Drug withdrawal is a physiologic response to an effectively lowered drug concentration in a patient tolerant to the drug in question. Withdrawal results in a predictable constellation of symptoms that are reversible if the drug is reintroduced. Withdrawal is a phenomenon of altered neurochemistry, and the central nervous system (CNS) is the most consequential target. Under normal conditions, the CNS maintains a balance between excitation and inhibition. Although such balance can be achieved by several means, excitation is constant and actions occur through removal of inhibitory tone.¹

Clinicians may encounter withdrawal symptoms as the primary reason for hospitalization or as a consequence of hospitalization when interruption of drug use occurs, either intentionally or unintentionally.

Withdrawal syndromes are well known to occur in hospitalized patients, particularly those admitted in intensive care units (ICUs). Up to 20% of pediatric ICU patients who receive sedative infusions of opioids or benzodiazepines experience withdrawal symptoms.² A case series examining pediatric ICU patients who received infusions of both fentanyl and midazolam noted that 50% exhibited withdrawal symptoms. In a representative study of children in critical care units who receive fentanyl sedation,³ it was recognized that avoidance of oversedation and appropriate medication tapering may reduce the incidence of drug withdrawal in hospitalized children.^4,5

In recent decades, overuse and abuse of prescription opioids have been epidemic in North America, Europe, and Australia. Opioid withdrawal has become a recognized issue associated with prescription opioid abuse.⁶

This chapter focuses on syndromes associated with withdrawal from the following classes of agents: ethanol, sedative-hypnotics such as benzodiazepines and barbiturates and gamma hydroxybutyrate (GHB), opioids, and selective serotonin reuptake inhibitors (SSRIs).

The onset, progression, duration, and severity of withdrawal symptoms depend on the patient’s degree of tolerance and the half-life of the drug involved. In general, drugs with shorter half-lives produce withdrawal symptoms sooner after discontinuation, and the symptoms tend to be more severe (Table 170-1).

ETHANOL WITHDRAWAL

Ethanol withdrawal is one of the most common withdrawal syndromes in the general population, behind those of nicotine and caffeine, but is extraordinarily rare in children. Pediatric alcohol withdrawal only rarely occurs in neonates born to alcohol abusing mothers. The neonatal alcohol withdrawal syndrome is multifaceted and should be considered a spectrum. The discrete aspects of alcohol withdrawal can follow a progression or occur independently. These aspects include tremulousness, hypertension, tachycardia, diaphoresis, agitation, crying, insomnia, poor sucking, poor feeding, and seizures.

SEDATIVE-HYPNOTIC WITHDRAWAL

Sedative-hypnotic agents include benzodiazepines, barbiturates, γ-hydroxybutyric acid (GHB), and γ-butyrolactone (GBL), and withdrawal from these drugs may be indistinguishable from alcohol withdrawal because the presenting symptoms are nearly identical. Thus, tremulousness, altered mental status, agitation, insomnia, hypertension, tachycardia, diaphoresis, and in severe cases seizures may occur. However, the chronology may offer a clue to the cause of the withdrawal.

Because of rapid metabolism and the lack of active metabolites, withdrawal from GHB or GBL generally occurs within 2 to 6 hours of cessation of drug use.⁷ In contrast, diazepam has active metabolites, and thus withdrawal symptoms may occur within several hours but might not be manifested for >24 hours. Seizures may result from any sedative-hypnotic withdrawal. Different sedative-hypnotic agents often share enough common receptor or metabolic activity that one drug can be substituted for the other to treat withdrawal—a phenomenon known as cross-tolerance.

OPIOID WITHDRAWAL

Opioid withdrawal can be divided into physical signs and symptoms and psychological symptoms. Piloerection, yawning, and lacrimation are some of the physical signs, whereas nausea, vomiting, and diarrhea are common symptoms. Infants may exhibit irritability, crying, insomnia, and poor feeding. Although there is no plausible pathophysiologic explanation for such, seizure has been well described in association with opioid withdrawal. This is unique, and opioid withdrawal in any other age patient is never associated with alteration of sensorium or seizure.

Withdrawing patients also have intense opioid craving associated with the feeling of being unwell. In contrast to sedative-hypnotic withdrawal, opioid withdrawal is associated with minimal autonomic instability. Patients may be tachycardic and have a slight elevation in blood pressure, but this is partly in response to their physical and emotional symptoms. Furthermore, other than agitation, opioid withdrawal is associated with normal mental status.

Opioid withdrawal may occur in a gradual manner when discontinuation begins, or may occur with abrupt onset of severe symptoms if an opioid antagonist such as naloxone or naltrexone is administered to an opioid-tolerant patient.

Opioid-tolerant adolescents with precipitated withdrawal secondary to naloxone or other opioid antagonists may exhibit extreme psychomotor agitation or become violent.

SELECTIVE SEROTONIN REUPTAKE INHIBITOR WITHDRAWAL

The most recently described withdrawal syndrome is that of SSRIs, probably related to temporary and self-limited serotonin dysregulation.^8,9 Signs and symptoms include dizziness, gastrointestinal disturbances, headaches, lethargy, anxiety or agitation (or both), paresthesias, tremors, sweating, insomnia, irritability and poor feeding. The onset is usually within 1 week of abrupt cessation of treatment, and symptoms generally resolve within 3 weeks. Most reports describe symptoms associated with withdrawal from venlafaxine, but the syndrome, which occurs in both neonates and children, has also been reported with citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.¹⁰

NEONATAL WITHDRAWAL SYNDROMES

Maternal addiction can lead to neonatal withdrawal. The time to symptom presentation after birth varies with the agent in question. Neonatal alcohol withdrawal typically begins within 3 days of parturition. Symptoms most typically include agitation, irritability, crying, tremors, tachycardia, hypertension, insomnia, and diaphoresis.¹¹ Opisthotonos, nystagmus, clonus, seizures, hypertonia, hyperactive or asymmetric reflexes, excessive rooting, diarrhea, vomiting, and inability to thermoregulate may also occur.¹² Opisthotonos and abdominal distention rarely occur in opioid withdrawal and can help differentiate the two when the mother has abused multiple substances. Although initially thought to occur only as a complication of fetal alcohol syndrome (FAS), neonatal alcohol withdrawal can occur independently of FAS. The presentation of neonates withdrawing from sedative-hypnotics such as benzodiazepines or barbiturates would be clinically similar to neonatal alcohol withdrawal.

Withdrawal from caffeine, inhalants, and SSRIs has been reported in neonates, and it is estimated that 20% to 30% of newborns exposed in the third trimester are affected. Symptoms include jitteriness, agitation, crying, shivering, increased muscle tone, breathing and sucking problems, and seizures.¹³

Neonatal opioid withdrawal (abstinence) syndrome is discussed in Chapter 131.

The withdrawal symptoms described have some distinguishing and overlapping features (see Table 170-2), and a number of nontoxic disorders may be mistaken for withdrawal (Table 170-3). In addition, certain toxic agents can mimic withdrawal symptoms. Organophosphate poisoning can result in constricted pupils, diaphoresis, vomiting, agitation, seizures, and altered mental status. A combination of these symptoms could easily be confused for either opioid or sedative-hypnotic withdrawal. Sympathomimetic intoxication can present in a manner similar to sedative-hypnotic withdrawal and create the same diagnostic dilemma. Additionally, a patient with anticholinergic toxicity may present with hallucinations, tachycardia, and hyperthermia. Other drugs that may mimic substance withdrawal in overdose are listed in Table 170-4.