Pathophysiology: - Opioids increase activity at one or more G-protein–coupled transmembrane molecules, known as the mu, delta, and kappa opioid receptors. Opioid receptors are activated by endogenous peptides and exogenous ligands (1). The receptors are widely distributed throughout the human body; those in the anterior and ventrolateral thalamus, the amygdala, and the dorsal-root ganglia mediate nociception (3). With contributions from dopaminergic neurons, brain-stem opioid receptors modulate respiratory responses to hypercarbia and hypoxemia, and receptors in the Edinger–Westphal nucleus of the oculomotor nerve control pupillary constriction. Opioid agonists bind to receptors in the gastrointestinal tract to decrease gut motility (1).
- The mu opioid receptor is responsible for the preponderance of clinical effects caused by opioids. Furthermore, the development of tolerance, in which drug doses must be escalated to achieve a desired clinical effect, involves the progressive inability of mu opioid receptors to propagate a signal after opioid binding. Receptor desensitization, a critical event in the development of tolerance, is a highly conserved process that involves the uncoupling of the receptors from G-protein, and their subsequent entry into an intracellular compartment during endocytosis. The receptors may then be returned to the membrane in a process that resensitizes the cell to opioid binding. This dynamic process of endocytosis and recycling is postulated to limit the tolerance of mu opioid receptors for endogenous opioid ligands as they undergo phasic secretion and rapid clearance. Whereas endogenous native ligands foster dynamic receptor cycling, opioid analgesics facilitate tolerance by persistently binding and desensitizing the receptors as they blunt receptor recycling (1).
- However, tolerance of the analgesic and respiratory depressive effects of opioids is not solely related to the desensitization of mu opioid receptors. Conditioned tolerance develops when patients learn to associate the reinforcing effect of opioids with environmental signals that reliably predict drug administration. Tolerance of respiratory depression appears to develop at a slower rate than analgesic tolerance; over time, this delayed tolerance narrows the therapeutic window, paradoxically placing patients with a long history of opioid use at increased risk for respiratory depression (1).
- Toxicokinetics: The pharmacokinetics of particular opioid analgesic agents — their absorption, onset of action, clearance, and biologic half-life — are often irrelevant in overdose. In the case of an overdose, however, high concentrations of the drug may overwhelm the ability of an enzyme to handle a substrate, a process known as saturation. Saturated biologic processes are characterized by a transition from first-order to zero-order elimination kinetics. Two phenomena occur in zero-order elimination. First, small increases in the drug dose can lead to disproportionate increases in plasma concentrations and hence to intoxication. Second, a constant amount (as opposed to a constant proportion) of drug is eliminated per unit of time (1).
Epidemiology: - Patients with depressive or anxiety disorders are at increased risk for overdose, as compared with patients without these conditions, because they are more likely to receive higher doses of opioids. Such patients are also more likely to receive sedative hypnotic agents (e.g., benzodiazepines) that have been strongly associated with death from opioid overdose (1).
- Data (US) indicate that the frequent prescription of opioid analgesics contributes to overdose-related mortality among children, who may find and ingest agents in the home that were intended for adults (children <=5y: change in visits to ED 2001-2008: 101%; change in admission rate 2001-2008: 86%; 20 deaths from prescription opoids 2001-2008) (2).
Symptoms: - Respiratory depression (-> decline in respiratory rate (<12/min) culminating in apnea), stupor (definition via medical subject heading from the National Library of Medicine), miosis (1).
- Pitfalls:
- Polysubstance ingestions may produce normally reactive or mydriatic pupils, as can poisoning from meperidine, propoxyphene, or tramadol (1).
- Overdose from antipsychotic drugs, anticonvulsant agents, ethanol, and other sedative hypnotic agents can cause miosis and coma, but the respiratory depression that defines opioid toxicity is usually absent (1).
References: - Management of Opioid Analgesic Overdose. N Engl J Med. 2012;367:146-155: full text | pdf.
- The growing impact of pediatric pharmaceutical poisoning. J Pediatr 2012;160:265-270: via ScienceDirect full text | pdf.
- The Control of Pain in Peripheral Tissue by Opoids. N Engl J Med 1995; 332:1685-1690: full text | pdf.
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