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Chapter 24 Opioid Analgesics

David S. Fries

Introduction Agents that decrease pain are referred to as analgesics, or analgetics. Although analgetic is grammatically correct, common use has made analgesic preferable to analgetic for the description of the pain-killing drugs. Pain relieving agents also are called antinociceptives.

A number of classes of drugs are used to relieve pain. The nonsteroidal anti-inflammatory agents have primarily a peripheral site of action, are useful for mild to moderate pain, and often have an anti- inflammatory effect associated with their pain-killing action. Local anesthetics inhibit pain transmission by inhibition of voltage-regulated sodium channels. These agents often are highly toxic when used in concentrations sufficient to relieve chronic or acute pain in ambulatory patients. Dissociative anesthetics (ketamine), and other compounds that act as inhibitors of N-methyl-D-aspartate (NMDA)–activated glutamate receptors in the brain, are effective antinociceptive agents when used alone or in combination with opioids. Compounds, such as the antiseizure drug pregabulin, which inhibits voltage regulated Ca2+ ion channels, are useful in treating neuropathic pain. Most central nervous system (CNS) depressants (e.g., ethanol, barbiturates, and antipsychotics) will cause a decrease in pain perception. Inhibitors of serotonin and norepinephrine reuptake (i.e., antidepressant drugs) are useful either alone and in combination with opioids in treating certain cases of chronic pain. Current research into the antinociceptive effects of centrally acting α-adrenergic-, cannabinoid-, and nicotinic-receptor agonists may yield clinically useful analgesics working by nonopioid mechanisms. Research in one or more of the above areas may lead to new drugs, but at present, severe acute or chronic pain generally is treated most effectively with opioid agents.

Historically, opioid analgesics have been called narcotic analgesics. Narcotic analgesic literally means that the agents cause sleep or loss of consciousness (narcosis) in conjunction with their analgesic effect. The term “narcotic” has become associated with the addictive properties of opioids and other CNS depressants. Because the great therapeutic value of the opioids is their ability to induce analgesia without causing narcosis, and because not all opioids are addicting, the term “narcotic analgesic” is misleading and will not be used further in this chapter.

History The juice (opium in Greek) or latex from the unripe seed pods of the poppy Papaver somniferum is among the oldest recorded medications used by humans. The writings of Theophrastus around 200 BC describe the use of opium in medicine; however, evidence suggests that opium was used in the Sumerian culture as early as 3500 BC. The initial use of opium was as a tonic, or it was smoked. The pharmacist Surtürner first isolated an alkaloid from opium in 1803. He named the alkaloid morphine, after Morpheus, the Greek god of dreams. Codeine, thebaine, and papaverine are other medically important alkaloids that were later isolated from the latex of opium poppies.

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Morphine was among the first compounds to undergo structure modification. Ethylmorphine (the 3-ethyl ether of morphine) was introduced as a medicine in 1898. Diacetylmorphine (heroin), which may be considered to be the first synthetic pro-drug, was synthesized in 1874 and marketed as a nonaddicting analgesic, antidiarrheal, and antitussive agent in 1898.

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Clinical Significance

Opioid agonists and partial agonist/antagonists generally act on δ, µ, and κ receptors. All of these receptors have subtypes that provide varying degrees of analgesia, euphoria or dysphoria, central nervous system depression, and perhaps, the potential for tolerance. By modifying their structures, properties can be changed to develop agents that require more or less hepatic metabolism and, thus, affect the duration of action and the bioavailability. Other changes in the chemical structures can yield agents with much higher affinity for analgesic receptors, which corresponds to more potency on a milligram-to-milligram basis. Other alterations of the chemical structures can lead to improved profiles regarding respiratory depression, emesis, tolerance, and allergenicity. By altering the affinities for some receptors more than others, the addictive properties also may be manipulated. Through an understanding of the relationship of chemical structures to biological activity, the clinician can improve the selection of drug to the specific patient. Jill T. Johnson, Pharm.D., BCPS Associate Professor Department of Pharmacy Practice College of Pharmacy University of Arkansas for Medical Sciences

Opiate/Opioid The use of the terms “opiate” and “opioid” requires clarification. Until the 1980s, the term “opiate” was used extensively to describe any natural or synthetic agent that was derived from morphine. One could say an opiate was any compound that was structurally related to morphine. In the mid-1970s, the discovery of peptides in the brain with pharmacological actions similar to morphine prompted a change in nomenclature. The peptides were not easily related to morphine structurally, yet their actions were like those produced by morphine. At this time, the term “opioid,” meaning opium- or morphine-like in terms of pharmacological action, was introduced. The broad group of opium alkaloids, synthetic derivatives related to the opium alkaloids, and the many naturally occurring and synthetic peptides with morphine-like pharmacological effects are called opioids. In addition to having pharmacological effects similar to morphine, a compound must be antagonized by an opioid antagonist, such as naloxone, to be classed as an opioid. The neuronal- located proteins to which opioid agents bind and initiate biological responses are called opioid receptors.

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Endogenous Opioid Peptides and Their Physiological Functions Scientists had postulated for some time, based on structure–activity relationships (SARs), that opioids bind to specific receptor sites to cause their actions. It also was reasoned that morphine and the synthetic opioid derivatives are not the natural ligands for the opioid receptors and that some analgesic substance must exist within the brain. Techniques to prove these two points were not developed until the mid-1970s. Hughes et al. (1) used the electrically stimulated contractions of guinea pig ileum and the mouse vas deferens, which are very sensitive to inhibition by opioids, as bioassays to follow the purification of compounds with morphine-like activity from mammalian brain tissue. These researchers were able to isolate and determine the structures of two pentapeptides, Tyr-Gly-Gly-Phe-Met (Met-enkephalin) and Tyr- Gly-Gly-Phe-Leu (Leu-enkephalin), that caused the opioid activity. The compounds were named enkephalins after the Greek word Kaphale, which translates as “from the head.”

At about the same time as Hughes and coworkers were making their discoveries, three other laboratories, using a different assay technique, were able to identify endogenous opioids and opioid receptors in the brain (2,3,4). These scientists used radiolabeled opioid compounds (radioligands), with high specific activity, to bind to opioid receptors in brain homogenates (5). They demonstrated saturable binding (i.e., the tissue contains a finite number of binding sites that can all be occupied) of the radioligands and that the bound radioligands could be displaced stereoselectively by nonradiolabeled opioids. Discovery of the enkephalins was soon followed by the identification of other endogenous opioid peptides, including β- endorphin (6), the dynorphins (7), and the endomorphins (8).

The opioid peptides isolated from mammalian tissue are known collectively as endorphins, a word that is derived from a combination of endogenous and morphine. The opioid alkaloids and all of the synthetic opioid derivatives are exogenous opioids. Interestingly, the isolation of morphine and codeine in small amounts has been reported from mammalian brain (9). The functional significance of endogenous morphine remains unknown.

Opioid Peptides The endogenous opioid peptides are synthesized as part of the structures of large precursor proteins (10). There is a different precursor protein for each of the major types of opioid peptides (Fig. 24.1). Proopiomelanocortin is the precursor for β-endorphin. Proenkephalin A is the precursor for Met- and Leu- enkephalin. Proenkephalin B (prodynorphin) is the precursor for dynorphin and P.654

α-neoendorphin. The pronociceptin protein has been identified and contains only one copy of the active peptide, whereas the precursor protein for the endomorphins remains to be identified. All of the pro-opioid proteins are synthesized in the cell nucleus and transported to the terminals of the nerve cells from which they are released. The active peptides are hydrolyzed from the large proteins by processing proteases that recognize double basic amino acid sequences positioned just before and after the opioid peptide sequences.

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Fig. 24.1. Precursor proteins to the endogenous opioid peptides.

Peptides with opioid activity have been isolated from sources other than mammalian brain. The heptapeptide β-casomorphin (Tyr-Pro-Phe-Pro-Gly-Pro-Ile), found in cow's milk, is a µ opioid agonist (11). Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), a µ-selective peptide isolated from the skin of South American frogs, is approximately 100-fold more potent than morphine in in vitro tests (12).

The endogenous opioids exert their analgesic action at spinal and supraspinal sites (Fig. 24.2). They also produce analgesia by a peripheral mechanism of action associated with the inflammatory process. In the CNS, the opioids exert an inhibitory neurotransmitter or neuromodulator action on afferent pain-signaling neurons in the dorsal horn of the spinal cord and on interconnecting neuronal pathways for pain signals within the brain. In the brain, the arcuate nucleus, periaqueductal gray, and the thalamic areas are especially rich in opioid receptors and are sites at which opioids exert an analgesic action. In the spinal cord, concentrations of endogenous opioids are high in laminae 1, laminae 2, and trigeminal nucleus areas. All of the endogenous opioid peptides and the three major classes of opioid receptors appear to be at least partially involved in the modulation of pain. The actions of opioids at the synaptic level are described in Figure 24.3.

Analgesia that results from acupuncture or is self-induced by a placebo or biofeedback mechanisms is caused by release of endogenous endorphins. Analgesia produced by these procedures can be prevented by the previous dosage of a patient with an opioid antagonist. Electrical stimulation from electrodes properly placed in the brain causes endorphin release and analgesia. This procedure is used for the “self-stimulated” release of endorphins in patients with chronic pain who do not respond to any other medical treatment. As with exogenously administered opioid drugs, tolerance develops to all procedures that work by release of endogenous opioids.

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Fig. 24.2. Location of endogenous opioid nerve tracts in the central nervous system. Endorphins and opioid receptors in the dorsal horn of the spinal cord, thalamus, and periaqueductal gray (PAG) areas are associated with the transmission of pain signals.

Opioid Receptors

There are the three major types of opioid receptors: µ, κ (13), and δ (14). All three of the receptor types have been well characterized and cloned (15). A nomenclature adopted by the International Union of Pharmacology (IU PHAR) in 1996 classifies the three opioid receptors by the order in which they were δ κ cloned (16). By this classification, opioid receptors are OP1 receptors, opioid receptors are OP2

receptors, and µ opioid receptors are OP3 receptors. The IUPHAR approved a new nomenclature in 2000, naming the receptors as MOP-µ, DOP-δ, and KOP-κ. In current literature, however, the opioid receptors often are referred to as DOR (δ), KOR (κ), and MOR (µ). There is evidence for subtypes of each of these receptors; however, the failure of researchers to find genomal evidence for http://thepointeedition.lww.com/pt/re/9780781768795/bo.../DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (5 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

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additional receptors indicates that the receptor subtypes are posttranslational modifications (splice variants) of known receptor types (17). Receptor subtypes also may be known receptor types that are coupled to different signal transduction systems. Table 24.1 lists the opioid receptor types and subtypes, their known physiological functions, and selective agonists and antagonists for each of the receptors. All three of the opioid receptor types are located in human brain or spinal cord tissues, and each has a role in the mediation of pain. At this time, only µ and κ agonists are in clinical use as opioid analgesic drugs.

Fig. 24.3. Schematic representation of a δ enkephalinergic nerve terminal. (1) Pro-opioid proteins (proenkephalin A) are synthesized in the cell nucleus. (2) Pro-opioid proteins undergo microtubular transport to the nerve terminal. (3) Active endogenous opioids (E) are cleaved from the pro-opioid proteins by the action of “processing” proteases. (4) The active peptides (E) are taken up and stored in presynaptic vesicles. (5) The peptides are released when the presynaptic neuron fires. (6) The endogenous opioid peptides bind to postsynaptic receptors and activate second messenger systems. (7) For all opioid receptors, the second messenger effect is primarily mediated by a G-inhibitory

(Gi/o) protein complex, which promotes the inactivation of adenylate cyclase (AC), a decrease in intracellular cyclic- adenosine-3′,5′-monophosphate (cAMP), and finally, an efflux of potassium ions (K+) from the cell. The net effect is the hyperpolarization of the postsynaptic neuron and inhibition of cell firing. (8). Exogenous opioids (Op), such as morphine, combine with opioid receptors and mimic the actions of E. (9) Opioid antagonists, such as naloxone (Nx), combine with opioid receptors and competitively inhibit the actions of E or Op. (10) The action of E is terminated by a membrane-bound endopeptidase [EC3.4.24.11] (enkephalinase), which hydrolyze the Gly3-Phe4 peptide bond of enkephalin. Other endopeptidases may be employed in the metabolism of different endogenous opioid peptides.

Orphan Opioid Receptor

A fourth receptor has been identified and cloned (OP4) based on homology with cDNA sequence of the known (µ, δ, and κ) opioid receptors (18). Despite the homology in cDNA sequence with known opioid receptors, this new receptor did not bind the classical opioid peptide or nonpeptide agonists or antagonists with high affinity. Thus, the receptor was called the orphan opioid receptor (NOP). In subsequent studies, two research groups found a heptadecapeptide (Phe-Gly-Gly-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Lys-Ala-Asn- http://thepointeedition.lww.com/pt/re/9780781768795/bo.../DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (6 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

Gln) to be the endogenous peptide for the orphan opioid receptor. One of the research groups (19) named the heptadecapeptide nociceptin, because they determined that it caused hyperalgesia (nociception) after intracerebral ventricular injection into mice. The other research group (20) named the heptapeptide orphanin FQ, after its affinity for the orphan opioid receptor and the first and last amino acids in the peptides sequence (i.e., F = Phe and Q = Gln) Nociceptin/orphanin FQ resembles dynorphin-A in structure, with the most notable difference being the replacement of Tyr at the N-terminus with Phe. Conflicting results have now been published regarding the ability of nociceptin/orphanin FQ to produce hyperalgesia versus analgesia in rodent pain assay models. One study has established this compound to be a potent initiator of pain signals in the periphery, where it acts by releasing substance P from nerve terminals (21). Injection of a nociceptin/orphanin antagonist into the brains of laboratory animals results in an analgesic effect, raising hope for the use of these agents in the management of pain (22).

Identification and Activation of Opioid Receptors Identification of multiple opioid receptors has depended on the discovery of selective agonists and antagonists, the identification of sensitive assay techniques (23), and ultimately, the cloning of the receptor proteins (15). The techniques that have been especially useful are the radioligand binding assays on brain tissues and the electrically stimulated peripheral muscle preparations. Rodent brain tissue contains all three opioid receptor types, and special evaluation procedures (computer-assisted line fitting) or selective blocking (with reversible or irreversible binding P.656

agents) of some of the receptor types must be used to sort out the receptor selectivity of test compounds. The myenteric plexus–containing longitudinal strips of guinea pig ileum contain µ and κ opioid receptors. The contraction of these muscle strips is initiated by electrical stimulation and is inhibited by opioids. The vas deferens from mouse contains µ, δ, and κ receptors and reacts similarly to the guinea pig ileum to electrical stimulation and to opioids. Homogenous populations of opioid receptors are found in rat (µ), hamster (δ), and rabbit (κ) vas deferentia.

Table 24.1. Opioid Receptor Types and Subtypes Receptor Type (Natural Ligand) Selective Agonists Agonist Properties Selective Antagonists

µ, mu, MOP, OP3 Morphine Analgesia (morphine-like) Naloxone (endomorphin 1) Sufentanil Euphoria Naltrexone (endomorphin 2) (β- DAMGO (Tyr-D-Ala-MePhe-NH-(CH2) Increased gastrointestinal CTOP endorphin) 2OH transit time Cyprodime β PLO17 (Tyr-Pro-MePhe-D-Pro-NH2 BIT Immune suppression -FNA (affinity label) (affinity label) Respiratory depression (volume)

µ1 (high affinity) Meptazinol Emetic effects Naloxonazine Etonitazene Tolerance Physical dependence

µ2 (low affinity) TRIMU-5 (Tyr-D-Ala-Gly-NH-(CH2)2-CH-(CH3)2 κ , kappa, KOP, OP2 Ethylketocyclazocine (EKC) Analgesia TENA nor-BNI (dynorphins) Bremazocine Sedation (β-endorphin) Mr2034 dyn (1–17) Miosis Trifluadom Diuresis Dysphoria http://thepointeedition.lww.com/pt/re/9780781768795/bo.../DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (7 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

κ 1 (high affinity) U-50,488 UPHIT Spiradoline (U-62,066) U-69,593 PD 117302 κ 2 dyn 1–17 κ 3 NalBzOH δ 2 5 , delta, DOP, OP1 DADLE (D-Ala -D-Leu - enkephalin) Analgesia ICI 174864 (enkephalins) DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr) Immune stimulation FIT (affinity label) (β-endorphin) DPDPE (D-Pen2-D-Pen5-Convulsions Respiratory depression (rate) SUPERFIT (affinity label) (?) Enkephalin) δ 2 DADLE Naltrindole (NTI) BNTX δ 2 2 D-Ala -deltorphin II Naltriben (NTB) Naltrindol isothiocyanate (NTII)

δ κ The signal transduction mechanism for µ, , and receptors is through Gi/o proteins. Activation of opioid receptors is linked through the G protein to an inhibition of adenylate cyclase* activity. The resultant decrease in cAMP production, efflux of potassium ions and closure of voltage-gated Ca2+ channels causes hyperpolarization of the nerve cell (24,25), and a strong inhibition of nerve firing.

µ Opioid Receptors

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Try-Pro-Phe-Phe-NH2) are endogenous opioid peptides with a high degree of selectivity for µ (MOP) receptors (8). A number of therapeutically useful compounds have been found that are selective for µ opioid receptors (Fig. 24.4). All of the opioid alkaloids and most of their synthetic derivatives are µ-selective agonists. Morphine, normorphine, and dihydromorphinone have 10- to 20-fold µ receptor selectivity and were particularly important in early studies to differentiate the opioid receptors. Sufentanil and the peptides DAMGO (26) and dermorphin (27), all with 100-fold selectivity for µ over other opioid receptors, frequently are used in the laboratory studies to demonstrate µ receptor-selectivity in cross-tolerance, receptor binding, and isolated smooth muscle assays. Studies with µ receptor knockout mice have confirmed that all the major pharmacological actions observed on injection of morphine (e.g., analgesia, respiratory depression, tolerance, withdrawal symptoms, decreased gastric motility, and emesis) occur by interactions with µ receptors (28).

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Fig. 24.4. Structures of compounds selective for µ (OP3) opioid receptors.

Naloxone and naltrexone are antagonists that have weak (5 to 10 times) selectivity for µ receptors. Cyprodime is a selective nonpeptide µ antagonist (~30-fold selective for µ over κ and 100-fold selective for µ over δ) available for laboratory use (29). CTOP, a cyclic peptide analogue of somatostatin, is a selective µ

antagonist (30). There is evidence that µ1 receptors are high-affinity binding sites that mediate pain

neurotransmission, whereas µ2 receptors control respiratory depression. Naloxoneazine is a selective

inhibitor of µ1 opioid receptors (31).

k Opioid Receptors

Ethylketazocine and bremazocine are 6,7-benzomorphan derivatives with κ opioid receptor selectivity (Fig. 24.5). These two compounds were used in early studies to investigate κ (KOP) receptors. They are not highly selective, however, and their use in research has diminished. A number of arylacetamides derivatives, having a high selectivity for κ over µ or δ receptors, have been discovered. The first of these compounds, (±)-U50488, has a 50-fold selectivity for κ over µ receptors and has been extremely important in the characterization of κ opioid activity (32). Other important agents in this class are (±) PD-117302 (33) and (-) CI-977 (34). Each of these agents has 1,000-fold selectivity for κ over µ or δ receptors. Evidence suggests that the arylacetamides bind to a subtype of κ receptors. In general, κ agonists produce analgesia in animals, including humans. Other prominent effects are diuresis, sedation, and dysphoria. Compared to µ agonists, κ agonists lack respiratory depressant, constipating, and strong addictive (euphoria and physical dependence) properties. It was hoped that κ agonists would become useful strong analgesics that lacked

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addictive properties; however, clinical trials with several highly selective and potent κ agonists were aborted because of the occurrence of unacceptable sedative and dysphoric side effects. κ-Selective opioids with only a peripheral action have been shown to be effective in relieving inflammation and the pain associated κ κ κ κ with it (35). The scientific evidence suggesting 1, 2, and 3 subtypes of receptors; however, the physiological effects initiated by the κ receptor subtypes are not well defined (36).

The peptides related to dynorphin are the natural agonists for κ receptors. Their selectivity for κ over µ receptors is not very high. Synthetic peptide analogues have been reported that are more potent and more selective than dynorphin for κ receptors (37,38).

The major antagonist with good selectivity for κ receptors is nor-binaltorphimine (39). This compound has approximately 100-fold selectivity for κ over δ receptors and an even greater selectivity for κ over µ receptors when tested during competitive binding studies in monkey brain homogenate. No medical use for a κ antagonist has been found.

d Opioid Receptors

Enkephalins, the natural ligands at δ (DOP) receptors, are only slightly selective for δ over µ receptors. Changes P.658

in the amino acid composition of the enkephalins can give compounds with high potency and selectivity for δ receptors. The peptides most often used as selective δ receptor ligands (Fig. 24.6) are [D-Ala2, D-Leu5] enkephalin (DADLE) (40), [D-Ser2, Leu5] enkephalin-Thr (DSLET) (41), and the cyclic peptide [D-Pen2, D- Pen5] enkephalin (DPDPE) (42). These and other δ receptor selective peptides have been useful for in vitro studies, but their metabolic instability and poor distribution properties (i.e., penetration of the blood-brain barrier is limited by their hydrophilicity) has limited their usefulness for in vivo studies. Nonpeptide agonists that are selective for δ receptors have been reported. Derivatives of morphindoles were the first nonpeptide molecules to show δ selectivity in in vitro assays (43). SNC-80 is a newer and more selective δ opioid receptor agonist (44). This compound produces analgesia after oral dose in several rodent models and side effects appear minimal. Clinical trials with SCN-80 and other nonpeptide δ receptor agonists were attempted and aborted, primarily because of the convulsant action of δ receptor agonists. Radioligand binding studies in rodent brain tissue and in electrically stimulated vas deferentia have provided evidence of δ δ 1 and 2 receptors (45). The functional significance of this differentiation has not been determined.

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κ Fig. 24.5. Structures of compounds selective for (OP2) opioid receptors. (–)-Stereoisomers are the most active compounds.

Naltrindol and naltriben are highly selective nonpeptide antagonist for δ receptors (46,47). Naltrindol penetrates the CNS and displays antagonist activity that is selective for δ receptors in in vitro and in vivo systems. Peptidyl antagonists TIPP and TIPP-ψ are selective for δ receptors (48,49); however, their usefulness for in vivo studies and as clinical agents is limited by their poor pharmacokinetic properties. The δ opioid receptor antagonists have shown clinical potential as immunosuppressants and in treatment of cocaine abuse.

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Receptor Affinity Labeling Agents A number of opioid receptor selective affinity labeling agents (i.e., compounds that form an irreversible covalent bond with the receptor protein) have been developed (Fig. 24.7). These compounds have been important P.659

in the characterization and isolation of the opioid receptor types. Each of the affinity-labeling agents contains a pharmacophore that allows initial reversible binding to the receptor. Once reversibly bound to the receptor, an affinity labeling agent must have an electrophilic group positioned so that it can react with a nucleophilic group on the receptor protein. The receptor selectivity of these agents is dependent on 1) the receptor type selectivity of the pharmacophore, 2) the location of the electrophile within the pharmacophore structure so that when bound to the receptor it is positioned near a nucleophile, and 3) the relative reactivities of the electrophilic and nucleophilic groups.

δ Fig. 24.6. Structures of compounds selective for (OP1) opioid receptors.

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Fig. 24.7. A representation of the concept of affinity labeling of receptors and affinity labeling agents for opioid receptors.

Examples of important affinity labeling agents are β-CNA, which because of its highly reactive 2- http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (13 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

chloroethylamine electrophilic group irreversibility binds to all three opioid receptor types (50). The structurally related compound β-FNA has a less reactive fumaramide electrophilic group and reacts irreversibly with only µ receptors (51). Derivatives of the fentanyl series, FIT and SUPERFIT, bind µ and δ receptors, but only the δ receptor is bound irreversibly (52,53). Apparently, when these agents are bound to µ receptors, the electrophilic isothiocyanate group is not oriented in proper juxtaposition to a receptor nucleophile for covalent bond formation to occur. Incorporation of the electrophilic isothiocyanate into the structure of the highly κ receptor–selective arylacetamides has provided affinity labeling agents (UPHIT and DIPPA) for κ receptors (54,55).

Neurobiology of Drug Abuse and Addiction The factors that drive some individuals to abuse drugs, with resultant tolerance and psychological and physical dependence, remains unknown. It has been proposed that a deficiency exists in the opioid- mediated self-reward system of individuals who have a predisposition to abuse addictive drugs (56). In the United States, the use of highly addictive drugs, such as heroin and cocaine, is treated as a crime rather than as a medical problem. New insights regarding the neurobiology of drug addiction is now providing an understanding of why individuals abuse drugs and how drug abuse and addiction can be avoided and treated.

Self-Reward Response It is now evident that all forms of drug addiction are driven by the stimulation of the brain's self-reward system (57), which originates in the ventral tegmental nucleus (VTN) and extends to the nucleus accumbens (NAC) area of the midbrain (Fig. 24.8). Self-reward is initiated by the release of dopamine (DA)

from the mesocorticolimbic DA neurons originating in the VTN and stimulating D1 and D2 receptors in the NAC. Cocaine acts by inhibiting the reuptake of DA at nerve terminals, thus increasing the intensity and duration of the reward response. Amphetamine, methamphetamine, and similar indirect acting adrenergic stimulants cause inhibition of DA reuptake, DA release, and inhibition of monoamine oxidase–mediated mediated of DA at this site. The µ opioid agonists work upstream in the reward neuronal system by exerting an inhibitory action on GABAergic neurons, thus removing the inhibitory GABAergic tonus on DA neurons and initiating the self-reward response. The κ opioid agonists work at a site more downstream in the system and cause the opposite effect of the µ agonists. The κ neurons synapse directly onto the DA nerve terminal in the NAC and exert an inhibitory effect (negative tonus) on DA release. Thus, a µ agonist will cause a self- reward and euphoric stimulus, and a κ agonist will cause an aversive and dysphoric stimulus. Alcohol (ethanol) also causes a stimulation of the self-reward system, partially by acting on the µ opioid neurons to facilitate the release of endogenous opioids P.660

(58). Nicotine, acting through nicotinic cholinergic receptors, also has been shown to stimulate the DA self- reward system (59).

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Fig. 24.8. The neurochemical basis of drug abuse and addiction. The diagram is a representation of the brain's self-

reward system. According to this theory, any agent that promotes stimulation of type-1 dopamine (D1) receptors in the nucleus accumbens (NCA) potentiates self-reward and has the potential to be abused. Major drugs of abuse exert their actions at various sites within the self-reward system to increase dopamine (DA) in the NCA and stimulate

D1 receptors. Site 1: Cocaine blocks DA reuptake by the DA transporter (DAT) and greatly enhances DA action at

D1. Site 2: Amphetamine, methamphetamine, and related drugs cause DA release with the resultant stimulation of κ D1. Site 3: Opioid agonists exert an inhibitory effect on DA neuronal firing, resulting in a decrease in DA release and aversion in animals. Site 4: Opioid µ agonists, such as morphine and heroin, exert an inhibitory action on γ- aminobutyric acid (GABA) interneurons in the VAT, thus removing the GABAergic inhibition on DA neuronal firing. Site 5: GABA agonists, such as gabapentin, enhance DA neuronal firing and DA release, and these agents may be useful in treating or preventing drug abuse and addiction. Other abused agents, such as nicotine and cannabis, also cause an increase in DA release in the NAC, but their exact neuronal connections to the self-reward system is not yet understood.

Thus, the common driving pathway in drug addiction is the euphoria experienced when a drug is taken and the self-reward system is activated by DA release. The self-reward response tends to be self-limiting, because feedback (adaptive) mechanisms in the nerve cells attenuate the reward delivered after prolonged or repeated activation of the system. Agents that slowly distribute to the brain have minor abuse potential, because the adaptive mechanisms in the self-reward neuronal system are able to respond quickly enough to attenuate the euphoric response. Highly abused substances tend to have high potency, full efficacy, and a fast onset of action so that the reward signal is initiated and fully activated before the adaptive process can take effect. Factors that contribute to fast onset of action are high lipophilicity of the drug and a dosing method that allows rapid distribution to the brain. Most abused drugs are highly lipophilic so that they rapidly cross the blood-brain barrier. The dosage routes preferred by drug addicts (smoking and intravenous injection) meet the criteria for fast distribution to the brain. Of course, agents that are rapidly distributed to and absorbed by the brain also are rapidly redistributed from the brain to other body tissues. Because of the redistribution phenomenon, the intense euphoric rush experienced by the addict is short-lived and must be frequently reinduced. Repeated exposure of the reward system to the drugs activates the adaptive mechanisms, which results in desensitization (tolerance) of the system to the abused substance. The addict must take a larger dose of the drug to get the euphoric high that she or he seeks, which results in increased

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tolerance and propagation of the addiction cycle.

Opioid Tolerance and Withdrawal Tolerance to and withdrawal from the opioids is explained by the cellular adaptation that occurs on repeated

activation of µ opioid receptors (60). When an agonist binds to the µ receptor, Gi/o second messenger proteins are activated, and inhibition of adenylate cyclase occurs. Continual activation of the receptors results in an upregulation of adenylate cyclase to compensate for the decrease in cellular concentrations of

cAMP. In addition, cellular mechanisms are activated that result in a decrease in the synthesis of Gi/o protein subunits and an internalization of the µ receptor protein. Together, these adaptations cause a decrease in the magnitude of the opioid response to a given dose of agonist and explain the development of tolerance in the system and the need for ever-higher doses to get the same degree of euphoric response.

When the nerve cells are pushed into a highly tolerant state, they have a great capacity to make cAMP because of the upregulation in adenylate cyclase; however, the capacity is held in check by inhibitory effect of the opioids on P.661

adenylate cyclase. On cessation of dosing the opioid (~4–6 hours with heroin), the inhibitory effect on the upregulated adenylate cyclase system is removed, and the cells overproduce cAMP. The increase in cellular cAMP induces a number of abnormal and unpleasant effects that are recognized collectively as opioid withdrawal symptoms. The acute phase of withdrawal lasts for days (i.e., the time required for cAMP levels and receptor mechanisms to return to a normal state). The long-term effect of drug addiction is a learned drug-craving behavior, which can last for a lifetime and is thought to be responsible for the high incidence of stress-induced relapses into drug abuse.

Interestingly, not all µ opioid agonists have the same capacity to initiate receptor internalization and downregulation, which are typical occurrences in the development of tolerance. Morphine has a high capacity to induce tolerance, whereas methadone has a much lower tolerance capacity. Clinical studies are in progress to see if coadministration of morphine and methadone will result in lower tolerance development (61).

Rehabilitation of Opioid Addiction Therapeutic programs that employ drugs in the rehabilitation of drug addicts have been in use for some time. The best-known treatment is the use of methadone maintenance in the rehabilitation of the opioid addict. In a well-run program, daily treatment with oral methadone maintains the addicted (tolerant) state while allowing minimal euphoric/aversive mood swings, attenuates drug craving, decreases the spread of HIV (by decreasing needle sharing), and minimizes the social destructive behavior (e.g., prostitution and theft) of the addicted patient (62). Other agents, such as the µ agonist L-α-acetylmethadol (levomethadyl) and the partial µ agonist buprenorphine, can be substituted for methadone and offer the advantage of dosing every third day (63,64). The biggest problem with addiction treatment programs is their failure to alleviate the drug-craving behavior of the recovering addict, and she or he resumes the habit of drug abuse. Evidence suggests that treatment of a detoxified opioid addict (i.e., an individual who has been weaned from opioid dependence through a methadone or other treatment program) with a long-acting opioid antagonist, such as naltrexone, can not only pharmacologically block readdiction but also curb the addict's

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drug-craving urge (65). Interestingly, naltrexone treatment has been shown to inhibit alcohol craving in recovering alcoholics (66). Naltrexone and buprenorphine have shown promise in treatment of cocaine abuse (67,68).

A number of possible neurobiological mechanisms have been identified by which drug intervention might prevent drug abuse or aid in the recovery of the addict (Fig. 24.8). The use of µ opioid agonists, partial agonists, and antagonists has been described in the preceding paragraph. Additional opioid-related mechanisms may be effective in the prevention of drug abuse and addiction. When a δ opioid agonist is given in combination with a µ opioid agonist, analgesia is enhanced, and there is minimal induction of tolerance and physical dependence (69). It also has been shown that administration of a µ agonist along with a δ antagonist to rodents resulted in analgesia without inducing tolerance and physical dependence (70). α-Adrenergic agonists are known to interact with many of the same neuronal systems as the opioids.

The centrally acting µ-agonist clonidine works through the same Gi/o second messenger system as the opioids, and it is used clinically to inhibit withdrawal symptoms in patients addicted to opioids. Testing of the long-acting indirect GABAergic agent vigabatrin (a suicide inhibitor of GABA aminotransferase) has been proposed for the treatment of drug addiction (71). One additional area of promise is the proposal that a high- affinity, slow-onset inhibitor of the DA transporter will be effective for the treatment of cocaine abuse (72).

Structure–Activity Relationships of µ Receptor Agonists

Morphine Morphine is the prototype opioid (Table 24.2). It is selective for µ opioid receptors. The structure of morphine is composed of five fused rings, and the molecule has five chiral centers with absolute stereochemistry 5(R), 6(S), 9(R), 13(S) and 14(R). The naturally occurring isomer of morphine is levo-[(–)] rotatory. (+)-Morphine has been synthesized, and it is devoid of analgesic and other opioid activities (73).

It is important to remember that a minor change in the structure of morphine (or any other opioid) will likely cause a different change in the affinity and intrinsic activity of the new compound at each of the opioid receptor types. Thus, the opioid receptor selectivity profile of the new compound may be different than the structure from which it was made or modeled (i.e., a selective µ agonist may shift to become a selective κ agonist, etc.). In addition, the new compound will have different physicochemical properties than its parent. The different physicochemical properties (e.g., solubility, partition P.662

coefficient, and pKa) will result in different pharmacokinetic characteristics for the new drug and can affect its in vivo activity profile. For example, a new drug (Drug A) that is more lipophilic than its parent may distribute better to the brain and appear to be more active, whereas in actuality, it may have lower affinity or intrinsic activity for the receptor. The greater concentration of Drug A reaching the brain is able to overcome its decreased agonist effect at the receptor. The SARs discussed in the following paragraphs describe the relative therapeutic potencies of the compounds and are a combination of pharmacokinetic and receptor binding properties of the drugs.

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Table 24.2 Structure, Numbering and Selected SAR for (-)-Morphine)

The A ring and the basic nitrogen, which exists predominantly in the protonated (ionized) form at physiological pH, are the two most common structural features found in compounds displaying opioid analgesic activity. The aromatic A ring and the cationic nitrogen may be connected either by an ethyl linkage (9,10-positions of the B ring) or a propyl linkage (either edge of the piperidine ring that forms the D ring). The A ring and the basic nitrogen are necessary components in every potent µ agonist known. These two structural features alone are not sufficient for µ opioid activity, however, and additional pharmacophoric groups are required. In compounds having rigid structures (i.e., fused A, B, and D rings), the 3-hydroxy group and a tertiary nitrogen either greatly enhance or are essential for activity. A summary of other important SAR features for morphine is given in Table 24.2.

Nitrogen Atom The substituent on the nitrogen of morphine and morphine-like structures is critical to the degree and type of activity displayed by an agent. A tertiary amine usually is necessary for good opioid activity. The size of the N-substituent can dictate the compound's potency and its agonist versus antagonist properties. Generally, N-methyl substitution results in a compound with good agonist properties. Increasing the size of the N-substituent to three to five carbons (especially where unsaturation or small carbocyclic rings are included) results in compounds that are antagonists at some or all opioid receptor types. Larger substituents on nitrogen return agonist properties to the opioid. An N-phenylethyl–substituted opioid usually is on the order of 10-fold more potent as a µ agonist than the corresponding N-methyl analogue.

Ideal Opioid Thousands of derivatives of morphine and other µ agonists have been prepared and tested (74,75). The objective of most of the synthetic efforts has been to find an analgesic with improved pharmacological properties over known µ agonists. Specifically, one would like to have an orally active drug that retains the strong analgesic properties of morphine yet lacks its ability to cause tolerance, physical dependence, respiratory depression, emesis, and constipation. The success of this search has been limited. Many compounds that are more potent than morphine have been discovered. Also, compounds with

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pharmacodynamic properties different from those of morphine have been discovered, and some of these compounds are preferred to morphine for selected medical uses. The ideal analgesic drug, however, is yet to be discovered. Research to find new centrally acting analgesics has turned away from classic µ agonists and now is focused on agents that act through other types or subtypes of opioid receptors or through nonopioid neurotransmitter systems.

3-Phenolic Hydroxy Group The SARs of compounds structurally related to morphine are outlined in Table 24.2. A number of the structural variations on morphine have yielded compounds that are available as drugs in the United States. The most important of these agents, in terms of prescription volume, is the alkaloid codeine. Codeine, the 3- methoxy derivative of morphine, is a relatively weak µ agonist, but it undergoes slow metabolic O- demethylation to morphine, which accounts for much of its action. Codeine also is a potent antitussive agent and is used extensively for this purpose.

Heroin The 3,6-diacetyl derivative of morphine is commonly known as heroin. It was synthesized from morphine in 1874 and was introduced to the market in 1898 by the Friedrich Bayer Co. in Germany. The 1906 Squibb's Materia Medica listed 10-mg tablets of heroin at $1.20 per 1,000. At the time of its introduction, heroin was described as “preferable to morphine because it does not disturb digestion or produce habit readily.” Heroin itself has relatively low affinity for µ opioid receptors; however, its high lipophilicity compared to morphine results in enhanced penetration of the blood-brain barrier. Once in the body (including the brain), serum and tissue esterases hydrolyze the 3-acetyl group to produce 6-acetylmorphine. This latter compound has µ agonist activity in excess of morphine. The combination of rapid penetration by heroin into the brain after intravenous dose and rapid conversion to a potent µ agonist provides a “euphoric rush” that makes this compound a popular drug of abuse. Repeated use of heroin results in the development of tolerance, physical dependence, and acquisition of a drug habit that often is destructive to the user and society. In addition, the use of unclean or shared hypodermic needles for self-administering heroin often results in the transmission of the HIV, hepatitis, and other infectious diseases.

C Ring Changes in the C-ring chemistry of morphine or codeine can lead to compounds with increased activity. Hydromorphone is the 7,8-dihydro-6-keto derivative of morphine, P.663

and it is 8 to 10 times more potent than morphine on a weight basis. Hydrocodone, the 3-methoxy derivative of hydromorphone, is considerably more active than codeine.

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Fig. 24.9. Diverse structural families that yield potent opioid agonists.

14a-Hydroxy-6-Keto Derivatives

The opium alkaloid thebaine can be synthetically converted to 14α-hydroxy-6-keto derivatives of morphine. The 14α-hydroxy group generally enhances µ agonist properties and decreases antitussive activity, but activity varies with the overall substitution on the structure. Oxycodone, the 3-methoxy-N-methyl derivative, is about as potent as morphine when given parenterally, but its oral to parenteral dose ratio is better than

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that for morphine. Oxymorphone is the 3-hydroxy-N-methyl derivative, and it is 10 times as potent as morphine on a weight basis. Substitution of an N-cyclobutylmethyl for N-methyl and reduction of the 6-keto group to 6α-OH of oxymorphone gives nalbuphine, which acts through κ receptors and has approximately half the analgesic potency of morphine. Nalbuphine is an antagonist at µ receptors. Interestingly, N-allyl- (naloxone) and N-cyclopropylmethyl- (naltrexone) noroxymorphone are “pure” opioid antagonists. Naloxone and naltrexone are slightly µ receptor selective and are antagonists at all opioid receptor types.

Figure 24.9 contains some of the diverse chemical structures that produce µ agonist activity. The structures shown in the figure illustrate that the morphine structure may be built up or broken down to yield compounds that produce potent agonist activity. Reaction of thebaine with dienophiles (i.e., Diels-Alder reactions) results in 6, 14-endo-ethenotetrahydrothebaine derivatives, which are commonly called oripavines (76). Some of the oripavine derivatives are extremely potent µ agonists. Etorphine and buprenorphine are the best known of these derivatives. Etorphine is approximately 1,000 times more potent than morphine as a µ agonist. Etorphine has a low therapeutic index in humans, and its respiratory depressant action is difficult to reverse with naloxone or naltrexone. Thus, the compound is not useful in medical practice. Etorphine (M-99) is available for use in veterinary medicine for the immobilization of large animals. The oripavine structure–based antagonist diprenorphine is used to reverse the tranquilizing effect of etorphine. Buprenorphine, a marketed oripavine derivative, is a P.664

partial agonist at µ receptors, with a potency of 20 to 30 times that of morphine. The compound's uses and properties are described in the section on clinically available agents.

3,4-Epoxide Bridge and the Morphinans Removal of 3,4-epoxide bridge in the morphine structure results in compounds that are referred to as morphinans. One cannot remove the epoxide ring from the morphine structure by simple synthetic means. Rather, the morphinans are prepared by total synthesis using a procedure described by Grewe (77). The synthetic procedure yields compounds as racemic mixtures and only the levo-(–)-isomers possess opioid activity. The dextro isomers have useful antitussive activity. The two morphinan derivatives that are marketed in the United States are levorphanol and butorphanol. Levorphanol is approximately eight times more potent than morphine as an analgesic in humans. Levorphanol's increased activity results from an increase in affinity for µ opioid receptors and its greater lipophilicity, which allows higher peak concentrations to reach the brain. Butorphanol is a µ antagonist and a κ agonist. The mechanism of action of the mixed agonist/antagonists is described in more detail later in this chapter.

Benzomorphans Synthetic compounds that lack both the epoxide ring and the C ring of morphine retain opioid activity. Compounds having only the A, B, and D rings are named chemically as derivatives of 6,7-benzomorphan (Fig. 24.9) or, using a different nomenclature system, of 2,6-methano-3-benzazocine. They are commonly referred to simply as benzomorphans. The only agent from this structural class that is marketed in the United States is pentazocine, which has an agonist action on κ opioid receptors—an effect that produces analgesia. Pentazocine is a weak antagonist at µ receptors. The dysphoric side effects that are produced by higher doses of pentazocine result from actions at κ opioid receptors and also at σ (PCP) receptors. The benzomorphan-derivative phenazocine (N-phenylethyl) is approximately 10 times as potent as morphine as http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (21 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

a µ agonist and is marketed in Europe.

Aminotetralins represent A- and B-ring analogues of morphine. A number of active compounds in this class have been described, but only dezocine, a mixed agonist/antagonist, has been marketed.

4-Phenylpiperidines Analgesic compounds in the 4-phenylpiperidine class may be viewed as A- and D-ring analogues of morphine (Fig. 24.9). The opioid activity of these agents was discovered serendipitously. The first of these agents, meperidine, was synthesized in 1937 by Eislab (78), who was attempting to prepare antispasmodic agents. The compound produced an S-shaped tail (Straub tail) in cats, an effect that had been recognized as a response caused by morphine and its derivatives. Meperidine proved to be a typical µ agonist, with approximately one-fourth the potency of morphine on a weight basis. It is particularly useful in certain medical procedures because of its short duration of action because of esterases hydrolysis to a zwitterionic metabolite. Reversed esters of meperidine have greater potency, and several of these derivatives have been marketed. The 3-methyl reversed ester derivatives of meperidine, α- and β-prodine, were available in the United States but have been removed from the market because of their low prescription volume and their potential to undergo elimination reactions to compounds that resemble the neurotoxic agent MPTP (see Chapter 25). Trimeperidine or µ-promedol, the 1,2,5-trimethyl reserved ester of meperidine, is used in Russia as an analgesic.

Anilidopiperidines Structural modification of the 4-phenylpiperidines has led to discovery of the 4-anilidopiperidine, or the fentanyl, group of analgesics (Fig. 24.9). Fentanyl and its derivatives are µ agonists, and they produce typical morphine-like analgesia and side effects. Structural variations of fentanyl that have yielded active compounds are substitution of an isosteric ring for the phenyl group, addition of a small oxygen containing group at the 4-position of the piperidine ring, and introduction of a methyl group onto the 3-position of the piperidine ring. Newer drugs that illustrate some of these structural changes are alfentanil and sufentanil. Both of these drugs have higher safety margins than other µ agonists. For unknown reasons, the compounds produce analgesia at much lower doses than is necessary to cause respiratory depression.

Diphenylheptanone In the period just before or during the Second World War, German scientists synthesized another series of open-chain compounds as potential antispasmodics. In a manner analogous to that of meperidine, animal testing showed some of the compounds to possess analgesic activity. Methadone was the major drug to come from this series of compounds (Fig. 24.9). Methadone is especially useful for its oral activity and its long duration of action. These properties make methadone useful in maintenance therapy for opioid addicts and for pain suppression in the terminally ill (i.e., hospice programs). Methadone is marketed in the United States as a racemic mixture, but the (–)-isomer possesses almost all of the analgesic activity. Many variations on the methadone structure have been made, but little success in finding more useful drugs in class has been achieved. Reduction of the keto and acetylation of the resulting hydroxyl group gives the acetylmethadols (see below). Variations of the methadone structure have led to the discovery of the useful antidiarrheal opioids diphenoxylate and loperamide.

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P.665

Propoxyphene is an open-chain compound that was discovered by structural variation of methadone. Propoxyphene is a weak µ opioid agonist having only one-fifteenth the activity of morphine. The (+)-isomer produces all of the opioid activity.

µ Antagonists The SAR for µ antagonists is relatively simple if one focuses just on marketed compounds. All of the marketed, rigid-structured opioid analogues that have the 3-phenolic group and an N-allyl, N- cyclopropylmethyl (N-CPM), or N-cyclobutylmethyl (N-CBM) substituent replacing the N-methyl are µ antagonists (Fig. 24.5). Compounds behaving as µ antagonists may retain agonist activity at other opioid receptor types. The only exception to this rule is buprenorphine, which has an N-CPM substituent and is a potent partial agonist (or partial antagonist) at µ receptors. Only two compounds are pure antagonists (i.e., act as antagonists at all opioid receptors). These compounds are the N-allyl (naloxone) and N-CPM (naltrexone) derivatives of noroxymorphone. The 14α-hydroxyl group is believed to be important for the pure antagonistic properties of these compounds. It is not understood how the simple change of an N- methyl to an N-allyl group can change an opioid from a potent agonist into a potent antagonist. The answer may lie in the ability of opioid receptor protein to effectively couple with signal transduction proteins (G proteins) when bound by an agonist but not to couple with the G proteins when bound by an antagonist. This explanation infers that an opioid having an N-substituent of three to four carbons in size induces a conformational change in the receptor or blocks essential receptor areas that prevent the interaction of the receptor and the signal transduction proteins.

Those interested in an in-depth understanding of the SAR for µ receptor antagonists should be aware that properly substituted N-methyl-4-phenylpiperidines, N-methyl-6,7-benzomorphans, and even nonphenolic opioid derivatives that have good antagonist activity are known.

Structure–Activity Relationships of k Receptor Agonists

The SAR for marketed κ agonists is somewhat related to that of µ antagonists (Fig. 24.5). All of the marketed κ agonists have structures related to the rigid opioids and N-allyl, N-CPM or N-CBM substitutions. The compounds are all µ receptor antagonists and κ receptor agonists. The κ agonist activity is enhanced if there is an oxygen group placed at the 8-position (e.g., ethylketazocine) or into the N-substituent (e.g., bremazocine). The oxygen group in a N-furanylmethyl substituent also enhances κ activity.

Potent and selective κ agonists that lack antagonistic properties at any of the opioid receptors are found in a number of trans-1-arylacetamido-2-aminocyclohexane derivatives. There are not enough compounds reported in this class to develop strong trends in SARs. The relative mode of receptor binding for the morphine-related verses the arylacetamide κ agonists is not known. Evidence exists for the selective κ κ κ binding of the arylacetamides to 1 and of the benzomorphan compounds (e.g., bremazocine) to 2 and 3 opioid receptor subtypes.

Structure–Activity Relationships of d Receptor Agonists

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compounds. Peptides with high selectivity for δ receptors are known. The SARs for some of these peptides are discussed in the following paragraphs. Nonpeptide δ selective agonists (Fig. 24.6) have been discovered, and SARs are being developed (79). Several selective δ agonists entered clinical trials but were withdrawn because of the potential convulsive (80) action of the agents.

Structure–Activity Relationships of Opioid Peptides Thousands of derivatives related to the endogenous opioid peptides have been prepared since the discovery of the enkephalins in 1975 (81) (Fig. 24.1). A thorough discussion of the SAR of these peptides would be a major task; however, some major trends have emerged and easily can be discussed. Some selected general SAR points for peptide opioids are:

● All of the endogenous opioid peptides, except for the endomorphans, have Leu- or Met-enkephalin as their first five amino acid residues.

● The tyrosine at the first amino acid residue position of all the endogenous opioid peptides is essential for activity. Removal of the phenolic hydroxyl group or the basic nitrogen (amino terminus group) will abolish activity. The Tyr1 free amino group may be alkylated (methyl or allyl groups to give agonists and antagonists), but it must retain its basic character. The structural resemblance between morphine and the Tyr1 group of opioid peptides is especially obvious.

● In addition to the phenol and amine groups of Tyr1, the next most important moiety in the enkephalin structure is the phenyl group of Phe4. Removal of this group or changing its distance from Tyr1 results in full or substantial loss in activity.

● The enkephalins have several low-energy conformations, and different conformations likely are bound at different opioid receptor types and subtypes.

● The replacement of the natural L-amino acids with unnatural D-amino acids can make the peptides resistant to the actions of several peptidases that generally rapidly degrade the natural endorphins. The use of a D-Ala in place of Gly2 has been P.666

especially useful for protecting the peptides from the action of nonselective aminopeptidases. The placement of bulky groups into the structure (e.g., the addition of N-Me to Phe4) also will slow the action of peptidases. When evaluating new peptides for opioid activity, it often is difficult to tell if changes are caused by metabolic stability or receptor affinity.

● Conversion of the terminal carboxyl group into an alcohol or an amide will protect the compound from carboxy peptidases.

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Any introduction of unnatural D- or L-amino acids or bulky groups into the enkephalin structure will affect its conformational stability. The resultant peptides will have an increase or decrease in affinity for each of the opioid receptor types. The right combination of increases and/or decreases in receptor affinity will result in selectivity for a receptor type.

● Structural changes that highly restrict the conformational mobility of the peptides (e.g., substitution of proline for Gly2 or cyclization of the peptide) have been especially useful for the discovery of receptor-selective opioid peptides.

For examples of the above SARs, see the structures of the peptides given in Figures 24.4, 24.5, and 24.6.

Enkephalin Peptides The effect of lengthening the amino acid chain of the enkephalin peptides deserves special consideration. As previously noted, the endogenous opioids found in mammals most often have Leu- or Met-enkephalin at their amino terminus end. Lengthening the carboxyl terminus can give the peptide greater affinity or selectivity for an opioid receptor type. This effect can be illustrated by the dynorphins, for which incorporation of the basic amino acids (especially Arg7) into the C-terminus chain results in a marked increase in affinity for κ receptors. The message-address analogy has been used to describe this effect. The first four amino acids [Tyr-Gly-Gly-Phe] are essential for peptide ligands to bind to and to activate all opioid receptor types. The N-terminus amino acids can then be referred to as carrying the “message” to the receptors. Adding additional amino acids to the C-terminus can “address” the message to a specific receptor type. The additional peptide chain may be affecting the address (selectivity) by providing new and favorable binding interactions to one of the receptor types. Alternatively, the additional peptide could be inducing a conformational change in the message portion of the peptide that favors interaction with one of the receptor types.

Metabolism of The Opioids Knowledge of the metabolism of the opioid drugs is essential to the understanding of the uses of these agents. The poor oral versus parenteral dose ratio (~6:1) of morphine is caused by extensive first-pass metabolic conjugation of morphine at the phenolic (3-OH) position (Fig. 24.10). The metabolism occurs predominantly in the liver and requires the action of sulfotransferase or glucuronyltransferase enzymes. The conjugates have low activity and poor distribution properties. The 3-glucuronide does undergo enterohepatic cycling, which explains the need for high initial oral doses of morphine, followed by lower maintenance doses. Glucuronidation of morphine at the 6-OH position results in the formation of an active metabolite. Morphine is also N-demethylated to give normorphine, a compound that has decreased opioid activity and decreased bioavailability to the CNS. Normorphine undergoes N- and O-conjugations and excretion. Geriatric patients metabolize morphine at a slower rate than normal adult patients; thus, they are likely to show greater sensitivity to the drug and require lower doses.

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Fig. 24.10. Metabolism of morphine and codeine.

In human subjects, approximately 10% of an oral dose of codeine is O-demethylated by CYP2D6 to produce morphine. The morphine produced as a metabolite of codeine is essential for the analgesic effect. A significant portion of the American population (8–10%) lacks CYP2D6, and these individuals do not experience analgesia P.667

when dosed with codeine (82). The antitussive activity of codeine is produced by the unmetabolized drug at nonopioid receptors and is not affected by the lack of CYP2D6. The bioactivation of codeine (versus the bioinactivation of morphine) results in an oral:parenteral dose ratio for codeine of 1.5:1; however, codeine is seldom given parenterally because of its strong effect to release histamine from mast cells. http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (26 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

Fig. 24.11. Metabolism of methadone and levomethadyl (LAAM).

Other rigid-structured opioid analogues undergo routes of metabolism similar to that of morphine. The amount of first-pass 3-O-conjugation varies from compound to compound; thus, the relative oral:parenteral http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (27 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

dosages of the agents will vary. In general, compounds that are more potent and lipophilic than morphine (e. g., levorphanol) tend to have better oral activity. Compounds with N-alkyl groups larger than methyl get N- dealkylated as a major route of inactivation.

The short duration of action of meperidine is the result of rapid metabolism. Plasma esterases cleave the ester bond to leave the inactive zwitterionic 4-carboxylate derivative. Meperidine also undergoes N- demethylation to give normeperidine. Normeperidine has little analgesic activity, but it contributes significantly to the toxicity of meperidine.

The metabolism of methadone, as outlined in Figure 24.11, is important to its action. The major route of inactivation results from N-demethylation and cyclization of the secondary amine into an inactive pyrrole derivative. If the keto group is reduced by alcohol dehydrogenase to give methadol, the demethylation product can no longer cyclize to the pyrrole derivatives. Methadol is less active than methadone as an analgesic, but the N-demethylation products of methadol, normethadol and dinormethadol, are active analgesics with increased half-lives compared to that of methadone. The buildup of these metabolites is responsible for the long duration of action and the mild, prolonged withdrawal symptoms associated with methadone.

Levo-α-acetylmethadol (LAAM, levomethadyl acetate) is longer acting than methadone. Its slow onset of action P.668

after oral dose (and the isolation of at least three active metabolites) suggests that LAAM itself is a pro- drug. The relative contributions of LAAM and its active metabolites to the analgesic and addition maintenance properties in humans have not been determined. It is clear that a 75- to 100-mg oral dose of this agent will suppress withdrawal symptoms in opioid addicts for 3 to 4 days.

µ Opioid Receptor Models A number of models have been proposed to represent the bonding interactions of agonists at µ opioid receptors. These models are “reflections” of complementary bonding interactions of µ agonists to the receptor as revealed from SAR studies. Beckett and Casy (83) published the first such receptor drawing in 1954. They studied the configurations and conformations of the µ agonists known at that time and proposed that all opioids could bind to the template (receptor model) shown in Figure 24.12. The model presumed that nonrigid opioids (e.g., meperidine and methadone) took a shape like that of morphine when binding to the receptor. It soon became apparent that the most stable conformations of meperidine and methadone were not able to be superimposed on the structure of morphine. New compounds that could not assume the shape of morphine also were being discovered, and it became apparent that the Beckett and Casy model could not explain the activity of all µ agonists.

In the mid-1960s, Portoghese (84) attempted to correlate the structures and analgesic activities of rigid and nonrigid opioids that contained the same series of N-substituents. He argued that if all opioids bound the receptor in the same conformation, then a substituent at a like position on any of the compounds should fall on the same surface area of the receptor. One would expect the same structural modification on any opioid structure to give the same type and degree of bonding interaction and, thus, the same contribution to analgesic activity. Portoghese found that parallel changes of the N-substituent on rigid (morphine, morphinan, or benzomorphan) analgesic parent structures gave parallel changes in activity. This finding

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supported the notion that rigid-structured opioid compounds bound to the receptor for analgesia in the same manner. When the same test was applied to nonrigid (meperidine-like) opioid structures, however, varying the N-substituent did not produce an activity change that paralleled that seen for the rigid-structured series. Apparently, the N-substituents in the rigid and nonrigid opioid series were falling on different surfaces of a receptor and, thus, making different contributions to analgesic activity. Portoghese concluded that the rigid and nonrigid series of compounds either were binding to different receptors or were interacting with the same receptor by different binding modes. He introduced the bimodal receptor binding model (Fig. 24.13) as one possible explanation of the results. Later, it was discovered that the activity of the rigid opioid compounds (Series 1) was enhanced by a 3-OH substituent on the aromatic ring, whereas a like substituent in some nonrigid opioids (Series 2) caused a loss of activity. Again, like substituents produced nonparallel changes in activity, indicating that the aromatic rings in the two series were not binding to the same receptor site. To provide an explanation for these results, the bimodal binding model was modified to incorporate the structure of the enkephalin (Fig. 24.14) (85). The rigid-structured opioids that benefit from the inclusion of a phenolic P.669

hydroxyl group were proposed to bind the µ receptor in a manner equivalent to the tyrosine (Tyr1 or T- subsite) of enkephalin. The nonrigid-structure opioids, which lose activity on introduction of a phenolic hydroxyl group into their structure, were proposed to interact with the receptor in a manner equivalent to the phenylalanine (Phe4 or P-subsite) of enkephalin. The free amino group of Tyr1 occupies the anionic binding site of the receptor that is the common binding point of both opioid series. This model closely resembles original bimodal binding proposal.

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Fig. 24.12. A representation of the original model for the opioid receptor as proposed by Beckett and Casy (83). The morphine structure would have to rotate 180º about a vertical axis before it could bind to the receptor site. The model is only good for µ-selective agents.

Fig. 24.13. A representation of the bimodal binding model of the µ opioid receptor as proposed by Portoghese (84). Different opioid series bind to different surface areas of the same receptor protein.

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Fig. 24.14. A representation of the enkephalin binding site of µ opioid receptors (85). (A) An enkephalin bound to the receptor. (B) Morphine binding the receptor by utilizing the T-subsite (i.e., the tyrosine-binding site). (C) A meperidine-type opioid binding the receptor by utilizing the P-subsite (i.e., the phenylalanine-binding site).

Models that attempt to explain the ability of Na+ to decrease the binding affinity of agonists, but not antagonists, for the opioid receptor have been made (86). Sodium ions also protect the receptor from alkylation by nonselective alkylating agents.

The Beckett and Casy model was extended to explain the increased potency of the oripavine analogues, such as etorphine (Fig. 24.15) (76). The affinity of the oripavines for the µ opioid receptor can be much greater than that seen for morphine. It is likely that the increased receptor affinity comes from auxiliary drug– receptor bonding interactions similar to those depicted in the receptor model.

Martin (87) has proposed a receptor model for κ opioid receptors. Martin's model considers just the binding of rigid morphine-related opioid structures. The relationship of how rigid morphine-related agents interact with the κ receptor compared to the arylacetamide κ agonist derivatives has not been well studied.

Models for the δ opioid receptors have not been proposed.

Specific Drugs

µ Agonists Structures of specific drugs and compounds are given in Table 24.3.

(–)-Morphine Sulfate Morphine sulfate is the analgesic used most often for severe, acute, and chronic pain. Morphine is a µ agonist and is a Schedule II drug. It is available in intramuscular, subcutaneous, oral, rectal, epidural, and intrathecal dosage forms. The epidural and intrathecal preparations are formulated without a preservative. Morphine is three- to six times more potent when given intramuscularly than when given orally. The difference in activity results from extensive first-pass 3-O-glucuronidation of morphine—an inactive metabolite. The half-life of intramuscularly dosed (10 mg) morphine is approximately 3 hours. The dose of morphine, by any dosage route, must be reduced in patients with renal failure and in geriatric and pediatric patients. The enhanced effects of morphine in renal failure is believed to be caused by a buildup of the active 6-glucuronide metabolite, which depends on renal function for elimination.

The analgesic effect of orally dosed morphine can equal that obtained by parenteral administration, if proper doses are given. When given orally, the initial P.670

dose of morphine is usually 60 mg, followed by maintenance doses of 20 to 30 mg every 4 hours. Addiction to clinically used morphine by the oral route generally is not a problem.

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Fig. 24.15. A representation of the binding of an oripavine-type analgesic to the µ opioid receptor (76). The hydroxyl and phenyl groups in the side chain are believed to form additional bonding interactions with the receptor compared to the Beckett and Casy receptor model.

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Table 24.3. Marketed Drugs that are Derivatives of Morphine

Overdoses of morphine, as well as all µ agonists in this section, can be effectively reversed with naloxone.

(–)-Codeine Phosphate Codeine is used extensively to treat moderate to mild pain. Codeine is a weak µ agonist, but approximately 10% of an oral dose (30–60 mg) is metabolized to morphine (see the section on metabolism in this chapter), which contributes significantly to its analgesic effect. The plasma half-life of codeine after oral dose is 3.5 hours. The dose of codeine needed to produce analgesia after parenteral dose causes releases of histamine sufficient to produce hypotension, pruritus, and other allergic responses. Thus, administration of codeine by parenteral route is not recommended.

(–)-Hydromorphone Hydrochloride (Dilaudid) Hydromorphone is a potent µ agonist (eight times greater than morphine) that is used to treat severe pain. It is available in intramuscular, intravenous, subcutaneous, oral, and rectal dosage forms. Like all strong µ agonists, hydromorphone is addicting and is a Schedule II drug. Hydromorphone has an oral:parenteral potency ratio of 5:1. The plasma half-lives after parenteral and oral dosage are 2.5 and 4 hours, respectively.

(–)-Oxymorphone Hydrochloride (Numorphan) Oxymorphone is a potent µ agonist (10 times greater than morphine) that is used to treat severe pain. It is used by intramuscular, subcutaneous, intravenous, and rectal routes of administration. The intramuscular dose of oxymorphone (1 mg) has a half-life of 3 to 4 hours. It is a Schedule II drug. Oxymorphone, because of its 14-hydroxy group, has low antitussive activity.

(–)-Levorphanol Bitartrate (Levo-Dromoran) Levorphanol is a potent µ agonist (approximately sixfold greater than morphine), and its uses, side effects, and physical dependence liability are like those of oxymorphone or hydromorphone. Levorphanol is available in oral, subcutaneous, and intravenous dosage forms. The oral dose of levorphanol is approximately twice the parenteral dose. This drug is unique among the µ agonists in that its analgesic duration of action is 4 to 6 hours, whereas its clearance half-life is 11.4 hours. Thus, effective analgesic doses of this agent can lead to a buildup of the drug in the body and result in excessive sedation.

(–)-Hydrocodone Bitartrate (Lortab, Vicodin in Combinations with Acetaminophen) Hydrocodone is a Schedule III drug that is used to treat moderate pain. It is used mostly by the oral route (5- mg tablets and solutions) in combination with acetaminophen. The compound has good oral bioavailability and is metabolized in a manner similar to codeine.

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(–)-Oxycodone Hydrochloride (Roxicodone, Oxycontin Sustained Release; and Percocet, Percodan, Tylox; in Combinations) Oxycodone is about equipotent with morphine, but because of the 3-OCH group, it has a much lower oral: parenteral dose ratio. Thus, oxycodone is used orally to treat severe to moderate pain. It is a Schedule II drug as a single agent and when combined in strong analgesic mixtures. Oxycodone has a plasma half-life of approximately 4 hours and requires dosing every 4 to 6 hours. Metabolism of this agent is comparable to that of codeine.

Meperidine Hydrochloride (Demerol)

Meperidine is a µ agonist with approximately one-tenth the potency of morphine after intramuscular dose. Meperidine produces the analgesia, respiratory depression, and euphoria caused by other µ opioid agonists, but it causes less constipation and does not inhibit cough. When given orally, meperidine has 40 to 60% bioavailability because of significant first-pass metabolism. Because of the limited bioavailability, it is one-third as potent after an oral dose compared to a parenteral dose.

Meperidine has received extensive use in obstetrics because of its rapid onset and short duration of action. When it is given intravenously in small (25-mg) doses during delivery, the respiratory depression in the newborn child is minimized. Meperidine is used as an analgesic P.671

in a variety of nonobstetric anesthetic procedures. Meperidine is extensively metabolized in the liver, with only 5% of the drug being excreted unchanged. Prolonged dosage of meperidine may cause an accumulation of the metabolite normeperidine (see the section on metabolism in this chapter). Normeperidine has only weak analgesic activity, but it causes CNS excitation and can initiate grand mal seizures. It is recommended that meperidine be discontinued in any patient who exhibits signs of CNS excitation.

Meperidine has a strong adverse reaction when given to patients receiving a monoamine oxidase inhibitor. This drug interaction has been seen recently in patients with Parkinson's disease taking the monoamine

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oxidase–selective inhibitor selegiline (Eldepryl).

The elimination half-life of meperidine is 3 to 4 hours, and it can double in patients with liver disease. Acidification of the urine will cause enhanced clearance of meperidine, but there is a lesser effect on the clearance of the toxic metabolite normeperidine.

(±)Tramadol HCl (Ultram)

The analgesic activity of tramadol is attributed to a synergistic effect caused by the opioid activity of the (+)- isomer and the neurotransmitter reuptake blocking effect of the (–)-isomer. The (+)-isomer possesses weak µ opioid agonist activity equivalent to approximately 1/3,800 that of morphine. The O-desmethyl metabolite (CYP2D6) of (±)-tramadol has improved µ opioid activity equivalent to 1/35 that of morphine. Affinity for both δ and κ receptors is improved. Despite its higher opioid potency, the contribution of O-desmethlytramedol to the overall analgesic effect has been questioned but not well studied. Individuals who lack CYP2D6 or are taking a CYP2D6 inhibitor have a reduced effect to tramadol (88). The fact that naloxone causes a decrease in the analgesic potency of tramadol argues strongly for an opioid component to the analgesic activity. (–)-Tramadol possesses only 1/20 the opioid activity of its (+)-isomer, but it has good activities for

inhibition of norepinephrine (Ki = 0.78 µM) and serotonin (Ki = 0.99 µM) reuptake. Tramadol's neurotransmitter reuptake activity is approximately 1/20 that of imipramine, a tricyclic antidepressant agent that is used widely in pain management. Although none of the individual pharmacological activities of tramadol is impressive, they interact to give a synergistic analgesic effect that is clinically useful.

Tramadol has been used in Europe since the 1980s and was introduced to the U.S. market in 1995. The drug is nonaddicting and, thus, is not a scheduled agent. In addition, tramadol does not cause respiratory depression or constipation.

(±)-Methadone Hydrochloride (Dolophine Hydrochloride)

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Methadone is a synthetic agent with about the same µ opioid potency as morphine. The drug is used as a racemic mixture in the United States, but nearly all of the activity is caused by the R-(–)-isomer. Methadone's usefulness is a result of its greater oral potency and longer duration compared to most other µ agonists. When given orally, a 20-mg dose given every 8 to 12 hours can provide effective analgesia. Methadone is an excellent analgesic for use in patients with cancer, and it often is used in hospice programs. Oral doses of 40 mg are commonly used for 24-hour suppression of withdrawal symptoms (addiction maintenance) in opioid addicts. When given parenterally in doses of 2.5 to 10 mg, methadone (Schedule II drug) has all the effects of morphine and other µ agonists.

The metabolism of methadone is extremely important in determining its long duration of action (see the section on metabolism in this chapter). The elimination of methadone is dependent on liver function and urinary pH. The typical half-life is 19 hours. When urinary pH is raised from normal values of 5.2 to 7.8, the half-life becomes 42 hours. At the higher pH, a lower percentage of methadone exists in the ionized form, and there is more renal reabsorption of the drug. The metabolism of methadone by liver enzymes is extensive, and there are at least two active metabolites. CYP3A4 is the major enzyme catalyzing methadone metabolism. Enzyme inducers (e.g., phenytoin and rifampin) can lead to the initiation of opioid withdrawal symptoms in patients using methadone for maintenance of addiction. Toxic concentrations of methadone can accumulate in patients with liver disease, in geriatric patients with a decreased oxidative metabolism capacity, or in patients taking an inhibitor of CYP3A4 (e.g., nifedipine, diazepam, and fluvoxamine).

Methadone is a good drug for maintenance of addiction, but it is not ideal. Methadone requires once-a-day dosing, usually at a clinic, to suppress withdrawal symptoms. Once-a-day dosing is expensive and, sometimes, logistically difficult to achieve. Levomethadyl acetate is available and is used in some treatment programs to overcome the problems of methadone. Levomethadyl acetate is more potent than methadone, and it has a longer duration of action. A single oral dose of this agent can suppress abstinence withdrawal for up to 3 days. Both P.672

methadone and levomethadyl are associated with rare induction of cardiac arrhythmias through increases in the QT interval.

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Propoxyphene Hydrochloride or Napsylate (Darvon, Dolene, Darvon-N & Generics)

Propoxyphene is a weak µ agonist that is used as a single agent and in mixtures with nonsteroidal anti- inflammatory agents to treat mild or moderate pain. The active (+)-isomer has (2S,3R) absolute configuration. Propoxyphene is only available in oral dosage forms. Propoxyphene has approximately one- twelfth the potency of morphine, and most studies show it to be equally or less effective than aspirin as an analgesic. Doses of propoxyphene that approach the analgesic efficacy of morphine are toxic. Propoxyphene's popularity results from the fact that physicians prescribe it for its lower abuse potential (Schedule IV) compared to that of codeine.

Fentanyl Citrate (Sublimaze; Also in Combination with Droperidol) The structure of fentanyl and related compounds are given in Table 24.4. Fentanyl is a µ agonist with approximately 80 times greater potency than morphine. Fentanyl has been used in combination with nitrous oxide for “balanced” anesthesia and in combination with droperidol for “neurolepalgesia.” The advantages of fentanyl over morphine for anesthetic procedures are its shorter duration of action (1–2 hours) and the fact that it does not cause histamine release on intravenous injection.

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Table 24.4. Analogues Related to Fentanyl [4-(phenylpropionamido) piperidines]

A fentanyl patch is available for the treatment of severe chronic pain. This dosage form delivers fentanyl transdermally and provides effective analgesia for periods of up to 72 hours. In 1999, fentanyl also became available in a lollipop dose form for absorption from the oral cavity.

Fentanyl's short duration of action after parenteral dose is caused by redistribution rather than by metabolism or excretion. Repeated doses of fentanyl can result in accumulation and toxicities. Elderly patients usually are more sensitive to fentanyl and require lower doses.

Opioids have a wide spectrum of P-glycoprotein (P-gp) activity, acting as both substrates and inhibitors, which might contribute to their varying CNS-related effects. Although fentanyl, sufentanil, and alfentanil did not behave as P-gp substrates, they inhibited the in vitro P-gp–mediated efflux of drugs known to be P-gp transported, such as digoxin, increasing their blood levels and the potential for important drug interactions by inhibition of P-gp efflux transporter.

Sufentanil Citrate (Sufenta) Addition of the 4-methoxymethyl group and bioisosteric replacement of the phenyl with a 2-thiophenyl on the fentanyl structure results in a 10-fold increase in µ opioid activity (Table 24.4). The resultant compound, sufentanil, is 600 to 800 times more potent than morphine. Despite its greater sedative and analgesic potency, sufentanil produces less respiratory depression at effective anesthetic doses. Sufentanil is available in an intravenous dosage form, and it is used for anesthetic procedures. It has a faster onset and shorter duration of action than fentanyl. The short duration is caused by redistribution from brain tissues after intravenous dosage.

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Alftentanil Hydrochloride (Alfenta) Substitution of tetrazol-5-one for the thiophene ring in sufentanil results in a decrease in potency (~25 times

that of morphine) and a decrease in the pKa of the resultant compound, alfentanil (Table 24.4). The lower

pKa of alfentanil results in a lower percentage of the drug existing in the ionized form at physiological pH. Being more un-ionized, alfentanil penetrates the blood-brain barrier faster than other fentanyl derivatives and has a faster onset and shorter duration of action. Alfentanil is 99% metabolized in the liver and has a half-life of only 1.3 hours. Alfentanil is available as an intravenous dosage form for use in ultrashort anesthetic procedures.

Remifentanil HCl (Ultiva) Remifentanil is much like alfentanil in its pharmacodynamic effects. It is a selective µ opioid agonist with 15 to 20 times greater potency than alfentanil (Table 24.4). Remifentanil has an onset of action of 1 to 3 minutes when given intravenously. Its unique property is its rapid P.673

offset of action, which is independent of the duration of administration of the compound. Thus, it is very useful for titration of antinociceptive effect, followed by a rapid and predictable recovery time of 3 to 5 minutes. The short duration of action is a result of the ester group, which has been rationally designed into the substituent on the piperidine nitrogen. This ester group is rapidly hydrolyzed to the inactive carboxylic acid by serum and tissue esterases, making the drug's duration of action essentially independent of the liver or renal function of the patient. Remifentanil is used extensively for analgesia associated with general anesthesia procedures. It often is used in combination with injectable general anesthetic agents, such as midazolam or propofol.

Mixed Agonist/Antagonists

(–)-Buprenorphine Hydrochloride (Buprenex)

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Buprenorphine is 20 to 50 times more potent than morphine in producing an ED50 analgesic effect in animal studies; however, it cannot produce an ED100 (compared to morphine) in these tests. Thus, buprenorphine is a potent partial agonist at µ opioid receptors. It also is a partial agonist at κ receptors but more of an antagonist at δ receptors. Buprenorphine, at 0.4 mg intramuscular dose, will produce the same degree of analgesia as 10 mg of morphine. Because of its partial agonist properties, it has a lower ceiling on its analgesic action but also produces less severe respiratory depression. It is incapable of producing tolerance and addiction comparable to full µ agonists. In fact, buprenorphine's partial agonist action, very high affinity for opioid receptors, and high lipophilicity combine to give buprenorphine a tolerance, addiction, and withdrawal profile that is unique among the opioids. When given by itself to opioid-naive patients, little tolerance or addictive potential (Schedule 5) is observed. A mild withdrawal can occur some 2 weeks after the last dose of buprenorphine. Buprenorphine will precipitate withdrawal symptoms in highly addicted individuals, but it will suppress symptoms in individuals who are undergoing withdrawal from opioids. It effectively blocks the effect of high doses of heroin. Because of these properties, buprenorphine has been approved for office-based use in treating opioid dependence (64). It also has been reported to suppress cocaine use and addiction.

Buprenorphine undergoes extensive first-pass 3-O-glucuronidation, which negates its usefulness after oral dose. It is available in parenteral and sublingual dosage forms. The typical dose is 0.3 to 0.6 mg three times per day by intramuscular injection for analgesia or 8 mg/day as a sublingual tablet for opioid-dependence maintenance. The duration of analgesic effect is 4 to 6 hours. After parenteral dose, approximately 70% of the drug is excreted in the feces, and the remainder appears as N-dealkylated and conjugated metabolites in the urine.

Naloxone is not an effective antagonist to buprenorphine because of the latter's high binding affinity to opioid receptors.

(–)-Butorphanol Tartrate (Stadol)

Butorphanol is a strong agonist at κ opioid receptors, and through this interaction, it is five times more potent than morphine as an analgesic. The κ agonists have a lower ceiling analgesic effect than full µ agonists; thus, they are not as effective in treating severe pain. Butorphanol is an antagonist at µ opioid http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (40 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

receptors with approximately one-sixth the potency of naloxone. If given to a person addicted to a µ agonist, butorphanol will induce an immediate onset of abstinence syndrome.

Butorphanol has a different spectrum of side effects than µ opioid analgesics. Respiratory depression occurs. There is a lower ceiling on this effect, however, and it is not generally lethal, as is the case with high doses of µ agonists. Major side effects after normal analgesic doses are sedation, nausea, and sweating, as well as dysphoric (hallucinogenic) effects at higher doses. Butorphanol causes an increase in pulmonary arterial pressure and pulmonary vascular resistance. There is an overall increased workload on the heart, and it should not be used in patients with congestive heart failure or to treat pain from acute myocardial infarction. Butorphanol has low abuse potential and is not a scheduled drug.

Because of first-pass metabolism, butorphanol is not used in an oral dose form. Given parenterally, it has a plasma half-life and duration of analgesic effectiveness of 3 to 4 hours. The outpatient use of butorphanol has been greatly increased by the introduction of a metered inhalant dosage form of the drug. The major metabolite of butorphanol is the inactive trans-3-hydroxycyclobutyl product, which is excreted primarily in the urine.

Nalbuphine Hydrochloride (Nubain)

Nalbuphine (Table 24.3) is an antagonist at µ receptors and an agonist at κ receptors. As an antagonist, it has approximately one-fourth the potency of naloxone, and it produces withdrawal when given to addicts. On a weight basis, the analgesic potency of nalbuphine P.674

approaches that of morphine. An intramuscular injection of 10 mg will give about the same degree and duration of analgesia as an equivalent dose of morphine.

Side effects of nalbuphine are like those of other κ. Dysphoria is not as common as with pentazocine. Sedation is the most common side effect. Nalbuphine does not have the adverse cardiovascular properties found with pentazocine and butorphanol. Nalbuphine has low abuse potential and is not listed under the Controlled Substances Act.

Nalbuphine is only available for parenteral dosage. Its elimination half-life is 2 to 3 hours. Metabolism of nalbuphine is by conjugation of the 3-OH group, and greater than 90% of the drug is excreted as conjugates in the feces.

(–)-Pentazocine Hydrochloride and Lactate (Talwin Nx and Talwin)

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Pentazocine is a weak antagonist (one-thirtieth the potency of naloxone) at µ receptors and an agonist at κ receptors. Pentazocine is one-sixth as potent as an analgesic compared to morphine after parenteral doses. Pentazocine also is dosed orally and has an oral:parenteral dose ratio of approximately 2:1. It is used to treat moderate pain. The µ antagonist properties of pentazocine are sufficient to produce abstinence signs in opioid addicts.

The side effects of pentazocine are like other κ agonists. It has a greater tendency to produce dysphoric episodes, and it causes an increase in blood pressure and heart rate similar to butorphanol. Pentazocine is a Schedule IV drug. The major abuse of pentazocine has been its injection along with the antihistaminic drug tripelennamine (the “T's and blues”). Inclusion of the antihistaminic drug reportedly causes an increase in the euphoric, while decreasing the dysphoric, effects of the pentazocine. The manufacturers of pentazocine have attempted to thwart this use by including naloxone in the oral dose formulation of pentazocine. When taken orally, as intended, the naloxone has no bioavailability, and the pentazocine is able to act as normal. When the tablet is dissolved and injected, the naloxone will effectively block the opioid actions of the pentazocine.

The elimination half-life of pentazocine is approximately 4 hours after parenteral dosage and 3 hours after oral dosage. Bioavailability after oral dose is only 20 to 50% because of first-pass metabolism. Pentazocine is metabolized extensively in the liver and is excreted via the urinary tract. The major metabolites are 3-O- conjugates and hydroxylation of the terminal methyl groups of the N-substituent. All metabolites are inactive.

Dezocine (Dulgan)

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Dezocine is classified as a mixed agonist/antagonist. The SAR of dezocine is unique among the opioids. It is a primary amine, whereas all other nonpeptide opioids are tertiary amines. Its exact receptor selectivity profile has not been reported; however, its pharmacology is most similar to that of buprenorphine. It seems to be a partial agonist at µ receptors, to have little effect at κ receptors, and to exert some agonist effect at δ receptors. On a weight basis, it is about equipotent with morphine, and like morphine, it is useful for the treatment of moderate to severe pain. It is available for intramuscular and intravenous dose. The drug is indicated for postoperative and cancer-induced pain.

Dezocine has a half-life of 2.6 to 2.8 hours in healthy patients and 4.2 hours in patients with liver cirrhosis. The onset of action of dezocine is faster (30 minutes) than equivalent analgesic doses of morphine, and its duration of action is longer (4–6 hours). Dezocine is extensively metabolized by glucuronidation of the phenolic hydroxyl group and by N-oxidation. Metabolites are inactive and excreted mostly via the renal tract.

Dezocine causes respiratory depression, but like buprenorphine, there is a ceiling to this effect. Presumably, there also is a ceiling to the analgesic effect of dezocine, but this point is not well documented. Dezocine has lower affinity for µ receptors than buprenorphine, allowing its respiratory depressant effect to be readily reversed by naloxone.

The major side effects of dezocine are dizziness, vomiting, euphoria, dysphoria, nervousness, headache, pruritus, and sweating. Normal volunteers and recovered addicts report the subjective effects of single doses of dezocine to be like morphine. Because of the partial agonist mechanism of dezocine, one would not expect it to have a high abuse potential.

Opioids Used as Antidiarrheal Agents Structure modification of 4-phenylpiperidines has led to the discovery of opioid analogues that are used extensively as antidiarrheal agents. Opioid agonists that act on µ and δ receptors have a strong inhibitory action on the peristaltic reflex on the intestine. This action occurs because endogenous opioid tracts innervate the intestinal wall, where they synapse onto cholinergic neurons. When opioids are released onto cholinergic neurons, they inhibit the release of acetylcholine and, thus, inhibit peristalsis. Any µ agonist used in medicine causes constipation as a side effect. Most µ agonists are not used as P.675

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antidiarrheal agents because of their potential for abuse and addiction.

Opium tincture and camphorated opium tincture (Paregoric) have long been used as effective antidiarrheal agents. The bad taste of these liquid preparations and their abuse potential (Schedule II and III, respectively) serve to limit their use and to favor newer agents. Codeine sulfate or phosphate salt, as a single agent, is sometimes used for the short-term treatment of mild diarrhea.

Synthetic agents that are structural combinations of meperidine and methadone are used extensively as antidiarrheal agents. Structures and uses of these agents are given below.

Diphenoxylate HCl with Atropine Sulfate (Lomotil)

Diphenoxylate HCl (2.5 mg) and atropine (0.025 mg) are combined in tablets or 5 mL liquid and are used effectively as symptomatic treatment for diarrhea. The typical dose is two tablets or 10 mL every 3 to 4 hours. The combination with atropine enhances the block of acetylcholine-stimulated peristalsis, and the adverse effects of atropine helps to limit the abuse of the opioid. The combination is Schedule V under the Controlled Substances Act. Diphenoxylate itself has low µ opioid agonist activity. It is metabolized rapidly by ester hydrolysis to the zwitterionic free carboxylate (difenoxin), which is five times more potent after oral dosing. The zwitterionic properties of difenoxin probably limits its penetration into the CNS and explains the low abuse potential of this agent. High doses of diphenoxylate (40–60 mg) will cause euphoria and addiction.

Difenoxin HCl with Atropine Sulfate (Motofen) Difenoxin, the active metabolite of diphenoxylate (as described above), also is used as an antidiarrheal agent. Tablets contain 1 mg of difenoxin and 0.025 mg of atropine sulfate. Dosage, uses, and effectiveness are similar to those of diphenoxylate.

Loperamide HCL (Imodium)

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Loperamide is a safe and effective opioid-derived antidiarrheal agent, and it is not listed under the Controlled Substances Act. This medication is now available as a nonprescription item in the United States. It is used extensively for traveler's diarrhea. It exerts its antidiarrheal effects through interaction with µ- opiate receptors in the intestine to reduce peristalsis. Loperamide is marketed as capsules (2 mg) and liquid (1 mg/5 mL) preparations. The recommended dose is 4 mg initially and an additional 2 mg following each diarrheal stool. The dose should not exceed 16 mg/day. It is too lipophilic to dissolve in water for an intravenous dosage form, a property that limits its abuse potential. The compound is highly lipophilic and undergoes slow dissolution, thus limiting the bioavailability of the agent to approximately 40% of the dose. Its low oral bioavailability also can be attributed to first-pass metabolism by both CYP2C8 and CYP3A4 to its primary N-demethyl metabolite. Peak plasma levels are reached in approximately 5 hours, with an elimination half-life of approximately 11 hours. Approximately 1% of the dose is excreted into the urine unchanged. Loperamide also is a potent inhibitor of intestinal CYP3A4, increasing the intestinal absorption of other CYP3A4 substrates. The clinically significant drug interactions of loperamide with coadministered CYP3A4 and CYP2C8 substrates or inhibitors would be limited, however, because of its two metabolic pathways.

The efflux transporter P-gp is a major determinant of the pharmacokinetics and pharmacodynamics of loperamide, a potent opiate. The main reason that loperamide does not produce opioid CNS effects at usual doses in patients is a combination of slow dissolution, first-pass metabolism, and P-gp–mediated efflux, which prevents brain absorption, perhaps contributing to its low addiction potential. Loperamide produced no respiratory depression when administered alone, but when administered with a P-gp inhibitor, respiratory depression occurred, which could not be explained by increased plasma loperamide concentrations. This effect demonstrates the potential for important drug interactions by inhibition of P-gp efflux transporter. The lack of respiratory depression produced by loperamide, which allows it to be safely used therapeutically, can be reversed by a drug causing P-gp inhibition, resulting in serious toxic and abuse potential.

Enkephalinase Inhibitors as Antidiarrheal Agents Although not available in the United States, inhibitors of enkephalinase, the major enzyme for the inactivation of endogenous opioid peptides, are available in Europe and much of the world for the treatment of diarrhea. Acetorphan (racecadotril), a pro-drug of thiorphan, is a good example of a clinically useful

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enkephalinase inhibitor used to treat diarrhea. The free thio group of thiorphan binds tightly to the zinc ion in the active site of the enzyme and inhibits its proteolytic action. Orally dosed acetorphan causes its antidiarrheal effect by inhibition of intestinal secretions and has a complementary effect when used in combination with loperamide, which exerts its effects by decreasing gastrointestinal transit time.

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Opioid Agents Used as Cough Suppressants (Antitussives) Many of the rigid-structured opioids have cough suppressant activity. This action is not a true opioid effect in that it is not always antagonized by opioid antagonists, the (+)-isomers are equally effective with the analgesic (–)-isomers as cough suppressants, and the SARs for opioid analgesia and cough suppression do not parallel each other. The 3-methoxy derivatives of morphine (codeine and hydrocodone) are nearly as effective antitussive agents as free phenolic agents. The better oral activity and decreased abuse potential of the methoxy derivatives make them preferred as antitussive agents. Incorporation of the 14α-hydroxyl into the structure (oxycodone) greatly decreases antitussive activity. If no cough suppression is desired in a patient being treated for pain, meperidine is the preferred agent.

Codeine is used extensively as a cough suppressant. It is available as a single agent or as mixtures in a variety of tablet and liquid cough suppressant formulations. As a simple agent, codeine is Schedule II, and in mixtures, it is Schedule V under the Controlled Substances Act. When used properly as a cough suppressant, codeine has little abuse potential; however, cough formulas of codeine often are abused.

Hydrocodone bitartrate is approximately threefold more effective on a weight basis as an oral antitussive medication compared to codeine. Hydrocodone also has greater analgesic activity and abuse potential than codeine. Hydrocodone is only available as a Schedule III prescription agent in combination formulations for cough suppression.

Dextromethorphan HBr is the (+)-isomer of the 3-methoxy form of the synthetic opioid levorphanol. It lacks the analgesic, respiratory depressant, and abuse potential of µ opioid agonists but retains the centrally acting antitussive action. Dextromethorphan is not an opioid and is not listed in the Controlled Substances Act. Its effectiveness as an antitussive is less than that of codeine. Dextromethorphan is available in a http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (46 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

number of nonprescription cough formulations.

Case Study

Victoria F. Roche S. William Zito SJ is a 75-year-old native Hawaiian woman with debilitating degenerative arthritis of the spine. She has been stabilized on 50 µg/hour transdermal patches of fentanyl for 2 years, and these patches have allowed her to resume normal activities of daily living, including playing bridge with friends, visiting grandchildren, walking, and gardening. Her quality of life was good until last month, when she began having significant bouts of breakthrough pain that compromised both her abilities and her spirit. She sought help from her physician to achieve better pain control, and he prescribed compound 1, administered intranasally. SJ has just presented the prescription at your pharmacy. On checking SJ's patient profile, you find that she is a poor CYP2C9 metabolizer who is on low- dose, delayed-release sodium valproate for the treatment of complex partial seizure disorder. Her seizures are being well-controlled on this medication. You evaluate the physician's therapeutic recommendation against the other analgesics you have available in your pharmacy and prepare to make a therapeutic decision on SJ's behalf.

● Identify the therapeutic problem(s) in which the pharmacist's intervention may benefit the patient.

● Identify and prioritize the patient-specific factors that must be considered to achieve the desired therapeutic outcomes.

● Conduct a thorough and mechanistically oriented structure–activity analysis of all therapeutic alternatives provided in the case.

● Evaluate the SAR findings against the patient-specific factors and desired therapeutic outcomes, and make a therapeutic decision.

● Counsel your patient.

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References

1. Hughes J, Smith TW, Kosterlitz HW, et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;258: 577–579.

2. Terenius L. Stereospecific interaction between narcotic analgesics and synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol Toxicol 1973;32:317–320.

3. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;70:2243– 2247.

4. Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic [3H] etorphine to rat brain homogenate. Proc Natl Acad Sci U S A 1973;70:1947–1949.

5. Goldstein A, Lowney LI, Pal BK. Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain. Proc Natl Acad Sci U S A 1971;68:1742– 1747.

6. Li CH, Lemaire S, Yamashiro D, et al. The synthesis and opiate activity of β-endorphin. Biochem Biophys Res Commun 1976;71:19–25.

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7. Goldstein A, Tachibana S, Lowney LI, et al. Procaine pituitary dynorphin: complete amino acid sequence of the biologically active heptadecapeptide. Proc Natl Acad Sci U S A 1979;76: 6666–6670.

8. Zadina JE, Hackler L, Ge LJ, et al. A potent and selective endogenous agonist for the µ-opiate receptor. Nature 1997;386:499–502.

9. Goldstein A, Barrett RW, James IF, et al. Morphine and other opiates from beef brain and adrenal. Proc Natl Acad Sci U S A 1985;82:5203–5207.

10. Akil H, Watson SJ, Young E, et al. Endogenous opioids: biology and function. Annu Rev Neurosci 1984;7:233–255.

11. Brantl V, Teshemacher H. A material with opioid activity in bovine milk and milk products. Naunyn Schmiedebergs Arch Pharmacol 1979;306:301–304.

12. Montecucchi PC, de Castiglioni R, Piani S, et al. Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei. Int J Pept Protein Res 1981;17:275–283.

13. Gilbert PE, Martin WR. The effects of morphine and nalorphine-like drugs in the nondependent, morphine-dependent, and cyclazocine-dependent chronic spinal dog. J Pharmacol Exp Ther 1976;198:66–82.

14. Lord JAH, Waterfield AA, Hughes J, et al. Endogenous opioid peptides: multiple agonists and receptors. Nature 1977;267:495–499.

15. Satoh M, Minami M. Molecular pharmacology of the opioid receptors. Pharmacol Ther 1995;68:343–364.

16. Dhawan BN, Cesselin R, Raghbir R, et al. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev 1996;48:567–592.

17. Pan L, Xu J, Yu R, et al. Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience 2005;133;209–220.

18. Henderson G, McKnight AT. The orphan opioid receptor and its endogenous ligand—nociceptin/ orphanin FQ. Trends Pharmacol Sci 1997;18:293–300.

http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (49 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

19. Meunier JC, Mollereau C, Toll L, et al. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 1995;377:532–535.

20. Reinscheid RK, Nothacker HP, Bourson A, et al. Orphanin FQ: a neuropeptide that activates an opioid-like G protein–coupled receptor. Science 1995;270:792–794.

21. Inoue M, Kobayashi M, Kozaki S, et al. Nociceptin/orphanin FQ-induced nociceptive responses through substance P release from peripheral nerve endings in mice. Proc Natl Acad Sci U S A 1998;95:10949–10953.

22. Zeilhofer HU, Calo G. Nociceptin/orphanin FQ and its receptor-potential targets for pain therapy? J Pharmacol Exp Ther 2003;306:423–429.

23. Leslie FM. Methods used for the study of opioid receptors. Pharmacol Rev 1987;39:197–249.

24. Childers SR. Opioid receptor-coupled second messengers systems. Life Sci 1991;48:1991–2003.

25. Connor M, Christie MD. Opioid receptor signaling mechanisms. Clin Exp Pharmacol Physiol 1999;26:493–499.

26. Handa BK, Land AC, Lord JA, et al. Analogues of β-LPH61–64 possessing selective agonist activity at µ-opiate receptors. Eur J Pharmacol 1981;70:531–540.

27. Negri L, Erspamer GF, Severini C, et al. Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogues activate two µ opioid receptor subtypes that modulate antinociception and catalepsy in the rat. Proc Natl Acad Sci U S A 1992;89:7203–7207.

28. Kieffer BL. Opioids: first lessons from knockout mice. Trends Pharmacol Sci 1999;20:19–25.

29. Schmidhammer H, Burkhard WP, Eggstein-Aeppi L, et al. Synthesis and biological evaluation of 14–alkoxymorphinans. 2. (–)-N-(cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one, a selective µ opioid receptor antagonist. J Med Chem 1989;32:418–421.

30. Pelton JT, Kazmierski W, Gulya K, et al. Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for µ opioid receptors. J Med Chem 1986;29:2370–2375.

http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (50 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

31. Paul D, Pasternak GW. Differential blockade by naloxonazine of two mu opiate actions: analgesia and inhibition of gastrointestinal transit. Eur J Pharmacol 1988;149:403–404.

32. Szmuszkovicz J, Von Voigtlander PF. Benzeneacetamide amines: structurally novel non-µ opioids. J Med Chem 1982;25:1125–1126.

33. Clark CR, Halfpenny PR, Hill RG, et al. Highly selective κ opioid analgesics. Synthesis and structure–activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2- aminocyclohexyl)aryloxy]acetamide derivatives. J Med Chem 1988;31:831–836.

34. Hunter JC, Leighton GE, Meecham KG, et al. CI-977, a novel and selective agonist for the κ- opioid receptor. Br J Pharmacol 1990;101:183–189.

35. Barber A, Bartoszyk GD, Bender HM, et al. A pharmacological profile of the novel, peripherally- selective κ-opioid receptor agonist, EMD 61753. Br J Pharmacol 1994;113:843–851.

36. Rothman RB, Bykov V, de Costa BR, et al. Evidence for four opioid κ binding sites in guinea pig brain. Prog Clin Biol Res 1990;328:9–12.

37. Choi H, Murray TF, DeLander GE, et al. N-terminal alkylated derivatives of [D-Pro10]dynorphin A- (1–11) are highly selective for κ-opioid receptors. J Med Chem 1992;35:4638–4639.

38. Lung FDT, Meyer JP, Li G, et al. Highly κ receptor–selective dynorphin A analogues with

modifications in position 3 of dynorphin A(1–11)-NH2. J Med Chem 1995;38:585–586.

39. Portoghese PS, Lipkowski AW, Takemori AE. Bimorphinans as highly selective, potent κ opioid receptor antagonists. J Med Chem 1987;30:238–239.

40. James IF, Goldstein A. Site-directed alkylation of multiple opioid receptors. I. Binding selectivity. Mol Pharmacol. 1984;25:337–342.

41. Gacel G, Fournie-Zaluski M-C, Roques BP. D-Tyr–Ser-Gly–Phe–Leu–Thr, a highly preferential ligand for δ-opiate receptors. FEBS Lett 1980;118:245–247.

42. Mosberg HI, Hurst R, Hruby VJ, et al. Bis-penicillamine enkephalins possess highly improved specificity toward δ opioid receptors. Proc Natl Acad Sci U S A 1983;80:5871–5874.

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43. Portoghese PS, Larson DL, Sultana M, et al. Opioid agonist and antagonist activities of morphindoles related to naltrindole. J Med Chem 1992;35: 4325–4329.

44. Bilsky EJ, Calderon SN, Wang T, et al. SNC 80, a selective, nonpeptidic, and systemically active opioid δ agonist. J Pharmacol Exp Ther 1995;273:359–366.

45. Jiang Q, Takemori AE, Sultana M, et al. Differential antagonism of opioid δ antinociception by [D- Ala2, Leu5, Cys6]- enkephalin and naltrindole 5′-isothiocyanate: evidence for δ receptor subtypes. J Pharmacol Exp Ther 1991;257:1069–1075.

46. Portoghese PS, Sultana M, Takemori AE. Naltrindole, a highly selective and potent nonpeptide δ opioid receptor antagonist. Eur J Pharmacol 1988;146:185–186.

47. Takemori AE, Sultana M, Nagase H, et al. Agonist and antagonist activities of ligands derived from naltrexone and oxymorphone. Life Sci 1992;149:1–5.

48. Schiller PW, Nguyen TM, Weltrowska G, et al. Differential stereochemical requirements of µ vs. δ opioid receptors for ligand binding and signal transduction: development of a class of potent and highly δ-selective peptide antagonists. Proc Natl Acad Sci U S A 1992;89:11871–11875.

49. Schiller PW, Weltrowska G, Nguyen TM, et al. TIPP[ψ]: a highly potent and stable pseudopeptide δ opioid receptor antagonist with extraordinary delta selectivity. J Med Chem 1993;36:3182–3187.

50. Portoghese PS, Larson DL, Jiang JB, et al. Synthesis and pharmacologic characterization of an alkylating analogue (chlornaltrexamine) of naltrexone with ultralong-lasting narcotic antagonist properties. J Med Chem 1979;22:168–173.

51. Portoghese PS, Larson DL, Sayre LM, et al. A novel opioid receptor site directed alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities. J Med Chem 1980;23:233– 234.

52. Burke TR Jr, Bajwa BS, Jacobson AE, et al. Probes for narcotic receptor mediated phenomena. 7. Synthesis and pharmacological properties of irreversible ligands specific for µ or δ opiate receptors. J Med Chem 1984;27: 1570–1574.

53. Burke TR Jr, Jacobson AE, Rice KC, et al. Probes for narcotic receptor mediated phenomena. 12.

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cis-(+)-3-Methylfentanyl isothiocyanate, a potent site-directed acylating agent for δ opioid receptors. Synthesis, absolute configuration, and receptor enantioselectivity. J Med Chem 1986;29:1087–1093.

54. de Costa BR, Band L, Rothman RB, et al. Synthesis of an affinity ligand (‘UPHIT') for in vivo acylation of the κ-opioid receptor. FEBS Lett 1989;249:178–182.

55. Chang AC, Takemori AE, Ojala WH, et al. κ Opioid receptor selective affinity labels: electrophilic benzeneacetamides as κ-selective opioid antagonists. J Med Chem 1994;37:4490–4498.

56. Goldstein A. Some thoughts about endogenous opioids and addiction. Drug Alcohol Depend 1983;11:11–14.

57. Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997;278:58–63.

58. Hyytia P. Involvement of µ-opioid receptors in alcohol drinking by alcohol-preferring AA rats. Pharmacol Biochem Behav 1993;45:697–701.

59. Kenny PJ, Markou A. Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 2006;31:1203–1211.

60. Sharma SK, Klee WA, Nirenberg M. Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc Natl Acad Sci U S A 1975;72:3092–3096.

61. Comparison of a single dose combination of methadone and morphine with morphine alone for treating postoperative pain. Available at: http://www.clinicaltrials.gov/ct/gui/show/NCT00142519? order=1. Accessed May 30, 2007.

P.678

62. Marsch LA. The efficacy of methadone maintenance interventions in reducing illicit opiate use, HIV risk behavior, and criminality: a meta-analysis. Addiction 1998;93:515–532.

63. Rawson RA, Hasson AL, Huber AM, et al. A 3-year progress report on the implementation of LAAM in the United States. Addiction 1998;93:533–540.

64. Fiellin DA, O'Connor PG. Office-based treatment of opioid-dependent patients. N Engl J Med 2002;347:817-823.

http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (53 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

65. Gonzalez JP, Brogden RN. Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 1988;35:192– 213.

66. Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 1992;49:876–880.

67. Walsh SL, Sullivan JT, Preston KL, et al. Effects of naltrexone on response to intravenous cocaine, hydromorphone, and their combination in humans. J Pharmacol Exp Ther 1996;279:524–538.

68. Compton PA, Ling W, Charuvastra VC, et al. Buprenorphine as a pharmacotherapy for cocaine abuse: a review of the evidence. J Addict Dis 1995;14:97–114.

69. Horan PJ, Mattia A, Bilsky EJ, et al. Antinociceptive profile of biphalin, a dimeric enkephalin analogue. J Pharmacol Exp Ther 1993;265:1446–1454.

δ 70. Miyamoto Y, Portoghese PS, Takemori AE. Involvement of 2 opioid receptors in acute dependence on morphine in mice. J Pharmacol Exp Ther 1993;265:1325–1327.

71. Dewey SL, Morgan AE, Ashby CR Jr, et al. A novel strategy for the treatment of cocaine addiction. Synapse 1998;30:119–129.

72. Kreek MJ. Opiate and cocaine addictions: challenge for pharmacotherapies. Pharmacol Biochem Behav 1997;57:551–569.

73. Iigima I, Minamikawa J, Jacobson AE, et al. Studies in the (+)-morphine series. 4. A markedly improved synthesis of (+)-morphine. J Org Chem 1978;43:1462–1463.

74. Casy AF, Parfitt RT. Opioid Analgesics: Chemistry and Receptors. New York: Plenum Press, 1986.

75. Rees DC, Hunter JC. Opioid receptors. In Emment JC, ed. Comprehensive Medicinal Chemistry: The Rational Design, Mechanistic Study, and Therapeutic Application of Chemical Compounds, vol 3, Membranes and Receptors. Oxford, UK: Pergamon Press, 1990:805–846.

76. Lewis JW, Bently KW, Cowan A. Narcotic analgesics and antagonists. Annu Rev Pharmacol 1971;11:241–270.

http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (54 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

77. Grewe R. Synthetic drugs with morphine action. Angew Chem 1947;A59:194–199.

78. Eisleb O, Schaumann O. Dolantin, a new antispasmodic and analgesic. Dtsch Med Wschr 1939;65: 967–968.

79. Calderon SN, Coop A. SNC 80 and related δ opioid agonists. Curr Pharm Des 2004;10:733–742.

80. Broom DC, Nitsche JF, Pinter JE, et al. Comparison of receptor mechanisms and efficacy requirements for δ-agonist–induced convulsive activity and antinociception in mice. J Pharmacol Exp Ther 2002;303:723–729.

81. Janecka A, Fichna J, Janecki T. Opioid receptors and their ligands. Curr Top Med Chem 2004;4:1– 17.

82. Lotsch J, Skarke C, Liefhold J, et al. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet 2004;43:983–1013.

83. Beckett AH, Casy AF. Synthetic analgesics: stereochemical considerations. J Pharm Pharmacol 1954;6:986–1001.

84. Portoghese PS. A new concept on the mode of interaction of narcotic analgesics with receptors. J Med Chem 1965;8:609–616.

85. Portoghese PS, Alreja BD, Larson DL. Allylprodine analogues as receptor probes. Evidence that phenolic and nonphenolic ligands interact with different subsites on identical opioid receptors. J Med Chem 1981;24:782–787.

86. Feinberg AP, Creese I, Snyder SH. The opiate receptor: a model explaining structure–activity relationships of opiate agonists and antagonists. Proc Natl Acad Sci U S A 1976:73:4215–4219.

87. Martin WR. Pharmacology of opioids. Pharmacol Rev 1984;35:283–318.

88. Laugesen S, Enggaard TP, Pedersen RS, et al. Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol. Clin Pharmacol Ther 2005;77:312-323.

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Suggested Readings

Aldrich JV, Virgil-Cruz SC. Narcotic analgesics. In: Abraham D, ed. Burger's Medicinal Chemistry and Drug discovery, 6th Ed. New York: John Wiley, 2003:329–481.

Bloom FE. The endorphins: a growing family of pharmacologically pertinent peptides. Annu Rev Pharmacol Toxicol 1983;23:151–170.

Buschmann T, Christoph T, Friderichs E, et al. Analgesics: From Chemistry and Pharmacology to Clinical Application. Weinheim, Germany: Wiley-VCH, 2002.

Cami J, Farre M. Drug addiction. N Engl J Med 2003;349:975–986.

Childers SR. Opioid receptors: pinning down the opiate targets. Curr Biol 1997;7:R695–R697.

Collier HOJ, Hughes J, Rance MJ, et al., eds. Opioids: Past, Present, and Future. London: Taylor and Francis, 1984.

Eisenstein TK, Hilburger ME. Opioid modulation of immune responses: effects on phagocyte and lymphoid cell populations. J Neuroimmunol 1998;83: 36–44.

Evans CJ. Secrets of the opium poppy revealed. Neuropharmacology 2004;47:293–299.

Fowler CJ, Fraser GL. µ-, δ-, and κ-opioid receptors and their subtypes. A critical review with emphasis on radioligand binding experiments. Neurochem Intl 1994;24:836–846.

Fries DS. Analgesic agonists and CNS receptors. In: Cannon JG, ed. CNS drug–receptor interactions. Greenwich, CT: JAI Press, 1991:1–21.

Gutstein HB, Akil H. Opioid analgesics. In: Burton L, Lazo J, Parker K, eds. Goodman and Gilman's The Pharmacological Basis of therapeutics, 11th Ed. New York: McGraw-Hill, 2006:547–590.

Höllt VR. Opioid peptide processing and receptor selectivity. Annu Rev Pharmacol Toxicol 1986:26:59–77.

Hruby VJ, Gehrig CA. Recent developments in the design of receptor specific opioid peptides. Med

http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (56 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

Res Rev 1989;9:343–401.

Jordan B, Devi LA. Molecular mechanisms of opioid receptor signal transduction. Br J Anaesth 1998;81:12–19.

Koob GF, Nestler EJ. The neurobiology of drug addiction. J Neuropsychiatry Clin Neurosci 1997;9:482–497.

Lentz R, Evans SM, Walters DE, et al. Opiates. Orlando, FL: Academic Press, 1986.

Olson GA, Olson RD, Kastin AJ. Endogenous opiates: 1996. Peptides 1997;18:1651–1688.

Ossipov MH, King LJ, Vanderah TW, et al. Antinociceptive and nociceptive actions of opioids. J Neurobiol 2004;61:126–148.

Reisine T, Bell GI. Molecular biology of opioid receptors. Trends Neurosci 1993;16:506–510.

Ulett GA, Han S, Han JS. Electroacupuncture: mechanisms and clinical application. Biol Psychiatry 1998;44:129–138.

Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther 2004;11:354–365.

Varga EV, Navratilova E, Stropova, et al. Agonist-specific regulation of δ-opioid receptor. Life Sci 2004;76:599–612.

Von Zastrow M. A cell biologist's perspective on physiological adaptation to opiate drugs. Neuropharmacology 2004;47:286–292.

Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem 2004;73:953–990.

Williams M, Kowaluk EA, Arneric SP. Emerging molecular approaches to pain therapy. J Med Chem 1999:42:1481–1500.

Zeilhofer HU, Calo G. Nociceptin/orphanin FQ and its receptor—potential targets for pain therapy. J Pharmacol Exp Ther 2003;306:423–429.

http://thepointeedition.lww.com/pt/re/9780781768795/b...DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes (57 of 58)11-09-2009 13:25:35 http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPan...DIVISIONA[3]/DIVISIONB[1]/CHAPTER[7]&highlightTo=&printPreview=yes

Zimmerman DM, Leander JD. Selective opioid receptor agonists and antagonists: research tools and potential therapeutic agents. J Med Chem 1990;33:895–902.

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