Nontherapeutic Effects

Endogenous opioid peptides are widely distributed in brainstem nuclei regulating respiration. All μ receptor-stimulating opioids cause dose-dependent depression of respiration in humans primarily through a direct action on brainstem respiratory centers.^[159] How the various respiratory centers involved with ventilatory drive, respiratory rhythm generation, chemoreception, and neural integration are affected by opioids is unclear.

The stimulatory effect of CO₂ on ventilation is significantly reduced by opioids. The hypercapneic response can be separated into the central component and the peripheral component. Morphine-induced changes in the central component were equal in men and women, whereas changes in the peripheral component were greater in women.^[160] In addition, the apneic threshold and resting end-tidal PCO₂ are increased by opioids ( Fig. 11-8 ). Opioids also decrease hypoxic ventilatory drive.

The respiratory rate is usually drastically slowed in opioid overdose, although hypoxic CNS insult can counter this effect. The prolonged expiratory time in the respiratory cycle induced by opioids frequently results in greater reductions in respiratory rate than in tidal volume. A recent report demonstrated that monitoring of breath intervals can sensitively detect fentanyl-induced respiratory depression and can be used as a measure of dynamic opioid effect.^[161] High doses of opioids usually eliminate spontaneous respirations without necessarily producing unconsciousness. Patients receiving high doses of opioids may still be responsive to verbal commands and often will breathe when directed to do so.

The peak onset of respiratory depression after an analgesic dose of morphine is slower than after comparable doses of fentanyl: 30 ± 15 minutes versus 5 to 10 minutes. Respiratory depression induced by small doses of morphine usually lasts longer than after equipotent doses of fentanyl. Sufentanil (0.1–0.4 µg/kg) produces shorter-lasting respiratory depression and longer-lasting analgesia than fentanyl (1.0–4.0 µg/kg).^[162] Plasma fentanyl concentrations of 1.5 to 3.0 ng/mL are usually associated with significant decreases in CO₂ responsiveness. With higher doses of fentanyl (50–100 µg/kg), respiratory depression can persist for many hours. When moderately large (20–50 µg/kg) or greater doses of fentanyl are used, the potential need for postoperative mechanical ventilation should be anticipated. Although adequate spontaneous

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Figure 11-8 Influence of morphine administration (bolus dose of 100 µg/kg given at time 0 minutes, followed by a continuous infusion of 30 µg/kg/hour) on resting inspired minute ventilation and resting pressure of end-tidal CO₂ (P_ET CO₂ ) in a single subject. A one-component exponential was fitted to the data. The estimated time constant for the V_i data is 3.0 minutes and for P_ET CO₂ data is 2.6 minutes. The time delays are between 1 and 2 minutes. (From Sarton E, Teppema L, Dahan A: Sex differences in morphine-induced ventilatory depression reside within the peripheral chemoreflex loop. Anesthesiology 90:1329–1338, 1999.)

Although the mechanism by which pain modulates ventilatory control is unknown, clinical daily practice provides indirect evidence that pain stimulates ventilation, especially during emergence from anesthesia. Combes and coworkers demonstrated that pain relief with nerve block in patients after knee surgery, who were previously treated with morphine PCA, increases the incidence of abnormal respiratory events associated with oxygen desaturation.^[165] Naloxone has been accepted as a standard therapy for opioid-induced respiratory depression. However, there have been reports of naloxone-resistant respiratory depression after intrathecal or epidural opioids.^{[166] [167]}