1. Mechanism of Opioid Analgesia
   1. Opioids modify both nociception (reception of signals in the CNS) and the perception of a noxious stimulus (emotional coloring of pain).
   2. Different types of peripheral sensory nociceptors, often free nerve endings, are stimulated by tissue damage, and the resulting pain information is transmitted to the spinal cord by two types of small-diameter peripheral afferent fibers: slow conducting, unmyelinated C fibers (which cause a dull burning pain) and faster, thinly myelinated Aδ fibers (which cause sharp, pricking pain).
   3. µ-Opioid–induced analgesia and descending inhibitory pathways may be activated not only by exogenous opioids but also by activation of endogenous opioid systems.
      1. Stress-induced analgesia . The endogenous opioid system is activated under stressful conditions, as demonstrated by the delayed onset of pain by soldiers wounded in battle.
      2. Placebo-induced analgesia. The endogenous opioid system also mediates placebo-induced analgesia, a reduction of pain resulting from an expectation of pain relief.
      3. Conditioning pain modulation (CPM) is a condition in which pain arising from a noxious stimulus applied to one part of the body is decreased by application of a second remote noxious stimulus. CPM is caused by the activation of descending inhibitory pathways.
2. Peripheral Opioid Analgesia
   1. Opioids are involved in peripheral analgesia by acting directly on sensory neurons (Aδ and C fibers) to inhibit pain signal transmission (important in inflammatory pain).
   2. The immune system is also widely involved in peripheral analgesia (opioid receptors are located not only on neurons but also on immune cells, such as human leukocytes (Fig. 19-3: Schematic diagram illustrating the role of opioids in analgesia of peripheral inflammation).
3. Opioid-Induced Hyperalgesia and Tolerance
   1. Opioids can induce the paradoxical effect of OIH (increase in pain sensitivity), which may limit the analgesic effects of opioids.
   2. During long-term or high-dose opioid treatment, rapid opioid dose escalation, or administration of an opioid with rapid onset and offset (e.g., remifentanil), a paradoxical increase in pain accompanies the treatment escalation. The high incidence of OIH after remifentanil infusions may be related to its rapid offset of analgesia. To prevent severe pain responses after remifentanil-based anesthesia, administration of morphine (0.1–0.25 mg/kg) 45 to 60 minutes before the end of surgery is advisable.
   3. OIH is not the same phenomenon as opioid tolerance.
      1. Acute opioid tolerance caused by tachyphylaxis requires increasing doses of the opioid to reach a specific analgesic end point during the initial hours of opioid treatment.
      2. Chronic tolerance, often seen in opioid abusers, occurs over days and manifests as a decreasing analgesic effect, resulting in dose escalation and increasing the likelihood of OIH.

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