Comparative efficacy of pregabalin and benzodiazepines in treating ...

International Journal of Neuropsychopharmacology (2010), 13, 229–241. Copyright f CINP 2009 doi:10.1017/S1461145709990460

ARTICLE

Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder R. Bruce Lydiard1, Karl Rickels2, Barry Herman3 and Douglas E. Feltner3 1

Psychiatry/Mental Health Ralph H. Johnson VA Medical Center, Charleston, SC, USA Department of Psychiatry, University of Pennsylvania Health System, Philadelphia, PA, USA 3 Pfizer Inc., Groton, CT, USA 2

Abstract Prior research suggests that SSRIs may have greater efficacy for psychic compared to somatic anxiety, while benzodiazepines show greater somatic efficacy. The goal of this analysis was to evaluate the efficacy of pregabalin (PGB) in treating psychic and somatic symptoms of anxiety. Data were combined from six short-term, double-blind, placebo-controlled, fixed-dose trials of PGB in patients with generalized anxiety disorder (GAD). The following PGB daily dose groups were studied : 150 mg (n=210), 300–450 mg (n=455), and 600 mg (n=406), benzodiazepines (6 mg/d lorazepam and 1.5 mg/d alprazolam, n=299), vs. placebo (n=484). Changes in Hamilton Anxiety Rating Scale (HAMA) psychic and somatic anxiety factors and individual items were analysed. Treatment with 300–600 mg PGB significantly improved both the HAMA psychic and somatic anxiety factors. In contrast, treatment with 150 mg PGB appeared to be less effective, achieving significance only on the psychic anxiety factor. PGB (300–450 mg) was associated with significant improvement on 13 out of 14 HAMA items, while treatment with 600 mg PGB was associated with significant improvement in 10 out of 14 HAMA items. Treatment with benzodiazepines was also associated with significant improvement in both psychic and somatic anxiety factors, with significant improvement occurring in 5 out of 14 HAMA items. The results of this pooled analysis indicate that both PGB and benzodiazepines had significant efficacy in treating both HAMA psychic and somatic anxiety. A dose–response effect was evident for PGB that reached a plateau at a dose of 300 mg/d. Received 9 March 2009 ; Reviewed 8 April 2009 ; Revised 15 June 2009 ; Accepted 21 July 2009 ; First published online 9 September 2009 Key words : Generalized anxiety disorder, pregabalin (PGB), psychic anxiety, somatic anxiety.

Introduction Generalized anxiety disorder (GAD) has received increasing attention in recent years as a prevalent disorder associated with significant impairment. The National Comorbidity Survey – Replication study reported a lifetime prevalence rate of 5.7 % for GAD (Kessler et al. 2005). In primary-care settings, a 4 % Address for correspondence : R. Bruce Lydiard, Ph.D., M.D., Psychiatry/Mental Health Ralph H. Johnson VA Medical Center, 109 Bee St, Charleston, SC 29401-5799, USA. Tel. : 843-789-6744 Fax : 843-789-6290 Email : [email protected] Portions of this paper were presented at the Anxiety Disorders Association of America 24th Annual Conference, 11–14 March 2004, Miami, FL ; and at the American Psychiatric Association 156th Annual Meeting, 17–22 May 2003, San Francisco, CA.

point prevalence of GAD has been reported, with >20 % of patients displaying sub-diagnostic GAD according to DSM-IV criteria (Wittchen et al. 2002). GAD usually has a chronic course, with >60 % of patients continuing to experience moderate-to-marked symptoms after 5 yr (Yonkers et al. 2003). Functional role impairment in community-based samples diagnosed with GAD (without current comorbidity) is similar to that associated with major depressive disorder (Kessler et al. 1999). Although the diagnostic criteria in DSM-IV (APA, 1994) increased the emphasis on psychic anxiety symptoms (particularly chronic excessive worry) by requiring fewer somatic and autonomic symptoms compared to the criteria in DSM-III/III-R (APA, 1980, 1987), somatic anxiety symptoms remain important in

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the presentation and severity of patients with GAD. For example, in a recent analysis of baseline data from six published randomized, clinical pharmacotherapy trials of DSM-IV-defined GAD, the somatic factor of the Hamilton Anxiety Rating Scale (HAMA ; Hamilton, 1959) contributed 42–46 % to total baseline HAMA score (Dahl et al. 2003). Levels of somatic symptoms are similar in persons with DSM-IV GAD regardless of the presence or absence of other psychiatric disorders, suggesting that these somatic symptoms are indeed inherent to the disorder (Brawman-Mintzer et al. 1994). Furthermore, in primary-care settings, the majority of patients with GAD present with chief complaints of somatic symptoms, pain, or sleep disturbance more often than for anxiety or other psychological symptoms (Wittchen et al. 2002), which underscores the importance of distress attributable to physical symptoms, and the potential clinical value of recognizing and treating physical symptoms associated with GAD (Roy-Byrne, 1996). Current pharmacotherapies have been shown to have differential effects on psychic and somatic symptoms associated with GAD. Benzodiazepines facilitate inhibitory GABAergic transmission, and have been reported to have relatively greater efficacy in treating somatic anxiety symptoms compared to psychic symptoms (Rickels et al. 1988, 1993). In contrast, medications that modulate monoamine neurotransmission, such as tricyclic antidepressants (TCAs), azapirones, selective serotonin reuptake inhibitors (SSRIs), and mixed serotonin-noradrenaline reuptake inhibitors (SNRIs), have typically (but not always) been reported to reduce psychic symptoms to a greater extent than somatic symptoms (Feighner & Cohn, 1989 ; Katz et al. 2002 ; Meoni et al. 2004 ; Pollack et al. 2001 ; Rickels et al. 1982, 1993, 2000, 2003). It is important to note that not all published studies consistently support inter-class differences in psychic vs. somatic efficacy. Recently, pregabalin (PGB) demonstrated efficacy in GAD (Feltner et al. 2003 ; Kasper et al. 2009 ; Montgomery et al. 2006 ; Pande et al. 2003 ; Pohl et al. 2005 ; Rickels et al. 2005). PGB binds to the a2-d subunit protein of neuronal N- and P/Q-type calcium channels required for neurotransmitter release (Gee et al. 1996 ; Taylor et al. 1993). In doing so, PGB reduces presynaptic calcium influx (Fink et al. 2002) and modulates the release of excitatory neurotransmitters, including glutamate (Dooley et al. 2000a, b ; Maneuf et al. 2001), substance P, calcitonin gene-related peptide (Fehrenbacher et al. 2003), and monoaminergic neurotransmitters (Dooley et al. 2000 a, b). PGB shows no activity at GABAA, GABAB, or benzodiazepine

receptors, and has no serotonin or norepinephrine reuptake-inhibiting activity (Pfizer Inc., data on file). Previous clinical trials with PGB have demonstrated efficacy in treating both HAMA psychic and somatic factors in patients diagnosed with GAD. The goal of this study was to further explore the efficacy of PGB by evaluating its specific benefit for the treatment of individual psychic and somatic anxiety symptoms of GAD. An additional objective was to evaluate whether treatment with PGB was associated with early (week 1) improvement in individual psychic and somatic anxiety symptoms when compared to the highpotency benzodiazepines, alprazolam and lorazepam.

Methods Study design All six randomized, double-blind, placebo-controlled studies of PGB in the treatment of GAD were pooled for this analysis. All trials were either 4 wk or 6 wk in duration, and all were fixed-dose studies (Table 1). In three of the studies, patients were randomized to receive either fixed doses of PGB (150 mg/d or 600 mg/d), lorazepam (6 mg/d), or placebo (Feltner et al. 2003 ; Pande et al. 2003 ; Pfizer Inc., data on file). One of these studies is an unpublished study (Pfizer Inc., data on file) which was considered to be an uninformative (failed) trial, since the active comparator, lorazepam, did not demonstrate anxiolytic efficacy that was superior to placebo ; we include it here for completeness. In the study by Rickels et al. (2005), patients were randomized to fixed-doses of PGB (300, 450, or 600 mg/d), alprazolam (1.5 mg/d), or placebo. In the fifth study (Pohl et al. 2005), patients were randomly assigned to receive fixed doses of either PGB (200, 400, or 450 mg/d) or placebo. In the sixth study (Montgomery et al. 2006), patients were randomized to PGB (400 or 600 mg/d), venlafaxine (75 mg/d), or placebo. Data from patients who received either placebo (n=484) or one of three PGB dose regimens [150 (n=210), 300–450 (n=456), or 600 mg (n=407)] were selected for pooled analysis from these six studies. These treatment sample groups were selected based on the manufacturer’s prescribing recommendations, which stipulate 150 mg and 600 mg as the minimum and maximum daily doses of PGB, respectively (Pfizer Inc., pregabalin full prescribing information). There were only 75 patients in one study who received the 200-mg dose. This limited sample provided insufficient power to perform valid subanalyses, and therefore was not included in this pooled analysis.

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Table 1. Summary of study designs Study treatment Sample size (n)

Duration of study treatment

Design

Initial dose (mg)

Final dose (mg)

Feltner et al. (2003) Randomized, DB, parallel-group, titration by 1 wk to fixed-dose

PGB 25 PGB 100 Lorazepam 1 Placebo


70 66 68 67

4 wk

Pande et al. (2003) Randomized, DB, parallel-group, titration by 1 wk to fixed-dose



69 70 68 69

4 wk

Study 1008-025 (Pfizer, data on file) Randomized, DB, parallel-group, titration by 1 wk to fixed-dose



71 71 70 70

4 wk

PGB 300 PGB 300 PGB 300 Alprazolam 0.5 Placebo

PGB 300 PGB 450 PGB 600 Alprazolam 1.5 Placebo

91 90 89 93 91

4 wk

Pohl et al. (2005) Randomized, DB, parallel-group, titration by 1 wk to fixed-dose

PGB 200 PGB 200 PGB 300 Placebo

PGB 200 PGB 400 PGB 450 Placebo

78 89 88 86

6 wk

Montgomery et al. (2006) Randomized, DB, parallel-group, titration by 1 wk to fixed-dose

PGB 100 PGB 150 Venlafaxine 75 Placebo

PGB 400 PGB 600 Venlafaxine 75 Placebo

97 110 113 101

6 wk

Rickels et al. (2005) Randomized, DB, parallel-group, titration by 1 wk to fixed-dose

DB, double-blind ; PGB, pregabalin. Study treatment was t.i.d., except for b.i.d. vs. t.i.d in Pohl et al. (2005).

Thus, patients receiving PGB in the six studies analysed here initiated PGB at doses ranging from 25 to 300 mg/d, and were titrated in