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

Table 18–8
Summary of Drug Target and Site of Action of Common Drug Classes and Relative Efficacy by Pain State
DRUG CLASS
(REPRESENTATIVE
AGENTS IN
SITE OF
PARENTHESES) DRUG ACTION ACTION a RELATIVE EFFICACY IN PAIN STATES b
NSAIDs Nonspecific Peripheral Tissue injury >> acute stimuli = nerve injury = 0
(ibuprofen, aspirin COX inhibitors and spinal (Hamza and Dionne, 2009, Svensson and Yaksh,
acetominophen) 2002)
COX 2 inhibitor COX2-selective Peripheral Tissue injury >> acute stimuli = nerve injury = 0
(celecoxib) inhibitor and spinal (Hamza and Dionne, 2009)
Opioids μ receptor agonist Supraspinal Tissue injury = acute stimuli ≥ nerve injury > 0
(morphine) and spinal (see this chapter)
Anticonvulsants Na + channel Supraspinal Nerve injury > tissue injury = acute stimuli = 0
(gabapentin) block, α 2
δ subunit and spinal (Lai et al., 2004; Taylor, 2009)
of Ca 2+ channel
Tricyclic Inhibit uptake of Supraspinal Nerve injury ≥ tissue injury >> acute stimuli = 0
antidepressants 5-HT/NE and spinal (Mochizucki, 2004)
(amitryptiline)
a
Studies based on local delivery in preclinical models, e.g., intracranial microinjection or intraventricular injections, lumbar intrathecal delivery or
topical/sq application at injury site. b Pain states are defined by preclinical models: acute: hot plate/tail flick/acute mechanical compression; tissue
injury: intraplantar injections of irritants, focal thermal injury; nerve injury: compression/ligation of sciatic nerve or its branches or of nerve roots;
systemic delivery of chemotherapeutics. See Mogil, 2009.
the injection of an opioid into chilled skin areas or in
patients with low blood pressure and shock. The drug is
not fully absorbed, and therefore, a subsequent dose
may be given. When normal circulation is restored, an
excessive amount may be absorbed suddenly. It is difficult
to define the exact amount of any opioid that is
toxic or lethal to humans. Recent experiences with
methadone indicate that in nontolerant individuals, serious
toxicity may follow the oral ingestion of 40-60 mg.
Older literature suggests that in the case of morphine, a
normal, opiate-naïve, pain-free adult is not likely to die
after oral doses <120 mg or to have serious toxicity
with <30 mg parenterally.
Symptoms and Diagnosis
The patient who has taken an overdose of an opioid usually is stuporous
or, if a large overdose has been taken, may be in a profound
coma. The respiratory rate will be very low, or the patient may be
apneic, and cyanosis may be present. As respiratory exchange
decreases, blood pressure, at first likely to be near normal, will fall
progressively. If adequate oxygenation is restored early, the blood
pressure will improve; if hypoxia persists untreated, there may be capillary
damage, and measures to combat shock may be required. The
pupils will be symmetrical and pinpoint in size; however, if hypoxia
is severe, they may be dilated. Urine formation is depressed. Body
temperature falls, and the skin becomes cold and clammy. The skeletal
muscles are flaccid, the jaw is relaxed, and the tongue may fall
back and block the airway. Frank convulsions occasionally may be
noted in infants and children. When death occurs, it is nearly always
from respiratory failure. Even if respiration is restored, death still may
occur as a result of complications that develop during the period of
coma, such as pneumonia or shock. Noncardiogenic pulmonary edema
is seen commonly with opioid poisoning. It probably is not due to contaminants
or to anaphylactic reactions, and it has been observed after
toxic doses of morphine, methadone, propoxyphene, and pure heroin.
The triad of coma, pinpoint pupils, and depressed respiration
strongly suggests opioid poisoning. The finding of needle
marks suggestive of addiction further supports the diagnosis.
Mixed poisonings, however, are not uncommon. Examination of
the urine and gastric contents for drugs may aid in diagnosis, but
the results usually become available too late to influence treatment.
Treatment
The first step is to establish a patent airway and ventilate the patient.
Opioid antagonists can produce dramatic reversal of the severe
respiratory depression, and the antagonist naloxone is the treatment
of choice. However, care should be taken to avoid precipitating withdrawal
in dependent patients, who may be extremely sensitive to
antagonists. The safest approach is to dilute the standard naloxone
dose (0.4 mg) and slowly administer it intravenously, monitoring
arousal and respiratory function. With care, it usually is possible to
reverse the respiratory depression without precipitating a major withdrawal
syndrome. If no response is seen with the first dose, additional
doses can be given. Patients should be observed for rebound
increases in sympathetic nervous system activity, which may result
in cardiac arrhythmias and pulmonary edema. For reversing opioid
poisoning in children, the initial dose of naloxone is 0.01 mg/kg. If
no effect is seen after a total dose of 10 mg, one can reasonably