Opioid Agonists and Antagonists

Chapter 11

Opioid Agonists and Antagonists

In the past, opium was used as a topical, intravenous, and inhaled analgesic. One of the earliest uses of opium is found in Greek literature dating from 300 bce. Opium sponges, referred to as soporific sponges, were used for the control of pain as early as the fourteenth century. An attempt to administer opioids by the intravenous route was attributed to Elscholtz in 1665, approximately 200 years before the invention of the syringe and needle. The first attempt to administer an opium vapor by inhalation was documented in 1778. It was not until 1853, when the syringe and needle were introduced into clinical practice by Wood, that an accurate dose of opioid could be administered intravenously.

In 1803, Sertürner reported the isolation of a pure substance from opium that he named morphine, after Morpheus, the Greek god of dreams. Other opium alkaloids were soon discovered—codeine by Robiquet in 1832 and papaverine by Merck in 1848. Abuse of opium and isolated alkaloids led to the synthetic production of potent analgesics. The goal of synthetic manufacture of analgesics was the creation of potent analgesics that would have high specificity for receptors, were not addictive, and were free of side effects. Synthetic production led to the development of opioid agonists, partial agonists, agonists-antagonists, and antagonists.1,2


Opioid is a term used to refer to a group of drugs, both naturally occurring and synthetically produced, that possess opium- or morphine-like properties. Opioids exert their effects by mimicking naturally occurring endogenous opioid peptides or endorphins. Narcotic is derived from the Greek word narkōtikos, “benumbing,” and refers to potent morphine-like analgesics with the potential to produce stupor, insensibility, and dependence. The term narcotic is not useful in a pharmacologic or clinical discussion because of its legal connotations.

Several systems of classification are used to describe opioids. One common method divides the opioids into four categories: agonists, partial agonists, agonists-antagonists, and antagonists (Table 11-1). Another system of categorization is based on the chemical derivation of the opioids and divides them into naturally occurring, semisynthetic, and synthetic compounds, with each group having subgroups (Box 11-1).3 Other classification systems describe the drugs as either weak or strong or hydrophilic and lipophilic.

The term opioid is derived from the word opium (from opos, Greek for “sap”), an extract from the poppy plant Papaver somniferum. The properties of opium are attributable to the 20 different isolated alkaloids, and the alkaloids are divided chemically into two types: phenanthrene (from which morphine and codeine are derived) and benzylisoquinoline (from which papaverine, a nonanalgesic drug, is derived). Modification of the morphine molecule with retention of the five-ring structure results in the semisynthetic drugs heroin and hydromorphone. When the furan ring is removed from morphine, the resulting four-ring synthetic opioid levorphanol is formed. The phenylpiperidines (e.g., fentanyl) and the diphenylheptane derivatives (e.g., methadone) all have only two of the original five rings of the basic morphine molecular structure. A close relationship exists between the stereochemical structure and potency of opioids, with the levo-isomers being the most potent. All opioids, despite the diverse molecular structures, share an N-methylpiperidine moiety, which seems to confer analgesic activity.1 Figure 11-1 illustrates the structures of the commonly used opioids.

Opioid drugs produce pharmacologic activity by binding to opiate receptors primarily located in the central nervous system (CNS), supraspinal and spinal; and several peripheral sites. These include the gastrointestinal (GI) system, vasculature, lung, heart, and immune systems. Supraspinal analgesia occurs through activation of opioid receptors in the medulla, midbrain, and other areas, which causes inhibition of neurons involved in pain pathways. Spinal analgesia occurs by activation of presynaptic opioid receptors, which leads to decreased calcium influx and decreased release of neurotransmitters involved in nociception. Clinically, supraspinal and spinal opioid analgesic mechanisms are synergistic.3 This explains why opioids such as fentanyl and sufentanil produce more profound analgesia when delivered epidurally than when delivered systemically, despite the similar blood concentrations measured with both routes of administration.1,4

Opiate Receptors

Opiate receptors are from the rhodopsin family of G-protein–coupled receptors (GPCRs). They have been DNA and amino acid sequenced and cloned. The discovery of opioid receptors can be traced back to the 1950s, when pharmaceutical companies were involved in research in anticipation of the development of an effective nonaddictive analgesic. In 1973, the examination of vertebrate species led to the discovery of three opiate receptor classes that mediate analgesia.5 Questions emerged as to why the receptors existed, and further research led to the hypothesis that the receptors possess endogenous functions.

After the discovery of opiate receptors in the early 1970s, the search began for endogenous substances that were their agonists. In 1975, three such agonists were identified: enkephalins, endorphins, and dynorphins.5 Each group is derived from a distinct precursor polypeptide and has a characteristic anatomic distribution. By the early 1980s, three precursor molecules to these agonists were identified and named after the active fragments: proenkephalin, proadrenocorticotropic hormone (ACTH)–endorphin (now called proopiomelanocortin), and prodynorphin.1,5 Opioid peptides share the common amino-terminal sequence of Try-Gly-Gly-Phe-(Met or Leu), which has been labeled the opioid motif or message and is necessary for interaction at the receptor site. The peptide selectivity resides in the carboxy-terminal extension, providing the address.1 Since then an additional precursor pronociceptin that results in nociceptin has been identified. Endomorphin 1 and 2, which are highly selective agonists at µ receptors, have been identified, but the precursor’s molecule has not yet been defined.3 In 1975, Hughes and Kosterlitz6 identified the first endogenous substance with opioid activity.

Martin et al.7 were the first to provide evidence for opiate receptor subtypes (Table 11-2). Their findings provided evidence for the existence of three opiate receptors: mu (µ), kappa (κ), and sigma, named after their respective agonists—morphine, ketocyclazocine, and SK&F 10047. The sigma receptor was later determined not to be an opiate receptor. A delta (δ) receptor was subsequently identified. Each major opioid receptor has a unique anatomic distribution in the brain, spinal cord, and periphery.8 The three receptor subtypes share 55% to 58% sequence homologies. Their diversity is greatest in their extracellular loops.1 A fourth receptor has been cloned and named opiate receptor like (ORL1) or the nociceptin orphanin FQ peptide receptor (NOP). Because this receptor family awaits further clarification as to its role in pain signaling and does not display opioid pharmacology, discussion of this category is not included here.

Stimulation of the mu receptor produces supraspinal analgesia, euphoria, and a decrease in ventilation and most of the classic clinical actions of the opioid agonists. Kappa receptor stimulation produces spinal analgesia, sedation, and miosis. Currently, kappa-opioid drugs are being investigated for antiinflammatory actions that reduce disease severity of arthritis and other inflammatory diseases.911 The delta receptor is responsible for spinal analgesia, responds to enkephalins, and serves to modulate activity of the mu receptors.3 Various subtypes of each of the three opiate receptors have been proposed but have not been well defined.8

At the cellular level, endogenous peptides and exogenous opioids produce effects by altering patterns of interneuronal communications. Receptor binding initiates a series of biochemical changes that result in cellular hyperpolarization and inhibition of neurotransmitter release, effects mediated by second messengers. Opioid receptors are GPCRs and inhibit the activity of adenylate cyclase inside of cells. This results in a decrease in intracellular cyclic adenosine monophosphate (cAMP), which decreases conductance of the voltage-gated calcium channels and opens potassium channels, resulting in decreased neuronal activity. This leads to a decrease in neuronal excitation and an inhibition of neurotransmitter or neuropeptide release.3 The mechanism of action of opioid drugs is shown in Figure 11-2. The endogenous ligands for opioid receptors are noted in Table 11-3.


Pharmacodynamic and pharmacokinetic considerations must be combined to reach an ideal analgesic clinical state. Surgical requirements for analgesic drugs are much different than nonoperative uses. These differences include a much higher analgesic requirement, the coadministration of potent anesthetic and sedative drugs and the ability to support respirations so that respiratory depression is not an issue until the patient emerges from anesthesia.

In anesthesia, opioids are most commonly administered by the parenteral, intrathecal, and epidural routes. They may also be given by oral, nasal, intramuscular, and transdermal administration. Physiochemical properties of opioids influence their pharmacokinetics. To reach effector sites in the CNS, opioids must cross biologic membranes from the blood to receptors on neural cell membranes. The ability of opioids to cross the blood-brain and placental barriers depends on molecular size, ionization, lipid solubility, and protein binding. The physicochemical characteristics, pharmacokinetic variables, and partition coefficients (octanol and water as a measure of lipid solubility) for several of the commonly used opioid analgesics are summarized in Table 11-4.

The wide variation in dosing of the opioids in anesthesia depending on the patient and surgical situation leads to vastly different durations even with the same drug. Fentanyl, for example, can last 30 minutes to 18 to 24 hours, depending on how and how much is given. The pharmacokinetic parameters are important, but the context of how they are used in clinical practice is a major factor in the ultimate patient response.

Opioids are modestly absorbed orally. Some opioids undergo extensive first-pass metabolism in the liver, greatly reducing their bioavailability and therapeutic efficacy after oral dosing. Orally administered morphine has limited absorption from the GI tract. Drugs with greater lipophilicity are better absorbed through nasal and buccal mucosa and the skin.

When small doses of the opioids are used, the effects are usually terminated by redistribution rather than metabolism. Larger or multiple doses or continuous infusions are much more dependent on metabolism for offset.12 Like most drugs, opioids are usually metabolized in the liver to more polar and less active or inactive compounds by both phase 1 and phase 2 processes. Some opioids, such as morphine, have active metabolites such as morphine 6 glucuronide, that can prolong the therapeutic effects of the parent compound. The meperidine metabolite, normeperidine, is neurotoxic and may accumulate in the elderly or in patients with decreased renal or hepatic function. This has led to a decline in its use. It is avoided in the elderly or patients with renal or hepatic dysfunction and where chronic use may be needed.1 The opioid drugs are metabolized by the usual cytochrome enzymes including CYP3A4, CYP2D6, and CYP2B6.1315 Remifentanil was designed with an ester group in its structure and is metabolized by hydrolysis in the plasma and tissues by non-specific esterases. Remifentanil has a low volume of distribution and a large clearance, which results in a short half-life of approximately 10 minutes. Opioids and their metabolites are excreted primarily by the kidneys and secondarily by the biliary system and GI tract.16 Clinicians become very adept in the art of administering opioids by bolus, incremental injection, or infusion to maximize analgesia during surgery as needed yet allowing for safe and rapid recovery and residual postoperative analgesia.


The wide variations in dosing and patient responses have both pharmacodynamic and pharmacokinetic causes. Pharmacogenetics appears to be an important factor as well. Opioids have a narrow therapeutic index, calling for a fine balance between optimizing pain control and sedative effects (without respiratory depression) and recognizing great variability from patient to patient in response and dose requirements. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction) contribute to this variability and to the possibility of adverse drug effects, toxicity, or therapeutic failure of pharmacotherapy. Significant variation in conversion of the prodrug codeine into the active metabolite morphine has been noted. Polymorphisms in CYP2D6 are responsible for the wide variations among different populations.17

The clinical use of opioids involves knowledge regarding patient characteristics, their perception, severity and likely duration of pain, lifestyle variables such as smoking habits and alcohol intake, and opioid drug and dosing regimen selection.17 Other factors affecting pharmacokinetics and pharmacodynamics of opioids include age, body weight, renal failure, hepatic failure, cardiopulmonary bypass, acid-base changes, and hemorrhagic shock.

In adults, advancing age requires lower opioid doses for the treatment of postsurgical pain. Also, in relatively similar patient groups, dosage requirements vary. Aubrun et al.18 reported that in more than 3000 patients, morphine dosage requirements for postoperative hip replacement therapy varied almost 40-fold. Large variabilities have been reported in cancer patients receiving morphine via various routes.17 Variability is contributed to by inherent pain sensitivity, tolerance, and other factors, including pharmacogenetics influencing the clinical pharmacology of opioids.19

Central Nervous System Effects: Analgesia, Sedation, and Euphoria

Opiate analgesia results from actions in the CNS, spinal cord, and peripheral sites (Table 11-5). They are most effective for visceral continuous dull pain; however, at high doses they will relieve any pain. They are less effective against neuropathic pain that requires chronic multimodal therapy.20 The sedative and euphoric actions contribute to the feeling of well-being in awake patients. The analgesic effects of opioids come from their ability to (1) directly inhibit the ascending transmission of nociception information from the spinal cord dorsal horn and (2) activate pain control pathways that descend from the midbrain, via the rostral ventromedial medulla to the spinal cord dorsal horn.1 The effect of opioids on electroencephalographic and evoked-potential activity is minimal; therefore neurophysiologic monitoring can be conducted during opioid anesthetic techniques. The opiates can increase intracranial pressure if respiratory depression–induced hypercarbia occurs. They have variable effects on cerebral vascular tone depending on the background anesthetic present. Possible untoward CNS effects when the opioids are used in neurosurgery are easily managed by controlling ventilation and maintaining adequate blood pressures.21 The comparative potency of the opioid agonists that are used in anesthesia is as follows: sufentanil > fentanyl = remifentanil > alfentanil.

The sedative and euphoric effects of the opiates vary depending on the agent. Patients will exhibit sedation and euphoria that is different with mu versus kappa agonists. Dysphoria can occur and appears more prominent with drugs that have strong kappa receptor effects or when opioids are taken in the absence of pain. Physical and psychological dependence occur with repeat administration as evidenced by physical withdrawal with abstinence and drug-seeking behaviors.1,22 The opiates are not anesthetics, so awareness under anesthesia is a concern when even high doses of opiates are used.23,24 Both acute and chronic tolerance occur with the opiates. Cross-tolerance among mu agonists will occur. Usually a decrease in duration is noted first, followed eventually by a decrease in effect. The mechanism of tolerance is complex and does not appear to be due to a change in receptor number. Receptor internalization, activation of N-methyl-d-aspartate (NMDA) receptors, second messenger changes, and G-protein uncoupling may all play a role. Hyperalgesia that can result from chronic administration may be related to these same mechanisms.1,22

Respiratory Depression

All opiate agonists produce a dose-dependent depression of respirations via effects on mu and delta receptors in the respiratory centers in the brainstem. They reduce the responsiveness of the respiratory centers to increasing carbon dioxide and decreasing oxygen. It requires higher partial pressure of carbon dioxide (pCO2) levels to maintain normal respiration. Stated in pharmacologic terms, they produce a shift to the right in the CO2 response curve for respiration. Respiratory rate is affected first, and a classic “narcotized” patient will take slow deep breaths. As doses increase, apnea is produced. Because both analgesia and respiratory depression are mediated via the same receptors, reversal of respiratory depression with antagonists such as naloxone also reverses analgesia. The goal of most clinical anesthetics is to leave some residual analgesia without respiratory depression upon emergence to address postoperative pain.1

May 31, 2016 | Posted by in ANESTHESIA | Comments Off on Opioid Agonists and Antagonists
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