Morphine, the prototype opioid, is derived from opium, a crude material obtained from the seed pod of the opium poppy plant. The chemical structure of morphine is shown in Figure Structure-activity relationships of opioids. Many other derivatives of the opium plant (opiates) and other drugs with similar effects (opioids) have been discovered or synthesized. Chemical modifications of the morphine structure results in significant alterations in potency and in the ratio of agonist to antagonist effects (Table Selected opioids). However, no major improvement in the analgesic effect of this class of opioids has been achieved; morphine is still one of the most widely used opioids. The opioids are classified in several ways: (1) strength of analgesic effect (strong and weak agents); (2) ratio of agonist to antagonist effects (pure agonists, mixed agonist-antagonists, and partial agonists that act both as an opioid agonist and antagonist, and antagonists), and (3) actions (analgesic, antitussive, and antidiarrheal drugs).
Figure: Structure-activity relationships of opioids
Table Selected opioids
|Strong opioid agonists||Notes|
|Morphine (also hydromorphone, oxymorphone, heroin)||See case descriptionHeroin is metabolized to morphine|
|Methadone||Indications are similar to morphine. Used to treat difficult to manage pain (e.g., cancer, neuropathic pain). Used as an oral opioid substitute to treat opioid dependence. Its long duration of action and slow metabolism result in less severe withdrawal than with other shorter acting opioids.|
|Fentanyl (also alfentanil, sufentanil, remifentanil)||Has a shorter duration of action than morphine. Available for parenteral use only. Used as a pre-anesthetic medication and for pre- and postoperative pain. Fentanyl (or morphine) is used to supplement the analgesia and sedative-hypnotic effects of nitrous oxide and halothane equals “balanced anesthesia.” Rapid IV administration of high doses may cause severe truncal muscle rigidity that can be reversed by naloxone. Available as a transdermal patch and lozenge.|
|Meperidine||Although still used, in overdose methadone may cause CNS excitation (tremors, delirium, and hyperreflexia) and seizures as a result of formation of an N-demethylated metabolite, normeperidine. With MAO inhibitors may cause severe restlessness, excitement, fever, and seizures (serotonin syndrome). It has weak anticholinergic activity that may result in mydriasis (not miosis) and tachycardia. Meperidine has weak or no effect on the cough reflex.|
|Codeine (also oxycodone, hydrocodone, dihydrocodeine)||Used for moderate pain. Has good bioavailability by the oral route (compared to morphine); 10% converted to morphine. Causes little respiratory depression and less dependence liability than morphine. An overdose may cause seizures. Codeine and other weak opioid agonists are often used in combination with other analgesics such as aspirin (Percodan) or acetaminophen (Percocet).|
|Weak opioid agonists||Notes|
|Diphenoxylate, Loperamide||Used for the symptomatic treatment of diarrhea. Insolubility of diphenoxylate limits its absorption across the GI tract. Loperamide does not cross the blood-brain barrier. Minimal dependence liability or other centrally mediated opioid effects. To limit its parenteral use, diphenoxylate is only available combined with atropine.|
|Mixed opioid agonist-antagonists/partial agonists||Notes|
|Buprenorphine (also pentazocine, nalbuphine, butorphanol, dezocine, tramadol)||Buprenorphine is a slowly dissociating partial agonist at the µ-opioid receptor. Its agonist actions are resistant to naloxone reversal. It is used primarily for heroin detoxification. It has less dependence liability than morphine. At higher doses it has antagonist activity at the |X-opioid receptor which limits its ability to cause respiratory depression.|
|Naloxone and Naltrexone (also nalmefene)||Competitive antagonists at opioid receptors which can precipitate opioid withdrawal. Naloxone is administered IV because of poor oral absorption. It is used to treat acute opioid overdose. Because of its short duration of action, multiple dosing may be necessary. Naltrexone is FDA approved for use in chronic alcoholics to reduce craving for alcohol.|
|Dextromethorphan||Dextromethorphan, a nonopioid drug, is nearly as effective as codeine as an antitussive agent, but with less constipating effect. It has no or limited analgesic activity or dependence liability. It may cause some dizziness, nausea, or drowsiness. Opioids other than codeine are not commonly used because of their dependence liability.|
The major therapeutic application for morphine and other strong opioids (e.g., fentanyl, hydromorphone, methadone) is the management of moderate to severe pain (e.g., pain associated with trauma, burns, cancer, acute myocardial infarction, and renal or biliary colic). Weaker opioids such as codeine and pentazocine are used to manage mild to moderate pain. Other important therapeutic uses include the management of diarrhea (e.g., codeine, diphenoxylate, loperamide), dyspnea associated with pulmonary edema secondary to acute left ventricular failure, suppression of the cough reflex (codeine, dextromethorphan), and maintenance and withdrawal therapy for opioid dependence (methadone, buprenorphine). The antitussive (cough suppressant) action and antidiarrheal action of the opioids are at least partially separable from their analgesic action. Separate drugs have been developed to exploit these effects.
The sites of opioid action include areas in the central nervous system (CNS) where they raise the threshold to pain (i.e., decrease the sensation of pain) including (1) the spinal cord, where opioids act directly on receptors on the terminals of primary afferent sensory neurons in the dorsal horn of the spinal cord to inhibit release of excitatory transmitters like substance P, (2) the thalamus, where opioids act on ascending pathways to directly inhibit pain transmission from the spinal cord to higher centers of the brain (via the spinothalamic tract and spinoreticular tract), and (3) the midbrain periaqueductal gray area and rostral ventral medulla (nucleus raphe magnus) where opioids activate descending inhibitory neurons to the spinal cord, thus preventing pain transmission. Opioids also act on the cerebral cortex, amygdala, and hippocampus to decrease the emotional reactivity to pain (i.e., decrease the perception of pain). There is also a direct inhibitory effect of opioids on sensory nerve endings. In addition to the CNS, opioids also act on other organs including, notably, the GI tract and kidney.
The most commonly observed effects when the opioids are used for the relief of pain are sedation, nausea and vomiting, and constipation. Large doses regularly induce respiratory depression and euphoria or mental clouding. The major adverse effects of selected opioids are presented in Table Adverse effects of opioids.
Table: Adverse effects of opioids (generally extensions of pharmacologic activity)
|Adverse effect: cause||Notes|
|Respiratory depression (major limiting effect) caused by direct inhibition of respiratory center in the brain stem results in decreased sensitivity to hypoxic drive by carbon dioxide.||Occurs at therapeutic doses of morphine. Tolerance develops that parallels tolerance to analgesia. Respiratory depression is generally not a serious clinical problem except in several special circumstances where opioids may be contraindi cated: (1) Decreased respiratory reserve (e.g., emphysema, obstructive lung disease); (2) Head injury or CNS tumors; and (3) Pregnancy (to avoid fetal respiratory depression). Respiratory depression is a serious and potentially fatal consequence of opioid overdose.|
|Sedation/drowsiness||A decreased ability to concentrate. Ambulatory patients and elderly are at risk for accidents. A paradoxical dysphoria and increased anxiety may occur in children and women.|
|Nausea (30%), vomiting (10%): Caused by direct stimulation of the CTZ in the area postrema of the medulla which activates the vomiting center.||More likely to occur in ambulatory patients. Self-limiting with continued administration because of subsequent direct inhibition by morphine of the vomiting center.|
|Dependence||See Clinical correlation.|
|Pneumonia: May result from inhibition of cough reflex.||Increased likelihood in patients whose respiration is already seriously compromised.|
|Miosis: Stimulation of the Edinger-Westphal nucleus of the oculomotor nerve (III) results in contraction of the pupillary sphincter with constriction of the pupils (“pin-point” pupils).||Occurs at therapeutic doses. Pupils do not dilate, even in the dark. Parasympathetic pathways involve release of ACh in the ciliary ganglion; miosis can be blocked by atropine. Sign of opioid (e.g., heroin) overdose.|
|Hypotension: Opioids inhibit the (tonically active) vasomotor center in the brain stem to cause some peripheral arterial and venous vasodilation.||Usually not a clinical problem but is a relative contraindication for patients in shock or who have low blood pressure or who are hypovolemic (reduced blood volume). The elderly are particularly susceptible.|
|Constipation (delayed fecal movement/increased absorption of water): Mechanism is uncertain, but probably due to peripheral action on the enteric nervous system to inhibit acetylcholine release. Effect is to increase GI tone with a concomitant decrease in coordinated propulsive activity and motility. Opioids also increase anal sphincter tone and decrease attention to the defecation reflex.||A major complaint of patients receiving opioids for analgesia. There is no clinically significant tolerance in humans. Stool softeners are used to treat (mineral oil/glycerin suppositories).|
|Urine retention: Opioids decrease urinary output due to decreased renal plasma flow, possible increased release of ADH from pituitary, decreased coordinated contractility of the ureters and bladder, increased urethral sphincter tone, and inattention to the urinary reflex.||Usually not a clinical problem except in patients with enlargement of the prostate. Catheterization may be necessary. More common in elderly. Increased tone of the ureters may result in a paradoxical increase in pain. A similar effect may occur when opioids are used to treat the pain of biliary colic.|
Tolerance to some effects of the opioids (Table Relative development of tolerance to opioids) occurs gradually (days) with repeated administration such that a larger dose is necessary to produce the same initial effect. The tolerance is because of a direct action of opioids on neurons (i.e., cellular tolerance) rather than to an increase in their metabolism (metabolic tolerance). Tolerance does not occur to all the effects of the opioid agonists or to the action of antagonists (see Table Relative development of tolerance to opioids). Tolerance to one opioid agonist can confer tolerance to other opioid agonists, that is, cross-tolerance. However, there is no cross-tolerance between opioid agonists and other nonopioid drugs that act on the CNS such as the benzodi-azepines, barbiturates, ethanol, stimulants, etc.
Table: Relative development of tolerance to opioids
|AnalgesiaRespiratory depression |
Nausea and vomiting
|ConstipationSeizures (meperidine, codeine) |
Antagonist activity (naloxone, naltrexone)
Opioid-induced respiratory depression may be potentiated in the presence of sedative-hypnotics agents, antipsychotic agents, or antidepressant agents. Opioids, particularly meperidine, may interact with MAOIs (tranyl-cypromine, phenelzine) to cause a “serotonin syndrome.”
Opioids may be full agonists (e.g., morphine, heroin) or partial agonists (e.g., buprenorphine, pentazocine). Morphine is a phenanthrene alkaloid with a phenylmethyl-piperidine ring structure. Simple chemical substitutions can markedly alter its pharmacologic properties (see Figure Structure-activity relationships of opioids).
Mechanism of Action
Opioid agonists bind to G-protein-coupled neural receptors (mu, delta, kappa) to reduce adenylyl cyclase activity, to reduce prejunctional calcium conductance, which causes a decrease in neurotransmitter release, and to enhance postjunctional potassium conductance, which causes a decrease in cell responsiveness to excitatory neurotransmitters.
Opioids are usually administered orally, but some like morphine can also be administered rectally or parenterally.
Patient controlled analgesia (PCA): By infusion (morphine/meperidine/hydromorphone). Regional analgesia: Epidural route is favored because it produces fewer adverse effects. May also be administered into subarachnoid or intrathecal spaces. There may be delayed respiratory depression, nausea, and vomiting that can be reversed with naloxone.
Transdermal fentanyl patch: Used for chronic pain
Buccal fentanyl lozenge/lollipop
Butorphanol nasal spray
Most opioids are absorbed well. Morphine, given orally, shows variable but significant first-pass metabolism (glucuronide conjugation) with a low oral to parenteral potency ratios (25%). It is usually given parenterally. Codeine and methadone are well absorbed after oral administration (approximately 60%) because of limited first-pass metabolism.
All opioids are metabolized by the liver. Metabolism usually results in more polar metabolites and frequently involves conjugation of the phenolic hydroxyl with glucuronic acid. Excretion is primarily by way of the kidneys. In addition to inactive metabolites, morphine is conjugated in the liver to morphine-3-glucuronide, which has neuroexcitatory properties. Morphine is also metabolized (10%) to morphine-6-glucuronide, which at high levels has analgesic potency greater than morphine itself. Codeine is metabolized, in part, to morphine. Heroin is also metabolized to morphine. Meperidine is metabolized to normeperidine that may be responsible for seizures in patients where it accumulates.
The fetal blood-brain barrier is readily crossed by the opioids, and infants born to mothers given (or self-administering) large doses of opioids may have severe respiratory depression.
Opioid overdose: Questions – Answers