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Chapter: Basic & Clinical Pharmacology : Opioid Analgesics & Antagonists

Pharmacodynamics - Basic Pharmacology of the Opioid Analgesics

Opioid agonists produce analgesia by binding to specific G pro-tein-coupled receptors that are located in brain and spinal cord regions involved in the transmission and modulation of pain.


A. Mechanism of Action

Opioid agonists produce analgesia by binding to specific G pro-tein-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.

1. Receptor types—As noted previously, three major classes ofopioid receptors (μ, δ, and κ) have been identified in various ner-vous 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 acidsequence homologies. Multiple receptor subtypes have been pro-posed based on pharmacologic criteria, including μ1, μ2; δ1, δ2; and κ1, κ2, and κ3. However, genes encoding only one subtype fromeach of the μ, δ, and κ receptor families have been isolated and characterized thus far. 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 vari-ants in mice and humans. Since an opioid may function with differ-ent 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 actions— At the molecular level, opioid receptorsform a family of proteins that physically couple to G proteins andthrough this interaction affect ion channel gating, modulate intra-cellular Ca2+ disposition, and alter protein phosphorylation . 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 these effects. The presynaptic action— depressed transmitter release—has been demonstrated for release of a large number of neurotransmitters including gluta-mate, the principal excitatory amino acid released from nocicep-tive nerve terminals, as well as acetylcholine, norepinephrine, serotonin, and substance P.

3. Relation of physiologic effects to receptor type—Themajority 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, opi-oid analgesic effects are complex and include interaction with δ and κ receptors. This is supported by the study of genetic knock-outs of the μ, δ, and κ genes in mice. Delta-receptor agonists retain analgesic properties in δ receptor knockout mice. The development of μ-receptor–selective agonists could be clinically useful if their side-effect profiles (respiratory depression, risk ofdependence) were more favorable than those found with current μ-receptor agonists, such as morphine. Although morphine doesact at κ and δ receptor sites, it is unclear to what extent this con-tributes 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 recep-tors have been developed. Butorphanol and nalbuphine have shown some clinical success as analgesics, but they can cause dys-phoric 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 analgesia—Opioid receptor binding sites have been localizedautoradiographically with high-affinity radioligands and with anti-bodies 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 the dorsal horn pain transmission neurons, they also inhibit the release of excitatorytransmitters from the primary afferents. Within the presynaptic terminals, there is evidence that heterodimerization of the μ-opioid and δ-opioid receptors contribute to μ-agonist efficacy (eg, inhibi-tion of presynaptic voltage-gated calcium channel activity). 

On the other hand, a recent study using a transgenic mouse that expresses a δ–receptor-enhanced green fluorescent protein (eGFP) fusion protein shows little overlap of μ receptor and δ receptor in the dorsal root ganglion neurons. Importantly, the μ receptor is associatedwith 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 is consistent with the action of intrathecal μ-receptor– and δ-receptor–selective ligands that are found to blockheat versus mechanical pain processing, respectively. 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.

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 adminis-tered 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) path-ways (Figure 31–3). At these sites as at others, opioids directly inhibit neurons; yet this action results in the activation of descend-ing 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 loca-tions (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 neuronal 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 μ receptor, but this action may evoke the release of endogenous opioids that additionally act at and κ receptors. Thus, even a receptor-selective ligand can initi-ate 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 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 physi-ologic peripheral μ-receptor activation. 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). Such compounds could have the additional benefit of reducing unwanted effects such as constipation.

5. Tolerance and dependence— With frequently repeatedtherapeutic doses of morphine or its surrogates, there is a gradual loss in effectiveness; this loss of effectiveness is denoted tolerance. To reproduce the original response, a larger dose must be admin-istered. 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 isadministered.

The mechanism of development of tolerance and physical dependence is poorly understood, but persistent activation ofreceptors such as occurs with the treatment of severe chronic pain appears to play a primary role in its induction and mainte-nance. Current concepts have shifted away from tolerance being driven by a simple up-regulation of the cyclic adenosine mono-phosphate (cAMP) system. Although this process is associated with tolerance, it is not sufficient to explain it. A second hypoth-esis 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 endocytosis fol-lowed by resensitization and recycling of the receptor to the plasma membrane . However, using geneticallymodified mice, research now shows that the failure of morphine to induce endocytosis of the μ-opioid receptor is an important com-ponent of tolerance and dependence. In contrast, methadone, a μ-receptor agonist used for thetreatmentof opioid tolerance anddependence, does induce receptor endocytosis. This suggests that maintenance of normal sensitivity of μ receptors requires reactiva-tion by endocytosis and recycling. Another area of research sug-gests that the δ opioid receptor functions as an independent component in the maintenance of tolerance. In addition, the con-cept of receptor uncoupling has gained prominence. Under this hypothesis, tolerance is due to a dysfunction of structural interac-tions 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 main-tenance because 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.

In addition to the development of tolerance, persistent admin-istration of opioid analgesics has been observed to increase the sensation of pain leading to a state of hyperalgesia. This phenom-enon has been observed with several opioid analgesics, including morphine, fentanyl, and remifentanil. Spinal dynorphin and acti-vation of the bradykinin receptor have emerged as important candidates for the mediation of opioid-induced hyperalgesia.

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 effects—The principal effects ofopioid 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 toler-ance occurs to all of these effects (Table 31–3).


a. Analgesia—Pain consists of both sensory and affective (emo-tional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience, especially the affective aspect. In contrast, nonsteroidal anti-inflammatory analgesic drugs have no significant effect on the emotional aspects of pain.

b. Euphoria—Typically, patients or intravenous drug users whoreceive intravenous morphine experience a pleasant floating sensa-tion with lessened anxiety and distress. However, dysphoria, an unpleasant state characterized by restlessness and malaise, may sometimes occur.

c. Sedation—Drowsiness and clouding of mentation are com-mon effects of opioids. There is little or no amnesia. Sleep isinduced 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 phenan-threne) 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 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 depression—All of the opioid analgesics canproduce significant respiratory depression by inhibiting brain-stem 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 depres-sion 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 pul-monary 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 μ-receptor phar-macology and serotonin signaling pathways in the brainstem respiratory control centers.

e. Cough suppression—Suppression of the cough reflex is awell-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 obstruc-tion and atelectasis.

f. Miosis—Constriction of the pupils is seen with virtually allopioid 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, mio-sis is seen. This action, which can be blocked by opioid antago-nists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine.

g. Truncal rigidity—An intensification of tone in the largetrunk 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 adminis-tered intravenously. Truncal rigidity may be overcome by admin-istration 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 vomiting— The opioid analgesics can activatethe 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.Temperature—Homeostatic regulation of body temperatureis mediated in part by the action of endogenous opioid peptides in

the brain. This has been supported by experiments demonstrating that administration of μ-opioid receptor agonists such as morphine administered to the anterior hypothalamus produces hyperthermia, whereas administration of κ agonists induces hypothermia.

2. Peripheral effects

a. Cardiovascular system—Most opioids have no significantdirect effects on the heart and, other than bradycardia, no major effects on cardiac rhythm. Meperidine is an exception to this gener-alization because its antimuscarinic action can result in tachycardia. Blood pressure is usually well maintained in subjects receiving opi-oids 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 tract—Constipation has long been recog-nized 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  as well as the CNS. In the stomach, motil-ity (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 tract—The opioids contract biliary smooth muscle,which can result in biliary colic. The sphincter of Oddi may con-strict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels.


d. Renal—Renal function is depressed by opioids. It is believedthat in humans this is chiefly due to decreased renal plasma flow. In addition, μ 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 reab-sorption. The role of opioid-induced changes in antidiuretic hor-mone (ADH) release is controversial. Ureteral and bladder tone are increased by therapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate urinary retention, espe-cially in postoperative patients. Occasionally, ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone.


e. Uterus—The opioid analgesics may prolong labor. Themechanism for this action is unclear, but both peripheral and central actions of the opioids can reduce uterine tone.


f. Neuroendocrine— Opioid analgesics stimulate the release ofADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone. These effects suggest that endogenous opi-oid peptides, through effects in the hypothalamus, regulate these systems (Table 31–1).


g. Pruritus—Therapeutic doses of the opioid analgesics produceflushing 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. Miscellaneous— The opioids modulate the immune systemby 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. Although the mechanisms involved are com-plex, activation of central opioid receptors could mediate a sig-nificant 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 μ receptor. Its slow rate of dissociation from the μ receptor has also made it an attractive alternative to methadone for the management of opioid with-drawal. It functions as an antagonist at the δ and κ 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 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. Pentazocine and nalbuphine are other examples of opioid analgesics with mixed agonist-antagonist prop-erties. Psychotomimetic effects, with hallucinations, nightmares, and anxiety, have been reported after use of drugs with mixed agonist-antagonist actions.

A combined buprenorphine HCl/naloxone HCl dihydrate preparation is now available as sublingual tablets and a sublingual film for use in a maintenance treatment plan that includes counsel-ing, psychosocial support, and direction by physicians qualified under the Drug Addiction Treatment Act. Both formulations can be abused in a manner similar to other opioids, legal or illicit. The combination formulations can cause serious respiratory depression and death, particularly when extracted and injected intravenously in combination with benzodiazepines or other CNS depressants (ie, sedatives, tranquilizers, or alcohol). It is extremely dangerous to self-administer benzodiazepines or other CNS depressants while taking the buprenorphine-naloxone combination.

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