The impact of migraine on daily activities: effect of topiramate compared with placebo

OBJECTIVE: Assess the impact of migraine preventive therapy on patient-reported routine daily activities using the Migraine Specific Questionnaire (MSQ) and the Medical Outcomes Study Short Form-36 (SF-36) in patients with migraine who participated in a 26-week, randomized, double-blind, placebo-controlled trial of topiramate for migraine prevention. METHODS: Patients were required to have 3-12 migraines and < or = 15 headache days/month during the baseline phase. Patients who failed > 2 adequate regimens of migraine preventive therapy were excluded. MSQ and SF-36 data were collected at baseline, weeks 8, 16, and 26 from 469 patients receiving either topiramate 50, 100, or 200 mg/day or placebo. Patients entered a double-blind, 8-week titration period followed by an 18-week maintenance period. Two activity-related MSQ domains (Role Restrictive [RR] and Role Prevention [RP]) and two activity-related SF-36 domains (Role Physical [SF-36-RP] and Vitality [SF-36-VT]) were prospectively designated as the outcome measures. Changes in MSQ and SF-36 scores during the double-blind phase relative to prospective baseline scores were compared between topiramate- and placebo-treated groups. Specifically, a mixed-effect piecewise linear regression model was used to estimate average domain score over time, and areas under the domain-over-time curve (AUC) were compared using a 2-sided t-test, with multiplicity adjustment. RESULTS: In the intent-to-treat population (N = 469), topiramate (all doses) significantly improved mean MSQ-RR domain scores versus placebo (topiramate 50 mg/day, p = 0.035; topiramate 100 mg/day; p < 0.001; topiramate 200 mg/day, p = 0.001). Topiramate-associated improvements in mean MSQ-RP domain scores were significant versus placebo only for topiramate 100 mg/day (p = 0.045). SF-36-RP and SF-36-VT domain scores improved (not significant versus placebo) for topiramate 100 and 200 mg/day. Changes in these MSQ and SF-36 domain scores significantly correlated with changes in mean monthly migraine frequency. CONCLUSION: Improvements in patient-reported outcomes specific for migraine (measured by the MSQ) were significantly better for patients receiving topiramate than for those receiving placebo. Improvements in the prospectively selected MSQ and SF-36 domains were significantly correlated with the decrease in mean monthly migraine frequency observed with topiramate treatment.     

Efficacy of almotriptan 12.5 mg in achieving migraine-related composite endpoints: a double-blind,randomized, placebo-controlled study in patients with previous poor response to sumatriptan 50 mg

ABSTRACT

Background: Triptans are not identical and migraine sufferers respond differently to different triptans. Few studies have evaluated the efficacy of switching triptans in migraine patients who have shown poor response to another agent.

Objective: To investigate the efficacy and tolerability of almotriptan 12.5?mg in patients who did not achieve 2‐h pain relief with sumatriptan 50?mg.

Methods: This double-blind, placebo-controlled study recruited patients with IHS-defined migraine and at least 2 previous unsatisfactory responses to sumatriptan. Those who did not achieve pain relief (moderate or severe pain decreasing to mild or no pain) 2?h after taking oral sumatriptan 50?mg on an open-label basis for the treatment of their first migraine attack during this trial (Attack 1) were randomized to receive either oral almotriptan 12.5?mg or placebo for the treatment of their next migraine attack (Attack 2).

Results: Of 302 patients receiving sumatriptan 50?mg for the treatment of their first migraine attack, 221 (73%) did not achieve 2‐h pain relief and were randomized to almotriptan 12.5?mg or placebo for the treatment of Attack 2. The majority (70%) of randomized patients treating their headache in Attack 2 reported severe pain at baseline characterizing this as a difficult-to-treat population. In the intent-to-treat population (n = 198), significantly more patients in the almotriptan group compared with the placebo group achieved 2‐h complete relief (free from pain and migraine-associated symptoms) at 2?h (17.1% vs. 4.4%; p < 0.05) and sustained pain free (20.9% vs. 9.0%; p < 0.05). Adverse events of mild-to-moderate intensity occurred in 7.1% of patients in the almotriptan group compared to 5.1% in the placebo group (not statistically different).

Conclusion: Almotriptan is more effective than placebo and similarly well-tolerated for the acute treatment of migraine in patients who responded poorly to oral sumatriptan.     

The multi-faceted assessment of independence in patients with rheumatoid arthritis: preliminary validation from the ATTAIN study*

ABSTRACT

Objective: To consider the feasibility of assessing multiple facets of independence in rheumatoid arthritis (RA) using a measure developed from existing items and examining its face validity, construct validity and responsiveness to change.

Methods: The ATTAIN (Abatacept Trial in Treatment of Anti-tumor necrosis factor [TNF] Inadequate responders) database was used. Patients with RA were randomized 2:1, abatacept (n?=?258) and placebo (n?=?133). A multi-faceted scale to measure physical and psychosocial independence was constructed using items from the Health Assessment Questionnaire (HAQ) and Short Form 36 Health Survey (SF?36). Questions assessing activity limitations and need for outside caregiver help were also examined. Interviews with 20 RA patients assessed face validity.

Results: Item Response Theory analysis yielded two traits – ‘Psychosocial Independence’, derived from the number of days with activity limitations plus the Role Emotional, Social Functioning and Role Physical subscale items from the SF?36; and ‘Physical Independence’, derived from 15 HAQ items assessing need for help from another. The two traits showed no significant differential item functioning for age or gender and demonstrated good face validity. Changes over 169 days on Psychosocial Independence were greater (mean 0.46?units, 95% confidence interval [CI]: 0.17–0.75) for the abatacept group than for placebo (?p?=?0.002). Changes in Physical Independence were greater (mean 0.59?units, 95% CI: 0.35–0.82) for the abatacept group than for placebo (?p?<?0.001).

Conclusions: The multi-faceted assessment of independence in RA based on items from commonly used instruments is feasible suggesting promise for evaluating independence in future clinical trials. This approach demonstrated good face and construct validity and responsiveness in RA patients who had previously failed anti-TNF therapy. However, we caution against an interpretation that these data suggest that abatacept improves independence because the component parts of this assessment came from instruments used in the ATTAIN trial where data had been previously analyzed.     

Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13‐week,randomized trial

ABSTRACT

Objective: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN).

Research design and methods: The 13‐week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600?mg/day BID) or placebo.

Main outcome measures: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing.

Results: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150?mg/day, –0.88, p = 0.0077; 300?mg/day, –1.07, p = 0.0016; 600?mg/day, –1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo (?p < 0.001), beginning at week 1 (?p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600?mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group.

Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%).

Conclusions: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13‐week study.     

Effects of a fast disintegrating/ rapid release oral formulation of sumatriptan on functional ability in patients with migraine

SUMMARY

Background: A new oral form of sumatriptan has been developed to facilitate tablet disintegration and drug dispersion and to mitigate the effects of gastric stasis that can accompany migraine.

Objective: To evaluate the effects on functional ability of the new fast disintegrating/rapid release formulation of sumatriptan.

Methods: Sumatriptan 50?mg (n = 137), 100?mg (n = 142), or placebo (n = 153) was administered early when pain was mild for the acute treatment of a single migraine attack in a randomized, double-blind, parallel-group, placebo-controlled clinical trial. For this report, main health-outcomes endpoints (which were secondary endpoints for this clinical trial that was primarily designed to assess pain-free efficacy) included functional ability measured through 2?h postdose on a 5-point scale and lost time equivalents, a composite measure of migraine-associated time missed from activities, and reduced effectiveness at activities through 24?h postdose.

Results: Normal functional ability was restored in a significantly (?p < 0.05) greater percentage of patients treated with sumatriptan than placebo beginning 45?min postdose for sumatriptan 100?mg and 1?h postdose for sumatriptan 50?mg. During the 24?h after initial dosing, the median (range) lost time equivalents for the combination of paid work activities and activities outside of paid work were significantly lower in the groups treated with sumatriptan (1.1 [0–10] sumatriptan 100?mg; 0.8 [0–36] sumatriptan 50?mg) compared with placebo (2.9 [0–24]) (?p ≤ 0.01 each sumatriptan group versus placebo). The corresponding mean ± SD values for lost time equivalents were 1.9 ± 2.3 and 2.5 ± 4.7 for sumatriptan 100?mg and 50?mg, respectively, compared with 3.5 ± 4.3 for placebo.

Conclusion: A new oral sumatriptan formulation confers rapid, sustained restoration of functional ability in the acute treatment of migraine so that patients can return rapidly to normal functioning at work and outside of work.     

The efficacy of tadalafil in improving sexual satisfaction and overall satisfaction in men with mild,moderate, and severe erectile dysfunction: a retrospective pooled analysis of data from randomized,placebo-controlled clinical trials

ABSTRACT

Background: Satisfaction with the sexual experience is considered important when evaluating the impact of treatments for erectile dysfunction (ED), yet satisfaction has been infrequently assessed in clinical trials.

Objective: To evaluate satisfaction with, and enjoyment of, the sexual experience in men with ED enrolled in 11 placebo-controlled clinical trials of tadalafil.

Study design and methods: Retrospective pooled analysis of data from 11 randomized, double blind, placebo-controlled clinical trials of tadalafil. Men with mild (N = 838), moderate (N = 558), or severe (N = 703) ED who were randomized to tadalafil 10?mg or 20?mg or placebo taken as needed for 12 weeks were included in this analysis. Efficacy measures included the International Index of Erectile Function (IIEF). Reported herein are the scores on the IIEF overall satisfaction domain and individual IIEF questions (IIEF‐Q7, satisfaction with intercourse; and IIEF‐Q8, enjoyment of intercourse).

Results: At least moderate satisfaction (IIEF overall satisfaction domain) was reported by 55% and 72% of patients with mild ED taking tadalafil 10?mg and 20?mg, respectively, compared with 33% taking placebo (?p < 0.002); 60% and 65% vs. 19% of patients with moderate ED (?p < 0.001); and 32% and 49% vs. 9% with severe ED (?p < 0.001). Satisfactory intercourse during most attempts or almost always/always (IIEF‐Q7) was reported by 59% and 79% of patients with mild ED taking tadalafil 10?mg and 20?mg vs. 32% taking placebo (?p < 0.001); 52% and 65% vs. 18% with moderate ED (?p < 0.001); and 28% and 49% vs. 5% with severe ED (?p < 0.001). Highly or very highly enjoyable intercourse (IIEF‐Q8) was reported by 45% and 63% of patients with mild ED taking tadalafil 10?mg and 20?mg vs. 21% taking placebo (?p < 0.001); 43% and 56% vs. 16% with moderate ED (?p < 0.001); and 19% and 44% vs. 5% with severe ED (?p < 0.001).

Conclusions: Compared with placebo, tadalafil 10?mg and 20?mg improved overall satisfaction with the sexual experience, intercourse satisfaction, and intercourse enjoyment in men with mild, moderate, and severe ED.     

Functionality and health-status benefits associated with reduction of osteoarthritis pain

ABSTRACT

Objective: To evaluate the association between pain intensity improvement and improvements in functionality and health status in patients with chronic osteoarthritis pain of the hip or knee.

Methods: Data were obtained from a 12-week, randomized, double-blind, placebo-controlled study of tramadol ER 100?mg, 200?mg, 300?mg, or 400?mg once daily. Patients reported pain intensity with a 100-mm visual analog scale (0?=?no pain, 100?=?extreme pain) and functionality and health status with the disease-specific Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire and the generic Short-Form-36 Health Survey (SF?36). Pain intensity improvement from baseline was categorized as <?0%, 0–14%, 15–29%, 30–49%, 50–69%, and ≥?70%, and mean changes in WOMAC and SF?36 scores were determined for patients in each category.

Results: A total of 1011 patients received placebo (n?=?205) or tramadol ER 100?mg (n?=?202), 200?mg (n?=?201), 300?mg (n?=?201), or 400?mg (n?=?202). The degree of pain intensity improvement was correlated with the degree of improvement in WOMAC and SF?36 scores; as little as 15% reduction of pain intensity was associated with notable improvements in function and health status. Potential limitations included the lack of established thresholds to assess clinically meaningful changes in these outcomes.

Conclusions: Pain intensity improvement is associated with corresponding improvements in function and health status. While large improvements in pain intensity are associated with large improvements in health status and functionality, modest pain reductions are also associated with improvement of certain health status parameters.     

A randomized controlled study comparing rofecoxib,diclofenac sodium,and placebo in post-bunionectomy pain

SUMMARY

Objective: The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery.

Research design and methods: This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50?mg (N = 85), enteric-coated diclofenac sodium 100?mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50?mg or placebo (diclofenac patients switched to placebo) over study Days 2–5 (Part II). Patients rated their pain at 16 time points over the first 24?h. Primary endpoint was total pain relief over 8?h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2–5, with the focus on Days 2–3. Adverse experiences were recorded over Days 1–5.

Results: For TOPAR8 scores, rofecoxib 50?mg was significantly more effective than placebo (9.5 vs. 3.7, p < 0.001) and diclofenac (9.5 vs. 5.0, p < 0.001). Onset of analgesia was more rapid with rofecoxib than placebo (?p = 0.003) and diclofenac (?p = 0.019); proportion of patients achieving onset within 4?h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p < 0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03?h vs. 4:02?h, p < 0.001 and 1:41?h vs. 4:02?h, p < 0.001). Rofecoxib patients used significantly less (?p < 0.001) supplemental analgesia than placebo patients over Days 2–3 (1.1?tablets/day vs. 2.1?tablets/day) and Days 2–5 (0.9?tablets/day vs. 1.8?tablets/day). No significant differences in adverse experiences between treatments were seen.

Conclusion: Rofecoxib 50?mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50?mg was significantly more effective than diclofenac sodium 100?mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.     

Association of anemia correction with health related quality of life in patients not on dialysis*

ABSTRACT

Objective: This was an open-label study to asses the association of changes in hemoglobin with changes in health related quality of life (HRQOL) in patients treated with darbepoetin alfa.

Methods: Originally, 81 chronic kidney disease (CKD) patients not on dialysis and naïve to erythropoiesis stimulating agents (ESA) were randomly assigned into two open-label groups (3?:?1). As a majority of control group patients opted out of control status, this study reports on the single arm study analysis that was performed on the 48 patients who received the drug through week 16. Sixty-two patients received once-weekly darbepoetin alfa in addition to conservative management for CKD. Instruments that measured general (SF‐36, FACT-anemia, FACT-fatigue, ADL and IADL) and disease specific (KDQOL) HRQOL domains were administered at baseline and after 8, 16, and 24 weeks.

Results: Compared to baseline values, mean HRQOL subscales were significantly improved in the treatment group at 16 weeks (?p < 0.05 for SF‐36 physical function; p < 0.001 for SF‐36 vitality, FACT anemia and FACT fatigue scales). At week 16, the SF‐36 mean increase for 48 treatment patients in the Vitality Subscale Score was 14.9 (SD 3.2) and the mean increase in the KDQOL Burden of Kidney Disease Subscale was 5.5 (SD 3.3). Multivariate regression analysis demonstrated a statistically significant association (?p < 0.05) between hemoglobin levels and higher HRQOL scores on several physical function, energy and fatigue scales.

Conclusion: Improvements in hemoglobin in CKD patients not on dialysis were associated with statistically significant (?p < 0.05), clinically meaningful (>?5 points) HRQOL improvements on scales measuring physical activity, vitality and fatigue. Our study did not show an association between increased hemoglobin levels and other aspects of HRQOL, such as those relating to emotional status, sexual activity or cognition. The interpretation of our results is limited by the lack of a control arm to assess whether conservative therapy for CKD, in the absence of ESA administration, would have a comparable effect on patients’ HRQOL scores. Further research needs to examine whether other aspects of HRQOL improve with anemia treatment, in the same way as those aspects of HRQOL more closely related to physical activity and fatigue.     

Effect of topiramate on choroidal thickness and anterior chamber parameters in the treatment of patients with migraine

Objective: To investigate the effects of topiramate on choroidal thickness and anterior chamber parameters using optical coherence tomography in the treatment of patients with migraine.

Methods: A total of 22 eyes of 22 adults (12 females, 10 males) diagnosed with migraine and scheduled to topiramate treatment for pain control were recruited in this prospective study. Choroidal thickness (CT), anterior chamber depth (ACD), anterior chamber angle (ACA), spherical refractive equivalent (SphEq) and intraocular pressure (IOP) measurements were recorded at baseline (prior the topiramate therapy), first and second month visits for the statistical analysis. One-way ANOVA with repeated measures test was used for the statistical evaluation.

Results: Mean age of the patients was 40.2?±?6.5?years. Mean CT at central fovea was 324?±?47?μm initially, 341?±?45?μm in the first month and 344?±?46?μm in the second month, thus first and second month measures were significantly higher than base values (p?p?=?0.001). Baseline ACD (3.66?±?0.22?mm) measures significantly decreased at the first month (3.63?±?0.22?mm) and second month (3.62?±?0.22?mm, p?=?0.009). Also, a significant reduction was detected in the first (36.2?±?4.9°) and second month (35.9?±?5.1°) ACA measures comparing with baseline (39.1?±?5.1°, p?=?0.05). A significant myopic shift was determined in the first and second month SphEq values (?0.08?±?0.6, ?0.10?±?0.6, respectively, p?=?0.05).

Conclusions: The study revealed increased CT and altered anterior chamber parameters and IOP due to topiramate therapy. Therefore, the patients using topiramate should be carefully monitored by an ophthalmologist considering the possible side effects.     

The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy

ABSTRACT

Objective: This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy.

Research design and methods: This was a multicenter double-blind study with 196 patients (aged 18–65 years) randomized to receive armodafinil 150?mg (n = 65), armodafinil 250?mg (n = 67), or placebo (n = 64) once daily for 12 weeks.

Main outcome measures: Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20‐min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory).

Results: Armodafinil significantly increased MWT mean sleep latency (at 0900–1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9?min in the 150‐mg, 250‐mg, and combined groups, respectively, compared with a decrease of 1.9?min for placebo (?p < 0.01 for all three comparisons). Mean late-day MWT latency (1500–1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8?min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGI-C rating from baseline to final visit in the armodafinil 150‐mg, 250‐mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (?p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (?p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness.

Conclusions: Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.     

The Effects of Single and Repeated Administration of Ebastine on Cognition and Psychomotor Performance in Comparison to Triprolidine and Placebo in Healthy Volunteers

Summary

Objective:The cognitive and psychomotor effects of 10?mg, 20?mg and 30?mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10mg (as averum) and placebo in 10 healthy volunteers in a double-blind, randomised crossover study.

Methods: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1?h, 2?h, 4?h and 8?h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ).

Results: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p?<?0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the I difference with placebo reaching statistical significance on day 1,8?h post-dose (p?<?0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8?h on day 1 (p?<?0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4?h and 8?h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2?h and 4?h following triprolidine administration on day 1 and ebastine (30?mg) was rated as sedative 4?h following administration on day 5. The perceived sedative activity of ebastine 30?mg was also reflected in the subjective reports on the LSEQ on day 1 (p?<?0.05).

Conclusions: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10–20?mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10?mg.     

Efficacy of a paracetamol–pseudoephedrine combination for treatment of nasal congestion and pain-related symptoms in upper respiratory tract infection

ABSTRACT

Objective: This study compared the efficacy of 1000?mg of paracetamol combined with 60?mg of pseudoephedrine, with that of either paracetamol or pseudoephedrine alone and placebo for the treatment of symptomatic URTI.

Research design and methods: A double‐blind, parallel group study was performed on 305 patients with URTI (nasal airflow resistance [NAR] of > 0.25 Pa cm³ s and a global pain score of at least moderate intensity). NAR and pain relief/intensity scores were measured over 4?h after initial dose. Patients then dosed up to three times daily for 3 days and recorded nasal congestion and pain intensity scores.

Main outcome measures: Nasal airflow conductance (NAC) and pain relief after the initial dose were primary objectives. NAC was calculated from NAR. Pain relief was measured on a 5‐point verbal rating scale (VRS) and pain intensity and nasal congestion on a 4‐point VRS. Data were analysed using analysis of covariance. Safety was assessed by adverse events.

Results: A single dose of the combination was superior to paracetamol and placebo for NAC (?p = 0.0001) and was superior to pseudoephedrine and placebo for pain relief (?p ≤ 0.048). Multiple doses of the combination were also superior to paracetamol and placebo for decongestion (?p ≤ 0.021) and were superior to pseudoephedrine and placebo for pain reduction (?p ≤ 0.0057). All treatments were well tolerated.

Conclusions: The combination treatment provided a greater decongestant effect than either paracetamol or placebo and better pain relief than either pseudoephedrine or placebo. The additive effect of the combination was apparent for both single and multiple doses.     

The efficacy of pregabalin in patients with moderate and severe pain due to diabetic peripheral neuropathy

Objective To compare the therapeutic response to pregabalin in patients with moderate or severe painful diabetic peripheral neuropathy (pDPN).

Research design and methods Data were pooled from 11 placebo-controlled trials to evaluate the efficacy of pregabalin flexible or fixed dose (150, 300 or 600?mg/day) in pDPN patients with mean baseline pain scores of ≥4 to <7 (moderate) or ≥7 to ≤10 (severe). Last observation carried forward imputation was used.

Study number/ClinicalTrials.gov identifier 1008-014/-, 1008-029/-, 1008-040/-, 1008-131/-, 1008-149/-, 1008-000-155/-, A0081030/NCT00156078, A0081060/NCT00159679, A0081071/NCT00143156, A0081081/NCT00301223, A0081163/NCT00553475.

Main outcome measures Pregabalin-mediated change in pain, pain-related sleep interference (PRSI) and patient global impression of change (PGIC) were compared versus placebo and between moderate and severe pain cohorts. Adverse events (AEs) were reported.

Results At baseline, 1816 patients had moderate pain (pregabalin, n?=?1189) and 1119 patients had severe pain (pregabalin, n?=?720). Pregabalin significantly reduced pain scores at endpoint compared with placebo when patients of all pain levels were combined (all doses; p?<?0.05). In the moderate and severe pain cohorts, pregabalin treatment (300, 600?mg/day or flexible) significantly reduced mean pain scores at endpoint compared with placebo (p?<?0.01). Pain reduction was greatest in patients with severe baseline pain compared with moderate baseline pain (pregabalin 300, 600?mg/day or flexible; p?<?0.0001). Pregabalin improved PRSI and PGIC in the moderate and severe cohorts compared with placebo. The greatest improvement in PRSI also occurred in the severe cohort. Treatment-emergent AEs, most commonly dizziness, somnolence and peripheral edema, occurred more frequently in patients treated with pregabalin compared with placebo.

Conclusions Pregabalin was effective in pDPN patients with both moderate and severe baseline pain. Patients with severe pain exhibited greater improvements in pain and PRSI than patients with moderate pain. Pain severity may, in part, predict therapeutic response to pregabalin.     

Randomized,placebo-controlled comparison of early use of frovatriptan in a migraine attack versus dosing after the headache has become moderate or severe

SUMMARY

Objective: To evaluate whether frovatriptan would provide greater relief if given early during a migraine attack.

Research design and methods: Adults with a history of migraine of at least 1?year, and who had 2–8 headaches in the previous month were recruited from 19 US centres for a prospective, placebo-controlled crossover study over 2 migraine attacks. Dose 1 was taken at the onset of mild migraine headache, Dose 2 was taken at least 2?h later if the headache progressed to moderate/severe. Patients were randomized to receive Dose 1 frovatriptan then Dose 2 placebo or Dose 1 placebo followed by Dose 2 frovatriptan. Treatment order was reversed for the second attack. This schedule enabled a comparison of frovatriptan with placebo and a comparison of early and later treatment with frovatriptan.

Main outcome measures: Freedom from pain at 2?h for frovatriptan versus placebo as Dose 1; use of Dose 2 and/or rescue medication, pain severity, functional impairment and headache recurrence.

Results: In 241 patients who each treated 2 migraine attacks, Dose 1 frovatriptan was more effective than placebo in terms of the proportion of patients who were pain free at 2?h (28% vs 20%, p = 0.04). This benefit was sustained up to 4?h post-dose (?p = 0.003). Early use of frovatriptan significantly reduced re-medication (?p < 0.001). Twenty-four-hour headache recurrence was low in both early (4%) and later use (6%) groups. Sustained pain-free response occurred in 40% of frovatriptan early use patients compared with 31% of later use patients (?p < 0.05). Early use prevented headache progression: 69%–78% had mild/no headache 2–4?h after Dose 1 frovatriptan compared with 54%–63% taking Dose 1 placebo (?p < 0.001). Early use reduced pain burden and functional disability (?p ≤ 0.001). More patients rated early use of frovatriptan as excellent or good (57% vs 46%).

Conclusions: Early use of frovatriptan resulted in a higher, earlier and sustained pain-free response, prevented progression to moderate/severe headache and reduced pain burden and functional disability.     

Escitalopram versus sertraline in the treatment of major depressive disorder: a randomized clinical trial*

ABSTRACT

Objective: This trial was conducted to compare the efficacy and tolerability of a fixed dose of escitalopram 10?mg/day with sertraline optimally dosed within its recommended dose range (50–200?mg/day) for the treatment of major depressive disorder.

Methods: In this multicenter trial, depressed patients (DSM?IV defined; baseline Montgomery–Asberg Depression Rating Scale [MADRS] ≥ 22) aged 18–80 years were randomly assigned to 8 weeks of double-blind treatment with escitalopram (10?mg/day) or sertraline (50–200?mg/day) following a 1?week single-blind placebo lead-in period. There was no placebo comparison arm. Sertraline was initiated at 50?mg/day, and could be increased by 50?mg/day at weekly intervals based on clinical need and tolerability at the lower dose level. The blind was maintained with matching double-blind placebo capsules for the escitalopram group. Change from baseline to endpoint in MADRS total score (last observation carried forward) was the primary efficacy measure.

Results: A total of 212 patients received double-blind medication. At week 8, the mean sertraline dosage was 144?mg/day (median = 150?mg/day). Mean changes from baseline to endpoint in MADRS scores were –19.1 and –18.4 for the escitalopram and sertraline groups, respectively. At endpoint, 75% and 70% of escitalopram- and sertraline-treated patients, respectively, were responders (≥ 50% improvement from baseline in mean MADRS scores). Both treatments were generally well tolerated; only 2% and 4% of patients prematurely discontinued escitalopram and sertraline treatment, respectively, due to adverse events.

Conclusion: No differences in efficacy were observed for fixed-dose escitalopram 10?mg/day and sertraline flexibly dosed from 50–200?mg/day. At these doses, both escitalopram and sertraline were generally well tolerated.     

Functional,Cognitive and Behavioral Effects of Donepezil in Patients with Moderate Alzheimer's Disease

Summary

Objective: To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer's disease (AD) of moderate severity from a previous trial.

Methods: Two hundred and seven patients with moderate AD (standardized Mini-Mental State Examination [sMMSE] score 10-17) were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil, 5mg/day for the first 28 days and 10mg/day thereafter according to the clinician's judgement (n?=?102), or placebo (n?=?105). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC-plus) at week 24 using a last observation carried forward (LOCF) analysis.

Results: Baseline patient demographics were similar between treatment groups. Mean age was 74.3 years (range 48–92). Least-squares (LS) mean sMMSE scores at baseline were 13.6?±?0.3 for the donepezil group and 13.9?±?0.3 for the placebo group. LS mean

CIBIC-plus scores for donepezil-treated patients were improved from, or close to, baseline severity at all visits, and were significantly different from placebo at weeks 8,12,18, and 24 (week 24 LOCF mean difference?=?0.53, p?=?0.0003). LS mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group improved throughout the study, and were significantly different from placebo at each visit for the sMMSE (week 24 LOCF mean difference?=?2.06, p?=?0.0002) and from week 8 for the SIB (week 24 LOCF mean difference?=??4.44, p?=?0.0026). LS mean change scores on the Disability Assessment for Dementia remained at or above baseline levels throughout the study for the donepezil group, while the placebo group showed a steady decline; treatment differences were significant at each visit (week 24 LOCF mean difference?=??9.25, p?<?0.0001). LS mean change scores on the Neuropsychiatric Inventory 12-item total improved throughout the study for the donepezil group and were significantly

different from placebo at weeks 4 and 24 (week 24 LOCF mean difference?=?5.92, p?=?0.0022). Eighty-one per cent of donepezil-treated and 89% of placebo-treated patients completed the trial, with 9% and 5%, respectively, discontinuing due to adverse events (AEs). Eighty-two per cent of donepezil-treated and 80% of placebo-treated patients experienced AEs, the majority of which were rated mild in severity and, in general, were similar between treatment groups.

Conclusion:The significant treatment responses observed with donepezil in these patients reinforce the findings from earlier studies that show donepezil to have important benefits, compared with placebo, across functional, cognitive, and behavioral symptoms, with good tolerability, in patients with AD of moderate severity.     

The efficacy of rofecoxib 50 mg and hydrocodone/acetamino­phen 7.5/750 mg in patients with post-arthroscopic pain

ABSTRACT

Objective: To compare the efficacy and tolerability of rofecoxib, hydrocodone/acetaminophen 7.5?mg/750?mg (H/A) and placebo in treating pain after arthroscopy of the knee.

Methods: A randomized, double-blind, placebo-controlled, single dose study enrolling patients experiencing moderate or severe pain after knee arthroscopy. Patients with moderate-to-severe postoperative pain received either rofecoxib 50?mg (n = 151), H/A (n = 145), or placebo (n = 147). Pain was measured over 24?h. The primary endpoint was total pain relief at 6?h for rofecoxib 50?mg compared with placebo.

Results: H/A (?p = 0.003), but not rofecoxib (?p = 0.256) was significantly more effective than placebo for total pain relief at 6?h (TOPAR6). Although analgesic onset and peak were significantly better for H/A than for both rofecoxib (?p < 0.01, p < 0.05, respectively) and placebo (?p < 0.05, p < 0.001, respectively), rofecoxib patients used significantly less rescue analgesia (?p < 0.001) over 24?h. Rofecoxib also provided better Brief Pain Inventory Severity (?p = 0.008) and Interference Domain (?p = 0.045) scores at 24?h compared to placebo and had lower 24?h Pain Severity scores than H/A (?p < 0.05). Treatments were generally well tolerated, with no significant difference in the frequency of patient-reported adverse events between groups.

Conclusions: Rofecoxib 50?mg did not provide significantly different pain relief than placebo at 6?h, and the primary endpoint TOPAR was not attained, although it did show several efficacy benefits at 24?h, including a significant opioid-sparing effect. All treatments were well tolerated, with no significant differences observed. The limited efficacy of rofecoxib in this study contrasts to the results of previous surgical studies evaluating rofecoxib, and may be partially explained by the postoperative dosing in this arthroscopic surgical model.     

Extended-release tramadol in the treatment of osteoarthritis:a multicenter,randomized, double-blind,placebo-controlled clinical trial

ABSTRACT

Objective: This study evaluated the efficacy and safety of tramadol extended-release (tramadol ER) tablets once daily in subjects with osteoarthritis pain.

Methods: This 12‐week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial included 1020 adults with osteoarthritis of the knee or hip and baseline pain intensity ≥ 40 on a 100‐mm pain visual analog scale (0 = no pain, 100 = extreme pain). Subjects took placebo or were titrated to a target dose of tramadol ER 100, 200, 300, or 400?mg once daily.

Main outcome measures: The co-primary efficacy variables were pain and physical function subscales of the WOMAC Osteoarthritis Index and subject global assessment of disease activity.

Results: Mean changes in WOMAC Osteoarthritis Index pain and physical function subscales were significantly different between tramadol ER and placebo, overall (?p ≤ 0.021) and for each dose (?p ≤ 0.050). However, the protocol-specified decision rule for the 3 co-primary endpoints was not satisfied because the overall comparison of subject global assessment of disease activity was not statistically significant (?p = 0.079). All doses of tramadol ER once daily were more effective than placebo (?p ≤ 0.050) for WOMAC Osteoarthritis Index joint stiffness subscale, WOMAC Osteoarthritis Index composite score, pain intensity of the index joint, and daily pain intensity scores. Tramadol ER 200 and 300?mg were significantly more effective than placebo (?p ≤ 0.050) for subject global assessment of disease activity and pain intensity of non-index joints. Adverse events (e.g., constipation, dizziness, nausea, somnolence, headache) occurred most often with tramadol ER 400?mg.

Conclusions: Tramadol ER 100–300?mg once daily was associated with significant improvement in pain intensity and physical function, and was well tolerated, despite the use of a fixed-dose study design not reflective of usual clinical practice. Tramadol ER is a useful treatment option for patients with osteoarthritis pain.     

Pharmacodynamic and pharmaco-kinetic interaction between fenofibrate and ezetimibe*

SUMMARY

Objective: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia.

Research design and methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C ≥ 130?mg/dL (3.37?mmol/L) were randomized to receive one of four oral treatments each morning for 14?days: fenofibrate 200?mg + ezetimibe 10?mg, fenofibrate 200?mg, ezetimibe 10?mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14.

Main outcome measures: The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate.

Results: Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C (?p ≤ 0.05 vs either drug alone or placebo), total cholesterol and triglycerides (?p ≤ 0.05 vs either fenofibrate or placebo), apolipoprotein C-III (?p ≤ 0.05 vs placebo), and LDL-III (?p ≤ 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean C_max and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant.

Conclusion: Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.