Benzodiazepines and stimulants for patients with substance use disorders
Careful assessment, close monitoring are essential when prescribing drugs with abuse potential
Although benzodiazepines and stimulants have well-documented efficacy for numerous psychiatric disorders, psychiatrists hesitate to prescribe these medications to patients with substance use disorders (SUDs)—even to those with a comorbid condition that likely would respond to a benzodiazepine or stimulant—because of risk of abuse or dependence. Conventional practice typically has focused on treating active substance use first rather than using simultaneous treatments. Prejudice, fear, and misinformation can influence this decision.
We believe these cases lie on a continuum. At one extreme, ignoring a past or present SUD may lead a remitted patient toward relapse, or further delay recovery for an active user. At the other end, psychiatrists who overreact to a remote history of substance use may deprive patients of legitimate pharmacologic symptom relief. Most cases lie somewhere in the middle.
A literature review does not support the assertion that the use of these medications leads to future substance use or worsens active use, especially for stimulants. In fact, stepwise—as opposed to concurrent—treatment for both conditions actually may delay recovery and increase patients’ risk for morbidity.
We outline issues involved in these complex clinical situations, point out controversies, review relevant research data, and offer guidelines for treatment.
CASE 1 Panic disorder in sobriety
Since he was a teen, Mr. A, age 51, drank heavily, which cost him jobs and relationships. After being convicted for driving under the influence, he was court-ordered to attend a rehabilitation facility, where, as he describes it, he “finally turned [his] life around.” He followed up residential treatment with regular attendance at Alcoholics Anonymous meetings.
After 1 year of sobriety, Mr. A develops increasingly frequent episodes of intense anxiety with sweating, nausea, chest pain, and hyperventilation and is diagnosed with panic disorder. His internist prescribes alprazolam, 0.5 mg 3 times a day, which provides some symptom relief, and refers him for follow-up psychiatric care. At his first visit, Mr. A confides to his psychiatrist that he is taking much more than the prescribed dosage of alprazolam, even when he is not experiencing anxiety, and is contemplating “buying it on the street” if his dosage is not raised to “at least 3 mg 3 times a day.”
CASE 2 Anxiety in controlled psychosis
Ms. B, age 40, had her first psychotic break at age 18 and was diagnosed with schizophrenia. Since then, she has had multiple psychiatric hospitalizations, usually presenting with auditory hallucinations and a recurring delusion that the person who calls herself Ms. B’s mother is really an actress “playing” her mother. At times this delusion has led Ms. B to attack her “imposter” mother. Over several years Ms. B began to drink heavily, but recently achieved a few months of sobriety by attending dual-diagnosis groups at her local community mental health center and individual psychotherapy sessions with her case manager. Fortunately, Ms. B’s psychosis has been stabilized with risperidone long-acting injection, 25 mg every 2 weeks, which she tolerates well.
When her beloved calico cat passes away, Ms. B experiences intense anxiety. Ms. B’s friend tells her she “needs some Valium,” but her psychiatrist, case manager, and the other patients in her dual-diagnosis group are not sure this is a good idea.
Pros. There are multiple legitimate uses of benzodiazepines in general medicine and psychiatric practice, based upon their considerable sedative/hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties (Table 1).1
Recommendations regarding benzodiazepine use for anxious patients with a history of SUD are not clear-cut. First, it often is difficult to determine whether the patient truly has an anxiety disorder or is suffering anxiety symptoms secondary to substance use and/or withdrawal. In addition, even if a diagnosis of a separate anxiety disorder is established, psychiatrists debate how to treat such patients. Some clinicians maintain that benzodiazepines should be used only for acute detoxification, and that ongoing benzodiazepine use will lead to relapse or benzodiazepine dependence. However, in a prospective study of 545 alcohol use disorder (AUD) patients receiving benzodiazepines for anxiety disorders, Mueller et al2 found no association—at 12 months or at 12 years—between benzodiazepine use and AUD recurrence. Furthermore, there was no difference in benzodiazepine usage when comparing patients with and without an AUD.3
Clinical uses of benzodiazepines
Anxiety disorders (eg, generalized anxiety disorder, panic disorder, posttraumatic stress disorder, social phobia, and obsessive-compulsive disorder)
Side effects of other psychiatric medications (eg, akathisia with antipsychotics or tremor with lithium)
Alcohol or benzodiazepine withdrawal
Acute agitation states, either as monotherapy or as adjuncts to antipsychotics or mood stabilizers
Source: Reference 1
Cons. Although widely prescribed—and despite their efficacy in numerous conditions— both acute or long-term benzodiazepine use frequently causes adverse effects.4 Patients may develop tolerance, which can lead to escalating dosages and/or to withdrawal symptoms when patients attempt to cut back. Benzodiazepines eventually become ineffective for sleep, and continued use can cause rebound insomnia. Also, with many patients taking benzodiazepines long-term, clinicians struggle to differentiate between “real” anxiety symptoms and subtle states of withdrawal from fluctuating benzodiazepine blood levels.5
Geriatric patients who take benzodiazepines are at risk for falls and hip fractures.4 Although older dementia patients are at particular risk for cognitive problems— including frank delirium—secondary to benzodiazepine use, patients of all ages are susceptible to these medications’ deleterious neurocognitive effects.
Benzodiazepines can lead to excessive sedation, thereby impairing performance at work or school, and have been implicated as a cause of motor vehicle accidents.6 Finally, a serious drawback to benzodiazepine use is possible lethality in overdose, especially when combined with alcohol.
Benzodiazepine prescribing should not be taken lightly. Always analyze the difference between benzodiazepines’ well-documented efficacy and their adverse effect profile. This risk-benefit analysis becomes much more complex for patients with SUDs.
Special considerations. Patients at higher risk for benzodiazepine abuse include those with:
- severe alcohol dependence (ie, long-term use, drinking since a young age [“Type II”])
- intravenous drug use
- comorbid alcoholism and antisocial personality disorder.7,8
Exercise special caution when considering benzodiazepines for patients with severe psychiatric illness such as schizophrenia-spectrum disorders, bipolar disorder, or severe depression. Patients with schizophrenia have high rates of alcohol, cocaine, cannabis, and benzodiazepine abuse.9,10 Bipolar disorder patients show similar vulnerability—up to 56% of patients screen positive for substance abuse or dependence.11 Vulnerability to addiction in severely ill psychiatric patients is thought to be related to several factors, including:
- use of drugs as self-medication
- genetic predisposition
- environment/lifestyle that supports substance abuse
- neurobiologic deficits that lead to lack of inhibition of reward-seeking behaviors.11
Bipolar disorder patients in particular score high on measures of sensation seeking, which leaves them vulnerable to abusing all classes of substances.12
In a 6-year study of 203 patients with severe psychiatric illnesses and SUDs, Brunette et al13 found that these patients were 2.5 times more likely than patients with severe psychiatric illness alone to abuse prescribed benzodiazepines. In an analysis of Medicaid records, Clark et al14 found similar vulnerability in patients with major depressive disorder (MDD) and SUD. Not only did these patients show a higher rate of benzodiazepine use than patients with MDD without SUD, but the dual-diagnosis group also gravitated toward more addictive high-potency/fast-acting benzodiazepines, such as alprazolam, estazolam, or triazolam.
Case discussion/suggestions. Initially, Mr. A may seem to be an appropriate candidate for closely monitored benzodiazepine use. However, he shows a pattern of misuse, likely related to his history of severe alcohol dependence and alprazolam use. This benzodiazepine is fast-acting and has a short half-life, and thus is highly reinforcing.
Similarly, Ms. B might benefit from benzodiazepine treatment. However, her history of schizophrenia and alcohol abuse makes her a risky candidate, and alternative treatments for anxiety symptoms should be considered. If prescribed at all, a benzodiazepine should be used only short-term (eg, 1 to 2 weeks).
In general, avoid prescribing benzodiazepines to most patients who have an ongoing or past SUD.15 Consider making an exception for SUD patients with comorbid anxiety disorders, with close monitoring of their benzodiazepine use. Clonazepam, chlordiazepoxide, clorazepate, and oxazepam may be less reinforcing for SUD patients than diazepam, lorazepam, alprazolam, estazolam, or triazolam.7,16 The drawbacks of benzodiazepines, especially in the situations described above, point to the need to find alternative treatments (Table 2).17 Keep in mind nonpharmacologic options, which completely avoid the risks of medication misuse and diversion. Cognitive-behavioral therapy (CBT), for instance, has well-documented efficacy in treating insomnia and anxiety disorders.18,19
Alternatives to benzodiazepines for anxiety and/or insomnia
CBT, relaxation techniques, sleep hygiene counseling
Many advantages to nonpharmacologic interventions (eg, fewer side effects, no risk of substance dependence)
Antihistamines (eg, diphenhydramine, 25 to 50 mg at bedtime* for sleep, or 2 to 3 times a day for anxiety)
Can be used for anxiety or insomnia; can cause confusion in older patients
Off-label use; many agents in this class have metabolic side effects
First-line for many anxiety disorders, including panic disorder, GAD; possible weight gain and sexual side effects
Mirtazapine (7.5 to 30 mg at bedtime*)
Sedation side effect helps with sleep; weight gain and oversedation limit use
Trazodone (25 to 100 mg at bedtime*)
Commonly used off-label as a sleep aid
Monoamine oxidase inhibitors
May be useful for social phobia; dietary restrictions and side effects limit use
Doxepin (3 to 6 mg at bedtime)
Minimal anticholinergic and alpha-blockade side effects at this dose; FDA-approved for insomnia
Gabapentin (300 to 2,000 mg/d* in divided doses)
Off-label use, mild anxiolytic and sedative properties, relatively weight neutral
Beta blockers (eg, propranolol, 20 to 80 mg twice a day*)
Useful for peripheral manifestations of anxiety; may be effective for social phobias
Pregabalin (50 to 200 mg 3 times a day*)
Off-label use; industry-sponsored studies show comparable to SNRIs for anxiety
Non-benzodiazepine GABAA receptor modulators
Short-term option for primary insomnia, some abuse potential
Melatonin (1 to 3 mg at bedtime*)
Mild and ‘natural’ but not always an effective sleep aid
*Off-label approximate doses based on the authors’ clinical experience and consensus of the literature; agents listed may require slow titration and close monitoring for adverse effects
CASE 3 Adult ADHD and marijuana use
Mr. C, age 30, presents to a psychiatrist with ongoing complaints of inattention, fatigue, and difficulty staying organized. A self-report screen yields symptoms consistent with adult attention-deficit/hyperactivity disorder (ADHD). Mr. C’s school and job history and collateral history from his wife appear to corroborate his assertion that his symptoms have been lifelong. He later admits to regular marijuana use. After further discussion and full evaluation of his substance use, Mr. C is started on bupropion, titrated to 300 mg/d. After 2 months, despite faithful attendance at appointments and openness about his continued marijuana use, Mr. C’s symptoms remain unchanged. He asks about atomoxetine.
Pros. Despite many clinicians’ hesitance to prescribe controlled substances to patients with SUDs, psychostimulants should be considered in a variety of scenarios. Although nonstimulant options are available, stimulants consistently have demonstrated superior efficacy over other treatments and remain first-line agents for adult ADHD.20 Methylphenidate, mixed amphetamine salts, lisdexamfetamine, and atomoxetine are FDA-approved for adult ADHD. Both stimulant classes (methylphenidate and amphetamine-based products) are equally effective for ADHD. In addition, stimulants are used to treat narcolepsy, cognitive disorders such as traumatic brain injury, and as augmentation to antidepressants for MDD.
ADHD affects 5% to 12% of children, and >60% of patients remain symptomatic into adulthood and require continued treatment.21 In particular, problematic inattention may persist throughout adulthood. ADHD does not appear to be an independent risk factor for SUDs in children and adolescents.22 However, substance use increases sharply as ADHD patients enter late adolescence and adulthood, and eventually becomes a problem for 20% of adolescents and adults with ADHD. Conversely, 17% to 50% of patients with alcohol, cocaine, or opioid dependence have co-occurring ADHD.23