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

peripheral sites led to the development of agents that have poor CNS
bioavailability such as methylnaltrexone (RELISTOR).
Pharmacological Properties
If endogenous opioid systems have not been activated,
the profile of opioid antagonist effects depend the presence
or absence of the exogenous opioid agonist and
on the degree to which physical dependence on an opioid
has developed.
Effects in the Absence of Opioid Agonists. Subcutaneous
doses of naloxone up to 12 mg produce no discernible
subjective effects in humans, and 24 mg causes only slight
drowsiness. Naltrexone also appears to be a relatively
pure antagonist but with higher oral efficacy and a longer
duration of action.
The effects of opiate receptor antagonists are usually both subtle
and limited. Most likely this reflects the low levels of tonic activity
and organizational complexity of the opioid systems in various
physiologic systems (Drolet et al., 2001). In the face of a variety of
physical (pain) or psychological stressors, an increased release of a
variety of opioid peptides occurs. Many stressors will activate central
circuits. Changes in circulating levels of endorphins in plasma
are often cited in events such as runner’s high, yet such peripheral
changes have little significance to central systems, given the minimal
ability of these peptides to penetrate the blood-brain barrier.
Pain. Opiate antagonism in humans is associated with variable
effects ranging from no effect to a mild hyperalgesia and even
hypoalgesia as measured in a variety of well-controlled experimental
pain paradigms (France et al., 2007). A number of studies have,
however, suggested that agents such as naloxone appear to attenuate
the analgesic effects of placebo medications and acupuncture
(Benedetti and Amanzio, 1997).
Stress. Even at high doses of different antagonists, normal subjects
typically show modest changes in blood pressure or heart rate. In
laboratory animals, the administration of naloxone will reverse or
attenuate the hypotension associated with shock of diverse origins,
including that caused by anaphylaxis, endotoxin, hypovolemia, and
injury to the spinal cord; opioid agonists aggravate these conditions
(Amir, 1988; Faden, 1988).
Affect. High doses of naltrexone appeared to cause mild dysphoria
in one study but little or no subjective effects in others (Gonzalez
and Brogden, 1988).
Endocrine Effects. Endogenous opioid peptides participate in the regulation
of pituitary secretion apparently by exerting tonic inhibitory
effects on the release of certain hypothalamic hormones (Chapter
38). Thus, the administration of naloxone or naltrexone increases the
secretion of gonadotropin-releasing hormone and corticotropinreleasing
hormone and elevates the plasma concentrations of LH,
FSH, and ACTH, as well as the steroid hormones produced by their
target organs. Antagonists do not consistently alter basal or stressinduced
concentrations of prolactin in plasma in men; paradoxically,
naloxone stimulates the release of prolactin in women. Opioid antagonists
augment the increases in plasma concentrations of cortisol
and catecholamines that normally accompany stress or exercise.
Endogenous opioid peptides probably have some role in the
regulation of feeding or energy metabolism: in laboratory models,
opioid antagonists increase energy expenditure, interrupt hibernation
in appropriate species, induce weight loss, and prevent stress-induced
overeating and obesity. These observations have led to the experimental
use of opioid antagonists in the treatment of human obesity,
especially that associated with stress-induced eating disorders.
However, naltrexone does not accelerate weight loss in very obese
subjects, even though short-term administration of opioid antagonists
reduces food intake in lean and obese individuals (Atkinson, 1987).
Even after prolonged administration of high doses of the
antagonist alone, discontinuation of naloxone is not followed by any
recognizable withdrawal syndrome, and the withdrawal of naltrexone,
another relatively pure antagonist, produces very few signs and
symptoms. However, long-term administration of antagonists
increases the density of opioid receptors in the brain and causes a
temporary exaggeration of responses to the subsequent administration
of opioid agonists (Yoburn et al., 1988). Naltrexone and naloxone
have no known potential for abuse.
Effects in the Presence of Opioid Agonists
Actions on Acute Opioid Effects. Small doses (0.4-0.8 mg)
of naloxone given intramuscularly or intravenously
prevent or promptly reverse the effects of receptor
agonists. In patients with respiratory depression, an
increase in respiratory rate is seen within 1-2 minutes.
Sedative effects are reversed, and blood pressure, if
depressed, returns to normal. Higher doses of naloxone
are required to antagonize the respiratory-depressant
effects of buprenorphine; 1 mg naloxone intravenously
completely blocks the effects of 25 mg heroin.
Naloxone reverses the psychotomimetic and dysphoric
effects of agonist–antagonist agents such as pentazocine,
but much higher doses (10-15 mg) are required.
The duration of antagonistic effects depends on the
dose but usually is 1-4 hours. Antagonism of opioid
effects by naloxone often is accompanied by an “overshoot”
phenomenon. For example, respiratory rate
depressed by opioids transiently becomes higher than
that before the period of depression. Rebound release of
catecholamines may cause hypertension, tachycardia,
and ventricular arrhythmias. Pulmonary edema also has
been reported after naloxone administration.
Effects in Opioid-Dependent Patients. In subjects who are
dependent on morphine-like opioids, small subcutaneous
doses of naloxone (0.5 mg) precipitate a moderate
to severe withdrawal syndrome that is very similar
to that seen after abrupt withdrawal of opioids, except
that the syndrome appears within minutes of administration
and subsides in ~2 hours. The severity and
duration of the syndrome are related to the dose of the
antagonist and to the degree and type of dependence.
Higher doses of naloxone will precipitate a withdrawal
511
CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT