Effects of solriamfetol treatment on body weight in participants with obstructive sleep apnea or narcolepsy.

OBJECTIVES: This analysis characterized changes in weight in participants with obstructive sleep apnea (OSA) or narcolepsy treated with solriamfetol (Sunosi™) 37.5 (OSA only), 75, 150, or 300 mg/d. METHODS: In two 12-week, randomized, placebo-controlled trials and one 1-year open-label extension study, changes in weight were evaluated from baseline to end of study (week 12 or week 40 of the open-label extension [after up to 52 weeks of solriamfetol treatment]) in participants with OSA or narcolepsy. RESULTS: After 12 weeks of solriamfetol treatment, median percent change in weight from baseline across all solriamfetol doses was -0.84%, compared with 0.54% for placebo, in participants with OSA; and -0.07%, compared with 3.08% for placebo, in participants with narcolepsy. After up to 52 weeks of solriamfetol treatment, overall median percent change in weight from baseline was -1.76%, which showed a dose-dependent pattern (75 mg, 0.57%; 150 mg, -1.2%; 300 mg, -2.5%). Results were similar in subgroups of participants with OSA or narcolepsy, with overall median percent changes in weight of -2.2% and -1.1%, respectively. After up to 52 weeks of solriamfetol treatment, the percentage of participants with weight loss ≥5% relative to baseline was 25.7% overall and increased in a dose-dependent manner (75 mg, 4.5%; 150 mg, 17.3%; 300 mg, 32.4%). Results were similar among subgroups of participants with OSA or narcolepsy, with 26.4% and 24.2% of participants experiencing weight loss ≥5%, respectively. No weight-related treatment-emergent adverse events were serious. CONCLUSIONS: Solriamfetol treatment was associated with decreases in body weight in a dose-related manner.

Solriamfetol treatment of excessive daytime sleepiness in participants with narcolepsy or obstructive sleep apnea with a history of depression.

Given the high rate of depression associated with narcolepsy or obstructive sleep apnea (OSA), this analysis compared effects of solriamfetol treatment of excessive daytime sleepiness (EDS) in participants with/without a history of depression (DHx+/DHx-). This secondary analysis included data from two randomized, controlled trials in which participants were randomized to 12 weeks placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg/day. Efficacy/safety (combined solriamfetol doses) was summarized for DHx+/DHx-subgroups. 27.5% (65/236) with narcolepsy and 23.4% (111/474) with OSA were DHx+. In narcolepsy (DHx+ and DHx-), 40-min Maintenance of Wakefulness Test (MWT40) mean sleep latency increased (5.4 and 7.0 min), Epworth Sleepiness Scale (ESS) score decreased (3.8 and 3.5 points), and percentage of participants improved on Patient Global Impression of Change (PGI-C) was higher (31.7% and 39.4%) relative to placebo. In OSA (DHx+ and DHx-), MWT40 mean sleep latency increased (7.7 and 10.7 min), ESS decreased (3.5 and 3.7 points), and percentage of participants improved on PGI-C was higher (41.1% and 29.4%) relative to placebo. Common treatment-emergent adverse events (headache, decreased appetite, nausea, anxiety) were similar in DHx+/DHx-. This study suggests that safety and efficacy of solriamfetol for treating EDS in narcolepsy and OSA are not affected by depression history. Moreover, the findings emphasize the high prevalence of depression in people with sleep disorders and suggest that increased awareness of this association may have clinical significance.

Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy.

STUDY OBJECTIVES: This post hoc analysis characterized the weekly incidence and overall duration of common early-onset, treatment-emergent adverse events (TEAEs) during solriamfetol treatment. METHODS: Participants (obstructive sleep apnea [OSA], n = 474; narcolepsy, n = 236) were randomized to 12 weeks of placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg. For common early-onset TEAEs (those occurring in ≥ 5% of participants in any solriamfetol dose group and with a higher incidence than that observed in placebo-treated participants during week 1), the incidence of new occurrence or change in severity over time was calculated for each subsequent study week. Data were analyzed separately for each study and summarized by placebo and combined solriamfetol groups. RESULTS: Common early-onset TEAEs (at doses ≤ 150 mg; ie, approved doses) included headache (OSA, 5.1%; narcolepsy, 8.5%), nausea (OSA, 2.5%; narcolepsy, 4.2%), decreased appetite (OSA, 4.2%; narcolepsy, 5.9%), as well as anxiety (2.1%), insomnia (1.3%), and feeling jittery (3.0%) in OSA and dry mouth (4.2%) in narcolepsy. Incidence of common early-onset TEAEs was highest at week 1 and decreased over time. In OSA at doses ≤ 150 mg, headache, nausea, and feeling jittery had median durations ≤ 8 days, whereas decreased appetite, anxiety, and insomnia had longer durations. In narcolepsy at doses ≤ 150 mg, headache and nausea had median durations ≤ 8 days, whereas decreased appetite and dry mouth had longer durations. Most TEAEs were mild to moderate in severity. CONCLUSIONS: Common early-onset TEAEs with solriamfetol are limited in duration, with the majority subsiding during the first week of treatment. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in Narcolepsy; URL: https://clinicaltrials.gov/ct2/show/NCT02348593; Identifier: NCT02348593; and Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348606; Identifier: NCT02348606. CITATION: Rosenberg R, Thorpy MJ, Dauvilliers Y, et al. Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy. J Clin Sleep Med. 2022;18(1):235-244.

Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea.

STUDY OBJECTIVES: Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment comparison meta-analysis was performed to compare efficacy and safety of medications (solriamfetol, modafinil, and armodafinil) approved to treat excessive daytime sleepiness associated with obstructive sleep apnea. METHODS: Efficacy and safety measures assessed in this indirect treatment comparison included Epworth Sleepiness Scale (ESS), 20-minute Maintenance of Wakefulness Test (MWT20), Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), and incidence of treatment-emergent adverse events (any, serious, or leading to discontinuation). RESULTS: A systematic literature review identified 6 parallel-arm, placebo-controlled randomized controlled trials that randomized 1,714 total participants to placebo, solriamfetol, modafinil, or armodafinil. In this indirect treatment comparison, all comparators were associated with greater improvements than placebo on the ESS, MWT20, and CGI-C after 4, 8, and 12 weeks of treatment. Relative to comparators and placebo at 12 weeks, solriamfetol at 150 mg or 300 mg had the highest probabilities of improvement in the ESS, MWT20, and CGI-C. Modafinil (200 or 400 mg) and solriamfetol (150 or 300 mg) were associated with greater improvement on the FOSQ than placebo at 12 weeks. Less than 2% of patients using placebo or comparators experienced serious or discontinuation-related treatment-emergent adverse events. CONCLUSIONS: The results of this indirect treatment comparison show 12 weeks of treatment with solriamfetol, modafinil, and armodafinil resulted in varying levels of improvement on the ESS, MWT20, and CGI-C and similar safety risks in participants with excessive daytime sleepiness associated with obstructive sleep apnea. CITATION: Ronnebaum S, Bron M, Patel D, et al. Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea. J Clin Sleep Med. 2021;17(12):2543-2555.

The Nexus Narcolepsy Registry: methodology, study population characteristics, and patterns and predictors of narcolepsy diagnosis.

OBJECTIVE/BACKGROUND: The real-world experience of people with narcolepsy is not well understood. PATIENTS/METHODS: The Nexus Narcolepsy Registry (NCT02769780) is a longitudinal, web-based patient registry of self-reported data from adults with physician-diagnosed narcolepsy. Surveys were electronically distributed every 6 months; the current analysis reports registry population demographics, narcolepsy diagnosis journey, and predictors of diagnostic delays. RESULTS: The registry population included in this analysis (N = 1024) was predominantly female (85%) and White (92%), with a mean age of 37.7 years. Most participants had education/training beyond high school (93%). Mean (median) reported ages at narcolepsy symptom onset, first consultation for symptoms, and narcolepsy diagnosis were 18.1 (16), 26.4 (24), and 30.1 (28) years, respectively. A majority (59%) of participants reported ≥1 misdiagnosis, and 29% reported consulting ≥5 physicians before narcolepsy diagnosis. More than half (56%) of participants' first consultations for narcolepsy symptoms were with a general practitioner, whereas the diagnosing clinician was usually a sleep specialist (64%) or neurologist (27%). Pediatric symptom onset was associated with a longer mean interval to first consultation than adult symptom onset (10.7 and 4.6 years, respectively; P < 0.001) and a longer mean interval between first consultation and diagnosis (4.5 and 2.2 years, respectively; P < 0.001). Overall, mean (95% CI) time from symptom onset to diagnosis was 11.8 (11.1-12.5) years. CONCLUSIONS: The Nexus Narcolepsy Registry data indicate that onset of narcolepsy symptoms frequently occurs in childhood or adolescence. In many individuals, the diagnostic process is long and involves multiple physicians and frequent misdiagnosis.

Prevalence of sleepiness and associations with quality of life in patients with sleep apnea in an online cohort.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a treatment target for many patients with obstructive sleep apnea (OSA). We aimed to understand the prevalence, risk factors, and quality of life associated with EDS in a nonclinical, "real world" sample of patients with OSA. METHODS: Cross-sectional survey of patients with OSA participating in an online peer support community, assessing demographics, comorbidities, treatment, and quality of life. Differences in those with and without EDS (Epworth Sleepiness Scale > and ≤ 10) were assessed. RESULTS: The sample (n = 422) was 54.2% male, 65.9% were ≥ 55 years, and 43.3% reported sleeping ≤ 6 hours/night. EDS was identified among 31.0% of respondents and 51.7% reported sleepiness as a precipitating factor for seeking initial OSA treatment. EDS was more prevalent in individuals reporting asthma, insomnia symptoms, positive airway pressure (PAP) use less than 6 hours/night on ≥ 5 nights/week, or sleep duration < 6 hours/night. After adjusting for demographics and comorbidities, patients with EDS reported poorer mental and physical health and well-being, lower disease-specific functional status, more activity and work impairment, and more driving impairment (P values < .05). In the subsample (n = 265) with high PAP adherence, 26.0% reported EDS, and similar associations between EDS and outcomes were observed. CONCLUSIONS: These "real world" data suggest that patients seeking online OSA support experience a high prevalence of EDS, which was associated with poorer quality of life and worse functional status. Associations persisted among respondents with high self-reported PAP-therapy adherence, potentially driving these individuals to seek online support for sleepiness-related symptoms. CITATION: Wanberg LJ, Rottapel RE, Reid ML, et al. Prevalence of sleepiness and associations with quality of life in patients with sleep apnea in an online cohort. J Clin Sleep Med. 2021;17(12):2363-2372.

The Xyrem® (Sodium Oxybate) Risk Evaluation and Mitigation Strategy (REMS) Program in the USA: Results From 2016 to 2017.

BACKGROUND: Sodium oxybate, which is approved for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy, is available in the USA only through the restricted-distribution Xyrem® Risk Evaluation and Mitigation Strategy Program (Xyrem REMS Program, XRP). The XRP requires prescriber enrollment and certification, patient enrollment, and prescriber attestation of patient counseling. Sodium oxybate is dispensed only by the certified pharmacy. After pharmacist/patient counseling, sodium oxybate is shipped only to enrolled patients, with documentation of safe use. Documentation of enrollments, prescriptions, counseling, shipments, and adverse events in a central database, and risk management reporting of any suspicion of abuse, misuse, or diversion, ensure provider notification and facilitate monitoring. OBJECTIVE: This analysis reports data from the XRP regarding assessment of the risks of serious adverse outcomes that may result from inappropriate prescribing, abuse, misuse, and diversion. METHODS: Data collected from December 2016 to December 2017 were analyzed. RESULTS: Prescriptions were from enrolled prescribers (n = 4524); 17,037 patients received one or more shipment of sodium oxybate. No patients were shipped sodium oxybate under more than one name/identifier or after being disenrolled; no individual patient had overlapping active prescriptions. Sodium oxybate was dispensed in 146,426 shipments containing 375,173 bottles; of those, 13 shipments (0.009%) and 26 bottles (0.007%) were lost in delivery and not recovered. Notifications regarding potential abuse (n = 31), misuse (n = 343), or diversion (n = 22) were discussed with prescribers. Most patients and prescribers were aware of the main safety risks of sodium oxybate. CONCLUSIONS: The XRP maintains controlled access to sodium oxybate; additional prescriber education on safety risks may be warranted.

Relationship between sleep efficacy endpoints and measures of functional status and health-related quality of life in participants with narcolepsy or obstructive sleep apnea treated for excessive daytime sleepiness.

This study examined the correlation between improvements in excessive daytime sleepiness in participants with obstructive sleep apnea or narcolepsy and changes in functional status, work productivity and health-related quality of life. Data from two 12-week randomized controlled trials of solriamfetol were analyzed. Participants completed the Epworth Sleepiness Scale, 10-item Functional Outcomes of Sleep Questionnaire, Work Productivity and Activity Impairment questionnaire and 36-Item Short Form Health Survey and performed the Maintenance of Wakefulness Test at baseline and weeks 4, 8 and 12. Patient Global Impression of Change was assessed at weeks 4, 8 and 12. Pearson correlations were calculated for change in scores from baseline to week 12. For both studies, changes in the 10-item Functional Outcomes of Sleep Questionnaire were highly correlated (absolute value >0.5) with changes in Epworth Sleepiness Scale scores; changes in multiple domain scores of the 36-Item Short Form Health Survey and Work Productivity and Activity Impairment questionnaire were moderately correlated (0.3-0.5) with changes in Epworth Sleepiness Scale scores in both studies and highly correlated for participants with narcolepsy. Changes in Maintenance of Wakefulness Test scores correlated moderately with changes in Epworth Sleepiness Scale scores in both studies. At week 12, Patient Global Impression of Change ratings correlated highly with Epworth Sleepiness Scale and 10-item Functional Outcomes of Sleep Questionnaire scores for both disorders. Other correlations were low. Self-reported assessments of sleepiness and global improvement appear to be more strongly correlated with measures of functioning and health-related quality of life than objectively assessed sleepiness.

Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy.

STUDY OBJECTIVES: To determine the time course and duration of common, early-onset treatment-emergent adverse events (TEAEs) associated with sodium oxybate (SXB) use in adults with narcolepsy. METHODS: These were post hoc analyses of two 8-week, randomized, double-blind, placebo-controlled trials. In SXB-15, participants (n = 246) received daily placebo (n = 60) or SXB (n = 186) initiated at 4.5 g. Participants assigned to SXB 6 or 9 g were titrated in 1.5-g increments. In SXB-22, participants entering on modafinil (n = 231) received placebo (n = 56), SXB (n = 55), modafinil (n = 63), or SXB and modafinil (n = 57). SXB was initiated at 6 g for weeks 1-4 and increased to 9 g for weeks 5-8. TEAEs reported more frequently in SXB-treated participants than placebo and in ≥5% of any SXB treatment group during week 1 were examined as TEAEs of interest. RESULTS: Dizziness and nausea met criteria as TEAEs of interest in both studies; headache also met criteria as a TEAE of interest in SXB-15. Incidence of new or worsened TEAEs was highest at week 1 (SXB-15: dizziness, 7.5%; headache, 7.5%; nausea, 5.9%; SXB-22: dizziness, 5.4%; nausea, 7.1%) and decreased over time in both studies. The longest median duration was reported for dizziness: 9.0 and 17.5 days in SXB-15 and SXB-22, respectively. Dizziness caused discontinuation in 2.2% and 3.6% of participants in SXB-15 and SXB-22, respectively; nausea caused discontinuation in 2.7% and 1.8%. CONCLUSIONS: Common early-onset TEAEs associated with SXB treatment were generally of short duration and their incidence decreased over time. These TEAEs accounted for few discontinuations overall. CLINICAL TRIALS REGISTRATION: Registry: ClinicalTrials.gov; Names: Safety and Efficacy of Xyrem Oral Solution (Sodium Oxybate) Compared With Placebo in Narcoleptic Patients; Trial Comparing Effects of Xyrem Taken Orally and Modafinil With Placebo in Treating Daytime Sleepiness in Narcolepsy; URLs: https://clinicaltrials.gov/ct2/show/NCT00049803 and https://clinicaltrials.gov/ct2/show/NCT00066170; Identifiers: NCT00049803 and NCT00066170.

Understanding the burden of illness of excessive daytime sleepiness associated with obstructive sleep apnea: a qualitative study.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness (EDS), which may go undiagnosed and can significantly impair a patient's health-related quality of life (HRQOL). This qualitative research examined timing and reasons patients sought medical care for their EDS and OSA symptoms, and the impact of EDS on HRQOL. METHODS: Focus groups were conducted in 3 US cities with 42 participants currently experiencing EDS with OSA. Transcripts were coded and analyzed using an adapted grounded theory approach common to qualitative research. RESULTS: Over three-fifths of study participants (n = 26, 62%) were currently using a positive airway pressure (PAP) or dental device; one-third (n = 14, 33%) had previously used a positive airway pressure (PAP) or dental device, and the remainder had either used another treatment (n = 1, 2%) or were treatment naïve (n = 1, 2%). Twenty-two participants (52%) reported experiencing OSA symptoms for ≥1 year, with an average duration of 11.4 (median 8.0, range 1-37) years before seeking medical attention. Several (n = 7, 32%) considered their symptoms to be "normal," rather than signaling a serious medical condition. Thirty participants (71%) discussed their reasons for ultimately seeking medical attention, which included: input from spouse/partner, another family member, or friend (n = 20, 67%); their own concern about particular symptoms (n = 7, 23%); and/or falling asleep while driving (n = 5, 17%). For all 42 participants, HRQOL domains impacted by EDS included: physical health and functioning (n = 40, 95%); work productivity (n = 38, 90%); daily life functioning (n = 39, 93%); cognition (n = 38, 90%); social life/relationships (n = 37, 88%); and emotions (n = 30, 71%). CONCLUSIONS: Findings suggest that patients may be unaware that their symptoms could indicate OSA requiring evaluation and treatment. Even following diagnosis, EDS associated with OSA can continue to substantially affect HRQOL and daily functioning. Further research is needed to address diagnostic delays and unmet treatment needs for patients with EDS associated with OSA.

Comorbidities, Health-Related Quality of Life, and Work Productivity Among People With Obstructive Sleep Apnea With Excessive Sleepiness: Findings From the 2016 US National Health and Wellness Survey.

STUDY OBJECTIVES: Few population-based studies have explored how excessive sleepiness (ES) contributes to burden of illness among patients with obstructive sleep apnea (OSA). METHODS: This study utilized data from the annual, cross-sectional 2016 US National Health and Wellness Survey. Respondents self-reporting an OSA diagnosis were categorized as having ES (Epworth Sleepiness Scale [ESS] score ≥ 11) or not having ES (ESS score < 11). Comorbidities, health-related quality of life (HRQoL), and productivity were examined in three groups: OSA with ES (n = 731), OSA without ES (n = 1,452), and non-OSA controls (n = 86,961). RESULTS: The OSA with ES group had significantly higher proportions of respondents reporting depression (62.4% versus 48.0%), gastroesophageal reflux disease (39.0% versus 29.4%), asthma (26.3% versus 20.7%), and angina (7.8% versus 6.7%) compared to the OSA without ES group (P < .05). After controlling for covariates, the OSA with ES group had significantly lower (worse) scores for mental component score (41.81 versus 45.65 versus 47.81), physical component score (46.62 versus 48.68 versus 51.36), and SF-6D (0.65 versus 0.69 versus 0.73) compared with OSA without ES and non-OSA controls (all P < .001). The OSA with ES group had significantly higher (greater burden) mean rates of presenteeism (25.98% impairment versus 19.24% versus 14.75%), work impairment (29.41% versus 21.82% versus 16.85%), and activity impairment (31.09% versus 25.46% versus 19.93%) compared with OSA without ES and non-OSA controls (all P < .01) after controlling for covariates. CONCLUSIONS: OSA with ES is associated with higher prevalence of comorbidities, reduced HRQoL, and greater impairment in productivity compared to OSA without ES and compared to non-OSA controls.

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Assessment of physical function and participation in chronic pain clinical trials: IMMPACT/OMERACT recommendations.

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Relationship between pain relief, reduction in pain-associated sleep interference, and overall impression of improvement in patients with postherpetic neuralgia treated with extended-release gabapentin.

BACKGROUND: Postherpetic neuralgia (PHN) interferes with patients' quality of life, and disturbed sleep is a prevalent complaint. Pain-associated sleep interference in turn enhances pain and/or reduces pain tolerance. Therefore, reducing sleep interference by pain, in addition to pain control, may improve patient care. To address this notion, we characterized relationships among changes in pain intensity, sleep interference, and overall impression of improvement in PHN patients treated with gastroretentive gabapentin (G-GR). METHODS: Patients with PHN (n = 556) received G-GR 1,800 mg once-daily in two phase 3 and one phase 4 study. Visual Analog Scale (VAS) and Brief Pain Inventory (BPI) were completed at baseline and the end of study. Patients' Global Impression of Change (PGIC) was completed at the end of study. Regression analyses examined relationships between VAS, BPI sleep interference by pain, and PGIC. RESULTS: At the end of treatment, 53.7 and 63.2 % of patients reported a ≥ 30 % reduction in VAS and BPI pain-associated sleep interference (BPISI) respectively; 46.3 % reported feeling "Much" or "Very Much" improved on the PGIC. There were positive correlations between the percent reductions in VAS and BPISI; both correlated with PGIC improvements. Percent changes in VAS and BPISI were significant (p < 0.0001 and p = 0.0082, respectively), and were independent predictors of feeling "Much" or "Very Much" improved on the PGIC. CONCLUSIONS: Reductions in pain intensity and in BPISI were correlated, and both also correlated with overall impression of improvement for patients with PHN treated with G-GR. Both pain relief and improvement BPISI independently predicted improvement in PGIC. For optimal patient care, clinicians should consider reducing the impact of pain on quality of sleep as well as overall pain reduction. TRIAL REGISTRATION: ClinicalTrials.gov numbers, NCT00335933 , NCT00636636 , NCT01426230.

Effect of dosing interval on pharmacokinetics of fentanyl pectin nasal spray from a crossover study.

OBJECTIVE: To evaluate the effects of different dosing intervals on multiple-dose pharmacokinetics, and safety and tolerability of fentanyl pectin nasal spray (FPNS). METHODS: This was an open-label study in healthy volunteers. Five FPNS treatments (1 × 100 µg; 2 × 100 µg at 4-, 2-, and 1-hour intervals, and 8 × 100 µg consecutively) were administered to the right nostril, with a ≥ 3-day washout period. Blood samples were collected at predose and up to 1,440 minutes postdose. Plasma fentanyl concentrations were determined. Pharmacokinetic parameters-peak concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve (AUC)-were derived using noncompartmental method. For the two-dose regimens, pharmacokinetic parameters were compared between doses using a paired t-test with p < 0.05 as statistically significant. RESULTS: Thirteen subjects were enrolled and 10 completed the study. Median tmax was 10-15 minutes across five regimens. Cmax post the second dose significantly increased for 1-hour (p < 0.0001) and 2-hour (p < 0.001) but not 4-hour intervals (p = 0.462). C(max) and AUC(0-24) following 8 × 100 µg were approximately fivefold of those following 1 × 100 µg. Dizziness (11.9 percent) and somnolence (4.9 percent) were most common adverse events (AEs). 12.9 percent of patients discontinued due to AEs. CONCLUSIONS: FPNS exhibited consistently rapid t(max). When intervals between two doses were shorter, the difference in C(max) between the first and second dose was larger. All regimens of FPNS were well tolerated. Exposure reached a plateau after eight consecutive doses, suggesting potential limited absorption through the nasal mucosa.

Assessment of rescue opioid use in patients with post-bunionectomy pain treated with diclofenac potassium liquid-filled capsules.

When used in multimodal analgesia for acute pain, nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the requirement for opioids during the perioperative period. To provide more insight into pain treatment during the outpatient period, we examined the use of opioid rescue medication (RM) and described the relationship between pain intensity and RM use in patients with acute pain after bunionectomy. Patients received placebo or 25 mg of a liquid-filled capsule version of the NSAID diclofenac potassium (DPLFC; n=188 patients/group) every 6 hours during the 48-hour inpatient period through the end of outpatient dosing on day 4. Opioid RM (hydrocodone/acetaminophen tablets, 5 mg/500 mg) was available as needed, but taken at least 1 hour post-study medication. Fewer patients taking DPLFC versus placebo requested opioid RM during the inpatient period (4.8%-44.7% versus 25.0%-90.4%) and also during the outpatient period (3.7%-16.0% versus 13.1%-46.4%). Moderate or severe pain after surgery (P=0.0307 and P=0.0002, respectively) or at second dose (P=0.0006 and P=0.0002, respectively) was predictive of RM use. Patients taking RM (placebo/DPLFC) reported more adverse events (RM 55.7%/40.6%; no RM 29.4%/26.0%). Most adverse events in the RM group were opioid-related. In summary, this study shows that DPLFC lowers the requirement for opioids, which is associated with a reduction in the occurrence of treatment side effects, while maintaining adequate analgesia for patients with moderate acute pain in both the outpatient and outpatient periods. Patients with more severe pain are more likely to use RM, but they still use fewer opioids when treated with DPLFC. This suggests that multimodal treatment using DPLFC and an opioid may offer an important clinical benefit in the treatment of acute pain, including in the home environment.

Differential pharmacokinetics of diclofenac potassium for oral solution vs immediate-release tablets from a randomized trial: effect of fed and fasting conditions.

OBJECTIVE: To compare the pharmacokinetics of, and food effect on, diclofenac potassium delivered as an oral solution vs an immediate-release tablet. BACKGROUND: Diclofenac potassium for oral solution is the only nonsteroidal anti-inflammatory drug approved as monotherapy for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older. It is formulated with potassium bicarbonate as a buffering agent to raise the pH and consequently increase the aqueous solubility of diclofenac in the acidic environment of the stomach following oral administration. The dosage is 50 mg of powdered diclofenac potassium dissolved in 1 to 2 ounces (30 to 60 mL) of water prior to administration, with dosing time in relation to food intake not specified - this was the case for the pivotal efficacy and safety trials in subjects with acute migraine attacks in which the primary endpoints were achieved. For acute treatment of migraine attacks, rapid onset of pain relief is desirable and is likely related to a rapid appearance of an effective concentration of the drug in the systemic circulation. The rate at which an orally administered drug reaches the blood is affected by both its formulation and the presence of food in the stomach. The present study was designed to investigate the pharmacokinetics of 2 formulations of diclofenac potassium, an immediate-release tablet and an oral solution, and to ascertain the effect of food. METHODS: This was an open-label, randomized, single-center, crossover trial in healthy volunteers. Subjects were randomized using computer-generated list to 1:1:1:1 ratio. They received a single 50-mg dose of diclofenac potassium in 4 sequences (ABCD, BADC, CDBA, and DCAB) during each of the 4 treatment periods. The 4 treatments were: A, oral solution fasting; B, tablet fasting; C, oral solution fed; and D, tablet fed. There was a ≥7-day washout period between dosing. Blood samples for pharmacokinetic analysis were taken for up to 12 hours post-dose and analyzed for diclofenac concentrations. Pharmacokinetic parameters, including peak concentration (Cmax ), time to Cmax (tmax ), area under the concentration-time curve (AUC) from time 0 to last measurable concentration (AUCt ), and extrapolation to infinity (AUC∞ ) were obtained using non-compartmental analysis. Comparative assessments for Cmax and AUC were performed between the solution and tablet under fed and fasting conditions and between fed and fasting states for both formulations. Bioequivalent exposure was defined as the geometric mean ratio and its 90% confidence interval falling within 80.0-125.0% for Cmax and AUC. Adverse events (AEs) were monitored throughout the trial. RESULTS: Sixty-one percent of the 36 randomized subjects were male, 91.7% were Caucasian, and the mean (standard deviation [SD]) age was 31.9 (7.6) years. Thirty-three (91.7%) subjects completed all 4 treatments. SOLUTION VS TABLET: When taken under fed conditions, the oral solution resulted in an approximately 80% faster median tmax (0.17 vs 1.25 hours, P = .00015) and a 21% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 835 ± 449, P = .00061) compared with the tablet. AUC values were similar between the 2 formulations. When taken under fasting conditions, the oral solution exhibited a 50% faster median tmax (0.25 vs 0.50 hours, P = .00035) to achieve a 77% higher Cmax (mean ± SD, ng/mL: 1620 ± 538 vs 1160 ± 452, P = .00032) compared with the tablet. AUCt and AUC∞ were similar between the 2 formulations. FED VS FASTING: When taken under fed conditions, the oral solution resulted in a similar median tmax (0.17 vs 0.25 hours, P = .185) and 64% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 1620 ± 538, P < .00001) compared with fasting conditions. In comparison, the tablets under fed conditions resulted in a statistically significantly delayed median tmax (1.25 vs 0.50, P = .00143) and ∼30% lower Cmax (mean ± SD, ng/mL: 835 ± 449 vs 1160 ± 452, P = .00377). AUC values were similar between fed and fasting conditions for both formulations. Twelve subjects (33%) experienced ≥1 treatment-emergent AE during the study. All AEs were mild and resolved without treatment; none resulted in study discontinuation. More treatment-emergent AEs were reported in subjects receiving the tablet compared with the solution formulation (20.0% vs 11.8 % in fasting and 17.1% vs 8.6% in fed conditions). CONCLUSIONS: Diclofenac potassium oral solution and tablet formulations produced statistically significantly different Cmax and tmax but similar AUC under fed and fasting conditions. Fed conditions produced significantly lower Cmax for both formulations and profoundly delayed tmax for the tablet, but had no effect on tmax for the solution formulation. These data provide insights into the importance of an earlier and greater exposure to diclofenac arising from the solution formulation than the tablet, which may account for the superiority in the onset and sustained pain reduction for the solution than the tablet formulation observed in the double-blind, efficacy/safety study in migraine patients conducted in Europe.

Reporting of intention-to-treat analyses in recent analgesic clinical trials: ACTTION systematic review and recommendations.

The intention-to-treat (ITT) principle states that all subjects in a randomized clinical trial (RCT) should be analyzed in the group to which they were assigned, regardless of compliance with assigned treatment. Analyses performed according to the ITT principle preserve the benefits of randomization and are recommended by regulators and statisticians for analyses of RCTs. The objective of this study was to determine the frequency with which publications of analgesic RCTs in 3 major pain journals report an ITT analysis and the percentage of the author-declared ITT analyses that include all randomized subjects and thereby fulfill the most common interpretation of the ITT principle. RCTs investigating noninvasive, pharmacologic and interventional (eg, nerve blocks, implantable pumps, spinal cord stimulators, surgery) treatments for pain, published between January 2006 and June 2013 (n=173), were included. None of the trials using experimental pain models reported an ITT analysis; 47% of trials investigating clinical pain conditions reported an ITT analysis, and 5% reported a modified ITT analysis. Of the analyses reported as ITT, 67% reported reasons for excluding subjects from the analysis, and 18% of those listing reasons for exclusion did not do so in the Methods section. Such mislabeling can make it difficult to identify traditional ITT analyses for inclusion in meta-analyses. We hope that deficiencies in reporting identified in this study will encourage authors, reviewers, and editors to promote more consistent use of the term "intention to treat" for more accurate reporting of RCT-based evidence for pain treatments.

A virulence attenuated amoebapore-less mutant of Entamoeba histolytica and its interaction with host cells.

Entamoeba histolytica, the protozoan parasite which causes amoebiasis, is an exclusively human pathogen so developing a vaccine could effectively impact the spread of the disease. Recently we developed a genetically modified avirulent strain, termed G3, from the virulent E. histolytica strain HM-1:IMSS. The new strain lacks the important virulence factor, the amoebapore-A. The objective of our current study was to investigate the avirulence of the attenuated strain as well as to examine the antigenic and immunogenic responses of these trophozoites as potential candidates for a live vaccine. Functional assays were conducted to characterise the virulent behaviour of the G3 strain. This behaviour was compared to the virulent strain HM-1:IMSS and the non-virulent strain Rahman. Western blots were conducted to confirm the lack of amoebapore-A in the E. histolytica G3 strain and to demonstrate that it had no influence on the presence of other virulence factors. Results of these two sets of tests proved the G3 strain to be phenotypically similar to the avirulent Rahman strain while antigenically identical to the virulent HM-1:IMSS, apart from the lack of the amoebapore-A protein. Intraperitoneal immunisation of hamsters with G3 trophozoites compared to sham immunised hamsters resulted in IgG anti-HM-1:IMSS antibodies. The level of humoral response was variable and further testing has to take place before introducing this new strain as a vaccine.

Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa.

We report a case of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to Kenya. Recurrent parasitemia occurred 30 days after directly observed therapy with a combination of atovaquone and proguanil. Treatment failure was confirmed by genetic fingerprinting and sequencing. The primary isolate had wild-type sequence of cytochrome b; however, the recrudescent isolate had a single mutation at position 268 (Tyr268Ser).