1. Variability in opioid dose needed to treat acute perioperative pain and chronic pain has been observed with all strong opioids (Fig. 19-5: The variability observed in morphine analgesic effect).
2. It is likely that the variability in opioid effect is related to both variability in pharmacokinetic-related and variability in pharmacodynamic-related parameters (genetic origin).
3. The safest approach to opioid analgesia is one of careful titration to analgesic effect during surgery and in the postoperative period, with acute awareness of the undesirable dose-related side effects. This admonition to carefully titrate the administration of opioids is perhaps even more crucial when administering long-acting opioids orally for the treatment of chronic pain.
   1. During anesthesia, one should be aware of hypotension and bradycardia, a common side effect of strong opioids.
   2. In the postoperative period, the most important side effects to be avoided are respiratory depression and severe sedation. Other non–life-threatening but important side effects in terms of patient satisfaction and health costs are nausea and vomiting and loss of bowel movement.
4. Morphine
   1. Although the initial onset of analgesia after IV administration of morphine occurs between 15 and 30 minutes, there is a lag of hours between peak plasma morphine concentration and peak analgesic effect (hysteresis).
   2. Given the long time to peak analgesia, a practical strategy for dosing morphine in adults is to give an initial morphine bolus dose 20 to 45 minutes before the end of surgery followed by 2-mg bolus doses postoperatively until visual analog pain scores decrease to ≤3 (on a scale from 0 to 10). At that point, the patient can be started on a PCA pump.
   3. Two considerations must accompany every postoperative acute pain plan.
      1. The postoperative analgesic regimen should be multimodal (i.e., use opioid-sparing drugs such as acetaminophen and nonsteroidal anti-inflammatory drugs).
      2. Some patients appear unresponsive to morphine, making it unwise to continue dosing. Instead, one should add an adjuvant drug (ketamine, clonidine) that is analgesic in its own right and enhances morphine's analgesic effect, presumably by reducing OIH.
5. Fentanyl is about 100 times more potent than morphine, and similar to all opioids, the analgesic response to IV fentanyl is highly variable. (Its lipophilic structure means it rapidly crosses the blood–brain barrier.)
   1. Fentanyl is used during anesthesia to dampen cardiovascular responses to noxious stimulation from laryngoscopy, intubation, skin incision, and surgical stress.
   2. On average, the requirements for inhalational anesthetics and propofol are reduced by about 50% when administering 1.5 to 3 µg/kg of IV fentanyl.
   3. A continuous infusion leads to the accumulation of the drug in the body as its 50% CSt½ increases rapidly with the duration of infusion (see Fig. 19-4: Context-sensitive half-times for remifentanil, fentanyl, and morphine). Similarly, frequent dosing of the drug may cause accumulation.
   4. Fentanyl is also used in the treatment of chronic pain (fentanyl patch, transcutaneous, transdermal, intranasal, sublingual). The home use of fentanyl in patients with chronic pain comes with the danger of misuse and abuse by the patients or by family members or friends (an increasing number of opioid fatalities).
6. Remifentanil (which is 100–200 times more potent than morphine) differs from the other strong opioids in its rapid onset and offset for all clinical effects, including respiration (Fig. 19-6: Effect of a short remifentanil infusion on breathing).
   1. Similar to other opioids, remifentanil displays large variability in effect among patients.
   2. The minimum alveolar concentration reduction observed with remifentanil use and its very short CSt½ make rapid awakening possible at the end of surgery (see Fig. 19-4: Context-sensitive half-times for remifentanil, fentanyl, and morphine).
   3. The occurrence of postoperative pain after remifentanil “fast-track” anesthesia is attributable to the rapid decline in µ-opioid concentration, causing a rapid decline in analgesic state combined with a persistence of OIH. Strategies to counteract this problem include starting morphine administration 30 to 45 minutes before the end of surgery or using a single fentanyl bolus of 50 µg or 0.125 mg/kg of ketamine at the end of surgery.

Opioids

1. Short History
2. The Endogenous Opioid System
3. Opioid Receptor Knockout Mice
4. Classification of Exogneous Opioids
5. Opioids Acting at Opioid and Nonopioid Receptors
6. Opioid Mechanisms
7. Routes of Administration
8. Pharmcokinetics (PK) and Pharmacodynamics (PD)
9. PKPD Models for Opioid Effect: which End Point Serves the Clinician Best?
10. Pharmacodynamics: Dose Effect on Pain Relief
11. Pharmacogenetics
12. Opioid-Induced Respiratory Depression
13. Other Opioid-Related Side Effects
14. Remifentanil for Obstetric Labor Pain
15. Gender Differences