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* This is the Professional Version. *

Opioid Toxicity and Withdrawal

By Gerald F. O’Malley, DO, Thomas Jefferson University and Hospital ; Rika O’Malley, MD

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Opioids are euphoriants that, in high doses, cause sedation and respiratory depression. Respiratory depression can be managed with specific antidotes (eg, naloxone) or with endotracheal intubation and mechanical ventilation. Withdrawal manifests initially as anxiety and drug craving, followed by increased respiratory rate, diaphoresis, yawning, lacrimation, rhinorrhea, mydriasis, and stomach cramps and later by piloerection, tremors, muscle twitches, tachycardia, hypertension, fever, chills, anorexia, nausea, vomiting, and diarrhea. Diagnosis is clinical plus with urine tests. Withdrawal can be treated by substitution with a long-acting opioid (eg, methadone) or buprenorphine (a mixed opioid agonist-antagonist).

“Opioid” is a term for a number of natural substances (originally derived from the opium poppy) and their semisynthetic and synthetic analogues that bind to specific opioid receptors. Opioids, which are potent analgesics with a limited role in management of cough and diarrhea, are also common drugs of abuse because of their wide availability and euphoriant properties; see also Opioid Analgesics and Opioid Use Disorder and Rehabilitation.

Pathophysiology

There are 3 main opioid receptors: delta, kappa, and mu. They occur throughout the CNS but particularly in areas and tracts associated with pain perception. Receptors are also located in some sensory nerves, on mast cells, and in some cells of the GI tract.

Opioid receptors are stimulated by endogenous endorphins, which generally produce analgesia and a sense of well-being. Opioids are used therapeutically, primarily as analgesics. Opioids vary in their receptor activity, and some (eg, buprenorphine) have combined agonist and antagonist actions. Compounds with pure antagonist activity (eg, naloxone, naltrexone) are available.

Exogenous opioids can be taken by almost any route: orally, intravenously, subcutaneously, rectally, through the nasal membranes, or inhaled as smoke. Peak effects are reached about 10 min after IV injection, 10 to 15 min after nasal insufflation, and 90 to 120 min after oral ingestion, although time to peak effects and duration of effect vary considerably depending on the specific drug.

Chronic effects

Tolerance develops quickly, with escalating dose requirements. Tolerance to the various effects of opioids frequently develops unevenly. Heroin users, for example, may become relatively tolerant to the drug’s euphoric and respiratory depression effects but continue to have constricted pupils and constipation.

A minor opioid withdrawal syndrome may occur after only several days’ use. Severity of the syndrome increases with the size of the opioid dose and the duration of dependence.

Long-term effects of the opioids themselves are minimal; even decades of methadone use appear to be well tolerated physiologically, although some long-term opioid users experience chronic constipation, excessive sweating, peripheral edema, drowsiness, and decreased libido. However, many long-term users who inject opioids have adverse effects from contaminants (eg, talc) and adulterants (eg, nonprescription stimulant drugs) and cardiac, pulmonary, and hepatic damage due to infections such as HIV infection and hepatitis B or C, which are spread by needle sharing and nonsterile injection techniques (see Injection Drug Use ).

Pregnancy

Use of opioids during pregnancy can result in opioid dependence in the fetus.

Symptoms and Signs

Acute effects

Acute opioid intoxication is characterized by euphoria and drowsiness. Mast cell effects (eg, flushing, itching) are common, particularly with morphine. GI effects include nausea, vomiting, decreased bowel sounds, and constipation.

Toxicity or overdose

The main toxic effect is decreased respiratory rate and depth, which can progress to apnea. Other complications (eg, pulmonary edema, which usually develops within minutes to a few hours after opioid overdose) and death result primarily from hypoxia. Pupils are miotic. Delirium, hypotension, bradycardia, decreased body temperature, and urinary retention may also occur.

Normeperidine, a metabolite of meperidine, accumulates with repeated use (including therapeutic); it stimulates the CNS and may cause seizure activity.

Serotonin syndrome occasionally occurs when fentanyl, meperidine, tramadol, or oxycodone is taken concomitantly with other drugs that have serotonergic effects (eg, SSRIs, MAOIs). This syndrome consists of one or more of the following:

  • Hypertonia

  • Tremor and hyperreflexia

  • Spontaneous clonus

  • Inducible clonus plus agitation or diaphoresis

  • Ocular clonus plus agitation or diaphoresis

  • Temperature > 38° plus ocular or inducible clonus

Withdrawal

The opioid withdrawal syndrome usually includes symptoms and signs of CNS hyperactivity. Onset and duration of the syndrome depend on the specific drug and its half-life. Symptoms may appear as early as 4 h after the last dose of heroin, peak within 48 to 72 h, and subside after about a week. Anxiety and a craving for the drug are followed by increased resting respiratory rate (> 16 breaths/min), usually with diaphoresis, yawning, lacrimation, rhinorrhea, mydriasis, and stomach cramps. Later, piloerection (gooseflesh), tremors, muscle twitching, tachycardia, hypertension, fever and chills, anorexia, nausea, vomiting, and diarrhea may develop.

Opioid withdrawal does not cause fever, seizures, or altered mental status. Although it may be distressingly symptomatic, opioid withdrawal is not fatal.

The withdrawal syndrome in people who were taking methadone (which has a long half-life) develops more slowly and may be less acutely severe than heroin withdrawal, although users may describe it as worse. Even after the withdrawal syndrome remits, lethargy, malaise, anxiety, and disturbed sleep may persist up to several months. Drug craving may persist for years.

Diagnosis

  • Clinically determined

Diagnosis of opioid use is usually made clinically and sometimes with urine drug testing; laboratory tests are done as needed to identify drug-related complications. Drug levels are not measured.

Treatment

  • Supportive therapy

  • For opioid withdrawal, sometimes drug therapy (eg, with an opioid agonist, opioid agonist-antagonist, opioid antagonist, or clonidine)

Toxicity or overdose

Treatment to maintain the airway and support breathing is the first priority.

  • Naloxone 0.4 mg IV

  • Sometimes endotracheal intubation

Patients with spontaneous respirations can be treated with an opioid antagonist, typically naloxone 0.4 mg IV (for children < 20 kg, 0.1 mg/kg); naloxone has no agonist activity and a very short half-life (see Table: Symptoms and Treatment of Specific Poisons). Naloxone rapidly reverses unconsciousness and apnea due to an opioid in most patients. If IV access is not immediately available, IM, sc, or intranasal administration is also effective. A 2nd or 3rd dose can be given if there is no response within 2 min. Almost all patients respond to three 0.4-mg doses (nasal spray is a single dose inhaler with 4 mg). If they do not, the patient’s condition is unlikely to be due to an opioid overdose, although massive opioid overdose may require higher doses of naloxone.

Because some patients become agitated, delirious, and combative as consciousness returns and because naloxone precipitates acute withdrawal, soft physical restraints should be applied before naloxone is given. To ameliorate withdrawal in long-term users, some experts suggest titrating very small doses of naloxone (0.1 mg) when the clinical situation does not require emergency total reversal.

Apneic patients can initially be treated with naloxone 2 mg IV if it can be given without delay; note that the dose is higher than for patients who are only somnolent. In some parts of the US and some countries, naloxone is available without a prescription so apneic patients can be rescued by friends or family. When naloxone is available and given quickly, endotracheal intubation is rarely required.

Patients should be observed for several hours after they regain spontaneous respirations. Because the duration of action of naloxone is less than that of some opioids, respiratory depression can recur within several hours of an overdose of methadone or sustained-released oxycodone or morphine tablets. Thus, the duration of observation should vary depending on the half-life of the opioid involved. Typically, patients who took longer-acting opioids should be admitted for observation; patients who took short-acting opioids may be discharged after several hours.

If respiratory depression recurs, naloxone should be readministered at an appropriate dose. The best dosing regimen is unclear. Many clinicians use repeat bolus doses of the same dose that was effective initially. Others use continuous naloxone infusion; they typically begin with about two thirds of the initially effective dose per hour. In theory, the continuous infusion should allow the dose to be titrated to maintain respiratory rate without triggering withdrawal; however, in practice this can be difficult to do and the patient's life is dependent on the security of the IV line—respiratory depression will quickly recur if the infusion is interrupted (eg, by the patient pulling out the IV). Both regimens require close monitoring, typically in an ICU.

Patients should be observed until no naloxone pharmacologic activity is present and they have no opioid-related symptoms. The serum half-life of naloxone is about 1 h, so an observation period of 2 to 3 h after use of naloxone should clarify disposition. The half-life of IV heroin is relatively short, and recurrent respiratory depression after naloxone reversal of IV heroin is rare.

Acute pulmonary edema is treated with supplemental oxygen and often noninvasive or invasive modalities of breathing support (eg, bilevel positive airway pressure [BiPAP], endotracheal intubation).

Withdrawal and detoxification

Treatment may involve several strategies:

  • No treatment (“cold turkey”)

  • Substitution with methadone or buprenorphine

  • Clonidine to relieve symptoms

  • Long-term support and possibly naltrexone

The opioid withdrawal syndrome is self-limited and, although severely uncomfortable, is not life threatening. Minor metabolic and physical withdrawal effects may persist up to 6 mo. Withdrawal is typically managed in outpatient settings, unless patients require hospitalization for concurrent medical or mental health problems.

Options for management of withdrawal include allowing the process to run its course (“cold turkey”) after the patient’s last opioid dose and giving another opioid (substitution) that can be tapered on a controlled schedule. Clonidine can provide some symptom relief during withdrawal. The US Substance Abuse and Mental Health Services Administration (SAMHSA) provides information on Medication-Assisted Treatment .

Methadone substitution is the preferred method of managing opioid withdrawal for more seriously addicted patients because at appropriate doses, it has a long half-life and less profound sedation and euphoria. Any physician can initiate methadone substitution during hospitalization or for 3 days in an outpatient setting, but further treatment is continued in a licensed methadone treatment program. Methadone is given orally in the smallest amount that prevents severe but not necessarily all symptoms of withdrawal. Typical dose range is 15 to 30 mg once/day; doses 25 mg can result in dangerous levels of sedation in patients who have not developed tolerance.

Symptom scales are available for estimating the appropriate dose. Higher doses should be given when evidence of withdrawal is observed. After the appropriate dose has been established, it should be reduced progressively by 10 to 20%/day unless the decision is made to continue the drug at a stable dose ( methadone maintenance). During tapering of the drug, patients commonly become anxious and request more of the drug.

Methadone withdrawal for addicts who have been in a methadone maintenance program may be particularly difficult because their dose of methadone may be as high as 100 mg once/day; in these patients, the dose should be gradually reduced to 60 mg once/day over several weeks before attempting complete detoxification.

Methadone has been reported to be associated with QTc prolongation and serious arrhythmias including torsades de pointes (see also Long QT Syndrome and Torsades de Pointes Ventricular Tachycardia ). Thus, it should be used very carefully with appropriate patient evaluation and monitoring during initiation and dose titration.

Buprenorphine, a mixed opioid agonist-antagonist usually given sublingually, also has been successfully used in withdrawal. It is available in a combination formulation with naloxone to prevent diversion to IV use. The first dose is given when the first signs of withdrawal appear. The dose needed to effectively control severe symptoms is titrated as quickly as possible; sublingual doses of 8 to 16 mg/day are typically used. Buprenorphine is then tapered over several weeks. The SAMHSA website provides additional information on buprenorphine and the training required to qualify for a waiver to prescribe the drug. Protocols for using buprenorphine for detoxification or maintenance therapy are available for download at the US Department of Health and Human Services web site.

Clonidine, a centrally acting adrenergic drug, can suppress autonomic symptoms and signs of opioid withdrawal. Starting dosages are 0.1 mg po q 4 to 6 h and may be increased to 0.2 mg po q 4 to 6 h as tolerated. Clonidine can cause hypotension and drowsiness, and its withdrawal may precipitate restlessness, insomnia, irritability, tachycardia, and headache.

Rapid and ultrarapid protocols have been evaluated for managing withdrawal and detoxification. In rapid protocols, combinations of naloxone, nalmefene, and naltrexone are used to induce withdrawal, and clonidine and various adjuvant drugs are used to suppress withdrawal symptoms. Some rapid protocols use buprenorphine to suppress opioid withdrawal symptoms. Ultrarapid protocols may use large boluses of naloxone and diuretics to enhance excretion of the opioids while patients are under general anesthesia; these ultrarapid protocols are not recommended because they have a high risk of complications and no substantial additional benefit.

Clinicians must understand that detoxification is not treatment per se. It is only the first step and must be followed by an ongoing treatment program, which may involve various kinds of counseling and possibly nonopioid antagonists (eg, naltrexone).

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* This is the Professional Version. *