DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Opioids, Analgesia, and
Pain Management
Tony L. Yaksh
and Mark S. Wallace
Pain is a component of virtually all clinical pathologies,
and management of pain is a primary clinical
imperative. Opioids are a mainstay of pain treatment,
but rational therapy may involve, depending upon the
pain state, one or more drug classes, such as NSAIDs,
anticonvulsants, and antidepressants. The properties of
these non-opioid agents are presented in Chapters 34,
21, and 15. This chapter focuses first on the biochemical,
pharmacological, and functional nature of the opioid
system that defines the effects of opioids on pain
processing, gastrointestinal-endocrine-autonomic functions,
and reward-addiction circuits. Subsequently, the
chapter presents principles that guide the use of opioid
and non-opioid agents in the management of clinical
pain states.
The term opiate refers to compounds structurally
related to products found in opium, a word derived from
opos, the Greek word for “juice,” natural opiates being
derived from the resin of the opium poppy, Papaver
somniferum. Opiates include the natural plant alkaloids,
such as morphine, codeine, thebaine, and many semisynthetic
derivatives. An opioid is any agent, regardless
of structure, that has the functional and pharmacological
properties of an opiate. Endogenous opioids, many
of which are peptides, are naturally occurring ligands
for opioid receptors found in animals. The term endorphin
is used synonymously with endogenous opioid
peptides but also refers to a specific endogenous opioid,
β-endorphin. The term narcotic was derived from
the Greek word narkotikos, for “benumbing” or “stupor.”
Although narcotic originally referred to any drug
that induced narcosis or sleep, the word has become
associated with opioids and is often used in a legal context
to refer to a variety of substances with abuse or
addictive potential.
History. The first undisputed reference to opium is found in the writings
of Theophrastus in the third century B.C. Arab physicians were
well-versed in the uses of opium; Arab traders introduced the drug
to the Orient, where it was employed mainly for the control of dysentery.
By 1680, Sydenham was lauding opium: “Among the remedies
which it has pleased Almighty God to give to man to relieve his sufferings,
none is so universal and so efficacious as opium.”
Opium contains >20 distinct alkaloids. In 1806, Frederich
Sertürner, a pharmacist’s assistant, reported the isolation by crystallization
of a pure substance in opium that he named morphine, after
Morpheus, the Greek god of dreams. By the middle of the 19th century,
the use of pure alkaloids in place of crude opium preparations began
to spread throughout the medical world, an event that coincided with
the development of the hypodermic syringe and hollow needle, permitting
direct delivery of such water-soluble formulations “under
the skin” into the body.
In addition to the remarkable beneficial effects of opioids,
the side effects and addictive potential of these drugs also have been
known for centuries. In the civil war in the U.S., the administration
of “soldier’s joy” often led to “soldier’s disease,” the opiate addiction
brought about by medication of chronic pain states arising from war
wounds. These problems stimulated a search for potent synthetic
opioid analgesics free of addictive potential and other side effects.
The early discovery of the synthetic product heroin by C.R. Alder
Wright in 1874 was followed by its widespread utilization as a
purportedly non-addictive cough suppressant and sedative.
Unfortunately, heroin and all subsequent synthetic compounds that
have been introduced into clinical use share the liabilities of classical
opioids, including their addictive properties. However, this search
for new opioid agonists led to the synthesis of opioid antagonists
and compounds with mixed agonist–antagonist properties, which
expanded therapeutic options and provided important tools for
exploring mechanisms of opioid actions.
Until the early 1970s, the effects of morphine, heroin, and
other opioids as anti-nociceptive and addictive agents, were well
described, but mechanisms mediating the interaction of the opioid
alkaloids with biological systems were unknown. In vivo and in vitro
physiological studies investigating the pharmacology of opiate agonists,
their antagonists, and cross-tolerance led to the hypothesis of
three separate opioid receptors: mu (μ), kappa (κ), and delta (δ)
(Martin et al., 1976). These results were paralleled by work showing
multiple radioligand binding sites for opiates on brain cell membranes
(Goldstein et al., 1971; Pert et al., 1973). The three-receptor
hypothesis was confirmed by subsequent cloning, which indicated