OPIOID ANTAGONISTS

Naloxone

Clinically, opioid antagonists are used to restore spontaneous ventilation in patients who breathe inadequately after opioid overdoses or opioid anesthesia. In addition, opioid antagonists can reduce or reverse opioid-induced nausea and vomiting, pruritus, urinary retention, rigidity, and biliary spasm associated with numerous therapies employing opioids, such as neuraxial analgesic techniques. It was reported that the potency ratio for naloxone: nalbuphine for antagonism of the pruritic effects of epidural morphine was approximately 40:1.^[498]

Morphine requirements were significantly less in patients receiving naloxone, suggesting that naloxone enhanced the analgesic effects of morphine.^[499] Proposed possible mechanisms for this apparent paradoxical effect of naloxone include enhanced release of endogenous opioids and opioid receptor upregulation.

Although naloxone is generally considered to be a pure opioid receptor antagonist, it delays gastric emptying of saline or milk, as does morphine in the rat.^[500] Furthermore, high doses of naloxone possess partial agonistic activity on the μ- and κ-opioid receptors in cultured cells.^[501]

Reversal of Respiratory Depression by Naloxone

In the early 1950s, nalorphine and levallorphan were evaluated as opioid antagonists. They were often found unacceptable because of a high incidence of side effects as well as incomplete reversal. Naloxone was introduced into clinical practice in the late 1960s. There have been reports of side effects (increases in heart rate and blood pressure) and more serious complications (e.g., pulmonary edema). ^{[502] [503]} Initial naloxone dose recommendations ranged from 0.4 to 0.8 mg. If intravenous access is not

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Several mechanisms produce increases in arterial blood pressure, heart rate, and other significant hemodynamic alterations after naloxone reversal of opioids. These include pain, rapid awakening, and sympathetic activation not necessarily due to pain. When patients receiving naloxone for opioid agonist reversal are hypothermic due to intraoperative heat loss, O₂ consumption and minute ventilation can increase two- to threefold.^[505] Such metabolic demands also stress the cardiovascular system, increasing cardiac output. In addition, greater degrees of hypercapnia at the time of opioid antagonism will result in greater degrees of cardiovascular stimulation because of associated sympathetic stimulation. Opioid reversal may be particularly hazardous in patients with pheochromocytoma or chromaffin tissue tumors.^[506] Naloxone may also have a nonspecific analeptic effect through activation of a CNS arousal system.^[507]

Onset of action of intravenous naloxone is rapid (1 to 2 minutes), and half-life and duration of effect are short, approximately 30 to 60 minutes. Most often, 1.0–2.0 µg/kg titrated in boluses of 0.5–1.0 µg/kg every 2 to 3 minutes will restore adequate spontaneous ventilation.^[492] Even smaller doses of naloxone may be adequate after alfentanil.

Recurrence of respiratory depression after naloxone is due to the short half-life of naloxone as well as to the reuptake of opioid from peripheral compartment tissues (e.g., muscle). "Renarcotization" occurs more frequently after the use of naloxone to reverse longer-acting opioids such as morphine. Short-acting opioids such as alfentanil rarely pose a danger of renarcotization, because of a rapid plasma decay curve, less chance of second plasma peaks due to reuptake of drug from peripheral tissues, and weak opioid receptor binding compared with fentanyl and sufentanil.

Naloxone, although active at μ-, δ- and κ-receptors, has the greatest affinity for μ-receptors, which mediate most potent opioid effects, including respiratory depression and analgesia. Careful titration of naloxone often can restore adequate spontaneous ventilation without reversal of adequate analgesia.

Other Applications of Naloxone

Naloxone may be useful in the treatment of postanesthetic apnea in infants, even when exogenous opioids have not been administered.^[508]

Although many conflicting reports and opinions exist, high doses of naloxone may reverse the effects of some nonopioid CNS depressants. Reversal of the effects of alcohol, barbiturates, and benzodiazepines by naloxone has been reported. The MAC of potent inhaled anesthetics is unaffected by naloxone. However, pretreatment of rats with naloxone does counteract halothane-induced depression of sympathetic nerve activity, but interestingly, not halothane-induced analgesia.^[509] Naloxone may partially antagonize ketamine and N₂ O analgesia.

Naloxone increases arterial blood pressure in laboratory animals, primates, and some patients in hypovolemic and septic shock.^[510] This effect may be due to centrally mediated increases in sympathetic tone and decreases in parasympathetic output and/or antagonism of endogenous opioids.

It has been reported that naloxone may ameliorate the neurologic deficit following an ischemic or traumatic neurologic insult in animals. Naloxone may also have a therapeutic role in heat stroke disorders,^[511] Alzheimer's disease, schizophrenia, intractable pruritus, and thalamic pain syndrome.