Anesthesia Pharmacology Chapter 13:  Opioid Pharmacology Advanced Topics

¹Intravenous Opioid Anesthetics:  Pruitus

•  The occurrence of opioid-induced pruritus is well established; however, the mechanism remains to be elucidated.  Histamine release does not appear to be the cause, given that certain opioids that do not promote histamine release still cause pruritus.  Allergic reactions in the presence of drug solution preservatives also do not account for this phenomenon.

¹Opioids: Some Therapeutic Actions

• ¹Ventilation: One consequence of pain/anxiety may be respiratory alkalosis secondary to increased spontaneous ventilation. 

  • Hyperventilation can also follow from some brainstem disorders. 

    • Management of hyperventilation is provided by opioids by means of reducing both pain and central ventilatory drive. 

    • Furthermore, postoperative respiratory dysfunction can follow from inadequate pain relief. 

    • Overall, opioid analgesic treatment can enhance synchronous breathing with a reduction in voluntary muscle tone, ultimately improving dynamic total respiratory compliance in awake but mechanically ventilated patients in the ICU setting. 

    • Of course, the caveat is that large doses of opioids can reduce pulmonary compliance (increased rigidity) as well as in directly impair ventilation.

• ¹Anti-cough: (antitussive):  Central mechanisms are responsible for opioid-induced antitussive effects.  

  • In about half of patients receiving IV bolus fentanyl, sufentanil and alfentanil can initiate brief coughing episodes, possibly due to a pulmonary chemoreflex mediated by C-fiber receptors. T

  • This cough reflex following opioid injection is not affected by atropine pretreatment, though suggesting a mechanism other than a vagal one. 

  • Opioid-induced cough could occur by stimulation of "Ericsson" receptors associated with tracheal smooth muscle. 

    • Finally, pretreatment using inhalational - adrenergic agonists decreases the likelihood of   IV opioid injection-induced cough.

• ¹Suppression of upper airway, tracheal and lower respiratory tract reflexes:  This type of reflex suppression although well accepted is not associated with and elucidated mechanism.

• ¹Opioid-induced suppression of somatic and autonomic reactions associated with endotracheal intubation: opioid administration permits endotracheal intubation without "bucking" or coughing, syndromes that can lead to hypoxemia, hemodynamic instability, hypercarbia and other pathophysiological conditions. 

  • Reduced lung volume is associated with bucking and this reduced lung volume along with disturbances in ventilatory pattern can result in nonphysiological gas exchange. 

  • Coughing and bucking on emergence might be expected in those patients who received a potent inhalational agent but did not receive opioids. 

  • Utilization of opioids, that is proper utilization, can lead to patient awakening without such problems even if the endotracheal tube remains in place.

• ¹Bronchomotor tone: opioids may prevent increased bronchomotor tone. 

  • These agents also are helpful in managing dyspnea and other respiratory manifestations associated with asthma and congestive heart failure. 

    • Fentanyl, which exhibits antihistaminergic, antiserotonergic, as well as antimuscarinic effects may be more effective than morphine for managing patients with asthma or bronchospastic disorders. 

    • Lastly, suctioning-induced tracheobronchial stimulation can induce a pulmonary vasoconstrictive response which may be prevented or reduced by opioids.

¹Opioids: Adverse Effects and Non-Therapeutic Effects

• ¹One of the prominent effects of opioids is respiratory depression. Opioid receptors have been found at high concentration in the number of sites in the brain, including the nucleus solitarius, nucleus retroambigualis, and nucleus ambiguus.  Opioid induced respiratory effects are mediated by specific chemosensitive brain regions.  Opioids also prevent normal physiological function in pontine and medullary respiratory centers.

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Attribution:  Dr. Al Ferguson, Queen's University at Kingston

• ¹-opioid receptors are stimulated by opioids, resulting dose-dependent respiratory depression by means of direct action on brain-stem respiratory centers.  CO₂ stimulatory effects on ventilation are diminished by opioids and in accordance with this finding, ventilatory slope and occlusion pressure responses to CO₂ are diminished with minute ventilatory responses to increases in PaCO₂ exhibit curve shifting to the right.  The apneic threshold and resting end-tidal PCO₂ are increased by opioids

"In this illustration, the slope of line A is approximately 2 L/min/mmHg, although wide range of responses in humans exists.  The slope of the ventilatory response to CO2 is reduced to 1 and 0.5 and lines B and C respectively.  Lines B and C are also shifted to the right of line A.   Line speed and see have the same intercept along the X axis, indicating no displacement or shift of line C compared with line B."  (Reference 1)

• ¹Hypoxic ventilatory drive is attenuated by the opioids with carotid body chemoreception and hypoxic drive also blunted or eliminated even by low, analgesic opioid doses. 

  • The increased respiratory drive associated with increasing airway resistance is also reduced by opioids. 

  • Dose-dependent reduction in spontaneous respiratory rate allows opioid titration to effect in the anesthetized patient. 

    • On the other hand, the extent of opioid-induced respiratory depression cannot be reliably judged by only observing respiratory rate, particularly in the postoperative environment. 

    • Elimination of spontaneous respiration by the opioids is not necessarily associated with loss of consciousness; therefore, individuals receiving high-dose opioids may be responsive to verbal commands even those which request that they breathe.

• ¹Opioid-induced influences on respiratory rhythm and pattern include the following changes:

  • Irregular and/or periodic breathing

  • Expiratory delay

  • Respiratory pausing

  • Alteration in tidal volume (decreased or increased)

• ¹Onset of respiratory depression following opioid administration:

  • Peak onset of respiratory depression following morphine (analgesic dose level) is slower than that observed following comparable fentanyl doses (the proportionality is about 30 minutes versus about seven minutes). 

    • Explanation for this difference references the lower lipid solubility associated with morphine;  this lower lipid solubility is responsible for morphine plasma concentrations in onset of action being nearly the same following IV versus IM administration. 

    • In the immediate postoperative timeframe, the use of morphine as an IV analgesic is therefore perhaps not the best choice.

  • Duration of respiratory depression:  small doses of morphine induce a respiratory depression that typically lasts longer than that observed following an equipotent fentanyl dose.

    • Another comparison involves IV fentanyl versus meperidine -- in that case IV fentanyl (100 and 200 g/70kg) administration induces respiratory depression that does not last as long as and equipotent meperidine dose (65-75 mg/70kg). 

      • In the same study, faster onset in peak effect following fentanyl was noted, compared to meperidine. 

      • The shorter onset include recovery associate with fentanyl compared to morphine and meperidine does not obviate the observation that small doses (2g/kg) induces respiratory depression that lasts for a rather longtime (> one hour). 

        • By contrast, sufentanil (0.1-0.4 g/kg) administration results in shorter-lasting respiratory depression but longer-lasting analgesia compared to fentanyl (1-4 g/kg).

  • Initial postoperative respiratory depression  is typically not observed when fentanyl (4-8 g/kg) is administered during induction; however, there is a possibility of significant respiratory depression noted five or more hours later. 

    • With higher doses of fentanyl (50-100g/kg) persistent respiratory depression may require ventilatory support for 6-18 hours.  Moreover, with intermediate dose levels (20-50 g/kg) the possibility of the need of postoperative mechanical ventilation should be considered.

• ¹Recovery of respiratory function

  • Alfentanil and sufentanil are associated with a more rapid recovery of respiratory function compared to fentanyl;  at least with fentanyl, a possible explanation at the molecular level is the more rapid dissociation of alfentanil from the receptor compared to other agents. 

    • This more rapid dissociation has been interpreted to possibly explain a decrease likelihood of respiratory depression.

  • With remifentanil, independent of dosage, and a residual effects dissipate extremely rapidly (5-15 minutes) following discontinuation of administration.

¹Factors that Influence Opioid-Induced Respiratory Depression

• ¹Duration and magnitude of respiratory depression following opioid administration can be influenced by a number of factors.

  • Factors that increase magnitude  and/or duration of opioid-induced respiratory depression include:

    • dose

    • Intermittent bolus (by contrast to continuous infusion)

    • Brain penetration/drug delivery

      • Distribution ( cardiac output)

      • Un-ionized fraction (respiratory alkalosis)

    • Reuptake from the brain (interoperative respiratory alkalosis)

    • Clearance (hepatic blood flow for example inter-abdominal surgery)

    • Secondary peaks in plasma opioid concentrations (reuptake of opioid from muscle, lung, fat, intestine reservoir)

    • Ionized opioid receptor site (postoperative respiratory acidosis)

    • Sleep

    • Age

    • Metabolic alkalosis

• ¹Sleep: Opioids potentiate the normal right shift of the PaCO₂-alveolar ventilation curve, observed during non-REM sleep. 

  • Respiratory, cognitive, and hemodynamic anomalies are probably responsible for the hypoxemia associated with sleep postoperative (several days). 

  • Natural sleep as well as morphine reduce the thoracic component of breathing with limited effect on the diaphragmatic component. 

  • Tonic and phasic upper airway muscle activity associated with breathing is also impair by sleep; this effect may be problematic one patients have an opioid-based anesthetic in the context of surgery which is associated with limited postoperative pain. 

    • In this eventuality, seemingly normal breathing while awake can transition to inadequate breathing during sleep. 

    • For those patients with impaired abdominal breathing or problems with their airway function (e.g.in significantly obese patients or in patients who exhibit sleep apnea), opioid analgesics may increase the probability of adverse respiratory events.

• ¹Age: Anesthetic and respiratory depressant effects of opioids are more apparent in older patients. 

  • Furthermore, older patients exhibit a higher opioid blood concentration as corrected for weight.  

  • More frequent incidences of apnea, periodic breathing is well as obstruction following morphine has been reported in older patients relative to young adults.

  • In neonates again with weight adjustment, morphine administration causes a greater degree of respiratory depression relative to the adult patient. 

    • This effect is probably due to a more ready penetration by morphine into the neonatal brain due to the underdeveloped blood-brain barrier. 

    • The sensitivity of morphine to the extent of blood brain barrier development is probably due to its relatively low intrinsic lipid-solubility  which would normally be limiting. 

    • By contrast, neonatal patients are not more sensitive to other more lipid-soluble opioid such as fentanyl, sufentanil, or meperidine; the intrinsic lipid solubility then would be more important than the status of the blood-brain barrier.

• ¹Effects of other drugs administered concurrently: opioid-induced respiratory depression would be enhanceed/prolonged if opioid administration is associated with administration of other CNS the presence which would include potent inhaled anesthetics, barbiturates, benzodiazepines, or ethanol.

  • Bradypnea are apnea can be induced by these drug interactions which depress ventilatory responses to hypercarbia and/or hypoxia.

    • Examples of agents which DO NOT enhance bradypnea or apnea in this setting include droperidol, scopolamine, and clonidine.

    • This conclusion was reached by noting that these agents do not increase fentanyl or other opioid-induced respiratory depression.

• ¹Pain: Respiratory depression may be influenced by pain and/or surgically-induced pain; however, some clinical research findings have not supported this assertion. 

  • (1) some postsurgical breathing patterns are not influenced by the level or type of pain relief. 

  • (2) sevoflurane-induced sedation that causes ventilatory response depression to hypoxemia is not reversed by acute pain.

• ¹Opioids and  Tolerance:

  • Some degree of acute tolerance to respiratory depression secondary to opioid administration can be noted rapidly. 

    • However, a longer period, perhaps one half-year of opioid exposure may be required to detect significant tolerance to respiratory-depressant opioid action on hypoxic ventilatory responses. 

      • Complicating the consideration is the observation that cross-tolerance to the respiratory depression action of differing opioids may be unpredictable and incomplete.

  • Abnormal physiological renal function can translate to abnormal opioid activity duration. 

    • This result occurs despite the conclusion that opioid action is mainly ended by redistribution and hepatic metabolism. 

    • The general idea is that greater respiratory depression can follow from the accumulation of morphine/meperidine/metabolites in the renal insufficiency case.

  • Postoperative respiratory depression following fentanyl (10 and 25 g/kg)  may be prolonged and enhanced by hypocapnic hyperventilation. 

    • The opposite consequence is associated with interoperative hypercarbia.  These results may be explained by the following:

    1. Increased brain opioid transfer to the brain would be expected with increased uncharged fentanyl (un-ionized)  associated with the hypocarbic state

    2. By contrast, increased removal may occur secondary to decrease cerebral blood flow with the hypocarbic state.

    3. Another factor might be reduced hepatic clearance secondary to reduced cardiac output with attenuated hepatic blood flow.

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• ⁵Substantia Gelatinosa Image:  Courtesy of The Digital Slice of Life, a cooperative project with the Slice of Life office, KUED Media Solutions, and the Knowledge Weavers Project.
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