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

produces a demonstrable antitussive effect, and higher
doses produce even more suppression of chronic cough.
A few other antitussive agents are noted below.
Dextromethorphan
Dextromethorphan (D-3-methoxy-N-methylmorphinan) is the D-isomer
of the codeine analog methorphan; however, unlike the L-isomer,
it has no analgesic or addictive properties and does not act
through opioid receptors. The drug acts centrally to elevate the
threshold for coughing. Its effectiveness in patients with pathological
cough has been demonstrated in controlled studies; its potency is
nearly equal to that of codeine. Compared with codeine, dextromethorphan
produces fewer subjective and GI side effects
(Matthys et al., 1983). In therapeutic dosages, the drug does not
inhibit ciliary activity, and its antitussive effects persist for 5-6 hours.
Its toxicity is low, but extremely high doses may produce CNS
depression.
Sites that bind dextromethorphan with high affinity have been
identified in membranes from various regions of the brain (Craviso
et al., 1983). Although dextromethorphan is known to function as an
NMDA-receptor antagonist, the dextromethorphan binding sites are
not limited to the known distribution of NMDA receptors (Elliott et
al., 1994). Thus, the mechanism by which dextromethorphan exerts
its antitussive effect still is not clear.
The average adult dosage of dextromethorphan hydrobromide
is 10-30 mg three to six times daily, not to exceed 120 mg daily. The
drug is marketed for over-the-counter sale in liquids, syrups, capsules,
soluble strips, lozenges, and freezer pops or in combinations with
antihistamines, bronchodilators, expectorants, and decongestants.
An extended-release dextromethorphan suspension (DELSYM) is
approved for twice daily administration.
Two other antitussives not currently recognized as generally
safe and effective (GRAS/E) by the FDA, carbetapentane
(pentoxyverine) and caramiphen, are known to bind avidly to the
dextromethorphan binding sites; codeine, levopropoxyphene, and
other antitussive opioids (as well as naloxone) do not bind. Although
noscapine (discussed later) enhances the affinity of dextromethorphan,
it appears to interact with distinct binding sites (Karlsson et al.,
1988). The relationship of these binding sites to antitussive actions
is not known; however, these observations, coupled with the ability
of naloxone to antagonize the antitussive effects of codeine but not
those of dextromethorphan, indicate that cough suppression can be
achieved by a number of different mechanisms.
Other Antitussives
Pholcodine [3-O-(2-morpholinoethyl) morphine] is used clinically in
many countries outside the U.S. Although structurally related to the
opioids, pholcodine has no opioid-like actions because the substitution
at the 3-position is not removed by metabolism. Pholcodine
is at least as effective as codeine as an antitussive; it has a long t 1/2
and
can be given once or twice daily.
Benzonatate (TESSALON, others) is a long-chain polyglycol
derivative chemically related to procaine and believed to exert its
antitussive action on stretch or cough receptors in the lung, as well
as by a central mechanism. It is available in oral capsules and the
dosage is 100 mg three times daily; doses as high as 600 mg daily
have been used safely.
ROUTES OF ANALGESIC DRUG
ADMINISTRATION
In addition to the traditional oral and parenteral formulations
for opioids, many other methods of administration
have been developed in an effort to improve
therapeutic efficacy while minimizing side effects.
These alternative routes generally improve the ease of
use of opioids and some increase patient satisfaction.
Patient-Controlled Analgesia (PCA)
With this modality, the patient has limited control of
the dosing of opioid from an infusion pump programmed
within tightly mandated parameters. PCA can
be used for intravenous, epidural, or intrathecal administration
of opioids. This technique avoids delays inherent
in administration by a caregiver and generally
permits better alignment between pain control and individual
differences in pain perception and responsiveness
to opioids. The PCA technique also gives the
patient a greater sense of control over the pain. With
shorter-acting opioids, serious toxicity or excessive use
rarely occurs; however, caution is warranted due to the
potential for serious medication errors associated with
this delivery method. PCA is suitable for adults and
children capable of understanding the principles
involved. It is generally conceded that PCA is preferred
over intramuscular injections for postoperative pain
control.
Spinal Delivery
Administration of opioids into the epidural or intrathecal
space provides more direct access to the first painprocessing
synapse in the dorsal horn of the spinal cord.
This permits the use of doses substantially lower than
those required for oral or parenteral administration
(Table 18–3). Systemic side effects of opoid administration
thus are decreased. In postoperative pain management
sustained release epidural injections are accomplished
through the incorporation of morphine into a liposomal
formulation (DEPODUR), providing up to 48 hours of
pain relief (Hartrick and Hartrick, 2008). The management
of chronic pain with spinal opiates has been
addressed by the use of chronically implanted intrathecal
catheters connected to subcutaneously implanted
refillable pumps (Wallace and Yaksh, 2000).
Though they have important therapeutic uses, epidural and
intrathecal opioids have their own dose-dependent side effects, such
as pruritis, nausea, vomiting, respiratory depression, and urinary
retention. Hydrophilic opioids such as morphine (DURAMORPH, others)
513
CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT