty and Friedman, 1988). Selective agonists produce similar effects. These actions may contribute to the seizures that are produced by some agents at doses only moderately higher than those required for analgesia, especially in children. However, with most opioids, convulsions occur only at doses far in excess of those required to produce profound analgesia, and seizures are not seen when potent agonists are used to produce anesthesia. Naloxone is more potent in antagonizing convulsions produced by some opioids (e.g., morphine, methadone, and propoxyphene) than those produced by others (e.g., meperidine). The production of convulsant metabolites of the latter agent may be partially responsible (see below). Anticonvulsant agents may not always be effective in suppressing opioid-induced seizures.

Respiration

Morphine-like opioids depress respiration, at least in part by virtue of a direct effect on the brainstem respiratory centers. The respiratory depression is discernible even with doses too small to disturb consciousness and increases progressively as the dose is increased. In human beings, death from morphine poisoning is nearly always due to respiratory arrest. Therapeutic doses of morphine in human beings depress all phases of respiratory activity (rate, minute volume, and tidal exchange) and also may produce irregular and periodic breathing. The diminished respiratory volume is due primarily to a slower rate of breathing, and with toxic amounts the rate may fall to 3 or 4 breaths per minute. Although effects on respiration are readily demonstrated, clinically significant respiratory depression rarely occurs with standard morphine doses in the absence of underlying pulmonary dysfunction. However, the combination of opioids with other medications, such as general anesthetics, tranquilizers, alcohol, or sedative-hypnotics, may present a greater risk of respiratory depression. Maximal respiratory depression occurs within 5 to 10 minutes after intravenous administration of morphine or within 30 or 90 minutes following intramuscular or subcutaneous administration, respectively.

Maximal respiratory depressant effects occur more rapidly with more lipid-soluble agents. Following therapeutic doses, respiratory minute volume may be reduced for as long as 4 to 5 hours. The primary mechanism of respiratory depression by opioids involves a reduction in the responsiveness of the brainstem respiratory centers to carbon dioxide. Opioids also depress the pontine and medullary centers involved in regulating respiratory rhythmicity and the responsiveness of medullary respiratory centers to electrical stimulation (see Martin, 1983).

Hypoxic stimulation of the chemoreceptors still may be effective when opioids have decreased the responsiveness to CO₂, and the inhalation of O₂ may thus produce apnea. After large doses of morphine or other agonists, patients will breathe if instructed to do so, but without such instruction they may remain relatively apneic.

Because of the accumulation of CO₂, respiratory rate and sometimes even minute volume can be unreliable indicators of the degree of respiratory depression that has been produced by morphine. Natural sleep also produces a decrease in the sensitivity of the medullary center to CO₂, and the effects of morphine and sleep are additive.

Numerous studies have compared morphine and morphine-like opioids with respect to their ratios of analgesic to respiratory-depressant activities. Most studies have found that, when equianalgesic doses are used, the degree of respiratory depression observed with morphine-like opioids is not significantly different from that seen with morphine. Severe respiratory depression is less likely after the administration of large doses of selective agonists. High concentrations of opioid receptors and of endogenous peptides are found in the medullary areas believed to be important in ventilatory control.

Cough

Morphine and related opioids also depress the cough reflex, at least in part by a direct effect on a cough center in the medulla. There is, however, no obligatory relationship between depression of respiration and depression of coughing, and effective antitussive agents are available that do not depress respiration (see below). Suppression of cough by such agents appears to involve receptors in the medulla that are less sensitive to naloxone than are those responsible for analgesia.

Nauseant and Emetic Effects

Nausea and vomiting produced by morphine-like drugs are unpleasant side effects caused by direct stimulation of the chemoreceptor trigger zone for emesis, in the area postrema of the medulla. Certain individuals never vomit after morphine, whereas others do so each time the drug is administered.

Nausea and vomiting are relatively uncommon in recumbent patients given therapeutic doses of morphine, but nausea occurs in approximately 40% and vomiting in 15% of ambulatory patients given 15 mg of the drug subcutaneously. This suggests that a vestibular component also is 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. 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. Drugs that are useful in motion sickness are sometimes helpful in reducing opioid-induced nausea in ambulatory patients; phenothiazines are also useful (see Chapter 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania).

Cardiovascular System

In the supine patient, therapeutic doses of morphine-like opioids have no major effect on blood pressure or cardiac rate and rhythm. Such doses do produce peripheral vasodilation, reduced peripheral resistance, and an inhibition of baroreceptor reflexes. Therefore, when supine patients assume the head-up position, orthostatic hypotension and fainting may occur. The peripheral arteriolar and venous dilation produced by morphine involves several mechanisms. Morphine and some other opioids provoke release of histamine, which sometimes plays a large role in the hypotension. However, vasodilation is usually only partially blocked by H₁ antagonists, but it is effectively reversed by naloxone. Morphine also blunts the reflex vasoconstriction caused by increased PCO

Effects on the myocardium are not significant in normal individuals. In patients with coronary artery disease but no acute medical problems, 8 to 15 mg of morphine administered intravenously produces a decrease in oxygen consumption, left ventricular end-diastolic pressure, and cardiac work; effects on cardiac index are usually slight (Sethna et al., 1982). 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 (see Roth et al., 1988).

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 oxygen 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 (Benson et al., 1999; McCleskey and Gold, 1999) or to a direct analgesic effect on nociceptive afferents from the heart.

When administered prior to 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 potassium channel in cardiac myocytes; the effect also is produced by other G protein-coupled receptors signaling through G_i subunits (Fryer et al., 2000; Liang and Gross, 1999; Schultz et al., 1996). It also has been suggested recently that opioids can be antiarrhythmic and antifibrillatory during and after periods of ischemia (Fryer et al., 2000). Other data, however, suggest that opioids can be arrythmogenic (McIntosh et al., 1992).

Very large doses of morphine can be used to produce anesthesia; however, decreased peripheral resistance and blood pressure are troublesome. Fentanyl and sufentanil, which are potent and selective agonists, are less likely to cause hemodynamic instability during surgery, in part because they do not cause the release of histamine (Monk et al., 1988).

Morphine-like opioids should be used with caution in patients who have a decreased blood volume, since these agents can aggravate hypovolemic shock. Morphine should be used with great care in patients with cor pulmonale, since deaths following ordinary therapeutic doses have been reported. The concurrent use of certain phenothiazines may increase the risk of morphine-induced hypotension.

Cerebral circulation is not directly affected by therapeutic doses of morphine. However, opioid-induced respiratory depression and CO₂ retention can result in cerebral vasodilation and an increase in cerebrospinal fluid pressure; the pressure increase does not occur when PCO is maintained at normal levels by artificial ventilation.

Gastrointestinal Tract

Stomach

Morphine and other agonists usually decrease the secretion of hydrochloric acid, although stimulation is sometimes 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 (see Kromer, 1988). Relatively low doses of morphine decrease gastric motility, thereby prolonging gastric emptying time; this can increase the likelihood of esophageal reflux (see Duthie and Nimmo, 1987). The tone of the antral portion of the stomach and of the first part of the duodenum is increased, which often makes therapeutic intubation of the duodenum more difficult. 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.

Small Intestine

Morphine diminishes biliary, pancreatic, and intestinal secretions (Dooley et al., 1988) and delays digestion of food in the small intestine. Resting tone is increased, and periodic spasms are observed. The amplitude of the nonpropulsive type of rhythmic, segmental contractions usually is enhanced, but propulsive contractions are markedly decreased. 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. Water is absorbed more completely because of the delayed passage of bowel contents, and intestinal secretion is decreased; this increases the viscosity of the bowel contents.

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. Enterocytes may possess opioid receptors, but this hypothesis is controversial. However, it is clear that opioids exert important effects on the submucosal plexus that lead to a decrease in the basal secretion by enterocytes and inhibition of the stimulatory effects of acetylcholine, prostaglandin E₂, and vasoactive intestinal peptide. The effects of opioids initiated either in the CNS or the submucosal plexus may be mediated in large part by the release of norepinephrine and stimulation of -adrenergic receptors on enterocytes (see Coupar, 1987). The actions of opioids on intestinal secretion have been reviewed by Manara and Bianchetti (1985) and Kromer (1988).

Large Intestine

Propulsive peristaltic waves in the colon are diminished or abolished after administration of morphine, and tone is increased to the point of spasm. The resulting delay in the passage of bowel contents causes considerable desiccation of the feces, which, in turn, retards their advance through the colon. The amplitude of the nonpropulsive type of rhythmic contractions of the colon usually is enhanced. The tone of the anal sphincter is greatly augmented, and reflex relaxation in response to rectal distension is reduced. These actions, combined with inattention to the normal sensory stimuli for defecation reflex due to the central actions of the drug, contribute to morphine-induced constipation.

Mechanism of Action on the Bowel

The usual gastrointestinal effects of morphine primarily are mediated by - and -opioid receptors in the bowel. However, injection of opioids into the cerebral ventricles or in the vicinity of the spinal cord can inhibit gastrointestinal propulsive activity as long as the extrinsic innervation to the bowel is intact. The relatively poor penetration of morphine into the CNS may explain how preparations such as paregoric can produce constipation at less than analgesic doses and may account for troublesome gastrointestinal side effects during the use of oral morphine for the treatment of cancer pain (see Manara and Bianchetti, 1985). Although some tolerance develops to the effects of opioids on gastrointestinal motility, patients who take opioids chronically remain constipated.

Biliary Tract

After the subcutaneous injection of 10 mg of morphine sulfate, the sphincter of Oddi constricts and the pressure in the common bile duct may rise more than tenfold 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 may experience exacerbation rather than relief of pain when given these drugs. Spasm of the sphincter of Oddi is probably responsible for elevations of plasma amylase and lipase that are sometimes found after patients are given morphine. Atropine only partially prevents morphine-induced biliary spasm, but opioid antagonists prevent or relieve it. Nitroglycerin (0.6 to 1.2 mg) administered sublingually also decreases the elevated intrabiliary pressure (see Staritz, 1988).

Other Smooth Muscle

Ureter and Urinary Bladder

Therapeutic doses of morphine may increase the tone and amplitude of contractions of the ureter, although the response is variable. When the antidiuretic effects of the drug are prominent and urine flow decreases, the ureter may become quiescent.

Morphine inhibits the urinary voiding reflex, and both the tone of the external sphincter and the volume of the bladder are increased; catheterization is sometimes required following therapeutic doses of morphine. Stimulation of either or receptors in the brain or in the spinal cord exerts similar actions on bladder motility (see Dray and Nunan, 1987). Tolerance develops to these effects of opioids on the bladder.

Uterus

If the uterus has been made hyperactive by oxytocics, morphine tends to restore tone, frequency, and the amplitude of contractions to normal. Parenteral administration of opioids within 2 to 4 hours of delivery may lead to transient respiratory depression in the neonate due to transplacental passage of opioids. This may be treated readily with naloxone.

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 occasionally follow the systemic administration of morphine (see below). Histamine release probably accounts for the urticaria commonly seen at the site of injection; this is not mediated by opioid receptors and is not blocked by naloxone. It is seen with morphine and meperidine, but not with oxymorphone, methadone, fentanyl, or sufentanil (see Duthie and Nimmo, 1987).

Pruritus is a common and potentially disabling complication of opioid use. It can be caused by intraspinal and systemic injections of opioids, but it appears to be more intense after intraspinal administration (Ballantyne et al., 1988). The effect appears to be mediated in large part by dorsal horn neurons and is reversible by naloxone (Thomas et al., 1992). An intriguing report suggested that systemic morphine could partially inhibit pruritus caused by intraspinal administration of morphine, implying the existence of an opioid-mediated, itch-inhibition system, possibly supraspinal in origin (Thomas et al., 1993).

Immune System

The effects of opioids on the immune system are complex. Opioids have been shown to modulate immune function by direct effects on cells of the immune system and indirectly via centrally mediated neuronal mechanisms (Sharp and Yaksh, 1997). It appears that acute, central immunomodulatory effects of opioids may be mediated by activation of the sympathetic nervous system, whereas the chronic effects of opioids may involve modulation of hypothalamic-pituitary-adrenal (HPA) axis function (Mellon and Bayer, 1998). Direct effects on immune cells may involve unique and as yet incompletely characterized variants of the classical neuronal opioid receptors, with -receptor variants being more 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 in spite of the observance of robust functional effects. In contrast, morphine-induced immune suppression is largely abolished in 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 potential mechanism for the immune suppressive effects of morphine on neutrophils was proposed recently by Welters et al. (2000), who demonstrated that NF-B activation induced by an inflammatory stimulus was inhibited by morphine in a nitric oxide-dependent manner. Another group of investigators has proposed that the induction and activation of MAP kinase also may play a role (Chuang et al., 1997).

The overall effects of opioids on immune function appear to be suppressive; increased susceptibility to infection and tumor spread have been observed in experimental settings. Infusion of the -receptor antagonist naloxone has been shown to improve survival after experimentally induced sepsis (Risdahl et al., 1998). Such effects have been inconsistent in clinical situations, possibly because of the use of confounding therapies and necessary opioid analgesics. In some situations, effects on immune function 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 increased 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 could actually worsen immune function. An intriguing recent paper indicated that the partial -receptor agonist buprenorphine (see below) did not alter immune function when injected centrally into the mesencephalic periaqueductal gray matter, while morphine did (Gomez-Flores and Weber, 2000). Taken together, these studies indicate that opioid-induced immune suppression may be clinically relevant to both the treatment of severe pain and in the susceptibility of opioid addicts to infection (e.g., HIV, tuberculosis). Different opioid agonists also may have unique immunomodulatory properties. Better understanding of these properties eventually should help guide rational use of opioids in patients with cancer or at risk for infection or immune compromise.

Tolerance and Physical Dependence

The development of tolerance and physical dependence with repeated use is a characteristic feature of all the opioid drugs. Tolerance to the effect of opioids or other drugs simply means that, over time, the drug loses its effectiveness and an increased dose is required to produce the same physiological response. Dependence refers to a complex and poorly understood set of changes in the homeostasis of an organism that cause a disturbance of the homeostatic set point of the organism if the drug is stopped. This disturbance often is revealed when administration of an opioid is abruptly stopped, resulting in withdrawal. Addiction is a behavioral pattern characterized by compulsive use of a drug and overwhelming involvement with its procurement and use. Tolerance and dependence are physiological responses seen in all patients and are not predictors of addiction (see Chapter 24: Drug Addiction and Drug Abuse). These processes appear to be quite distinct. For example, cancer pain often requires prolonged treatment with high doses of opioids, leading to tolerance and dependence. Yet, abuse in this setting is very unusual (Foley, 1993). Neither the presence of tolerance and dependence nor the fear that they may develop should ever interfere with the appropriate use of opioids. Opioids can be discontinued in dependent patients once the need for analgesics is gone without subjecting them to withdrawal (see Chapter 24: Drug Addiction and Drug Abuse). Clinically, the dose can be decreased by 10% to 20% every other day and eventually stopped without signs and symptoms of withdrawal.

In vivo studies in animal models demonstrate the importance of other neurotransmitters and their interactions with opioid pathways in the development of tolerance to morphine. Blockade of glutamate actions by NMDA (N-methyl-D-aspartate)-receptor antagonists blocks morphine tolerance (Trujillo and Akil, 1997). Since NMDA antagonists have no effect on the potency of morphine in naive animals, their effect cannot be attributed to potentiation of opioid actions. Interestingly, the clinically used antitussive dextromethorphan (see Dextromethorphan) has been shown to function as an NMDA antagonist. In animals, it can attenuate opioid tolerance development and reverse established tolerance (Elliott et al., 1994). Nitric oxide production, possibly induced by NMDA-receptor activation, also has been implicated in tolerance, as inhibition of nitric oxide synthase (NOS) also blocks morphine tolerance development (Kolesnikov et al., 1993). Administering NOS inhibitors to morphine-tolerant animals also may reverse tolerance in certain circumstances. Although the NMDA antagonists and nitric oxide synthase inhibitors are effective against tolerance to morphine and agonists such as DPDPE, they have little effect against tolerance to the agonists. Dependence seems to be closely related to tolerance, since the same treatments that block tolerance to morphine also block dependence. Other related signaling systems also are being investigated as mediators of opioid tolerance and dependence. The selective actions of drugs on tolerance and dependence demonstrate that specific mechanisms can be targeted to minimize these two unwanted actions.

There are now many compounds with pharmacological properties similar to those of morphine, yet morphine remains the standard against which new analgesics are measured. However, responses of an individual patient may vary dramatically with different -opioid receptor agonists. For example, some patients unable to tolerate morphine may have no problems with an equianalgesic dose of methadone, whereas others can take morphine and not methadone. If problems are encountered with one drug, another should be tried. Mechanisms underlying variations in individual responses to morphine-like agonists are not yet well understood.

Source and Composition of Opium

Because the laboratory synthesis of morphine is difficult, the drug is still 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 fewmorphine, codeine, and papaverinehave clinical usefulness. 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 (1.0%), which is a smooth muscle relaxant (see the seventh and earlier editions of this book), and noscapine (6.0%).

Chemistry of Morphine and Related Opioids

The structure of morphine is shown in Table 235. Many semisynthetic derivatives are made by relatively simple modifications of morphine or thebaine. Codeine is methylmorphine, the methyl substitution being on the phenolic hydroxyl group. Thebaine differs from morphine only in that both hydroxyl groups are methylated and that the ring has two double bonds ( ). Thebaine has little analgesic action but is a precursor of several important 14-OH compounds, such as oxycodone and naloxone. Certain derivatives of thebaine are more than 1000 times as potent as morphine (e.g., etorphine). Diacetylmorphine, or heroin, is made from morphine by acetylation at the 3 and 6 positions. Apomorphine, which also can be prepared from morphine, is a potent emetic and dopaminergic agonist. Hydromorphone, oxymorphone, hydrocodone, and oxycodone also are made by modifying the morphine molecule. The structural relationships between morphine and some of its surrogates and antagonists are shown in Table 235.

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; these are indicated by the heavy lines in the structure of morphine shown in Table 235. Among the important properties of the opioids that can be altered by structural modification are their affinities for various species 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 to the potent analgesics morphine and 6-acetyl morphine, respectively, in vivo.

Absorption, Distribution, Fate, and Excretion

Absorption

In general, the opioids are readily absorbed from the gastrointestinal tract; absorption through the rectal mucosa is adequate, and a few agents (e.g., morphine, hydromorphone) are available in suppositories. The more lipophilic opioids also are readily absorbed through the nasal or buccal mucosa (Weinberg et al., 1988). Those with the greatest lipid solubility also can be absorbed transdermally (Portenoy et al., 1993). Opioids are absorbed readily after subcutaneous or intramuscular injection and can adequately penetrate the spinal cord following epidural or intrathecal administration (also see section on Alternative Routes of Administration). Small amounts of morphine introduced epidurally or intrathecally into the spinal canal can produce profound analgesia that may last 12 to 24 hours. However, due to the hydrophilic nature of morphine, there is rostral spread of the drug in spinal fluid, and side effects, especially respiratory depression, can emerge up to 24 hours later as the opioid reaches supraspinal respiratory control centers. With highly lipophilic agents such as hydromorphone or fentanyl, rapid absorption by spinal neural tissues produces very localized effects and segmental analgesia. The duration of action is shorter because of distribution of the drug in the systemic circulation, and the severity of respiratory depression may be more directly proportional to its concentration in plasma, due to a lesser degree of rostral spread (Gustafsson and Wiesenfeld-Hallin, 1988). However, patients receiving epidural or intrathecal fentanyl still should be monitored for respiratory depression.

With most opioids, including morphine, the effect of a given dose is less after oral than after parenteral administration, due to variable but significant first-pass metabolism in the liver. For example, the bioavailability of oral preparations of morphine is only about 25%. The shape of the time-effect curve also varies with the route of administration, so that the duration of action is often somewhat longer with the oral route. If adjustment is made for variability of first-pass metabolism and clearance, it is possible to achieve adequate relief of pain by the oral administration of morphine. Satisfactory analgesia in cancer patients has been associated with a very broad range of steady-state concentrations of morphine in plasma (16 to 364 ng/ml; Neumann et al., 1982).

When morphine and most opioids are given intravenously, they act promptly. However, the more lipid-soluble compounds act more rapidly than morphine after subcutaneous administration because of differences in the rates of absorption and entry into the CNS. Compared with other more lipid-soluble opioids such as codeine, heroin, and methadone, morphine crosses the bloodbrain barrier at a considerably lower rate.

Distribution and Fate

When therapeutic concentrations of morphine are present in plasma, about one-third of the drug is protein bound. 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 can cross the bloodbrain barrier to exert significant clinical effects (Christup, 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 human beings (Osborne et al., 1988). With chronic administration, it accounts for a significant portion of morphine's analgesic actions (Osborne et al., 1988; Osborne et al., 1990; Portenoy et al., 1991; Portenoy et al., 1992). Indeed, with chronic oral dosing, the blood levels of morphine-6-glucuronide typically exceed those of morphine. Given its greater potency as well as its higher concentrations, 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 young adults, the half-life of morphine is about 2 hours; the half-life of morphine-6-glucuronide is somewhat longer. Children achieve adult renal function values by 6 months of age. In elderly patients, lower morphine doses are recommended, based on its smaller volume of distribution (Owen et al., 1983) and the general decline in renal function in the elderly. The 3-glucuronide, also an important metabolite of morphine (Milne et al., 1996), has little affinity for opioid receptors but may contribute to excitatory effects of morphine (Smith, 2000). Some investigators also have shown that morphine-3-glucuronide can antagonize morphine-induced analgesia (Smith et al., 1990), but this finding is not universal (Christup, 1997). Morphine also is metabolized by other pathways. N-demethylation to normorphine is a minor metabolic pathway in human beings but is more prominent in rodents (Yeh et al., 1977). N-dealkylation is important in the metabolism of some congeners of morphine.

Excretion

Very little morphine is excreted unchanged. It is eliminated by glomerular filtration, primarily as morphine-3-glucuronide; 90% of the total excretion takes place during the first day. Enterohepatic circulation of morphine and its glucuronides occurs, which accounts for the presence of small amounts of morphine in the feces and in the urine for several days after the last dose.

Codeine

In contrast to morphine, codeine is approximately 60% as effective orally as parenterally, both as an analgesic and as a respiratory depressant. Codeine, like levorphanol, oxycodone, and methadone, has a high oral to parenteral potency ratio. The greater oral efficacy of these drugs is due to less first-pass metabolism in the liver. Once absorbed, codeine is metabolized by the liver, and its metabolites are excreted chiefly in the urine, largely in inactive forms. A small fraction (approximately 10%) of administered codeine is O-demethylated to form morphine, and both 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, its antitussive actions may involve distinct receptors that bind codeine itself. The half-life of codeine in plasma is 2 to 4 hours.

The conversion of codeine to morphine is effected by the cytochrome P450 enzyme CYP2D6. Well-characterized genetic polymorphisms in CYP2D6 lead to the inability to convert codeine to morphine, thus making codeine ineffective as an analgesic for about 10% of the Caucasian population (Eichelbaum and Evert, 1996). Other polymorphisms can lead to enhanced metabolism and thus increased sensitivity to codeine's effects (Eichelbaum and Evert, 1996). Interestingly, there appears to be variation in metabolic efficiency among different ethnic groups. For example, Chinese produce less morphine from codeine than do Caucasians and also are less sensitive to morphine's effects than are Caucasians (Caraco et al., 1999). 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 does not receive adequate analgesia from codeine or an adequate response to other administered prodrugs.

Tramadol

Tramadol ULTRAM) is a synthetic codeine analog that is a weak -opioid receptor agonist. Part of its analgesic effects are produced by inhibition of uptake of norepinephrine and serotonin. Tramadol appears to be as effective as other weak opioids. 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.

Tramadol is 68% bioavailable after a single oral dose and 100% available when administered intramuscularly. Its affinity for the opioid receptor is only 1/6000 that of morphine. However, the primary O-demethylated metabolite of tramadol is 2- to 4-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 -adrenergic receptors (Lewis and Han, 1997). The compound undergoes hepatic metabolism and renal excretion, with an elimination half-life of 6 hours for tramadol and 7.5 hours for its active metabolite. Analgesia begins within an hour of oral dosing, and the effect peaks within 2 to 3 hours. The duration of analgesia is about 6 hours. The maximum recommended daily dose is 400 mg.

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 can be reversed by naloxone. However, the use of naloxone increases the risk of seizure. Physical dependence on and abuse of tramadol have been reported. Although its abuse potential is unclear, tramadol probably should be avoided in patients with a history of addiction. Because of its inhibitory effect on serotonin uptake, tramadol should not be used in patients taking monoamine oxidase (MAO) inhibitors (Lewis and Han, 1997; see also section on Interactions with Other Drugs, below).

Heroin

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

The absorption, fate, and distribution of heroin and other morphine-like drugs have been reviewed by (Misra, 1978) and by (Chan and Matzke, 1987).

Untoward Effects and Precautions

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

A number of factors may alter a patient's sensitivity to opioid analgesics, including the integrity of the bloodbrain barrier. For example, when morphine is administered to a newborn infant in weight-appropriate doses extrapolated from adults, unexpectedly profound analgesia and respiratory depression may be observed. This is due to the immaturity of the bloodbrain barrier in neonates (Way et al., 1965). As mentioned previously, morphine is hydrophilic, so in the normal situation, proportionately less morphine crosses into the CNS than with more lipophilic opioids. In neonates and in other situations with a compromised bloodbrain barrier, 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. The reasons for this effect are unclear.

All the opioid analgesics are metabolized by the liver, and the drugs should be used with caution in patients with hepatic disease, since increased bioavailability after oral administration or cumulative effects may occur (see Sawe et al., 1981). Renal disease also significantly alters the pharmacokinetics of morphine, codeine, drocode (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 (see 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 (Kaiko et al., 1983). Similarly, the repeated administration of propoxyphene may lead to naloxone-insensitive cardiac toxicity caused by the accumulation of norpropoxyphene (see Chan and Matzke, 1987).

Morphine and related opioids must be used cautiously in patients with compromised respiratory function, such as those with emphysema, kyphoscoliosis, or severe obesity. In patients with chronic cor pulmonale, death has occurred following therapeutic doses of morphine. Although many patients with such conditions seem to be functioning within normal limits, they are already utilizing 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 of 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.

Morphine causes histamine release, which can cause bronchoconstriction and vasodilation. Morphine has the potential to precipitate or exacerbate asthmatic attacks. The use of morphine should be avoided in patients with a history of asthma. Other -receptor agonists that do not release histamine, such as the fentanyl derivatives, may be better choices for such patients.

Patients with reduced blood volume are considerably more susceptible to the vasodilatory effects of morphine and related drugs, and these agents must be used cautiously in patients with hypotension from any cause.

Allergic phenomena occur with opioid analgesics, but they are not common. They 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 probably secondary to the release of histamine. Anaphylactoid reactions have been reported after intravenous administration of codeine and morphine, but such reactions are rare. It has been suggested, but not proven, that such reactions are responsible for some of the sudden deaths, episodes of pulmonary edema, and other complications that occur among addicts who use heroin intravenously (see Chapter 24: Drug Addiction and Drug Abuse).

Interactions with Other Drugs

The depressant effects of some opioids may be exaggerated and prolonged by phenothiazines, monoamine oxidase inhibitors, and tricyclic antidepressants; the mechanisms of these supraadditive effects are not fully understood but may involve alterations in the rate of metabolic transformation of the opioid or alterations in neurotransmitters involved in the actions of opioids. Some, but not all, phenothiazines reduce the amount of opioid required to produce a given level of analgesia. However, depending on the specific agent, the respiratory-depressant effects also seem to be enhanced, the degree of sedation is increased, and the hypotensive effects of phenothiazines become an additional complication. Some phenothiazine derivatives enhance the sedative effects, but at the same time seem to be antianalgesic and increase the amount of opioid required to produce satisfactory relief from pain. Small doses of amphetamine substantially increase the analgesic and euphoriant effects of morphine and may decrease its sedative side effects. A number of antihistamines exhibit modest analgesic actions; some (e.g., hydroxyzine) enhance the analgesic effects of low doses of opioids (Rumore and Schlichting, 1986). Antidepressants such as desipramine 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; Pick et al., 1992b). The analgesic synergism between opioids and aspirin-like drugs is discussed below and in Chapter 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout.

Acute opioid toxicity may result from clinical overdosage, accidental overdosage in addicts, or attempts at suicide. Occasionally, a delayed type of toxicity may occur from the injection of an opioid into chilled skin areas or in patients with low blood pressure and shock. The drug is not fully absorbed, and, therefore, a subsequent dose may be given. When normal circulation is established, an excessive amount may be absorbed suddenly. It is difficult to define the exact amount of any opioid that is toxic or lethal to human beings. Recent experiences with methadone indicate that, in nontolerant individuals, serious toxicity may follow the oral ingestion of 40 to 60 mg. Older literature suggests that, in the case of morphine, a normal, pain-free adult is not likely to die after oral doses of less than 120 mg or to have serious toxicity with less than 30 mg parenterally.

Symptoms and Diagnosis

The patient who has taken an overdose of an opioid usually is stuporous or, if a large overdose has been taken, may be in a profound coma. The respiratory rate will be very low or the patient may be apneic, and cyanosis may be present. 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 due to 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 anaphylactoid reactions, and it has been observed following toxic doses of morphine, methadone, propoxyphene, and uncontaminated 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 (see Opioid Antagonists) can produce dramatic reversal of the severe respiratory depression, and the antagonist naloxone (see below) 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 (see Duthie and Nimmo, 1987). 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 and propoxyphene, 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 due 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 must be watched carefully, lest they slip back into coma. This is particularly important when the overdosage is due to methadone or l-acetylmethadol. The depressant effects of these drugs may persist for 24 to 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 due to overdose of pentazocine and other opioids with mixed actions may require higher doses of naloxone. The pharmacological actions of opioid antagonists are discussed in more detail in Opioid Antagonists.

The drugs described in this section differ from clinically used -opioid receptor agonists. Drugs such as nalbuphine and butorphanol are competitive -receptor antagonists but exert their analgesic actions by acting as agonists at receptors. Pentazocine qualitatively resembles these drugs, but it may be a weaker -receptor antagonist or partial agonist while retaining its -agonist activity. Buprenorphine, on the other hand, is a partial agonist at receptors. The stimulus for the development of mixed agonist/antagonist drugs was a need for analgesics with less respiratory depression and addictive potential. Currently, the clinical use of these compounds is limited by undesirable side effects and by limited analgesic effects.

Pentazocine

Pentazocine was synthesized as part of a deliberate effort to develop an effective analgesic with little or no abuse potential. It has both agonistic actions and weak opioid antagonistic activity. The pharmacology of pentazocine has been reviewed by (Brogden et al., 1973).

Chemistry

Pentazocine is a benzomorphan derivative with the following structural formula:

The compound has a large substituent on the nitrogen atom that is analogous to position 17 of morphine. This structural feature is common to a number of opioids with antagonist or agonist/ antagonist activity. The analgesic and respiratory-depressant activity of the racemate is due mainly to the l isomer.

Pharmacological Actions

The pattern of CNS effects produced by pentazocine is generally 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 to 90 mg) elicit dysphoric and psychotomimetic effects. The mechanisms responsible for these side effects are not known but might involve activation of supraspinal receptors, since 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. In patients with coronary artery disease, pentazocine administered intravenously elevates mean aortic pressure, left ventricular end-diastolic pressure, and mean pulmonary artery pressure and causes an increase in cardiac work (Alderman et al., 1972; Lee et al., 1976). A rise in the concentrations of catecholamines in plasma may account for its effects on blood pressure.

Pentazocine acts as a weak antagonist or partial agonist at -opioid receptors. Low doses (20 mg given parenterally) depress respiration as much as does 10 mg of morphine, but increasing the pentazocine dose does not produce a proportionate increase in respiratory depression. Pentazocine does not antagonize the respiratory depression produced by morphine. However, when given to patients dependent on morphine or other -receptor agonists, pentazocine may precipitate withdrawal. In patients tolerant to morphine-like opioids, pentazocine reduces the analgesia produced by their administration, even when clear-cut withdrawal symptoms are not precipitated. Ceiling effects for both analgesia and respiratory depression are observed above 50 to 100 mg of pentazocine (Bailey and Stanley, 1994).

Absorption, Fate, and Excretion

Pentazocine is well absorbed from the gastrointestinal tract and from subcutaneous and intramuscular sites. Peak analgesia occurs 15 minutes to 1 hour after intramuscular administration and 1 to 3 hours after oral administration. The half-life in plasma is 4 to 5 hours. First-pass metabolism in the liver is extensive, and somewhat less than 20% of pentazocine enters the systemic circulation. Drug action is terminated by hepatic metabolism and renal excretion.

Side Effects, Toxicity, and Precautions

The most commonly reported untoward effects are sedation, sweating, and dizziness or lightheadedness; nausea also occurs, but vomiting is less common than with morphine. Psychotomimetic effects, such as uncontrollable or weird thoughts, anxiety, nightmares, and hallucinations, occur with parenteral doses above 60 mg. Epidemiological data suggest that overdose with pentazocine alone rarely causes death. High doses produce marked respiratory depression associated with increased blood pressure and tachycardia. The respiratory depression is antagonized by naloxone. Pentazocine is irritating when administered subcutaneously or intramuscularly. Repeated injections over long periods may cause extensive fibrosis of subcutaneous and muscular tissue. Patients who have been receiving opioids on a regular basis may experience abstinence signs and symptoms when given pentazocine. After an opioid-free interval of 1 to 2 days, it is usually possible to administer pentazocine without producing such withdrawal effects.

Tolerance and Physical Dependence

With frequent and repeated use, tolerance develops to the analgesic and subjective effects of pentazocine. However, pentazocine does not prevent or ameliorate the morphine withdrawal syndrome. Instead, when high doses of pentazocine are given to subjects dependent on morphine, it precipitates withdrawal symptoms because of its antagonistic actions at the receptor.

After long-term administration (60 mg every 4 hours), postaddicts develop physical dependence that can be demonstrated by abrupt withdrawal or by the administration of naloxone. The withdrawal syndrome after chronic doses of more than 500 mg per day, although milder in intensity than withdrawal from morphine, includes abdominal cramps, anxiety, chills, elevated temperature, vomiting, lacrimation, and sweating. Pentazocine withdrawal symptoms can be managed by gradual reduction of pentazocine itself or by substitution of -receptor agonists, such as morphine or methadone. A syndrome of withdrawal from pentazocine also has been observed in neonates.

Therapeutic Uses

Pentazocine is used as an analgesic. Although the risk of drug dependence exists, it may be lower than that associated with the use of morphine-like drugs in similar circumstances. Because abuse patterns appear to be less likely to develop with oral administration, this route should be used whenever possible.

Pentazocine lactate TALWIN) is available as a solution for injection. In an effort to reduce the use of tablets as a source of injectable pentazocine, tablets for oral use now contain pentazocine hydrochloride (equivalent to 50 mg of the base) and naloxone hydrochloride (equivalent to 0.5 mg of the base; TALWIN NX). After oral ingestion, naloxone is destroyed rapidly by the liver; however, if the material is dissolved and injected, the naloxone produces aversive effects in subjects dependent on opioids. Tablets containing mixtures of pentazocine with aspirin (TALWIN COMPOUND) or acetaminophen (TALCEN) also are available. In terms of analgesic effect, 30 to 60 mg of pentazocine given parenterally is approximately equivalent to 10 mg of morphine. An oral dose of about 50 mg of pentazocine results in analgesia equivalent to that produced by 60 mg of codeine orally.

Nalbuphine

Nalbuphine is related structurally to both naloxone and oxymorphone (see Table 235). It is an agonist/antagonist opioid with a spectrum of effects that qualitatively resembles that of pentazocine; however, nalbuphine is a more potent antagonist at receptors and is less likely to produce dysphoric side effects than is pentazocine.

Pharmacological Actions and Side Effects

An intramuscular dose of 10 mg of nalbuphine is equianalgesic to 10 mg of morphine, with similar onset and duration of both 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. However, a ceiling effect for analgesia also is reached at this point. In contrast to pentazocine and butorphanol, 10 mg of 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 (see Roth et al., 1988). Its gastrointestinal effects are probably 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 (dysphoria, racing thoughts, and distortions of body image) can occur. Nalbuphine is metabolized in the liver and has a half-life in plasma of 2 to 3 hours. Given orally, nalbuphine is 20% to 25% as potent as when given intramuscularly.

Tolerance and Physical Dependence

In subjects dependent on low doses of morphine (60 mg per 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 is probably similar to that of parenteral pentazocine.

Therapeutic Uses

Nalbuphine hydrochloride NUBAIN) 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 to 6 hours; this may be increased to 20 mg in nontolerant individuals.

Butorphanol

Butorphanol is a morphinan congener with a profile of actions similar to those of pentazocine. The structural formula of butorphanol is shown in Table 235.

Pharmacological Actions and Side Effects

In postoperative patients, a parenteral dose of 2 to 3 mg of butorphanol produces analgesia and respiratory depression approximately equal to that produced by 10 mg of morphine or 80 to 100 mg of meperidine; the onset, peak, and duration of action are similar to those that follow the administration of morphine. The plasma half-life of butorphanol is about 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. Physical dependence on butorphanol can occur.

Therapeutic Uses

Butorphanol tartrate STADOL) is better suited for the relief of acute rather than chronic pain. 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 between 1 and 4 mg of the tartrate given intramuscularly, or 0.5 to 2 mg given intravenously every 3 to 4 hours. A nasal formulation (STADOL NS) is available and has proven to be effective. This formulation is particularly useful for patients with severe headaches who may be unresponsive to other forms of treatment.

Buprenorphine

Buprenorphine is a semisynthetic, highly lipophilic opioid derived from thebaine (see Table 235). It is 25 to 50 times more potent than morphine.

Pharmacological Actions and Side Effects

Buprenorphine produces analgesia and other CNS effects that are qualitatively similar to those of morphine. About 0.4 mg of buprenorphine is equianalgesic with 10 mg of morphine given intramuscularly (Wallenstein et al., 1986). Although variable, the duration of analgesia is usually longer than that of morphine. Some of the subjective and respiratory-depressant effects are unequivocally slower in onset and longer lasting than those of morphine. For example, peak miosis occurs about 6 hours after intramuscular injection, while maximal respiratory depression is observed at about 3 hours.

Buprenorphine appears to be a partial -receptor agonist. Depending on the dose, buprenorphine may cause symptoms of abstinence in patients who have been receiving -receptor agonists (morphine-like drugs) for several weeks. It antagonizes the respiratory depression produced by anesthetic doses of fentanyl about as well as does naloxone, without completely preventing opioid pain relief (Boysen et al., 1988). Although respiratory depression has not been a major problem in clinical trials, it is not clear whether or not 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 half-life 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 (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 to 0.8 mg) produces satisfactory analgesia in postoperative patients. Concentrations in blood peak within 5 minutes after intramuscular injection and within 1 to 2 hours after oral or sublingual administration. While the half-life in plasma has been reported to be about 3 hours, this value bears little relationship to the rate of disappearance of effects (see above). 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 days to 2 weeks; this consists of typical, but generally not very severe, morphine-like withdrawal signs and symptoms, and it persists for about 1 to 2 weeks (Bickel et al., 1988; Fudala et al., 1989).

Therapeutic Uses

Buprenorphine. BUPRENEX) may be used as an analgesic and also has proven to be useful as a maintenance drug for opioid-dependent subjects (Johnson et al., 2000). The drug was approved provisionally for use in the treatment of heroin addiction when the Drug Addiction Treatment Act was passed by the United States Congress and signed by the President in October of 2000. Approval by the Food and Drug Administration is pending.

The usual intramuscular or intravenous dose for analgesia is 0.3 mg, given every 6 hours. Sublingual doses of 0.4 to 0.8 mg produce effective analgesia, and doses of 6 to 8 mg appear to be about equal to 60 mg of methadone as a maintenance agent.

Other Agonist/Antagonists

Meptazinol is an agonist/antagonist opioid that is about one-tenth as potent as morphine in producing analgesia. Its duration of action is somewhat shorter than that of morphine. Meptazinol also has cholinergic actions that may contribute to its analgesic effects (see Holmes and Ward, 1985). Nevertheless, its analgesic actions are antagonized by naloxone, and it can precipitate withdrawal in animals dependent on -receptor agonists. The potential for abuse of meptazinol is less than that of morphine because dysphoric side effects appear when the dose is increased. Dezocine (DALGAN), an aminotetralin, is another agonist/antagonist; its potency and duration of analgesic effect are similar to those of morphine. Increasing the dose above 30 mg does not produce progressively more severe respiratory depression. In postaddicts, its subjective effects are similar to those of -agonist opioids (Jasinski and Preston, 1985).

Under ordinary circumstances, the drugs to be discussed in this section produce few effects unless opioids with agonistic actions have been administered previously. However, when the endogenous opioid systems are activated, as in shock or certain forms of stress, the administration of an opioid antagonist alone may have visible consequences. These agents have obvious therapeutic utility in the treatment of overdosage with opioids. As the understanding of the role of endogenous opioid systems in pathophysiological states increases, additional therapeutic indications for these antagonists may develop.

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 -receptor agonists. Such substitutions transform morphine to nalorphine, levorphanol to levallorphan, and oxymorphone to naloxone or naltrexone (see Table 235). In some cases, congeners are produced that are competitive antagonists at receptors but that also have agonistic actions at receptors. Nalorphine and levallorphan have such properties. Other congeners, especially naloxone and naltrexone, appear to be devoid of agonistic actions and probably interact with all types of opioid receptors, albeit with widely different affinities (see Martin, 1983).

Nalmefene REVIX) is a relatively pure -receptor antagonist that is more potent than naloxone (Dixon et al., 1986). A number of other nonpeptide antagonists have been developed that are relatively selective for individual types of opioid receptors. These include cypridime and -funaltrexamine (-FNA) (), naltrindole (), and nor-binaltorphimine () (see Portoghese, 1989; Pasternak, 1993).

Pharmacological Properties

If endogenous opioid systems have not been activated, the pharmacological actions of opioid antagonists depend on whether or not an opioid agonist has been administered previously, on the pharmacological profile of that opioid, and on the degree to which physical dependence on an opioid has developed.

Effects in the Absence of Opioid Drugs

Subcutaneous doses of naloxone (NARCAN; up to 12 mg) produce no discernible subjective effects in human beings, and 24 mg causes only slight drowsiness. Naltrexone (REVIA) also appears to be a relatively pure antagonist but with higher oral efficacy and a longer duration of action. At high doses, both naloxone and naltrexone may have some special agonistic effects. However, these are of little clinical significance. At doses in excess of 0.3 mg/kg of naloxone, normal subjects show increased systolic blood pressure and decreased performance on tests of memory. High doses of naltrexone appeared to cause mild dysphoria in one study but almost no subjective effect in several others (see Gonzalez and Brogden, 1988).

Although high doses of antagonists might be expected to alter the actions of endogenous opioid peptides, the detectable effects are usually both subtle and limited (Cannon and Liebeskind, 1987). Most likely, this reflects the low levels of tonic activity of the opioid systems. In this regard, analgesic effects can be differentiated from endocrine effects, in which naloxone causes readily demonstrable changes in hormone levels (see below). It is interesting that naloxone appears to block the analgesic effects of placebo medications and acupuncture. 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). Naloxone apparently acts to antagonize the actions of endogenous opioids that are mobilized by pain or stress and that are involved in the regulation of blood pressure by the CNS. Although neural damage that follows trauma to the spinal cord or cerebral ischemia also appears to involve endogenous opioids, it is not certain whether opioid antagonists can prevent damage to these or other organs and/or increase rates of survival. Nevertheless, opioid antagonists can reduce the extent of injury in some animal models, perhaps by blocking receptors (Faden, 1988).

As noted above, endogenous opioid peptides participate in the regulation of pituitary secretion, apparently by exerting tonic inhibitory effects on the release of certain hypothalamic hormones (see Chapter 56: Pituitary Hormones and Their Hypothalamic Releasing Factors). Thus, the administration of naloxone or naltrexone increases the secretion of gonadotropin-releasing hormone and corticotropin-releasing factor and elevates the plasma concentrations of LH, FSH, and ACTH, as well as the 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. The neuroendocrine effects of opioid antagonists have been reviewed (Howlett and Rees, 1986). Endogenous opioid peptides probably have some role in the regulation of feeding or energy metabolism, because opioid antagonists increase energy expenditure and interrupt hibernation in appropriate species and induce weight loss in genetically obese rats. The antagonists also prevent stress-induced overeating and obesity in rats. 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 reduce food intake in both lean and obese individuals (Atkinson, 1987).

Antagonistic Actions

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

Effects in Physical Dependence

In subjects who are dependent on morphine-like opioids, small subcutaneous doses of naloxone (0.5 mg) precipitate a moderate-to-severe withdrawal syndrome that is very similar to that seen after abrupt withdrawal of opioids, except that the syndrome appears within minutes after administration and subsides in about 2 hours. The severity and duration of the syndrome are related to the dose of the antagonist and to the degree and type of dependence. Higher doses of naloxone will precipitate a withdrawal syndrome in patients dependent on pentazocine, butorphanol, or nalbuphine. Naloxone produces 'overshoot' phenomena suggestive of early acute physical dependence 6 to 24 hours after a single dose of a agonist (see Heishman et al., 1989).

Tolerance and Physical Dependence

Even after prolonged administration of high doses, 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 little or no potential for abuse.

Absorption, Fate, and Excretion

Although absorbed readily from the gastrointestinal tract, naloxone is almost completely metabolized by the liver before reaching the systemic circulation and thus must be administered parenterally. The drug is absorbed rapidly from parenteral sites of injection and is metabolized in the liver, primarily by conjugation with glucuronic acid; other metabolites are produced in small amounts. The half-life of naloxone is about 1 hour, but its clinically effective duration of action can be even less.

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 to 2 hours and then decline with an apparent half-life of approximately 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 half-life of about 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 (see Gonzalez and Brogden, 1988).

Therapeutic Uses

Opioid antagonists have established uses in the treatment of opioid-induced toxicity, especially respiratory depression; in the diagnosis of physical dependence on opioids; and as therapeutic agents in the treatment of compulsive users of opioids, as discussed in Chapter 24: Drug Addiction and Drug Abuse. Their potential utility in the treatment of shock, stroke, spinal cord and brain trauma, and other disorders that may involve mobilization of endogenous opioid peptides remains to be established. Naltrexone is approved by the United States Food and Drug Administration for treatment of alcoholism (see Chapters 18: Ethanol and 24: Drug Addiction and Drug Abuse).

Treatment of Opioid Overdosage

Naloxone hydrochloride is used to treat opioid overdose. As discussed earlier, it acts rapidly to reverse the respiratory depression associated with high doses of opioids. However, it should be used cautiously, since 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 antagonize the respiratory-depressant actions without eliciting a full 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 effectively employed 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 g/kg, given intravenously, intramuscularly, or subcutaneously.

Cough is a useful physiological mechanism that serves to clear the respiratory passages of foreign material and excess secretions. It should not be suppressed indiscriminately. There are, however, many situations in which cough does not serve any useful purpose but may, instead, only annoy the patient or prevent rest and sleep. Chronic cough can contribute to fatigue, especially in elderly patients. In such situations the physician should use a drug that will reduce the frequency or intensity of the coughing. The cough reflex is complex, involving the central and peripheral nervous systems as well as the smooth muscle of the bronchial tree. It has been suggested that 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 involve several mechanisms or centers that are distinct from the mechanisms involved in the regulation of respiration.

The drugs that directly or indirectly can affect this complex mechanism are diverse. For example, cough may be the first or only symptom in bronchial asthma or allergy, and in such cases bronchodilators (e.g., -adrenergic receptor agonists; see Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists) have been shown to reduce cough without having any significant central effects; other drugs act primarily on the central or the peripheral nervous system components of the cough reflex. The early literature on antitussives has been reviewed by Eddy et al. (1969).

A number of drugs are known to reduce cough as a result of their central actions, although the exact mechanisms are still not entirely clear. Included among them are the opioid analgesics discussed above (codeine and hydrocodone are the opioids most commonly used to suppress cough), as well as a number of nonopioid agents. Cough suppression often occurs with lower doses of opioids than those needed for analgesia. A 10- or 20-mg oral dose of codeine, although ineffective for analgesia, produces a demonstrable antitussive effect, and higher doses produce even more suppression of chronic cough.

In selecting a specific centrally active agent for a particular patient, the significant considerations are its antitussive efficacy against pathological cough and the incidence and type of side effects to be expected. In the majority of situations requiring a cough suppressant, liability for abuse need not be a major consideration. Most of the nonopioid agents now offered as antitussives are effective against cough induced by a variety of experimental techniques. However, the ability of these tests to predict clinical efficacy is limited.

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 gastrointestinal side effects (Matthys et al., 1983). In therapeutic dosages, the drug does not inhibit ciliary activity, and its antitussive effects persist for 5 to 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 and Musacchio, 1983). Although dextromethorphan is known to function as an NMDA-receptor antagonist, these 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 effects is still unclear. Two other known antitussives, carbetapentane and caramiphen, also bind avidly to this site, but codeine, levopropoxyphene, and other antitussive opioids (as well as naloxone) are not bound. Although noscapine (see below) 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. The average adult dosage of dextromethorphan hydrobromide is 10 to 30 mg three to six times daily; however, as is the case with codeine, higher doses often are required. The drug is generally marketed for 'over-the-counter' sale in numerous syrups and lozenges or in combinations with antihistamines and other agents.

Other Drugs

Levopropoxyphene napsylate, the l-isomer of dextropropoxyphene, in doses of 50 to 100 mg orally, appears to suppress cough to about the same degree as does 30 mg of dextromethorphan. Unlike dextropropoxyphene, levopropoxyphene has little or no analgesic activity.

Noscapine is a naturally occurring opium alkaloid of the benzylisoquinoline group; except for its antitussive effect, it has no significant actions on the CNS in doses within the therapeutic range. The drug is a potent releaser of histamine, and large doses cause bronchoconstriction and transient hypotension.

Other drugs that have been used as centrally acting antitussives include carbetapentane, caramiphen, chlophedianol, diphenhydramine, and glaucine. Each is a member of a distinct pharmacological class unrelated to the opioids. The mechanism of action of diphenhydramine, an antihistamine, is unclear. Although sedative effects are common, paradoxical excitement may be seen in infants; dryness of mucous membranes caused by anticholinergic effects and thickening of mucus may be a disadvantage. In general, the toxicity of these agents is low, but controlled clinical studies are still insufficient to determine whether or not they merit consideration as alternatives to more thoroughly studied agents.

Pholcodine [3-O-(2-morpholinoethyl)morphine] is used clinically in many countries outside the United States. Although structurally related to the opioids, it 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 half-life and can be given once or twice daily (see Findlay, 1988).

Benzonatate TESSALON) 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 has been administered by all routes; the oral dosage is 100 mg three times daily, but higher doses have been used.

Sir William Osler called morphine 'God's own medicine.' Opioids are still the mainstay of pain treatment. However, the development of new analgesic compounds and new routes of administration have increased the therapeutic options available to clinicians, while at the same time helping to minimize undesirable side effects. In this section, we will outline guidelines for rational drug selection, discuss routes of administration other than the standard oral and parenteral methods, and outline general principles for the use of opioids in acute and chronic pain states.

Extensive efforts by many individuals and organizations have resulted in the publication of many useful guidelines for the administration of opioids. These have been developed for a number of clinical situations, including acute pain, trauma, cancer, nonmalignant chronic pain, and treatment of pain in children (Agency for Health Care Policy and Research, 1992a, 1992b, 1994; International Association for the Study of Pain, 1992; American Pain Society, 1999; Grossman et al., 1999; World Health Organization, 1998; Berde et al., 1990). These guidelines provide comprehensive discussions of dosing regimens and drug selection and also provide protocols for the management of complex conditions. In the case of cancer pain, adherence to standardized protocols for cancer pain management (Agency for Health Care Policy and Research, 1994) has been shown to improve pain management significantly (Du Pen et al., 1999). Guidelines for the oral and parenteral dosing of commonly used opioids are presented in Table 236.

These guidelines are for acute pain management in opioid-nave patients. Adjustments will need to be made for use in opioid-tolerant patients and in chronic pain states. For children under 6 months of age, especially those who are ill or premature, expert consultation should be obtained. The pharmacokinetics and potency of opioids can be substantially altered in these patients, and in some cases there is a significant risk of apnea. It also should be noted that there is substantial individual variability in responses to opioids. A standard intramuscular dose of 10 mg of morphine sulfate will relieve severe pain adequately in only 2 of 3 patients. Adjustments will have to be made based on clinical response.

In general, it is recommended that opioids always be combined with other analgesic agents, such as nonsteroidal anti-inflammatory drugs (NSAIDS) or acetaminophen. In this way, one can take advantage of additive analgesic effects and minimize the dose of opioids and thus undesirable side effects. In some situations, NSAIDS can provide analgesia equal to that produced by 60 mg of codeine. Potentiation of opioid action by NSAIDs may be due to increased conversion of arachidonic acid to 12-lipoxygenase products that facilitate effects of opioids on K⁺ channels (Vaughan et al., 1997). This 'opioid-sparing' strategy is the backbone of the 'analgesic ladder' for pain management proposed by the World Health Organization (1990). Weaker opioids can be supplanted by stronger opioids in cases of moderate and severe pain. In addition, analgesics always should be dosed in a continuous or 'around the clock' fashion rather than on an as needed basis for chronic severe pain. This provides more consistent analgesic levels and avoids unnecessary suffering. Knowledge of the pharmacological profiles of analgesics allows the rational selection of dosing intervals without risk of overdosage.

Factors guiding the selection of specific opioid compounds for pain treatment include potency, pharmacokinetic characteristics, and the routes of administration available. A more potent compound could be useful when high doses of opioid are required, so the medicine can be given in a smaller volume. Duration of action also is an important consideration. For example, a long-acting opioid such as methadone may be appropriate when less-frequent dosing is desired. For short, painful procedures, a quick-acting, fast-dissipating compound such as remifentanil would be a useful choice. In special cases, where a lower addiction risk is required or in patients unable to tolerate other opioids, a partial agonist or mixed agonist/antagonist compound might be a rational choice. The properties of some commonly used orally-administered opioids are discussed in more detail below.

Morphine is available for oral use in standard and controlled-release preparations. Due to first-pass metabolism, morphine is two- to sixfold less potent orally than parenterally. This is important to remember when converting a patient from parenteral to oral medication. There is wide variability in the first-pass metabolism, and the dose should be titrated to the patient's needs. In children who weigh less than 50 kg, morphine can be given at 0.1 mg/kg every 3 to 4 hours parenterally or at 0.3 mg/kg orally.

Codeine is widely used only due to its high oral/parenteral potency ratio. Orally, codeine at 30 mg is approximately equianalgesic to 325 to 600 mg of aspirin. Combinations of codeine with aspirin or acetaminophen usually provide additive actions, and at these doses analgesic efficacy can exceed that of 60 mg of codeine (see Beaver, 1988). Many drugs can be used instead of either morphine or codeine, as shown in Table 236. Oxycodone, with its high oral/parenteral potency ratio, is widely used in combination with aspirin (PERCODAN, others) or acetaminophen (PERCOCET 2.5/325, others), although it is available alone (ROXICODINE, others).

Heroin (diacetylmorphine) is not available for therapeutic use in the United States, although it has been used in the United Kingdom. Given intramuscularly, it is approximately twice as potent as morphine. Pharmacologically, heroin is very similar to morphine and does not appear to have any unique therapeutic advantages over the available opioids (Sawynok, 1986; Kaiko et al., 1981). It also may be helpful to employ other agents (adjuvants) that enhance opioid analgesia and that may add beneficial effects of their own. For example, the combination of an opioid with a small dose of amphetamine may augment analgesia while reducing the sedative effects. Certain antidepressants, such as amitriptyline and desipramine, also may enhance opioid analgesia, and they may have analgesic actions in some types of neuropathic (deafferentation) pain (see McQuay, 1988). Other potentially useful adjuvants include certain antihistamines, anticonvulsants such as carbamazepine and phenytoin, and glucocorticoids.

Alternative Routes of Administration

In addition to the traditional oral and parenteral formulations for opioids, many other methods have been developed in an effort to improve therapeutic efficacy while minimizing side effects. These routes also improve the ease of use of opioids, and increase patient satisfaction.

Patient-Controlled Analgesia (PCA)

With this modality, the patient has limited control of the dosing of opioid from an infusion pump within tightly mandated parameters. PCA can be used for intravenous or epidural infusion. This technique avoids any delays in administration and permits greater dosing flexibility than other regimens, better adapting to individual differences in responsiveness to pain and to opioids. It also gives the patient a greater sense of control. With shorter-acting opioids, serious toxicity or excessive use rarely occurs. An early concern that self-administration of opioids would increase the probability of addiction has not materialized. PCA is suitable for both adults and children, and it is preferred over intramuscular injections for postoperative pain control (Rodgers et al., 1988).

Computer-Assisted Continuous Infusion (CACI)

The idea behind this mode of administration is to enable clinicians to titrate intravenous agents in a fashion similar to that used in delivering volatile agents (Sanford and Gutstein, 1995). CACI based on detailed pharmacokinetic models has been used successfully to administer opioids (Shafer et al., 1990; Bailey et al., 1993). However, true 'closed-loop' control of opioid administration requires the capability of continuously measuring plasma opioid levels with indwelling sensors. Until such real-time measurement is available, accurate assessment of dose-effect relationships in patients is not possible.

Intraspinal Infusion

Administration of opioids into the epidural or intrathecal space provides more direct access to the first pain-processing synapse in the dorsal horn of the spinal cord. This permits the use of doses substantially lower than those required for oral or parenteral administration (see Table 237). Systemic side effects are thus decreased. However, epidural opioids have their own dose-dependent side effects, such as itching, nausea, vomiting, respiratory depression, and urinary retention. The use of hydrophilic opioids such as preservative-free morphine (DURAMORPH, others) permits more rostral spread of the compound, allowing it to directly affect supraspinal sites. As a consequence, after intraspinal 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 patients receiving intraspinal narcotics. Nausea and vomiting also are more prominent symptoms with intraspinal morphine. However, supraspinal analgesic centers also can be stimulated, possibly leading to synergistic analgesic effects.

Analogous to the relationship between systemic opioids and NSAIDS, intraspinal narcotics often are combined with local anesthetics. This permits the use of lower concentrations of both agents, minimizing local anesthetic-induced complications of motor blockade and the opioid-induced complications listed above. 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). Intrathecal ('spinal' anesthesia) administration of opioids as a single bolus also is popular for acute pain management. Chronic intrathecal infusions generally are reserved for use in chronic pain patients.

Peripheral Analgesia

As previously mentioned, opioid receptors on peripheral nerves have been shown to respond to locally applied opioids during inflammation (Stein, 1995). Peripheral analgesia permits the use of lower doses, applied locally, than those necessary to achieve a systemic effect. The effectiveness of this technique has been demonstrated in studies of postoperative pain (Stein et al., 1991). These studies also suggest that peripherally acting opioid compounds would be effective in other selected circumstances without entering the CNS to cause many undesirable side effects. Development of such compounds and expansion of clinical applications of this technique currently 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 (De Conno et al., 1995). This route is not well tolerated in most children. Onset of action is seen within 10 minutes. In the United States, morphine, hydromorphone, and oxymorphone are available in rectal suppository formulation (American Pain Society, 1999).

Administration by Inhalation

Preliminary studies have shown that opioids delivered by nebulizer can be an effective means of analgesic drug delivery (Worsley et al., 1990; Higgins et al., 1991). However, constant supervision is required when administering the drug, and variable delivery to the lungs can cause differences in therapeutic effect. In addition, possible environmental contamination is a concern. However, development of the inhaled route could provide a more convenient and cost-effective, adjunctive method of analgesic delivery for patients experiencing chronic pain.

Oral Transmucosal Administration

Opioids can be absorbed through the oral mucosa more rapidly than through the stomach. Bioavailability is greater due to avoidance of first pass metabolism, and lipophilic opioids are better absorbed by this route than are hydrophilic compounds such as morphine (Weinberg et al., 1988). A transmucosal delivery system that suspends fentanyl in a dissolvable matrix has been approved for clinical use (ACTIQ). Its primary indication is for treatment of breakthrough cancer pain (Ashburn et al., 1989). In this setting, transmucosal fentanyl relieves pain within 15 minutes, and patients easily can titrate the appropriate dose. Transmucosal fentanyl also has been studied as a premedicant for children. However, this technique has been largely abandoned due to a substantial incidence of undesirable side effects such as respiratory depression, sedation, nausea, vomiting, and pruritus.

Transdermal or Iontophoretic Administration

Transdermal fentanyl patches are approved for use with 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 of heat (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 these kinetics do not appear to change with repeated applications (Portenoy, 1993). However, there may be a great deal of variability in plasma levels after a given dose. The plasma half-life after patch removal is about 17 hours. Thus, if excessive sedation or respiratory depression is experienced, antagonist infusions may need to be maintained for an extended period (Payne, 1992). 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). Fentanyl and sufentanil have been chemically modified and applied by iontophoresis in rats (Thysman and Preat, 1993). Effective analgesia was achieved in less than 1 hour, suggesting that iontophoresis could be a promising modality for postoperative pain. It should be noted that increasing the applied current will increase drug delivery and could lead to overdose. However, unlike transdermal opioids, a drug reservoir does not build up in the skin, thus limiting the duration of both main and side effects.

General Principles of Opioid Use

Opioid analgesics provide symptomatic relief of pain, but the underlying disease remains. The physician must weigh the benefits of this relief against any potential risk to the patient, which may be quite different in an acute compared with a chronic disease.

In acute problems, opioids will reduce the intensity of pain. However, physical signs (such as abdominal rigidity) will generally remain. Relief of pain also can facilitate history taking, examination, and the patient's ability to tolerate diagnostic procedures. Patients should not be evaluated inadequately because of the physician's unwillingness to prescribe analgesics, nor in most cases should analgesics be withheld for fear of obscuring the progression of underlying disease.

The problems that arise in the relief of pain associated with chronic conditions are more complex. Repeated daily administration eventually will produce tolerance and some degree of physical dependence. The degree will depend on the particular drug, the frequency of administration, and the quantity administered. The decision to control any chronic symptom, especially pain, by the repeated administration of an opioid must be made carefully. When pain is due to chronic, nonmalignant disease, measures other than opioid drugs should be employed to relieve chronic pain if they are effective and available. Such measures include the use of nonsteroidal antiinflammatory agents, local nerve block, antidepressant drugs, electrical stimulation, acupuncture, hypnosis, or behavioral modification (see Foley, 1985). However, highly selected subpopulations of chronic nonmalignant pain patients can be adequately maintained on opioids for extended periods of time (Portenoy, 1990).

In the usual doses, morphine-like drugs relieve suffering by altering the emotional component of the painful experience as well as by producing analgesia. Control of pain, especially chronic pain, must include attention to both psychological factors and the social impact of the illness that sometimes play dominant roles in determining the suffering experienced by the patient. In addition to emotional support, the physician also must consider the substantial variability in both the patient's capacity to tolerate pain and the response to opioids. As a result, some patients may require considerably more than the average dose of a drug to experience any relief from pain; others may require dosing at shorter intervals. Some clinicians, out of an exaggerated concern for the possibility of inducing addiction, tend to prescribe initial doses of opioids that are too small or given too infrequently to alleviate pain and then respond to the patient's continued complaints with an even more exaggerated concern about drug dependence, despite the high probability that the request for more drug is only the expected consequence of the inadequate dosage initially prescribed (see Sriwatanakul et al., 1983). It also is important to note that infants and children are probably more apt to receive inadequate treatment for pain than are adults due to communication difficulties, lack of familiarity with appropriate pain assessment methodologies, and inexperience with the use of strong opioids in children. If an illness or procedure causes pain for an adult, there is no reason to assume that it will produce less pain for a child (see Yaster and Deshpande, 1988).

Pain of Terminal Illness and Cancer Pain

Opioids are not indicated in all cases of terminal illness, but the analgesia, tranquility, and even the euphoria afforded by the use of opioids can make the final days far less distressing for the patient and family. Although physical dependence and tolerance may develop, this possibility should not in any way prevent physicians from fulfilling their primary obligation to ease the patient's discomfort. The physician should not wait until the pain becomes agonizing; no patient should ever wish for death because of a physician's reluctance to use adequate amounts of effective opioids. This may sometimes entail the regular use of opioid analgesics in substantial doses. Such patients, while they may be physically dependent, are not 'addicts' even though they may need large doses on a regular basis. Physical dependence is not equivalent to addiction (see Chapter 24: Drug Addiction and Drug Abuse).

Most clinicians who are experienced in the management of chronic pain associated with malignant disease or terminal illness recommend that opioids be administered at sufficiently short, fixed intervals so that pain is continually under control and patients do not dread its return (Foley, 1993). Less drug is needed to prevent the recurrence of pain than to relieve it. Morphine remains the opioid of choice in most of these situations, and the route and dose should be adjusted to the needs of the individual patient. Many clinicians find that oral morphine is adequate in most situations. Sustained-release preparations of oral morphine are now available that can be administered at 8- to 12-hour intervals. Superior control of pain often can be achieved with fewer side effects using the same daily dose; a decrease in the fluctuation of plasma concentrations of morphine may be partially responsible.

Constipation is an exceedingly common problem when opioids are used, and the use of stool softeners and laxatives should be initiated early. Amphetamines have demonstrable mood-elevating and analgesic effects and enhance opioid-induced analgesia. However, not all terminal patients require the euphoriant effects of amphetamine, and some experience side effects, such as anorexia. Controlled studies demonstrate no superiority of oral heroin over oral morphine. Similarly, after adjustment is made for potency, parenteral heroin is not superior to morphine in terms of analgesia, effects on mood, or side effects (see Sawynok, 1986). Although tolerance does develop to oral opioids, many patients obtain relief from the same dosage for weeks or months. In cases where one opioid loses effectiveness, switching to another may provide better pain relief. 'Cross-tolerance' among opioids exists, but, both clinically and experimentally, cross-tolerance among related -receptor agonists is not complete. The reasons for this are unclear, but they may relate to differences between agonists in receptor-binding characteristics and subsequent cellular signaling interactions, as discussed earlier in the chapter.

When opioids and other analgesics are no longer satisfactory, nerve block, chordotomy, or other types of neurosurgical intervention such as neurostimulation may be required if the nature of the disease permits. Epidural or intrathecal administration of opioids may be useful when administration of opioids by usual routes no longer yields adequate relief of pain (see above). This technique has been used with ambulatory patients over periods of weeks or months (see Gustafsson and Wiesenfeld-Hallin, 1988). Moreover, portable devices have been developed that permit the patient to control the parenteral administration of an opioid while remaining ambulatory (Kerr et al., 1988). These devices use a pump that infuses the drug from a reservoir at a rate that can be tailored to the needs of the patient, and they include mechanisms to limit dosage and/or allow the patient to self-administer an additional 'rescue' dose if there is a transient change in the intensity of pain.

Nonanalgesic Therapeutic Uses of Opioids

Dyspnea

Morphine is used to alleviate the dyspnea of acute left ventricular failure and pulmonary edema, and the response to intravenous morphine may be dramatic. The mechanism underlying this relief still 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 due 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 (see Vismara et al., 1976). Nitroglycerin, which also causes vasodilation, may be superior to morphine in this condition (see Hoffman and Reynolds, 1987). In patients with normal blood gases but severe breathlessness due to chronic obstruction of airflow ('pink puffers'), drocode (dihydrocodeine), 15 mg orally before exercise, reduces the feeling of breathlessness and increases exercise tolerance (Johnson et al., 1983). Opioids are relatively contraindicated in pulmonary edema due to respiratory irritants unless severe pain also is present; relative contraindications to the use of histamine-releasing opioids in asthma already have been discussed.

Special Anesthesia

High doses of morphine or other opioids have been used as the primary anesthetic agents in certain surgical procedures. Although respiration is so depressed that physical assistance is required, patients can retain consciousness (see Chapter 14: General Anesthetics).

Great strides are being made in understanding structure-function relationships between opioids and endogenous opioid peptides and their receptors. The complex signaling mechanisms and neural circuitry mediating both the salutary and undesirable effects of opioids also are beginning to be understood. The recent discovery of new receptor-selective endogenous opioid ligands and the opioid-related N/OFQ system also will provide opportunities to improve our understanding of opioid pharmacology and physiology. The development of new opioid analgesics and novel delivery routes are improving the care and quality of life for patients requiring opioids. Over the next several years, pursuing these lines of basic and clinical investigation should provide many valuable insights that may allow better targeting of the therapeutic effects of opioid compounds, thereby minimizing undesirable acute side effects and the potentially serious long-term consequences of tolerance and physical dependence. It also is hoped that these efforts will help overcome the less common, but devastating, problem of addiction.

Dedication

The authors would like to dedicate this chapter to the memory of Dr. Thomas F. Burks, colleague and friend, who had a major impact on the field of opioid pharmacology.

Acknowledgment

The authors wish to acknowledge Drs. Terry Reisine and Gavril Pasternak, authors of this chapter in the ninth edition of Goodman and Gilman's The Pharmacological Basis of Therapeutics, some of whose text has been retained in this edition.