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

cells of the immune system and indirectly through centrally mediated
neuronal mechanisms (Sharp and Yaksh, 1997). The acute central
immunomodulatory effects of opioids may be mediated by activation
of the sympathetic nervous system; the chronic effects of opioids
may involve modulation of the hypothalamic-pituitary-adrenal
(HPA) axis (Mellon and Bayer, 1998).
Direct effects on immune cells may involve unique, incompletely
characterized variants of the classical neuronal opioid receptors,
with MOR variants being most prominent (Sharp and Yaksh,
1997). Atypical receptors could account for the fact that it has been
very difficult to demonstrate significant opioid binding on immune
cells despite the observance of robust functional effects. In contrast,
morphine-induced immune suppression largely is abolished in
knockout mice lacking the receptor gene, suggesting that the receptor
is a major target of morphine’s actions on the immune system
(Gaveriaux-Ruff et al., 1998). A proposed mechanism for the
immune suppressive effects of morphine on neutrophils is through a
nitric oxide–dependent inhibition of NF-kB activation (Welters et al.,
2000). Others have proposed that the induction and activation of
MAP kinase also may play a role (Chuang et al., 1997).
Overall, the effects of opioids appear to be modestly immunosuppressive,
and increased susceptibility to infection and tumor
spread have been observed. In some situations, immune effects
appear more prominent with acute administration than with chronic
administration, which could have important implications for the care
of the critically ill (Sharp and Yaksh, 1997). In contrast, opioids have
been shown to reverse pain-induced immunosuppression and
increase tumor metastatic potential in animal models (Page and Ben-
Eliyahu, 1997). Therefore, opioids may either inhibit or augment
immune function depending on the context in which they are used.
These studies also indicate that withholding opioids in the presence
of pain in immunocompromised patients actually could worsen
immune function. Taken together, these studies indicate that opioidinduced
immune suppression may be clinically relevant both to the
treatment of severe pain and in the susceptibility of opioid addicts to
infection (e.g., human immunodeficiency virus (HIV) infection and
tuberculosis). Different opioid agonists also may have unique
immunomodulatory properties. Better understanding of these properties
eventually should help to guide the rational use of opioids in
patients with cancer or at risk for infection or immune compromise.
Temperature Regulation. Opioids alter the equilibrium point of the
hypothalamic heat-regulatory mechanisms such that body temperature
usually falls slightly. Systematic studies have shown that MOR agonists
such as alfentanil and meperidine, acting in the CNS, will result
in slightly increased thresholds for sweating and significantly lower the
threshold temperatures for evoking vasoconstriction and shivering
(Sessler, 2008). In precipitated withdrawal, elevated body temperatures
are observed, an observation consistent with the report that chronic
high dosage may increase body temperature (Martin, 1983).
FUNCTIONAL OPIOID DRUG TYPES
Most of the clinically used opioid agonists presented
below are relatively selective for MOR. They produce
analgesia, affect mood and rewarding behavior, and
alter respiratory, cardiovascular, GI, and neuroendocrine
function. KOR agonists, with few exceptions (e.g.,
butorphanol), are not typically employed for long-term
therapy since they may produce dysphoric and psychotomimetic
effects. DOR agonists, while analgesic in
animal models, have not found clinical utility, and NOR
agonists have largely proven to lack analgesic effects.
Opiates that are relatively receptor selective at lower
doses will interact with additional receptor types when
given at high doses. This is especially true as doses are
escalated to overcome tolerance.
The mixed agonist–antagonist agents frequently
interact with more than one receptor class at usual clinical
doses. The actions of these drugs are particularly
interesting because they may act as an agonist at one
receptor and as an antagonist at another. Mixed
agonist–antagonist compounds were developed with the
hope that they would have less addictive potential and
less respiratory depression than morphine and related
drugs. In practice, however, for the same degree of analgesia,
the same intensity of side effects occurs. A “ceiling
effect” limiting the amount of analgesia attainable
often is seen with these drugs, such as buprenorphine,
which is approved for the treatment of opioid dependence.
Some mixed agonist–antagonist drugs, such as
pentazocine and nalorphine (not available in the U.S.),
can precipitate withdrawal in opioid-tolerant patients.
For these reasons, except for the sanctioned use of
buprenorphine to manage opioid addiction, the clinical
use of these mixed agonist–antagonist drugs is generally
limited.
The dosing guidelines and duration of action for
the numerous drugs that are part of opioid therapy are
summarized in Table 18–2.
MORPHINE AND STRUCTURALLY
RELATED AGONISTS
Even though there are many compounds with pharmacological
properties similar to those of morphine, morphine
remains the standard against which new
analgesics are measured.
Source and Composition of Opium
Because the synthesis of morphine is difficult, the drug still is
obtained from opium or extracted from poppy straw. Opium is
obtained from the unripe seed capsules of the poppy plant, Papaver
somniferum. The milky juice is dried and powdered to make powdered
opium, which contains a number of alkaloids. Only a few—
morphine, codeine, and papaverine—have clinical utility. These
alkaloids can be divided into two distinct chemical classes, phenanthrenes
and benzylisoquinolines. The principal phenanthrenes are
morphine (10% of opium), codeine (0.5%), and thebaine (0.2%).
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CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT