• CNS effects: mu receptor-mediated: analgesia, sedation, euphoria, respiratory depression

  • Analgesia: Pain Components

    • Affective (emotional)-- opioids have greater effect on this element

    • Sensory

    • Analgesia results from complex interactions involving:

      • Sites in the brain, spinal cord, peripheral tissue

        • Selective action on neuronal modulators and transmitters of pain (other sensory modality/motor functions: remain intact)

      • Major receptor types: m₁ and m₂

    •   Spinal cord:-- sites of action

      1. Presynaptic on primary afferent nociceptors -- decreasing substance P release.

      2. Hyperpolarization of substantia gelatinosa interneurons-- decreasing nociceptive impulse afferent transmission

      3. Spinal morphine analgesia: m₂ opioid receptors

    • Supraspinal Sites of Action:

      1. periaqueductal gray

      2. locus ceruleus

      3. medullary nuclei (mainly nucleus raphe magnus)

      4. Supraspinal morphine analgesia: m₁ opioid receptors

    • Clinical Implications-analgesia:

      1. Bolus dosing (e.g.intramuscular): not correlated well with analgesic effects

      2. Constant/slowly changing (i.e., steady-state) plasma concentrations: well correlated with analgesic effect intensity

      3. Patients using patient-controlled analgesia delivery systems:

         • achieve more constant plasma opioid concentration (desirable)

         • maintained effective analgesic morphine plasma concentration

  • Euphoria:

    • Anxiolytic;pleasant; "floating sensation";

    • Individuals not in pain may experience dysphoria

  • Sedation:

    • Common consequence of opioid administration

    • Limited amnesia

    • Given as monotherapy, opioids may produce sleep from which individual can be easily awakened

    • Opioids in combination with sedative-hypnotics produce a very deep sleep

    • Significant sedation is more likely with phenanthrene derivatives (e.g., morphine, oxycodone (Roxicodone), hydrocodone, oxymorphone (Numorphan), hydromorphone (Dilaudid))

    • Significant sedation: less likely with synthetic agents (e.g. fentanyl (Sublimaze), meperidine (Demerol))

•  Respiratory Depression:

  •   All opioid analgesics: significant respiratory depression (inhibiting brain stem respiratory centers)

  • Characterized by reduced response to carbon dioxide challenge

  • Respiratory depression is:

    • dose-related

    • influenced by extent of sensory input

    • opioid induced --slight respiratory depression: tolerated in patients with no prior respiratory difficulty

    •   opioid induced -- slight respiratory depression: poorly or not tolerated in patients with asthma, chronic obstructive pulmonary disease (COPD), cor pulmonale, and increased intracranial pressure

• Cough Suppression

  • Significant action of opioids

  • Especially effective: codeine

    • management of pathologic cough

    • management of patients with endotracheal tubes

  • Associated with secretion accumulation which may lead to atelectasis and/or airway obstruction

•  Miosis

  • Pupillary constriction: commonly seen with opioid agonists

  • blocked by opioid antagonists

  • No tolerance develops

  • Mechanism:

    • Edinger-Westphal nucleus of the oculomotor nerve

    • Parasympathetic system -- may be blocked by atropine

  • Clinical Implications-miosis:

    •  Assuming no other drugs present: miosis correlates with opioid-induced respiratory depression

    •   Severe opioid-induced respiratory depression which causes hypoxemia will precipitate pupillary dilation

• Truncal Rigidity:

  • Increased large trunk muscle tone-- supraspinal action

  •   Decreased thoracic compliance; interferes with ventilation

  • Most often seen with highly lipophilic opioids, upon rapid IV administration:

    • fentanyl (Sublimaze)

    • sufentanil (Sufenta)

    • alfentanil (Alfenta)

  • Reversal of truncal rigidity: opioid antagonists

  • Maintenance of analgesia with reduced truncal rigidity is a basis for concurrent neuromuscular blocking drug use.

• Nausea and Vomiting:

  • Opioid analgesics: stimulate brain stem chemoreceptor trigger zone (CTZ)

  • Vestibular component may also be present

• Cardiovascular Effects:

  • Usually minimal effects (some bradycardia)

  • BP -- in the absence of stress, well maintained;

  • With stress hypotension may occur

    • Hypotensive reaction -- mechanism

      • Peripheral arterial dilation

      • Venous dilation

      • May be due to central vasomotor effects and histamine release

    •  Reduced blood volume:

      • Increased susceptibility to opioid hypotensive effects

  • With respiratory depression (secondary to opioid administration), PCO₂ increases and causes:

    1. cerebral vasodilation (decrease in cerebral vascular resistance)

    2. an increase in cerebral blood flow

    3. an increase in intracranial pressure

• Gastrointestinal Opioid Effects:

  • Constipation:

    • Mechanism: local enteric mechanisms and CNS effects

    • Stomach:

      • Motility {rhythmic contraction/relaxation} decreases

      • Tone {constant muscle contraction level} increases

      • Gastric acid (HCl) decreases

    • Small Intestinal Effects:

      • Tone: increases; with spasm

      • Nonpropulsive contractile amplitudes decreases

    • Large Intestinal Effects

      • Propulsive peristaltic waves are diminished

      • Tone increased

      • These effects:

        1. Delay fecal passage (constipating)

        2. Promote water reabsorption (constipating)

      • Opioid pharmacological actions in the large intestine are the basis for opioid use in management of diarrhea

• Biliary tract:

  • Opioids: promote biliary smooth muscle constriction: biliary colic

  •  Sphincter of Oddi may constrict:

    • Biliary and pancreatic secretion reflux

    • Elevated plasma lipase/amylase

• Genitourinary tract:

  • Renal Function:depressed

    • Decreased renal plasma flow

    • Bladder and ureteral tone:increased

      • Urinary retention (particularly in postoperative patients)

      • Increased opioid-induced ureteral tone may worsen ureteral colic due to renal calculus

  • Uterus:

    • prolongation of  labor

• Neuroendocrine:

  • Opioid analgesics promote release of:

    1. Antidiuretic hormone

    2. Prolactin

    3. Somatotropin

  • Opioid analgesics inhibit released of:

    • Luteinizing hormone which is probably a hypothalamic effect

• Other Effects:

  • Flushing, sweating, itching: central effects & histamine early

  • Opioid affecting the immune system by influencing:

    1. Chemotaxis

    2. Antibody production

• Common effect: sedation + analgesia-- therapeutic doses

• Sweating, dizziness, nausea -- common at higher doses;significant respiratory depression less likely than with pure opioid agonists

  • Respiratory depression: reversible by naloxone; agonist antagonists (nalorphine) less likely to be effective in reversing respiratory depression

• Psychotomimetic effects: agonist-antagonists

  • nightmares

  • anxiety

  • hallucinations

• Summary of Opioid Analgesic Toxic Effects

  • Dysphoria --behavioral restlessness; hyperactivity

  •   Respiratory depression

    • All opioid analgesics: significant respiratory depression (inhibiting brain stem respiratory centers)

    • Characterized by: reduced response to carbon dioxide challenge

    • Respiratory depression:

      • Dose-related

      • Influenced by extent to sensory input

      • Opioid induced --slight respiratory depression: tolerated in patients with no prior respiratory difficulty

      • Opioid induced -- slight respiratory depression: poorly or not tolerated in patients with:

        • Asthma

        • Chronic obstructive pulmonary disease (COPD)

        • Cor pulmonale

        • Increased intracranial pressure

  • Nausea and vomiting

  • Increased intracranial pressure

    •  With respiratory depression (secondary to opioid administration), PCO₂ increases and is associated with:

      1. cerebral vasodilation (decrease in cerebral vascular resistance)

      2. an increase in cerebral blood flow

      3. an increase in intracranial pressure

       

  • hypotensive states -- worsened by preexisting hypovolemia or by other medications given concurrently (e.g. nitroglycerin in acute management of myocardial infarction)

  • constipation

  • urinary retention

  • urticaria, itching

adapted from Table 31-5: Way, W.L., Fields, H.L. and Way, E. L. Opioid Analgesics and Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange

1. Way, W.L., Fields, H.L. and Way, E. L. Opioid Analgesics and Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 496-515;

2. Schuckit, M.A. and Segal D.S., Opioid Drug Abuse and Dependence, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2508-2512;

3. Coda, B.A. Opioids, In Clinical Anesthesia, 3rd Edition (Barash, P.G., Cullen, B.F. and Stoelting, R.K.,eds) Lippincott-Ravin Publishers, Philadelphia, New York, 1997, pp 329-358.