These agents have obvious therapeutic utility in the treatment of opioid overdose. As the understanding of the role of endogenous opioid systems in pathophysiological states (e.g., shock, stroke, spinal cord and brain trauma) increases, additional therapeutic indications for these antagonists may develop.
If endogenous opioid systems have not been activated, the pharmacological actions of opioid antagonists depend on whether or not an opioid agonist has been administered previously, on the pharmacological profile of that opioid, and on the degree to which physical dependence on an opioid has developed.
EFFECTS IN THE ABSENCE OF OPIOID DRUGS Subcutaneous doses of naloxone (narcan) up to 12 mg produce no discernible subjective effects, and 24 mg causes only slight drowsiness. Naltrexone (REVIA) also appears to be a relatively pure antagonist but with higher oral efficacy and a longer duration of action. At doses in excess of 0.3 mg/kg naloxone, normal subjects show increased systolic blood pressure and decreased performance on tests of memory. High doses of naltrexone appeared to cause mild dysphoria in one study but almost no subjective effect in several others.
Although high doses of antagonists might be expected to alter the actions of endogenous opioid peptides, the detectable effects usually are both subtle and limited. This most likely reflects the low levels of tonic activity of the opioid systems. In this regard, analgesic effects can be differentiated from endocrine effects, in which naloxone causes readily demonstrable changes in hormone levels (see below). Interestingly, naloxone appears to block the analgesic effects of placebo medications and acupuncture.
Endogenous opioid peptides participate in the regulation of pituitary secretion by exerting tonic inhibitory effects on the release of certain hypothalamic releasing hormones (see Chapter 55). Thus, the administration of naloxone or naltrexone increases the secretion of GnRH and CRH and elevates the plasma concentrations of LH, FSH, and ACTH, as well as the steroid hormones produced by their target organs. Naloxone stimulates the release of prolactin in women.
ANTAGONISTIC ACTIONS 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 "overshoot" phenomena. For example, respiratory rate depressed transiently by opioids 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.
EFFECTS IN PHYSICAL DEPENDENCE In subjects who are dependent on morphinelike 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 syndrome in patients dependent on pentazocine, butorphanol, or nalbuphine. Naloxone produces overshoot phenomena suggestive of early acute physical dependence 6-24 hours after a single dose of a m agonist.
TOLERANCE AND PHYSICAL DEPENDENCE Even after prolonged administration of high doses, 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. Naltrexone and naloxone have little or no potential for abuse.
ABSORPTION, FATE, AND EXCRETION Although absorbed readily from the GI tract, naloxone is almost completely metabolized by the liver before reaching the systemic circulation and thus must be administered parenterally. The t1/2 of naloxone is ~1 hour, but its clinically effective duration of action can be even less.
Compared with naloxone, naltrexone retains much more of its efficacy by the oral route, and its duration of action approaches 24 hours after moderate oral doses. Peak concentrations in plasma are reached within 1-2 hours and the t1/2 of ~3 hours does not change with long-term use. Naltrex-one is much more potent than naloxone, and l00-mg oral doses given to patients addicted to opi-oids produce concentrations in tissues sufficient to block the euphorigenic effects of 25-mg intravenous doses of heroin for 48 hours.
Opioid antagonists have established uses in the treatment of opioid-induced toxicity, especially respiratory depression; in the diagnosis of physical dependence on opioids; and as therapeutic agents in the treatment of compulsive users of opioids (Chapter 23). Naltrexone is also FDA-approved for the treatment of alcohol abuse.
TREATMENT OF OPIOID OVERDOSAGE Naloxone hydrochloride should be used cautiously for opiate overdose because it also can precipitate withdrawal in dependent subjects and cause undesirable cardiovascular side effects. By carefully titrating the dose of naloxone, it usually is possible to antagonize the respiratory-depressant actions without eliciting a full withdrawal syndrome. The duration of action of naloxone is relatively short, and it often must be given repeatedly or by continuous infusion. Opioid antagonists also have been employed effectively to decrease neonatal respiratory depression secondary to the intravenous or intramuscular administration of opioids to the mother. In the neonate, the initial dose is 10 mg/kg given intravenously, intramuscularly, or subcutaneously.
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