Opioid analgesic overdose is a life-threatening condition, and the antidote naloxone may have limited effectiveness in patients with poisoning from long-acting agents. The unpredictable clinical course of intoxication demands empirical management of this potentially lethal condition.
Opioid analgesic overdose is a preventable and potentially lethal condition that results from prescribing practices, inadequate understanding on the patient’s part of the risks of medication misuse, errors in drug administration, and pharmaceutical abuse. Three features are key to an understanding of opioid analgesic toxicity. First, opioid analgesic overdose can have life-threatening toxic effects in multiple organ systems. Second, normal pharmacokinetic properties are often disrupted during an overdose and can prolong intoxication dramatically. Third, the duration of action varies among opioid formulations, and failure to recognize such variations can lead to inappropriate treatment decisions, sometimes with lethal results.
Epidemiology of Overdose
The number of opioid analgesic overdoses is proportional to the number of opioid prescriptions and the dose prescribed. Between 1997 and 2007, prescriptions for opioid analgesics in the United States increased by 700%; the number of grams of methadone prescribed over the same period increased by more than 1200%. In 2010, the National Poison Data System, which receives case descriptions from offices, hospitals, and emergency departments, reported more than 107,000 exposures to opioid analgesics, which led to more than 27,500 admissions to health care facilities. There is considerable overlap between psychiatric disease and chronic pain syndromes; 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. In addition, data 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.
Pathophysiology of Opioid Analgesics
Opioids increase activity at one or more G-protein–coupled transmembrane molecules, known as the mu, delta, and kappa opioid receptors, that develop operational diversity from splice variants, post-translational modification and scaffolding of gene products, and the formation of receptor heterodimers and homodimers. Opioid receptors are activated by endogenous peptides and exogenous ligands; morphine is the prototypical compound of the latter. 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. 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.
The mu opioid receptor is responsible for the preponderance of clinical effects caused by opioids. Studies in knockout mice confirm that agonism of these receptors mediates both analgesia and opioid dependence. 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. In contrast, opioid analgesics, which are administered repetitively in long-acting formulations, persist in the extracellular matrix and signal through mu opioid receptors for prolonged periods. Whereas endogenous native ligands foster dynamic receptor cycling, opioid analgesics facilitate tolerance by persistently binding and desensitizing the receptors as they blunt receptor recycling.
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. Opioid use in the presence of these signals has attenuated effects; conversely, opioid use in the absence of these stimuli or in new environments results in heightened effects. 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.
Although the classic toxidrome of apnea, stupor, and miosis suggests the diagnosis of opioid toxicity, all of these findings are not consistently present. The sine qua non of opioid intoxication is respiratory depression. Administration of therapeutic doses of opioids in persons without tolerance to opioids causes a discernible decline in all phases of respiratory activity, with the extent of the decline dependent on the administered dose. At the bedside, however, the most easily recognized abnormality in cases of opioid overdose is a decline in respiratory rate culminating in apnea. A respiratory rate of 12 breaths per minute or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Miosis alone is insufficient to infer the diagnosis of opioid intoxication. Polysubstance ingestions may produce normally reactive or mydriatic pupils, as can poisoning from meperidine, propoxyphene, or tramadol. Conversely, 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.
Failure of oxygenation, defined as an oxygen saturation of less than 90% while the patient is breathing ambient air and with ventilation adequate to achieve normal arterial carbon dioxide tension (partial pressure of carbon dioxide), is often caused by pulmonary edema that becomes apparent later in the clinical course. There are several potential causes of pulmonary edema. One likely cause is that attempted inspiration against a closed glottis leads to a decrease in intrathoracic pressure, which causes fluid extravasation. Alternatively, acute lung injury may arise from a mechanism similar to that postulated for neurogenic pulmonary edema. In this scenario, sympathetic vasoactive responses to stress in a patient who has reawakened after reversal of intoxication culminate in leakage from pulmonary capillaries.
Hypothermia may arise from a persistently unresponsive state in a cool environment or from misguided attempts by bystanders to reverse opioid intoxication by immersing a patient in cold water. In addition, persons who have been lying immobile in an opioid-induced stupor may be subject to rhabdomyolysis, myoglobinuric renal failure, and the compartment syndrome. Other laboratory abnormalities include elevated serum aminotransferase concentrations in association with liver injury caused by acetaminophen or hypoxemia. Seizures have been associated with overdose of tramadol, propoxyphene, and meperidine.
Considerations in Special Populations
Opioid overdose in children is often characterized by a delayed onset of toxicity, unexpectedly severe poisoning, and prolonged toxic effects. These seemingly paradoxical effects result from ontogeny-related pharmacokinetics: children have rates of drug absorption, distribution into the central nervous system, and metabolism that differ from those in adults. Children 3 years of age or younger who have been exposed to any opioid analgesic other than immediate-release opioid formulations (e.g., methadone, fentanyl patches, and extended-release formulations) should be admitted for a 24-hour observation period, even if ingestion of these agents cannot be confirmed. Similarly, all toddlers exposed to buprenorphine formulations, including buprenorphine–naloxone products, must be admitted for close observation. The reported “ceiling effect” of buprenorphine, in which escalating doses do not cause additional respiratory depression, has not been observed in children. Children who ingest opioid formulations often ingest a higher dose than adults per kilogram of body weight and therefore require larger doses of naloxone to reverse the effects of overdose.Elderly patients also have increased susceptibility to opioid effects and should be watched closely. A coexisting condition (e.g., renal insufficiency, chronic obstructive pulmonary disease, or sleep apnea) may exacerbate the inhibitory effects of opioids on respiration; age-related changes in physiology (e.g., decreased stroke volume, leading to diminished hepatic blood flow) and in body composition (leading to reduced binding of the drug to plasma proteins) may cause unexpected, persistent intoxication. These pharmacokinetic effects have been implicated in the failure of naloxone to successfully reverse cases of intoxication caused by short-acting opioid analgesics.
Pitfalls of Overdose Management
Lack of knowledge about several aspects of opioid analgesic toxicity may complicate patient care. First, even clinicians with experience treating heroin overdose may believe that naloxone will prevent the recurrence of opioid analgesic toxicity. Naloxone, with its transient duration of action, does not truncate opioid toxicity; in many patients with intoxication from opioid analgesics, naloxone treatment does not forestall recrudescent respiratory depression. Second, clinicians may incorrectly assume that the dose of naloxone that is required to restore respiration correlates with the severity of intoxication. Because patients with opioid dependence frequently require low initial doses of antidote, physicians often provide only a brief period of patient observation, decide not to readminister the antidote, or admit patients to units that cannot perform intensive monitoring. Third, clinicians may associate peak plasma opioid concentrations with the greatest degree of respiratory depression. Opioid-induced respiratory depression is unrelated to the peak concentration, the timing of which cannot be reliably determined in cases of overdose. Fourth, early acetaminophen toxicity may go unrecognized at the time when intervention is most effective. Finally, clinicians may believe that pharmacologic responses in children and elderly patients are in keeping with the pharmacokinetic findings in healthy young adults and thus may inappropriately curtail the observation period.
Prevention of Overdose
Several strategies may limit the harm of opioid analgesics, which are among the most effective drugs used to treat pain. Clinicians who prescribe these agents should understand the basics of safe opioid dosing, screen for mental illness in potential recipients of opioids, perform behavioral testing and urine screens to detect problematic opioid use, and use electronic prescription-drug monitoring programs to help identify patients who may be receiving opioids inappropriately from multiple prescribers. The manufacturers of opioid analgesics should be assiduously honest in marketing their products, fund the independent development of objective prescribing information, and help prevent opioid exposure in children by distributing child-safety devices and educational materials for prescribers, patients, and families. Finally, patients should understand that opioid analgesics are not effective in treating all painful conditions, can engender long-term use, and are highly lethal when used inappropriately.