Opioid withdrawal in adolescents

INTRODUCTION — Opioids have analgesic and central nervous system (CNS) depressant effects and the potential to cause euphoria. Morphine is the prototypic opioid. Heroin is a derivative of morphine and is a commonly abused opioid.

Opioids are effective in the treatment of acute and chronic pain as analgesics and sedatives and as anesthetic agents. They have the potential to be abused for these effects and the associated feeling of euphoria.

The epidemiology, pharmacology, clinical manifestations, and management of opioid withdrawal in adolescents are reviewed here. Opioid withdrawal in the neonate and opioid use disorder in adolescents are discussed separately:

●(See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

●(See "Substance use disorder in adolescents: Treatment overview".)

EPIDEMIOLOGY — Opioid abuse and addiction is a serious problem among adolescents. As an example, nationally representative surveys estimate approximately 17 percent of high school seniors in the United States had used prescription opioids in their lifetime for medical purposes and approximately 13 percent had used prescription opioids for nonmedical purposes [1]. Approximately 8 percent of children between the ages of 14 to 20 surveyed at a university based emergency department had reported nonmedical prescription opioid use [2]. In addition, between 1994 and 2007, the proportion of ambulatory visits where an adolescent or young adult was prescribed a controlled medication nearly doubled [3]. Lastly, per the Substance Abuse and Mental Health Services Administration (SAMHSA), opioids represent approximately 1 to 2 percent of all adolescent substance abuse treatment admissions and in 2008, 63 percent of these were due to prescription opioids [4].

Information on worldwide opioid use in adolescents is more limited but includes the following:

●A 2007 survey of 2914 Canadian students aged 12 to 19 showed that approximately 20 percent had lifetime nonmedical use of prescription opioids [5].

●A 2010 nationwide survey of students in England aged 11 to 15 showed approximately 1 percent lifetime opioid use [6].

●The estimated number of patients (of all ages) in opioid substitution treatment programs in the European Union has increased from approximately 450,000 in 2003 to approximately 700,000 in 2010, which is believed to be largely due to increased abuse of prescription opioids rather than heroin abuse [7].

●According to the United Nations, opioid use among all ages has been rising in Asia since 2009 [8].

PHARMACOLOGY — Tolerance is defined as a decrease of an individual’s response to given drug as the drug is administered repeatedly or for prolonged periods. A withdrawal state may occur as the body adapts to higher and higher drug concentrations. Opioid withdrawal symptoms are thought to primarily involve changes in the locus ceruleus (LC). Opioids inhibit the activity of LC neurons. When opioids are continuously present, increased activity of the LC neurons compensates for the inhibition. When opioids or their activity are abruptly removed, the increased activity of the LC neurons results in withdrawal symptoms [9,10]. The mesolimbic system is also important in mediating withdrawal symptoms [11,12].

SYMPTOMS OF OPIOID WITHDRAWAL — Tolerance and physical and psychologic dependence on opioids usually occur after three weeks of daily usage. Higher tolerance is created as the user decreases the interval and increases the dose to achieve euphoria. Tolerance does not develop to the following physiologic effects: miosis and constipation.

Heroin, hydromorphone, and methadone have great addictive potential. Heroin provides a "rush" because it easily crosses the blood brain barrier and can be used by multiple routes. Hydromorphone is almost 100 times more potent than is codeine for analgesic effect. Methadone is long-acting. Codeine, a prescription drug that must be ingested orally, has weaker analgesic effects and a lower addictive potential.

The discontinuation of opioids leads to a constellation of withdrawal symptoms known as the abstinence syndrome (table 1). The severity of the abstinence syndrome depends upon the type and frequency of the drug used. The abstinence syndrome usually is elicited if opioid use is discontinued after several months of daily usage.

Withdrawal symptoms occur in stages, depending upon the time of the last dose and the elimination time of the drug, the typical findings are as follows:

●3 to 4 hours after blood levels decline – Drug craving, anxiety, fear of withdrawal

●8 to 14 hours – Anxiety, restlessness, insomnia, yawning, rhinorrhea, lacrimation, diaphoresis, stomach cramps, and mydriasis

●One to three days – Tremor, muscle spasms, vomiting, diarrhea, hypertension, tachycardia, fever, chills, and piloerection

CLINICAL FEATURES AND DIAGNOSIS — Clinical features of opioid withdrawal in adolescents are similar to those seen in adults (table 2).

●History — In individuals with opioid use disorder, opioid withdrawal may begin immediately after receiving an antagonist, or after cessation of use. Partial agonists (eg, buprenorphine) and agonist-antagonists (eg, pentazocine) can also produce withdrawal, so for the purpose of this review, the term "antagonist" will be discussed in relation to these drugs as well.

Signs and symptoms of withdrawal may begin 6 to 12 hours after the last dose of a short-acting opioid and 24 to 48 hours after cessation of methadone. Withdrawal symptoms typically peak within 24 to 48 hours of onset, but may persist for several days with short-acting agents and up to two weeks with methadone.

Patients experiencing opioid withdrawal may complain of the following:

•Dysphoria and restlessness

•Rhinorrhea and lacrimation

•Myalgias and arthralgias

•Nausea, vomiting, abdominal cramping, and diarrhea

Some or all of these symptoms may be present, and the severity depends on the individual's tolerance to opioids, the continued presence of opioid in the serum and end organs, and the duration of time over which the withdrawal has occurred. As an example, a person who is tolerant to 200 mg/day of methadone who was administered two milligrams of naloxone intravenously would experience much more severe symptoms than someone taking 10 mg of methadone daily who stopped abruptly (ie, "cold turkey"). A thorough history should ascertain why the patient discontinued opioid use to ensure there is not another underlying medical condition that precluded them from obtaining the drug.

●Physical examination — Opioid withdrawal is characterized by mydriasis (pupillary dilation), yawning, increased bowel sounds, and piloerection (table 2). If the patient is in severe distress, heart rate, blood pressure, and respiratory rate may be increased. Hypotension may be present in the setting of volume depletion from vomiting and diarrhea. Temperature is normal, and with the exception of very severe cases, mental status is preserved.

●Diagnosis – Most patients in opioid withdrawal have good insight into their problem, and the diagnosis is usually established by history alone. When present, the findings of yawning and lacrimation are helpful because of their specificity.

DIFFERENTIAL DIAGNOSIS — Opioid withdrawal may appear similar to other withdrawal or intoxication syndromes. Patients with opioid withdrawal typically have a normal mental status and do not develop seizures. In addition, significant tachycardia or hypertension is rare. Many patients in opioid withdrawal have a pulse and blood pressure within normal limits. Although some in opioid withdrawal have a tachycardia that reflects their agitation, discomfort, or hypovolemia, only a small minority of patients manifest both hypertension and tachycardia. When present, these signs are almost always a result of a surge in catecholamines from iatrogenically-induced withdrawal. (See "Opioid withdrawal in the emergency setting", section on 'Differential diagnosis'.)

Ethanol withdrawal — Ethanol withdrawal may present with a broad spectrum of severity and vital sign abnormalities. It is much more likely to cause tachycardia and hypertension than opioid withdrawal. In contrast to opioid withdrawal, seizures and altered mental status may be prominent.

A rapid overview of moderate and severe ethanol withdrawal is provided (table 3). (See "Management of moderate and severe alcohol withdrawal syndromes".)

Sedative-hypnotic withdrawal — Similar to ethanol withdrawal, patients with sedative-hypnotic withdrawal are more likely to have tachycardia and hypertension than patients with opioid withdrawal. Unlike typical opioid withdrawal, sedative-hypnotic withdrawal may cause seizures and hyperthermia. (See "Benzodiazepine poisoning".)

Sympathomimetic intoxication — Cocaine, amphetamine, or other sympathomimetic intoxication may produce mydriasis, agitation, tachycardia, and hypertension, but these findings are usually much more severe than occur in opioid withdrawal. Severe sympathomimetic intoxication is associated with seizures and hyperthermia which is not seen with typical opioid withdrawal. (See "Cocaine: Acute intoxication" and "Methamphetamine: Acute intoxication" and "Acute amphetamine and synthetic cathinone ("bath salt") intoxication", section on 'Clinical features of overdose'.)

Cholinergic poisoning — Poisoning with cholinergic agents (eg, organophosphates or carbamates) may cause diarrhea and vomiting, but can be distinguished from opioid withdrawal by the presence of altered mental status, bradycardia, and salivation. In patients with organophosphate poisoning, fasciculations, muscle weakness, and seizures may occur, which would further differentiate that clinical entity from opiate withdrawal. (See "Organophosphate and carbamate poisoning", section on 'Clinical features'.)

A rapid overview for the treatment of organophosphate and carbamate poisoning is provided (table 4).

ACUTE MANAGEMENT OF OPIOID WITHDRAWAL

Approach — The approach to managing acute opioid withdrawal in adolescents is generally consistent with the approach in adult patients (table 5). Commonly used medications in this setting include buprenorphine, methadone, and clonidine (table 6); evidence supporting the use of these agents in adolescent patients is limited [13]. Acute treatment of opioid withdrawal is discussed in detail separately. (See "Opioid withdrawal in the emergency setting".)

Of note, ultrarapid opioid detoxification, which is a controversial procedure that has been used in adult patients, is not used in adolescents because it has associated risks (ie, risks of general anesthesia, seizures, hemodynamic instability) without a clear benefit. (See "Opioid withdrawal in the emergency setting", section on 'Ultrarapid opioid detoxification'.)

Methadone is a reasonable alternative if buprenorphine is unavailable or unfamiliar.

Buprenorphine — Buprenorphine, a partial opioid agonist, is also effective for treatment of acute withdrawal in the emergency setting and is preferred for medically supervised detoxification in adults, but experience in adolescents is limited. Advantages to is use in supervised withdrawal include a long duration of action, higher affinity for mu-opioid receptor than all opioids except fentanyl, slow dissociation from the receptor, and greater safety in overdose than full agonists such as methadone. However, careful administration is needed to avoid precipitating or worsening withdrawal. (See "Opioid withdrawal in the emergency setting" and "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder", section on 'Buprenorphine versus methadone'.)

Methadone — Methadone, a long-acting opioid with a half-life of 24 to 36 hours, is the medical therapy sometimes used for opioid withdrawal in adults in the emergency setting (table 6). Its use relieves opioid craving and withdrawal symptoms and when given in sufficient doses, blocks the euphoric effects of opioids. However, buprenorphine is preferred to methadone during medically supervised withdrawal after emergency treatment because methadone poses a much greater risk of lethal overdose and intravenous abuse. (See "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder".)

A method of treating opioid withdrawal symptoms using methadone without causing over-sedation or severe patient discomfort is discussed in detail elsewhere. (See "Opioid withdrawal in the emergency setting".)

Other withdrawal symptoms (eg, pain, muscle spasm, diarrhea) can be treated with nonsteroidal antiinflammatory drugs (NSAIDs), analgesics, muscle relaxants, and antidiarrheals (table 6).

Patients who need analgesia for coexisting medical problems during methadone treatment should be treated with NSAIDs if possible. Narcotics with antagonist action (eg, pentazocine [Talwin], nalbuphine [Nubain], and butorphanol [Stadol]) should be avoided because they can precipitate immediate withdrawal.

Clonidine — Clonidine may be used as an alternative to methadone or buprenorphine treatment. It decreases withdrawal symptoms by blocking the release of norepinephrine. It can be used with methadone when methadone is tapered below 15 mg. In higher doses (greater than 1.2 mg per day), clonidine can cause dry mouth, sedation, orthostasis, and constipation. Patients taking clonidine should be monitored for hypotension. The use of clonidine to manage acute withdrawal from opioids is discussed in detail elsewhere. (See "Opioid withdrawal in the emergency setting".)

Rapid detoxification — Ultrarapid opioid detoxification has been extensively promoted as a faster, more comfortable means of stopping use. In this practice, opioid antagonists are administered under general anesthesia or heavy sedation with the intent of producing withdrawal. The procedure is controversial in adults and is not used in adolescents because it exposes people to the risks of general anesthesia, as well as seizures and hemodynamic instability, without a clear benefit. (See "Opioid withdrawal in the emergency setting", section on 'Ultrarapid opioid detoxification'.)

MEDICALLY SUPERVISED DETOXIFICATION — Medically supervised opioid withdrawal for adolescents is discussed in detail separately. (See "Substance use disorder in adolescents: Treatment overview", section on 'Medically supervised withdrawal'.)

Opioid detoxification of pregnant adolescents is discussed separately. (See "Opioid use disorder: Overview of treatment during pregnancy", section on 'MOUD or medically assisted withdrawal?'.)

Drug use disorder is pharmacologic (withdrawal symptoms occur when drug use is discontinued) and psychologic (compulsive drug use despite problems related to use, inability to reduce the frequency or intensity of use, preoccupation with drug-seeking behavior). Thus, the treatment of adolescents with opioid addiction requires medical, behavioral, and psychologic therapy. (See "Substance use disorder in adolescents: Treatment overview".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opioid use disorder and withdrawal" and "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use".)

SUMMARY AND RECOMMENDATIONS

●Diagnosis

•The discontinuation of opioids leads to a constellation of withdrawal symptoms known as the abstinence syndrome (table 1). The severity of the abstinence syndrome depends upon the type and frequency of the drug used. The withdrawal syndrome usually is elicited if opioid use is discontinued after several months of daily usage (three to four times per day). (See 'Symptoms of opioid withdrawal' above.)

•Most patients in opioid withdrawal have good insight into their problem, and the diagnosis is usually established by history alone. When present, the findings of yawning and lacrimation are helpful because of their specificity. Other findings of opioid withdrawal are provided in the table (table 2). (See 'Clinical features and diagnosis' above.)

•Opioid withdrawal can be distinguished from other withdrawal or intoxication syndromes in adolescents by a normal mental status and the absence of seizures. Tachycardia or hypertension also tend to be less prominent in adolescents presenting with opioid withdrawal. (See 'Differential diagnosis' above.)

●Treatment

•The approach to managing acute opioid withdrawal in adolescents is generally consistent with the approach in adult patients (table 5). Commonly used medications in this setting include buprenorphine, methadone, and clonidine; evidence supporting the use of these agents in adolescent patients is limited. Acute treatment of opioid withdrawal is discussed in detail separately. (See "Opioid withdrawal in the emergency setting" and "Substance use disorder in adolescents: Treatment overview", section on 'Opioid use disorder'.)  

•After treatment of withdrawal, initial and maintenance therapy for opioid use disorder in adolescents is essential. The management of substance use disorder in adolescents is discussed separately. (See "Substance use disorder in adolescents: Treatment overview".)