Chapter 116: Opioids

• The classical triad of central nervous system depression, respiratory depression, and pinpoint pupils characterizes opioid toxicity.

• Some opioids, such as methadone can have delayed or prolonged effects.

• Opioids can cause acute lung injury or noncardiogenic pulmonary edema in severe overdoses.

• Toxicity from propoxyphene, meperidine, and tramadol, as well as neonatal opioid withdrawal, can result in seizure activity.

• Airway management and the use of the pure opioid antagonist naloxone are the mainstays of opioid toxicity treatment.

Opioids are naturally occurring or synthetic drugs that have activity similar to opium or morphine. The term opioid is a broad term and includes both natural and synthetic drugs. The term opiate is more specific and refers only to those drugs derived from natural opium, such as morphine, codeine, and thebaine. A semisynthetic opioid, such as oxycodone, is derived from the chemical modification of an opioid. A synthetic opioid is a xenobiotic, not structurally related to or derived from an opioid that acts at the opioid receptor or produces an opioid-like effect. The term narcotic is derived from the Greek word for stupor and was originally used to describe any drug that could induce sleep. The term has ambiguously been used to describe any drug that binds to opioid receptors or, in law enforcement circles, to any illicit substance. The poppy plant, Papaver somniferum, is the source of opium and its derivatives.

Opioids are used primarily as analgesics. They can also be used as antitussive and antidiarrheal agents. Opioids are available in many formulations and can be taken in many routes: oral, inhalational, parenteral, transdermal, and rectal.

Neonates can experience lethargy at birth if there was recent maternal opioid use, whether administered during labor or maternal illicit use. The neonate is prone to withdrawal symptoms during the newborn period if the mother was chronically using or abusing opioids during pregnancy.

Toddlers are prone to accidental opioid poisoning in environments where opioid preparations are not appropriately stored out of the reach of the child.¹ Clinical experience and case studies show that toddlers have exhibited toxicity when exposed to heroin, liquid methadone, various prescription opioid pills, and fentanyl transdermal patches.^2,3 Opioid withdrawal symptoms are not often encountered in younger children who have limited or no exposure to chronic opioid therapy.

When caring for adolescents and teenagers who present with signs and symptoms of opioid toxicity, illicit use has to be considered. In an attempt at mood elevation, adolescents and teenagers may abuse opioids in various forms: inhalational (smoking), intranasal (snorting), ingestion or intravenous. In a suicide attempt or accidental overdose, opioid poisoning can be life-threatening. In addition, opioids may have a synergistic effect on mental status depression when combined with agents such as ethanol or benzodiazepines. Conversely, the clinical presentation can present with a mixed pattern if co-ingestants include sympathomimetic agents such as cocaine or amphetamines. Teenagers who abuse opioids or who use them chronically for analgesia for painful medical conditions are at risk of withdrawal symptoms if the opioids are stopped abruptly or treated clinically with an opioid antagonist such as naloxone.

Opioids produce clinical effects by interacting with specific receptors located throughout the central nervous system, the peripheral nervous system, and the gastrointestinal tract. Endorphins are endogenous substances that have activity at the aforementioned opioid receptors. Exogenous opioids also work at these receptors. The three main classes of opioid receptors are mu, kappa, and delta.⁴

The mu1 receptor is responsible for supraspinal (brain) analgesia, euphoria, and sedation. The mu2 receptor is responsible for spinal-level analgesia and respiratory depression. There are mu receptors in the medullary cough center and in gastrointestinal tract, which account for the use of opioids in the treatment of cough and diarrhea. Stimulation of the kappa receptor is responsible for spinal analgesia and miosis. Little is known about the delta receptors, but they may play a role in spinal analgesia, supraspinal analgesia, and cough suppression.⁴

The pharmacokinetics of opiates are dependent upon the specific substance. In general, the pharmacokinetics for morphine and morphine derivatives in children aged 1 to 15 are comparable to adults.⁵ Most immediate-acting opioid preparations are well absorbed from the gastrointestinal tract and peak within 60 to 90 minutes with a duration of effect between 3 and 6 hours. There are many exceptions. For example, fentanyl (nontransdermal preparation) and methadone can have durations of effect of 1 hour and up to 72 hours, respectively.^2,6 Sustained-release opioid products can have delayed onset of effects and prolonged duration of effects. There are other preparations of opioids besides immediate and sustained release. For example, fentanyl is available as a transdermal patch and as a lollipop. See Table 116-1 for commonly prescribed opioid compounds with their generic and trade names.

Tolerance, or tachyphylaxis, can complicate chronic opioid therapy. The development of tolerance is characterized by a shortened duration of effect and a decreased intensity of analgesia, euphoria, and sedation. This may create the situation where larger doses of opioids are necessary to attain the desired effect. Tolerance does not develop uniformly for all actions of opioids. Dependence is the physiologic and psychologic changes that necessitate the continued presents of a drug to prevent withdrawal. This can occur with opioids. The intensity and character of the physical symptoms experienced during opioid withdrawal are directly related to the particular drug involved, the total daily dose, the frequency of dosing, and the duration of use. Although unpleasant, opioid withdrawal is rarely life-threatening.

Respiratory depression from opioids is primarily mediated via the opioid m2 receptors, causing reduced sensitivity of the medullary chemoreceptors to hypercapnia. Acute lung injury is described in some cases of opioid overdose. While the exact mechanism of development of acute lung injury is not completely understood, it classically presents minutes to hours after the development of spontaneous ventilation following opioid-associated respiratory depression.⁷

The mechanism or mechanisms responsible for miosis seen in patients taking opioids remains controversial. Some opioids do not cause miosis with meperidine and propoxyphene being examples. Constipation, mediated by the intestinal m2 receptors is an adverse effect seen in both therapeutic and recreational use of opioids.

Seizures have been described with opioid use.⁴ This is often because of hypoxemia. Experimental animal models demonstrate a proconvulsant effect of morphine. Morphine-induced seizures have been reported in neonates; however, neonatal opioid withdrawal seizures are more common.⁸ Meperidine, propoxyphene, and tramadol are opioids that are epileptogenic and seizures should be anticipated in patients with overdose of these drugs.

Opioid use can cause both arteriolar and venous dilation, leading to a mild reduction in blood pressure. Propoxyphene has cardiac sodium channel blocking effects and can cause wide-complex tachydysrhythmias in overdose. Methadone can interfere with cardiac potassium channels, leading to a prolongation of the QT interval.

Opioid poisoning classically presents with an altered level of consciousness. The triad of acute toxicity consists of CNS depression, respiratory depression, and constriction of the pupils or “pinpoint pupils.” CNS depression ranges from mild sedation to stupor and coma. Patients are typically hypotensive, hypothermic, bradycardic, and hyporeflexic. Many patients experience central-mediated vomiting. This, coupled with respiratory depression and a diminished gag reflex, places the patient at risk for aspiration pneumonitis. Other respiratory effects may also include bronchospasm from histamine release or from insufflating or inhaling fumes of opioid compounds cut with impurities or adulterants. In massive overdoses, the respiratory toxicity can also cause severe hypoxia, hypercarbia, and acute lung injury.

While miotic or “pinpoint” pupils are a classic opioid-induced clinical finding, mydriasis or pupillary dilation has been described with meperidine, propoxyphene, and diphenoxylate-atropine (Lomotil^®) overdoses. With Lomotil^® overdose, a two-phase toxicity has been described. Phase I manifests with anticholinergic symptoms such as dry mouth, flushing, and mydriasis, whereas phase II consists of opioid effects causing respiratory and central nervous system depression, with associated miosis.

Less common effects of opioid toxicity include generalized seizure activity following overdose of propoxyphene, meperidine, tramadol,⁹ fentanyl, or pentazocine. Neonates receiving continuous intravenous morphine can also suffer seizures from toxicity or during acute opioid withdrawal.¹⁰

Dermatologic effects include flushing and pruritus secondary to histamine release. Gastrointestinal effects include decreased gut motility and constipation. Finally, medical complications common among chronic users arise from adulterants found in street drugs and the nonsterile practices of injecting drugs. Patients who chronically use opioids intravenously or by “skin popping” can contract bacterial endocarditis, septic pulmonary emboli, skin infections, tetanus, wound botulism, hepatitis, and human immunodeficiency virus infection.

Patients who presents with suspicion or confirmation of opioid toxicity should have continuous monitoring of oxygenation status. In patients, especially children, who present with suspicion of opioid toxicity, obtain a capillary blood glucose measurement as hypoglycemia can present with similar symptoms to opioid overdose. If head trauma is suspected, obtain a brain CT. In cases of severe respiratory depression or when there is acute lung injury or aspiration, obtain a chest radiograph. If propoxyphene is the suspected intoxicant, obtain an electrocardiogram.

The primary management of the unstable opioid-poisoned patient is airway stabilization and administration of the opioid antagonist naloxone. Prompt administration of naloxone can prevent intubation. In addition to the intravenous route, naloxone can be given subcutaneously, intramuscularly, intranasally, or by nebulization. In the overdose setting, the naloxone dose is 0.1 mg/kg in children from birth to 5 years of age and less than 20 kg in body weight, although larger doses may be necessary.¹¹ In older children and children greater than 20-kg body weight, the dose is 2 mg given rapidly. The dose can be repeated every 2 to 3 minutes until a response is achieved. If there is no response, consider other causes of respiratory depression. Use caution when giving naloxone to patients who have chronic opioid exposure and who are not in extremis as naloxone administration can precipitate opioid withdrawal. Keep in mind, however, that opioid withdrawal is not generally life-threatening. In the newborn setting, withdrawal seizures have been documented in neonates born to opioid-dependent mothers.⁸

Naloxone has a duration of action of 20 to 90 minutes. This is shorter than the duration of many opioid agents. Repeated doses of naloxone may be necessary to avoid intubation and to maintain appropriate oxygenation and ventilation.¹² In cases where repeated doses are necessary, a naloxone infusion could be considered.¹³ The infusion rate is generally one-half to two-thirds of the naloxone dose required to achieve the desired effect infused hourly. The infusion can be adjusted as necessary.

Nalmefene may be considered in non–opioid-dependent children exposed to longer-acting opioids. While studies are limited, nalmefene has been used safely in the setting of reversing iatrogenic opioid sedation in children.¹⁴ Doses of 0.5 to 2.0 mg have been reported to be effective with a duration of action of up to 8 hours.¹⁵ Nalmefene should only be considered in children not likely to experience withdrawal symptoms. In the setting of an opioid-dependent patient, naloxone would be a more humane approach as any withdrawal symptoms would be relatively short-lived compared to the expected duration of symptoms with the longer-acting nalmefene.

Any child presenting to the emergency department with opioid-related CNS and respiratory depression requiring naloxone for treatment should be admitted. Most opioids have a duration of action longer than naloxone, and repeated doses may be required. When long-acting opioids are responsible for the symptoms, consider admitting for at least 24 hours. Adolescent or teenage patients, who develop symptoms from a known heroin exposure and require naloxone, may be safely discharged from the emergency department after a 4- to 6-hour observation, assuming there are no other circumstances that require admission such as suicidality or exposure to other illicit drugs. Patient addicted to prescription or illicit drugs should be referred to counseling and detoxification programs.