Basic & Clinical Pharmacology, 10th Edition

31. Opioid Analgesics & Antagonists - Mark A. Schumacher, PhD, MD, Allan I. Basbaum, PhD, & Walter L. Way, MD

INTRODUCTION

Morphine, the prototypical opioid agonist, has long been known to relieve severe pain with remarkable efficacy. The opium poppy is the source of crude opium from which Serturner in 1803 isolated morphine, the pure alkaloid and named 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 opioid analgesics and include not only the natural and semisynthetic alkaloid derivatives from opium but also include synthetic surrogates, other opioid-like drugs whose actions are blocked by the nonselective antagonist naloxone, plus several endogenous peptides that interact with the several subtypes of opioid receptors.

I. BASIC PHARMACOLOGY OF THE OPIOID ANALGESICS

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 principle one being morphine, which is present in a concentration of about 10%. Codeine is synthesized commercially from morphine.

Classification & Chemistry

Opioid drugs include full agonists, partial agonists, and antagonists (see Chapter 2 for definitions). Morphine is a full agonist at the u (mu) opioid receptor, the major analgesic opioid receptor (Table 31-1). In contrast, codeine functions as a partial (or "weak") u-receptor agonist. 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 u-receptor antagonist. The structures of some of these compounds are shown later in this chapter. Some opioids, eg, nalbuphine, are capable of producing an agonist (or partial agonist) effect at one opioid receptor subtype and an antagonist effect at another. Not only can the activating properties of opioid analgesics be manipulated by pharmaceutical chemistry, certain opioid analgesics are modified in the liver, resulting in compounds with greater analgesic action (see Pharmacokinetics, Metabolism).

Endogenous Opioid Peptides

Opioid alkaloids (eg, morphine) produce analgesia through actions at regions in the central nervous system (CNS) that contain 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 in detail: the endorphins, the pentapeptides methionine-enkephalin (met-enkephalin) and leucine-enkephalin (leu-enkephalin), and the dynorphins. The three families of opioid receptors have overlapping affinities for these endogenous peptides (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, b-endorphin, and several nonopioid peptides, including adrenocorticotropic hormone (ACTH), b-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 d (delta) than for the u opioid receptor (Table 31-1). Preprodynorphin yields several active opioid peptides that contain the leu-enkephalin sequence. These are dynorphin A, dynorphin B, and a and bneoendorphins. More recently, the endogenous peptides endomorphin-1 and endomorphin-2 have been found to possess many of the properties of opioid peptides, notably analgesia and high-affinity binding to the u-receptor. Research is focused on whether endomorphins selectively activate u-receptor subtypes and much remains unknown, including the identity of their gene. Both the endogenous opioid precursor molecules and the endomorphins are present at CNS sites that have been implicated in pain modulation. Evidence suggests that they can be released during stressful conditions such as pain or the anticipation of pain to diminish the sensation of noxious stimuli.

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A¾through its binding to k (kappa) opioid receptors¾remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it plays a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is believed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system. Rather, dynorphin A can bind and activate the N-methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development.

Recently, a novel receptor-ligand system homologous to the opioid peptides has been found. The principle receptor for this 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. Although widely expressed in the CNS and periphery, this system has a diverse pharmacology, capable of opposing classic u receptor-mediated analgesia as well as modulating drug reward, reinforcement, learning, and memory processes.

Pharmacokinetics

Some properties of clinically important opioids are summarized in Table 31-2.

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) may need to be much higher than the parenteral dose to elicit a therapeutic effect. Considerable interpatient variability exists in first-pass opioid metabolism, making prediction of an effective oral dose difficult. Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism. Nasal insufflation of certain opioids can result in rapid therapeutic blood levels by avoiding first-pass metabolism. Other routes of opioid administration include oral mucosa via lozenges, and transdermal via transdermal 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 tissues that are highly perfused 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 u receptors but rather by the GABA/glycinergic system. 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 morphine given acutely. Nevertheless, 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 coadministration with probenecid or with drugs that inhibit the P-glycoprotein drug transporter. Like morphine, hydromorphone is metabolized by conjugation, yielding hydromorphone-3-glucuronide (H3G), which has CNS excitatory properties. However, hydromorphone has not been shown to form significant amounts of a 6-glucuronide metabolite.

The effects of these active metabolites should be considered before the administration of morphine or hydromorphone, especially when given at high doses.

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

Hepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids (meperidine, fentanyl, 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. Genetic polymorphism of CYP2D6 has been documented and linked to the variation in analgesic response seen among patients. Nevertheless, the metabolites of oxycodone and hydrocodone may be of minor consequence because the parent compounds are currently believed to be directly responsible for the majority of their analgesic actions. In the case of codeine, conversion to morphine may be of greater importance because codeine itself has relatively low affinity for opioid receptors.

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.

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.

1. Receptor types¾ As noted, three major classes of opioid receptors (u, d, and k) 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 u₁, u₂; d₁, d₂; and k₁, k₂, and k₃. However, genes encoding only one subtype from each of the u, d, and k receptor families have been isolated and characterized thus far. One plausible explanation is that u-receptor subtypes arise from alternate splice variants of a common gene. Since an opioid drug 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. The N/OFQ-ORL1 receptor has not been as extensively studied.

2. Cellular actions¾ At 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 G protein-coupled actions on neurons: (1) they close voltage-gated Ca²⁺ channels on presynaptic nerve terminals and thereby reduce transmitter release, and (2) they hyperpolarize and thus inhibit postsynaptic neurons by opening K⁺ channels. Figure 31-1 schematically illustrates the presynaptic action at all three receptor types and the postsynaptic effect at u receptors on nociceptive afferents in the spinal cord. The presynaptic action¾depressed transmitter release¾has been demonstrated for release of a large number of neurotransmitters including glutamate, the principle excitatory amino acid released from nociceptive nerve terminals, as well as acetylcholine, norepinephrine, serotonin, and substance P.

3. Relation of physiologic effects to receptor type¾ The majority of currently available opioid analgesics act primarily at the u opioid receptor. Analgesia, as well as the euphoriant, respiratory depressant, and physical dependence properties of morphine result principally from actions at u receptors. In fact, the u 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 d and k receptors. This is supported by the study of genetic knockouts of the u, d, and k genes in mice. Delta-receptor agonists retain analgesic properties in u receptor knockout mice. The development of d-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 u-receptor agonists, such as morphine. Although morphine does act at k and d 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 d and k 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 k 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. The reason for this difference is not known.

4. Receptor distribution and neural mechanisms of analgesia¾ Opioid 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). Opioid agonists inhibit the release of excitatory transmitters from these primary afferents, and they directly inhibit the dorsal horn pain transmission neuron. Thus, opioids exert a powerful analgesic effect directly on the spinal cord. This spinal action has been exploited clinically by direct application of opioid agonists to the spinal cord, which 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 so 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.

When pain-relieving opioid drugs are given systemically, they presumably act upon brain circuits normally regulated by endogenous opioid peptides. Part of the pain-relieving action of exogenous opioids involves the release of endogenous opioid peptides. An exogenous opioid agonist (eg, morphine) may act primarily and directly at the u receptor, but this action may evoke the release of endogenous opioids that additionally act at d and k 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 opioid-mediated analgesia at sites outside the CNS. Pain associated with inflammation seems especially sensitive to these peripheral opioid actions. The identification of functional u receptors on the peripheral terminals of sensory neurons supports this hypothesis. Furthermore, activation of peripheral u receptors results in a decrease in sensory neuron activity and transmitter release. Peripheral administration of opioids, eg, into the knees of patients following arthroscopic knee surgery, has shown clinical benefit up to 24 hours after administration. If they can be developed, opioids selective for a peripheral site would be useful adjuncts in the treatment of inflammatory pain (see Box: Ion Channels & Novel Analgesic Targets). Moreover, new peripherally acting dynorphins may provide a novel means to treat visceral pain. Such compounds could have the additional benefit of reducing unwanted effects such as constipation.

5. Tolerance and physical dependence¾ With frequently repeated therapeutic doses of morphine or its surrogates, there is a gradual loss in effectiveness, ie, 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 tolerance and physical dependence is poorly understood, but persistent activation of u 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 tolerance was based on the proposal that repeated exposure to agonist caused u receptors to be down-regulated by endocytosis. However, emerging research now implicates the failure of morphine to induce endocytosis of the u opioid receptor as an important component of tolerance development. This suggests that maintenance of normal sensitivity of u receptors requires reactivation by endocytosis and recycling (see Chapter 2). Another area of research suggests that the d opioid receptor functions as an independent component in the maintenance of tolerance. In addition, the concept of receptor uncoupling has gained prominence. Under this hypothesis, tolerance is due to a dysfunction of structural interactions between the u receptor and G proteins, second-messenger systems, and their target ion channels. Moreover, a particular ion channel complex, the NMDA receptor, has been shown to play a critical role in tolerance development and maintenance because NMDA-receptor antagonists such as ketamine can block tolerance development. The development of novel NMDA-receptor antagonists or other strategies to recouple u receptors to their target ion channels provides hope for achieving a clinically effective means to prevent or reverse opioid analgesic tolerance.

In addition to the development of tolerance, persistent administration of opioid analgesics has been observed to increase the sensation of pain leading to a state of hyperalgesia. This phenomenon has been observed with several opioid analgesics, including morphine, fentanyl, and remifentanyl. Spinal dynorphin has emerged as one important candidate for the mediation of opioid-induced pain and hyperalgesia.


ION CHANNELS & NOVEL ANALGESIA TARGETS

Even the most severe acute pain (lasting hours to days) can usually be well controlled¾with significant but tolerable adverse effects¾with 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, presynaptic 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 appear to be important in chronic inflammatory and neuropathic pain states.

In the effort to discover better analgesic drugs for chronic pain, renewed attention is being paid to synaptic transmission in nociception and peripheral sensory transduction. Potentially important ion channels associated with these processes in the periphery include members of the transient receptor potential family such as the capsaicin receptor, TRPV1 (which is activated by multiple noxious stimuli such as heat, mechanical injury, protons, and products of inflammation) as well as P2X receptors (which are responsive to purines released from tissue damage). A special type of tetrodotoxin-resistant voltage-gated sodium channel (Nav1.8), also known as the PN3/SNS channel, is apparently 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 channel. Given 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. Such products that specifically target peripheral capsaicin receptors and sodium channel function are becoming available.

Ziconotide, a blocker of voltage-gated N-type calcium channels, has recently been approved for intrathecal analgesia in patients with refractory chronic pain. It is a synthetic peptide related to the marine snail toxin w-conotoxin, which selectively blocks these calcium channels. Gabapentin, an anticonvulsant analog of GABA (see Chapter 24), is an effective treatment for neuropathic (nerve injury) pain. It has recently been shown to block the pain and hyperalgesia associated with inflammation. Potential sites of action of gabapentin include the a₂d family of 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 at very small doses appears to improve analgesia and reduce opioid requirements under conditions of opioid tolerance. 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. Finally, work on cannabinoids and vanilloids and their receptors suggest that D⁹-tetrahydrocannabinol, which acts primarily on CB1 cannabinoid receptors, can 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, which allows the use of complementary compounds resulting in improved analgesia with fewer adverse effects.



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 effects¾ The principal effects of opioid analgesics with affinity for u 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).

a. Analgesia¾ Pain consists of both sensory and affective (emotional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience, especially the affective aspect.

b. Euphoria¾ Typically, 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 sometimes occur.

c. Sedation¾ Drowsiness and clouding of mentation are common concomitants of opioid action. 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 REM and non-REM sleep patterns. This disrupting effect is probably characteristic of all opioids. In contrast to humans, a number of species (cats, horses, cows, pigs) may manifest excitation rather than sedation when given opioids. These paradoxic effects are at least partially dose-dependent.

d. Respiratory depression¾ All 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 stimulation of various sorts. 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. Research is ongoing to understand and develop analgesic agents and adjuncts that avoid this effect. Research to overcome this problem is focused on d receptor pharmacology and serotonin signaling pathways in the brainstem respiratory control centers.

e. Cough suppression¾ Suppression 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 and in patients in whom it is necessary to maintain ventilation via an endotracheal tube. However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis.

f. Miosis¾ Constriction of the pupils is seen with virtually all opioid agonists. Miosis is a pharmacologic action to which little or no tolerance develops (Table 31-3); thus, it is valuable in the diagnosis of opioid overdose. Even in highly tolerant addicts, miosis is seen. This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine.

g. Truncal rigidity¾ An intensification of tone in the large trunk muscles has been noted with a number of opioids. It was originally believed that truncal rigidity involved a spinal cord action of these drugs, but there is now evidence that it results from an action at supraspinal levels. 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 vomiting¾ The opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting. There may also be a vestibular component in this effect because ambulation seems to increase the incidence of nausea and vomiting.

i. Temperature¾ Homeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain. This has been supported by experiments demonstrating that u opioid receptor agonists such as morphine administered to the anterior hypothalamus produces hyperthermia, whereas administration of k agonists induce hypothermia.

2. Peripheral effects¾

a. Cardiovascular system¾ Most 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 tract¾ Constipation 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 increase¾particularly 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.

c. Biliary tract¾ The 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. Renal¾ Renal function is depressed by opioids. It is believed that in humans this is chiefly due to decreased renal plasma flow. In addition, u opioids have been found to 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. Uterus¾ The opioid analgesics may prolong labor. The mechanism for this action is unclear, but both peripheral and central actions of the opioids can reduce uterine tone.

f. Neuroendocrine¾ Opioid analgesics stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone. These effects suggest that endogenous opioid peptides, through effects in the hypothalamus, regulate these systems (Table 31-1).

g. Pruritus¾ Therapeutic doses of the opioid analgesics produce flushing and warming of the skin accompanied sometimes by sweating and itching; CNS effects and peripheral histamine release may be responsible for these reactions. Opioid-induced pruritus and occasionally urticaria appear more frequently when opioid analgesics are administered parenterally. In addition, when opioids such as morphine are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso.

h. Miscellaneous¾ The opioids modulate the immune system by effects on lymphocyte proliferation, antibody production, and chemotaxis. Natural killer cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids. Although the mechanisms involved are complex, activation of central opioid receptors could mediate a significant component of the changes observed in peripheral immune function. In general, 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.

C. EFFECTS OF OPIOIDS WITH BOTH AGONIST AND ANTAGONIST ACTIONS
Buprenorphine is an opioid agonist that displays high binding affinity but low intrinsic activity at the u receptor. Its slow rate of dissociation from the u receptor has also made it an attractive alternative to methadone for the management of opioid withdrawal. It functions as an antagonist at the d and k receptors and for this reason is referred to as a "mixed agonist-antagonist." Although buprenorphine is used as an analgesic, it can antagonize the action of more potent u agonists such as morphine. Buprenorphine also binds to ORL1, the orphanin receptor. Whether this property also participates in opposing u receptor function is under study. Pentazocine and nalbuphine are other examples of opioid analgesics with mixed agonist-antagonist properties. Psychotomimetic effects, with hallucinations, nightmares, and anxiety, have been reported after use of drugs with mixed agonist-antagonist actions.

II. CLINICAL PHARMACOLOGY OF THE OPIOID ANALGESICS

Introduction

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 numeric visual analog scale (VAS) with word descriptors ranging from no pain (0) to excruciating pain (10). A similar scale can be used with children and with patients who cannot speak; this scale depicts five faces ranging from smiling (no pain) to crying (maximum pain).

For a patient in severe pain, the 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 adequately assess 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 may 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 with 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. Research in the hospice movement has 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 (MSContin) and oxycodone (OxyContin). Their purported advantage is a longer and more stable level of analgesia.

If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, the fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for episodes of breakthrough pain (see G. Alternative Routes of Administration). Administration of strong opioids by nasal insufflation has been shown to be 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 have been shown to enhance the analgesic actions of the 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 dyspnea from pulmonary edema associated with left ventricular 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). 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 a number of effective synthetic compounds have been developed 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, are used. Several preparations are available specifically for this purpose (Chapter 63).

E. SHIVERING
Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to have the most pronounced anti-shivering properties. It is interesting that meperidine apparently blocks shivering through its action on subtypes of the a₂ 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 superficial neurons of the spinal cord dorsal horn, 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 if necessary. Currently, the epidural route is favored because adverse effects are less common. Morphine is the most frequently used agent, but the use of low doses of local anesthetics in combination with fentanyl infused through a thoracic epidural catheter has also become an accepted method of pain control in patients recovering from major upper abdominal surgery. In rare cases, chronic pain management specialists may elect to surgically implant a programmable infusion pump connected to a spinal catheter for continuous infusion of opioids or other analgesic compounds.

G. ALTERNATIVE ROUTES OF ADMINISTRATION
Rectal suppositories of morphine and hydromorphone have long been used when oral and parenteral routes are undesirable. The transdermal patch provides stable blood levels of drug and better pain control while avoiding the need for repeated parenteral injections. Fentanyl has been the most successful opioid in transdermal application and finds great use in patients experiencing chronic pain. 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.

Another type of pain control called patient-controlled analgesia (PCA) is now in widespread use for the management of breakthrough pain. With PCA, the patient controls a parenteral (usually intravenous) infusion device by depressing a button to deliver a preprogrammed dose of the desired opioid analgesic. Claims of better pain control using less opioid 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 respiratory depression with hypoxia that requires careful monitoring of vital signs and sedation level.

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). In addition, tolerance and dependence, diagnosis and treatment of overdosage, as well as contraindications must be considered.

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 psychologic 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 psychologic dependence of the partial agonist-antagonist opioids appears to be less than that of the agonist drugs.

1. Tolerance¾ Although development of tolerance begins with the first dose of an opioid, tolerance generally does not become clinically manifest until after 2-3 weeks of frequent exposure to ordinary therapeutic doses. 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.

Depending on the compound and the effect measured, the degree of tolerance may be as great as 35-fold. Marked tolerance may develop to the analgesic, sedating, and respiratory depressant effects. It is possible to produce respiratory arrest in a nontolerant person with a dose of 60 mg of morphine, whereas in addicts maximally tolerant to opioids as much 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).

Tolerance to the sedating and respiratory effects of the opioids dissipates within a few days after the drugs are discontinued. Tolerance to the emetic effects may persist for several months after withdrawal of the drug. The rates at which tolerance appears and disappears, as well as the degree of tolerance, may also differ considerably among the different opioid analgesics and among individuals using the same drug. For instance, tolerance to methadone develops more slowly and to a lesser degree than to morphine.

Tolerance also develops to analgesics with mixed receptor effects but to a lesser extent than to the agonists. Such effects 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 show a reduction in analgesic response to other agonist opioids. This is particularly true of those agents with primarily u-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 u-receptor agonists can often be partial or incomplete. This clinical observation has led to the concept of "opioid rotation," which has been used in the treatment of cancer pain for many years. 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 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 these agents, especially ketamine, is increasing because well-controlled studies have shown clinical effectiveness in reducing postoperative pain and opioid requirements in opioid-tolerant patients.

The novel use of d-receptor antagonists with u-receptor agonists is also emerging as a strategy to avoid the development of tolerance. This idea has developed around the observation that mice lacking the d opioid receptor fail to develop tolerance to morphine.

2. Physical dependence¾ The development of physical dependence is an invariable accompaniment of tolerance to repeated administration of an opioid of the u 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 (see Chapter 32). 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. After the abstinence syndrome subsides, tolerance also disappears, as evidenced by a restoration in sensitivity to the opioid agonist. However, despite the loss of physical dependence on the opioid, craving for it may persist for many months.

A transient, explosive abstinence syndrome¾antagonist-precipitated withdrawal¾can 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. Psychologic dependence¾ The euphoria, indifference to stimuli, and sedation usually caused by the opioid analgesics, especially when injected intravenously, tend to promote their compulsive use. In addition, the addict experiences abdominal effects that have been likened to an intense sexual orgasm. These factors constitute the primary reasons for opioid abuse liability and are strongly reinforced by the development of physical dependence.

Obviously, the risk of causing dependence is an important consideration in the therapeutic use of these 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 a therapeutic dose is established, attempt to limit dosage to this level. This goal is facilitated by use of a written treatment contract which specifically prohibits early refills and having multiple prescribing physicians.

Instead of opioid analgesics¾especially in chronic management¾consider 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 Antagonists section below and Chapter 59.

C. CONTRAINDICATIONS AND CAUTIONS IN THERAPY

1. Use of pure agonists with weak partial agonists¾ When 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; combining full agonist with partial agonist opioids should be avoided.

2. Use in patients with head injuries¾ Carbon 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 pregnancy¾ In 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 with 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 function¾ In 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 function¾ Because 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 disease¾ Patients 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.

SPECIFIC AGENTS

INTRODUCTION

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

1. Phenanthrenes

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



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.

2. 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.



Methadone is not only a potent u-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.

Methadone is widely known for its use 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. Buprenorphine, a partial u-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.

3. Phenylpiperidines

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



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 widely 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.

4. Morphinans

Levorphanol is a synthetic opioid analgesic closely resembling morphine in its action.

MILD TO MODERATE AGONISTS

1. Phenanthrenes

Codeine, oxycodone, dihydrocodeine, and hydrocodone are all somewhat less efficacious than morphine (they are partial agonists) or have adverse effects that limit the maximum tolerated dose when one attempts to achieve analgesia comparable to that of morphine.



These compounds are rarely used alone but are combined in formulations containing aspirin or acetaminophen and other drugs.

2. Phenylheptylamines

Propoxyphene is chemically related to methadone but has low analgesic activity. Various studies have reported its potency at levels ranging from no better than placebo to half as potent as codeine; that is, 120 mg propoxyphene = 60 mg codeine. Its true potency probably lies somewhere between these extremes, and its analgesic effect is additive to that of an optimal dose of aspirin. However, its low efficacy makes it unsuitable, even in combination with aspirin, for severe pain. Although propoxyphene has a low abuse liability, the increasing incidence of deaths associated with its misuse has caused it to be scheduled as a controlled substance with low potential for abuse.

3. 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 Schedule of Controlled Drugs) 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. Its potential for abuse is considered very low because of its limited access to the brain. It is therefore available without a prescription.

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

INTRODUCTION

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.

1. Phenanthrenes

Nalbuphine is a strong k receptor agonist and a u receptor antagonist; it is given parenterally. At higher doses there seems to be a definite ceiling¾not noted with morphine¾to the respiratory depressant effect. Unfortunately, when respiratory depression does occur, it may be relatively resistant to naloxone reversal.

Buprenorphine is a potent and long-acting phenanthrene derivative that is a partial u receptor agonist. When administered orally, the sublingual route is preferred to avoid significant first-pass effect. Its long duration of action is due to its slow dissociation from u receptors. This property renders its effects resistant to naloxone reversal. Its clinical applications are much like those of nalbuphine. In addition, studies continue to suggest that buprenorphine is as effective as methadone in the detoxification and maintenance of heroin abusers. Buprenorphine was approved by the US Food and Drug Administration (FDA) in 2002 for the management of opioid dependence. In contrast to methadone, high-dose administration of buprenorphine results in a u opioid antagonist action, limiting its properties of analgesia and respiratory depression. Moreover, buprenorphine is also available combined with a pure u opioid antagonist to help prevent its diversion for illicit intravenous abuse.

2. Morphinans

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

3. Benzomorphans

Pentazocine is a k agonist with weak u 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 it is only partially antagonized by naloxone, it is believed to be only a weak u-receptor agonist. 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. Other side effects include nausea and dizziness, but these symptoms typically abate after several days of therapy. It is surprising that 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 u receptor action, tramadol may serve as an adjunct with pure opioid agonists in the treatment of chronic neuropathic pain.

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 is 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). Although these agents (other than codeine) are largely free of the adverse effects associated with the opioids, they should be used with caution in patients taking monoamine oxide inhibitors (see Table 31-5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions.

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 u-receptor agonists.

Codeine, as noted, has a useful antitussive action at doses lower than those required for analgesia. Thus, 15 mg are 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

Introduction

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 u opioid binding sites. They have lower affinity for the other receptors but can also reverse agonists at d and k sites.



Pharmacokinetics

Naloxone is usually given by injection and has 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 59). 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. Oral naloxone, and more recently developed nonabsorbable analogs of naloxone, have been shown to be efficacious in the treatment of opioid-induced ileus or constipation. The principal mechanism behind this selective therapeutic effect is believed to be local inhibition of u receptors in the gut with minimal systemic absorption. Several of these compounds are in the final stages of evaluation by the FDA.

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. There is evidence that naltrexone decreases the craving for alcohol in chronic alcoholics, and it has been approved by the FDA for this purpose (see Chapter 23).



PREPARATIONS AVAILABLE¹

ANALGESIC OPIOIDS

Alfentanil (Alfenta)
Parenteral: 0.5 mg/mL for injection
Buprenorphine (Buprenex, others)
Oral: 2, 8 mg sublingual tablets
Parenteral: 0.3 mg/mL for injection
Butorphanol (generic, Stadol)
Parenteral: 1, 2 mg/mL for injection
Nasal (generic, Stadol NS): 10 mg/mL nasal spray
Codeine (sulfate or phosphate) (generic)
Oral: 15, 30, 60 mg tablets, 15 mg/5 mL solution
Parenteral: 15, 30 mg/mL for injection
Fentanyl
Parenteral (generic, Sublimaze): 50 mg/mL for injection
Fentanyl Transdermal System (Duragesic): 12.5, 25, 50, 75, 100 mcg/h delivery
Fentanyl Oralet: 100, 200, 300, 400 mcg oral lozenge
Fentanyl Actiq: 200, 400, 600, 800, 1200, 1600 mcg lozenge on a stick
Hydromorphone (generic, Dilaudid)
Oral: 1, 2, 3, 4, 8 mg tablets; 1 mg/mL liquid
Parenteral: 1, 2, 4, 10 mg/mL for injection
Levomethadyl acetate (Orlaam)
Oral: 10 mg/mL solution. Note: Orphan drug approved only for the treatment of narcotic addiction.
Levorphanol (generic, Levo-Dromoran)
Oral: 2 mg tablets
Parenteral: 2 mg/mL for injection
Meperidine (generic, Demerol)
Oral: 50, 100 mg tablets; 50 mg/5 mL syrup
Parenteral: 25, 50, 75, 100 mg per dose for injection
Methadone (generic, Dolophine)
Oral: 5, 10 mg tablets; 40 mg dispersible tablets; 1, 2, 10 mg/mL solutions
Parenteral: 10 mg/mL for injection
Morphine sulfate (generic, others)
Oral: 15, 30 mg tablets; 15, 30 mg capsules; 10, 20, 100 mg/5 mL solution
Oral sustained-release tablets (MS-Contin, others): 15, 30, 60, 100, 200 mg tablets);
Oral sustained-release capsules (Avinza, Kadian): 20, 30, 50, 60, 90, 100, 120 mg capsules
Parenteral: 0.5, 1, 2, 4, 5, 8, 10, 15, 25, 50 mg/mL for injection
Rectal: 5, 10, 20, 30 mg suppositories
Nalbuphine (generic, Nubain)
Parenteral: 10, 20 mg/mL for injection
Oxycodone (generic)
Oral: 5 mg tablets, capsules; 1, 20 mg/mL solutions
Oral sustained-release (OxyContin): 10, 20, 40, 80 mg tablets
Oxymorphone (Numorphan)
Parenteral: 1, 1.5 mg/mL for injection
Rectal: 5 mg suppositories
Pentazocine (Talwin)
Oral: See combinations
Parenteral: 30 mg/mL for injection
Propoxyphene (generic, Darvon Pulvules, others)
Oral: 65 mg capsules, 100 mg tablets. Note: This product is not recommended.
Remifentanil (Ultiva)
Parenteral: 1, 2, 5 mg powder for reconstitution for injection
Sufentanil (generic, Sufenta)
Parenteral: 50 mcg /mL for injection

OTHER ANALGESICS

Tramadol (Ultram)
Oral: 50 mg tablets
Ziconotide (Prialt)
Intrathecal: 25, 100 mcg/mL for programmable pump

ANALGESIC COMBINATIONS²

Codeine/acetaminophen (generic, Tylenol w/ Codeine, others)
Oral: 15, 30, 60 mg codeine plus 300 or 325 mg acetaminophen tablets or capsules; 12 mg codeine plus 120 mg acetaminophen tablets
Codeine/aspirin (generic, Empirin Compound, others)
Oral: 30, 60 mg codeine plus 325 mg aspirin tablets
Hydrocodone/acetaminophen (generic, Norco, Vicodin, Lortab, others)
Oral: 2.5, 5, 7.5, 10 mg hydrocodone plus 500 or 650 mg acetaminophen tablets
Hydrocodone/ibuprofen (Vicoprofen)
Oral: 7.5 mg hydrocodone plus 200 mg ibuprofen
Oxycodone/acetaminophen (generic, Percocet, Tylox, others). Note: High-dose acetaminophen has potential for hepatic toxicity with repeated use.
Oral: 5 mg oxycodone plus 325 or 500 mg acetaminophen tablets
Oxycodone/aspirin (generic, Percodan)
Oral: 4.9 mg oxycodone plus 325 mg aspirin
Propoxyphene/aspirin or Propoxyphene/acetaminophen (Darvon Compound-65, others) Note: This product is not recommended.
Oral: 65 mg propoxyphene plus 389 mg aspirin plus 32.4 mg caffeine; 50, 65, 100 mg propoxyphene plus 325 or 650 mg acetaminophen

OPIOID ANTAGONISTS

Nalmefene (Revex)
Parenteral: 0.1, 1 mg/mL for injection
Naloxone (Narcan, various)
Parenteral: 0.4, 1 mg/mL; 0.02 mg/mL (for neonatal use) for injection
Naltrexone (ReVia, Depade)
Oral: 50 mg tablets

ANTITUSSIVES

Codeine (generic)
Oral: 15, 30, 60 mg tablets; constituent of many proprietary syrups²
Dextromethorphan (generic, Benylin DM, Delsym, others)
Oral: 5, 7.5 mg lozenges; 7.5, 10, 15, 30 mg/5 mL syrup; 30 mg sustained-action liquid; constituent of many proprietary syrups<sup>2

1</sup>Antidiarrheal opioid preparations are listed in Chapter 63.

²Dozens of combination products are available; only a few of the most commonly prescribed ones are listed here. Codeine combination products available in several strengths are usually denoted No. 2 (15 mg codeine), No. 3 (30 mg codeine), and No. 4 (60 mg codeine). Prescribers should be aware of the possible danger of renal damage with acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs contained in these analgesic combinations.



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