Pharmacology - An Illustrated Review

13. Opiate Receptor Agonists and Antagonists

Opioids or opiates are a class of drugs with opiumlike properties that interact with a set of specific membrane receptors, the opiate receptors. Opioids are used mainly to treat pain.

Pain Modulation

Pain can be modulated at several sites, from its point of origin through the various synaptic junctions in the pain pathways (Fig. 13.1). These pathways may correlate with both the perception of pain and the reaction to that sensation. Opioids act in the spinal cord to decrease the sensation of pain (spinal analgesia) and act at higher centers to both decrease the sensation of pain and increase the patient's ability to tolerate the pain (supraspinal analgesia).

Postcentral gyrus

Pain pathways Pain is transmitted from the periphery by Aδ fibers, activated by noxious heat and mechanical stimuli, and by C fibers, which respond to intense mechanical, chemical, and thermal stimuli. The cell bodies of these nerve fibers are in the dorsal root ganglion. Centrally, they innervate cells in the dorsal horn of the cord. Most of the axons from these cells cross and relay this information to the brain in the spinothalamic tracts. Most of these fibers synapse below the level of the thalamus, but some do go on to the thalamus. The impulses are then relayed to the limbic system and cortex. There are also descending fibers involved in pain, mainly serotonergic fibers from the midbrain raphe nuclei.


Endogenous opioids: Endorphins, enkephalins, and dynorphins

Endorphins, enkephalins, and dynorphins are endogenous neuropeptide neurotransmitters that are agonists at opiate receptors. Endorphins are found in the pituitary gland, whereas enkephalins and dynorphins are found throughout the nervous system and gut. Endorphins principally cause pain reduction, but they also produce euphoria, cause the release of sex hormones, and modulate appetite. The release of endorphins during prolonged/strenuous exercise results in the sense of euphoria and well-being accompanying exercise (“runner's high”). Enkephalins and dynorphins are also involved in the regulation and modulation of pain.


Opiate Receptors

There are three major categories of opiate receptors: µ (mu), δ (delta), and κ (kappa). The actions of opioids in current use are interpreted with regard to their actions at µ, δ, and κ receptors, as shown in Table 13.1.

  Table 13.1 image Actions Mediated by Opiate Receptors

Opiate Receptor

CNS Location*



Dorsal horn of the spinal cord, nucleus of the solitary tract, periaqueductal gray region, thalamus, nucleus accumbens, amygdala, cerebral cortex

Supraspinal analgesia

Respiratory depression




Dorsal horn of the spinal cord, periaqueductal gray region, hypothalamus

Spinal analgesia

Miosis (pupillary constriction)



Pontine nucleus, nucleus accumbens, amygdala, cerebral cortex

Involved in affective behaviors (related to feelings or mental state)

* Opiate receptors are also found in the enteric nervous system, placenta, vas deferens, and immune system.

Abbreviation: CNS, central nervous system.

13.1 Opiate Agonists

Exogenous Opioid Agonists

Morphine and Related Compounds

Morphine is the standard for comparison among opioids. Many semisynthetic compounds are made by modifying the morphine molecule.

– Diacetylmorphine (heroin) is made by acetylation at the three and six carbon positions.

– Hydromorphone, oxymorphone, oxycodone, and hydrocodone are also made by altering the morphine molecule.

Mechanisms of action

– Morphine and related compounds act at all opiate receptors, but with the highest affinity at µ receptors. Activation of µ receptors decreases the spontaneous activity of neurons in the gut and in the central nervous system (CNS).

Fig. 13.1 image Pain mechanisms and pathways.

Nociceptors detect painful stimuli and relay nociceptive impulses via Aδ fibers and C fibers to the brain. Impulses that are conveyed to specific areas of the postcentral gyrus produce short, sharp, well-localized pain, whereas impulses conveyed to more than one area of the cortex are perceived as dull, poorly localized pain. Drugs can act at multiple levels of the pain pathway to produce analgesia or alter the perception of pain.


— Morphine acts on areas known to be involved in respiration, pain perception, mood, and emotion.

– At the cellular level, all three subtypes of opiate receptors couple to Gi and Go. Activation of these G proteins by opioid-binding to opiate receptors decrease cyclic adenosine mono-phosphate levels (cAMP), increase K+ currents, and decrease Ca2+ currents. This results in hyperpolarization and decreased release of neurotransmitters (Fig. 13.2).

– Morphine selectively inhibits the excitatory inputs to neurons involved in transmitting information about noxious stimuli without changing the responses to other types of stimuli.


– Morphine is readily absorbed from the gastrointestinal (GI) tract, nasal mucosa, and lungs.

– Bioavailability of oral preparation ranges from 15 to 50% due to first-pass metabolism in the liver.

– Metabolized by glucuronide conjugation (Fig. 13.3)

– Excreted as a glucuronide conjugate in the urine

– Diacetylmorphine (heroin) is rapidly deacetylated in the liver to monoacetylmorphine, which is further deacetylated to morphine.

Fig. 13.2 image Actions of endogenous and exogenous opioids at opiate receptors.

Endogenous opioids are all cleaved from the precursor peptides proenkephalin, pro-opiomelanocortin, and prodynorphin. Endogenous and exogenous opioids reduce neuronal excitability by increasing K+ permeability leading to hyperpolarization of the neuronal membrane. Ca2+ influx into nerve terminals during excitation is also reduced causing decreased release of transmitter substances and decreased synaptic activity. Stimulant or depressant effects then occur depending on the transmitters and receptors affected.


Fig. 13.3 image Metabolism of morphine.

Morphine has a free hydroxyl group and is conjugated to glucuronic acid in the liver and excreted renally.



The effects of opioids are summarized in Table 13.2.

  Table 13.2 image Effects of Morphine





Analgesia without loss of consciousness

Opioids are more selective for pain than other CNS drugs

Other sensory modalities remain intact


Respiratory depression

Direct inhibition of 5-HT4A receptors in the rhythm-generating respiratory neurons in the pre–Boetzinger complex of the brainstem



Excitation at the nucleus of the oculomotor nerve. This is pathognomonic of opiate intoxication (so-called pinpoint pupils)




Antitussive (cough suppressant)

Inhibition of central cough reflex


Nausea and vomiting

Opiates have a direct action on the chemoreceptor trigger zone in the medulla


Warmth and drowsiness


Itchy nose


Cardiovascular system

Peripheral vasodilation

Inhibition of baroreceptor reflexes

Orthostatic hypotension

There is little or no direct effect on the heart

GI system


Decreased stomach motility, increased tone and nonpropulsive contractions in the small and large intestine, and increased tone of the anal sphincter


Increased biliary tract pressure


Abbreviations: CNS, central nervous system; GI, gastrointestinal.

Abnormal pupillary reactions to drugs

Many drugs cause miosis (constriction of the pupils), including opioids, antipsychotics (e.g., haloperidol), and parasympathomimetic cholinergic drugs (e.g., pilocarpine). Likewise, drugs can cause mydriasis (dilation of the pupils), including anticholinergics (e.g., atropine), hallucinogens (e.g., lysergic acid diethylamide [LSD]), cocaine, and some antidepressant drugs.



– Acute relief of pain (symptomatic treatment only)

– Chronic treatment of pain

– Antitussives

– Useful in diarrhea to produce constipation. Small amounts of opium tincture or paregoric are ingested. This effect is of particular use following ileostomy or colostomy and in diarrhea and dysentery.

Side effects. Nausea, vomiting, mental cloudiness, dysphoria, constipation, and increased biliary pressure.

Drug interactions. Opioid action is potentiated by phenothiazines, monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants. Some phenothiazines will enhance the sedative effects of morphine while decreasing the analgesic effects.

Tolerance and dependence. They are characteristics of the opioid drugs.


– It may not be advisable to use opioids in patients with head injury, as mental clouding, vomiting, and miosis may interfere with neurologic assessment of the patient.

– Caution must be used in patients with lung disease due to respiratory depression.

Opioid poisoning

Opioid poisoning may result from clinical use, abuse, or suicide attempt. Symptoms include coma, pinpoint pupils, and depressed respiration. Overdose is frequently accompanied by other drugs, which may confound the diagnosis and treatment. Treatment involves supporting ventilation and administering naloxone intravenously.



– Meperidine is a synthetic opiate.

– Fentanyl is a meperidine analogue 80 times as potent as morphine.

– Sufentanil is a meperidine analogue 6000 times as potent as morphine.

Mechanism of action. Meperidine acts in the same way as morphine, that is, as an agonist at opiate receptors.

Pharmacokinetics. Meperidine has better bioavailability than morphine: 50% of absorbed meperidine escapes first-pass metabolism.


– Analgesia

– May cause CNS excitement at toxic doses (unlike morphine)

– Respiratory depression

– Cardiovascular: postural (orthostatic) hypotension but no significant effects

– Smooth muscle: spasmogenic like morphine, but less intense in relation to its analgesia

Note: Meperidine does not have antitussive or constipating actions.


– Analgesia

Side effects. The side effects are the same as for morphine, except there is less constipation. The metabolite normeperidine accumulates with repeated dosing. Normeperidine is not an analgesic, but it produces CNS excitation.

Drug interactions. Meperidine may react with MAOIs, causing excitation, delirium, hyper-pyrexia, convulsions, and severe respiratory depression.

Methadone and Levo-α-acetylmethadol (LAAM)

Mechanism of action. These agents are synthetic, long-acting opiate agonists with similar pharmacological effects as morphine.


– Long half-life (1−1.5 days)


– Analgesia (equally as potent as morphine)

– Treatment of opioid withdrawal symptoms

Side effects

– Constipation and biliary spasm

Propoxyphene (Darvon)

Mechanism of action. Propoxyphene is an agonist at opiate receptors.

Pharmacokinetics. It is not as potent or effective as codeine, but it does have less potential for dependence.


– Previously used as an analgesic agent but has recently been removed from the market.

13.2 Mixed Opiate Agonist-Antagonists


Mechanism of action. Pentazocine is a µ-receptor antagonist and a δ- and κ-receptor a gonist.


– Produces analgesia, sedation, and respiratory depression

– May block the analgesia produced by morphine


– Primarily used as an analgesic, but not effective against severe pain

Side effects

– Respiratory depression

– May cause confusion and hallucinations

Tolerance, dependence, and withdrawal

– Originally thought to have less potential for abuse and released for general use, but then drug abusers combined pentazocine and tripelennamine as a substitute for heroin. Talwin Nx™ (pentazocine and naloxone) includes naloxone to prevent intravenous (IV) use.

– May precipitate withdrawal symptoms in patients who have been receiving opioids


Mechanism of action. Buprenorphine is a partial agonist at µ receptors.


– Given IM or IV


– Analgesia

Side effects

– Respiratory depression

13.3 Opiate Antagonists

Naloxone, Naltrexone, and Nalmefene

Mechanism of action. These antagonists bind with high affinity to all opiate receptors but have highest affinity for µ receptors. They act as competitive inhibitors.


– Naloxone and nalmefene are only effective IV, with nalmefene having a longer duration of action (10 hours versus 1 hour for naloxone).

– Naltrexone is effective orally.


– Naloxone and nalmefene are used to treat opioid poisoning

– Naltrexone has been tested for treating drug and alcohol addictions

Withdrawal. In patients dependent on opiates, antagonists will induce withdrawal symptoms.

13.4 Related Compounds


Dextromethorphan is an opioid analogue that is available over the counter but has no analgesic or addictive properties.

Mechanism of action

– Unclear, but may involve µ and κ receptors


– Antitussive


Tramadol is chemically unrelated to opioids.

Mechanism of action. Tramadol is a weak opiate receptor agonist. It also inhibits norepinephrine and 5-hydroxytryptamine (5-HT) reuptake. It is only partially inhibited by naloxone. It is equal to or less effective than codeine plus aspirin or to codeine plus acetaminophen.


– Neuropathic pain

Side effects

– Constipation, nausea, vomiting, dizziness, and drowsiness


Ziconotide is not an opioid.

Mechanism of action. Ziconotide is a peptide blocker of neuronal N-type Ca2+ channels.


– Given by intrathecal infusion


– Management of severe chronic pain

Side effects

– Severe psychiatric symptoms, such as hallucinations, paranoia, and delirium. Drunklike reactions also occur (e.g., dizziness, sleepiness, confusion, incoordination, and mental slowness). These symptoms take days or weeks to resolve after discontinuation.

– Bacterial meningitis

Table 13.3 provides a summary of the primary indications for the opioid analgesics.

  Table 13.3 image Primary Indications for Opioid Analgesics




Morphine and related compounds

Acute pain

Chronic pain

Cough (codeine)*



Meperidine and analogues


Regional analgesia (fentanyl)

Preanesthetic (fentanyl)


Methadone and LAAM

Opioid withdrawal



Analgesia for moderate pain





Naloxone and nalmefene

Opioid poisoning






Neuropathic pain



Severe chronic pain


* Opioids and related compounds are used for severe cough when nonopioid cough suppressants have failed.

Abbreviation: LAAM, levo-α-acetylmethadol.