Longer Term Use vs CBT

A Well-Designed “Longer-Term” Alprazolam Study

Although much of the research on benzodiazepines and Z-drugs has not been performed long-term to clarify what happens to efficacy beyond 4 weeks, it is instructive to look at data that is available regarding alprazolam, the most studied of all the agents.

A well-designed study involving two research sites by Marks et al^[1] examined the efficacy of alprazolam (short-acting formulation) in Panic Disorder with agoraphobia over an 8-week treatment phase, an 8-week drug taper phase, and a 6-month treatment-free follow-up. The study was designed in such a fashion to address the deficiencies identified in prior research.   In this particular study, 154 patients were randomized to the following four groups:
– Alprazolam plus relaxation (a psychological placebo)
– Alprazolam plus exposure therapy (combined treatment)
– Placebo pill plus exposure therapy
– Placebo pill plus relaxation (double placebo)

The abstract of the article outlines the major findings as follows (bold added; “exposure” refers to Exposure Therapy, a type of Cognitive Behavioral Therapy):

A cross-national randomised trial of alprazolam for chronic panic disorder with agoraphobia was run. Compared with previous trials it had three new features: an exposure therapy contrast group, a six-month treatment-free follow-up, and a low rate of early placebo drop-outs (‘non-evaluables’). The dose of alprazolam was high (5 mg/day).  The 154 patients had eight weeks of: alprazolam and exposure (combined treatment); or alprazolam and relaxation (a psychological placebo); or placebo and exposure; or placebo and relaxation (double placebo).  Drug taper was from weeks 8 to 16. Follow-up was to week 43.  Results were similar at both sites.  Treatment integrity was good.  All four treatment groups, including double placebo, improved well on panic throughout.  On non-panic measures, by the end of treatment, both alprazolam and exposure were effective, but exposure had twice the effect size of alprazolam.  During taper and follow-up, gains after alprazolam were lost, while gains after exposure were maintained.  Combining alprazolam with exposure marginally enhanced gains during treatment, but impaired improvement thereafter.  The new features put previous trails in a fresh light.  By the end of treatment, though gains on alprazolam were largely as in previous studies, on phobias and disability they were half those with exposure.  Relapse was usual after alprazolam was stopped, whereas gains persisted to six-month follow-up after exposure ceased.  Panic improved as much with placebo as with alprazolam or exposure.

This study was rigorously structured and measured.  Notable features included the following:

• Baseline features among the groups were comparable.
• Intention to Treat analysis took place.
• Dropouts did not significantly vary among the randomized groups.
• Main effects did not differ between the two research sites.
• It was a naturalistic study in that clinicians were allowed to increase the dose of alprazolam during the treatment phase up to three times if in their judgment patient symptoms warranted an increase.
• Treatment integrity was good, as measured by pill counts, alprazolam blood levels, and randomized review of audiotaped psychological treatment sessions.
• Multiple outcome measures were used:
  1. For phobic disorder: Global phobia score, Phobia Questionnaire, ratting scores for 4 phobic targets for each avoidance and fear,
  2. For panic: Attack and Anticipatory Anxiety Scale,
  3. For mood: Hamilton depression and anxiety scores, Beck Depression Inventory,
  4. For function: disability rating (work, social, family, leisure, home) and adjustment (family, social, work), and
  5. For global assessment: Symptom Checklist-90, Clinicians Global Improvement, Patient Global Improvement.
• To patients the most clinically relevant outcome is total panic attacks. For both alprazolam arms of the study, the significant benefit seen at 4 weeks of active treatment reversed to some degree by week 8 of active treatment.

[1]Marks IM, Swinson RP, Başoğlu M, et al. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. Br J Psychiatry. 1993;162:776-87.  Article