Organ System Effects:

• 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 than 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 they produce sleep from which individual can be easily awakened

    •  opioids in combination with sedative-hypnotics:very deep sleep

    • Significant Sedation: 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 responds 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

• Cough Suppression

  • Significant action of opioids

  • Especially effective: codeine

    • management of pathologic cough

    • management of patients with endotracheal tubes

  • Associated with:

    •  secretion accumulation-- leading to

      • atelectasis

      •  airway obstruction

•  Miosis

  • pupillary constriction: commonly seen with opioid agoniststhan

  • 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: 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

    • 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:

    • cerebral vasodilation (decreasein cerebral vascular resistance)

    • an increasein cerebral blood flow

    • an increasein 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: 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:

    • prolong labor

• Neuroendocrine:

  • Opioid analgesics promote release of:

    1. antidiuretic hormone

    2. prolactin

    3. somatotropin

  • Opioid analgesics inhibit released of:

    • luteinizing hormone

    • Probably hypothalamic effects

• Other Effects:

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

  • Opioid affecting the immune system by influencing:

    1. chemotaxis

    2. antibody production

    3. the disciple effort of responses

Pentazocine (and other)-- agonist-antagonists

• common: 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

adapted from Table 31-2: 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, p. 501; selection of an appropriate analgesic will depend on the severity and type of pain.