Introduction

Morphine and most other clinically used opioid agonists exert their effects through m opioid receptors. These drugs affect a wide range of physiological systems. They produce analgesia, affect mood and rewarding behavior, and alter respiratory, cardiovascular, gastrointestinal, and neuroendocrine function. d Opioid receptor agonists also are potent analgesics in animals, and in some cases they have proved useful in humans (Moulin et al., 1985). Agonists selective for k receptors produce analgesia that has been shown in animals to be mediated primarily at spinal sites. Respiratory depression and miosis may be less severe with k agonists. Instead of euphoria, k receptor agonists produce dysphoric and psychotomimetic effects (Pfeiffer et al., 1986). In neural circuitry mediating reward and analgesia, m and k agonists have been shown to have antagonistic effects.

Mixed agonist-antagonist compounds were developed 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. 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 humans, 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 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 Therapeutic Uses of Opioid Analgesics, below). 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 generally is agreed that all types of painful experiences, whether produced experimentally or occurring clinically as a result of pathology, include 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, whereas 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 crucial to place them in their anatomical and physiological context to fully understand the opioid system. Pain control by opioids must be considered in the context of brain circuits modulating analgesia and the functions of the various receptor types in these circuits (Fields et al., 1991).

It is well established that the analgesic effects of opioids arise from their ability to directly inhibit 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). m-Opioid receptor mRNA and/or ligand binding is seen throughout the periaqueductal gray (PAG), pontine reticular 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 m-opioid receptor-mediated analgesia. For instance, the presence of significant m-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 m-receptor ligand-binding sites are located presynaptically on the terminals of primary afferent nociceptors. This conclusion is consistent with the high levels of m-opioid receptor mRNA observed in dorsal root ganglia (DRG). A similar mismatch between m-receptor ligand binding and mRNA expression is seen in the dorsolateral PAG (a high level of binding and sparse mRNA) (Gutstein et al., 1998). d-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 m-opioid receptor, there are significant numbers of d-opioid receptor-binding sites in the dorsal horn but no detectable mRNA expression, suggesting an important role for presynaptic actions of the d-opioid receptor in spinal analgesia. k-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, k-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. m-Opioid receptor mRNA is present in medium- and large-diameter DRG cells, d-opioid receptor mRNA in large-diameter cells, and k-opioid receptor mRNA in small- and medium-diameter cells (Mansour et al., 1995). This differential localization may be linked to functional differences in pain modulation.

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

As mentioned earlier, 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 may 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. Recently, the significance of this effect has been questioned. Trafton and colleagues (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 either that 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.

Paralleling the important insights into mechanisms of opioid-induced analgesia at the brainstem and spinal levels, progress also has been made in understanding forebrain mechanisms. The actions of opioids in bulbospinal pathways are crucial in their analgesic efficacy, but the precise role of forebrain actions of opioids and whether these actions are independent of those in bulbospinal pathways are less well defined. Opioid actions in the forebrain clearly 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 is 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. 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 by 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.

Simultaneous administration of morphine at 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., 1992). In addition to the well-described spinal/supraspinal synergy, synergistic m/m- and m/d-agonist interactions also have been observed within the brainstem between the PAG, 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 and will respond to peripherally applied opioids and locally released endogenous opioid compounds when up-regulated during inflammatory pain states (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). 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 peptides 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 is 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 is 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 (Koster et al., 1999). Intratheca1 injections of N/OFQ are analgesic (Xu et al., 1996); however, supraspinal administration has produced either hyperalgesia, antiopioid effects, or a biphasic hyperalgesic/analgesic response (Mogil and Pasternak, 2001). These conflicting findings may be explained in part by a study in which it was shown that N/OFQ inhibits 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 and the specific neural circuitry inhibited by N/OFQ (Heinricher, 2003).

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 data point 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), whereas the dorsal striatum is involved in sensorimotor and cognitive functions (Willner et al., 1991). The dorsal and ventral striata 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 called the core and the shell (Heimer et al., 1991). It is important to note that other reward-relevant brain regions (e.g., the lateral hypothalamus and the 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 m and d receptor agonists are rewarding when defined by place preference (Shippenberg et al., 1992) and intracranial self-administration (Devine and Wise, 1994) paradigms. Conversely, selective k receptor agonists produce aversive effects (Cooper, 1991; Shippenberg et al., 1992). Naloxone and selective m antagonists also produce aversive effects (Cooper, 1991). Positive motivational effects of opioids are mediated partially by dopamine release at the level of the NAcc. Thus k-receptor activation in these circuits inhibits dopamine release (Mulder and Schoffelmeer, 1993), whereas m and d receptor activation increases dopamine release (Devine et al., 1993). Distinctive cell clusters in the shell of the NAcc contain proenkephalin, prodynorphin, m receptors, and k receptors, as well as dopamine receptors. These clusters may constitute a region where the motivational properties of dopaminergic and opioid drugs are processed.

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

Other CNS Effects

Whereas 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 in the brain and the periphery. A brief summary of some of these effects is presented below. High doses of opioids can produce muscular rigidity in humans. Chest wall rigidity severe enough to compromise respiration is not uncommon during anesthesia with fentanyl, alfentanil, remifentanil, and sufentanil (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 (Martin, 1983).

Neuroendocrine Effects

Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and b-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 plasma concentrations of testosterone and cortisol decline. Secretion of thyrotropin is relatively unaffected.

The administration of m 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 b-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. 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 usually are within the normal range.

Although k-receptor agonists inhibit the release of antidiuretic hormone and cause diuresis, the administration of m-opioid receptor agonists tends to produce antidiuretic effects in humans.

Miosis

Morphine and most m and k agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. After toxic doses of m 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 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 (McGinty and Friedman, 1988). Selective d 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 m 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 (see Chapter 19).

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 humans, death from morphine poisoning is nearly always due to respiratory arrest. Therapeutic doses of morphine in humans 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 three or four 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. One important exception is when opioids are administered parenterally to women within 2 to 4 hours of delivery, which can lead to transient respiratory depression in the neonate because of transplacental passage of opioids. 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 of intravenous administration of morphine or within 30 or 90 minutes of intramuscular or subcutaneous administration, respectively.

Maximal respiratory depressant effects occur more rapidly with more lipid-soluble agents. After therapeutic doses, respiratory minute volume may be reduced for as long as 4 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 (Martin, 1983).

Hypoxic stimulation of chemoreceptors still may be effective when opioids have decreased the responsiveness to CO2, and the inhalation of O2 thus may produce apnea. After large doses of morphine or other m 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, and most have found that when equianalgesic doses are used, there is no significant difference. Severe respiratory depression is less likely after the administration of large doses of selective k agonists. High concentrations of opioid receptors and 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. Suppression of cough by such agents appears to involve receptors in the medulla that are less sensitive to naloxone than those responsible for analgesia.

Nauseant and Emetic Effects. Nausea and vomiting produced by morphine-like drugs are side effects caused by direct stimulation of the chemoreceptor trigger zone for emesis in the area postrema of the medulla. 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 m agonists produce some degree of nausea and vomiting. Careful, controlled clinical studies usually demonstrate that, in equianalgesic dosage, the incidence of such side effects is not significantly lower than that seen with morphine. Antagonists to the 5-HT3 serotonin receptor have supplanted phenothiazines and drugs used for motion sickness as the drugs of choice for the treatment of opioid-induced nausea and vomiting. Gastric prokinetic agents such as metoclopramide also are useful antinausea and antiemetic drugs.

Cardiovascular System

In the supine patient, therapeutic doses of morphinelike 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 usually is only partially blocked by H1 antagonists, but it is effectively reversed by naloxone. Morphine also blunts the reflex vasoconstriction caused by increased PCO2.

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 morphine administered intravenously produces a decrease in oxygen consumption, left ventricular end-diastolic pressure, and cardiac work; effects on cardiac index usually are slight. In patients with acute myocardial infarction, the cardiovascular responses to morphine may be more variable than in normal subjects, and the magnitude of changes (e.g., the decrease in blood pressure) may be more pronounced (Roth et al., 1988).

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

When administered before experimental ischemia, morphine has been shown to produce cardioprotective effects. Morphine can mimic the phenomenon of ischemic preconditioning, where a short ischemic episode paradoxically protects the heart against further ischemia. This effect appears to be mediated through d receptors signaling through a mitochondrial ATP-sensitive potassium channel in cardiac myocytes; the effect also is produced by other GPCRs signaling through Gi (Fryer et al., 2000). It also has been suggested recently that d opioids can be antiarrhythmic and antifibrillatory during and after periods of ischemia (Fryer et al., 2000), although other data suggest that d opioids can be arrhythmogenic (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 m 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 because these agents can aggravate hypovolemic shock. Morphine should be used with great care in patients with cor pulmonale because deaths after ordinary therapeutic doses have been reported. The concurrent use of certain phenothiazines may increase the risk of morphine-induced hypotension.

Cerebral circulation is not affected directly by therapeutic doses of 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 PCO2 is maintained at normal levels by artificial ventilation.

Gastrointestinal Tract

Stomach: Morphine and other m agonists usually decrease the secretion of hydrochloric acid, although stimulation sometimes is evident. Activation of opioid receptors on parietal cells enhances secretion, but indirect effects, including increased secretion of somatostatin from the pancreas and reduced release of acetylcholine, appear to be dominant in most circumstances (Kromer, 1988). Relatively low doses of morphine decrease gastric motility, thereby prolonging gastric emptying time; this can increase the likelihood of esophageal reflux. 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 (De Luca and Coupar, 1996) 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 decreased markedly. 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 (De Luca and Coupar, 1996; Kromer, 1988). Enteric muscle cells also may possess opioid receptors (Holzer, 2004). 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 in the submucosal plexus may be mediated in large part by the release of norepinephrine and stimulation of a2 adrenergic receptors on enterocytes.

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 augmented greatly, and reflex relaxation in response to rectal distension is reduced. These actions, combined with inattention to the normal sensory stimuli for defecation reflex owing to the central actions of the drug, contribute to morphine-induced constipation.

Mechanism of Action on the Bowel: The usual gastrointestinal effects of morphine primarily are mediated by m and d 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. 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 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 experience exacerbation rather than relief of pain when given opioids. Spasm of the sphincter of Oddi probably is responsible for elevations of plasma amylase and lipase that occur sometimes after morphine administration. All opioids can cause biliary spasm. Atropine only partially prevents morphine-induced biliary spasm, but opioid antagonists prevent or relieve it. Nitroglycerin (0.6 to 1.2 mg) administered sublingually also decreases the elevated intrabiliary pressure (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 increases the tone of the external sphincter and the volume of the bladder; catheterization sometimes is required after therapeutic doses of morphine. Stimulation of either m or d receptors in the brain or in the spinal cord exerts similar actions on bladder motility (Dray and Nunan, 1987). Tolerance develops to these effects of opioids on the bladder.

Uterus

If the uterus has been made hyperactive by oxytocics, morphine tends to restore the tone, frequency, and amplitude of contractions to normal.

Skin

Therapeutic doses of morphine cause dilation of cutaneous blood vessels. The skin of the face, neck, and upper thorax frequently becomes flushed. These changes may be due in part to the release of histamine and may be responsible for the sweating and some of the pruritus that occasionally follow the systemic administration of morphine (see below). Histamine release probably accounts for the urticaria commonly seen at the site of injection, which 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.

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 largely by dorsal horn neurons and is reversed by naloxone (Thomas et al., 1992).

Immune System

The effects of opioids on the immune system are complex. Opioids modulate immune function by direct effects on cells of the immune system and indirectly via centrally mediated neuronal mechanisms (Sharp and Yaksh, 1997). The acute central immunomodulatory effects of opioids may be mediated by activation of the sympathetic nervous system, whereas the chronic effects of opioids may involve modulation of the hypothalamic-pituitary-adrenal (HPA) axis (Mellon and Bayer, 1998). Direct effects on immune cells may involve unique, incompletely characterized variants of the classical neuronal opioid receptors, with d-receptor variants being most prominent (Sharp and Yaksh, 1997). Atypical receptors could account for the fact that it has been very difficult to demonstrate significant opioid binding on immune cells despite the observance of robust functional effects. In contrast, morphine-induced immune suppression largely is abolished in knockout mice lacking the m receptor gene, suggesting that the m receptor is a major target of morphine’s actions on the immune system (Gaveriaux-Ruff et al., 1998). A proposed mechanism for the immune suppressive effects of morphine on neutrophils is through a nitric oxide-dependent inhibition of NF-kB activation (Welters et al., 2000). Others have proposed that the induction and activation of MAP kinase also may play a role (Chuang et al., 1997).

The overall effects of opioids appear to be immunosuppressive, and increased susceptibility to infection and tumor spread have been observed. Infusion of the m-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, immune effects appear more prominent with acute administration than with chronic administration, which could have important implications for the care of the critically ill (Sharp and Yaksh, 1997). In contrast, opioids have been shown to reverse pain-induced immunosuppression and increase tumor metastatic potential in animal models (Page and Ben-Eliyahu, 1997). Therefore, opioids may either inhibit or augment immune function depending on the context in which they are used. These studies also indicate that withholding opioids in the presence of pain in immunocompromised patients actually could worsen immune function. An intriguing paper indicated that the partial m-receptor agonist buprenorphine (see below) did not alter immune function when injected centrally into the mesencephalic PAG, whereas morphine did (Gomez-Flores and Weber, 2000). Taken together, these studies indicate that opioid-induced immune suppression may be clinically relevant both to the treatment of severe pain and in the susceptibility of opioid addicts to infection [e.g., human immunodeficiency virus (HIV) infection and tuberculosis]. Different opioid agonists also may have unique immunomodulatory properties. Better understanding of these properties eventually should help to guide the rational use of opioids in patients with cancer or at risk for infection or immune compromise.

Sources: GOODMAN & GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, CHAPTER 21. OPIOID ANALGESICS – Howard B. Gutstein and Huda Akil

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