Physiology and Pharmacology of Opioid Analgesics

Chapter 11


Physiology and Pharmacology of Opioid Analgesics



THIS chapter expands on the underlying mechanisms of the opioid analgesics presented in Section I of this book. Several pharmacokinetic and pharmacodynamic concepts are explained. Terms such as opioid naïve and opioid tolerant are distinguished, and addiction, pseudoaddiction, physical dependence, tolerance, and cross tolerance are defined. The research and recommended diagnostic and treatment approaches for opioid-induced hyperalgesia are presented.



Groups of Opioids


The opioid agonist drugs can be divided into two major groups. The largest group is the morphine-like agonists. The terms morphine-like drugs, mu agonists, pure agonists, and full agonists are used interchangeably. Throughout this book, the term mu agonist will be used when referring to opioid drugs in this group. The other group of opioids is the agonist-antagonist group and is further divided into the mixed agonist-antagonists and the partial agonists. Opioid agonist drugs can be distinguished from opioid compounds more generally. Opioid compounds include both drugs and endogenous chemicals (generically called the endorphins); they also refer to both agonists, which produce effects at opioid receptors, and antagonists, which block or reverse effects produced by the agonists.



Underlying Mechanisms of Opioid Analgesia and Adverse Effects


To understand the appropriate use of opioids in the treatment of pain, it is valuable to review the mechanisms that are described by the term nociception. Nociception refers to the normal functioning of physiologic systems that lead to the perception of noxious stimuli as painful. In short, it means “normal” pain transmission. Nociception is described in Section I of this book. Review of Section I is advised so that the following discussion of the underlying mechanisms of the analgesia and adverse effects of opioids is clear.



Endogenous Opioid System


As explained in the discussion of nociception in Section I, the modulation (inhibition) of pain involves the release of dozens of neurochemicals by peripheral and central systems. Endogenous opioids (internal naturally-occurring), for example, are found throughout the periphery and central nervous system (CNS), including in the cardiovascular (CV) and gastrointestinal (GI) systems, pituitary gland, and in immune cells (Machelska, 2007; Mousa, 2003; Murphy, 2006; Rittner, Brack, 2007). It is thought that opioids given therapeutically activate endogenous pain-modulating systems and produce analgesia and other effects by binding to opioid receptor sites and mimicking the action of endogenous opioid compounds. Endogenous opioids are composed of three distinct families of peptides (naturally occurring compounds of two or more amino acids), all pharmacologically related to morphine: enkephalins, dynorphins, and β-endorphins (Gutstein, Akil, 2006; Inturrisi, 2002). Other endogenous peptides that have been more recently discovered—the endomorphins and orphanin-FQ—also appear to be important in pain processing, but their roles are yet poorly understood; the endomorphins bind selectively to the mu receptor, and orphanin-FQ is a ligand for another receptor, which is known as opioid receptor–like 1 (ORL1).


Although discovered in the 1970s (Gutstein, Akil, 2006), not everything is known about the physiologic role of endogenous opioids (Fine, Portenoy, 2007). They may serve as neurotransmitters, neuromodulators, and neurohormones (Inturrisi, 2002). Research is ongoing to identify more endogenous opioid compounds and add to the understanding of this role and the potential for new analgesics (Noble, Roques, 2007; Wisner, Dufour, Messaoudi, et al., 2006). Among other important activities, they are involved in hemostasis and the stress response.



Opioid Receptors


Drugs exert their effects on the body by interacting with specialized macromolecular components in cells called drug receptors. Drug receptors usually are cellular proteins, but can be enzymes, carbohydrate residues, and lipids. The binding of drug molecules to their specific receptor molecules often is described as similar to a key fitting a lock (Figure 11-1). Binding affinity refers to the strength of attachment of a drug to the receptor site, and drugs bind with varying strength. The electromagnetic forces produced by the bond between a drug and receptor distort the configuration of the receptor molecule, changing its biochemical properties and functions. The body’s responses to the drug are a result of these changes (Bateman, Eddleston, 2007).



Researchers think that receptors evolved for the purpose of interacting with endogenous compounds. The endogenous opioid system is an excellent example of this interaction. Opioid receptors are particularly abundant in the periacqueductal gray (PAG) and dorsal horn of the spinal cord. They are also located in the brainstem, thalamus, and cortex. Their presence in the midbrain PAG, nucleus raphe magnus, and the rostral ventral medulla help to inhibit pain via the descending modulatory system (Inturrisi, 2002). (See Section I and Figure I-2, D on pp. 4-5.)


Nociceptors—the primary afferent neurons that carry information about noxious stimuli from the periphery—terminate in the dorsal horn of the spinal cord. These cells release neurotransmitters, such as adenosine triphosphate, glutamate, and substance P, to further pain transmission. This is one of the sites at which endogenous and exogenous opioids play an important role in pain control by binding with opioid receptors, reducing the influx of calcium at the cellular level, and, among other functions, blocking the release of presynaptic neurotransmitters, principally substance P (Inturrisi, 2002). They also increase potassium influx, resulting in a decrease in synaptic transmission.


Opioids also reduce pain transmission by activating inhibitory pathways that originate segmentally (in the spinal cord) and supraspinally (Inturrisi, 2002). For example, the gamma aminobutyric acid (GABA) pathway is one of the major inhibitory neurotransmitter systems (see Section I), and opioids can activate the GABA system, leading to inhibition of pain transmission (Bridges, Thompson, Rice, 2001).


For many years, opioid analgesics were thought to produce analgesia only through the CNS. However, more recently, opioid receptors have been found also on peripheral terminals of sensory nerves and cells of the immune system (Fine, Portenoy, 2007; Inturrisi, 2002; Machelska, 2007; Mousa, 2003; Rittner, Brack, 2007). Their location in peripheral tissues has led to research suggesting that opioids also can produce analgesia following local administration by binding to the peripheral opioid receptors (Inturrisi, 2002; Zajaczkowska, Wlodzimierz, Wordliczek, et al., 2004). This may account for the antiinflammatory actions of opioid drugs on peripheral tissues (Nunez, Lee, Zhang, et al., 2007).



Classes of Opioid Receptor Sites


Three major classes or types of opioid receptor sites are involved in analgesia: mu, delta, and kappa. The pharmacologic differences in the various opioids are the result of their interaction with these three opioid receptor types (Inturrisi, 2002). A fourth receptor, structurally similar to the opioid receptor and designated as ORL-1 (opioid receptor–like 1), has been identified (Fine, Portenoy, 2007). The ligand for ORL-1, orphanin FQ or OFQ, induces spinal analgesia and appears to be involved in the modulation of pain but is not associated with respiratory depression. Research is needed to develop drugs that take advantage of this receptor site (Murphy, 2006). Subtypes of each of the main opioid receptor types have also been identified and may account for the wide variability in patient response to the various opioid analgesics (Fine, Portenoy, 2007; Pasternak, 2005).


When an opioid binds to the mu, delta, or kappa opioid receptor sites as an agonist, it produces analgesia as well as unwanted effects, such as nausea, constipation, and respiratory depression. Antagonists are drugs that also bind to opioid receptors but produce no analgesia. If an antagonist is present, it competes with opioid molecules for binding sites on the receptors. When a drug binds to any of the opioid receptor sites as an antagonist, analgesia and other effects are blocked. For example, naloxone, an opioid antagonist, can bind to the mu site and reverse analgesia and other opioid adverse effects, such as respiratory depression and sedation (Gutstein, Akil, 2006). See Table 11-1 for a summary of actions at opioid receptor type.



Table 11-1


Summary of Actions at Opioid Receptor Type


image


CV, Cardiovascular; GI, gastrointestinal.


The effects (activity) a drug produces depends on the type(s) of opioid receptor(s) to which the drug binds and whether the drug acts as an agonist or an antagonist at that opioid receptor type. When a drug binds to any of these receptor sites as an agonist, it produces analgesia and other effects. When a drug binds to any of the opioid receptor sites as an antagonist, analgesia and other effects are blocked. Table 11-1 summarizes the activity of drugs when they bind to any of three opioid receptor types that are involved in analgesia.


From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, p. 285, St. Louis, Mosby. Data from Fine, P., & Portenoy, R. K. (2007). A clinical guide to opioid analgesia. New York, Vendome Group, LLC; Gutstein, H. B., & Akil, H. (2006). Opioid analgesics. In L. L. Brunton, J. S. Lazo, & K. L. Parker (Eds.), Goodman & Gilman’s the pharmacological basis of therapeutics, ed 11, New York, McGraw-Hill; Hanks, G., Cherny, N. I., & Fallon, M. Opioid analgesic therapy. In D. Doyle, G. Hanks, N. I. Cherny, et al. (Eds.), Oxford textbook of palliative medicine, ed 3, New York, Oxford Press. Pasero C, McCaffery M. May be duplicated for use in clinical practice.


Opioid drugs that produce analgesia all have agonist effects at one or more of the opioid receptor site types and are classified based on the receptors to which they bind and act (Pasternak, 2005). Most of the clinically useful opioid analgesics bind primarily to mu opioid receptor sites (Gutstein, Akil, 2006). These are the mu agonist opioid analgesics, which are considered the mainstay of analgesia for acute pain and cancer pain. Examples of mu agonist opioid analgesics are morphine, hydromorphone (Dilaudid), fentanyl, oxycodone, hydrocodone, codeine, methadone (Dolophine), and meperidine (Demerol). Mu agonists can be administered by numerous routes, and onset of analgesia is within minutes by some routes. They can be combined with almost any of the nonopioid and adjuvant analgesics.


The mixed agonist-antagonist opioid analgesics are designated as mixed because they bind to more than one opioid receptor site. They bind as agonists, producing analgesia at the kappa opioid receptor sites, and as weak antagonists at the mu opioid receptor sites (Gutstein, Akil, 2006). Mixed agonist-antagonists opioid analgesics include butorphanol (Stadol), nalbuphine (Nubain), pentazocine (Talwin), and dezocine (Dalgan). Their clinical usefulness is limited because of undesirable adverse effects (Gutstein, Akil, 2006). Some of the mixed agonist-antagonists produce more dysphoria and psychotomimetic effects than the pure mu agonists, and all appear to have a ceiling effect to the respiratory depression effects.


Although buprenorphine (Buprenex) has some kappa agonist activity, it is known primarily as a partial mu agonist drug. It is referred to as partial because it binds as an agonist at the mu opioid receptors but has limited intrinsic efficacy (Gutstein, Akil, 2006). In the clinical setting, this means that analgesia plateaus as the dose is increased. Buprenorphine also has very high affinity for the mu receptor. It is not readily reversed by opioid antagonists, such as naloxone, which suggests the drug dissociates very slowly from the mu opioid receptor sites (Gutstein, Akil, 2006). The drug is used most often as a maintenance drug for the treatment of addictive disease (Suboxone, Subutex) (see Chapter 13).



Opioid Receptors and Adverse Effects


The type of opioid receptor site and its location determine the effects an opioid drug produces. As mentioned, in addition to producing analgesia, opioid drugs produce a number of other effects, including constipation, nausea and vomiting, sedation, respiratory depression, and urinary retention (Gutstein, Akil, 2006) (see Table 11-1).


The main GI effect of opioid drugs is inhibition of GI peristalsis and diminished GI, biliary, and pancreatic secretions, which can lead to constipation and predispose to ileus and other adverse effects as a result of opioid binding to receptors located in the GI tract and CNS (Gutstein, Akil, 2006; Kraft, 2007; Thomas, 2008). Opioid bowel syndrome is described as a “constellation” of undesirable outcomes, including but not limited to constipation (McNicol, Boyce, Schumann, et al., 2008). Nausea and vomiting are the result of opioid binding to receptors located in the fourth ventricle of the brain and direct stimulation of the chemoreceptor trigger zone in the area postrema of the medulla (Freye, 2008). Urinary retention may occur when opioid binding leads to inhibition of the release of acetylcholine (Freye, 2008). Respiratory depression may follow binding in the pontine and ventral medulla of the brainstem (Freye, 2008), and sedation occurs from binding to receptors in the brain (Gutstein, Akil, 2006) (see Chapter 19 for discussion of opioid adverse effects).



Pharmacologic Concepts


After systemic (oral or parenteral) administration, an opioid drug is absorbed into the vascular system. For the drug to produce a pharmacologic effect, it must leave the plasma, diffuse into tissue, reach opioid receptors, and activate them (Gutstein, Akil, 2006). Topical administration may rely on both peripheral and systemic absorption (LeBon, Zeppetella, Higginson, et al., 2009; Ribeiro, Joel, Zeppetella, 2004; Sawynok, 2003). When administered by intraspinal routes of administration, opioids are carried via the cerebrospinal fluid (CSF) to opioid receptor sites in the spinal cord and brain (Freye, 2008). Appropriate use of opioid analgesics requires an understanding of these processes and some important pharmacologic concepts. The following is a discussion of pharmacokinetics (the movement of the drug through the body) and pharmacodynamics (what effects are produced). Tolerance, cross-tolerance, opioid-induced hyperalgesia, physical dependence, addiction, pseudoaddiction, and equianalgesia also are discussed.



Pharmacokinetics


Pharmacokinetics is the science of what the body does to a drug after its administration. Pharmacokinetic processes include absorption, distribution, metabolism, and elimination and are discussed in the following sections along with other related key concepts.



Absorption, Bioavailability, First Pass Effect, and Solubility


Absorption is the rate and extent to which a drug leaves its site of administration and moves to plasma or other tissues. A more clinically important concept than absorption is bioavailability, which is the extent to which a dose of a drug reaches its site of action (Buxton, 2006), or how much drug is available for therapeutic effect. Opioid drugs are 100% bioavailable when administered intravenously because they are introduced directly into the systemic circulation. After oral administration, opioids are absorbed from the GI tract and transported by the portal vein to the liver, the primary site of drug metabolism, before they reach systemic circulation. This process reduces the bioavailability of an opioid when administered orally (Buxton, 2006). Oral bioavailability depends on how much of the drug is absorbed in the GI tract and inactivated as it passes through the liver. This is called first pass effect. First pass effect is why the dose of an opioid drug by the oral route must be much larger than by the parenteral route to produce equal analgesia (Buxton, 2006). For example, the bioavailability of morphine when given orally usually is between 20% and 30% because of first pass losses (De Pinto, Dunbar, Edwards, 2006; Gutstein, Akil, 2006; Stevens, Ghazi, 2000) (Figure 11-2).



Many factors influence a drug’s absorption and bioavailability besides route of administration. The site of absorption, including its surface area and vascularity, is important. Drugs are absorbed rapidly from large surface areas, such as the intestinal mucosa, and when there is increased blood flow at the site (Buxton, 2006). A high concentration of drug in a small volume leads to faster absorption compared with a low concentration in a large volume. The presence of a pathologic condition also affects bioavailability. For example, bioavailability is increased in hepatic dysfunction because the liver cannot metabolize and excrete the drug efficiently (Johnson, 2007).


Characteristics of the drug itself also help to determine its bioavailability (Buxton, 2006). A drug’s bioavailability will be decreased if it is a drug for which the liver has a great capacity to metabolize and excrete, such as hydromorphone. When given intravenously, hydromorphone is 100% bioavailable and the recommended starting adult dose for severe pain is 1.5 mg given over a 4-hour period; when given orally, which subjects the drug to a significant first-pass effect, the equianalgesic dose is approximately five times greater at 7.5 mg (see later in this chapter for more on equianalgesia).


A drug’s solubility also influences its bioavailability. The more lipid soluble (also referred to as lipophilic, meaning readily dissolved into fatty tissues) the drug, the more readily it moves through membranes, which may increase bioavailability. Lipid solubility also is related to other pharmacokinetic parameters, which may be more important in practice (Buxton, 2006). For example, when highly lipid soluble opioids, such as fentanyl and sufentanil, are administered to opioid-naïve patients, the analgesic and other effects have a rapid onset and a short duration; in contrast, comparable doses of drugs that are less lipid soluble, like morphine and hydromorphone, lead to effects that have a slower onset of action and longer duration; meperidine is intermediate between these drugs. Lipophilicity and all the other factors discussed in this section can affect the efficacy and toxicity of a drug and therefore must be considered when establishing an opioid analgesic regimen.




Metabolism, Metabolites, and Prodrugs


When a drug passes through the liver, and often through other tissues, it is subjected to multiple biochemical processes and reactions (metabolism) that change part of the drug into different compounds. Enzymes mediate most of these processes and reactions. The resulting products are called metabolites. Many opioid analgesics have metabolites, including morphine (morphine-6-glucuronide [M6G] and morphine-3-glucuronide [M3G]), meperidine (normeperidine), and propoxyphene (norpropoxyphene). Metabolites are referred to as being active (having pharmacologic action) or inactive (having no pharmacologic action) (Buxton, 2006).


Metabolites often have properties and characteristics different from their parent drug. Sometimes their pharmacologic actions are indistinguishable from the parent drug, but their biologic activity may be increased, decreased, or eliminated. For example, the major metabolite of morphine, M6G, is analgesic like its parent but is significantly more potent (Buxton, 2006) (see Chapter 13).


Prodrugs are pharmacologically inactive compounds (sometimes called inactive precursors) that are converted quickly to active metabolites following administration (Buxton, 2006). Prodrugs are sometimes used to maximize the amount of the active drug that reaches the site of action. Codeine is an example of a prodrug. To produce analgesia, it must be catalyzed by the cytochrome (CY) P450 enzyme CYP2D6 to morphine.



Cytochrome P450 Enzyme System: Two major hepatic enzyme systems are responsible for metabolism of opioids: CYP450 and, to a lesser extent, the UDP-glucuronosyltransferases (UGTs) (Holmquist, 2009). The UGTs are involved in the formation of glucuronides and the metabolism of hydromorphone, morphine, and oxymorphone. The CYP450 enzyme system is important to the metabolism of codeine, fentanyl, methadone, oxycodone, and oxymorphone (Holmquist, 2009). CYP450 enzymes also are located in other tissues of the body and are the primary enzymes involved in drug metabolism and the production of cholesterol, steroids, prostacylins, and other essential substances (Holmquist, 2009).


Drugs interact with the CYP450 enzyme system by acting as a substrate (metabolized by one or more of the CYP450 enzymes); an inhibitor (slowing the activity of CYP450 enzyme metabolism); or an inducer (boosting the activity of CYP450 metabolism) (Holmquist, 2009). There are more than 50 different CYP450 enzymes, but not all are involved in drug metabolism. The CYP2D6 and CYP3A4 are the most important to opioid metabolism (Fine, Portenoy, 2007). Patients may lack normal levels of these enzymes as a result of genetics, hepatic disease, or competition with other medications that are metabolized by the same enzymes (Fine, Portenoy, 2007).


There are four major CYP2D6 phenotypes, which render patients poor, intermediate, extensive, or ultra-rapid metabolizers (Holmquist, 2009). There are interethnic variations in phenotypes (Palmer, Giesecke, Body, et al., 2005); it is estimated that 7% to 10% of Caucasians and 1% of Asians are poor metabolizers (Holmquist, 2009; Paice, 2008). Patients who are poor metabolizers have altered pharmacokinetics of 2D6-metabolized drugs, which may cause clinically important effects in some. For example, whereas hydromorphone, morphine, and oxymorphone are not metabolized by the CYP450 enzymes to a great extent (UGT is their primary metabolic pathway) and genetic polymorphisms of the CYP450 enzymes have little effect, the prodrug codeine relies on 2D6 to become the active compound morphine, and slow metabolizers may not respond well to codeine as a result (Fine, Portenoy, 2007; Palmer, Giesecke, Body, et al., 2005). Ultra-rapid metabolizers at 2D6 may have an exaggerated (i.e., toxic) response to codeine (Voronov, Przybylo, Jagannathan, et al., 2007; United States Food and Drug Administration [U.S. FDA], 2007a; Palmer, Giesecke, Body, et al., 2005).


Some drugs compete with opioids for metabolism by specific enzymes, which may result in drug-drug interactions. Table 11-2 lists potential drug interactions for the CYP2D6 and CYP3A4 enzymes. Box 11-1 provides websites where information can be found regarding drugs that are metabolized by the cytochrome P450 enzyme system and their potential drug-drug interactions.



Box 11-1   Cytochrome P450 Enzyme System: Information Websites




• CYP450 Interactions: Flockhart, D. A. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/flockhart/table.htm


• Cytochrome P450 and Drug Interactions (Drugs that Induce or Inhibit Various Cytochrome P-450 Systems): http://www.edhayes.com/CYP450-3.html


• P450 Enzyme Drug Interactions By Erowid: http://www.erowid.org/psychoactives/pharmacology/pharmacology_enzymes1.shtml#4


• An excellent resource for information about drug interactions and that contains a list of online sites that offer specific information about drug interactions can be found in Leavitt SB. (2005). Methadone-drug interaction, ed 3. Addiction Treatment Forum. http://www.atforum.com/SiteRoot/pages/addiction_resources/Drug_Interactions.pdf


The following are interactive websites and require the user to enter the drug the patient is taking (or the drug that is being considered). The application returns a list of potential interactions.



From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, p. 289, St. Louis, Mosby. Pasero C, McCaffery M. May be duplicated for use in clinical practice.



Table 11-2


Potential Drug Interactions for Major Cytochrome P-450 Enzymes CYP3A4 and CYP2D6


image


From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, p. 289, St. Louis, Mosby. Data from Clinical Pharmacology Online. Gold Standard, Inc. Available at http://clinicalpharmacology.com; Cytochrome P450 Interactions ©GlobalRPh Inc. Available at http://www.globalrph.com/cytochrome.htm; Cytochrome P450 and Drug Interactions (Drugs that Induce or Inhibit Various Cytochrome P-450 Systems). Available at http://www.edhayes.com/CYP450-3.html. Pasero C, McCaffery M. May be duplicated for use in clinical practice.



Half-Life, Clearance, Steady State, and Accumulation


Drugs are eliminated from the body either unchanged or as metabolites. The kidney is the primary organ for elimination of drugs and metabolites. Drugs are also excreted in the feces, breast milk, sweat, saliva, tears, hair, and skin. The pulmonary route of excretion is important mainly for anesthetic gases and vapors (Buxton, 2006).


Terminal half-life provides an estimate of how fast a drug leaves the body. By definition, half-life is the time it takes for the amount of drug in the body to be reduced by 50% (Buxton, 2006). Half-life varies significantly from one drug to another. For example, the half-life of morphine is 2 to 4 hours, whereas the half-life of methadone ranges from 4.2 hours to 130 hours in some individuals (Lynch, 2005). Terminal half-life is different from, but sometimes confused with, distribution half-life, which reflects the time necessary for a drug to move from the blood and plasma to other tissues.


Clearance is also a measure of the body’s ability to eliminate a drug from the body. The clearance of a drug depends on the organs of elimination coming in contact with the blood or plasma containing the drug (Buxton, 2006). Because the kidney is the major organ of elimination, renal insufficiency can alter drug clearance. Creatinine clearance analysis is a measure of kidney function and a tool to determine the body’s ability to handle drugs that are primarily eliminated by the kidney. A high creatinine level may be an indication of reduced kidney function and, therefore, a reduced ability to eliminate a drug. Normally, men tend to have higher creatinine levels than women. Aging is associated with decreased body mass and total body water and an increased proportion of body fat which can alter the rates of clearance and elimination (American Geriatrics Society [AGS], 2009; Cook, Rooke, 2003). Box 11-2 provides serum creatinine and creatinine clearance values for all age groups and the formula for calculating creatinine clearance.



Box 11-2   Creatinine Values and Formula for Calculating Creatinine Clearance

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Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Physiology and Pharmacology of Opioid Analgesics

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