Basic and Clinical Pharmacology, 13th Ed.

Opioid Agonists & Antagonists*

Mark A. Schumacher, PhD, MD,

Allan I. Basbaum, PhD, & Ramana K. Naidu, MD

CASE STUDY

A 60-year-old man with a history of moderate chronic obstructive pulmonary disease presents in the emergency department with a broken hip suffered in an automobile accident. He complains of severe pain. What is the most appropriate immediate treatment for his pain? Are any special precautions needed?

Morphine, the prototypic opioid agonist, has long been known to relieve severe pain with remarkable efficacy. The opium poppy is the source of crude opium from which Sertürner in 1803 isolated morphine, the pure alkaloid, naming it after Morpheus, the Greek god of dreams. It remains the standard against which all drugs that have strong analgesic action are compared. These drugs are collectively known as opioids and include not only the natural and semisynthetic alkaloid derivatives from opium but also synthetic surrogates, other opioid-like drugs whose actions are blocked by the nonselective antagonist naloxone, plus several endogenous peptides that interact with the different subtypes of opioid receptors.

image BASIC PHARMACOLOGY OF THE OPIOIDS

Source

Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album. After incision, the poppy seed pod exudes a white substance that turns into a brown gum that is crude opium. Opium contains many alkaloids, the principal one being morphine, which is present in a concentration of about 10%. Codeine is synthesized commercially from morphine.

Classification & Chemistry

The term opioid describes all compounds that work at opioid receptors. The term opiate specifically describes the naturally occurring alkaloids: morphine, codeine, thebaine, and papaverine. In contrast, narcotic was originally used to describe sleep-inducing medications, but in the United States, its usage has shifted into a legal term.

Opioid drugs include full agonists, partial agonists, and antagonists–measures of intrinsic activity or efficacy. Morphine is a full agonist at the l (mu)-opioid receptor, the major analgesic opioid receptor (Table 31–1). Opioids may also differ in receptor binding affinity. For example, morphine exhibits a greater binding affinity at the μ-opioid receptor than does codeine. Other opioid receptor subtypes include c (delta)and j (kappa) receptors. Simple substitution of an allyl group on the nitrogen of the full agonist morphine plus addition of a single hydroxyl group results in naloxone, a strong μ-receptor antagonist. The structures of some of these compounds are shown later in this chapter. Some opioids, eg, nalbuphine, a mixed agonist-antagonist, are capable of producing an agonist (or partial agonist) effect at one opioid receptor subtype and an antagonist effect at another. The receptor-activating properties and affinities of opioid analgesics can be manipulated by pharmaceutical chemistry; in addition, certain opioid analgesics are modified in the liver, resulting in compounds with greater analgesic action. Chemically, the opioids derived from opium are phenanthrene derivatives and include four or more fused rings, while most of the synthetic opioids are simpler molecules.

TABLE 31–1 Opioid receptor subtypes, their functions, and their endogenous peptide affinities.

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Endogenous Opioid Peptides

Opioid alkaloids (eg, morphine) produce analgesia through actions at central nervous system (CNS) receptors that also respond to certain endogenous peptides with opioid-like pharmacologic properties. The general term currently used for these endogenous substances is endogenous opioid peptides.

Three families of endogenous opioid peptides have been described: the endorphins, the pentapeptide enkephalins (methionine-enkephalin [met-enkephalin] and leucine-enkephalin [leu-enkephalin]), and the dynorphins.These three families of endogenous opioid peptides have overlapping affinities for opioid receptors (Table 31–1).

The endogenous opioid peptides are derived from three precursor proteins: prepro-opiomelanocortin (POMC), preproenkephalin (proenkephalin A), and preprodynorphin (proenkephalin B). POMC contains the met-enkephalin sequence, β-endorphin, and several nonopioid peptides, including adrenocorticotropic hormone (ACTH), β-lipotropin, and melanocyte-stimulating hormone. Preproenkephalin contains six copies of met-enkephalin and one copy of leu-enkephalin. Leu- and met-enkephalin have slightly higher affinity for the δ (delta) than for the μ-opioid receptor (Table 31–1). Preprodynorphin yields several active opioid peptides that contain the leu-enkephalin sequence. These are dynorphin A, dynorphin B, and α and β neoendorphins. Painful stimuli can evoke release of endogenous opioid peptides under the stress associated with pain or the anticipation of pain, and they diminish the perception of pain.

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to κ-opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord. Increased levels of dynorphin occur in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting sensitization and hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system. This pronociceptive effect may involve an action via dynorphin A binding to the N-methyl-D-aspartate (NMDA)-receptor complex and possibly to a novel receptor-ligand system homologous to the opioid peptides.

The principal receptor for this novel system is the G protein-coupled orphanin opioid-receptor-like subtype 1 (ORL1). Its endogenous ligand has been termed nociceptin by one group of investigators and orphanin FQ by another group. This ligand-receptor system is currently known as the N/OFQ system. Nociceptin is structurally similar to dynorphin except for the absence of an N-terminal tyrosine; it acts only at the ORL1 receptor, now known as NOP. The N/OFQ system is widely expressed in the CNS and periphery, reflecting its equally diverse biology and pharmacology. As a result of experiments using highly selective NOP receptor ligands, the N/OFQ system has been implicated in both pro- and anti-nociceptive activity as well as in the modulation of drug reward, learning, mood, anxiety, and cough processes, and of parkinsonism.

Pharmacokinetics

Properties of clinically important opioids are summarized in Table 31–2.

TABLE 31–2 Common opioid analgesics.

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A. Absorption

Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes. However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) to elicit a therapeutic effect may need to be much higher than the parenteral dose. As there is considerable interpatient variability in first-pass opioid metabolism, prediction of an effective oral dose is difficult. Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism. By avoiding first-pass metabolism, nasal insufflation of certain opioids can rapidly result in therapeutic blood levels. Other routes of opioid administration include oral mucosa via lozenges, and the transdermal route via patches. The latter can provide delivery of potent analgesics over days.

B. Distribution

The uptake of opioids by various organs and tissues is a function of both physiologic and chemical factors. Although all opioids bind to plasma proteins with varying affinity, the drugs rapidly leave the blood compartment and localize in highest concentrations in highly perfused tissues such as the brain, lungs, liver, kidneys, and spleen. Drug concentrations in skeletal muscle may be much lower, but this tissue serves as the main reservoir because of its greater bulk. Even though blood flow to fatty tissue is much lower than to the highly perfused tissues, accumulation can be very important, particularly after frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl.

C. Metabolism

The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys. For example, morphine, which contains free hydroxyl groups, is primarily conjugated to morphine-3-glucuronide (M3G), a compound with neuroexcitatory properties. The neuroexcitatory effects of M3G do not appear to be mediated by μ receptors and are under further study. In contrast, approximately 10% of morphine is metabolized to morphine- 6-glucuronide (M6G), an active metabolite with analgesic potency four to six times that of its parent compound. However, these relatively polar metabolites have limited ability to cross the blood-brain barrier and probably do not contribute significantly to the usual CNS effects of a single dose of morphine. Importantly, accumulation of these metabolites may produce unexpected adverse effects in patients with renal failure or when exceptionally large doses of morphine are administered or high doses are administered over long periods. This can result in M3G-induced CNS excitation (seizures) or enhanced and prolonged opioid action produced by M6G. CNS uptake of M3G and, to a lesser extent, M6G can be enhanced by co-administration of probenecid or of drugs that inhibit the P-glycoprotein drug transporter.

1. Hepatic P450 metabolismHepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids (fentanyl, meperidine, alfentanil, sufentanil) and eventually leaves only small quantities of the parent compound unchanged for excretion. However, accumulation of a demethylated metabolite of meperidine, normeperidine, may occur in patients with decreased renal function and in those receiving multiple high doses of the drug. In high concentrations, normeperidine may cause seizures. In contrast, no active metabolites of fentanyl have been reported. The P450 isozyme CYP3A4 metabolizes fentanyl by N-dealkylation in the liver. CYP3A4 is also present in the mucosa of the small intestine and contributes to the first-pass metabolism of fentanyl when it is taken orally.

Codeine, oxycodone, and hydrocodone undergo metabolism in the liver by P450 isozyme CYP2D6, resulting in the production of metabolites of greater potency. For example, codeine is demethylated to morphine, which is then conjugated. Hydrocodone is metabolized to hydromorphone and, like morphine, hydromorphone is conjugated, yielding hydromorphone-3-glucuronide (H3G), which has CNS excitatory properties. Hydromorphone cannot form a 6-glucuronide metabolite. Similarly, oxycodone is metabolized to oxymorphone, which is then conjugated to oxymorphone-3-glucuronide (O3G).

Genetic polymorphism of CYP2D6 has been documented and linked to the variation in analgesic and adverse responses seen among patients. In contrast, the metabolites of oxycodone and hydrocodone may be of minor consequence; the parent compounds are currently believed to be directly responsible for the majority of their analgesic actions. However, oxycodone and its metabolites can accumulate under conditions of renal failure and have been associated with prolonged action and sedation. In the case of codeine, conversion to morphine may be of greater importance because codeine itself has relatively low affinity for opioid receptors. As a result, some patients (so-called poor metabolizers) may experience no significant analgesic effect. In contrast, there have been case reports of an exaggerated response to codeine due to enhanced metabolic conversion to morphine (ie, ultra rapid metabolizers; see Chapters 45) resulting in respiratory depression and death. For this reason, routine use of codeine, especially in pediatric age groups, is now being eliminated in the United States.

2. Plasma esterase metabolismEsters (eg, heroin, remifentanil) are rapidly hydrolyzed by common plasma and tissue esterases. Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid.

D. Excretion

Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine. Small amounts of unchanged drug may also be found in the urine. In addition, glucuronide conjugates are found in the bile, but enterohepatic circulation represents only a small portion of the excretory process of these polar metabolites. In patients with renal impairment the effects of active polar metabolites should be considered before the administration of potent opioids such as morphine or hydromorphone—especially when given at high doses—due to the risk of sedation and respiratory depression.

Pharmacodynamics

A. Mechanism of Action

Opioid agonists produce analgesia by binding to specific G protein-coupled receptors that are located in brain and spinal cord regions involved in the transmission and modulation of pain (Figure 31–1). Some effects may be mediated by opioid receptors on peripheral sensory nerve endings.

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FIGURE 31–1 Potential receptor mechanisms of analgesic drugs. The primary afferent neuron (cell body not shown) originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters with the secondary neuron. Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at μ-opioid receptors (MOR) or blocked in the afferent axon by local anesthetics (not shown). Action potentials reaching the dorsal horn can be attenuated at the presynaptic ending by opioids and by calcium blockers (ziconotide), α2 agonists, and possibly, by drugs that increase synaptic concentrations of norepinephrine by blocking reuptake (tapentadol). Opioids also inhibit the postsynaptic neuron, as do certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.

1. Receptor typesAs noted previously, three major classes of opioid receptors (μ, δ, and κ) have been identified in various nervous system sites and in other tissues (Table 31–1). Each of the three major receptors has now been cloned. All are members of the G protein-coupled family of receptors and show significant amino acid sequence homologies. Multiple receptor subtypes have been proposed based on pharmacologic criteria, including μ1, μ2; δ1, δ2; and κ1, κ2, and κ3. However, genes encoding only one subtype from each of the μ, δ, and κ receptor families have thus far been isolated and characterized. One plausible explanation is that μ-receptor subtypes arise from alternate splice variants of a common gene. This idea has been supported by the identification of receptor splice variants in mice and humans, and a recent report pointed to the selective association of a μ-opioid receptor splice variant (MOR1D) with the induction of itch rather than the suppression of pain.

Since an opioid may function with different potencies as an agonist, partial agonist, or antagonist at more than one receptor class or subtype, it is not surprising that these agents are capable of diverse pharmacologic effects.

2. Cellular actionsAt the molecular level, opioid receptors form a family of proteins that physically couple to G proteins and through this interaction affect ion channel gating, modulate intracellular Ca2+disposition, and alter protein phosphorylation (see Chapter 2). The opioids have two well-established direct Gi/0 protein-coupled actions on neurons: (1) they close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release, and (2) they open K+ channels and hyperpolarize and thus inhibit postsynaptic neurons. Figure 31–1 schematically illustrates these effects. The presynaptic action—depressed transmitter release—has been demonstrated for a large number of neurotransmitters, including glutamate, the principal excitatory amino acid released from nociceptive nerve terminals, as well as acetylcholine, norepinephrine, serotonin, and substance P.

3. Relation of physiologic effects to receptor typeThe majority of currently available opioid analgesics act primarily at the μ-opioid receptor (Table 31–2). Analgesia and the euphoriant, respiratory depressant, and physical dependence properties of morphine result principally from actions at μ receptors. In fact, the μ receptor was originally defined using the relative potencies for clinical analgesia of a series of opioid alkaloids. However, opioid analgesic effects are complex and include interaction with δ and κ receptors. This is supported in part by the study of genetic knockouts of the μ, δ, and κ genes in mice. The development of μ-receptor–selective agonists could be clinically useful if their side-effect profiles (respiratory depression, risk of dependence) were more favorable than those found with current μ-receptor agonists, such as morphine. Although morphine does act at κ and δ receptor sites, it is unclear to what extent this contributes to its analgesic action. The endogenous opioid peptides differ from most of the alkaloids in their affinity for the δ and κ receptors (Table 31–1).

In an effort to develop opioid analgesics with a reduced incidence of respiratory depression or propensity for addiction and dependence, compounds that show preference for κ opioid receptors have been developed. Butorphanol and nalbuphine have shown some clinical success as analgesics, but they can cause dysphoric reactions and have limited potency. It is interesting that butorphanol has also been shown to cause significantly greater analgesia in women than in men. In fact, gender-based differences in analgesia mediated by μ- and δ-receptor activation have been widely reported.

4. Receptor distribution and neural mechanisms of analgesiaOpioid receptor binding sites have been localized autoradiographically with high-affinity radioligands and with antibodies to unique peptide sequences in each receptor subtype. All three major receptors are present in high concentrations in the dorsal horn of the spinal cord. Receptors are present both on spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them (Figure 31–2, sites A and B). Although opioid agonists directly inhibit dorsal horn pain transmission neurons, they also inhibit the release of excitatory transmitters from the primary afferents. Although there are reports that heterodimerization of the μ-opioid and δ-opioid receptors contributes to μ-agonist efficacy (eg, inhibition of presynaptic voltage-gated calcium channel activity), a recent study using a transgenic mouse that expresses a δ-receptor–enhanced green fluorescent protein (eGFP) fusion protein showed little overlap of μ receptor and δ receptor in dorsal root ganglion neurons. Importantly, the μ receptor is associated with TRPV1 and peptide (substance P)-expressing nociceptors, whereas δ-receptor expression predominates in the non-peptidergic population of nociceptors, including many primary afferents with myelinated axons. This finding is consistent with the action of intrathecal μ-receptor– and δ-receptor–selective ligands that are found to block heat versus mechanical pain processing, respectively. Very recently, an association of the δ but not the μ receptor with large diameter mechanoreceptive afferents has been described. To what extent the differential expression of the μ receptor and δ receptor in the dorsal root ganglia is characteristic of neurons throughout the CNS remains to be determined.

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FIGURE 31–2 Putative sites of action of opioid analgesics. Sites of action on the afferent pain transmission pathway from the periphery to the higher centers are shown. A: Direct action of opioids on inflamed or damaged peripheral tissues (see Figure 31–1 for detail). B: Inhibition also occurs in the spinal cord (see Figure 31–1). C: Possible sites of action in the thalamus.

The fact that opioids exert a powerful analgesic effect directly on the spinal cord has been exploited clinically by direct application of opioid agonists to the spinal cord. This spinal action provides a regional analgesic effect while reducing the unwanted respiratory depression, nausea and vomiting, and sedation that may occur from the supraspinal actions of systemically administered opioids.

Under most circumstances, opioids are given systemically and thus act simultaneously at multiple sites. These include not only the ascending pathways of pain transmission beginning with specialized peripheral sensory terminals that transduce painful stimuli (Figure 31–2) but also descending (modulatory) pathways (Figure 31–3). At these sites as at others, opioids directly inhibit neurons; yet this action results in the activation of descending inhibitory neurons that send processes to the spinal cord and inhibit pain transmission neurons. This activation has been shown to result from the inhibition of inhibitory neurons in several locations (Figure 31–4). Taken together, interactions at these sites increase the overall analgesic effect of opioid agonists.

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FIGURE 31–3 Brainstem local circuitry underlying the modulating effect of μ-opioid receptor (MOR)–mediated analgesia on descending pathways. The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord (see Figure 31–4).

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FIGURE 31–4 Opioid analgesic action on the descending inhibitory pathway. Sites of action of opioids on pain-modulating neurons in the midbrain and medulla including the midbrain periaqueductal gray area (A), rostral ventral medulla (B), and the locus caeruleus indirectly control pain transmission pathways by enhancing descending inhibition to the dorsal horn (C).

When pain-relieving opioid drugs are given systemically, they presumably act upon neuronal circuits normally regulated by endogenous opioid peptides and part of the pain-relieving action of exogenous opioids may involve the release of endogenous opioid peptides. For example, an exogenous opioid agonist (eg, morphine) may act primarily and directly at the μ receptor, but this action may evoke the release of endogenous opioids that additionally act at δ and κ receptors. Thus, even a receptor-selective ligand can initiate a complex sequence of events involving multiple synapses, transmitters, and receptor types.

Animal and human clinical studies demonstrate that both endogenous and exogenous opioids can also produce analgesia at sites outside the CNS. Pain associated with inflammation seems especially sensitive to these peripheral opioid actions. The presence of functional μ receptors on the peripheral terminals of sensory neurons supports this hypothesis. Furthermore, activation of peripheral μ receptors results in a decrease in sensory neuron activity and transmitter release. The endogenous release of β-endorphin produced by immune cells within injured or inflamed tissue represents one source of physiologic peripheral μ-receptor activation. Intra-articular administration of opioids, eg, following arthroscopic knee surgery, has shown clinical benefit for up to 24 hours. For this reason opioids selective for a peripheral site of action may be useful adjuncts in the treatment of inflammatory pain (see Box: Ion Channels & Novel Analgesic Targets). Such compounds could have the additional benefit of reducing unwanted effects such as nausea.

5. Tolerance and dependenceWith frequently repeated therapeutic doses of morphine or its surrogates, there is a gradual loss in effectiveness; this loss of effectiveness is termed tolerance. To reproduce the original response, a larger dose must be administered. Along with tolerance, physical dependence develops. Physical dependence is defined as a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered (see also Chapter 32).

The mechanism of development of opioid tolerance and physical dependence is poorly understood, but persistent activation of μ receptors such as occurs with the treatment of severe chronic pain appears to play a primary role in its induction and maintenance. Current concepts have shifted away from tolerance being driven by a simple up-regulation of the cyclic adenosine monophosphate (cAMP) system. Although this process is associated with tolerance, it is not sufficient to explain it. A second hypothesis for the development of opioid tolerance and dependence is based on the concept of receptor recycling.Normally, activation of μ receptors by endogenous ligands results in receptor endocytosis followed by resensitization and recycling of the receptor to the plasma membrane (see Chapter 2). However, using genetically modified mice, research now shows that the failure of morphine to induce endocytosis of the μ-opioid receptor is an important component of tolerance and dependence. In further support of this idea, methadone, a μ-receptor agonist used for the treatment of opioid tolerance and dependence, induces receptor endocytosis. This suggests that maintenance of normal sensitivity of μ receptors requires reactivation by endocytosis and recycling.

The concept of receptor uncoupling has also gained prominence. Under this hypothesis, tolerance results from a dysfunction of structural interactions between the μ receptor and G proteins, second-messenger systems, and their target ion channels. Uncoupling and recoupling of μ receptor function is likely linked to receptor recycling. Moreover, the NMDA-receptor ion channel complex has been shown to play a critical role in tolerance development and maintenance. Consistent with this hypothesis, NMDA-receptor antagonists such as ketamine can block tolerance development. Although a role in endocytosis is not yet clearly defined, the development of novel NMDA-receptor antagonists or other strategies to recouple μ receptors to their target ion channels provides hope for achieving a clinically effective means to prevent or reverse opioid analgesic tolerance.

6. Opioid-induced hyperalgesiaIn addition to the development of tolerance, persistent administration of opioid analgesics can increase the sensation of pain, resulting in a state of hyperalgesia. This phenomenon can be produced with several opioid analgesics, including morphine, fentanyl, and remifentanil. Spinal dynorphin and activation of the bradykinin and NMDA receptors have emerged as important candidates for the mediation of opioid-induced hyperalgesia. This is one more reason why the use of opioids for chronic pain is controversial.

B. Organ System Effects of Morphine and Its Surrogates

The actions described below for morphine, the prototypic opioid agonist, can also be observed with other opioid agonists, partial agonists, and those with mixed receptor effects. Characteristics of specific members of these groups are discussed below.

1. Central nervous system effectsThe principal effects of opioid analgesics with affinity for μ receptors are on the CNS; the more important ones include analgesia, euphoria, sedation, and respiratory depression. With repeated use, a high degree of tolerance occurs to all of these effects (Table 31–3).

TABLE 31–3 Degrees of tolerance that may develop to some of the effects of the opioids.

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Ion Channels & Novel Analgesic Targets

Even the most severe acute pain (lasting hours to days) can usually be well controlled—with significant but tolerable adverse effects—using currently available analgesics, especially the opioids. Chronic pain (lasting weeks to months), however, is not very satisfactorily managed with opioids. It is now known that in chronic pain, receptors on sensory nerve terminals in the periphery contribute to increased excitability of sensory nerve endings (peripheral sensitization). The hyperexcitable sensory neuron bombards the spinal cord, leading to increased excitability and synaptic alterations in the dorsal horn (central sensitization). Such changes are likely important contributors to chronic inflammatory and neuropathic pain states.

In the effort to discover better analgesic drugs for chronic pain, renewed attention is being paid to the molecular basis of peripheral sensory transduction. Potentially important ion channels associated with the primary afferent nociceptor include members of the transient receptor potential family, notably the capsaicin receptor, TRPV1 (which is activated by multiple noxious stimuli such as heat, protons, and products of inflammation) as well as TRPA1, activated by inflammatory mediators; and P2X receptors (which are responsive to purines released from tissue damage). Special subtypes of voltage-gated sodium channels (Nav 1.7, 1.8, 1.9) are uniquely associated with nociceptive neurons in dorsal root ganglia. Lidocaine and mexiletine, which are useful in some chronic pain states, may act by blocking this class of channels. Certain centipede toxins appear to selectively inhibit Nav 1.7 channels and may also be useful in the treatment of chronic pain. Genetic polymorphisms of Nav 1.7 are associated with either absence or predisposition to pain. Because of the importance of their peripheral sites of action, therapeutic strategies that deliver agents that block peripheral pain transduction or transmission have been introduced in the form of transdermal patches and balms. In addition, products that systemically target peripheral TRPV1, TRPA1 and sodium channel function are in development.

Ziconotide, a blocker of voltage-gated N-type calcium channels, is approved for intrathecal analgesia in patients with refractory chronic pain. Ziconotide is a synthetic peptide related to the marine snail toxin ω-conotoxin, which selectively blocks N-type calcium channels. Gabapentin/pregabalin, anticonvulsant analogs of GABA (see Chapter 24) that are effective treatments for neuropathic (nerve injury) pain act at the α2δ1 subunit of voltage-gated calcium channels. N-methyl-d-aspartate (NMDA) receptors appear to play a very important role in central sensitization at both spinal and supraspinal levels. Although certain NMDA antagonists have demonstrated analgesic activity (eg, ketamine), it has been difficult to find agents with an acceptably low profile of adverse effects or neurotoxicity. However, ketamine infused at very small doses improves analgesia and can reduce opioid requirements under conditions of opioid tolerance, eg, after major abdominal and spinal surgery. GABA and acetylcholine (through nicotinic receptors) appear to control the central synaptic release of several transmitters involved in nociception. Nicotine itself and certain nicotine analogs cause analgesia, and their use for postoperative analgesia is under investigation. Use of antibodies that bind nerve growth factor (NGF) has been shown to block inflammatory and back pain and is awaiting FDA approval. Finally, work on cannabinoids and vanilloids and their receptors suggest that Δ9- tetrahydrocannabinol, which acts primarily on CB1 cannabinoid receptors, can synergize with μ-receptor analgesics and interact with the TRPV1 capsaicin receptor to produce analgesia under certain circumstances.

As our understanding of peripheral and central pain transduction improves, additional therapeutic targets and strategies will become available. Combined with our present knowledge of opioid analgesics, a “multimodal” approach to pain therapy is emerging. Multimodal analgesia involves the administration of multiple agents (eg, NSAIDs, gabapentinoids, selective norepinephrine receptor inhibitors, etc) with complementary mechanisms of action to provide analgesia that is superior to that provided by an individual compound. Another benefit of multimodal analgesia is reduced opioid requirements with fewer adverse effects.

a. AnalgesiaPain consists of both sensory and affective (emotional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience. In contrast, nonsteroidal anti-inflammatory analgesic drugs, eg, ibuprofen, have no significant effect on the emotional aspects of pain.

b. EuphoriaTypically, patients or intravenous drug users who receive intravenous morphine experience a pleasant floating sensation with lessened anxiety and distress. However, dysphoria, an unpleasant state characterized by restlessness and malaise, may also occur.

c. SedationDrowsiness and clouding of mentation are common effects of opioids. There is little or no amnesia. Sleep is induced by opioids more frequently in the elderly than in young, healthy individuals. Ordinarily, the patient can be easily aroused from this sleep. However, the combination of morphine with other central depressant drugs such as the sedative-hypnotics may result in very deep sleep. Marked sedation occurs more frequently with compounds closely related to the phenanthrene derivatives and less frequently with the synthetic agents such as meperidine and fentanyl. In standard analgesic doses, morphine (a phenanthrene) disrupts normal rapid eye movement (REM) and non-REM sleep patterns. This disrupting effect is probably characteristic of all opioids. In contrast to humans, a number of other species (cats, horses, cows, pigs) may manifest excitation rather than sedation when given opioids. These paradoxical effects are at least partially dose-dependent.

d. Respiratory depressionAll of the opioid analgesics can produce significant respiratory depression by inhibiting brainstem respiratory mechanisms. Alveolar PCO2 may increase, but the most reliable indicator of this depression is a depressed response to a carbon dioxide challenge. The respiratory depression is dose-related and is influenced significantly by the degree of sensory input occurring at the time. For example, it is possible to partially overcome opioid-induced respiratory depression by a variety of stimuli. When strongly painful stimuli that have prevented the depressant action of a large dose of an opioid are relieved, respiratory depression may suddenly become marked. A small to moderate decrease in respiratory function, as measured by PaCO2 elevation, may be well tolerated in the patient without prior respiratory impairment. However, in individuals with increased intracranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated. Opioid-induced respiratory depression remains one of the most difficult clinical challenges in the treatment of severe pain. Ongoing research to overcome this problem is focused on μ-receptor pharmacology and serotonin signaling pathways in the brainstem respiratory control centers.

e. Cough suppressionSuppression of the cough reflex is a well-recognized action of opioids. Codeine in particular has been used to advantage in persons suffering from pathologic cough. However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis.

f. MiosisConstriction of the pupils is seen with virtually all opioid agonists. Miosis is a pharmacologic action to which little or no tolerance develops, even in highly tolerant addicts (Table 31–3); thus, it is valuable in the diagnosis of opioid overdose. This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine.

g. Truncal rigiditySeveral opioids can intensify tone in the large trunk muscles. It was originally believed that truncal rigidity involved a spinal cord action of these drugs, but a supraspinal action is likely. Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly lipid-soluble opioids (eg, fentanyl, sufentanil, alfentanil, remifentanil) are rapidly administered intravenously. Truncal rigidity may be overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.

h. Nausea and vomitingThe opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting. As ambulation seems to increase the incidence of nausea and vomiting there may also be a vestibular component in this effect.

i. TemperatureHomeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain. For example, administration of μ-opioid receptor agonists, such as morphine to the anterior hypothalamus produces hyperthermia, whereas administration of κ agonists induces hypothermia.

j. Sleep architectureAlthough the mechanism by which opioids interact with circadian rhythm is unclear, they can decrease the percentage of stage 3 and 4 sleep, which may result in fatigue and other sleep disorders, including sleep-disordered breathing and central sleep apnea.

2. Peripheral effects

a. Cardiovascular systemMost opioids have no significant direct effects on the heart and, other than bradycardia, no major effects on cardiac rhythm. Meperidine is an exception to this generalization because its antimuscarinic action can result in tachycardia. Blood pressure is usually well maintained in subjects receiving opioids unless the cardiovascular system is stressed, in which case hypotension may occur. This hypotensive effect is probably due to peripheral arterial and venous dilation, which has been attributed to a number of mechanisms including central depression of vasomotor-stabilizing mechanisms and release of histamine. No consistent effect on cardiac output is seen, and the electrocardiogram is not significantly affected. However, caution should be exercised in patients with decreased blood volume, because the above mechanisms make these patients susceptible to hypotension. Opioid analgesics affect cerebral circulation minimally except when PCO2 rises as a consequence of respiratory depression. Increased PCO2 leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.

b. Gastrointestinal tractConstipation has long been recognized as an effect of opioids, an effect that does not diminish with continued use. That is, tolerance does not develop to opioid-induced constipation (Table 31–3). Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the opioids are mediated through an action on the enteric nervous system (see Chapter 6) as well as the CNS. In the stomach, motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase—particularly in the central portion; gastric secretion of hydrochloric acid is decreased. Small intestine resting tone is increased, with periodic spasms, but the amplitude of nonpropulsive contractions is markedly decreased. In the large intestine, propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation. The large bowel actions are the basis for the use of opioids in the management of diarrhea, and constipation is a major problem in the use of opioids for control of severe cancer pain.

c. Biliary tractThe opioids contract biliary smooth muscle, which can result in biliary colic. The sphincter of Oddi may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels.

d. RenalRenal function is depressed by opioids. It is believed that in humans this is chiefly due to decreased renal plasma flow. In addition, μ opioids have an antidiuretic effect in humans. Mechanisms may involve both the CNS and peripheral sites. Opioids also enhance renal tubular sodium reabsorption. The role of opioid-induced changes in antidiuretic hormone (ADH) release is controversial. Ureteral and bladder tone are increased by therapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate urinary retention, especially in postoperative patients. Occasionally, ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone.

e. UterusThe opioid analgesics may prolong labor. Although the mechanism for this action is unclear, both μ- and κ-opioid receptors are expressed in human uterine muscle. Fentanyl and meperidine (pethidine) inhibit uterine contractility but only at supraclinical concentrations; morphine had no reported effects. In contrast, the κ agonist [3H]-D-ala2,L-met5-enkephalinamide (DAMEA) inhibits contractility in human uterine muscle strips.

f. EndocrineOpioids stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone (Table 31–1). These effects suggest that endogenous opioid peptides, through effects in the hypothalamus, modulate these systems. Patients receiving chronic opioid therapy can have low testosterone resulting in decreased libido, energy, and mood. Women can experience dysmenorrhea or amenorrhea.

g. PruritusThe opiates, such as morphine and codeine, produce flushing and warming of the skin accompanied sometimes by sweating, urticaria, and itching. Although peripheral histamine release is an important contributor, all opioids can cause pruritus via a central (spinal cord and medullary) action on pruritoceptive neural circuits. When opioids are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso. The incidence of opioid-induced pruritus via the neuraxial route is high, estimated at 70–100%. However, studies have demonstrated the efficacy of selective κ agonists (eg, nalfurafine) in the treatment of itch.

h. ImmuneThe opioids modulate the immune system by effects on lymphocyte proliferation, antibody production, and chemotaxis. In addition, leucocytes migrate to the site of tissue injury and release opioid peptides, which in turn help counter inflammatory pain. However, natural killer cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids, which may play a role in tumor progression. Although the mechanisms involved are complex, activation of central opioid receptors could mediate a significant component of the changes observed in peripheral immune function. These effects are mediated by the sympathetic nervous system in the case of acute administration and by the hypothalamic-pituitary-adrenal system in the case of prolonged administration of opioids.

image CLINICAL PHARMACOLOGY OF THE OPIOID ANALGESICS

Successful treatment of pain is a challenging task that begins with careful attempts to assess the source and magnitude of the pain. The amount of pain experienced by the patient is often measured by means of a pain Numeric Rating Scale (NRS) or less frequently by marking a line on a Visual Analog Scale (VAS) with word descriptors ranging from no pain (0) to excruciating pain (10). In either case, values indicate the magnitude of pain as: mild (1–3), moderate (4–6), or severe (7–10). A similar scale can be used with children (Face, Legs, Activity, Cry, Consolability [FLACC] or Wong-Baker scales) and with patients who cannot speak; the Wong-Baker scale depicts five faces ranging from smiling (no pain) to crying (maximum pain). There are specialized scales for patients with specific conditions including rheumatoid arthritis and dementia. More comprehensive questionnaires such as the McGill Pain Questionnaire address the multiple facets of pain.

For a patient in severe pain, administration of an opioid analgesic is usually considered a primary part of the overall management plan. Determining the route of administration (oral, parenteral, neuraxial), duration of drug action, ceiling effect (maximal intrinsic activity), duration of therapy, potential for adverse effects, and the patient’s past experience with opioids all should be addressed. One of the principal errors made by physicians in this setting is failure to assess adequately a patient’s pain and to match its severity with an appropriate level of therapy. Just as important is the principle that following delivery of the therapeutic plan, its effectiveness must be reevaluated and the plan modified, if necessary, if the response was excessive or inadequate.

Use of opioid drugs in acute situations should be contrasted with their use in chronic pain management, in which a multitude of other factors must be considered, including the development of tolerance to and physical dependence on opioid analgesics.

Clinical Use of Opioid Analgesics

A. Analgesia

Severe, constant pain is usually relieved with opioid analgesics having high intrinsic activity (see Table 31–2), whereas sharp, intermittent pain does not appear to be as effectively controlled.

The pain associated with cancer and other terminal illnesses must be treated aggressively and often requires a multidisciplinary approach for effective management. Such conditions may require continuous use of potent opioid analgesics and are associated with some degree of tolerance and dependence. However, this should not be used as a barrier to providing patients with the best possible care and quality of life. The World Health Organization Ladder (see http://www.who.int/cancer/palliative/painladder/en/) was created in 1986 to promote awareness of the optimal treatment of pain for individuals with cancer and has helped improve pain care for cancer patients worldwide. Research in the hospice setting has also demonstrated that fixed-interval administration of opioid medication (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand. New dosage forms of opioids that allow slower release of the drug are now available, eg, sustained-release forms of morphine (MS Contin) and oxycodone (OxyContin). Their purported advantage is a longer and more stable level of analgesia. However, there is little evidence to support long-term (greater than 6 months) use of sustained release opioids to manage chronic pain in the non-cancer patient.

If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, then a fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for short episodes of breakthrough pain (see Alternative Routes of Administration). Administration of strong opioids by nasal insufflation is also efficacious, and nasal preparations are now available in some countries. Approval of such formulations in the USA is growing. In addition, stimulant drugs such as the amphetamines can enhance the analgesic actions of opioids and thus may be very useful adjuncts in the patient with chronic pain.

Opioid analgesics are often used during obstetric labor. Because opioids cross the placental barrier and reach the fetus, care must be taken to minimize neonatal depression. If it occurs, immediate injection of the antagonist naloxone will reverse the depression. The phenylpiperidine drugs (eg, meperidine) appear to produce less depression, particularly respiratory depression, in newborn infants than does morphine; this may justify their use in obstetric practice.

The acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief. However, the drug-induced increase in smooth muscle tone may cause a paradoxical increase in pain secondary to increased spasm. An increase in the dose of opioid is usually successful in providing adequate analgesia.

B. Acute Pulmonary Edema

The relief produced by intravenous morphine in patients with dyspnea from pulmonary edema associated with left ventricular heart failure is remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath) and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). However, if respiratory depression is a problem, furosemide may be preferred for the treatment of pulmonary edema. On the other hand, morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema.

C. Cough

Suppression of cough can be obtained at doses lower than those needed for analgesia. However, in recent years the use of opioid analgesics to allay cough has diminished largely because of the availability of a number of effective synthetic compounds that are neither analgesic nor addictive. These agents are discussed below.

D. Diarrhea

Diarrhea from almost any cause can be controlled with the opioid analgesics, but if diarrhea is associated with infection such use must not substitute for appropriate chemotherapy. Crude opium preparations (eg, paregoric) were used in the past to control diarrhea, but now synthetic surrogates with more selective gastrointestinal effects and few or no CNS effects, eg, diphenoxylate or loperamide, are used. Several preparations are available specifically for this purpose (see Chapter 62).

E. Shivering

Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to have the most pronounced anti-shivering properties. Meperidine apparently blocks shivering mainly through an action on subtypes of the α2 adrenoceptor.

F. Applications in Anesthesia

The opioids are frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties. They are also used intraoperatively both as adjuncts to other anesthetic agents and, in high doses (eg, 0.02–0.075 mg/kg of fentanyl), as a primary component of the anesthetic regimen (see Chapter 25). Opioids are most commonly used in cardiovascular surgery and other types of high-risk surgery in which a primary goal is to minimize cardiovascular depression. In such situations, mechanical respiratory assistance must be provided.

Because of their direct action on the neurons of the superficial dorsal horn of the spine, opioids can also be used as regional analgesics, by administration into the epidural or subarachnoid spaces of the spinal column. A number of studies have demonstrated that long-lasting analgesia with minimal adverse effects can be achieved by epidural administration of 3–5 mg of morphine, followed by slow infusion through a catheter placed in the epidural space. It was initially assumed that the epidural application of opioids might selectively produce analgesia without impairment of motor, autonomic, or sensory functions other than pain. However, respiratory depression can occur after the drug is injected into the epidural space and may require reversal with naloxone. Effects such as pruritus and nausea and vomiting are common after epidural and subarachnoid administration of opioids and may also be reversed with naloxone. Currently, the epidural route is favored over subarachnoid administration because adverse effects are less common and robust outcome studies have shown a significant reduction in perioperative mortality and morbidity with the use of thoracic epidural analgesia. The use of low doses of local anesthetics in combination with fentanyl infused through a thoracic epidural catheter has become an accepted method of pain control in patients recovering from thoracic and major upper abdominal surgery. In rare cases, chronic pain management specialists may elect to implant surgically a programmable infusion pump connected to a spinal catheter for continuous infusion of opioids or other analgesic compounds.

G. Alternative Routes of Administration

Patient-controlled analgesia (PCA) is widely used for the management of breakthrough pain. With PCA, the patient controls a parenteral (usually intravenous) infusion device by pressing a button to deliver a preprogrammed dose of the desired opioid analgesic. A programmable lockout interval prevents administration of another dose for a set period of time. Claims of better patient satisfaction are supported by well-designed clinical trials, making this approach very useful in postoperative pain control. However, health care personnel must be very familiar with the use of PCAs to avoid overdosage secondary to misuse or improper programming. There is a proven risk of PCA-associated respiratory depression and hypoxia that requires careful monitoring of vital signs and sedation level, and provision of supplemental oxygen. Continuous pulse oximetry is also recommended for patients receiving PCA-administered opioids; this is not a fail-safe method for early detection of hypoventilation or apnea but rather serves as a safety net for an unrecognized adverse event. The risk of sedation is increased if medications with sedative properties, such as benzodiazepines and certain types of antiemetics, are concurrently prescribed.

Rectal suppositories of morphine and hydromorphone have been used when oral and parenteral routes are undesirable. The transdermal fentanyl patch provides stable blood levels of drug and better pain control while avoiding the need for repeated parenteral injections. Fentanyl is the most successful opioid in transdermal application and is indicated for the management of persistent unremitting pain. Because of the complication of fentanyl-induced respiratory depression, the Food and Drug Administration (FDA) recommends that introduction of a transdermal fentanyl patch (25 mcg/h) be reserved for patients with an established oral morphine requirement of at least 60 mg/d for 1 week or more. Extreme caution must be exercised in any patient initiating therapy or undergoing a dose increase because the peak effects may not be realized until 24–48 hours after patch application. The buprenorphine patch (BuTrans) is an example of the transdermal delivery of a mixed agonist-antagonist for the treatment of chronic pain in addition to opioid maintenance or detoxification. The intranasal route avoids repeated parenteral drug injections and the first-pass metabolism of orally administered drugs. Butorphanol is the only opioid currently available in the USA in a nasal formulation, but more are expected. Another alternative to parenteral administration is the buccal transmucosal route, which uses a fentanyl citrate lozenge or a “lollipop” mounted on a stick.

Toxicity & Undesired Effects

Direct toxic effects of the opioid analgesics that are extensions of their acute pharmacologic actions include respiratory depression, nausea, vomiting, and constipation (Table 31–4). Tolerance, dependence, diagnosis and treatment of overdosage, and contraindications must be considered.

TABLE 31–4 Adverse effects of the opioid analgesics.

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A. Tolerance and Dependence

Drug dependence of the opioid type is marked by a relatively specific withdrawal or abstinence syndrome. Just as there are pharmacologic differences between the various opioids, there are also differences in psychological dependence and the severity of withdrawal effects. For example, withdrawal from dependence on a strong agonist is associated with more severe withdrawal signs and symptoms than withdrawal from a mild or moderate agonist. Administration of an opioid antagonist to an opioid-dependent person is followed by brief but severe withdrawal symptoms (see antagonist-precipitated withdrawal, below). The potential for physical and psychological dependence of the partial agonist-antagonist opioids appears to be less than that of the strong agonist drugs.

1. Opioid toleranceis the phenomenon whereby repeated doses of opioids have a diminishing analgesic effect. Clinically, it has been described as an increasing opioid dose requirement to achieve the analgesia observed at the initiation of opioid administration. Although development of tolerance begins with the first dose of an opioid, tolerance may not become clinically manifest until after 2–3 weeks of frequent exposure to ordinary therapeutic doses. Nevertheless, perioperative and critical care use of ultrapotent opioid analgesics such as remifentanil have been shown to induce opioid tolerance within hours. Tolerance develops most readily when large doses are given at short intervals and is minimized by giving small amounts of drug with longer intervals between doses.

A high degree of tolerance may develop to the analgesic, sedating, and respiratory depressant effects of opioid agonists. It is possible to produce respiratory arrest in a nontolerant person with a dose of 60 mg of morphine. However, in a patient who is opioid-dependent or requires escalating opioid administration to manage intractable cancer pain, doses such as 2000 mg of morphine taken over a 2- or 3-hour period may not produce significant respiratory depression. Tolerance also develops to the antidiuretic, emetic, and hypotensive effects but not to the miotic, convulsant, and constipating actions (Table 31–3). Following discontinuation of opioids, loss of tolerance to the sedating and respiratory effects of opioids is variable, and difficult to predict. However, tolerance to the emetic effects may persist for several months after withdrawal of the drug. Therefore, opioid tolerance differs by effect, drug, time, and the individual (genetic-epigenetic factors).

Tolerance also develops to analgesics with mixed receptor effects but to a lesser extent than to the agonists. Adverse effects such as hallucinations, sedation, hypothermia, and respiratory depression are reduced after repeated administration of the mixed receptor drugs. However, tolerance to the latter agents does not generally include cross-tolerance to the agonist opioids. It is also important to note that tolerance does not develop to the antagonist actions of the mixed agents or to those of the pure antagonists.

Cross-tolerance is an extremely important characteristic of the opioids, ie, patients tolerant to morphine often show a reduction in analgesic response to other agonist opioids. This is particularly true of those agents with primarily μ-receptor agonist activity. Morphine and its congeners exhibit cross-tolerance not only with respect to their analgesic actions but also to their euphoriant, sedative, and respiratory effects. However, the cross-tolerance existing among the μ-receptor agonists can often be partial or incomplete. This clinical observation has led to the concept of “opioid rotation,” which has been used for many years in the treatment of cancer pain. A patient who is experiencing decreasing effectiveness of one opioid analgesic regimen is “rotated” to a different opioid analgesic (eg, morphine to hydromorphone; hydromorphone to methadone) and typically experiences significantly improved analgesia at a reduced overall equivalent dosage. Another approach is to recouple opioid receptor function as described previously through the use of adjunctive nonopioid agents. NMDA-receptor antagonists (eg, ketamine) have shown promise in preventing or reversing opioid-induced tolerance in animals and humans. Use of ketamine is increasing because well-controlled studies have shown clinical efficacy in reducing postoperative pain and opioid requirements in opioid-tolerant patients. Agents that independently enhance μ-receptor recycling may also hold promise for improving analgesia in the opioid-tolerant patient.

2. DependenceThe development of physical dependence is an invariable accompaniment of tolerance to repeated administration of an opioid of the μ type. Failure to continue administering the drug results in a characteristic withdrawal or abstinence syndrome that reflects an exaggerated rebound from the acute pharmacologic effects of the opioid.

The signs and symptoms of withdrawal include rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility. The number and intensity of the signs and symptoms are largely dependent on the degree of physical dependence that has developed. Administration of an opioid at this time suppresses abstinence signs and symptoms almost immediately.

The time of onset, intensity, and duration of abstinence syndrome depend on the drug previously used and may be related to its biologic half-life. With morphine or heroin, withdrawal signs usually start within 6–10 hours after the last dose. Peak effects are seen at 36–48 hours, after which most of the signs and symptoms gradually subside. By 5 days, most of the effects have disappeared, but some may persist for months. In the case of meperidine, the withdrawal syndrome largely subsides within 24 hours, whereas with methadone several days are required to reach the peak of the abstinence syndrome, and it may last as long as 2 weeks. The slower subsidence of methadone effects is associated with a less intense immediate syndrome, and this is the basis for its use in the detoxification of heroin addicts. However, despite the loss of physical dependence on the opioid, craving for it may persist. In addition to methadone, buprenorphine and the α2 agonist clonidine are FDA-approved treatments for opioid analgesic detoxification (see Chapter 32).

A transient, explosive abstinence syndrome—antagonist-precipitated withdrawal—can be induced in a subject physically dependent on opioids by administering naloxone or another antagonist. Within 3 minutes after injection of the antagonist, signs and symptoms similar to those seen after abrupt discontinuance appear, peaking in 10–20 minutes and largely subsiding after 1 hour. Even in the case of methadone, withdrawal of which results in a relatively mild abstinence syndrome, the antagonist-precipitated abstinence syndrome may be very severe.

In the case of agents with mixed effects, withdrawal signs and symptoms can be induced after repeated administration followed by abrupt discontinuance of pentazocine, cyclazocine, or nalorphine, but the syndrome appears to be somewhat different from that produced by morphine and other agonists. Anxiety, loss of appetite and body weight, tachycardia, chills, increase in body temperature, and abdominal cramps have been noted.

3. AddictionAs defined by the American Society of Addiction Medicine, addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychological, and social manifestations. This is reflected in an individual’s pathologic pursuit of reward and relief through substance use and other behaviors. Addiction is characterized by inability to abstain consistently, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response (see Chapter 32).

The risk of inducing dependence and, potentially, addiction is clearly an important consideration in the therapeutic use of opioid drugs. Despite that risk, under no circumstances should adequate pain relief ever be withheld simply because an opioid exhibits potential for abuse or because legislative controls complicate the process of prescribing narcotics. Furthermore, certain principles can be observed by the clinician to minimize problems presented by tolerance and dependence when using opioid analgesics:

•Establish therapeutic goals before starting opioid therapy. This tends to limit the potential for physical dependence. The patient and his or her family should be included in this process.

•Once an effective dose is established, attempt to limit dosage to this level. This goal is facilitated by use of a written treatment contract that specifically prohibits early refills and having multiple prescribing physicians.

•Non-opioid analgesics—especially in chronic management—consider using other types of analgesics or compounds exhibiting less pronounced withdrawal symptoms on discontinuance.

•Frequently evaluate continuing analgesic therapy and the patient’s need for opioids.

B. Diagnosis and Treatment of Opioid Overdosage

Intravenous injection of naloxone dramatically reverses coma due to opioid overdose but not that due to other CNS depressants. Use of the antagonist should not, of course, delay the institution of other therapeutic measures, especially respiratory support. (See also The Opioid Antagonists, below, and Chapter 58.)

C. Contraindications and Cautions in Therapy

1. Use of pure agonists with weak partial agonistsWhen a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; thus combining a full agonist with partial agonist opioids should be avoided.

2. Use in patients with head injuriesCarbon dioxide retention caused by respiratory depression results in cerebral vasodilation. In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.

3. Use during pregnancyIn pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period. A daily dose as small as 6 mg of heroin (or equivalent) taken by the mother can result in a mild withdrawal syndrome in the infant, and twice that much may result in severe signs and symptoms, including irritability, shrill crying, diarrhea, or even seizures. Recognition of the problem is aided by a careful history and physical examination. When withdrawal symptoms are judged to be relatively mild, treatment is aimed at control of these symptoms using such drugs as diazepam; with more severe withdrawal, camphorated tincture of opium (paregoric; 0.4 mg of morphine/mL) in an oral dose of 0.12–0.24 mL/kg is used. Oral doses of methadone (0.1–0.5 mg/kg) have also been used.

4. Use in patients with impaired pulmonary functionIn patients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure.

5. Use in patients with impaired hepatic or renal functionBecause morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate; dosage can often be reduced in such patients.

6. Use in patients with endocrine diseasePatients with adrenal insufficiency (Addison’s disease) and those with hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids.

Drug Interactions

Because seriously ill or hospitalized patients may require a large number of drugs, there is always a possibility of drug interactions when the opioid analgesics are administered. Table 31–5 lists some of these drug interactions and the reasons for not combining the named drugs with opioids.

TABLE 31–5 Opioid drug interactions.

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image SPECIFIC AGENTS

The following section describes the most important and widely used opioid analgesics, along with features peculiar to specific agents. Data about doses approximately equivalent to 10 mg of intramuscular morphine, oral versus parenteral efficacy, duration of analgesia, and intrinsic activity (maximum efficacy) are presented in Table 31–2.

STRONG AGONISTS

Phenanthrenes

Morphine, hydromorphone, and oxymorphone are strong agonists useful in treating severe pain. These prototypic agents have been described in detail above.

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Heroin (diamorphine, diacetylmorphine) is potent and fast-acting, but its use is prohibited in the USA and Canada. In recent years, there has been considerable agitation to revive its use. However, double-blind studies have not supported the claim that heroin is more effective than morphine in relieving severe chronic pain, at least when given by the intramuscular route.

Phenylheptylamines

Methadone has undergone a dramatic revival as a potent and clinically useful analgesic. It can be administered by the oral, intravenous, subcutaneous, spinal, and rectal routes. It is well absorbed from the gastrointestinal tract and its bioavailability far exceeds that of oral morphine.

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Methadone is not only a potent μ-receptor agonist but its racemic mixture of D- and L-methadone isomers can also block both NMDA receptors and monoaminergic reuptake transporters. These nonopioid receptor properties may help explain its ability to relieve difficult-to-treat pain (neuropathic, cancer pain), especially when a previous trial of morphine has failed. In this regard, when analgesic tolerance or intolerable side effects have developed with the use of increasing doses of morphine or hydromorphone, “opioid rotation” to methadone has provided superior analgesia at 10–20% of the morphine-equivalent daily dose. In contrast to its use in suppressing symptoms of opioid withdrawal, use of methadone as an analgesic typically requires administration at intervals of no more than 8 hours. However, given methadone’s highly variable pharmacokinetics and long half-life (25–52 hours), initial administration should be closely monitored to avoid potentially harmful adverse effects, especially respiratory depression. Because methadone is metabolized by CYP3A4 and CYP2B6 isoforms in the liver, inhibition of its metabolic pathway or hepatic dysfunction has also been associated with overdose effects, including respiratory depression or, more rarely, prolonged QT-based cardiac arrhythmias.

Methadone is widely used in the treatment of opioid abuse. Tolerance and physical dependence develop more slowly with methadone than with morphine. The withdrawal signs and symptoms occurring after abrupt discontinuance of methadone are milder, although more prolonged, than those of morphine. These properties make methadone a useful drug for detoxification and for maintenance of the chronic relapsing heroin addict.

For detoxification of a heroin-dependent addict, low doses of methadone (5–10 mg orally) are given two or three times daily for 2 or 3 days. Upon discontinuing methadone, the addict experiences a mild but endurable withdrawal syndrome.

For maintenance therapy of the opioid recidivist, tolerance to 50–100 mg/d of oral methadone may be deliberately produced; in this state, the addict experiences cross-tolerance to heroin, which prevents most of the addiction-reinforcing effects of heroin. One rationale of maintenance programs is that blocking the reinforcement obtained from abuse of illicit opioids removes the drive to obtain them, thereby reducing criminal activity and making the addict more amenable to psychiatric and rehabilitative therapy. The pharmacologic basis for the use of methadone in maintenance programs is sound and the sociologic basis is rational, but some methadone programs fail because nonpharmacologic management is inadequate.

The concurrent administration of methadone to heroin addicts known to be recidivists has been questioned because of the increased risk of overdose death secondary to respiratory arrest. As the number of patients prescribed methadone for persistent pain has increased, so, too, has the incidence of accidental overdose and complications related to respiratory depression. Variability in methadone metabolism, protein binding, distribution, and nonlinear opioid dose conversion all play a role in adverse events. Buprenorphine, a partial μ-receptor agonist with long-acting properties, has been found to be effective in opioid detoxification and maintenance programs and is presumably associated with a lower risk of such overdose fatalities.

Phenylpiperidines

Fentanyl is one of the most widely used agents in the family of synthetic opioids. The fentanyl subgroup now includes sufentanil, alfentanil, and remifentanil in addition to the parent compound, fentanyl.

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These opioids differ mainly in their potency and biodisposition. Sufentanil is five to seven times more potent than fentanyl. Alfentanil is considerably less potent than fentanyl, but acts more rapidly and has a markedly shorter duration of action. Remifentanil is metabolized very rapidly by blood and nonspecific tissue esterases, making its pharmacokinetic and pharmacodynamic half-lives extremely short. Such properties are useful when these compounds are used in anesthesia practice. Although fentanyl is now the predominant analgesic in the phenylpiperidine class, meperidine continues to be used. This older opioid has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem. Meperidine is also reported to have a negative inotropic action on the heart. In addition, it has the potential for producing seizures secondary to accumulation of its metabolite, normeperidine, in patients receiving high doses or with concurrent renal failure. Given this undesirable profile, use of meperidine as a first-line analgesic is becoming increasingly rare.

Morphinans

Levorphanol is a synthetic opioid analgesic closely resembling morphine that has μ-, δ-, and κ-opioid agonist actions, serotonin-norepinephrine reuptake inhibition, and NMDA receptor antagonist properties.

MILD TO MODERATE AGONISTS

Phenanthrenes

Codeine, dihydrocodeine, and hydrocodone have lower binding affinity to μ-opioid receptors than morphine and often have adverse effects that limit the maximum tolerated dose when one attempts to achieve analgesia comparable to that of morphine.

Oxycodone is more potent and is prescribed alone in higher doses as immediate-release or controlled-release forms for the treatment of moderate to severe pain. Combinations of hydrocodone or oxycodone with acetaminophen are the predominant formulations of orally administered analgesics in the United States for the treatment of mild to moderate pain. However, there has been a large increase in the use of controlled-release oxycodone at the highest dose range. An intravenous formulation of oxycodone is available outside the United States.

Since each controlled-release tablet of oxycodone contains a large quantity of oxycodone to allow for prolonged action, those intent on abusing the old formulation have extracted crushed tablets and injected high doses, resulting in abuse and possible fatal overdose. In 2010, the FDA approved a new formulation of the controlled-release form of oxycodone that reportedly prevents the tablets from being cut, broken, chewed, crushed, or dissolved to release more oxycodone. It is hoped that this new formulation will lead to less abuse by snorting or injection. The FDA is now requiring a Risk Evaluation and Mitigation Strategy (REMS) that will include the issuance of a medication guide to patients and a requirement for prescriber education regarding the appropriate use of opioid analgesics in the treatment of pain. (See Box: Educating Opioid Prescribers.)

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Phenylheptylamines

Propoxyphene is chemically related to methadone but has extremely low analgesic activity. Its low efficacy makes it unsuitable, even in combination with aspirin, for severe pain. The increasing incidence of deaths associated with its use and misuse caused it to be withdrawn in the United States.

Phenylpiperidines

Diphenoxylate and its metabolite, difenoxin, are not used for analgesia but for the treatment of diarrhea. They are scheduled for minimal control (difenoxin is Schedule IV, diphenoxylate Schedule V; see inside front cover) because the likelihood of their abuse is remote. The poor solubility of the compounds limits their use for parenteral injection. As antidiarrheal drugs, they are used in combination with atropine. The atropine is added in a concentration too low to have a significant antidiarrheal effect but is presumed to further reduce the likelihood of abuse.

Loperamide is a phenylpiperidine derivative used to control diarrhea. Due to action on peripheral μ-opioid receptors and lack of effect on CNS receptors, investigations are ongoing as to whether it could be an effective analgesic. Its potential for abuse is considered very low because of its limited access to the brain. It is therefore available without a prescription.

Educating Opioid Prescribers

The treatment of pain is a difficult clinical-pharmacologic problem, and prescribers of opioids have often failed to appreciate this difficulty. As a result, there have been large increases of drug abuse cases in the USA and a nearly fourfold increase in overdose deaths due to prescription opioids between 1999 and the present. These statistics have prompted the Food and Drug Administration to formulate plans for opioid manufacturers to provide training for all opioid prescribers. The FDA is working to devise methods by which this training would be mandatory for all prescribers and would emphasize the thorough understanding of opioid clinical pharmacology with special education about long-acting and extended-release formulations. The educational emphasis on the long-acting and sustained-release formulations (eg, methadone, oxycodone) reflects their association with skyrocketing morbidity and mortality.

The usual dose with all of these antidiarrheal agents is two tablets to start and then one tablet after each diarrheal stool.

OPIOIDS WITH MIXED RECEPTOR ACTIONS

Care should be taken not to administer any partial agonist or drug with mixed opioid receptor actions to patients receiving pure agonist drugs because of the unpredictability of both drugs’ effects; reduction of analgesia or precipitation of an explosive abstinence syndrome may result.

Phenanthrenes

As noted above, buprenorphine is a potent and long-acting phenanthrene derivative that is a partial μ-receptor agonist (low intrinsic activity) and an antagonist at the δ and κ receptors and is therefore referred to as a mixed agonist-antagonist. Although buprenorphine is used as an analgesic, it can antagonize the action of more potent μ agonists such as morphine. Buprenorphine also binds to ORL1, the orphanin receptor. Whether this property also participates in opposing μ receptor function is under study. Administration by the sublingual route is preferred to avoid significant first-pass effect. Buprenorphine’s long duration of action is due to its slow dissociation from μ receptors. This property renders its effects resistant to naloxone reversal. Buprenorphine was approved by the FDA in 2002 for the management of opioid dependence and studies suggest it is as effective as methadone for the management of opioid withdrawal and detoxification in programs that include counseling, psychosocial support, and direction by physicians qualified under the Drug Addiction Treatment Act. In contrast to methadone, high-dose administration of buprenorphine results in a μ-opioid antagonist action, limiting its properties of analgesia and respiratory depression. However, buprenorphine formulations can still cause serious respiratory depression and death, particularly when extracted and injected intravenously in combination with benzodiazepines or used with other CNS depressants (ie, sedatives, antipsychotics, or alcohol). Buprenorphine is also available combined with naloxone, a pure μ-opioid antagonist (as Suboxone), to help prevent its diversion for illicit intravenous abuse. A slow-release transdermal patch preparation that releases drug over a 1-week period is also available (Butrans). Psychotomimetic effects, with hallucinations, nightmares, and anxiety, have been reported after use of drugs with mixed agonist-antagonist actions.

Pentazocine (a benzomorphan) and nalbuphine are other examples of opioid analgesics with mixed agonist-antagonist properties. Nalbuphine is a strong κ-receptor agonist and a partial μ-receptor antagonist; it is given parenterally. At higher doses there seems to be a definite ceiling—not noted with morphine—to the respiratory depressant effect. Unfortunately, when respiratory depression does occur, it may be relatively resistant to naloxone reversal due to its greater affinity for the receptor than naloxone.

Morphinans

Butorphanol produces analgesia equivalent to nalbuphine but appears to produce more sedation at equianalgesic doses. Butorphanol is considered to be predominantly a κ agonist. However, it may also act as a partial agonist or antagonist at the μ receptor.

Benzomorphans

Pentazocine is a κ agonist with weak μ-antagonist or partial agonist properties. It is the oldest mixed agent available. It may be used orally or parenterally. However, because of its irritant properties, the injection of pentazocine subcutaneously is not recommended.

MISCELLANEOUS

Tramadol is a centrally acting analgesic whose mechanism of action is predominantly based on blockade of serotonin reuptake. Tramadol has also been found to inhibit norepinephrine transporter function. Because its analgesic effect is only partially antagonized by naloxone, it is thought to not depend on its low-affinity binding to the μ receptor for therapeutic activity. The recommended dosage is 50–100 mg orally four times daily. Toxicity includes association with seizures; the drug is relatively contraindicated in patients with a history of epilepsy and for use with other drugs that lower the seizure threshold. Another serious risk is the development of serotonin syndrome, especially if selective serotonin reuptake inhibitor antidepressants are being administered (see Chapter 16). Other adverse effects include nausea and dizziness, but these symptoms typically abate after several days of therapy. No clinically significant effects on respiration or the cardiovascular system have thus far been reported. Given the fact that the analgesic action of tramadol is largely independent of μ-receptor action, tramadol may serve as an adjunct with pure opioid agonists in the treatment of chronic neuropathic pain.

Tapentadol is an analgesic with modest μ-opioid receptor affinity and significant norepinephrine reuptake-inhibiting action. In animal models, its analgesic effects were only moderately reduced by naloxone but strongly reduced by an α2-adrenoceptor antagonist. Furthermore, its binding to the norepinephrine transporter (NET, see Chapter 6) was stronger than that of tramadol, whereas its binding to the serotonin transporter (SERT) was less than that of tramadol. Tapentadol was approved in 2008 and has been shown to be as effective as oxycodone in the treatment of moderate to severe pain but with a reduced profile of gastrointestinal complaints such as nausea. Tapentadol carries risk for seizures in patients with seizure disorders and for the development of serotonin syndrome. It is unknown how tapentadol compares in clinical utility to tramadol or other analgesics whose mechanism of action is not based primarily on opioid receptor pharmacology.

ANTITUSSIVES

The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability (see below).

The physiologic mechanism of cough is complex, and little is known about the specific mechanism of action of the opioid antitussive drugs. It appears likely that both central and peripheral effects play a role.

The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). They should be used with caution in patients taking monoamine oxidase inhibitors (Table 31–5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions. Importantly, due to increasing reports of death in young children taking dextromethorphan in formulations of over-the-counter “cold/cough” medications, its use in children younger than 6 years of age has been banned by the FDA. Moreover, because of variations in the metabolism of codeine, its use for any purpose in young children is being reconsidered.

Dextromethorphan is the dextrorotatory stereoisomer of a methylated derivative of levorphanol. It is purported to be free of addictive properties and produces less constipation than codeine. The usual antitussive dose is 15–30 mg three or four times daily. It is available in many over-the-counter products. Dextromethorphan has also been found to enhance the analgesic action of morphine and presumably other μ-receptor agonists. However, abuse of its purified (powdered) form has been reported to lead to serious adverse events including death.

Codeine, as noted, has a useful antitussive action at doses lower than those required for analgesia. Thus, 15 mg is usually sufficient to relieve cough.

Levopropoxyphene is the stereoisomer of the weak opioid agonist dextropropoxyphene. It is devoid of opioid effects, although sedation has been described as a side effect. The usual antitussive dose is 50–100 mg every 4 hours.

THE OPIOID ANTAGONISTS

The pure opioid antagonist drugs naloxone, naltrexone, and nalmefene are morphine derivatives with bulkier substituents at the N17 position. These agents have a relatively high affinity for μ-opioid binding sites. They have lower affinity for the other receptors but can also reverse agonists at δ and κ sites.

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Pharmacokinetics

Naloxone is usually given by injection and has a short duration of action (1–2 hours) when given by this route. Metabolic disposition is chiefly by glucuronide conjugation like that of the agonist opioids with free hydroxyl groups. Naltrexone is well absorbed after oral administration but may undergo rapid first-pass metabolism. It has a half-life of 10 hours, and a single oral dose of 100 mg blocks the effects of injected heroin for up to 48 hours. Nalmefene, the newest of these agents, is a derivative of naltrexone but is available only for intravenous administration. Like naloxone, nalmefene is used for opioid overdose but has a longer half-life (8–10 hours).

Pharmacodynamics

When given in the absence of an agonist drug, these antagonists are almost inert at doses that produce marked antagonism of agonist opioid effects.

When given intravenously to a morphine-treated subject, the antagonist completely and dramatically reverses the opioid effects within 1–3 minutes. In individuals who are acutely depressed by an overdose of an opioid, the antagonist effectively normalizes respiration, level of consciousness, pupil size, bowel activity, and awareness of pain. In dependent subjects who appear normal while taking opioids, naloxone or naltrexone almost instantaneously precipitates an abstinence syndrome.

There is no tolerance to the antagonistic action of these agents, nor does withdrawal after chronic administration precipitate an abstinence syndrome.

Clinical Use

Naloxone is a pure antagonist and is preferred over older weak agonist-antagonist agents that had been used primarily as antagonists, eg, nalorphine and levallorphan.

The major application of naloxone is in the treatment of acute opioid overdose (see also Chapter 58). It is very important that the relatively short duration of action of naloxone be borne in mind, because a severely depressed patient may recover after a single dose of naloxone and appear normal, only to relapse into coma after 1–2 hours.

The usual initial dose of naloxone is 0.1–0.4 mg intravenously for life-threatening respiratory and CNS depression. Maintenance is with the same drug, 0.4–0.8 mg given intravenously, and repeated whenever necessary. In using naloxone in the severely opioid-depressed newborn, it is important to start with doses of 5–10 mcg/kg and to consider a second dose of up to a total of 25 mcg/kg if no response is noted.

Low-dose naloxone (0.04 mg) has an increasing role in the treatment of adverse effects that are commonly associated with intravenous or epidural opioids. Careful titration of the naloxone dosage can often eliminate the itching, nausea, and vomiting while sparing the analgesia. For this purpose, oral naloxone, and modified analogs of naloxone and naltrexone, have been approved by the FDA. These include methylnaltrexone bromide for the treatment of constipation in patients with late-stage advanced illness and alvimopan for the treatment of postoperative ileus following bowel resection surgery. Methylnaltrexone has a quaternary amine preventing it from crossing the blood-brain barrier. Alvimopan has a high affinity for peripheral μ receptors and does not impair the central effects of μ-opioid agonists. The principal mechanism for the selective therapeutic effect of these agents is peripheral enteric μ-receptor antagonism with minimal CNS penetration.

Because of its long duration of action, naltrexone has been proposed as a maintenance drug for addicts in treatment programs. A single dose given on alternate days blocks virtually all of the effects of a dose of heroin. It might be predicted that this approach to rehabilitation would not be popular with a large percentage of drug users unless they are motivated to become drug-free. A related use is in combination with morphine sulfate in a controlled-release formulation (Embeda) in which 20–100 mg of morphine is slowly released over 8–12 hours or longer for the control of prolonged postoperative pain. Naltrexone, 0.4–4 mg, is sequestered in the center of the formulation pellets and is present to prevent the abuse of the morphine (by grinding and extraction of the morphine from the capsules).

There is evidence that naltrexone decreases the craving for alcohol in chronic alcoholics by increasing baseline β-endorphin release, and it has been approved by the FDA for this purpose (see Chapter 23). Naltrexone also facilitates abstinence from nicotine (cigarette smoking) with reduced weight gain. In fact, a combination of naltrexone plus bupropion (Chapter 16) may also offer an effective and synergistic strategy for weight loss. If current trials demonstrate cardiovascular safety during prolonged use, this and other weight-loss medications combined with naltrexone may eventually win FDA approval.

SUMMARY Opioids, Opioid Substitutes, and Opioid Antagonists

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PREPARATIONS AVAILABLE*

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CASE STUDY ANSWER

In this case, the treatment of severe pain should be managed with the administration of a potent intravenous opioid analgesic such as morphine, hydromorphone, or fentanyl. Before an additional dose of an opioid analgesic is administered, it is expected that the patient will require frequent reevaluation of both the severity of his pain and the presence of potential side effects. Given his history of pulmonary disease, he is also at increased risk of developing respiratory depression. Frequent reevaluation of his level of consciousness, respiratory rate, fractional oxygen saturation, and other vital parameters can help achieve the goal of pain relief and minimize respiratory depression. Concurrent use of sedative agents such as benzodiazepines should be avoided if possible and proceed only with great caution.

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* In memory of Walter (Skip) Way, MD.