1. Opium is among the oldest drugs in the world. (Fossilized opium poppies have been found in Neanderthal excavation sites dating back to 30,000 BCE).
   1. The first written reference to the medicinal use of the opium poppy is described in a Sumerian text dated near 4,000 BCE.
   2. Just over 200 years ago, the German pharmacist and chemist Friedrich Sertürner isolated a stable alkaloid crystal from the opium sap and named it “morphine” after the Greek god of dreams, Morpheus.
      1. Morphine was tenfold more potent than opium and soon replaced it, not only for the treatment of severe pain but also for a myriad of other purposes such as cough and diarrhea.
      2. After the invention of the hypodermic syringe in the 1850s, the Englishman Alexander Wood was the first to inject morphine in a controlled fashion.
      3. Morphine revolutionized the treatment of the wounded in battlefield medicine, but its euphoric and addictive properties led to the addiction of thousands of soldiers to morphine during the American Civil War.
2. The synthesis of heroin in 1874 was based on the empirical finding that boiling morphine with specific acids caused the replacement of the two morphine —OH groups by —OCOH₃ producing diamorphine or heroin (Fig. 19-1: Chemical structure of common opioids).
3. In 1937, meperidine (pethidine) became the first synthetic opioid synthesized based on the central structure of morphine. Since then, many synthetic and semisynthetic opioids have been produced, including the clinically important opioid antagonists naloxone and naltrexone, by replacing the N-methyl substituent in morphine with allyl and cyclopropylmethyl groups, respectively (see Fig. 19-1: Chemical structure of common opioids).
4. For clinical use during anesthesia, the most important opioids are the piperidines fentanyl, sufentanil, alfentanil, and remifentanil. These opioids produce potent analgesia and suppression of cardiovascular responses to noxious stimulation from surgery with predictable pharmacokinetics and pharmacodynamics.
   1. The continued development of opioids with complex simultaneous actions at opioid and nonopioid target sites is facilitated by new information gained about mechanisms involved in endogenous pain and analgesia as well as advances in pain-related pharmacology.
   2. Development of new opioids is also driven by concerns that the side effect profile of potent opioids, which presents a serious risk to patients, needs to be minimized.

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