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

Pharmacological Interventions. Opioid withdrawal signs and
symptoms can be treated by three different approaches. The first
and most commonly used approach depends on cross-tolerance and
consists of transfer to a prescription opioid medication and then
gradual dose reduction. The same principles of detoxification apply
as for other types of physical dependence. It is convenient to
change the patient from a short-acting opioid such as heroin to a
long-acting one such as methadone. Detoxification and subsequent
maintenance of opiate dependence with methadone is specifically
limited to accredited opioid treatment programs (OTPs) and is regulated
by Federal Opioid Treatment Standards. The initial dose of
methadone is typically 20-30 mg. This is a test dose to determine
the level needed to reduce observed withdrawal symptoms. The
first day’s total dose then can be calculated depending on the
response and then reduced by 20% per day during the course of
detoxification.
A second approach to detoxification involves the use of oral
clonidine (CATAPRES, others), a medication approved only for the
treatment of hypertension. Clonidine is an α 2
adrenergic agonist that
decreases adrenergic neurotransmission from the locus ceruleus.
Many of the autonomic symptoms of opioid withdrawal such as nausea,
vomiting, cramps, sweating, tachycardia, and hypertension
result from the loss of opioid suppression of the locus ceruleus system
during the abstinence syndrome. Clonidine, acting upon distinct
receptors but by cellular mechanisms that mimic opioid effects, can
alleviate many of the symptoms of opioid withdrawal, but not the
generalized aches and opioid craving. When using clonidine to treat
withdrawal, the dose must be titrated according to the stage and
severity of withdrawal, beginning with 0.2 mg orally; postural
hypotension is commonly a side effect. A similar drug, lofexidine
(currently in clinical trials in the U.S.), has greater selectivity for α 2A
adrenergic receptors and is associated with less of the hypotension
that limits the usefulness of clonidine in this setting.
A third method of treating opioid withdrawal involves activation
of the endogenous opioid system without medication. The techniques
proposed include acupuncture and several methods of CNS
activation using transcutaneous electrical stimulation. While attractive
theoretically, this has not yet been found to be practical. Rapid
antagonist-precipitated opioid detoxification under general anesthesia
has received considerable publicity because it promises detoxification
in several hours while the patient is unconscious and not
experiencing withdrawal discomfort. A mixture of medications has
been used, but morbidity and mortality as reported in the lay press
are unacceptable, with no demonstrated advantage in long-term outcome
(Collins et al., 2005).
Long-Term Management. If patients are simply discharged from the
hospital after withdrawal from opioids, there is a high probability of
a quick return to compulsive opioid use. Addiction is a chronic disorder
that requires long-term treatment. Numerous factors influence
relapse. One factor is that the withdrawal syndrome does not end in
5-7 days. There are subtle signs and symptoms often called the
protracted withdrawal syndrome (Table 24–7) that persist for up to
6 months. Physiological measures tend to oscillate as though a new
set point were being established; during this phase, outpatient drugfree
treatment has a low probability of success, even when the patient
has received intensive prior treatment while protected from relapse
in a residential program.
The most successful treatment for heroin addiction consists
of stabilization on methadone in accordance with state and federal
regulations. Patients who relapse repeatedly during drug-free
treatment can be transferred directly to methadone without requiring
detoxification. The dose of methadone must be sufficient to prevent
withdrawal symptoms for at least 24 hours. The introduction of
buprenorphine, a partial agonist at μ opioid receptors (Chapter 18),
represents a major change in the treatment of opiate addiction. This
drug produces minimal withdrawal symptoms when discontinued
and has a low potential for overdose, a long duration of action, and
the ability to block heroin effects. Treatment can take place in a qualified
physician’s private office rather than in a special center, as
required for methadone. When taken sublingually, buprenorphine
(SUBUTEX) is active, but it also has the potential to be dissolved and
injected (abused). A buprenorphine-naloxone combination (SUBOX-
ONE) is also available. When taken orally (sublingually), the naloxone
moiety is not effective, but if the patient abuses the medication
by injecting, the naloxone will block or diminish the subjective high
that could be produced by buprenorphine alone.
Agonist or Partial-Agonist Maintenance. Patients receiving
methadone or buprenorphine will not experience the ups and downs
produced by heroin (Figure 24–4). Drug craving diminishes and may
disappear. Neuroendocrine rhythms eventually are restored (Kreek et
al., 2002). Because of cross-tolerance (from methadone to heroin),
patients who inject street heroin report a reduced effect from usual
heroin doses. This cross-tolerance effect is dose-related, so higher
methadone maintenance doses result in less illicit opioid use, as
determined by random urine testing. Buprenorphine, as a partial agonist,
has a ceiling effect at ~16 mg of the sublingual tablet equaling
no more than 60 mg methadone. If the patient has a higher level of
physical dependence, a full agonist (methadone) must be used.
Patients become tolerant to the sedating effects of methadone and
can attend school or function in a job. Opioids also have a persistent,
mild, stimulating effect noticeable after tolerance to the sedating
effect, such that reaction time is quicker and vigilance is increased
while on a stable dose of methadone.
Antagonist Treatment. Another pharmacological option is opioid
antagonist treatment. Naltrexone (REVIA, others; Chapter 18) is an
antagonist with a high affinity for the μ opioid receptor (MOR); it
will competitively block the effects of heroin or other MOR agonists.
Naltrexone has almost no agonist effects of its own and will
not satisfy craving or relieve protracted withdrawal symptoms. For
these reasons, naltrexone treatment does not appeal to the average
heroin addict, but it can be used after detoxification for patients with
high motivation to remain opioid-free. Physicians, nurses, and pharmacists
who have frequent access to opioid drugs make excellent
candidates for this treatment approach. A depot formulation of naltrexone
that provides 30 days of medication after a single injection
(VIVITROL) has been approved for the treatment of alcoholism. This
formulation eliminates the necessity of daily pill-taking and prevent
relapse when the recently detoxified patient leaves a protected
environment.
Cocaine and Other Psychostimulants
Cocaine. More than 23 million Americans have used
cocaine at some time. Although chronic use and use by
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CHAPTER 24
DRUG ADDICTION