Ed Whalen

A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease

Objective: To investigate the efficacy and safety of donepezil in patients with moderate to severe AD (standardized Mini-Mental State Examination [sMMSE] scores of 5 to 17; Functional Assessment Staging score ≤6 at baseline). Methods: Two-hundred ninety patients were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil 5 mg/day for the first 28 days and 10 mg/day thereafter as per the clinician’s judgment (n = 144) or placebo (n = 146). The primary outcome measure was the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+). Results: Patients’ mean age was 73.6 years (range 48 to 92 years). Baseline demographics were similar between the treatment groups. Least squares (LS) mean ± SE sMMSE scores at baseline were 11.7 ± 0.35 for the donepezil group and 12.0 ± 0.34 for the placebo group. Patients receiving donepezil showed benefits on the CIBIC+, compared with placebo, at all visits up to week 24 (p < 0.001) and at week 24 last observation carried forward (LOCF) (p < 0.0001). All other secondary measures (including sMMSE, Severe Impairment Battery, Disability Assessment for Dementia, Functional Rating Scale, and Neuropsychiatric Inventory) showed significant differences between the groups in favor of donepezil at week 24 LOCF. Eighty-four percent of donepezil- and 86% of placebo-treated patients completed the trial. Adverse events (AE) were experienced by 83% of donepezil- and 80% of placebo-treated patients, the majority of which were rated mild in severity; 8% of donepezil- and 6% of placebo-treated patients discontinued because of AE. Laboratory and vital sign abnormalities were similar between the treatment groups. Conclusion: These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with very good tolerability.

Pregabalin for Postherpetic Neuralgia: Placebo-Controlled Trial of Fixed and Flexible Dosing Regimens on Allodynia and Time to Onset of Pain Relief

UNLABELLED Time to onset of pain relief and improvement in allodynia in 269 patients with postherpetic neuralgia was examined in a 4-week randomized trial comparing flexibly dosed pregabalin (150-600 mg/d), fixed-dose pregabalin (300 mg/d), and placebo. For each patient with clinically meaningful pain reduction (>or=30%) at end point, onset of pain relief was defined as the first study day on which a patient reported >or=1-point reduction in pain relative to baseline. Average dose achieved was 396 mg/d in the flexible-dose group compared with 295 mg/d in the fixed-dose group. Median pain relief onset times were 3.5 days (flexible-dose), 1.5 days (fixed-dose), and >4 weeks (placebo). Compared with placebo, significantly more patients in both pregabalin treatment groups achieved >or=30% and >or=50% pain reduction at end point. Almost 95% of patients had brush-evoked allodynia, with 68% having moderate to severe allodynia (>or=40/100 mm). At baseline, pain and allodynia were highly correlated. Independent of treatment assignment, improvement in pain and improvement in allodynia were significantly correlated. Allodynia could serve as a useful surrogate outcome measure in future studies. Pregabalin was significantly better than placebo in alleviating allodynia (flexible-dose reduction, 26 mm; fixed-dose, 21 mm; placebo, 12 mm). Discontinuation rates due to adverse events were more frequent in the fixed-dose group. PERSPECTIVE A flexible-dose regimen reduces discontinuations, facilitates higher final doses, and results in a slightly greater pain relief. Allodynia (touch-evoked pain) can be of disabling severity and is present in nearly all patients with postherpetic neuralgia. Allodynia severity is correlated with pain severity and improvement in allodynia is correlated with clinical response.

A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury

Objective: To assess the efficacy and tolerability of pregabalin for the treatment of central neuropathic pain after spinal cord injury (SCI). Methods: Patients with chronic, below-level, neuropathic pain due to SCI were randomized to receive 150 to 600 mg/d pregabalin (n = 108) or matching placebo (n = 112) for 17 weeks. Pain was classified in relation to the neurologic level of injury, defined as the most caudal spinal cord segment with normal sensory and motor function, as above, at, or below level. The primary outcome measure was duration-adjusted average change in pain. Key secondary outcome measures included the change in mean pain score from baseline to end point, the percentage of patients with ≥30% reduction in mean pain score at end point, Patient Global Impression of Change scores at end point, and the change in mean pain-related sleep interference score from baseline to end point. Additional outcome measures included the Medical Outcomes Study–Sleep Scale and the Hospital Anxiety and Depression Scale. Results: Pregabalin treatment resulted in statistically significant improvements over placebo for all primary and key secondary outcome measures. Significant pain improvement was evident as early as week 1 and was sustained throughout the treatment period. Adverse events were consistent with the known safety profile of pregabalin and were mostly mild to moderate in severity. Somnolence and dizziness were most frequently reported. Conclusions: This study demonstrates that pregabalin is effective and well tolerated in patients with neuropathic pain due to SCI. Classification of evidence: This study provides Class I evidence that pregabalin, 150 to 600 mg/d, is effective in reducing duration-adjusted average change in pain compared with baseline in patients with SCI over a 16-week period (p = 0.003, 95% confidence interval = −0.98, −0.20).

Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder.

BACKGROUND Pregabalin is a novel compound that has been shown to have efficacy in the treatment of generalised anxiety disorder and is licensed for the treatment of the disorder in the European Union. AIMS The current study was designed to evaluate the safety and efficacy of pregabalin, an alpha(2)delta-ligand, in the treatment of generalised anxiety disorder in people 65 years and older. METHOD This was a double-blind, randomised (2:1), placebo-controlled, 8-week trial of pregabalin, in flexible doses of 150-600 mg/day, in the treatment of DSM-IV generalised anxiety disorder with a baseline Hamilton Rating Scale for Anxiety (HRSA) total score >/=20. The primary outcome was end-point (week 8 or last visit, with last observation carried forward (LOCF)) change in HRSA total score. RESULTS A total of 273 patients (women, 78%; mean age, 72 years (s.d.=6); mean baseline HRSA total score, 26 (s.d.=4.6)) were randomised and received study treatment. On the primary intent-to-treat LOCF analysis, pregabalin was associated with a 2-point greater reduction in HRSA total score than placebo (12.87 v. 10.7; P<0.05). In a post hoc repeated measures mixed-effect model analysis, pregabalin was associated with significantly greater improvement than placebo in the HRSA total score from week 2 (-9.8 (s.d.=0.6) v. -7.2 (s.d.=0.8); P=0.0052) through week 8 (-14.4 (s.d.=0.6) v. -11.6 (s.d.=0.8); P=0.0070). Significant improvement was observed in the pregabalin group on both the HRSA psychic and somatic anxiety factors. There was a significantly greater decrease from baseline in mean Hamilton Rating Scale for Depression (HRSD) score with pregabalin compared with placebo (-5.48 (s.d.=0.46) v. -4.02 (s.d.=0.59); P=0.041). Pregabalin was well-tolerated, with almost all adverse events in the mild-to-moderate range, and self-limiting (median duration of 4-16 days). Discontinuations due to adverse events were similar for pregabalin (10.7%) and placebo (9.4%). CONCLUSIONS Pregabalin, in doses of 150-600 mg/day, was a safe and effective treatment of generalised anxiety disorder in patients 65 years and older. The anxiolytic efficacy of pregabalin had an early onset (by 2 weeks) and significantly improved both psychic and somatic symptoms of anxiety.

Effect of pregabalin on sleep in patients with fibromyalgia and sleep maintenance disturbance: A randomized, placebo‐controlled, 2‐way crossover polysomnography study

To assess the effect of pregabalin on polysomnographic (PSG) measures of sleep and patient‐rated sleep, tiredness, and pain in fibromyalgia patients.

Relationship Between Pain Relief and Improvements in Patient Function/Quality of Life in Patients With Painful Diabetic Peripheral Neuropathy or Postherpetic Neuralgia Treated With Pregabalin

BACKGROUND In patients with chronic pain due to diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN), pregabalin treatment results in pain relief and improved patient function/quality of life (QoL). Few studies, however, have examined the exact relationship between pain relief and improvements in patient function/QoL. It is unclear, for example, whether pregabalin has a direct independent effect on patient function/QoL or whether improvements in function/QoL are an indirect consequent of pain relief. OBJECTIVES To determine whether improvements in function/QoL in response to pregabalin treatment are related to the extent of pain relief in patients with neuropathic pain due to DPN or PHN and to determine whether pregabalin has a direct independent effect on patient function/QoL that is distinct from its effects on pain. METHODS Data from 11 randomized, double-blind, placebo-controlled trials of pregabalin for the treatment of DPN or PHN were pooled for this analysis. Changes in patient function/QoL scores were plotted according to the extent of pain relief to assess whether greater levels of pain relief were associated with greater improvement in function/QoL. A novel mediation analysis was used to asses to what extent the effects of pregabalin on function/QoL scores are a direct treatment effect as opposed to an indirect effect mediated through improvements in pain or sleep. RESULTS Moderate-to-substantial pain relief (a ≥30% decrease in pain) in response to pregabalin treatment was associated with significant (P < 0.05) improvements in 36-Item Short Form Health Survey (SF-36) scores (used to assess patient function/QoL). In many patients, greatest improvement in SF-36 scores was reported by patients achieving ≥50% decrease in pain. Analysis of Patient Global Impression of Change scores revealed a similar trend, where >80% of patients who achieved substantial pain relief also reported their status as much or very much improved. A substantial direct pregabalin treatment effect was evident for many SF-36 domains that could not be explained by pain relief or improvement in sleep. CONCLUSIONS In patients with chronic pain due to DPN or PHN, improvements in patient function/QoL in response to pregabalin treatment are correlated with the extent of pain relief. However, such improvements in function/QoL are not mediated entirely through pain relief but are the result of a combination of pregabalins effects on pain and sleep disturbance and a direct effect on patient function itself.

Relationships among pain and depressive and anxiety symptoms in clinical trials of pregabalin in fibromyalgia.

Background Fibromyalgia, as defined by the American College of Rheumatology, is characterized by widespread pain lasting for at least 3 months, with pain in at least 11 out of 18 tender points when palpated with digital pressure. Objective The authors investigated the relationship between changes in pain and symptoms of anxiety and depression, using data from pregabalin clinical trials. Method Results from three double-blind, placebo-controlled trials of pregabalin monotherapy in fibromyalgia (8–14 weeks) were pooled, and baseline to end-point changes in pain and Hospital Anxiety and Depression Scale (HADS) scores were analyzed. Path-analysis evaluated the association between improvements in anxiety and depression and pain relief. Results Baseline HADS scores indicated moderate-to-severe anxiety in 38% of patients and moderate-to-severe depressive symptoms in 27%. The improvement in pain was not related to baseline levels of anxiety or depression. The correlation between changes in pain and depressive or anxiety symptoms was low-to-moderate. Pathanalysis showed that most of the pain relief observed with pregabalin treatment was a direct analgesic effect and was not explained by improvement in mood. Conclusion Response to treatment of pain in the pregabalin trials did not depend on baseline levels of anxiety or depressive symptoms, and pregabalin improved pain in fibromyalgia patients with or without depressive or anxiety symptoms. Changes in the level of anxiety or depression had a low-tomoderate impact on pain reduction. Pain reduction with pregabalin treatment appeared to result mostly from a direct treatment effect, rather than an indirect effect mediated through improvement in anxiety or depressive symptoms.

Characterizing and understanding body weight patterns in patients treated with pregabalin

Abstract Objective: We examined patterns of weight change among patients treated with pregabalin for up to 1 year. Methods: Patients with ≥1 pre-treatment weight measurement, ≥2 measurements in Period 1 (day 2–56), and ≥2 during Period 2 (day 57–356) were identified from pooled data of 106 studies including 43,525 patients. Seven patterns were developed and used for exploratory ‘change point’ analyses (day on-treatment when weight-change trend changed from initial trajectory) and to assess patterns of weight change by baseline weight/body mass index (BMI). Results: A total of 3187 patients (from 41 studies) were eligible. 98.9% of patients were described by three of the seven patterns. The majority of patients (2607/3187 [81.8%]) remained within ±7% of baseline weight (‘Pattern 4’). Fewer patients (463/3187 [14.5%]) were ‘delayed weight gainers’ (exceeded 7% weight gain in Period 2 but not Period 1 [‘Pattern 6’]), fewer still (82/3187 [2.6%]) were ‘early weight gainers’ (exceeded ≥7% baseline weight in Period 1 and remained above 7% or continued to gain weight in Period 2 [‘Pattern 7’]). Overall weight gainers (Patterns 6, 7) experienced 1-year weight gain (median [% change]) of +6.20 kg [+9.12%] and 5.46 kg [+13.9%] vs. 2.22 kg [+2.10%] for non-weight gainers (Pattern 4). Average baseline weight/BMI was lower for weight gainers (Patterns 6, 7) versus other patterns. Early weight gainers (Pattern 7) had change point day at day 40 versus day 54 for Pattern 4 and day 69 for Pattern 6. Use of concomitant medications and influence of comorbid conditions on weight should be considered as inherent variables when interpreting the study. Conclusions: The majority of patients treated with pregabalin (150–600 mg/day) for 1 year maintained weight within ±7% baseline weight. One in six patients gained ≥7% weight from baseline, and generally exceeded 7%, 2–12 months after treatment onset.

Designing a new proof-of-principle trial for treatment of partial seizures to demonstrate efficacy with minimal sample size and duration—-A case study

The ideal proof-of-principle study design provides a strong efficacy signal over the shortest duration, while exposing the fewest patients possible. Data from a large database (Pfizer Inc) which studied add-on pregabalin for the treatment of partial seizures was used to model how duration of baseline, post-randomization treatment period, and number of subjects impact the likelihood of an interpretable efficacy signal. Data from four double-blind, randomized, placebo-controlled, phase III studies that had at least one 600 mg/day treatment arm were combined. The common 6-week baseline period was divided into weekly intervals, as was the 12-week post-randomization period. Two methods of analysis were used: logistic regression performed on 50% responder rate and the Hodges-Lehmann estimate on percentage reduction from baseline seizure rate. A simulation-based re-sampling approach was used to determine sufficient sample size. Four weeks of baseline with 3 weeks of treatment were determined to be clinically and statistically sufficient. A reasonable sample size was estimated to be 40-50 patients per group, if a highly efficacious drug was used. These modeling results indicate that the efficacy of an antiepileptic drug can be demonstrated in a relatively short period of time with a reasonable sample size.

Sensory Pain Qualities in Neuropathic Pain

UNLABELLED The qualities of chronic neuropathic pain (NeP) may be informative about the different mechanisms of pain. We previously developed a 2-factor model of NeP that described an underlying structure among sensory descriptors on the Short-Form McGill Pain Questionnaire. The goal of this study was to confirm the correlated 2-factor model of NeP. Individual descriptive scores from the Short-Form McGill Pain Questionnaire were analyzed. Confirmatory factor analysis was used to test a correlated 2-factor model. Factor 1 (stabbing pain) was characterized by high loadings on stabbing, sharp, and shooting sensory items; factor 2 (heavy pain) was characterized by high loadings on heavy, gnawing, and aching items. Results of the confirmatory factor analysis strongly supported the correlated 2-factor model. PERSPECTIVE This article validates a model that describes the qualities of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. These data suggest that specific pain qualities may be associated with pain mechanisms or may be useful for predicting treatment response.