TGI Friday! Our weekly round-up of recently published research study abstracts and news | 21 December 2012

December 21, 2012

From Cochrane Database Syst Rev 12 December 2012.

Amitriptyline for neuropathic pain and fibromyalgia in adults.

Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ.
Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, UK, OX3 7LE.



Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage) and fibromyalgia, and is recommended in many guidelines. These types of pain can be treated with antidepressant drugs in doses below those at which the drugs act as antidepressants.


To assess the analgesic efficacy of amitriptyline for chronic neuropathic pain and fibromyalgia.To assess the adverse events associated with the clinical use of amitriptyline for chronic neuropathic pain and fibromyalgia.


We searched CENTRAL, MEDLINE, and EMBASE to September 2012, together with reference lists of retrieved papers, previous systematic reviews, and other reviews; we also used our own handsearched database for older studies.


We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.


We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using two tiers of evidence. The first tier used data meeting current best standards, where studies reported the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, reported an intention-to-treat (ITT) analysis, lasted 8 to 12 weeks or longer, had a parallel-group design, and where there were at least 200 participants in the comparison. The second tier used data that failed to meet this standard and were therefore subject to potential bias.


Twenty-one studies (1437 participants) were included; they individually involved between 15 and 235 participants, only four involved over 100 participants, and the median study size was 44 participants. The median duration was six weeks. Ten studies had a cross-over design.

Doses of amitriptyline were generally between 25 mg and 125 mg, and dose escalation was common.There was no top-tier evidence for amitriptyline in treating neuropathic pain or fibromyalgia. Second-tier evidence indicated no evidence of effect in cancer-related neuropathic pain or HIV-related neuropathic pain, but some evidence of effect in painful diabetic neuropathy (PDN), mixed neuropathic pain, and fibromyalgia.

Combining the classic neuropathic pain conditions of PDN, postherpetic neuralgia (PHN) and post-stroke pain with fibromyalgia for second-tier evidence, in eight studies and 687 participants, there was a statistically significant benefit (risk ratio (RR) 2.3, 95% confidence interval (CI) 1.8 to 3.1) with a number needed to treat (NNT) of 4.6 (3.6 to 6.6).

The analysis showed that even using this potentially biased data, only about 38% of participants benefited with amitriptyline and 16% with placebo; most participants did not get adequate pain relief.

Potential benefits of amitriptyline were supported by a lower rate of lack of efficacy withdrawals; 8/153 (5%) withdrew because of lack of efficacy with amitriptyline and 14/119 (12%) with placebo. More participants experienced at least one adverse event; 64% of participants taking amitriptyline and 40% taking placebo. The RR was 1.5 (95% CI 1.4 to 1.7) and the number needed to treat to harm was 4.1 (95% CI 3.2 to 5.7). Adverse event and all-cause withdrawals were not different.


Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many patients with neuropathic pain or fibromyalgia.

There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain or fibromyalgia, but only a minority of patients will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.It is unlikely that any large randomised trials of amitriptyline will be conducted in specific neuropathic pain conditions or in fibromyalgia to prove efficacy.

MEA note
Our medical adviser, Dr Charles Shepherd, comments: Low dose amitriptyline, along with some other sedating tricyclic drugs, is one of the commonest drugs to be prescribed for the relief of moderate to severe pain in ME/CFS, especially where this has a neuropathic quality, that has not responded to other types of treatment. Some people with ME/CFS gain considerable benefit whereas others fail to do so and/or experience a range of side-effects. The MEA has an information leaflet on amitriptyline.

From Journal of Clinical Sleep Medicine, 11 December 2012

Sleep Abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Review

Melinda L. Jackson, Ph.D.; Dorothy Bruck, Ph.D.
School of Social Sciences and Psychology, Victoria University, Victoria, Australia


Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a chronic, disabling illness that affects approximately 0.2% of the population. Non-restorative sleep despite sufficient or extended total sleep time is one of the major clinical diagnostic criteria; however, the underlying cause of this symptom is unknown.

This review aims to provide a comprehensive overview of the literature examining sleep in CFS/ME and the issues surrounding the current research findings. Polysomnographic and other objective measures of sleep have observed few differences in sleep parameters between CFS/ME patients and healthy controls, although some discrepancies do exist.

This lack of significant objective differences contrasts with the common subjective complaints of disturbed and unrefreshed sleep by CFS/ME patients. The emergence of new, more sensitive techniques that examine the microstructure of sleep are showing promise for detecting differences in sleep between patients and healthy individuals.

There is preliminary evidence that alterations in sleep stage transitions and sleep instability, and other physiological mechanisms, such as heart rate variability and altered cortisol profiles, may be evident.

Future research investigating the etiology of non-restorative sleep in CFS/ME may also help us to undercover the causes of non-restorative sleep and fatigue in other medical conditions.

From Critical Reviews in Toxicology, 19 November 2012

Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review

Sarah Mackenzie Ross(1), I. C. McManus(1), Virginia Harrison(2), Oliver Mason(1)

(1) Research Department of Clinical, Educational and Health Psychology, University College London,Gower Street, London WC1E 6BT, UK
(2) Department of Psychology, Open University,Walton Hall, Milton Keynes, MK7 6AA, UK


Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes.

The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning.

Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis.

This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported).

Data were assimilated from more than 1600 participants.

The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed.

From BMC Immunology (open access publication, provisional full text available), 17 December 2012

Humoral and cellular immune responses after influenza vaccination in patients with chronic fatigue syndrome

Hetty Prinsen(1), I Jolanda de Vries(1,2), Ruurd Torensma(2), Jeanette M Pots(2), Sasja F Mulder(1), Carla M van Herpen(1), Lammy D Elving(3), Gijs Bleijenberg(4), Foekje F Stelma(5), Hanneke W van Laarhoven(1,6)

(1) Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 8, 6525, GA Nijmegen, the Netherlands
(2) Department of Tumor Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
(3) Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
(4) Expert Centre for Chronic Fatigue, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
(5) Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
(6) Department of Medical Oncology, Academic Medical Center University of Amsterdam, Amsterdam, the Netherlands



Chronic fatigue syndrome (CFS) is a clinical condition characterized by severe and disabling fatigue that is medically unexplained and lasts longer than 6 months. Although it is possible to effectively treat CFS, the nature of the underlying physiology remains unclear. Various studies have sought evidence for an underlying disturbance in immunity. The aim of this study was to compare the humoral and cellular immune responses upon influenza vaccination in CFS patients and healthy controls.


Identical antibody titers were observed in CFS patients and healthy controls. Patients and controls demonstrated similar seroprotection rates against all three virus-strains of the influenza vaccine, both pre- and post-vaccination. Functional T cell reactivity was observed in both CFS patients and healthy controls. CFS patients showed a non-significant, numerically lower cellular proliferation at baseline compared to controls. Vaccination induced a significant increase in cellular proliferation in CFS patients, but not in healthy controls. Cytokine production and the number of regulatory T cells were comparable in patients and controls.


The humoral and cellular immune responses upon influenza vaccination were comparable in CFS patients and healthy controls. Putative aberrations in immune responses in CFS patients were not evident for immunity towards influenza. Standard seasonal influenza vaccination is thus justified and, when indicated, should be recommended for patients suffering from CFS.

From the Global Journal of Health Science (open access, full text available), 12 December 2012

Dyspnea in Chronic Fatigue Syndrome (CFS): Comparison of Two Prospective Cross-Sectional Studies

Murugan K Ravindran(1), Oluwatoyin Adewuyi(1), Yin Zheng(1), Rakib U Rayhan(1), Uyenphuong Le(1), Christian R Timbol(1), Samantha Merck(1), Rania Esteitie(1), Michelle Cooney(2), Charles Read(2),James N. Baraniuk(1)

(1) Division of Rheumatology, Immunology and Allergy, Georgetown University, Washington DC, USA
(2) Division of Pulmonary, Critical Care and Sleep Medicine, Georgetown University, Washington DC, USA


Chronic Fatigue Syndrome (CFS) subjects have many systemic complaints including shortness of breath. Dyspnea was compared in two CFS and control cohorts to characterize pathophysiology.

Cohort 1 of 257 CFS and 456 control subjects were compared using the Medical Research Council Chronic Dyspnea Scale (MRC Score; range 0-5). Cohort 2 of 106 CFS and 90 controls answered a Dyspnea Severity Score (range 0-20) adapted from the MRC Score.

Subsets of both cohorts completed CFS Severity Scores, fatigue, and other questionnaires. A subset had pulmonary function and total lung capacity measurements.

Results show MRC Scores were equivalent between sexes in Cohort 1 CFS (1.92 [1.72-2.16]; mean [95% C.I.]) and controls (0.31 [0.23-0.39]; p<0.0001). Receiver-operator curves identified 2 as the threshold for positive MRC Scores in Cohort 1. This indicated 54% of CFS, but only 3% of controls, had significant dyspnea.In Cohort 2, Dyspnea Score threshold of 4 indicated shortness of breath in 67% of CFS and 23% of controls. Cohort 2 Dyspnea Scores were higher for CFS (7.80 [6.60-9.00]) than controls (2.40 [1.60-3.20]; p<0.0001).CFS had significantly worse fatigue and other complaints compared to controls. Pulmonary function was normal in CFS, but Borg scores and sensations of chest pain and dizziness were significantly greater during testing than controls. General linear model of Cohort 2 CFS responses linked Dyspnea with rapid heart rate, chest pain and dizziness.In conclusion, sensory hypersensitivity without airflow limitation contributed to dyspnea in CFS. Correlates of dyspnea in controls were distinct from CFS suggesting different mechanisms.

From the website of ME Research UK, December 2012

Comparison of criteria for ME and CFS: focus on neurocognitive performance, physical recovery, physical activity and autonomic manifestations

Prof. Jo Nijs, Dr J Van Oosterwijck, Kelly Ickmans and colleagues

Faculty of Physical Education and Pyshiotherapy, Vrije Universiteit Brussel, Brussels, Belgium

Background and aims

The diagnosis of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) is not straightforward, and multiple attempts have been made to provide diagnostic guidelines (see ME/CFS: A research and clinical conundrum).

The original criteria for CFS established by the United States Center for Disease Control (CDC) were revised in 1994, and these Fukuda criteria are the most frequently used in scientific research.

In 2001, an expert medical consensus panel, established by the expert subcommittee of Health Canada, held a three-day consensus workshop generating a new clinical working case definition for “ME/CFS”, including a diagnostic protocol. These Canadian criteria for ME/CFS have received relatively little attention in medical and scientific circles, and relatively few studies using the Canadian criteria have been published.

As regards ME, very few studies using specific criteria, including the London criteria for ME, have been published. The London criteria were established in 1990, and focus on “severe muscle fatigue following trivial exertion” and multisystem (nervous, cardiovascular, endocrine and other systems) involvement.

Since controversy regarding the diagnosis of ME/CFS continues in the scientific and medical literature and among patient groups, studies comparing the various sets of criteria for diagnosing ME/CFS are warranted.

Two have already been conducted. One study has compared the Canadian with the CDC criteria, and found the Canadian criteria selecting cases with less psychiatric co-morbidity, and more functional impairment, fatigue, neuropsychiatric, and neurological symptoms (Jason et al, Journal of Chronic Fatigue Syndrome 2004; 12(1): 37–52).

Another study compared the London and CDC criteria for ME/CFS, and concluded that individuals meeting the London criteria are more symptomatic in the neurological and neurocognitive areas (Jason et al, 2003). However, several methodological issues preclude generalising the findings from both studies: the sample size was low and the results rely on self-reported measures rather than objective study findings. Nevertheless, the results point towards potential differences between the London, Canadian and CDC criteria, and reiterate the sense that further independent investigations are warranted.

The main aim of this 24-month investigation is to compare the Canadian, 1994-CDC, and London criteria with a control group comprising patients with an established, severe and fatiguing illness like multiple sclerosis (MS) which has previously been used as an appropriate comparison group for ME/CFS patients.

Patients fulfilling these different criteria will be examined with respect to several characteristics of ME/CFS, including physical behaviour/amount of physical activity, muscle recovery following fatiguing exercise, psychomotor speed, cognitive performance, symptoms of autonomic dysfunction, and descending nociceptive inhibition.

Likewise, it will be determined whether the three ME/CFS groups differ from patients diagnosed with MS and healthy sedentary controls. A secondary aim of the study is to examine the diagnostic overlap between groups, and whether they differ as regards the proportion of patients fulfilling the diagnostic criteria for fibromyalgia syndrome.

MEA note:
Our medical adviser, Dr Charles Shepherd. comments: The MEA Ramsay Research Fund is also funding a new research study involving Prof Jo Nijs et. The study, which will examine the underlying pathology and physiology that causes post-exertional malaise, will start in January 2013.

New ME/CFS research journal

Finally, watch out for the launch of a new ME/CFS research journal next month. Fatigue, Biomedicine, Health and Behaviour is being launched by the the International Association for CFS/ME and will be edited by their director, Fred Friedberg PhD, who works at Stony Brook University Medical Centre in New York.

In his latest newsletter to members, Dr Friedberg writes:

The mission of the IACFS/ME is to promote, stimulate and coordinate the exchange of ideas related to CFS, ME, and fibromyalgia (FM) research, patient care and treatment.The board of directors believes that these challenging medical conditions will benefit from a journal that, while continuing to support research on CFS/ME and FM, also encourages thinking outside the box of a particular disease or condition.

In support of this idea, major advances in biomedicine have more often evolved from broad cross- disciplinary collaborations in comparison to the efforts of a single research laboratory. One example: large scale collaborations produced the central sensitization model of pain in FM and other pain conditions — which has led to new, more effective medications for pain.

Consistent with this multidisciplinary approach, our new journal welcomes all fatigue-related research and clinical approaches to the treatment of this often debilitating symptom. Scientific papers on all aspects of CFS/ME are particularly encouraged and will be published in this new journal. We view side-by-side articles on CFS/ME and other fatiguing illnesses as facilitating comparisons and collaborative discussions that could generate innovative thinking and new directions in research.

The journal will be subscription-based and appear quarterly.

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