Well-Loved Music Robustly Relieves Pain: A Randomized,Controlled Trial

Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly preferred music. A two-session experiment was performed with 48 healthy, pain experiment-naïve participants. In a first cohort, 36 were randomized into 3 treatment groups, including music enhanced with positive expectancy, non-musical sound enhanced with positive expectancy, and no expectancy enhancement. A separate replication cohort of 12 participants received only expectancy-enhanced music following the main experiment to verify the results of expectancy-manipulation on music. Primary outcome measures included the change in subjective pain ratings to calibrated experimental noxious heat stimuli, as well as changes in treatment expectations. Without conditioning, expectations were strongly in favor of music compared to non-musical sound. While measured expectations were enhanced by conditioning, this failed to affect either music or sound analgesia significantly. Strongly preferred music on its own was as pain relieving as conditioning-enhanced strongly preferred music, and more analgesic than enhanced sound. Our results demonstrate the pain-relieving power of personal music even over enhanced expectations.

Trial Information

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01835275","term_id":"NCT01835275"}}NCT01835275.     

Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia

Pain reduces itch-a commonly known effect of scratching the skin. Experimentally produced itch from histamine is sometimes accompanied by secondary sensations of pain. The present study investigated the effects of eliminating this pain, by means of a local anesthetic, on the itch and the enhanced mechanically evoked itch and pain that occur after an intradermal injection of histamine. In ten human subjects, the volar forearm was injected with either 20 microl of 2% chloroprocaine (experimental arm), or 20 microl of saline (control arm). Histamine 10 microl was injected into each bleb, and the resulting magnitude of itch estimated. The borders of three cutaneous areas were mapped within which mechanical stimulation of the skin surrounding the bleb elicited abnormal sensations (dysesthesiae): alloknesis, defined as itch evoked by innocuous stroking, and hyperalgesia and hyperknesis, characterized, respectively, by enhanced pain and enhanced itch evoked by pricking the skin with a fine tipped filament. The magnitude and duration of itch were significantly greater and the areas of dysesthesia significantly larger for the experimental than for the control arm. It is hypothesized that there exist two classes of histamine-sensitive primary afferent neurons. One class is "pruritic", and mediates itch whereas the other is "antipruritic", and evokes a centrally mediated reduction in histamine-evoked itch and dysesthesiae. It is further suggested that the anesthetic blocked the discharges of the antipruritic afferents, preventing the central inhibition from occurring and thereby unmasking the effects of the pruritic afferents.     

Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia

Pain reduces itch - a commonly known effect of scratching the skin. Experimentally produced itch from histamine is sometimes accompanied by secondary sensations of pain. The present study investigated the effects of eliminating this pain, by means of a local anesthetic, on the itch and the enhanced mechanically evoked itch and pain that occur after an intradermal injection of histamine. In ten human subjects, the volar forearm was injected with either 20 mul of 2% chloroprocaine (experimental arm), or 20 mul of saline (control arm). Histamine 10 mul was injected into each bleb, and the resulting magnitude of itch estimated. The borders of three cutaneous areas were mapped within which mechanical stimulation of the skin surrounding the bleb elicited abnormal sensations (dysesthesiae): alloknesis, defined as itch evoked by innocuous stroking, and hyperalgesia and hyperknesis, characterized, respectively, by enhanced pain and enhanced itch evoked by pricking the skin with a fine tipped filament. The magnitude and duration of itch were significantly greater and the areas of dysesthesia significantly larger for the experimental than for the control arm. It is hypothesized that there exist two classes of histamine-sensitive primary afferent neurons. One class is 'pruritic', and mediates itch whereas the other is 'antipruritic', and evokes a centrally mediated reduction in histamine-evoked itch and dysesthesiae. It is further suggested that the anesthetic blocked the discharges of the antipruritic afferents, preventing the central inhibition from occurring and thereby unmasking the effects of the pruritic afferents.     

A randomized,double-blind,multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia

Introduction

Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Prior trials have demonstrated the efficacy of pregabalin for the relief of fibromyalgia symptoms, and it is approved for the treatment of fibromyalgia in the United States. However, prior to this study, there has not been a large-scale efficacy trial in patients with fibromyalgia in Japan.

Methods

This randomized, double-blind, multicenter, placebo-controlled trial was conducted at 44 centers in Japan to assess the efficacy and safety of pregabalin for the symptomatic relief of pain in fibromyalgia patients. Patients aged ≥18 years who had met the criteria for fibromyalgia were randomized to receive either pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day, or placebo, for 15 weeks. The primary efficacy endpoint was mean pain score at final assessment. Secondary endpoints included Patient Global Impression of Change (PGIC) together with measures of sleep, physical functioning and quality of life.

Results

A total of 498 patients (89% female) were randomized to receive either pregabalin (n = 250) or placebo (n = 248). Pregabalin significantly reduced mean pain score at final assessment (difference in mean change from baseline, compared with placebo -0.44; P = 0.0046) and at every week during the study (P <0.025). Key secondary endpoints were also significantly improved with pregabalin treatment compared with placebo, including PGIC (percentage reporting symptoms "very much improved" or "much improved", 38.6% vs 26.7% with placebo; P = 0.0078); pain visual analog scale (difference in mean change from baseline, compared with placebo -6.19; P = 0.0013); Fibromyalgia Impact Questionnaire total score (-3.33; P = 0.0144); and quality of sleep score (-0.73; P <0.0001). Treatment was generally well tolerated, with somnolence and dizziness the most frequently reported adverse events.

Conclusions

This trial demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.

Trial Registration

ClinicalTrials.gov: NCT00830167     

An educational and physical program to reduce headache, neck/shoulder pain in a working community: a cluster-randomized controlled trial

Background

Noninvasive physical management is often prescribed for headache and neck pain. Systematic reviews, however, indicate that the evidence of its efficacy is limited. Our aim was to evaluate the effectiveness of a workplace educational and physical program in reducing headache and neck/shoulder pain.

Methodology/Principal Findings

Cluster-randomized controlled trial. All municipal workers of the City of Turin, Italy, were invited to participate. Those who agreed were randomly assigned, according to their departments, to the intervention group (IG) or to the control group and were given diaries for the daily recording of pain episodes for 1 month (baseline). Subsequently, only the IG (119 departments, 923 workers) began the physical and educational program, whereas the control group (117 departments, 990 workers) did not receive any intervention. All participants were again given diaries for the daily recording of pain episodes after 6 months of intervention. The primary outcome was the change in the frequency of headache (expressed as the proportion of subjects with a ≥50% reduction of frequency; responder rate); among the secondary outcomes there were the absolute reduction of the number of days per month with headache and neck/shoulder pain. Differences between the two groups were evaluated using mixed-effect regression models. The IG showed a higher responder rate [risk ratio, 95% confidence interval (CI)] for headache (1.58; 1.28 to 1.92) and for neck/shoulder pain (1.53; 1.27 to 1.82), and a larger reduction of the days per month (95% CI) with headache (−1.72; −2.40 to −1.04) and with neck/shoulder pain (−2.51; −3.56 to −1.47).

Conclusions

The program effectively reduced headache and neck/shoulder pain in a large working community and appears to be easily transferable to primary-care settings. Further trials are needed to investigate the program effectiveness in a clinical setting, for highly selected patients suffering from specific headache types.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00551980","term_id":"NCT00551980"}}NCT00551980     

Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease

Although pain and itch are distinct sensations, most noxious chemicals are not very specific to one sensation over the other, and recent discoveries are revealing that Trp channels function as transducers for both. A key difference between these sensations is that itch is initiated by irritation of the skin, whereas pain can be elicited from almost anywhere in the body; thus, itch may be encoded by the selective activation of specific subsets of neurons that are tuned to detect harmful stimuli at the surface and have specialized central connectivity that is specific to itch. Within the spinal cord, cross-modal inhibition between pain and itch may help sharpen the distinction between these sensations. Moreover, this idea that somatosensory modalities inhibit one another may be generalizable to other somatosensory subtypes, such as cold and hot. Importantly, just as there are inhibitory circuits in the dorsal horn that mediate cross-inhibition between modalities, it appears that there are also excitatory connections that can be unmasked upon injury or in disease, leading to abnormally elevated pain states such as allodynia. We are now beginning to understand some of this dorsal horn circuitry, and these discoveries are proving to be relevant for pathological conditions of chronic pain and itch.     

A Dietary Supplement Containing Cinnamon,Chromium and Carnosine Decreases Fasting Plasma Glucose and Increases Lean Mass in Overweight or Obese Pre-Diabetic Subjects: A Randomized,Placebo-Controlled Trial

Background

Preventing or slowing the progression of prediabetes to diabetes is a major therapeutic issue.

Objectives

Our aim was to evaluate the effects of 4-month treatment with a dietary supplement containing cinnamon, chromium and carnosine in moderately obese or overweight pre-diabetic subjects, the primary outcome being change in fasting plasma glucose (FPG) level. Other parameters of plasma glucose homeostasis, lipid profile, adiposity and inflammatory markers were also assessed.

Methods

In a randomized, double-blind, placebo-controlled study, 62 subjects with a FPG level ranging from 5.55 to 7 mmol/L and a body mass index ≥25 kg/m², unwilling to change their dietary and physical activity habits, were allocated to receive a 4-month treatment with either 1.2 g/day of the dietary supplement or placebo. Patients were followed up until 6 months post-randomization.

Results

Four-month treatment with the dietary supplement decreased FPG compared to placebo (-0.24±0.50 vs +0.12±0.59 mmol/L, respectively, p = 0.02), without detectable significant changes in HbA1c. Insulin sensitivity markers, plasma insulin, plasma lipids and inflammatory markers did not differ between the treatment groups. Although there were no significant differences in changes in body weight and energy or macronutrient intakes between the two groups, fat-free mass (%) increased with the dietary supplement compared to placebo (p = 0.02). Subjects with a higher FPG level and a milder inflammatory state at baseline benefited most from the dietary supplement.

Conclusions

Four-month treatment with a dietary supplement containing cinnamon, chromium and carnosine decreased FPG and increased fat-free mass in overweight or obese pre-diabetic subjects. These beneficial effects might open up new avenues in the prevention of diabetes.

Trial Registration

ClinicalTrials.gov NCT01530685     

Exercise as an Intervention to Reduce Study-Related Fatigue among University Students: A Two-Arm Parallel Randomized Controlled Trial

Background

Many university students experience high levels of study-related fatigue. This high prevalence, and the negative impact of fatigue on health and academic performance, call for prevention and reduction of these symptoms. The primary aim of the current study was to investigate to what extent an exercise intervention is effective in reducing three indicators of study-related fatigue (emotional exhaustion, overall fatigue, and need for recovery). Effects of exercise on secondary outcomes (sleep quality, self-efficacy, physical fitness, and cognitive functioning) were also investigated.

Methods

Participants were students with high levels of study-related fatigue, currently not exercising or receiving other psychological or pharmacological treatments, and with no medical cause of fatigue. They were randomly assigned to either a six-week exercise intervention (low-intensity running three times a week, n = 49) or wait list (no intervention, n = 48). All participants were measured before the intervention (T0), and immediately after the intervention (T1). Exercisers were also investigated 4 weeks (T2) and 12 weeks (T3) after the intervention.

Results

Participants in the exercise condition showed a larger decrease in two of the three indicators of study-related fatigue (i.e., overall fatigue and need for recovery) as compared to controls. Additionally, sleep quality and some indicators of cognitive functioning improved more among exercisers than among controls. No effects were found for self-efficacy, and physical fitness. The initial effects of the exercise intervention lasted at follow-up (T2 and T3). At 12-week follow up (T3), 80% of participants in the exercise condition still engaged in regular exercise, and further enhancements were seen for emotional exhaustion, overall fatigue, and sleep quality.

Conclusions

These results underline the value of low-intensity exercise for university students with high levels of study-related fatigue. The follow-up effects that were found in this study imply that the intervention has the potential to promote regular exercise and accompanying beneficial effects in the longer run.

Trial Registration

Netherlands Trial Register NTR4412     

Effects of High-Intensity Interval Training versus Continuous Training on Physical Fitness,Cardiovascular Function and Quality of Life in Heart Failure Patients

Introduction

Physical fitness is an important prognostic factor in heart failure (HF). To improve fitness, different types of exercise have been explored, with recent focus on high-intensity interval training (HIT). We comprehensively compared effects of HIT versus continuous training (CT) in HF patients NYHA II-III on physical fitness, cardiovascular function and structure, and quality of life, and hypothesize that HIT leads to superior improvements compared to CT.

Methods

Twenty HF patients (male:female 19:1, 64±8 yrs, ejection fraction 38±6%) were allocated to 12-weeks of HIT (10*1-minute at 90% maximal workload—alternated by 2.5 minutes at 30% maximal workload) or CT (30 minutes at 60–75% of maximal workload). Before and after intervention, we examined physical fitness (incremental cycling test), cardiac function and structure (echocardiography), vascular function and structure (ultrasound) and quality of life (SF-36, Minnesota living with HF questionnaire (MLHFQ)).

Results

Training improved maximal workload, peak oxygen uptake (VO_2peak) related to the predicted VO_2peak, oxygen uptake at the anaerobic threshold, and maximal oxygen pulse (all P<0.05), whilst no differences were present between HIT and CT (N.S.). We found no major changes in resting cardiovascular function and structure. SF-36 physical function score improved after training (P<0.05), whilst SF-36 total score and MLHFQ did not change after training (N.S.).

Conclusion

Training induced significant improvements in parameters of physical fitness, although no evidence for superiority of HIT over CT was demonstrated. No major effect of training was found on cardiovascular structure and function or quality of life in HF patients NYHA II-III.

Trial Registration

Nederlands Trial Register NTR3671     

Psyllium supplementation in adolescents improves fat distribution & lipid profile: a randomized, participant-blinded, placebo-controlled, crossover trial

Aims

We aimed to assess the effects of psyllium supplementation on insulin sensitivity and other parameters of the metabolic syndrome in an at risk adolescent population.

Methods

This study encompassed a participant-blinded, randomized, placebo-controlled, crossover trial. Subjects were 47 healthy adolescent males aged 15–16 years, recruited from secondary schools in lower socio-economic areas with high rates of obesity. Participants received 6 g/day of psyllium or placebo for 6 weeks, with a two-week washout before crossing over. Fasting lipid profiles, ambulatory blood pressure, auxological data, body composition, activity levels, and three-day food records were collected at baseline and after each 6-week intervention. Insulin sensitivity was measured by the Matsuda method using glucose and insulin values from an oral glucose tolerance test.

Results

45 subjects completed the study, and compliance was very high: 87% of participants took >80% of prescribed capsules. At baseline, 44% of subjects were overweight or obese. 28% had decreased insulin sensitivity, but none had impaired glucose tolerance. Fibre supplementation led to a 4% reduction in android fat to gynoid fat ratio (p = 0.019), as well as a 0.12 mmol/l (6%) reduction in LDL cholesterol (p = 0.042). No associated adverse events were recorded.

Conclusions

Dietary supplementation with 6 g/day of psyllium over 6 weeks improves fat distribution and lipid profile (parameters of the metabolic syndrome) in an at risk population of adolescent males.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12609000888268     

Rapid and sustained improvements in health-related quality of life,fatigue, and other patient-reported outcomes in rheumatoid arthritis patients treated with certolizumab pegol plus methotrexate over 1 year: results from the RAPID 1 randomized controlled trial

Introduction

The objective of this study was to assess the impact of certolizumab pegol (CZP) treatment on health-related quality of life (HRQoL), fatigue and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA).

Methods

Patients with active RA (N = 982) were randomized 2:2:1 to subcutaneous CZP (400 mg at weeks 0, 2 and 4; followed by CZP 200 mg or 400 mg) plus methotrexate (MTX) every other week, or placebo (PBO) plus MTX. PRO assessments included HRQoL, fatigue, physical function, arthritis pain and disease activity. Adjusted mean changes from baseline in all PROs were obtained using analysis of covariance (ANCOVA) applying last observation carried forward (LOCF) imputation. The proportion of patients achieving clinically meaningful improvements in each PRO was obtained using logistic regression and by applying non-responder imputation to missing values after rescue medication or withdrawal. The correlations between PRO responses and clinical responses were also assessed by tetrachoric correlation using non-responder imputation.

Results

Patients treated with CZP plus MTX reported significant (P < 0.001), clinically meaningful improvements in HRQoL at the first assessment (week 12); reductions in fatigue, disease activity and pain and improvements in physical function were reported at week 1. In particular, CZP-treated patients reported improvements in mental health. Mean changes from baseline in the SF-36 Mental Component Summary (MCS) at week 52 for CZP 200 mg and 400 mg plus MTX, and PBO plus MTX were 6.4, 6.4 and 2.1, respectively (P < 0.001). In addition, mental health and vitality scores in CZP-treated patients approached age- and gender-adjusted US population norms. Improvements in all PROs were sustained. Similar benefits were reported with both CZP doses. Changes in SF-36 MCS scores had the lowest correlation with disease activity scores (DAS28) and American College of Rheumatology 20% improvement (ACR20) response rates, while improvements in pain showed the highest correlation.

Conclusions

Treatment with CZP plus MTX resulted in rapid and sustained improvements in all PROs, indicating that the benefits of CZP extend beyond clinical efficacy endpoints into areas that are more relevant and meaningful for patients on a daily basis.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00152386","term_id":"NCT00152386"}}NCT00152386.     

Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial

Background

Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST).

Methods

This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups.

Results

64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation.

Conclusion

Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00755573","term_id":"NCT00755573"}}NCT00755573     

The cell biology of acute itch

IntroductionThe average human is covered in 1.8 to 2.0 m² of skin (Ogden et al., 2004). With such a large surface area, a sensory modality we call itch has evolved to alert us to potentially dangerous external stimuli. Unlike the sensation of pain, where an organism will actively try and withdraw from an unpleasant stimuli, itch compels the affected to seek out the source and respond with a scratch. Acute itch serves us well in guarding against environmental threats; however, chronic or severe itch (pruritus) is a burdensome illness that affects millions every year (Nutten, 2015). Fortunately, great strides have been made over the past few decades in understanding the cellular biology that underlies both acute and chronic itch, providing hope for new medical treatments.Compared with its sensory cousin, pain, the understanding of itch is still nascent. New discoveries within the past few years have brought excitement, however. Work uncovering receptors, agonists, and the interplay of different cell types has begun to widen the field and offer new avenues for study. In this review, we will look at the cell biology of itch, with an emphasis on the receptors, cell types, and pruriceptors that are involved in the processing of itch, focusing on the periphery and how itch is coded in the spinal cord.KeratinocytesAs the primary cell type found in skin, keratinocytes are capable of producing a variety of defenses against pathogens. In response to noxious stimuli, keratinocytes can release a host of inflammatory mediators, including nerve growth factor, IL-6, and serotonin, sensitizing peripheral neurons (Luo et al., 2015). Keratinocytes have also been shown to directly activate neurons via the release of the cytokine thymic stromal lymphopoietin, triggering itch behavior (Fig. 1; Wilson et al., 2013). Keratinocytes interact with the immune system via the release of chemoattractants, such as monocyte chemoattractant protein 1, chemokine ligand 5, and IL-8, recruiting immune cells to the site of injury or pruritinergic stimuli. These chemokines were found to be elevated in patients with atopic dermatitis and psoriasis, implicating keratinocytes in the pathology of itch (Giustizieri et al., 2001).Open in a separate windowFigure 1.Multiple cell types contribute to peripheral itch. Prurinergic stimuli, here a mosquito bite, generates itch via the interaction of a variety of cell types. Keratinocytes release endogenous pruritogens, including thymic stromal lymphopoietin (TSLP), contributing directly to itch sensation by activating the TSLP receptor (TSLPR) on peripheral afferent neurons (Wilson et al., 2013). Keratinocytes also release chemoattractants that recruit immune cells, including mast cells. Histamine released from stored granules in mast cells binds H1 receptors, activating pruriceptors and transmitting itch signals to the spinal cord. Along with histamine, other pruritogens, including serotonin, proteases, and IL-6, are released by resident immune cells such as T cells and dendritic cells (Schmelz et al., 2003). The blue squares at the nerve endings represent the receptor for itchy substances.ConclusionProgress has been made in identifying distinct receptors and sensory neurons that encode itch, which was formerly thought to be a submodality of pain. Characterization of primary afferents expressing Mrgprs and GRP, as well as those spinal neurons that are positive for GRPR, BNP, and NPY, have broadened our understanding of the cell types underlying itch. The focus of this review has been acute itch, and questions still remain about whether pathological or chronic itch alters the expression and molecular underpinnings of the mechanisms outlined in this review. However, the research outlined here provides hope for the future, as the identification of unique itch pathways will aid in the development of novel clinical therapies for those suffering from debilitating pruritus.     

The Effectiveness of Individualized Acupuncture Protocols in the Treatment of Gulf War Illness: A Pragmatic Randomized Clinical Trial

Background

Gulf War Illness is a Complex Medical Illness characterized by multiple symptoms, including fatigue, sleep and mood disturbances, cognitive dysfunction, and musculoskeletal pain affecting veterans of the first Gulf War. No standard of care treatment exists.

Methods

This pragmatic Randomized Clinical Trial tested the effects of individualized acupuncture treatments offered in extant acupuncture practices in the community; practitioners had at least 5 years of experience plus additional training provided by the study. Veterans with diagnosed symptoms of Gulf War Illness were randomized to either six months of biweekly acupuncture treatments (group 1, n = 52) or 2 months of waitlist followed by weekly acupuncture treatments (group 2, n = 52). Measurements were taken at baseline, 2, 4 and 6 months. The primary outcome is the SF-36 physical component scale score (SF-36P) and the secondary outcome is the McGill Pain scale.

Results

Of the 104 subjects who underwent randomization, 85 completed the protocol (82%). A clinically and statistically significant average improvement of 9.4 points (p = 0.03) in the SF-36P was observed for group 1 at month 6 compared to group 2, adjusting for baseline pain. The secondary outcome of McGill pain index produced similar results; at 6 months, group 1 was estimated to experience a reduction of approximately 3.6 points (p = 0.04) compared to group 2.

Conclusions

Individualized acupuncture treatment of sufficient dose appears to offer significant relief of physical disability and pain for veterans with Gulf War Illness. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Gulf War Illness Research Program under Award No. W81XWH-09-2-0064. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01305811","term_id":"NCT01305811"}}NCT01305811     

Effects of extreme-duration heavy load carriage on neuromuscular function and locomotion: a military-based study

Trekking and military missions generally consist of carrying heavy loads for extreme durations. These factors have been separately shown to be sources of neuromuscular (NM) fatigue and locomotor alterations. However, the question of their combined effects remains unresolved, and addressing this issue required a representative context.

Purpose

The aim was to investigate the effects of extreme-duration heavy load carriage on NM function and walking characteristics.

Methods

Ten experienced infantrymen performed a 21-h simulated military mission (SMM) in a middle-mountain environment with equipment weighing ∼27 kg during battles and ∼43 kg during marches. NM function was evaluated for knee extensors (KE) and plantar flexors (PF) pre- and immediately post-SMM using isometric maximal voluntary contraction (MVC) measurement, neural electrical stimulation and surface EMG. The twitch-interpolation method was used to assess central fatigue. Peripheral changes were examined by stimulating the muscle in the relaxed state. The energy cost, mechanical work and spatio-temporal pattern of walking were also evaluated pre−/post-SMM on an instrumented treadmill in three equipment conditions: Sportswear, Battle and March.

Results

After the SMM, MVC declined by −10.2±3.6% for KE (P<0.01) and −10.7±16.1% for PF (P = 0.06). The origin of fatigue was essentially peripheral for both muscle groups. A trend toward low-frequency fatigue was detected for KE (5.5%, P = 0.08). These moderate NM alterations were concomitant with a large increase in perceived fatigue from pre- (rating of 8.3±2.2) to post-SMM (15.9±2.1, P<0.01). The SMM-related fatigue did not alter walking energetics or mechanics, and the different equipment carried on the treadmill did not interact with this fatigue either.

Conclusion

this study reports the first data on physiological and biomechanical consequences of extreme-duration heavy load carriage. Unexpectedly, NM function alterations due to the 21-h SMM were moderate and did not alter walking characteristics.

Clinical Trial Registration

Name: Effect of prolonged military exercises with high load carriage on neuromuscular fatigue and physiological/biomechanical responses. Number: {"type":"clinical-trial","attrs":{"text":"NCT01127191","term_id":"NCT01127191"}}NCT01127191.     

Evaluation of the anti-fatigue effects of a traditional herbal drug,Gongjin-dan,under insufficient sleep conditions: study protocol for a randomised controlled trial

BackgroundMany herbal medicines are traditionally used as anti-fatigue agents in east Asian countries; however, there is a dearth of clinical evidence supporting the anti-fatigue effects of such medicines and their mechanisms. This study is a feasibility trial to assess the clinical efficacy of Gongjin-dan (GJD) and verify its mechanisms by exploring fatigue outcomes, including endocrine and immunological biomarkers in humans.Methods/DesignTo investigate the anti-fatigue effects of GJD and the mechanism underlying these effects, a randomised, double-blind, placebo-controlled crossover clinical trial was designed. Participants (24 healthy male volunteers) will be hospitalised for 4 days (3 nights), during which acute fatigue and stress conditions will be induced by sleep deprivation, and GJD or a placebo will be administered (twice daily). The primary outcome will be changes in serum cortisol levels, measured in the morning, as an objective biomarker of sleep deprivation-induced fatigue and stress. The secondary outcomes will include: the Fatigue Severity Scale; the Brief Fatigue Inventory, and the Leeds Sleep Evaluation Questionnaire scores; levels of salivary cortisol, epinephrine, norepinephrine, oxidative stress-related biomarkers, homocysteine, and immunological factors; and heart rate variability. After a washout period of more than 4 weeks, a second treatment phase will commence in which participants who were previously administered the placebo will receive the drug and vice versa, following the same treatment regime as in the first phase.DiscussionThis study protocol provides a unique opportunity to enhance our understanding of fatigue and the effects of GJD on fatigue in terms of endocrine and immunological mechanisms by validating the study design and determining feasibility. Findings from this trial will help researchers to design a pilot or definitive clinical trial of traditional herbal medicine for chronic fatigue.

Trial registration

Korean National Clinical Trial Registry CRIS; KCT0001681, registered on 29 October 2015.     

Effect of aerobic exercise training and cognitive behavioural therapy on reduction of chronic fatigue in patients with facioscapulohumeral dystrophy: protocol of the FACTS-2-FSHD trial

Background

In facioscapulohumeral dystrophy (FSHD) muscle function is impaired and declines over time. Currently there is no effective treatment available to slow down this decline. We have previously reported that loss of muscle strength contributes to chronic fatigue through a decreased level of physical activity, while fatigue and physical inactivity both determine loss of societal participation. To decrease chronic fatigue, two distinctly different therapeutic approaches can be proposed: aerobic exercise training (AET) to improve physical capacity and cognitive behavioural therapy (CBT) to stimulate an active life-style yet avoiding excessive physical strain. The primary aim of the FACTS-2-FSHD (acronym for Fitness And Cognitive behavioural TherapieS/for Fatigue and ACTivitieS in FSHD) trial is to study the effect of AET and CBT on the reduction of chronic fatigue as assessed with the Checklist Individual Strength subscale fatigue (CIS-fatigue) in patients with FSHD. Additionally, possible working mechanisms and the effects on various secondary outcome measures at all levels of the International Classification of Functioning, Disability and Health (ICF) are evaluated.

Methods/Design

A multi-centre, assessor-blinded, randomized controlled trial is conducted. A sample of 75 FSHD patients with severe chronic fatigue (CIS-fatigue ≥ 35) will be recruited and randomized to one of three groups: (1) AET + usual care, (2) CBT + usual care or (3) usual care alone, which consists of no therapy at all or occasional (conventional) physical therapy. After an intervention period of 16 weeks and a follow-up of 3 months, the third (control) group will as yet be randomized to either AET or CBT (approximately 7 months after inclusion). Outcomes will be assessed at baseline, immediately post intervention and at 3 and 6 months follow up.

Discussion

The FACTS-2-FSHD study is the first theory-based randomized clinical trial which evaluates the effect and the maintenance of effects of AET and CBT on the reduction of chronic fatigue in patients with FSHD. The interventions are based on a theoretical model of chronic fatigue in patients with FSHD. The study will provide a unique set of data with which the relationships between outcome measures at all levels of the ICF could be assessed.

Trial registration

Dutch Trial Register, NTR1447.

     

A randomized controlled trial of qigong for fibromyalgia

Introduction

Fibromyalgia is difficult to treat and requires the use of multiple approaches. This study is a randomized controlled trial of qigong compared with a wait-list control group in fibromyalgia.

Methods

One hundred participants were randomly assigned to immediate or delayed practice groups, with the delayed group receiving training at the end of the control period. Qigong training (level 1 Chaoyi Fanhuan Qigong, CFQ), given over three half-days, was followed by weekly review/practice sessions for eight weeks; participants were also asked to practice at home for 45 to 60 minutes per day for this interval. Outcomes were pain, impact, sleep, physical function and mental function, and these were recorded at baseline, eight weeks, four months and six months. Immediate and delayed practice groups were analyzed individually compared to the control group, and as a combination group.

Results

In both the immediate and delayed treatment groups, CFQ demonstrated significant improvements in pain, impact, sleep, physical function and mental function when compared to the wait-list/usual care control group at eight weeks, with benefits extending beyond this time. Analysis of combined data indicated significant changes for all measures at all times for six months, with only one exception. Post-hoc analysis based on self-reported practice times indicated greater benefit with the per protocol group compared to minimal practice.

Conclusions

This study demonstrates that CFQ, a particular form of qigong, provides long-term benefits in several core domains in fibromyalgia. CFQ may be a useful adjuvant self-care treatment for fibromyalgia.

Trial registration

clinicaltrials.gov NCT00938834.     

Effectiveness of YouRAction, an intervention to promote adolescent physical activity using personal and environmental feedback: a cluster RCT

Background

In this study the one and six months effects of the computer-tailored YouRAction (targeting individual level determinants) and YouRAction+e (targeting in addition perceived environmental determinants) on compliance with the moderate-to-vigorous physical activity (MVPA) guideline and weight status are examined. In addition the use and appreciation of both interventions are studied.

Methods

A three-armed cluster randomized trial was conducted in 2009–2010 with measurements at baseline, one and six months post intervention. School classes were assigned to one of the study arms (YouRaction, YouRAction+e and Generic Information (GI) control group). MVPA was derived from self-reports at baseline, one and six months post intervention. Body Mass Index and waist circumference were measured at baseline and six months post intervention in a random sub-sample of the population. Use of the interventions was measured by webserver logs and appreciation by self-reports. Multilevel regression analyses were conducted to study the effects of the intervention against the GI control group. ANOVA''s and chi-square tests were used to describe differences in use and appreciation between study arms.

Results

There were no statistically significant intervention effects on compliance with the MVPA guideline, overweight or WC. Access to the full intervention was significantly lower for YouRAction (24.0%) and YouRAction+e (21.7%) compared to the GI (54.4%).

Conclusion

This study could not demonstrate that the YouRAction and YouRAction+e interventions were effective in promoting MVPA or improve anthropometric outcomes among adolescents, compared to generic information. Insufficient use and exposure to the intervention content may be an explanation for the lack of effects.

Trial Registration

TrialRegister.nl NTR1923     

Effective group training for patients with unexplained physical symptoms: a randomized controlled trial with a non-randomized one-year follow-up

Background

Although cognitive-behavioral therapy for Unexplained Physical Symptoms (UPS) is effective in secondary care, studies done in primary care produced implementation problems and conflicting results. We evaluated the effectiveness of a cognitive-behavioral group training tailored to primary care patients and provided by a secondary community mental-health service reaching out into primary care.

Methodology/Principal Findings

The effectiveness of this training was explored in a randomized controlled trial. In this trial, 162 patients with UPS classified as undifferentiated somatoform disorder or as chronic pain disorder were randomized either to the training or a waiting list. Both lasted 13 weeks. The preservation of the training''s effect was analyzed in non-randomized follow-ups, for which the waiting group started the training after the waiting period. All patients attended the training were followed-up after three months and again after one year. The primary outcomes were the physical and the mental summary scales of the SF-36. Secondary outcomes were the other SF-36-scales and the SCL-90-R. The courses of the training''s effects in the randomized controlled trial and the follow-ups were analyzed with linear mixed modeling. In the randomized controlled trial, the training had a significantly positive effect on the quality of life in the physical domain (Cohen''s d = 0.38;p = .002), but this overall effect was not found in the mental domain. Regarding the secondary outcomes, the training resulted in reporting an improved physical (Cohen''s d = 0.43;p = 0.01), emotional (Cohen''s d = 0.44;p = .0.01), and social (Cohen''s d = 0.36;p = 0.01) functioning, less pain and better functioning despite pain (Cohen''s d = 0.51;p = <0.001), less physical symptoms (Cohen''s d = −.23;p = 0.05) and less sleep difficulties (Cohen''s d = −0.25;p = 0.04) than time in the waiting group. During the non-randomized follow-ups, there were no relapses.

Conclusions/Significance

The cognitive-behavioral group training tailored for UPS in primary care and provided by an outreaching secondary mental-health service appears to be effective and to broaden the accessibility of treatment for UPS.

Trial Registration

TrialRegister.nl NTR1609 <rctview.asp?TC = 1609>