Definitions

The opioids are addicting; that is, they produce a well-defined syndrome of repeated self-administration over time, tolerance to the effects of the drug, and an abstinence syndrome when the drug is no longer available. "Cross-tolerance" refers to the ability of any drug in the opioid class to produce similar effects and to block the abstinence syndrome associated with opioids in general. The primary effects of opiates are mediated through their action at the opioid mu, kappa, and delta receptors. Morphine, codeine, and thebaine are naturally occurring phenanthrene alkaloids in opium, the milky exudate from the unripe capsule of the poppy plant, Papaver somniferum. Raw opium contains 4-21% morphine and 0.7-2.5% codeine, and is refined to produce these medically useful products. In practice, most codeine is actually converted directly from morphine, which also can be used to produce hydromorphone (Dilaudid). Thebaine, found in very small concentrations in raw opium, is similar to morphine. It is converted into medically useful compounds such as codeine, hydrocodone (Vicodin), oxycodone (Percodan, Percocet, Tylox), oxymor-phone (Numorphan), nalbuphine (Nubain), and diacetylmorphine (heroin). Naloxone (Narcan) is also produced from morphine but lacks euphoric and analgesic properties; its use in humans is discussed later in this chapter. Etor-phine (M99), which is produced from thebaine, is a potent opioid useful mainly in the immobilization of large animals. Raw opium, morphine, codeine, and thebaine are referred to as naturally occurring opioids or opiates, whereas those compounds mentioned previously, which are produced directly from these naturally occurring compounds, are called semisynthetic opioids or opiates.

Attempts to synthesize opioid-like compounds have produced a variety of agents that are chemically distinct from morphine yet seem to act via similar mechanisms and also exhibit cross-tolerance. These include meperidine (Demerol), propoxyphene (Darvon), methadone (Dolophine), and levo-alpha-acetyl methadol (LAAM). Fentanyl (Sublimaze) and sufentanil (Sufenta) are very potent short-acting opioids used mainly in anesthesia. Buprenorphine, a partial mu agonist, is useful in the treatment of heroin addiction. These compounds are collectively referred to as the synthetic opioids.

With the exception of methadone and LAAM, most opiates have short half-lives. Extended release preparations of oxycodone (Oxycontin) and morphine (MSContin) have become increasingly popular in pain management, because they offer fewer peaks and troughs over 24 hours. Most opioids are legitimately used medically for pain relief; however, the addicting properties of opiates have prompted the search for a nonaddicting analgesic with the same potent pain-relieving properties as the opioids; unfortunately, this has not come to pass, and the following examples are known to produce dependence along with analgesia. Pentazocine (Talwin) and butorphanol (Stadol) produce anal gesia in the opioid-free individual but are addicting, and when given to someone who is opioid dependent produce an abstinence syndrome. The semisynthetic compound nalbuphine, mentioned earlier, has similar properties. Tramadol (Ultram), a synthetic aminocyclohexanol, binds to mu opioid receptors and also inhibits reuptake of norepinephrine and serotonin; there have been increasing reports of tramadol abuse.

Despite their similarities, opioids may have varying effects on opioid receptors. For example, the mu receptor is occupied preferentially by the classic morphine-like opioids, but butorphanol (Stadol) and nalbuphaine (Nubain) prefer the kappa receptor. Both receptors are highly specific, and an abstinence syndrome mediated by the kappa receptor will not be relieved if a mu receptor compound is administered. Like pentazocine, butorphanol, and tramadol, buprenorphine (Subutex) is a mixed opiate agonist-antagonist, with partial mu receptor agonism and full kappa agonism. Partial agonists show a "ceiling effect"; unlike full agonists, dose escalation does not produce ever-increasing pharmacological effects. There are also compounds that bind selectively to the receptor site, yet produce no agonistic action. These compounds are antagonistic in nature, because they occupy the receptor site and exclude agonist opioids; examples include naloxone (Narcan) and naltrexone (ReVia). These opioid antagonists, useful for the treatment of opioid intoxication and addiction, are discussed later. Relative to full agonists, partial agonists may act as antagonists. Also of interest is the discovery and description of endogenous opioid substances in humans, operating at the kappa receptor site along the spectrum from agonistic to antagonistic function. To date, no endogenous mu receptor opioid has been discovered (Jaffe, 1989).

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