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Medical Pharmacology Chapter 44:  Opioids
 

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Organ System Effects

CNS effects: mu  (μ) 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: μ1 and μ2

    •   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: μ2 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 (decrease↓in cerebral vascular resistance)

      • An increase↑in cerebral blood flow

      • 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: 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 which can lead to 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 and histamine early

    • Opioid affecting the immune system by influencing:

      1. Chemotaxis

      2. Antibody production

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

Opioid Analgesics: Efficacy; Oral/Parenteral Potency Ratio
Generic name Trade name Oral/ Parenteral Potency Maximum Efficacy

morphine

generic

low

high

hydromorphone

Dilaudid

low

high

oxymorphone

Numorphan

low

high

methadone

Dolophine

high

high

meperidine

Demerol

medium

high

fentanyl

Sublimaze

parenteral only

high

sufentanil

Sufenta

parenteral only

high

alfentanil

Alfenta

parenteral only

high

levorphanol

Levo-Dromoran

high

high

codeine

generic

high

medium

oxycodone

Percodan

medium

medium

dihydrocodeine

Drocode

medium

medium

propoxyphene

Darvon

oral only

low

pentazocine

Talwin

medium

low

nalbuphine

Nubain

parenteral only

low

buprenorphine

Buprenex

parenteral only

low

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.

 

Summary of Opioid Analgesic Toxic Effects

  • Dysphoria may include behavioral restlessness; hyperactivity

  • 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

  • Nausea and vomiting

  • Increased intracranial pressure

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

      1. Cerebral vasodilation (decrease in cerebral vascular resistance)

      2. An increase in cerebral blood flow

      3. An increase in intracranial pressure

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

  • Constipation

  • Urinary tension

  • 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

 

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.

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.

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.

 

 

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