There is ample evidence that long-term benzodiazepine use produces tolerance and severe withdrawal effects. Discontinuing benzodiazepines after long-term use (>3 months) can be challenging, with patients reporting irritability, insomnia, and anxiety. Several strategies to ease the withdrawal process have been explored.
A 2000 RCT compared the overlapping use of imipramine or buspirone vs placebo when tapering patients off their long-term benzodiazepine regimen.29 The study found that patients who took imipramine before and during their benzodiazepine taper were significantly more likely to discontinue their benzodiazepines compared with those using placebo. Successful discontinuation for those using buspirone—a 5-HT1A receptor agonist—approached statistical significance.29 (Buspirone has also been studied as a primary treatment for GAD, and found to have a relatively small effect and a side effect profile that includes dizziness, nausea, and asthenia.30 And there is preliminary evidence that bupropion XL may be as efficacious as escitalopram in treating GAD, with both drugs being well tolerated.31)
Another study focusing on the discontinuation of benzodiazepines found that adding cognitive behavioral therapy (CBT) to a gradual taper regimen significantly improved patients’ chances of complete cessation. Seventy-five percent of patients receiving CBT stopped taking benzodiazepines, compared with 37% of patients in the placebo-plus-taper group.32
CASE 2 After educating Janet about the risks of continued long-term use of benzodiazepines, you propose a plan to enable her to decrease her dose of alprazolam over many weeks. It involves a referral to CBT to give Janet the opportunity to find nonpharmacologic ways of managing her anxiety, and a prescription for imipramine 75 mg daily, which she would take while she tapers her benzodiazepine use at a rate of 25% per week. Reluctantly, Janet agrees.
At her 1-month follow-up, Janet reports that she has followed the tapering schedule, but that she frequently feels nervous and is having trouble sleeping. She states that she does not want to be dependent on drugs, and asks if there is a natural treatment to calm her nerves.
Is it GAD?
Signs and symptoms of generalized anxiety disorder (GAD) include excessive, and largely uncontrollable, worry; tenseness or restlessness; fatigue; difficulty concentrating; irritability; muscle tension; and sleep disturbances, lasting for at least 6 months.45 But GAD is associated with a wide range of physical and psychiatric comorbidities, and patients frequently present with somatic complaints, as well.
A medical history and physical exam to look for causes, comorbidities, and conditions that mimic GAD is an important first step when you suspect that a patient has an anxiety disorder. The differential diagnosis for GAD includes hyperthyroidism and Cushing’s disease, arrhythmias, anginal symptoms, pheochromocytoma, mitral valve prolapse, and excessive caffeine intake.46
Screening for major depression, the most common psychiatric comorbidity, and for alcohol and drug use is indicated, as is a medication history. Prescription medications or illicit drugs (and even some over-the-counter products) may be the cause of anxiety symptoms, or be surreptitiously used to alleviate them.
What to tell patients about “natural” alternatives
Patients may express a preference for “natural” treatments for GAD, and ask about valerian, kava extract, or St. John’s wort (hypericum). All 3 are available in the United States and marketed for the treatment of anxiety and insomnia (valerian), depression (hypericum), and as a euphoric (kava).
Valerian. A Cochrane review found insufficient evidence to draw any conclusion about the efficacy of valerian for the treatment of GAD because of the paucity of RCTs available for review.33 The single RCT found to be acceptable for review had a small sample size (N=36) and showed no significant difference in symptom reduction among the valerian, diazepam, and placebo groups.34
Kava extract. Cochrane published a systematic review of kava extract in 2002, including a meta-analysis of 5 RCTs.35 The meta-analysis showed a significant reduction in the Hamilton Anxiety Scale (HAMA) score for kava users vs placebo, although the effect size was small. The authors of this meta-analysis chose to exclude a 2002 RCT by Connor et al36 because that study used a different kava preparation than the others. However, Connor found that kava extract was not superior to placebo in reducing anxiety symptoms as measured by the HAMA, and inclusion of this study would have reduced the meta-analysis conclusion to borderline significance.
In addition, there are serious concerns about the association of kava with hepatotoxicity, including liver failure.37 According to the National Center for Complementary and Alternative Medicine (NCCAM), there is some evidence that kava may be beneficial in treating anxiety.38 However, NCCAM-funded studies of kava were suspended after the US Food and Drug Administration issued a warning in 2002 about a link between kava supplements and the risk of severe liver damage.38,39