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

systems. Although this research has led to advances in
understanding the physiology of pain, the standard medications
for severe pain remain the derivatives of the
opium poppy (opiates) and synthetic drugs that activate
the same receptors (opioids). Drugs modeled after
the endogenous opioid peptides may one day provide
more specific options for the treatment of pain, but none
of these currently is available for clinical use. Analgesic
medications that do not act at opioid receptors, such as
the nonsteroidal anti-inflammatory drugs (NSAIDs),
have an important role in mild to moderate types of pain,
but for severe pain, the opioid drugs are most effective.
Progress in pain control stems from a greater understanding
of the mechanism of tolerance to μ opiate
receptor–mediated analgesia, which involves NMDA
receptors (Trujillo and Akil, 1991). Experimentally, by
combining morphine with dextromethorphan, an NMDAreceptor
antagonist, tolerance is impaired and analgesia
is enhanced without an increase in the dose of opioid.
The subjective effects of opioid drugs are useful in the management
of acute pain. This is particularly true in high-anxiety situations,
such as the crushing chest pain of myocardial infarction,
when the relaxing, anxiolytic effects complement the analgesia.
Normal volunteers with no pain given opioids in the laboratory may
report the effects as unpleasant because of side effects such as nausea,
vomiting, and sedation. Patients with pain usually do not
develop abuse or addiction problems. Of course, patients receiving
opioids over time develop tolerance routinely, and if the medication
is stopped abruptly, they will show the signs of an opioid-withdrawal
syndrome, the evidence for physical dependence.
Opioids should never be withheld from patients with cancer
out of fear of producing addiction. If chronic opioid medication is
indicated, it is preferable to prescribe an orally active, slow-onset
opioid with a long duration of action. These qualities reduce the likelihood
of producing euphoria at onset and withdrawal symptoms as
the medication wears off. In selected patients, methadone is an excellent
choice for the management of chronic severe pain. Controlledrelease
oral morphine (MS CONTIN, others) and controlled-release
oxycodone (OXYCONTIN, others) are other possibilities. Rapid-onset,
short-duration opioids are excellent for acute short-term use, such
as during the postoperative period. As tolerance and physical
dependence develop, however, the patient may experience the early
symptoms of withdrawal between doses, and during withdrawal, the
threshold for pain decreases. Thus, for chronic administration, longacting
opioids are preferred. While methadone is long acting because
of its metabolism to active metabolites, the long-acting version of
oxycodone has been formulated to release slowly, thereby changing
a short-acting opioid into a long-acting one. Unfortunately, this
mechanism can be subverted by breaking the tablet and making the
full dose of oxycodone immediately available. This has led to diversion
of oxycodone to illicit traffic because high-dose oxycodone produces
euphoria that is sought by opiate abusers. The diversion of
prescription opioids such as oxycodone and hydrocodone to illegal
markets has become an important source of opiate abuse in the U.S.
The risk for addiction is highest in patients complaining of pain
with no clear physical explanation or in patients with evidence of a
chronic, non-life-threatening disorder. Examples are chronic headaches,
backaches, abdominal pain, or peripheral neuropathy. Even in these
cases, an opioid may be considered as a brief emergency treatment,
but long-term treatment with opioids should be used only after other
alternatives have been exhausted. In the relatively rare patient who
develops abuse, the transition from legitimate use to abuse often
begins when the patient returns to his physician earlier than scheduled,
asking for a new prescription, or visits emergency rooms of
multiple hospitals, complaining of acute pain and asking for an opioid
injection.
Heroin is the most frequently abused opiate. There
is no legal supply of heroin for clinical use in the U.S.
Despite claims that heroin has unique analgesic properties
for the treatment of severe pain, double-blind trials
have found it to be no more effective than hydromorphone.
However, heroin is widely available on the illicit
market, and its price dropped sharply in the 1990s, continuing
to the present, with purity increased 10-fold.
Previously, street heroin in the U.S. was highly diluted: Each
100-mg bag of powder had only ~4 mg heroin (range: 0-8 mg), and
the rest was filler such as quinine. In the mid-1990s, street heroin
reached 45-75% purity in many large cities, with some samples testing
as high as 90%. This increase in purity has led to increased levels
of physical dependence among heroin addicts. Users who
interrupt regular dosing develop more severe withdrawal symptoms.
Whereas heroin previously required intravenous injection, the more
potent supplies can be smoked or administered nasally (snorted),
making the initiation of heroin use accessible to people who would
not insert a needle into their veins. There is no accurate way to count
the number of heroin addicts, but based on extrapolation from overdose
deaths, number of applicants for treatment, and number of
heroin addicts arrested, the estimates range from 800,000 to 1 million
in the U.S.; based on a stratified national sample of adults, ~1 in 4
individuals who report any use of heroin become addicted (Anthony
et al., 1994). Recent law enforcement actions may presage the emergence
of a domestic supply of heroin precursor (raw opium) harvested
from Papaver somniferum grown in the Pacific Northwest of
the U.S. (Baer, 2009).
Tolerance, Dependence, and Withdrawal. Injection of a
heroin solution produces a variety of sensations described
as warmth, taste, or high and intense pleasure (“rush”)
often compared with sexual orgasm. There are some differences
among the opioids in their acute effects, with
morphine producing more of a histamine-releasing effect
and meperidine producing more excitation or confusion.
Even experienced opioid addicts, however, cannot distinguish
between heroin and hydromorphone in doubleblind
tests.
Thus, the popularity of heroin may be due to its availability on
the illicit market and its rapid onset. After intravenous injection, the
effects begin in less than a minute. Heroin has high lipid solubility,
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CHAPTER 24
DRUG ADDICTION