Vaccine strategies for prevention of community-acquired pneumonia in Canada: Who would benefit most from pneumococcal immunization?

OBJECTIVE: To describe the burden of pneumococcal disease and associated risk factors in the Canadian adult population, delineate available pneumococcal vaccines and associated efficacy and effectiveness data, and review current pneumococcal vaccine recommendations and community-acquired pneumonia (CAP) prevention strategies in Canada. QUALITY OF EVIDENCE: Pneumococcal vaccination guidelines from the Canadian National Advisory Committee on Immunization in 2013 and 2016 constitute level III evidence for CAP prevention in the Canadian adult population. MAIN MESSAGE: It is recommended that immunosuppressed adults of all ages receive the 13-valent pneumococcal conjugate vaccine (PCV13) (grades A and B recommendations). In 2016, the National Advisory Committee on Immunization also recommended that all adults aged 65 years and older receive PCV13 (grade A recommendation) on an individual basis, followed by the 23-valent pneumococcal polysaccharide vaccine (grade B recommendation). This update is based on a large clinical study that demonstrated PCV13 efficacy against vaccine-type CAP in this population. CONCLUSION: Physicians should focus on improving pneumococcal vaccination rates among adults, which remain low. Vaccination with PCV13 should also be considered for adults with chronic conditions, whose baseline risk is often higher than that for healthy individuals aged 65 years and older.

NEO6860, modality-selective TRPV1 antagonist: a randomized, controlled, proof-of-concept trial in patients with osteoarthritis knee pain.

INTRODUCTION: NEO6860 is a TRPV1 antagonist when activated by capsaicin but not by heat or pH, developed to relieve pain without the adverse events reported with non-modality-selective TRPV1 antagonists. OBJECTIVE: The primary Objective of this study was to evaluate the analgesic efficacy and safety of NEO6860 after 1 day oral dosing in patients with Kellgren-Lawrence stage I, II or III osteoarthritis of the knee. METHOD: This randomized, double-blinded, 3-period crossover, phase II study compared 1 day (2 doses) of NEO6860 (500 mg twice a day), placebo, and naproxen in 54 patients with osteoarthritis knee pain. Primary endpoint was reduction in pain intensity (PI) on Numerical Rating Scale after exercise, using the staircase test, 8 hours after dose. RESULTS: Level of PI, compared with baseline, was numerically lower during NEO6860 and naproxen periods vs placebo at 3 and 24 hours, but not at 8 hours after first dose. A statistically significant effect for naproxen and a trend for NEO6860 were observed at 3 and 24 hours. Least square means' (95% confidence interval) change in PI at 24 hours was -0.67 (-1.09 to -0.26), -0.97 (-1.39 to -0.55), -0.29 (-0.71 to 0.13) for NEO6860, naproxen, and placebo, respectively. NEO6860 exposure was ∼1.6 times higher compared with previous phase I. In this study, NEO6860 safety profile was less favorable than naproxen or placebo. Possibly NEO6860-related adverse events included: feel hot, headache, nausea, dizziness, fatigue, hypoaesthesia, and increased blood pressure. CONCLUSION: In this exploratory study, NEO6860 did not statistically significantly outperform placebo but showed an analgesic trend, without impacting body temperature and heat pain perception. Further studies are warranted to explore the potential of NEO6860 in other pain indications. We intent to optimize the dose and evaluate analgesic synergism with other mechanism.

Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial.

PURPOSE: Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. METHODS: Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. FINDINGS: Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. IMPLICATIONS: Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.).

Efficacy and Safety of Pregabalin in Patients with Fibromyalgia and Comorbid Depression Taking Concurrent Antidepressant Medication: A Randomized, Placebo-controlled Study.

OBJECTIVE: To assess pregabalin efficacy and safety in patients with fibromyalgia (FM) with comorbid depression taking concurrent antidepressant medication. METHODS: This randomized, placebo-controlled, double-blind, 2-period, 2-way crossover study was composed of two 6-week treatment periods separated by a 2-week taper/washout phase. Patients with FM (aged ≥ 18 yrs) taking a stable dose of a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) for depression were randomized 1:1 to receive pregabalin/placebo or placebo/pregabalin (optimized to 300 or 450 mg/day). Antidepressant medication was continued throughout the study. The primary efficacy outcome was the mean pain score on an 11-point numerical rating scale. Secondary efficacy outcomes included measures of anxiety, depression, patient function, and sleep. RESULTS: Of 197 patients randomized to treatment, 181 and 177 received ≥ 1 dose of pregabalin and placebo, respectively. At baseline, 52.3% of patients were taking an SSRI and 47.7% an SNRI, and mean pain score was 6.7. Mean pain scores at endpoint were statistically significantly reduced with pregabalin (least squares mean difference from placebo -0.61, 95% CI -0.91 - -0.31, p = 0.0001). Pregabalin significantly improved Hospital Anxiety and Depression Scale-Anxiety (difference -0.95, p < 0.0001) and -Depression (difference -0.88, p = 0.0005) scores, Fibromyalgia Impact Questionnaire total score (difference -6.60, p < 0.0001), and sleep quality (difference 0.57, p < 0.0001), but not EuroQol 5-Dimensions score (difference 0.02, p = 0.3854). Pregabalin safety was consistent with previous studies and current product labeling. CONCLUSION: Compared with placebo, pregabalin statistically significantly improved FM pain and other symptoms in patients taking antidepressant medication for comorbid depression. ClinicalTrials.gov identifier: NCT01432236.

Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study.

OBJECTIVE: Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. RESEARCH DESIGN AND METHODS: This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as <30% pain reduction relative to single-blind baseline or discontinuation owing to lack of efficacy or adverse event (AE). Secondary endpoints included measures of pain severity, global assessment, functional status, tiredness/fatigue, and sleep. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01271933. RESULTS: A total of 441 patients entered the single-blind phase, and 63 were randomized to pregabalin CR and 58 to placebo. The median time to LTR (Kaplan-Meier analysis) was significantly longer in the pregabalin CR group than placebo (58 vs. 22 days, p = 0.02). By trial end, 34/63 (54.0%) pregabalin CR and 41/58 (70.7%) placebo patients experienced LTR. Significantly more patients reported 'benefit from treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). CONCLUSIONS: Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.

Effect of ventilatory variability on occurrence of central apneas.

OBJECTIVE: To compare the influence of 2 ventilation strategies on the occurrence of central apneas. METHODS: This was a prospective, comparative, crossover study with 14 unsedated subjects undergoing weaning from mechanical ventilation in the medical ICU of Hôpital du Sacré-Cœur, Montréal, Québec, Canada. The subjects were ventilated alternately in neurally adjusted ventilatory assist (NAVA) and pressure support ventilation (PSV) modes. Inspiratory flow/time and pressure/time waveforms and diaphragmatic electrical activity were used to detect central apneas. Ventilatory variability and breathing pattern were evaluated in both modes. Breathing patterns just before central apneas, and associations between apneas and sleep patterns (electroencephalogram) were studied. RESULTS: Switching from PSV to NAVA did not change mean minute ventilation, tidal volume, or breathing frequency. However, tidal volume variability, defined as the coefficient of variability (standard error/mean), was significantly greater with NAVA than with PSV (17.2 ± 8 vs 10.3 ± 4, P = .045). NAVA induced a greater decrease in central apneas, compared to PSV (to 0 with NAVA vs 10.5 ± 11 with PSV, P = .005). Central apneas during PSV were detected only during non-rapid-eye-movement sleep. CONCLUSIONS: NAVA was associated with increased ventilatory variability, compared to constant-level PSV. With NAVA the absence of over-assistance during sleep coincided with absence of central apneas, suggesting that load capacity and/or neuromechanical coupling were improved by NAVA and that this improvement decreased or abolished central apneas.

An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. METHODS: This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. RESULTS: Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (-0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score -5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

Sleep quality in mechanically ventilated patients: comparison between NAVA and PSV modes.

BACKGROUND: Mechanical ventilation seems to occupy a major source in alteration in the quality and quantity of sleep among patients in intensive care. Quality of sleep is negatively affected with frequent patient-ventilator asynchronies and more specifically with modes of ventilation. The quality of sleep among ventilated patients seems to be related in part to the alteration between the capacities of the ventilator to meet patient demand. The objective of this study was to compare the impact of two modes of ventilation and patient-ventilator interaction on sleep architecture. METHODS: Prospective, comparative crossover study in 14 conscious, nonsedated, mechanically ventilated adults, during weaning in a university hospital medical intensive care unit. Patients were successively ventilated in a random ordered cross-over sequence with neurally adjusted ventilatory assist (NAVA) and pressure support ventilation (PSV). Sleep polysomnography was performed during four 4-hour periods, two with each mode in random order. RESULTS: The tracings of the flow, airway pressure, and electrical activity of the diaphragm were used to diagnose central apneas and ineffective efforts. The main abnormalities were a low percentage of rapid eye movement (REM) sleep, for a median (25th-75th percentiles) of 11.5% (range, 8-20%) of total sleep, and a highly fragmented sleep with 25 arousals and awakenings per hour of sleep. Proportions of REM sleep duration were different in the two ventilatory modes (4.5% (range, 3-11%) in PSV and 16.5% (range, 13-29%) during NAVA (p = 0.001)), as well as the fragmentation index, with 40 ± 20 arousals and awakenings per hour in PSV and 16 ± 9 during NAVA (p = 0.001). There were large differences in ineffective efforts (24 ± 23 per hour of sleep in PSV, and 0 during NAVA) and episodes of central apnea (10.5 ± 11 in PSV vs. 0 during NAVA). Minute ventilation was similar in both modes. CONCLUSIONS: NAVA improves the quality of sleep over PSV in terms of REM sleep, fragmentation index, and ineffective efforts in a nonsedated adult population.

Preliminary evaluation of a new index to predict the outcome of a spontaneous breathing trial.

BACKGROUND: The available predictors of spontaneous-breathing-trial (SBT) success/failure lack accuracy. We devised a new index, the CORE index (compliance, oxygenation, respiration, and effort). OBJECTIVE: To compare the CORE index to the CROP index (compliance, rate, oxygenation, and pressure), airway-occlusion pressure 0.1 s after the start of inspiratory flow (P(0.1)), and rapid shallow breathing index (RSBI) for predicting SBT success/failure in a critical care environment. METHODS: With 47 mechanically ventilated patients recovering from respiratory failure, of various causes, we prospectively examined the SBT success/failure prediction accuracy and calculated receiver operating characteristic curves, sensitivity, specificity, and likelihood ratios of CORE, CROP, P(0.1), and RSBI. RESULTS: The specificities were CORE 0.95, P(0.1) 0.70, CROP 0.70, and RSBI 0.65. The sensitivities were CORE 1.00, CROP 1.00, P(0.1) 0.93, and RSBI 0.89. The areas under the receiver operating characteristic curve were CORE 1.00 (95% CI 0.92-1.00), CROP 0.91 (95% CI 0.79-0.97), P(0.1) 0.81 (95% CI 0.67-0.91), and RSBI 0.77 (95% CI 0.62-0.88). The positive likelihood ratios were CORE 20.0, CROP 3.3, P(0.1) 3.1, and RSBI 2.5. The negative likelihood ratios were CORE 0.0, CROP 0.0, P(0.1) 0.1, and RSBI 0.2. CONCLUSIONS: The CORE index was the most accurate predictor of SBT success/failure.

A new application of sound resonance technology therapy for the treatment of fibromyalgia: a retrospective analysis.

OBJECTIVE: Chart review to evaluate the effectiveness of a three-phase sound resonance technology therapy (SRTT) protocol for the treatment of fibromyalgia. RESULTS: Initial FIQ scores of 159 consecutive patients ranged from 24 to 80 (mean=58). After Phase 1, ( approximately 1 month into the protocol), FIQ scores had decreased on average by 26 points (n=128, 95% CI 23-30, p<.001). After phase 3 of the protocol 53 patients completed an FIQ questionnaire and the mean decrease in FIQ score was 38 points (95% CI 32-44, p=.004). CONCLUSIONS: This retrospective analysis suggests considerable and rapid relief of the symptoms of fibromyalgia following the use of the three-phase SRTT treatment protocol, which appears to be maintained over several years. Although these results are not conclusive they are remarkable as no other therapy reported in the scientific literature seems as efficacious for fibromyalgia. A follow-up study using an RCT design is warranted.

Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses.

Several factors have been proposed to account for the differences observed between men and women in pain perception. One of these is female and male gonadal hormones. In order to verify this assumption, a hormone replacement (pellets inserted subcutaneously) of (1) 17beta-estradiol, (2) progesterone, (3) 17beta-estradiol + progesterone or (4) testosterone have been performed in gonadectomized female and male Sprague-Dawley rats. Twenty-one days after the hormonal replacement, a formalin test was performed. The nociceptive responses were divided in three distinct phases: acute (phase I), inhibitory (interphase) and tonic (phase II). After analysis, we observed that testosterone has a hypoalgesic effect on phases I and II of the formalin test. At the opposite, female hormones act only on the interphase: the combination of 17beta-estradiol and progesterone in gonadectomized rats reestablishes the weaker nociceptive pain reduction during the interphase as it is observed in the intact female. These effects were not gender specific since they had the same action in female and male. Our results permit to believe that testosterone plays a protective role in pain perception. Moreover, the female hormones act mainly on pain inhibition mechanisms (interphase), suggesting that the prevalence of certain chronic pain conditions in women could be related to a deficit of these pain inhibitory mechanisms rather than an increased nociceptive activity.

Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition.

A deficit of endogenous pain inhibitory systems has been suggested to contribute to some chronic pain conditions, one of them being fibromyalgia. The aim of the investigation was to test whether endogenous pain inhibitory systems were activated by a spatial summation procedure in 30 fibromyalgia, 30 chronic low back pain, and 30 healthy volunteers who participated in a cross-over trial (two sessions). Each session consisted of visual analog scale ratings of pain during the immersion of different surfaces of the arm in circulating noxious cold (12 degrees C) water. The arm was arbitrarily divided into eight segments from the fingertips to the shoulder. One session was ascending (from the fingertips to the shoulder) and the other was descending (from the shoulder to the fingertips); they included eight consecutive 2-min immersions separated by 5-min resting periods. For healthy and low back pain subjects, pain was perceived differently during the ascending and descending sessions (P=0.0001). The descending session resulted in lower pain intensity and unpleasantness. This lowering of the perception curve seems to be due to a full recruitment of inhibitory systems at the beginning of the descending session as opposed to a gradual recruitment during the ascending session. For fibromyalgia subjects, no significant differences were found between the increasing and decreasing sessions (P>0.05). These data support a deficit of endogenous pain inhibitory systems in fibromyalgia but not in chronic low back pain. The treatments proposed to fibromyalgia patients should aim at stimulating the activity of those endogenous systems.

The role of sex hormones on formalin-induced nociceptive responses.

Many chronic pain conditions are more frequent in women than in men. This observation suggests that there is a potential role of sex hormones on pain perception. In the present study, we measured nociceptive responses to the formalin test in normal and gonadectomized male and female rats. The nociceptive responses to formalin injection were divided in four phases: acute (phase I), interphase and late phases (phases II and III). Four groups of rats were tested: (a) males (n = 15), (b) females (n = 16), (c) ovariectomized females (OVX) (n = 15) and (d) castrated males (CAST) (n = 15). Females presented significantly more nociceptive responses than males during phase I, interphase and phase II (P < 0.01). They also presented significantly more nociceptive responses than OVX females during the interphase (P < 0.05). CAST males presented significantly more nociceptive responses during the phases I (P < 0.01), II (P < 0.01) and III (P < 0.05) than the male rats. Finally, the responses of CAST males and OVX females were virtually identical, suggesting that the differences recorded between males and females in the formalin test were related to an activational effect of the sex hormones rather than an organizational effect. In conclusion, these results permit the support of the role of sex hormones on the modulation of pain perception. Interestingly, male and female sex hormones seem to act specifically on the different phases of the formalin test, suggesting some specific roles for sex hormones in different pain conditions.

Odors modulate pain perception: a gender-specific effect.

Odors naturally provoke emotions that are pleasant or unpleasant. Prior studies have demonstrated the effects of pleasing odors on cognition and mood perception, but no studies have reported if they influence pain perception. In the present study, we measured the effect of, and relationship between, different odors on mood and experimental pain perception. Results show that odors significantly influence mood in both women and men. Compared to a neutral odor, pleasant odors produced a positive mood while unpleasant odors produced a negative mood. However, the effect of odor on pain was gender specific, as only women experienced the effects of odor on pain perception. Because no relationship was found between mood and pain perception, it could suggest that different mechanisms are involved in the emotional aspects of mood and pain perception. These results and their potential clinical implications are discussed.

Spatial summation for pain perception: interaction of inhibitory and excitatory mechanisms.

To study the relation between size of the surface stimulated and perceived pain intensity (spatial summation effect), subjects sequentially immersed predetermined segments of the surface of their arm, between the fingertips and the shoulder, in circulating nociceptive hot water. Immersion sessions were of three types: (i) increasing session (immersion beginning at fingertips and increasing to shoulder); (ii) decreasing session (immersion beginning at shoulder and decreasing to fingertips); and (iii) whole arm+increasing session (preliminary immersion of the whole arm up to shoulder, followed by an increasing session from fingertips to shoulder). Results showed a positive spatial summation effect (pain perception positively correlated to the size of the surface stimulated) during both the decreasing session and the whole arm+increasing session. However, no spatial summation effect was found during the increasing session (fingertips to shoulder). In addition, pain perceived for a surface area was less intense during the decreasing session compared to the increasing session. One possible explanation for the lack of a spatial summation effect during the increasing session is that inhibitory mechanisms are gradually recruited at the same time as excitatory afferences, thus 'cancelling out' any measurable spatial summation effect. The results obtained during the decreasing session and the whole arm+increasing session may be explained by inhibitory mechanisms being fully recruited at the beginning of the session with the immersion of the largest surface area (whole arm). The results are a shift of the pain perception curve and a positive relation between the surface stimulated and pain perception.