Opioid Analgesics and Antagonists

Opioid Analgesics and Antagonists

Pain and Analgesic Agents

Pain is an unpleasant sensory and emotional experience that serves to alert an individual to actual or potential tissue damage. This damage can be caused by exposure to noxious chemical, mechanical, or thermal stimuli (e.g., acids, pressure, percussion, and extreme heat) or by the presence of a pathologic process (e.g., a tumor, muscle spasm, inflammation, nerve damage, organ distention, or other mechanism that activates nociceptors on sensory neurons). Although pain serves a protective function by alerting a person to the presence of a health problem, its unbridled expression often leads to considerable morbidity and suffering. For this reason, analgesics or drugs that relieve pain are used for symptomatic treatment of pain from a wide variety of disease states, ranging from acute and chronic physical injuries to terminal cancer.

Based on their mechanisms of action, analgesics can be classified as opioid analgesics or nonopioid analgesics. Opioid analgesics act primarily in the spinal cord and brain to inhibit the neurotransmission of pain. In contrast, nonopioid analgesics act primarily in peripheral tissues to inhibit the formation of algogenic or pain-producing substances such as prostaglandins. Because most of the nonopioid analgesics also exhibit significant antiinflammatory activity, they are called nonsteroidal antiinflammatory drugs (NSAIDs). The NSAIDs are described in greater detail in Chapter 30.

To facilitate the selection of an appropriate analgesic or anesthetic medication, patients are usually asked to describe their pain in terms of its intensity, duration, and location. In some cases patients report an intense, sharp, or stinging pain. In other cases they describe a dull, burning, or aching pain. These two types of pain are transmitted by different types of neurons and their primary afferent fibers (Box 23-1). Pain can be further distinguished on the basis of whether it is somatic, visceral, or neuropathic in origin. Somatic pain is often well localized to specific dermal, subcutaneous, or musculoskeletal tissue. Visceral pain originating in thoracic or abdominal structures is often poorly localized and may be referred to somatic structures. For example, cardiac pain is often referred to the chin, neck, shoulder, or arm. Neuropathic pain is usually caused by nerve damage, such as that resulting from nerve compression or inflammation, or from diabetes. Neuropathic pain is characteristic, for example, of trigeminal neuralgia (tic douloureux), postherpetic neuralgia, and fibromyalgia.

Pain Pathways

Exposure to a noxious stimulus activates nociceptors on the peripheral free nerve endings of primary afferent neurons. The cell bodies of these neurons sit alongside the spinal cord in the dorsal root ganglia and send one axon to the periphery and one to the dorsal horn of the spinal cord. With noxious stimulation, substance P, glutamate, and other excitatory neurotransmitters are released from the central terminations of the primary afferent fibers onto neurons of the spinal cord. Many of these terminals synapse directly on spinothalamic tract neurons in the dorsal horn, which send long fibers up the contralateral side of the spinal cord to transmit pain impulses via ascending pain pathways to the medulla, midbrain, thalamus, limbic structures, and cortex.

As shown in Box 23-1, the primary afferent fibers transmitting nociceptive information are Aδ fibers and C fibers, which are responsible for sharp pain and dull pain, respectively. Spinal reflexes activated by these fibers can lead to withdrawal from a noxious stimulus before pain is perceived by higher structures. Ascending pain pathways consist of two main anatomic-functional projections: the sensory-discriminative component, to the cerebral cortex, and the motivational-affective component, to the limbic cortex. Projections to the sensory cortex alert an individual to the presence and anatomic location of pain, whereas projections to limbic structures (e.g., the amygdala) enable the individual to experience discomfort, suffering, and other emotional reactions to pain.

The activation of spinothalamic neurons in the spinal cord is modulated by descending inhibitory pathways from the midbrain and by sensory Aβ fibers arising in peripheral tissues. These two systems constitute the neurologic basis of the gate-control hypothesis. According to this hypothesis, pain transmission by spinothalamic neurons can be modulated, or gated, by the inhibitory activity of other types of large fibers impinging on them. The activation of spinothalamic neurons is also inhibited by peripheral Aβ sensory fibers that stimulate the release of met-enkephalin from spinal cord interneurons. The Aβ fibers are thought to also mediate the analgesic effect produced by several types of tissue stimulation, including acupuncture and transcutaneous electrical nerve stimulation (TENS). These mechanisms explain the pain relief that may be produced by simply rubbing or massaging a mildly injured tissue.

The descending inhibitory pathways arise from periaqueductal gray (PAG) in the midbrain, and they project to medullary nuclei that transmit impulses to the spinal cord (see Box 23-1). The medullary neurons include serotonergic nerves arising in the nucleus magnus raphe (NMR) and noradrenergic nerves arising in the locus ceruleus (LC). When these nerves release serotonin and norepinephrine in the spinal cord, they inhibit dorsal spinal neurons that transmit pain impulses to supraspinal sites. Nerve fibers from the PAG also activate spinal interneurons that release an endogenous opioid peptide, met-enkephalin. The enkephalins act presynaptically to decrease the release of pain transmitters from the central terminations of primary afferent neurons. They also act on postsynaptic receptors on spinothalamic tract neurons in the spinal cord to decrease the rostral transmission of the pain signal. Opioid analgesics activate the descending PAG, NMR, and LC neuronal pathways, and they also directly activate opioid receptors in the spinal cord.

Opioid Peptides and Receptors

Since ancient times, opium, the raw extract of the poppy plant Papaver somniferum, has been used for the treatment of pain and diarrhea. During the 19th century, morphine was isolated from opium, and its pharmacologic effects were characterized. Later, specific sites in CNS tissue were discovered that bound morphine and other opioid agonists. The presence of stereoselective receptors for morphine in brain tissue indicated the likelihood of an endogenous ligand for these receptors, and this eventually led to the discovery of the three major families of endogenous opioid peptides: enkephalins, β-endorphins, and dynorphins.

The opioid peptides are derived from larger precursor proteins that are widely distributed in the brain. Endorphins and dynorphins are large peptides, whereas the two types of enkephalins are small pentapeptides containing Tyr-Gly-Gly-Phe-Met/Leu. Therefore the two types of enkephalins are called met-enkephalin and leu-enkephalin.

The enkephalins are released from neurons throughout the pain axis, including those in the PAG, medulla, and spinal cord. Enkephalins activate opioid receptors in these areas and thereby block the transmission of pain impulses. The enkephalins appear to act as neuromodulators in that they exert a long-acting inhibitory effect on the release of excitatory neurotransmitters by several neurons.

Opioid agonists mediate their effects at three types of opioid receptors: µ (mu) opioid receptors, δ (delta) opioid receptors, and κ (kappa) opioid receptors. Most of the clinically useful opioid analgesics, however, have preferential or strong selectivity for µ opioid receptors. Some of the mixed opioid agonist-antagonist agents have κ opioid receptor selectivity, but attempts to develop useful opioid analgesics selective for δ receptors have not been successful.

Opioid Drugs


The opioid drugs can be classified as full agonists, mixed agonist-antagonists, or pure antagonists.

Based on their maximal clinical effectiveness, the full agonists can be characterized as strong or moderate agonists. In experimental pain models, all of the full agonists exert a maximal analgesic effect. In humans, the strong opioid agonists are well tolerated when they are given in a dosage sufficient to relieve severe pain. The moderate opioid agonists, however, will cause intolerable adverse effects if they are given in a dosage sufficient to alleviate severe pain. For this reason, the moderate opioid agonists are administered in submaximal doses to treat moderate to mild pain, and they are usually formulated in combination with NSAIDs to enhance their clinical effectiveness.

The mixed opioid agonist-antagonists are analgesic drugs that have varying combinations of agonist, partial agonist, and antagonist activity and varying degrees of affinity for the different opioid receptor types.

The opioid antagonists have no analgesic effects. They are used to counteract the adverse effects of opioids taken in overdose and for the treatment of drug dependence.

Drug Properties

Mechanism of Action

The opioid receptors are prominent members of the G protein–coupled receptor superfamily. Activation of opioid receptors leads to inhibition of adenylyl cyclase and a decrease in the concentration of cyclic adenosine monophosphate, an increase in K+ conductance, and a decrease in Ca2+ conductance (Fig. 23-1). The activated Gai subunit of the G protein directly inhibits the adenylyl cyclase enzyme, and the Gβγ subunits are thought to mediate the changes at the Ca2+ and K+ channels. These actions cause both presynaptic inhibition of neurotransmitter release from the central terminations of small-diameter primary afferent fibers and postsynaptic inhibition of membrane depolarization of dorsal horn nociceptive neurons.

Pharmacologic Effects

Central Nervous System

Morphine acts in the CNS to produce analgesia, sedation, euphoria or dysphoria, miosis, nausea, vomiting, respiratory depression, and inhibition of the cough reflex (Box 23-3).

Analgesia is produced by activation of opioid receptors in the spinal cord and at several supraspinal levels, as illustrated in Box 23-1. Sedation and euphoria can be caused by effects on midbrain dopaminergic, serotonergic, and noradrenergic nuclei. Surprisingly, many patients experience dysphoria after administration of opioids. Miosis (constricted pupils) is produced by the direct stimulation of the Edinger-Westphal nucleus of the oculomotor nerve (cranial nerve III), which activates parasympathetic stimulation of the iris sphincter muscle. Because little or no tolerance develops to miosis, this sign can be diagnostic of an opioid overdose.

Codeine and other opioids inhibit the cough reflex at sites in the medulla where this reflex is integrated. The antitussive actions of opioids are discussed in greater detail in Chapter 27.

Gastrointestinal, Biliary, and Genitourinary System

Morphine and most other opioids act to increase smooth muscle tone in the gastrointestinal, biliary, and genitourinary systems. In the gastrointestinal tract, increased muscle tone leads to inhibition of peristalsis and causes constipation. For this reason the opioids are the oldest and most widely used medication for the treatment of diarrhea (see Chapter 28). Unfortunately, patients with chronic pain do not appear to become tolerant to the constipating effects of opioids, necessitating a continual need for laxatives and other agents.

Morphine and other opioids also increase the tone of the biliary sphincter (sphincter of Oddi) and can cause an exacerbation of pain in patients with biliary dysfunction or a gallbladder attack. Opioids also increase the tone of the bladder sphincter and can cause urinary retention in some patients. Because the opioid agonist meperidine has less-pronounced action on smooth muscle, it is the drug of choice for these patients and for the pain associated with labor.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Opioid Analgesics and Antagonists

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