Page 581 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 31 Opioid Agonists & Antagonists 567

some of these drug interactions and the reasons for not combining when analgesic tolerance or intolerable side effects have developed
the named drugs with opioids. with the use of increasing doses of morphine or hydromorphone,
“opioid rotation” to methadone has provided superior analgesia at
10–20% of the morphine-equivalent daily dose. In contrast to its
■ SPECIFIC AGENTS use in suppressing symptoms of opioid withdrawal, use of metha-
done as an analgesic typically requires administration at intervals
of no more than 8 hours. However, given methadone’s highly
The following section describes the most important and widely
used opioid analgesics, along with features peculiar to specific variable pharmacokinetics and long half-life (25–52 hours), initial
agents. Data about doses approximately equivalent to 10 mg of administration should be closely monitored to avoid potentially
intramuscular morphine, oral versus parenteral efficacy, dura- harmful adverse effects, especially respiratory depression. Because
tion of analgesia, and intrinsic activity (maximum efficacy) are methadone is metabolized by CYP2B6 and CYP3A4 isoforms in
presented in Table 31–2. the liver, inhibition of its metabolic pathway or hepatic dysfunc-
tion has also been associated with overdose effects, including
respiratory depression or, more rarely, prolonged QT-based cardiac
STRONG AGONISTS arrhythmias.
Methadone is widely used in the treatment of opioid misuse.
Phenanthrenes Tolerance and physical dependence develop more slowly with
methadone than with morphine. The withdrawal signs and symp-
Morphine, hydromorphone, and oxymorphone are strong ago- toms occurring after abrupt discontinuance of methadone are
nists useful in treating severe pain. These prototypic agents have milder, although more prolonged, than those of morphine. These
been described in detail above. properties make methadone a useful drug for detoxification and
for maintenance of the chronic relapsing heroin addict.
N
10 17 CH 3 For detoxification of a heroin-dependent addict, low doses of
1 CH 2
methadone (5–10 mg orally) are given two or three times daily for
CH 2 7 2 or 3 days. Upon discontinuing methadone, most addicts experi-
3 6 ence a mild but endurable withdrawal syndrome.
HO O OH
For maintenance therapy of the opioid recidivist, tolerance to
Morphine
50–100 mg/d of oral methadone may be deliberately produced; in
Heroin (diamorphine, diacetylmorphine) is potent and fast- this state, the addict experiences cross-tolerance to heroin, which
acting, but its use is prohibited in the USA and Canada. In recent prevents most of the addiction-reinforcing effects of heroin. One
years, there has been considerable agitation to revive its use. rationale of maintenance programs is that blocking the reinforce-
However, double-blind studies have not supported the claim that ment obtained from misuse of illicit opioids removes the drive to
heroin is more effective than morphine in relieving severe chronic obtain them, thereby reducing criminal activity and making the
pain, at least when given by the intramuscular route. addict more amenable to psychiatric and rehabilitative therapy.
The pharmacologic basis for the use of methadone in maintenance
Phenylheptylamines programs is sound and the sociologic basis is rational, but some
methadone programs fail because nonpharmacologic management
Methadone has undergone a dramatic revival as a potent and is inadequate.
clinically useful analgesic. It can be administered by the oral, intra- The concurrent administration of methadone to heroin addicts
venous, subcutaneous, spinal, and rectal routes. It is well absorbed known to be recidivists has been questioned because of the
from the gastrointestinal tract, and its bioavailability far exceeds increased risk of overdose death secondary to respiratory arrest. As
that of oral morphine. the number of patients prescribed methadone for persistent pain
has increased, so, too, has the incidence of accidental overdose
and complications related to respiratory depression. Variability
N
in methadone metabolism, protein binding, distribution, and
O nonlinear opioid dose conversion all play a role in adverse events.
Buprenorphine, a partial μ-receptor agonist with long-acting
properties, has been found to be effective in opioid detoxification
and maintenance programs and is presumably associated with a
Methadone
lower risk of such overdose fatalities.
Methadone is not only a potent μ-receptor agonist but its
racemic mixture of d- and l-methadone isomers can also block Phenylpiperidines
both NMDA receptors and monoaminergic reuptake transporters.
These nonopioid receptor properties may help explain its ability Fentanyl is one of the most widely used agents in the family
to relieve difficult-to-treat pain (neuropathic, cancer pain), espe- of synthetic opioids. The fentanyl subgroup now includes suf-
cially when a previous trial of morphine has failed. In this regard, entanil, alfentanil, and remifentanil in addition to the parent