29.25 Opioid Receptor Antagonists: Naltrexone, Nalmefene, and Naloxone
1005
in the United States. Nalmefene (Revex) is an opioid receptor
antagonist that is sometimes used in the management of alcohol
dependence.
Pharmacological Actions
Oral opioid receptor antagonists are rapidly absorbed from
the gastrointestinal (GI) tract, but because of first-pass hepatic
metabolism, only 60 percent of a dose of naltrexone and 40 to
50 percent of a dose of nalmefene reach the systemic circula-
tion unchanged. Peak concentrations of naltrexone and its
active metabolite, 6-
b
-naltrexol, are achieved within 1 hour of
ingestion. The half-life of naltrexone is 1 to 3 hours and the
half-life of 6-
b
-naltrexol is 13 hours. Peak concentrations of
nalmefene are achieved in about 1 to 2 hours, and the half-life is
8 to 10 hours. Clinically, a single dose of naltrexone effectively
blocks the rewarding effects of opioids for 72 hours. Traces of
6-
b
-naltrexol may linger for up to 125 hours after a single dose.
Naltrexone and nalmefene are competitive antagonists of
opioid receptors. Understanding the pharmacology of opioid
receptors can explain the difference in adverse effects caused
by naltrexone and nalmefene. Opioid receptors in the body
are typed pharmacologically as
m
,
k
, or
d
. Whereas activa-
tion of the
k
- and
d
-receptors is thought to reinforce opioid
and alcohol consumption centrally, activation of
m
-receptors is
more closely associated with central and peripheral antiemetic
effects. Because naltrexone is a relatively weak antagonist of
k
-
and
d
-receptors and a potent
m
-receptor antagonist, dosages of
naltrexone that effectively reduce opioid and alcohol consump-
tion also strongly block
m
-receptors and therefore may cause
nausea. Nalmefene, in contrast, is an equally potent antagonist
of all three opioid receptor types, and dosages of nalmefene
that effectively reduce opioid and alcohol consumption have no
particularly increased effect on
m
-receptors. Thus, nalmefene is
associated clinically with few GI adverse effects.
Naloxone has the highest affinity for the
m
-receptor but is a
competitive antagonist at the
m
-,
k
-, and
d
-receptors.
Whereas the effects of opioid receptor antagonists on opioid
use are easily understood in terms of competitive inhibition of
opioid receptors, the effects of opioid receptor antagonists on
alcohol dependence are less straightforward and probably relate
to the fact that the desire for and the effects of alcohol consump-
tion appear to be regulated by several neurotransmitter systems,
both opioid and nonopioid.
Therapeutic Indications
The combination of a cognitive-behavioral program plus use of
opioid receptor antagonists is more successful than either the
cognitive-behavioral program or use of opioid receptor antago-
nists alone. Naltrexone is used as a screening test to ensure that
the patient is opioid-free before the induction of therapy with
naltrexone (see “Naloxone Challenge Test” in Table 29.25-1).
Opioid Dependence
Patients in detoxification programs are usually weaned from
potent opioid agonists such as heroin over a period of days to
weeks, during which emergent adrenergic withdrawal effects are
treated as needed with clonidine (Catapres). A serial protocol is
sometimes used in which potent agonists are gradually replaced
by weaker agonists followed by mixed agonist–antagonists and
then finally by pure antagonists. For example, an abuser of the
potent agonist heroin would switch first to the weaker agonist
methadone (Dolophine), then to the partial agonist buprenor-
phine (Buprenex) or levomethadyl acetate (ORLAAM)—commonly called LAAM—and finally, after a 7- to 10-day
washout period, to a pure antagonist, such as naltrexone or
nalmefene. However, even with gradual detoxification, some
persons continue to experience mild adverse effects or opioid
withdrawal symptoms for the first several weeks of treatment
with naltrexone.
As the opioid receptor agonist potency diminishes, so do the
adverse consequences of discontinuing the drug. Thus, because
there are no pharmacological barriers to discontinuation of pure
opioid receptor antagonists, the social environment and frequent
cognitive-behavioral intervention become extremely important
factors supporting continued opioid abstinence. Because of
poorly tolerated adverse symptoms, most persons not simulta-
neously enrolled in a cognitive-behavioral program stop taking
opioid receptor antagonists within 3 months. Compliance with
the administration of an opioid receptor antagonist regimen can
also be increased with participation in a well-conceived voucher
program.
Table 29.25-1
Naloxone (Narcan) Challenge Test
The naloxone challenge test should not be performed in
a patient showing clinical signs or symptoms of opioid
withdrawal or in a patient whose urine contains opioids. The
naloxone challenge test may be administered by either the
intravenous (IV) or the subcutaneous route.
IV challenge:
After appropriate screening of the patient, 0.8 mg
of naloxone should be drawn into a sterile syringe. If the IV
route of administration is selected, 0.2 mg of naloxone should
be injected, and while the needle is still in the patient’s vein,
the patient should be observed for 30 seconds for evidence
of withdrawal signs or symptoms. If there is no evidence of
withdrawal, the remaining 0.6 mg of naloxone should be
injected and the patient observed for an additional 20 minutes
for signs and symptoms of withdrawal.
Subcutaneous challenge:
If the subcutaneous route is selected,
0.8 mg should be administered subcutaneously and the
patient observed for signs and symptoms of withdrawal for
20 minutes.
Conditions and technique for observation of patient:
During
the appropriate period of observation, the patient’s vital signs
should be monitored, and the patient should be monitored for
signs of withdrawal. It is also important to question the patient
carefully. The signs and symptoms of opioid withdrawal
include, but are not limited to, the following:
Withdrawal signs:
Stuffiness or running nose, tearing,
yawning, sweating, tremor, vomiting, or piloerection
Withdrawal symptoms:
Feeling of temperature change,
joint or bone and muscle pain, abdominal cramps, and
formication (feeling of bugs crawling under skin)
Interpretation of the challenge: Warning
—the elicitation of the
enumerated signs or symptoms indicates a potential risk for
the subject, and naltrexone should not be administered. If
no signs or symptoms of withdrawal are observed, elicited,
or reported, naltrexone may be administered. If there is any
doubt in the observer’s mind that the patient is not in an
opioid-free state or is in continuing withdrawal, naltrexone
should be withheld for 24 hours and the challenge repeated.
