DESCRIPTION

• Drug withdrawal is a physiologic response to an effectively lowered drug concentration in a patient with tolerance to that drug.
• Withdrawal results in a predictable pattern of symptoms that are reversible if the drug in question or another appropriate substitute is reintroduced.
• Sedative-hypnotic withdrawal is the most common life-threatening withdrawal syndrome in children. This includes withdrawal from barbiturates, benzodiazepines, baclofen, as well as γ-hydroxybutyrate and similar substances.
• Other substances that are associated with withdrawal syndromes include nicotine, opioids, selective serotonin reuptake inhibitors (SSRIs), and caffeine.

EPIDEMIOLOGY

• The most common life-threatening withdrawal syndrome, alcohol withdrawal, rarely occurs in children.
• Neonates born to alcohol-dependent mothers are at risk.

RISK-FACTORS

• Patients receiving sedatives or analgesics capable of causing tolerance are at risk.
• Any inpatient use of sedative or opioids >5 days is a risk factor for withdrawal.
• This risk is particularly important to consider with infusions or high doses of such substances in previously naive patients.

GENERAL-PREVENTION

• Clinician familiarity with tolerance and withdrawal associated with prescribed medications allows appropriate drug tapering.
• Drug abuse prevention is appropriate for all children.

PATHOPHYSIOLOGY

• Altered CNS neurochemistry is the most important and clinically relevant aspect of withdrawal pathophysiology.
• Under normal conditions, the CNS maintains a balance between excitation and inhibition. Although there are several ways to achieve this balance, excitation is constant and actions occur through removal of inhibitory tone.
• Relative to adults and younger children, adolescents are more prone to develop dependence and withdrawal syndrome due to immaturity of their prefrontal cortex.

ETIOLOGY

• Neonates
  • Maternal alcohol, caffeine, opioid, sedative-hypnotic, or SSRI use may result in a neonatal abstinence syndrome.
  • Treatment with caffeine, opioids, or sedative-hypnotics and subsequent discontinuation may result in subsequent development of an abstinence syndrome.
• Older children
  • Subsequent to treatment with opioids, or sedative-hypnotics, an abstinence syndrome may result.
  • Substance abuse, particularly opioids, γ-hydroxybutyrate, or other sedative-hypnotics, may result in an abstinence syndrome.
  • Frequent caffeine or nicotine use may lead to an abstinence syndrome.
• Use of opioid antagonists such as naloxone, naltrexone, and nalmefene is associated with development of opioid withdrawal.

HISTORY

• Typically, a history of substance exposure, either direct exposure or maternal use, will be elicited.
  • Exposure may be to prescribed medication or abusable substances.
  • Substance use by the mother or child might intentionally be concealed.
• The timing of withdrawal varies depending on the half-life of the substance involved.
  • Shorter half-life causes quicker onset of withdrawal with greater severity.
• Alcohol or sedative-hypnotics
  • Causes tremor, diaphoresis, agitation, insomnia, altered mental status, or withdrawal seizures
  • Baclofen withdrawal is more frequently severe or life-threatening relative to benzodiazepine withdrawal. History of pump manipulation or malfunction should be sought.
• Caffeine
  • Withdrawal may result in dysphoria, headache, behavioral changes, or agitation.
• Opioids
  • Nausea, vomiting, diarrhea, irritability, yawning, sleeplessness, diaphoresis, lacrimation, tremor, and hypertonicity may result.
  • Neonates can also have seizures, a high-pitched cry, skin mottling, and excoriation. These latter signs and symptoms are more typical of opioid withdrawal and rarely occur with neonatal alcohol withdrawal.
• Nicotine
  • Dysphoria, agitation, behavioral changes, and increased appetite may all occur.
• SSRIs
  • Neonatal withdrawal from SSRIs may result in jitteriness, agitation, crying, shivering, increased muscle tone, breathing and sucking problems, as well as seizure.
  • Children withdrawing from SSRIs may have jitteriness, agitation, dysphoria, behavioral changes, shivering, increased muscle tone, and seizure.

PHYSICAL-EXAM

• A clinically appropriate, validated scoring tool (e.g., Withdrawal Assessment Tool, Version 1 [WAT-1] for children or adolescents or the Finnegan Neonatal Abstinence Syndrome Scale for newborns) should be completed with the physical exam to obtain objective, valid assessment of severity of withdrawal.
• Vital signs including temperature should be evaluated regularly. Vital sign changes such as tachycardia and hypertension may occur concomitantly with acute drug withdrawal.
• Technology-dependent patients, such as children with an intrathecal baclofen pump, should have evaluation of the machine to determine if it is working properly.
• Most cases of substance withdrawal only result in behavioral changes. Opioid withdrawal may be accompanied by diaphoresis, mydriasis, yawning, and lacrimation.
• Sedative-hypnotic withdrawal may result in hypertension, tachycardia, hyperthermia, agitation, hallucinations, and seizure.

DIFF-DIAGNOSIS

• Hypoglycemia
• Intoxication with sympathomimetics, anticholinergics, theophylline, caffeine, aspirin, or lithium
• Thyroid storm
• Serotonin syndrome
• Neuroleptic malignant syndrome
• Encephalitis
• Meningitis
• Sepsis

TESTS

GENERAL-MEASURES

• Initial stabilization
  • Initial management is aimed at evaluating and supporting airway, breathing, circulation, serum glucose, and ECG (“A, B, C, D, E”).
• Supportive care is the most important general principle.
• The illness is managed with intent of close monitoring and addressing issues as they arise.

MEDICATION

• In adolescents and probably most children, symptom-triggered treatment is superior to fixed-regimen treatment in terms of patient outcome and length of stay.
• For neonates, a standardized regimen of drug tapering appears to be superior with regard to shorter length of stay.
• Patients with benzodiazepines or barbiturate withdrawal may be treated by reinstituting the drug and then tapering.
• Iatrogenic withdrawal induced by use of opioid antagonists should not be treated by opioid administration.
  • Withdrawal induced by naloxone should abate rapidly due to the brief half-life of naloxone.
  • Withdrawal induced by naltrexone or nalmefene will be much longer lasting. Symptomatic treatment may be indicated.
• There is no fixed quantity of drug to use for any withdrawal syndrome. Each patient requires a unique quantity of drug, and use of 80% of the previous dosing is a useful rough estimate.
  • Repeated dosing should continue until the symptoms are controlled, at which point maintenance and then tapering can occur.
• Sedative-hypnotic withdrawal
  • Ideally, withdrawal is treated with the same class of substance, such as benzodiazepine or barbiturate, if not the precise same drug.
  • Benzodiazepines are particularly useful due to the rapid onset of effect.
  • Diazepam has active metabolites that may assist in tapering the drug in older children and neonates.
  • In neonates, diazepam efficacy is poor.
  • Lorazepam 0.1 mg/kg IV (maximum initial dose 4 mg) may be repeated q30min until symptoms have improved.
  • Propofol is an outstanding medication for treatment of severe alcohol or sedative-hypnotic withdrawal in adults.
    • Propofol may be used in pediatric cases refractory to benzodiazepines and barbiturates.
    • Use is associated with respiratory depression.
    • Clinicians must be capable of airway management and expect airway support to be necessary when propofol is used.
    • Propofol use is safe in children, but rare cases of metabolic acidemia have occurred when prolonged infusions are used. Prolonged use of propofol infusion should be accompanied by close observation for acidemia.
• Opioid withdrawal
  • Heroin (as well as other opioids) withdrawal is best treated with an opioid of similar potency and equal or longer duration of action.
  • Buprenorphine, which has been introduced to pediatric and neonatal practice recently, is extremely promising as therapy for opioid withdrawal.
  • Buprenorphine is a partial opioid agonist, does not cause respiratory depression, and does not result in the pleasurable or euphoric sensation associated with morphine or methadone.
  • Buprenorphine is currently only prescribable by specific clinicians with a special Drug Enforcement Agency (DEA) approval to give this therapy.
  • Methadone is currently a preferred treatment for withdrawal in adolescents and adults.
  • 5 to 10 mg of methadone empirically is an appropriate initial dose to treat adolescents and adults.
  • For neonates, 0.05 mg/kg/dose PO or IV q6h with increase in dose by 0.05 mg/kg until symptoms are controlled, then the dosing interval can be increased to q12–24h
  • Patients who experience opioid withdrawal in the setting of chronic or intensive care may be treated by reinstituting infusion or dosing of the drug they were on before withdrawal symptoms and then tapering this, typically by 10% daily.
• Caffeine withdrawal
  • Caffeine as soft drink or tea taken to treat headache or agitation
  • Neonatal caffeine abstinence symptoms may be treated by reinstituting 75–100% of the caffeine dosage that was discontinued. This amount is then tapered, typically by 10% daily.
• Nicotine withdrawal is not typically treated in children.
• Use of nicotine patch, gum, or other delivery methods is used to increase success rate of abstinence rather than for medical management of the withdrawal syndrome.
• SSRI withdrawal in neonates may be treated with phenobarbital or a benzodiazepine such as diazepam or lorazepam.
  • Lorazepam dosing for SSRI withdrawal is 0.05 mg/kg IV q6h.
  • Phenobarbital dosing for SSRI withdrawal is 2.5 mg/kg/dose q12h. An optional loading dose either IV or PO may be used.
  • The quantity of SSRI excreted in breast milk varies between these medications, but generally, they are in breast milk in low quantities.
  • It is reasonable to permit or recommend breastfeeding for neonates experiencing SSRI withdrawal syndrome, despite medication instruction warnings to avoid breastfeeding.

ISSUES-FOR-REFERRAL

• Any patient with substance abuse issues should be referred for appropriate psychiatric or drug counseling.
• Most cases of substance withdrawal are best handled by an addiction specialist, medical toxicologist, intensivist, or other clinician experienced with management of withdrawal.

IN-PATIENT-CONSIDERATIONS

• Inpatient treatment for alcohol or sedative-hypnotic withdrawal is mandatory.
• Although withdrawal from opioids and SSRIs is not life-threatening, admission with initial management as an inpatient may be preferable.
• Maintenance IV fluid may be required in patients who are unable to take PO.
• Dehydration was once a leading cause of death among patients with alcohol withdrawal.
• Inpatients who have been converted from parenteral to oral medications and are controlled with oral medications may be discharged for home tapering.
• Patients who never require parenteral therapy may be discharged with oral replacement medication after consultation with the appropriate specialist.

FOLLOWUP-RECOMMENDATIONS

• If disposition will be discharge, it is crucial to ensure that the patient’s condition is stable before discharge.
• If there is any question regarding whether the patient can be appropriately managed as an outpatient, initial inpatient management is preferable.

PATIENT-TEACHING

Patients or parents should be aware of withdrawal symptoms to be vigilant for detecting future events.

PROGNOSIS

• With appropriate therapy, withdrawal is well tolerated.
• Poor prognostic factors are primarily related to comorbidities.

COMPLICATIONS

Complications of hypertension, tachycardia, hyperthermia, and CNS agitation or seizure may occur with sedative-hypnotic withdrawal.

ICD9

• 779.5 Drug withdrawal syndrome in newborn
• 779.4 Drug reactions and intoxications specific to newborn
• 292 Drug withdrawal
• 291.81 Alcohol withdrawal

ICD10

• P96.1 Neonatal w/drawal symp from matern use of drugs of addiction
• P96.2 Withdrawal symptoms from therapeutic use of drugs in newborn
• F13.939 Sedatv/hyp/anxiolytc use, unsp w withdrawal, unsp
• F11.93 Opioid use, unspecified with withdrawal
• F10.988 Alcohol use, unspecified with other alcohol-induced disorder
• F19.939 Other psychoactive substance use, unsp with withdrawal, unsp

SNOMED

• 414819007 neonatal Abstinence Syndrome (disorder)
• 206572008 Neonatal withdrawal symptoms from maternal use of drugs of addiction (finding)
• 2.3601000119e+013 Sedative withdrawal (disorder)
• 87132004 Opioid withdrawal (disorder)
• 191480000 Alcohol withdrawal syndrome (disorder)
• 363101005 Drug withdrawal (disorder)