From PAIN, 15 March 2016 (published online ahead of print).
Combination of pregabalin with duloxetine for fibromyalgia: A randomized controlled trial.
Ian Gilron(1), Luis E. Chaparro(2), Dongsheng Tu(3), Ronald R. Holden(4), Roumen Milev(5), Tanveer Towheed(6), Deborah DuMerton-Shore(7), Sarah Walker(8).
1) Director of Clinical Pain Research and Professor, Departments of Anesthesiology & Perioperative Medicine and Biomedical & Molecular Sciences, Queen’s University.
2) Anesthesia Resident, University of Toronto.
3) Professor, Departments of Public Health Sciences and Mathematics & Statistics, Queen’s
4) Professor, Department of Psychology, Queen’s University.
5) Professor and Head, Department of Psychiatry, Queen’s University.
6) Professor, Department of Medicine (Division of Rheumatology).
7) Research Coordinator, Department of Anesthesiology, Kingston General Hospital.
8) Research Nurse, Department of Anesthesiology, Kingston General Hospital.
Fibromyalgia is a syndrome characterized by chronic widespread pain and associated with sleep disturbance, depression, fatigue and cognitive dysfunction.
Polypharmacy is commonly used but supportive evidence is limited. Most fibromyalgia trials focus primarily on pain reduction with monotherapy. This trial compares a pregabalin-duloxetine combination to each monotherapy.
Using a randomized, double-blind, four-period crossover design, participants received maximally tolerated doses of placebo, pregabalin, duloxetine and pregabalin-duloxetine combination – for six weeks.
Primary outcome was daily pain (0-10); secondary outcomes included global pain relief, Fibromyalgia Impact Questionnaire (FIQ), SF-36 survey, MOS sleep scale, Beck Depression Inventory (BDI-II), adverse events and other measures.
Of 41 participants randomized, 39 completed >=2 treatments. Daily pain during placebo, pregabalin, duloxetine, and combination was 5.1, 5.0, 4.1 and 3.7, respectively (p<0.05 only for combination versus placebo, and pregabalin). Participants (%) reporting >= moderate global pain relief were 18%, 39%, 42% and 68%, respectively (p<0.05 for combination versus placebo, pregabalin, and duloxetine). FIQ scores were 42.9, 37.4, 36.0 and 29.8, respectively (p<0.05 for combination versus placebo, pregabalin, and duloxetine). SF-36 scores were 50.2, 55.7, 56.0 and 61.2, respectively (p<0.05 for combination versus placebo, pregabalin, and duloxetine). MOS Sleep scores were 48.9, 35.2, 46.1 and 32.1, respectively (p<0.05 only for combination versus placebo, and duloxetine). BDI-II scores were 11.9, 9.9, 10.7 and 8.9, respectively (p<0.05 only for combination versus placebo). Moderate-severe drowsiness was more frequent during combination versus placebo. Combining pregabalin and duloxetine for fibromyalgia improves multiple clinical outcomes versus monotherapy. Continued research should compare this and other combinations to monotherapy for fibromyalgia. SUMMARY This double-blind randomized controlled trial demonstrates improved outcomes with a pregabalin-duloxetine combination over either single drug for fibromyalgia.
SOPHIE LOUP, the ME Association’s research assistant, writes:
The results of this study suggest that combining pregabalin with duloxetine can safely improve some outcomes in fibromyalgia, especially pain relief, for some patients.
This article looks at the use of a combination of pregabalin and duloxetine for symptom management in fibromyalgia. Pregabalin, also known under the trade name Lyrica, is used to treat epilepsy, nerve pain and anxiety. Duloxetine, also known under the trade name Cymbalta, is used to treat depression and sometimes used for pain relief, including fibromyalgia pain. Fibromyalgia has a number of overlapping symptoms with ME/CFS, and some people with ME/CFS experience fibromyalgic pain. Therefore, treatment that is safe and effective in fibromyalgia may be of use for some people with ME/CFS.
The study compares treatment with a combination of pregabalin and duloxetine to treatment with only pregabalin or only duloxetine. It had a four-period crossover design, which means each patient went through four separate treatment periods of six weeks in which they received the four treatments (placebo, duloxetine, pregabalin and combination) in randomized order. The maximally tolerated doses of the drugs for each patient were used. The study was double-blind, which means that neither the researchers nor the patients knew who received what until the results were analysed. Of the 41 participants, 39 completed at least two treatments, and 33 completed all four treatments. Those who did not complete all treatments did so because of adverse effects.
The primary outcome measure was daily pain (‘average pain intensity over the past 24 hours’ rated each morning upon arising and averaged over seven days at maximal tolerated dose). A primary outcome is the specific criterion used to measure whether a treatment is successful, so it is specified before the study starts. It answers the most important question being asked by a trial. In this case, the question is whether a combination of duloxetine and pregabalin reduces daily pain more than either medication taken on its own. Secondary outcomes answer other relevant questions. Secondary outcome measures in this study included global pain relief, adverse effects/serious adverse effects, short-form McGill Pain Questionnaire (SF-MPQ), Fibromyalgia Impact Questionnaire, Beck Depression Inventory-II (BDI-II), SF-36 Health Survey (SF-36, measures quality of life) and Medical Outcomes Study Sleep Scale (MOS-S), among others.
Daily pain was lower for combination than for placebo or pregabalin but not lower than for duloxetine. The reduction in pain with combination when compared to duloxetine was not significant, which means we cannot rule out that it might be due to chance. However, combination was superior to duloxetine and pregabalin monotherapy for global pain relief, Fibromyalgia Impact Questionnaire, SF-36 and SF-MPQ. Differences in MOS-S scores were significant for combination versus placebo and duloxetine but not versus pregabalin. Differences in BDI-II scores were significant only for combination versus placebo.
The main side effect of the combination was drowsiness, which was more frequent than with duloxetine or placebo. Headaches were more frequent with the combination than with placebo in the phase of the trial where the dose of treatment is gradually reduced and stopped. The side-effects of the combination were similar to the side-effects of either drugs taken alone, but were reached at lower doses of treatment.
One caveat of this study is that drowsiness with duloxetine and pregabalin is not uncommon, and so the authors cannot rule out the possibility that reduced physical activity was a contributor to the pain reduction observed.
Some of the researchers have received financial support in the past from the manufacturers of some brands of duloxetine and pregabalin. Furthermore, this research was supported in part by Pfizer, who manufactures Lyrica, through the Canadian Institutes of Health. These conflicts of interest are however disclosed at the end of the article.
The ME Association has leaflets on duloxetine, pregabalin and coping with pain. They are available from the online shop: www.meassociation.org.uk/shop/
MEA website item on a phase 3 clinical trial involving duloxetine:
From Arthritis Care and Research (Hoboken), January 2016.
Gene Expression Factor Analysis to Differentiate Pathways Linked to Fibromyalgia, Chronic Fatigue Syndrome, and Depression in a Diverse Patient Sample.
Iacob E, Light AR, Donaldson GW, Okifuji A, Hughen RW, White AT, Light KC.
University of Utah, Salt Lake City
To determine if independent candidate genes can be grouped into meaningful biologic factors, and whether these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS), while controlling for comorbid depression, sex, and age.
We included leukocyte messenger RNA gene expression from a total of 261 individuals, including healthy controls (n = 61), patients with FMS only (n = 15), with CFS only (n = 33), with comorbid CFS and FMS (n = 79), and with medication-resistant (n = 42) or medication-responsive (n = 31) depression. We used exploratory factor analysis (EFA) on 34 candidate genes to determine factor scores and regression analysis to examine whether these factors were associated with specific diagnoses.
EFA resulted in 4 independent factors with minimal overlap of genes between factors, explaining 51% of the variance. We labeled these factors by function as 1) purinergic and cellular modulators, 2) neuronal growth and immune function, 3) nociception and stress mediators, and 4) energy and mitochondrial function. Regression analysis predicting these biologic factors using FMS, CFS, depression severity, age, and sex revealed that greater expression in factors 1 and 3 was positively associated with CFS and negatively associated with depression severity (Quick Inventory for Depression Symptomatology score), but not associated with FMS.
Expression of candidate genes can be grouped into meaningful clusters, and CFS and depression are associated with the same 2 clusters, but in opposite directions, when controlling for comorbid FMS. Given high comorbid disease and interrelationships between biomarkers, EFA may help determine patient subgroups in this population based on gene expression.
From Medicine and Science in Sports & Exercise, published online 16 May 2016.
Fatigue Exacerbation by Interval or Continuous Exercise in Chronic Fatigue Syndrome.
Sandler, Carolina X.; Lloyd, Andrew R.; Barry, Benjamin K.
To determine if the typical exacerbation of symptoms in patients with chronic fatigue syndrome (CFS) following a bout of exercise differs between high-intensity interval training (HIIT) or continuous (CONT) aerobic exercise of the same duration and mechanical work.
Participants with specialist-diagnosed CFS performed two 20-minute bouts of cycling in a randomised crossover study. The bouts were either moderate-intensity-continuous (70% age predicted heart rate max (APHRM)) or high-intensity-interval exercise, separated by at least 2 weeks. Self-report questionnaires capturing fatigue and related symptoms, and actigraphy were collected across 2 days before and 4 days following the exercise. Comparisons between exercise bouts were made using paired sample t-tests.
Fourteen moderately affected participants who were unable to work, but not bed bound, completed the study (9 female, 32 +/- 10 years, 67 +/- 11 kg). Mechanical work was matched successfully between the exercise bouts (HIIT 83,037 vs CONT 83,348 J, p=0.84). Mean heart rate (HIIT 76 +/- 5 vs CONT 73 +/- 6 %APHRM, p<0.05) and RPE (6-20) in the legs (HIIT 15.4 +/- 1.4 vs CONT 13.2 +/- 1.2, p<0.001) were higher for the interval compared to continuous exercise. Mean fatigue scores (0-10) were similar before each exercise challenge (HIIT 4.5 +/- 1.8 vs CONT 4.1 +/- 1.7, p=0.43). Participants reported an increase in fatigue scores following both challenges (Mean difference: HIIT 1.0 +/- 1.3, p<0.01; CONT 1.5 +/- 0.7, p<0.001), but these exacerbations in fatigue were not statistically or clinically different (p=0.20). CONCLUSIONS High-intensity interval exercise did not exacerbate fatigue any more than continuous exercise of comparable workload. This finding supports evaluation of HIIT in graded exercise therapy interventions for patients with CFS.
From the American Journal of Case Reports, 11 May 2016.
Reversal of Refractory Ulcerative Colitis and Severe Chronic Fatigue Syndrome Symptoms Arising from Immune Disturbance in an HLA-DR/DQ Genetically Susceptible Individual with Multiple Biotoxin Exposures.
Gunn SR(1), Gunn GG(1), Mueller FW(2).
1) Department of Genomic Pathology, Targeted Genomics, San Antonio, TX, USA.
2) Family Practice, Huebner Family Medicine, San Antonio, TX, USA.
Patients with multisymptom chronic conditions, such as refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS), present diagnostic and management challenges for clinicians, as well as the opportunity to recognize and treat emerging disease entities. In the current case we report reversal of co-existing RUC and CFS symptoms arising from biotoxin exposures in a genetically susceptible individual.
A 25-year-old previously healthy male with new-onset refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS) tested negative for autoimmune disease biomarkers. However, urine mycotoxin panel testing was positive for trichothecene group and air filter testing from the patient’s water-damaged rental house identified the toxic mold Stachybotrys chartarum. HLA-DR/DQ testing revealed a multisusceptible haplotype for development of chronic inflammation, and serum chronic inflammatory response syndrome (CIRS) biomarker testing was positive for highly elevated TGF-beta and a clinically undetectable level of vasoactive intestinal peptide (VIP). Following elimination of biotoxin exposures, VIP replacement therapy, dental extractions, and implementation of a mind body intervention-relaxation response (MBI-RR) program, the patient’s symptoms resolved. He is off medications, back to work, and resuming normal exercise.
This constellation of RUC and CFS symptoms in an HLA-DR/DQ genetically susceptible individual with biotoxin exposures is consistent with the recently described CIRS disease pathophysiology. Chronic immune disturbance (turbatio immuno) can be identified with clinically available CIRS biomarkers and may represent a treatable underlying disease etiology in a subset of genetically susceptible patients with RUC, CFS, and other immune disorders.
From the Journal of Psychosomatic Research, June 2016.
Why patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis improve or deteriorate with graded exercise therapy
A. Cheshire, D. Ridge, L. Clark, P. White
Graded exercise therapy, GET, (along with cognitive behaviour therapy, CBT) is one of only two treatments recommended by the 2007 National Institute of Health Care Excellence (NICE) CFS/ME guidelines as having an evidence-base. NICE describes GET as an “approach to CFS/ME that involves physical assessment, mutually negotiated goal-setting and education”. However, lay surveys show that GET is considered unacceptable or harmful by many patients. Further investigation is needed to understand why some people seem to benefit from GET, and not others.
The study aimed to answer the question, “What are the differences and similarities in treatment perceptions and experiences of GET, among participants who improved and got worse in a pragmatic randomised controlled trial of Guided graded Exercise Self-help (GETSET).”?
This qualitative, one-to-one interview study was situated within the GETSET Trial. A sub-sample of patients were stratified into improved and deteriorated and recruited: 9 were better, 10 were worse (according to Clinical Global Impression (CGI) scale). Interviews were semi-structured to ensure all participants discussed all relevant topics to the study. Interviews were transcribed in full and a thematic, “constant comparison” approach was used in the analysis, using NVivo software to ensure all relevant data were analysed.
Participants generally found GET challenging, especially during initiation, as participants had to wait considerable time for any benefit. The deteriorated group reported experiencing more barriers to GET, including a worse exacerbation of symptoms in response to GET, which interfered with their life commitments (e.g. work, caring duties). They also reported greater interference with GET from comorbid conditions and other things happening in their lives. Additionally, they had had CFS for considerably longer than the improved group. The improved group on the other hand reported more facilitators to doing GET (e.g. using other therapies), and were more likely to report exceptionally high levels of motivation. Paradoxically, GET engagement could be supported by having worse levels of CFS/ME, as participants felt too ill to do activities that could distract them from GET.
Our findings flesh out the deeper meanings behind polarized experiences of GET, pointing to the specific conditions under which GET is most likely to work, and how health professionals could assist patients to benefit from GET.
From Biological Psychology, published online 17 May 2016.
Sanae Fukuda(a,b,c),Junzo Nojima(d), Yukari Motoki(d), Kouzi Yamaguti(c,e), Yasuhito Nakatomi(c,e), Naoko Okawa(a), Kazumi Fujiwara(a), Yasuyoshi Watanabe(b,c), Hirohiko Kuratsune(a,b,c,e).
a) University of Kansai Welfare Sciences, Kashiwara, Osaka 582-0026, Japan
b) RIKEN Center for Life Science Technologies, Kobe, Hyogo 650-0047, Japan
c) Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
d) Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, 755-8505, Japan
e) Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
• Fatigue is a frequent symptom in both healthy individuals and patients, therefore, biomarkers indicating several differential levels of fatigue would be needed for evaluating fatigue and its improvement.
• Following the hard work term, the mean values of oxidative stress increased; however, anti-oxidative activity did not decrease, except only one case.
• Measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.
We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions.
We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls.
Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease.
Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls.
BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls.
Thus, measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.
From Neuroscience and Biobehavioural Reviews, 18 May 2016.
Dysregulated stress signal sensitivity and inflammatory disinhibition as a pathophysiological mechanism of stress-related chronic fatigue
Jana Strahler (a), Nadine Skoluda (a), Nicolas Rohleder(b), Urs M Nater(a)
a) Clinical Biopsychology, University of Marburg, Gutenbergstrasse 18, Marburg, 35037, Germany
b) Health Psychology, Friedrich-Alexander-University Erlangen-Nuremberg, Nägelsbachstrasse 49a, Erlangen 91052, Germany
• We review stress signal sensitivity of immune cells in chronic stress and fatigue.
• Chronic stress seems to result in resistance of immune cells to stress signals.
• Findings on stress signal sensitivity under acute stress were inconclusive.
• Pathological consequences (self-maintaining inflammation, fatigue) are discussed.
Chronic stress and its subsequent effects on biological stress systems have long been recognized as predisposing and perpetuating factors in chronic fatigue, although the exact mechanisms are far from being completely understood.
In this review, we propose that sensitivity of immune cells to glucocorticoids (GCs) and catecholamines (CATs) may be the missing link in elucidating how stress turns into chronic fatigue.
We searched for in vitro studies investigating the impact of GCs or CATs on mitogen-stimulated immune cells in chronically stressed or fatigued populations, with 34 original studies fulfilling our inclusion criteria. Besides mixed cross-sectional findings for stress- and fatigue-related changes of GC sensitivity under basal conditions or acute stress, longitudinal studies indicate a decrease with ongoing stress.
Research on CATs is still scarce, but initial findings point towards a reduction of CAT sensitivity under chronic stress. In the long run, resistance of immune cells to stress signals under conditions of chronic stress might translate into self-maintaining inflammation and inflammatory disinhibition under acute stress, which in turn lead to fatigue.
From PloSOne, 1 June 2916.
Correction: Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome
Lucy P. Goldsmith, Graham Dunn, Richard P. Bentall, Shôn W. Lewis, Alison J. Wearden
The dataset originally included as S1 Dataset was removed in consideration of possible restrictions for the public availability of the data related to the wording of the original consent form for the trial. Upon consultation with the authors’ university it has been established that the file may be publicly shared as it reports de-identified data. Please view S1 Dataset here.
The Data Availability statement for the article is revised to read: The authors have prepared a dataset that fulfills requirements in terms of anonymity and confidentiality of trial participants, and which contains only those variables which are relevant to the present study. Data are available as Supporting Information.
S1 Dataset. De-identified trial data.
1. Goldsmith LP, Dunn G, Bentall RP, Lewis SW, Wearden AJ (2015) Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome. PLoS ONE 10(12): e0144623. doi:10.1371/journal.pone.0144623. pmid:26657793
View Article PubMed/NCBI Google Scholar
2. Goldsmith LP, Dunn G, Bentall RP, Lewis SW, Wearden AJ (2016) Correction: Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome. PLoS ONE 11(5): e0156120. doi:10.1371/journal.pone.0156120. pmid:27191956
View Article PubMed/NCBI Google Scholar
Citation: Goldsmith LP, Dunn G, Bentall RP, Lewis SW, Wearden AJ (2016) Correction: Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome. PLoS ONE 11(6): e0157199. doi:10.1371/journal.pone.0157199
From the Journal of Psychosomatic Research, June 2016.
Is chronic fatigue syndrome heterogeneous? A review of the literature and new study of the lumping versus splitting debate for functional somatic syndromes
T.E. Williams, L. Pangiotopoulou, T. Chalder, M. Sharpe, P.D. White
There is evidence for and against functional somatic syndromes being either lumped together or separated apart. The aim of this presentation is to review the evidence regarding the heterogeneity of chronic fatigue syndrome (CFS) and to provide new data addressing this issue.
From BioMed Central, 31 May 2016 (open access).
Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients
T. Nguyen, D. Staines, B. Nilius, P. Smith and S. Marshall-Gradisnik
Transient receptor potential melastatin 3 (TRPM3) cation channels are ubiquitously expressed by multiple cells and have an important regulatory role in calcium-dependent cell signalling to help maintain cellular homeostasis.
TRPM3 protein expression has yet to be determined on Natural Killer (NK) cells and B lymphocytes. Multiple single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) patients and have been proposed to correlate with illness presentation.
The object of the study was to assess TRPM3 surface expression on NK and B lymphocytes from healthy controls, followed by a comparative investigation examining TRPM3 surface expression, and cytoplasmic and mitochondrial calcium influx in CD19+ B cells, CD56bright and CD56dim cell populations from CFS/ME patients.
TRPM3 cell surface expression was identified for NK and B lymphocytes in healthy controls (CD56bright TRPM3 35.72 % ± 7.37; CD56dim 5.74 % ± 2.00; B lymphocytes 2.05 % ± 0.19, respectively). There was a significant reduction of TRPM3 surface expression on CD19+ B cells (1.56 ± 0.191) and CD56bright NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls. Anti-CD21 and anti-IgM conjugated biotin was cross-linked with streptavidin,and subsequently treatment with thapsigargin. This showed a significant reduction in cytoplasmic calcium ion concentration in CD19+ B lymphocytes. CD56bright NK cells also had a significant decrease in cytoplasmic calcium in the presence of 2-APB and thapsigargin in CFS/ME patients.
The results from this preliminary investigation identify, for the first time, TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients. This warrants further examination of these pathways to elucidate whether TRPM3 and impaired calcium mobilisation has a role in CFS/ME.