Michael, who’s 9, is brought in by his parents for his first psychiatric assessment. His parents report that lately, Michael has been worrying all the time. He asks to sleep in his parents’ bed. This past month, he also began having problems separating from his parents in the morning for school. Michael’s therapist suggested a medication assessment. His parents are distressed, and his mother recently gave Michael half of her own 0.5 mg tablet of alprazolam, which “worked beautifully.” Michael now declines to go to therapy and asks for the “fear pill.” However, his parents tell him this must be prescribed by his own “worry doctor.”

Michael may be like a lot of your patients. Because of their quick action, benzodiazepines (BZDs) are frequently prescribed to treat patients with anxiety and other conditions. However, as we already see with Michael and his family, clinicians need to consider the potential for unintended and problematic consequences of benzodiazepine use. The following is a primer that might help you decide how to approach these challenging situations.

First, though, here’s a brief history of benzodiazepines. In 1955, while working to replace barbiturates, Polish chemist Leo Sternbach discovered chlordiazepoxide. Further investigations showed the compound to have potent sedative, anticonvulsant, anxiolytic, and muscle-relaxing effects. In the 1970s, BZDs became the world’s most commonly prescribed medications. The Rolling Stones’ 1966 hit “Mother’s Little Helper” was about diazepam. In the 1980s, research uncovered how chronic benzodiazepine use could cause dependence and withdrawal (Lader M, J Clin Psychiatry 1987;1(48):12-6).

How do benzodiazepines work? They increase the efficiency of gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the brain. GABA’s function is to slow or calm neural processes, which may explain why enhancing its efficiency helps to treat anxiety disorders in adults and children.

About child/adolescent anxiety
Anxiety disorders affect 15%–20% of youth (Kessler RC et al, Int J Methods Psychiatric Res 2012;21(3):169–184). Clinical research in pediatric anxiety focuses on three main syndromes: generalized anxiety disorder, social phobia, and separation anxiety disorder, which all share a similar neurophysiology, comorbidity, and treatment response.

All three of these conditions respond to benzodiazepines, SSRIs, and cognitive behavioral therapy (CBT), which includes psychoeducation of children and caregivers, relaxation training and breathing techniques, cognitive restructuring, problem solving, and systematic exposure to feared stimuli, among other strategies.

Medication studies for anxiety have focused more on SSRIs than benzodiazepines. As an example of SSRI research, the efficacy of both medication and therapy was demonstrated in the CAMS (Child/Adolescent Anxiety Multimodal Study), which randomly assigned 488 children and adolescents ages 7–17 to CBT, sertraline, sertraline plus CBT, and placebo. All active treatments were superior to placebo. The combination therapy was superior to medication or CBT alone, and over 80% of acute responders maintained positive response at 24- and 36-week follow-ups (Piacentini J et al, J Am Acad Child Adolesc Psychiatry 2014;53:297–310).

Reasons to use benzodiazepines in children
Although SSRIs are usually the medication treatment of choice for anxiety in children, benzodiazepines are becoming increasingly popular. A study in the United Kingdom showed a significant increase in anxiolytic prescriptions for youth seen in primary care settings between 2003 and 2011 (John A et al, Journal of Affective Disorders (2015);183:134–141). As the authors hypothesize, controversies about the suicide risk of SSRIs may be steering general practitioners away from these meds and toward benzodiazepines, which are seen as less risky.

There is good evidence that benzodiazepines are effective in children for a narrow set of situations, in particular episodic stressors like surgical procedures that may trigger acute anxiety, leading to concentration problems, insomnia, behavioral issues, and functional impairment. In a meta-analysis on the efficacy of BZDs as acute anxiolytics in children undergoing procedures, 21 trials involving 1,416 participants were reviewed, and the conclusion was that BZDs are effective and well-tolerated when used as short-term anxiolytics for pediatric patients (Kuang H et al, Depress Anxiety 2017;34:888–896). In particular, there was no difference in the emergence of irritability in the BZD vs control groups.

Another condition where BZDs can be helpful is pediatric catatonia. This likely under-recognized condition presents with motor, vocal, and behavioral features. Its specific symptoms may include rigidity, posturing, stupor, negativism, and echopraxia/echolalia, among many others. A BZD challenge with lorazepam may help with both the diagnosis and treatment of pediatric catatonia (Benarous X et al, Schizophr Res 2017;30(17):430–439).

Checklists are also helpful for diagnostic clarification. These include SCARED (the Screen for Child Anxiety Related Emotional Disorders), SCAS (the Spence Children’s Anxiety Scale), PARS (Pediatric Anxiety Rating Scale), and others.

The psychiatrist meets with Michael and his parents (both separately and together) and obtains relevant checklists (SCARED, PARS). He decides Michael meets criteria for generalized anxiety disorder as well as separation anxiety disorder. He prescribes lorazepam 0.5 mg daily, because lorazepam has a longer half-life and therefore may be less likely than alprazolam to cause dependence.

If you decide that a specific situation warrants use of benzodiazepines, which are the best ones to prescribe for children? In our experience, it is usually better to favor mid-range half-life medications, such as lorazepam, over either the shorter-range alprazolam or the longer-range diazepam. Drugs with shorter half-lives may bring rebound anxiety and craving, and those with longer half-lives can lead to accumulation of the drug and over-sedation. Although some clinicians use PRN dosing for specific events, many will use a fixed dosing schedule when treating an ongoing symptom—this helps avoid withdrawal and craving that might lead to psychological and physiological dependence.

At follow-up a few weeks later, the parents note that Michael becomes irritable more often now, particularly before taking the lorazepam. The lorazepam also doesn’t seem to be working as well for Michael’s core anxiety symptoms as it had initially. The parents ask if Michael can take 2 pills to see if that will work better.

Problems with benzodiazepine usage
Common BZD withdrawal symptoms, such as anxiety and insomnia, occur in both children and adults. But since younger children can’t always effectively articulate what they are feeling, it may be more difficult to differentiate their withdrawal symptoms from symptoms of the underlying anxiety issue. Long-term use of BZDs typically leads to tolerance, dependence, and withdrawal. In controlled BZD studies in children, irritability, fatigue/drowsiness, and dry mouth appear to be common problems. Additionally, these medications have a high abuse and diversion potential, so they must be carefully controlled.

Before prescribing BZDs, you should get informed consent from parents, making sure they understand the risks of dependency (mostly an issue with teenagers) and withdrawal. Children who are treated with BZDs chronically may have BZD withdrawal if the dosage is abruptly reduced, or if the medication is stopped—make sure parents understand this danger.

Tolerance, dependence, and withdrawal are potential issues in all patients using BZDs, including children. As with adults, tolerance and dose escalation may be a higher risk for individuals with past use of psychotropics and with a longer duration of use (Tvete I et al, BMJ Open 2013;3(10):e003296). Risk factors for benzodiazepine dependence also include alcohol dependence, sleep issues, and use of antidepressants.

The psychiatrist explains to the family that, despite the initially positive effect, the lorazepam is not working well for Michael’s anxiety and is causing withdrawal side effects between doses. He prescribes a modest 25 mg daily dose of sertraline, plans for gradual reduction and discontinuation of the lorazepam, and encourages the family to return to the referring therapist for CBT. Michael’s providers work together well, and within a few months his separation issues and fears gradually improve. His parents are instructed to avoid benzodiazepines in treating Michael’s symptoms.

Care must be taken in the reduction and discontinuation of benzodiazepines to reduce the risk of withdrawal and craving. Benzodiazepines are thought to interfere with therapy, specifically CBT, partly due to memory impairment. Because BZDs reduce anxiety, they can leave patients less motivated to participate in therapy that is important to their long-term recovery.

Conclusions
Anxiety disorders, such as generalized anxiety disorder, social phobia, and separation anxiety disorder, are very common in children and adolescents. Current research supports use of psychological interventions (e.g., CBT) and, in moderate to severe cases, the addition of SSRIs. When faced with dental or surgical procedures, BZDs may have a limited but helpful role in children with acute anxiety. Keep their use very short term and monitor closely.

CCPR Verdict: While benzodiazepines can be helpful for children, their most established uses are for acute anxiety management prior to dental and surgical procedures, and for catatonia. Try to avoid them when treating anxiety disorders—here, SSRIs and CBT are the treatments of choice.