REVIEW ARTICLE Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome - Euromene
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British Journal of British Journal of Pharmacology (2017) •• ••–•• 1
BJP Pharmacology
REVIEW ARTICLE
Treatment and management of chronic
fatigue syndrome/myalgic encephalomyelitis:
all roads lead to Rome
Correspondence Jesus Castro-Marrero, Vall d’Hebron University Hospital, Collserola Research Institute, CFS/ME Unit (Lab. 145 – Floor 1),
Passeig de Vall d’Hebron 119-129, E-08035 – Barcelona, Spain. E-mail: jesus.castro@vhir.org
Received 8 June 2016; Revised 25 November 2016; Accepted 14 December 2016
Jesus Castro-Marrero1, Naia Sáez-Francàs2, Dafna Santillo1 and Jose Alegre1
1
CFS/ME Unit, Vall d’Hebron University Hospital, Collserola Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain, and
2
Psychiatry Unit, Sant Rafael Hospital (FIDMAG), Barcelona, Spain
This review explores the current evidence on benefits and harms of therapeutic interventions in chronic fatigue syndrome/myalgic
encephalomyelitis (CFS/ME) and makes recommendations. CFS/ME is a complex, multi-system, chronic medical condition whose
pathophysiology remains unknown. No established diagnostic tests exist nor are any FDA-approved drugs available for treatment.
Because of the range of symptoms of CFS/ME, treatment approaches vary widely. Studies undertaken have heterogeneous de-
signs and are limited by sample size, length of follow-up, applicability and methodological quality. The use of rintatolimod and
rituximab as well as counselling, behavioural and rehabilitation therapy programs may be of benefit for CFS/ME, but the evidence
of their effectiveness is still limited. Similarly, adaptive pacing appears to offer some benefits, but the results are debatable: so is the
use of nutritional supplements, which may be of value to CFS/ME patients with biochemically proven deficiencies. To summarize,
the recommended treatment strategies should include proper administration of nutritional supplements in CFS/ME patients with
demonstrated deficiencies and personalized pacing programs to relieve symptoms and improve performance of daily activities,
but a larger randomized controlled trial (RCT) evaluation is required to confirm these preliminary observations. At present, no firm
conclusions can be drawn because the few RCTs undertaken to date have been small-scale, with a high risk of bias, and have used
different case definitions. Further, RCTs are now urgently needed with rigorous experimental designs and appropriate data
analysis, focusing particularly on the comparison of outcomes measures according to clinical presentation, patient characteristics,
case criteria and degree of disability (i.e. severely ill ME cases or bedridden).
Abbreviations
APT, adaptive pacing therapy; CBT, cognitive behavioural therapy; CDC, Centres for Disease Control and Prevention; CFS/
ME, Chronic fatigue syndrome/myalgic encephalomyelitis; CoQ10, Coenzyme Q10; DHA, docosa; EPA, eicosapentenoic
acid; FINE, Fatigue intervention by nurses evaluation trial; GET, graded exercise therapy; GLA, γ-linolenic acid; HADS,
Hospital anxiety and depression scale; Max HR, maximum heart rate; ICC-ME, 2011 International Consensus criteria for
ME; IOM, Institute of Medicine; NSAIDs, Non-steroidal anti-inflammatory drugs; PACE, Pacing, graded activity, and cog-
nitive behaviour therapy; a randomized evaluation for CFS patients; PVFS, Post-viral fatigue syndrome; RCT, randomized
controlled trial; SEID, systemic exertion intolerance disease; SMC, standard medical care; SSRI, selective serotonin-reuptake
inhibitor; SSNRI, selective serotonin-noradrenaline reuptake inhibitor
© 2017 The British Pharmacological Society DOI:10.1111/bph.13702J Castro-Marrero et al.
BJP
Tables of Links
TARGETS LIGANDS
a
Other protein targets Acetyl-L-carnitine Imipramine
CD20 Magnesium Mirtazapine
b
Enzymes Acyclovir Morphine
COX-2 α-lipoic acid GLA, γ-linolenic acid
c
Transporters Amitriptyline EPA, eicosapentaenoic acid
Acyl-L-carnitine ATP NADH
Bupropion Naproxen
Clomipramine Nefazodone
Codeine Noradrenaline
Cortisol Nortriptyline
Desipramine Paroxetine
DHA, docosahexaenoic acid Pregabalin
Doxepin Rituximab
Duloxetine Serotonin
Fludrocortisone Sertraline
Fluoxetine Tramadol
Folate Valacyclovir
Gabapentin Valganciclovir
Ibuprofen Vitamin C
These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org,
the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise
a,b,c
Guide to PHARMACOLOGY 2015/16 ( Alexander et al., 2015a,b,c).
Background or is associated with a current infection. Important differ-
ences are that the presence of mental fatigue is necessary to
The condition known as chronic fatigue syndrome or myalgic satisfy the criteria and symptoms are accepted, which may
encephalomyelitis (CFS/ME), also recently renamed systemic suggest a psychiatric disorder (Sharpe, 1991). Among the
exertion intolerance disease (SEID), is a complex, heteroge- most widely used diagnostic criteria for CFS are the 1994
neous and extremely debilitating medical condition with no Centres for Disease Control and Prevention (CDC)/Fukuda
known specific cause and for which no clinically established definition (Fukuda et al., 1994). In 2003, a clinical case defini-
diagnostic tests are available. Its symptoms are characterized tion was developed using the term ME/CFS. These criteria be-
by an extreme disabling fatigue that does not improve with came known as the 2003 clinical Canadian Consensus
rest; it persists for more than 6 months, and cannot be Criteria for diagnosis and treatment of ME/CFS (Carruthers,
explained by any underlying medical condition. CFS/ME is 2003). A revised version was subsequently presented as the
often associated with muscle pain, sleep dysfunction, cogni- 2011 International Consensus Criteria for Myalgic Encepha-
tive problems and post-exertional malaise; it may worsen lomyelitis (ICC-ME) for both adult and paediatric cases of
with physical and mental activity, and exercise intolerance ME in clinical and research settings (Carruthers et al., 2011),
is a frequent complaint (Reeves et al., 2007). CFS/ME is com- in an attempt to provide a selective case definition for
monly found after infection by viruses, bacteria or parasites, identifying patients with post-exertional neuroimmune
and its pathophysiological consequences are mainly multi- exhaustion, a pathologically low threshold of fatigability
systemic (Bested and Marshall, 2015) Prior to developing and symptom flare after exertion.
CFS/ME, most patients are healthy, fully functional and have The claim that CFS and ME are distinct clinical entities is
active social lives. Around 80% of CFS/ME patients start controversial. In this comprehensive review, we will apply
suddenly with a flu-like illness from which they never recover the term CFS/ME pragmatically. The recently proposed
(Bested and Marshall, 2015). 2015 NIH/Institute of Medicine (IOM) definition (SEID) di-
At present, there are at least 20 sets of case definitions or agnostic criteria developed by the US IOM redefine
diagnostic criteria for CFS/ME (Brurberg et al., 2014). One of CFS/ME for clinical applications. The IOM recommended
these sets, the 1991 Oxford criteria, includes both CFS of that the name of the illness be changed from CFS/ME to
unknown aetiology and a subtype of CFS called post-viral SEID (Clayton, 2015). All CFS/ME (SEID) case definitions
fatigue syndrome (PVFS), which either follows an infection are assessed in terms of sensitivity (i.e. the ability to identify
2 British Journal of Pharmacology (2017) •• ••–••Therapy and management in CFS/ME BJP
CFS/ME patients correctly) and specificity (i.e. the ability to Mild pain relievers and NSAIDs
exclude patients who do not have CFS/ME). Subgroup anal- CFS/ME patients may benefit from NSAIDs, which are com-
ysis suggests that, depending on the case definition applied, monly used to relieve pain and reduce inflammation. In this
the CFS/ME (SEID) population may represent a variety of context, the NSAIDs include ibuprofen and naproxen. They
conditions rather than a single disease entity. If patient sometimes relieve frequent or severe joint and muscle pain,
samples include participants with different conditions, it is headaches, and fevers (Theoharides et al., 2011).
impossible to determine the core domains or symptoms or Other prescription medicines include anticonvulsants,
to apply proper treatment strategies. So, it is essential to also called anti-seizure medicines. These drugs (e.g. gab-
identify patient subsets correctly in order to implement per- apentin and pregabalin) are sometimes prescribed for pain
sonalized treatments; failure to do so will also have detri- and sleep problems. They seem to work best when used for
mental consequences for research in the interpretation of nerve pain. Antidepressant medicine is also prescribed to
epidemiological, aetiological factors and treatment (Bested ease depression and anxiety, to enhance the ability to con-
and Marshall, 2015). centrate and to improve sleep quality (Calandre et al.,
Currently, there are no universal or specific FDA-approved 2015). For their part, narcotic medicines (tramadol, codeine
drugs for CFS/ME treatment, although some medications are or morphine) are sometimes prescribed for pain that is not
used off-label for the illness. The therapy options available for relieved by over-the-counter drugs. Narcotics are generally
CFS/ME focus on symptom relief (Whiting et al., 2001). Treat- reserved for the most severe cases because of the risk of ad-
ment of CFS/ME is variable and uncertain, and the condition diction, and are used only for a short time (Degenhardt
is primarily managed rather than cured (Rimes and Chalder, et al., 2016).
2005). Drugs such as isoprinosine and rintatolimod have
been used in experimental studies of the illness but have
not been approved for marketing for any condition in the COX-2 inhibitors
USA (Smith et al., 2015). Other proposed treatments include COX-2 inhibitors are NSAIDs designed to selectively inhibit
medical approaches and complementary and alternative the inflammation-promoting enzyme called COX-2. This
medicine. Even when treated, the prognosis of CFS/ME is drug class provides pain relief and anti-inflammatory benefits
often poor (Luyten et al., 2008). Another study comparing equal to those of other NSAIDs while causing less gastrointes-
the use of pragmatic rehabilitation and supportive listening tinal distress and bleeding (Mantovani et al., 2010).
indicated that there was no significant therapist effect on out-
come measures (physical functioning or fatigue) (Goldsmith
et al., 2015). Antidepressants
In this review, we reflect on our experience in assessing Because of the association between depression and CFS/ME,
and managing CFS/ME patients and review the current CFS/ME patients often take antidepressants, with varying de-
evidence of the treatment and management approaches for grees of success (Attree et al., 2014) Almost all antidepressants
illness. Research is currently making progress, but the evi- interact with other drugs, and some of these interactions are
dence available is limited and many questions with regard very serious (Cleare et al., 2015). CFS/ME patients are fre-
to diagnostic criteria, therapy and management approaches quently prescribed antidepressants to treat secondary depres-
remain unanswered. We start with a consideration of the sion or mood swings, and tricyclic antidepressants may be
pharmacological interventions available in CFS/ME. prescribed in low doses to increase sleep quality and reduce
pain. However, the use of antidepressants is controversial
(Jackson et al., 2006; Pae et al., 2009) A review of pharmaco-
Pharmacological therapy logical treatments for CFS/ME included five trials of antide-
pressants, but only one recorded significantly improved
Very few randomized controlled trials (RCTs) have evaluated symptoms, in a cohort who had been assigned to cognitive
pharmacological treatments for CFS/ME. There is no pharma- behavioural therapy (CBT) for 12 weeks before initiating
cological cure for the illness, but various drugs are used in mirtazapine (Kreijkamp-Kaspers et al., 2011).
order to help relieve and manage the symptoms, especially
in cases in which there is a specific medical cause using highly
individualized treatments. Because CFS/ME remains poorly Tricyclic antidepressants
understood, many patients have problems finding good care. Tricyclic antidepressants affect brain chemicals which are
The list of pharmaceuticals prescribed for CFS/ME is involved in managing pain. These medications may be
extensive, ranging from over-the-counter medications such particularly helpful for CFS/ME patients. For example, the
as pain relievers and non-steroidal anti-inflammatory drugs tricyclic amitriptyline is known to relieve many symptoms,
(NSAIDs), anticonvulsants, antidepressants and narcotics to including sleeplessness and low energy levels in CFS/ME.
antiviral and immunomodulatory drugs. The reason is that Other tricyclics (doxepin, desipramine, nortriptyline, clo-
treatments are aimed both at alleviating the numerous symp- mipramine and imipramine) improve sleep and relieve pain,
toms and at correcting the secondary infections found in the although it can take 3 to 4 weeks for symptoms to improve.
majority of CFS/ME patients. Therefore, we have classified CFS/ME patients normally respond to much lower doses of
the different drugs according to the most commonly found tricyclics than those used to treat people with depression;
core symptoms in CFS/ME: myalgia and muscle pain, immu- in fact, many CFS/ME patients cannot tolerate the higher
nological abnormalities, comorbid anxiety/depression and doses commonly used in depression therapy (Clemons
mood swings, sleep disturbances and cognitive dysfunction. et al., 2011).
British Journal of Pharmacology (2017) •• ••–•• 3J Castro-Marrero et al.
BJP
Other antidepressants Rintatolimod (Ampligen) has undergone years of clinical
Other antidepressants (bupropion, nefazodone and trials. Ampligen (poly I: poly C12U) has a long and chequered
mirtazapine) affect combinations of neurotransmitters. Some history in CFS/ME. After the Incline Village outbreak in 1984,
may have moderate benefits for CFS/ME patients: for exam- the FDA invited the pharmaceutical company Hemispherx to
ple, nefazodone may improve mood, fatigue and sleep distur- develop a drug to treat the illness. The positive results of this
bances (Cleare et al., 2015). trial seemed to indicate that Ampligen worked by enhancing
the NK-cell function and influencing the 2-5A-synthetase
pathway, which plays a vital role in the defence against viral
Selective serotonin-reuptake inhibitors infections. Some CFS/ME patients present defects in key com-
The widely-used antidepressants (fluoxetine, sertraline, and
ponents in the antiviral system, the most notable being low
paroxetine) known as selective serotonin-reuptake inhibi-
latent 2-5A synthetase and up-regulated RNase-L activity
tors (SSRIs) may be helpful for CFS/ME subjects who expe-
(Suhadolnik et al., 1997). Ampligen is believed to correct both
rience significant chronic neuropathic pain, fibromyalgia,
these defects.
anxiety/depression and other mood disorders. Duloxetine
Dr Peterson along with Dr Cheney had reported the In-
is a new antidepressant classified as a selective serotonin–
cline village outbreak in 1984, used Ampligen in a severely
noradrenaline reuptake inhibitor (SSNRI) because it affects
ill CFS case in 1988 (Strayer et al., 1994). After a year of ther-
both neurotransmitters. SSRIs should not be taken with tri-
apy, patient function in some areas had almost returned to
cyclics, because the combination may have dangerous side
normal and IQ had increased by 46 points. In view of these
effects (Theoharides et al., 2011). However, neither SSRIs
impressive results, Dr Peterson designed another multi-centre
nor SSNRIs directly address the immune system dysregula-
pilot study and, along with other independent research
tion that underlies the disease, and there are no FDA-
(Suhadolnik et al., 1994), this paved the way for a large-scale
approved treatments that specifically do so. Any treatment
FDA-approved double-blind study of 92 CFS/ME patients in
used to lessen symptoms is considered ‘palliative’.
four US cities (Strayer et al., 2012). Once more, the results
were very promising: More than half of the patients adminis-
tered Ampligen presented improved overall function, energy
Antiviral and immunomodulatory levels and cognitive performance, and many could now per-
therapy form daily activities with only minimal assistance. Unfortu-
nately, since 1996, little progress has been made in
With the possible exception of the immunomodulatory drug obtaining FDA approval for the drug. The FDA advised
rintatolimod, a recent systematic review did not find any Hemispherx to conduct at least one additional clinical trial,
pharmaceutical therapies for CFS/ME to be effective. The complete various non-clinical studies and perform a number
drugs tested were immunoglobulins, hydrocortisone, SSRIs of data analyses.
and antiviral agents (Smith et al., 2015).
Antiviral drugs Valganciclovir
Acyclovir, valacyclovir and ganciclovir are nucleotide ana-
Several viruses have been tentatively identified as causative
logue inhibitors which inhibit viral replication during DNA
agents in subsets of CFS/ME patients, though no fully con-
multiplication (for DNA- and retroviruses) or RNA multiplica-
vincing evidence has been provided to date (Sanders and
tion (for RNA viruses) (De Clercq and Neyts, 2009). In 1988, a
Korf, 2008). Treatment studies of CFS/ME subtypes may help
small RCT assessing acyclovir reported no difference in im-
to provide this evidence (Jason et al., 2005), though the re-
provement compared with placebo; the conclusion was that
sults of the antiviral drugs treatment studies conducted so
the improvement was due either to spontaneous remission
far are inconclusive.
or to the placebo effect (Straus et al., 1988). Three patients ad-
ministered acyclovir withdrew from the trial because of re-
Rintatolimod versible renal failure (Whiting et al., 2001).
Nucleic acid (double-stranded RNA) compounds represent a
potential new class of pharmaceutical products that are
designed to act at the molecular level. These are inducers of Interferons
interferon and are considered to be antiviral and immuno- Two small RCTs have evaluated the effect of interferon α
modulatory. One RCT evaluating rintatolimod found an over- versus placebo in CFS/ME (Whiting et al., 2001). The first
all beneficial effect (Whiting et al., 2001). In December 2009, crossover RCT (30 CFS/ME subjects according to the 1994
the US FDA rejected a New Drug Application (NDA) by the CDC/Fukuda definition) only found treatment benefit in
developer of the drug (Hemispherx Biopharma) to market subgroup analysis of participants with diminished NK cell
and sell rintatolimod (as Ampligen) for the treatment of function but normal lymphocyte proliferation. In the
CFS/ME, on the grounds that the two RCTs submitted did active arm, two out of 13 participants (15%) developed
not provide credible evidence of efficacy. Hemispherx neutropenia (Ridsdale et al., 2001). The results of the sec-
Biopharma performed additional analyses and then sub- ond crossover RCT trial (20 CFS/ME patients based on the
mitted an NDA in 2012 (Strayer et al., 2012). After review, 1994 CDC/Fukuda definition) did not allow a clear inter-
the FDA refused the application, citing insufficient safety pretation of the effect of therapy (Brook et al., 1993).
and efficacy data (http://www.fda.gov/drugs/newsevents/ Both studies were considered poor quality (Whiting
ucm337750.htm). et al., 2001).
4 British Journal of Pharmacology (2017) •• ••–••Therapy and management in CFS/ME BJP
Immunoglobulins CFS/ME patients (as opposed to 13% of controls). Four of
A systematic review identified five RCTs evaluating the effect the rituximab patients showed improvement past the study
of immunoglobulin in CFS (Whiting et al., 2001). Two of period. The authors concluded that the delay in the re-
these trials found an overall benefit, and two presented some sponses, starting 2–7 months after rituximab infusions in
positive results, although in one case, only in relation to spite of rapid B-cell depletion, suggests that CFS/ME is an au-
physiological effects. The largest RCT did not report any toimmune condition in which the clinical response could be
effect, and another review concluded that the potential dan- preceded by a gradual elimination of autoantibodies (Fluge
gers of immunotherapy for CFS/ME outweighed its possible et al., 2015). These two trials have been completed and a
advantages (Reid et al., 2011). new open-label trial is in progress (Fluge et al., 2011; Fluge
et al., 2015). Rituximab is also undergoing a large trial in
CFS/ME patients, privately funded by Invest in ME, a UK
Corticosteroids and hormones charity. Both treatments are available in the USA, but they
Treatment with steroids such as cortisol and thyroid hor-
are not FDA-approved for CFS/ME and so insurance compa-
mones has been also studied. Seven RCTs have been per-
nies do not cover the costs.
formed, four trialling hydrocortisone (McKenzie et al., 1998;
Despite the latest advances of Rituximab immunotherapy
Cleare et al., 1999; Friedman et al., 1999; Cleare et al., 2001),
in CFS/ME, the risk of adverse effects is unclear: Reports of ad-
two fludrocortisone (Peterson et al., 1998; Rowe et al., 2001)
verse events in other contexts such as neutropenia and infec-
and one with hydrocortisone plus fludrocortisone
tions give reason for caution (Rashidi et al., 2015). The new
(Blockmans et al., 2003). Two RCTs found an overall benefit
RituxME project, a multicenter, RCT study, will recruit 152
for hydrocortisone, but this drug has not been recommended
participants at five sites in Norway. The purpose of the study
for clinical use. A 2006 systematic review found one low-
is to confirm or disprove the results of the two earlier and
quality RCT of hydrocortisone which found a significant dif-
smaller Phase II trials, which indicated improvements in
ference between groups for fatigue, but two other RCTs found
symptoms in a subgroup of CFS/ME patients after rituximab
no benefit for steroid treatment (Chambers et al., 2006). An
infusions. The results of the RituxME study are scheduled to
RCT conducted between 1992 and 1996 in a tertiary care re-
be published in early 2018.
search institution, studied 70 CFS/ME patients who met the
1994 CDC/Fukuda definition; many had psychiatric comor-
bidity but, in all patients, concomitant treatment with other
Staphylococcal toxoid vaccine
Two RCTs have been carried out with staphylococcal toxoid
medications were withheld. Although hydrocortisone treat-
vaccine. The first trial showed considerable benefit
ment (at a higher dose of 20–30 mg) was associated with some
(Andersson et al., 1998) and a large follow-up RCT for
statistical improvement in CFS/ME symptoms, the authors
6 months in which repeated administration of the staphylo-
concluded that a degree of adrenal suppression precludes its
coccal toxoid vaccine Staphypan Berna (Berna Biotech,
practical use for CFS/ME (McKenzie et al., 1998).
Switzerland) and testing against placebo showed overall
benefit (Zachrisson et al., 2004).
Rituximab The results further showed that this response was related
Rituximab is a monoclonal antibody active against CD20, a B- to an improvement of the clinical outcome due to treatment.
cell receptor. Rituximab works by depleting B-cells, thus re- However, the quality of the follow-up RCT was low and there
ducing inflammation. It was first approved by the FDA to were relatively high levels of adverse effects. A review con-
treat non-Hodgkin’s lymphoma in 1997. It is also used in cluded that there is insufficient evidence for treatments of
the immunotherapy treatment of autoimmune disorders. this type (Chambers et al., 2006).
Its effect on CFS/ME was discovered by accident. Two Nor-
wegian physicians, Dr Fluge and Prof Mella who were treating
a CFS/ME patient for Hodgkin’s lymphoma with rituximab, Faecal microbiota transplantation
noticed that her symptoms remitted. A small pilot, open-
label trial from Norway followed, using rituximab in three Faecal microbiota transplantation (FMT) is the infusion of
CFS/ME patients. All three patients experienced significant liquid filtrate faeces from a healthy donor into the gut of a re-
improvement; two of them responded within 6 weeks, and cipient to cure a specific disease. The interest in microbiota-
the third presented a delayed response after 6 months. The gut-brain axis and faecal microbiota transplantation is in-
positive effects lasted for between 16 and 44 weeks. After creasing rapidly. With the high success and safety rate in the
relapse, the patients were administered another dose of ritux- short term reported for recurrent Clostridium difficile infec-
imab, with the same positive results. The researchers hypoth- tion, FMT has emerged as a treatment for a wide range of
esized that B-cells might play a significant role in at least a gut disorders, but is yet to be confirmed for CFS/ME. Many
subset of CFS/ME patients, and that CFS/ME may be amena- questions regarding its application in CFS/ME remain unan-
ble to therapeutic interventions aimed at modifying B-cell swered including donor selection and screening, standard-
phenotype and function (Fluge and Mella, 2009). These pos- ized application protocols, long-term safety and risk, and
itive results encouraged a larger study with a more rigorous regulatory issues (Brussow, 2016).
design to test the drug’s effects and, in 2009, an RCT with In an uncontrolled study of 60 CFS/ME individuals who
30 CFS/ME patients who met the 1994 CDC/Fukuda defini- were given FMT and followed up 15–20 years later, 50% pre-
tion was intitiated (Fluge et al., 2011). As in the earlier open- sented significant symptom improvement (Smits et al.,
label study, the responses to rituximab were significant. 2013). A study in which CFS/ME individuals received FMT
Sustained overall improvements were noted in 67% of therapy found that 41% achieved persistent relief of
British Journal of Pharmacology (2017) •• ••–•• 5J Castro-Marrero et al.
BJP
symptoms over a period of 11–28 months (Aroniadis and and mental fatigue, and the experimental group presented
Brandt, 2013). Another study reported that the response improvements in both the cognitive status and physical func-
rate of 60 CFS cases after FMT was 70%. After a time lapse tion (Malaguarnera et al., 2008).
of 15–20 years, 12 of the patients were contacted and infor-
mation about their condition was obtained. Seven of the Essential fatty acids
patients reported full recovery, and five reported that they A RCT of 63 patients who met the 1991 Oxford criteria for a
had not experienced CFS for between 1.5 and 3 years (Smits subtype of CFS called PVFS, used high doses of evening prim-
et al., 2013). rose oil containing γ-linolenic acid (GLA) together with fish
Gastrointestinal disturbances are well documented in oil concentrate containing eicosapentaenoic acid (EPA) and
CFS/ME (Logan et al., 2003; Sheedy et al., 2009; Fremont DHA and either it, or the placebo, over 3 months. All partici-
et al., 2013; Giloteaux et al., 2016; Navaneetharaja et al., pants were evaluated at baseline, and at 1 and 3 months. The
2016; Wallis et al., 2016). However, the association of essential fatty acid composition of their RBC membrane
CFS/ME with an altered microbiota-gut-brain axis and faecal phospholipids was analysed at the first and last visits. This
microbiota transplantation remains unclear. Despite the trial showed significant overall improvements in symptoms
findings of altered diversity and stability of the gut microbi- (fatigue, myalgia, dizziness, poor concentration and depres-
ota in CFS/ME, it is not yet possible to claim that CFS/ME sion) and higher levels of essential fatty acid in RBC (all
has a specific microbial signature, and that, as a result, an P < 0.0001) at the end of study (Behan et al., 1990). However,
FMT trial can be conducted in these patients. a subsequent RCT attempting to replicate this study in an-
other CFS subject cohort meeting 1991 Oxford criteria for
CFS but found no significant differences in symptoms after
Complementary and alternative treatment between the experimental and placebo groups or
medicine in the pretreatment RBC membrane lipids (Warren et al.,
1999). The discrepant results in these two studies may be
CFS/ME patients tend to use more alternative medicine treat- due to the case selection criteria used. Also the first trial used
ments than people without (Jones et al., 2007). Patients often paraffin, while the second trial used sunflower oil, which is
leave orthodox medical care because they feel that their con- better tolerated and less likely to adversely affect the placebo
dition has been unjustifiably attributed to psychological (Reid et al., 2011).
causes: they are given the message that ‘it is all in the mind’.
In a twin study, 91% of twins with CFS/ME and 71% without Magnesium
CFS/ME used at least one alternative treatment. A large pro- A trial of intramuscular magnesium sulfate delivered by injec-
portion of the study participants stated that alternative treat- tion to magnesium-deficient CFS/ME patients reported
ments were helpful (Afari et al., 2000). positive results (Cox et al., 1991). This RCT found that
magnesium improved Nottingham Health Profile pain
Nutritional supplements (P = 0.022) and emotional reaction (P = 0.013) domain scores
A 2006 updated systematic review concluded that supple- compared with placebo. In this RCT, plasma and whole blood
ments of essential fatty acids and magnesium showed benefi- magnesium levels were normal and only the RBC magnesium
cial effects in only one or two trials, and that further rigorous content was slightly lower than the normal range (Cox et al.,
trials of these interventions were required (Chambers et al., 1991). In contrast, three subsequent case-report studies did
2006). A 2011 review found insufficient evidence to recom- not find magnesium deficiency in CFS/ME cohorts (Clague
mend dietary supplements as a treatment for CFS/ME (Alraek et al., 1992; Hinds et al., 1994; Swanink et al., 1995). In these
et al., 2011). One RCT compared a polynutrient supplement previous studies, blood magnesium levels were in the normal
(containing several vitamins, minerals and coenzymes, taken range and did not differ from healthy controls. However,
twice daily) with a placebo for 10 weeks, but found no differ- none of the studies stated how the normal range was
ence in fatigue scores (Reid et al., 2011). Supplements may established, so it is difficult to confirm whether they were
benefit CFS/ME patients with specific nutritional deficien- equivalent. A 2008 review concluded that there is no good ev-
cies. A biochemical test for deficiencies should be performed idence that intramuscular magnesium offers any benefit in
before treatment in order to guide treatment choices. CFS/ME (Reid et al., 2011). Testing for magnesium deficiency
in RBC would be useful in CFS/ME, with further administra-
Acetyl-L-carnitine tion of nutritional supplements if a deficiency is found. The
The amino acid L-carnitine and its derivative acyl-L- fact that not all CFS/ME subjects have magnesium deficiency
carnitines, are required for the transport of fatty acids into does not mean that nutritional supplementation should be
the mitochondria during the breakdown of lipids for the gen- dismissed.
eration of metabolic energy in muscles and in the brain
(Inazu and Matsumiya, 2008). Two RCTs found benefits after Vitamin B12
supplementation with dietary L-carnitine or its esters. A 2006 Both oral and injected vitamin B12 has been proposed as
systematic review reported one RCT with overall benefit, al- treatments for generalized fatigue since the 1950s. Previous
though there was no placebo control (Chambers et al., studies have not suggested any benefit, either for general-
2006). In 2008, a 6 month RCT trial of acetyl-L-carnitine in ized fatigue or more specifically for symptoms relief in
96 aged subjects with CFS/ME symptoms was reported. By CFS/ME (Bjorkegren, 1999; Hagglof, 2000). However, further
the end of the treatment, significant differences between research is needed because the studies carried out to date
the two groups were found for both self-reported physical have been small and have used inconsistent dosing
6 British Journal of Pharmacology (2017) •• ••–••Therapy and management in CFS/ME BJP
regimens and/or non-biologically active forms of vitamin that these RCTs presented several methodological problems,
B12 (hydroxocobalamin) (Swanink et al., 1995; Bjorkegren, and a review concluded that there was still no good evidence
1999; Norberg, 1999; Hagglof, 2000). Recently, this question that NADH supplementation alone was of benefit for CFS/ME
has been addressed (Regland et al., 2015), drawing on (Reid et al., 2011).
15 years’ experience of treating CFS/ME patients with vita-
min B12 (methylcobalamin, as the biologically active form).
During this time, the CFS/ME patients were shown to Coenzyme Q10 plus NADH and mitochondrial
respond best to the injected form of vitamin B12. dysfunction
This research group concluded (Regland et al., 2015) that Coenzyme Q10 (CoQ10) and NADH are common antioxidant
frequent injections of highly concentrated methylcobalamin supplements that have been used for several decades as die-
combined with an individual daily high dose of oral folic acid tary supplements for general maintenanceof health. The ben-
may be safe and effective for fatigue and other CFS/ME symp- efits of their administration have been extensively evaluated
toms. Moreover, CFS/ME patients should be tested for certain in several conditions (Braun et al., 1991; Porter et al., 1995;
opioid and analgesic drugs and for co-existing thyroid Malm et al., 1997; Cooke et al., 2008). However, several stud-
dysfunction. Therefore, the use of methylcobalamin is ies have shown that there is a mitochondrial dysfunction,
recommended to find the optimal dose of vitamin B12 and which reduces the ATP production, as an immediate effect
folate for each individual. primary or secondary to symptoms in most CFS/ME patients
(Twisk and Maes, 2009; Booth et al., 2012; Castro-Marrero
Antioxidants et al., 2013; Myhill et al., 2013; Castro-Marrero et al., 2016).
Antioxidants (including α-lipoic acid, vitamin E or C) are a In the UK, Myhill et al. highlighted the power and useful-
group of vitamins, minerals and enzymes that help protect ness of the ‘ATP profile’ test as a diagnostic tool for differenti-
cells from damage by oxidative stress and also improve mito- ating between patients who have CFS/ME and other
chondrial function (Nicolson, 2014). A prospective RCT symptoms as a result of energy wastage due to stress and psy-
recruiting 38 women CFS consecutively diagnosed with the chological factors and those who have insufficient energy due
1994 CDC/Fukuda definition were treated with a multivita- to cellular respiration dysfunction. The biochemical tests
min and mineral supplement for 2 months with follow-up. should be performed in CFS/ME patients before and after ap-
Before and after the 2 month supplementation, superoxide propriate interventions, and possibly in other disabling fa-
dismutase activity was determined and patients self-assessed tigue conditions as well (Myhill et al., 2009).
their improvement in two questionnaires (FibroFatigue scale In a later study, this group noted that although mitochon-
and the SF-36 subscale). There was a significant improvement drial function tests do not constitute a biochemcal diagnostic
in superoxide dismutase activity levels (P = 0.005), significant tool for CFS/ME because the symptoms of fatigue may be due
decreases in fatigue (P = 0.0009), sleep problems (P = 0.008), to many possible causes, they are nonetheless the single most
autonomic dysfunction symptoms (P = 0.018), frequency useful diagnostic and therapeutic aid in the management and
and intensity of headaches (P = 0.0001), and subjective treatment of CFS/ME (Myhill et al., 2013). These authors also
feeling of infection (P = 0.0002). No positive effect on SF-36 reported symptom relief and improve of quality of life in
quality of life was found. The conclusion was that reatment patients receiving a combination of a stone-age diet, sleep
with a multivitamin and mineral supplement could be a safe quality and hygiene, nutritional supplements and recom-
and easy way to improve symptoms and quality of life in mendations for achieving a balance between work and rest,
CFS/ME (Maric et al., 2014). plus additional interventions based on the deficiencies
identified.
NADH, reduced form Because CoQ10 and NADH increase cellular ATP produc-
In 1999, an RCT crossover study of NADH 10 mg·day 1 for tion via mitochondrial oxidative phosphorylation, their sup-
4 weeks in 26 CFS patients reported positive results. No severe plementation could help improve fatigue and other
adverse effects were observed (Forsyth et al., 1999), and CFS symptoms in CFS/ME (Nicolson, 2014; Castro-Marrero et al.,
patients who received this NADH supplementation for 2016). For its part, CoQ10 supplementation alone has been
12 weeks obtained more effective symptoms relief than those evaluated in many illnesses (such as fibromyalgia) with con-
assigned to the placebo (31% vs. 8%, P < 0.05). Another study flicting findings, but not yet in CFS/ME (Garrido-Maraver
comparing oral NADH supplementation with conventional et al., 2014). Data regarding the effects of CoQ10 and NADH
therapy for 24 months in 31 CFS patients showed a higher supplementation on exercise performance and cardinal
effectiveness of NADH (in terms of reductions in mean self- symptoms in CFS remain limited and inconsistent. Addition-
reported symptom scores) compared with nutritional supple- ally, no specific assessment of cardiovascular functioning
ments and psychotherapy (Santaella et al., 2004). A previous (haemodynamic parameters as cardiac output, blood volume,
study by our group in 77 Spanish CFS patients showed that HR, blood pressure, stroke volume, and so on) with CoQ10
oral NADH (20 mg·day 1) administration for 8 weeks was as- plus NADH supplementation during an exercise challenge
sociated with reductions in anxiety [as assessed by Hospital test in CFS has been performed to date.
Anxiety and Depression Scale (HADS)] and maximum heart Recently our working group (Castro-Marrero et al., 2016)
rate (max HR) after an exercise challenge test (Alegre et al., conducted a proof-of-concept, 8 week RCT in 80 Spanish
2010). Earlier studies had shown that oral NADH administra- CFS/ME patients who met the 1994 CDC/Fukuda definition
tion had a good safety profile, with no observed adverse ef- and were allocated to receive CoQ10 plus NADH or matching
fects or toxicity (Forsyth et al., 1999; Santaella et al., 2004; placebo. Our findings suggested that the combination of
Alegre et al., 2010). However, a systematic review concluded CoQ10 plus NADH was safe and potentially effective in
British Journal of Pharmacology (2017) •• ••–•• 7J Castro-Marrero et al.
BJP
reducing the max HR (P = 0.022) during the exercise chal- (Dougall et al., 2014; Larun et al., 2015; Smith et al., 2015).
lenge test. There was also a trend towards a reduction in While accepting that a subgroup of CFS subjects may find
self-reported measures of fatigue (FIS 40) in the active group CBT helpful when they develop comorbid depression, anxi-
compared with placebo (P = 0.030). However, no effect on ety and other mental health problems, we believe that CBT
pain and sleep was found. Additional larger RCT trials are should not be used as a primary intervention for CFS/ME as
now needed to confirm these findings. reported in the NIH Pathways to Prevention Workshop
Relatively few pharmacological or other therapies for (Green et al., 2015). Patient surveys, in particular, are more
CFS/ME have been tested in large RCTs. Overall, a report in favour of pacing therapy than CBT. Pacing has consis-
commissioned by the AHRQ based on a systematic review tently been shown to be the most effective, safe, acceptable
for a US NIH Pathways to Prevention Workshop concluded and preferred form of activity management for CFS/ME and
that no available pharmacotherapy is of proven benefit in should therefore be a key component of any illness manage-
CFS/ME. Table 1 summarizes the current drug therapeutic ment programme (Results and in-depth analysis of the 2012
strategies for CFS/ME. ME Association patient survey examining the acceptability,
efficacy and safety of CBT, GET and pacing, as interventions
used as management strategies for ME/CFS). The minimal risk
of adverse effects suggests that failing to treat the most se-
Non-pharmacological approaches:
verely ill ME/CFS patients is more risky than providing this
counselling, behavioural & treatment. It is particularly useful for defining and setting
rehabilitation interventions limits, behaviours that are extremely important for these pa-
tients. One review reported that, of all therapies available to
Cognitive behavioural therapy (CBT) CFS/ME patients, only CBT and GET showed conclusive ben-
Experimental management approaches for CFS/ME include efits (White et al., 2011). CBT was able to relieve the symp-
behavioural interventions such as CBT, a form of psycholog- toms of fatigue, and it appeared to be more effective than
ical therapy, and graded exercise therapy (GET), a form of other psychological therapies. However, the patients re-
physical activity that starts very slowly and increases gradu- cruited in this study fulfilled the 1991 Oxford criteria for
ally in intensity over time. In published reports, CBT has of- CFS, which many today regard as outdated and unreliable.
ten been inappropriately recommended as a cure for Cognitive therapy may also be an effective treatment for
CFS/ME patients who are able to change their belief system. adolescents with CFS/ME. Adolescents with CFS who re-
However, CFS/ME is a physical illness, not a psychological ceived internet-based CBT reported improvement in fatigue,
one, and therefore CBT cannot cure it. Based on evidence physical function and school attendance (Nijhof et al.,
from several RCTs, a systematic review concluded that CBT 2012). However, not all studies support cognitive therapy
interventions showed promising results, appearing to reduce for CFS/ME. A 2011 systematic review of RCTs found moder-
fatigue and improving physical functioning and school at- ate evidence of a benefit, but its effectiveness for CFS/ME out-
tendance, but did not prove effective in restoring the ability side specialist settings has been questioned and the quality of
to work (Chambers et al., 2006). CBT and GET have both re- the evidence is low (Cooke et al., 2008). A 2008 Cochrane re-
ceived wide support and have demonstrated reproducible ev- view of CBT concluded that it is more effective than usual
idence for their efficacy in non-severely ill CFS outpatients care for relieving fatigue symptoms in adults with CFS. How-
(Whiting et al., 2001; Van Cauwenbergh et al., 2012). Earlier ever, the review expressed doubts about its ability to sustain a
studies found evidence after assessing the effectiveness of all clinical response at follow-up, and did not report conclusive
trials that have been evaluated so far for use in the treatment improvements in physical functioning, depression/anxiety
and management of CFS in adults and children. They sub- or psychological distress either post-treatment or at a later
stantiate their proposal that GET and CBT are beneficial for date. Data on adverse effects were not systematically pre-
CFS patients, but in fact neither treatment has been shown sented by any of the studies. The authors also concluded that
to reverse the illness nor have any well-designed double- while the quantity and quality of the evidence has grown in
blind interventions comparing these therapies with placebo recent years, there is a surprising lack of high quality evidence
been published. All conclusions about effectiveness should on the effectiveness of CBT alone or in combination with
be considered together with the methodological quality inad- other treatments able to guide the development of clinical
equacies of the trials. Further research into these and other management programs for CFS (Price et al., 2008).
therapies using standardized outcome measures is now re- Another 2008 meta-analysis found that the effectiveness
quired. A further systematic review concluded that CBT is of CBT depends on the diagnostic criteria used, with studies
the treatment with the most evidence to support it (Butler using the 1991 Oxford criteria presenting a trend towards sig-
et al., 2006). nificantly higher effect sizes than those using the 1994
This conclusion has subsequently been reinforced by sev- CDC/Fukuda definition. The authors also noted that CBT
eral large-scale studies in adults and adolescents with CFS/ME for CFS/ME has about the same efficacy as diverse psycholog-
(Nijhof et al., 2012; Brurberg et al., 2014; Janse et al., 2015). ical treatments for a variety of psychological disorders
However, the effect size obtained is modest, and there is lim- (Malouff et al., 2008). A 2010 meta-analysis of trials that ob-
ited evidence of efficacy in the most severely ill patients. CBT jectively measured physical activity before and after CBT
can be given either individually or in groups (Wiborg et al., showed that, although the therapy effectively reduced pa-
2015). In children and adolescents with CFS/ME, internet- tients’ self-reported fatigue scores, it did not improve activity
based consultations may be effective (Nijhof et al., 2012). levels, and changes in physical activity were not related to
There is no sign of any increase in serious adverse events changes on fatigue questionnaire scores. The authors
8 British Journal of Pharmacology (2017) •• ••–••Table 1
Overview of the included pharmacological interventions for CFS/ME
Population characteristics and case definition Outcomes reported
Participants Physical
Intervention Duration of Case functioning Quality Author
(Study ID) Study design follow-up definition Fatigue measures status rating (year)
Rintatolimod Phase II RCT. 92 patients 1988 Exercise duration: KPS: P = 0.023 FAIR (Strayer et al., 1994)
(AMP-502) i.v. rintatolimod 6 months. CDC/Holmes (P = 0.007) ADL: P = 0.034
versus placebo Exercise work: SCL-90R: P = 0.05
(P = 0.011)
Rintatolimod Phase III RCT. 234 patients 1998 ET on a treadmill KPS, ADLs, Vitality FAIR (Strayer et al., 2012)
(AMP-516) i.v. rintatolimod 10 months CDC/Holmes with ECG testing and SF-36 scores
versus placebo (P = 0.047) were measured
pre-and post-tto,
but not compared
between groups
Rituximab Case cohort, 3 patients 1994 NR Improved physical FAIR (Fluge and Mella,
(RTX; Pilot study) Open-label study. 10 months CDC/Fukuda health and function 2009)
Infusions of RTX scores
versus placebo
Rituximab Small RCT phase 30 patients 1994 Fatigue levels Improved physical FAIR (Fluge et al., 2011)
(KTS-1-2008) II study. Infusions 12 months CDC/Fukuda (P = 0.51) health and function
of RTX versus scores
placebo
Rituximab Single-centre 29 patients 1994 Fatigue score (at Baseline function FAIR (Fluge et al., 2015)
(KTS-2-2010) open-label, one 15 month CDC/Fukuda least 6 weeks) level: 15% (5–50)
armed, treatment to Fatigue: 8 (6.3–10) Baseline total SF-36
non-randomized 36 months Cognitive: 7.5 Physical health:
Phase II study. (4.7–10) 25.6 ± 6.6
Infusions of RTX Pain: 7.2 (4–9) Mental health:
versus placebo ME/CFS overall: 44.6 ± 10.4
8.2 (6–10)
Valganciclovir RCT. 30 patients 1994 Change at 9 months Physical function: FAIR (Montoya et al.,
(EVOLVE) Oral valganciclovir 48 weeks. CDC/Fukuda for MFI-20: P = 0.224 P = 0.217 2013)
versus placebo 6 months tto and and FFS: P = 0.006 Cognitive
6 more months. functioning:
follow-up (unbinding P = 0.025
and outcomes
measured at
9 months)
Therapy and management in CFS/ME
continues
British Journal of Pharmacology (2017) •• ••–••
BJP
910
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Table 1 (Continued)
Population characteristics and case definition Outcomes reported
Participants Physical
Intervention Duration of Case functioning Quality Author
(Study ID) Study design follow-up definition Fatigue measures status rating (year)
Hydrocortisone + Crossover RCT. 80 patients 1994 VAS score (0–10) SF-36 physical FAIR (Blockmans et al.,
Fludrocortisone Oral hydrocortisone 6 months CDC/Fukuda Fatigue degree: score: P = 0.34 2003)
J Castro-Marrero et al.
+ fludrocortisone P = 0.76 SF-36 mental score:
versus placebo AFQ score (4–28): P = 0.02
P = 0.69
Hydrocortisone RCT, single centre. 65 patients 1988 Mean changes Mean changes FAIR (McKenzie et al.,
Oral hydrocortisone 3 months CDC/Holmes POMS subscales Activity scale: 1998)
versus placebo Fatigue: P = 0.21 P = 0.32
British Journal of Pharmacology (2017) •• ••–••
Vigour: P = 0.45 Global wellness score:
P < 0.001
Immunoglobulins RCT. 30 patients 1988 NR MOS-SF-12 FAIR (Peterson et al.,
i.v. IgG versus 6 months follow-up CDC/Holmes (0–100 score) 1998)
placebo Physical subscale,
mental health and
social functions:
all P = NS
Health perception:
P < 0.05
Isoprinosine RCT. 16 patients 1988 NR SCL-90R: P = 0.25 POOR (Diaz-Mitoma
(Immunovir) Oral isoprinosine 3 months tto to CDC/Holmes KPS: P = 0.46 et al., 2003)
tablets 7 months follow-up and 1994 ADL: data not provide
versus placebo CDC/Fukuda
Acetyl-L-carnitine Exploratory, 90 patients 1994 MFI-20 (4–20 score) NR FAIR (Vermeulen and
(ALC) versus Propionyl- open-label RCT. 6 months CDC/Fukuda General fatigue Scholte, 2004)
L-carnitine (PLC) versus Oral ALC versus (at 4 months):
combination PLC versus placebo P = 0.0003
Physical fatigue
(at 4 months):
P = 0.007
Mental fatigue
(at 4 months):
P = 0.010
General fatigue
(at 6 months):
P = 0.004
Physical fatigue
continuesTable 1 (Continued)
Population characteristics and case definition Outcomes reported
Participants Physical
Intervention Duration of Case functioning Quality Author
(Study ID) Study design follow-up definition Fatigue measures status rating (year)
(at 6 months):
P = 0.009
Mental fatigue
(at 6 months):
P = 0.015
Essential fatty RCT 63 patients 1991 Oxford Self reported Physical symptom: FAIR (Behan et al., 1990)
acids Oral linoleic acid, 3 months criteria for PVFS fatigue (0–3) P = NS
GLA, EPA and DHA At 1 month:
versus placebo p=:0.09
At 3 months:
P = 0.0003
Behan’s RCT 50 patients 1991 Oxford Self reported Physical symptom: FAIR (Warren et al.,
replication Oral Efamol marine 3 months fatigue (0–3) P = NS 1999)
study versus placebo At 1 and 3 months:
all P = NS
Magnesium RCT 32 patients 1990 Australian Mean change in Pain: P = 0.011 FAIR (Cox et al., 1991)
i.m. 50% (non magnesium definition NHPES (at Emotional reaction:
magnesium sulfate deficiency) 1.5 months): P = 0.013
injections versus 1.5 months P = 0.002 Overall NHPES:
placebo follow-up P = 0.001
Vitamin B12 Crossover RCT 29 patients General Fatigue level: Rating general FAIR (Ellis and Nasser,
i.m. injections of 1.5 months practitioners P = 0.09 well-being: P = 0.006 1973)
hydroxocobalamin and hospital staff Rating happiness:
versus placebo inquiry on P = 0.032
tiredness
and fatigue
Vitamin B12 Crossover RCT. 15 patients 1988 P = NS P = NS POOR (Kaslow et al.,
i.m. injections of a Follow-up NR CDC/Holmes 1989)
liver extract-folic
acid cyanocobalamin
(LEFAC) combination
versus placebo
Vitamin B12 Case report. 2 women with CFS 1998 Self-reported NR FAIR (Wiebe, 1996)
High dose of i.m. Follow-up NR CDC/Holmes energy
vitamin B12 injections P = NS
twice weekly
Vitamin B12 Cross-sectional survey. 38 female patients 1994 NR FFS score (0–6): FAIR (Regland et al.,
Therapy and management in CFS/ME
plus folic acid i.m. cyanocobalamin Follow-up NR CDC/Fukuda P = NS 2015)
British Journal of Pharmacology (2017) •• ••–••
and 2003
BJP
continues
1112
BJP
Table 1 (Continued)
Population characteristics and case definition Outcomes reported
Participants Physical
Intervention Duration of Case functioning Quality Author
(Study ID) Study design follow-up definition Fatigue measures status rating (year)
injections plus oral Canadian criteria PGIC score (1–7):
folic acid (40% fulfilled P < 0.0005
J Castro-Marrero et al.
1990 FMS
criteria)
NADH Cross-over RCT. 26 patients 1994 NR NR FAIR (Forsyth et al., 1999)
(ENADA study) Oral NADH versus 3 months CDC/Fukuda
placebo
British Journal of Pharmacology (2017) •• ••–••
NADH RCT 31 patients 1994 Symptoms score at NR FAIR (Santaella et al.,
Oral NADH or 24 months CDC/Fukuda 3 months: P = 0.001; 2004)
nutritional at 6, 12 and
supplements versus 24 months: P = NS
psychotherapy
NADH RCT 77 patients 1994 P = NS Reduction in FAIR (Alegre et al., 2010)
(VitaNADH) Oral NADH versus 3 months CDC/Fukuda self-reported
placebo symptoms
by HADS
Anxiety: P < 0.05
Depression: P = NS
CoQ10 + NADH A proof of concept 80 patients 1994 Total FIS 40 score Self-report outcomes GOOD (Castro-Marrero
(ReConnect) RCT. 2 months CDC/Fukuda Baseline:P = 0.32 for pain and sleep et al., 2016)
Oral CoQ10 plus 1 month: P = 0.71 1 month: P = NS
NADH versus 2 months: P = 0.03 2 months: P = NS
placebo
All outcomes indicate % change from baseline.
ADL, Activities of Daily Living index (range 0–100; higher score means better health); AFQ, Abbreviated Fatigue Questionnaire (range 4–28, lower total score indicates a higher degree of subjective
fatigue); AMP, ampligen study ID numbers; ET, Exercise Tolerance testing; FFS, FibroFatigue scale (range 0–6, higher score means maximal degree of the symptoms); GLA, omega-6 fatty acid made in
the body from the essential omega-6 fatty acid, linoleic acid (LA); KPS, Karnofsky Performance Status (range 0–100; higher score means better health); KTS, Rituximab study ID numbers; MFI-20,
Multidimensional Fatigue Inventory (range 4–20; negative changes indicate better health); MOS-SF-12, a 12-item Short Form Survey developed for the Medical Outcomes Study; NHPES, Nottingham
Health Profile (range 0–100, higher score indicates greater numbers and severity of health problems); PGIC, Patients’ Global Impression of Change (range 1–7, higher scores indicate worse health
status); POMS, Profile Of Mood States (range 0–5, higher score means worse mood status); SCL-90R, Symptom Checklist-90 Revised (range 0–4; where 0 indicate the absence of impairment and 4
reflected extreme impairment); SF-36 PF, 36-item Short Form Survey Physical Function scales (range 0–100, higher score means less disability and better health status); tto, treatment; VAS, Visual
Analogue Scale (range 0–10, higher score indicate greater pain intensity).Therapy and management in CFS/ME BJP
concluded that the effect of CBT on fatigue scores is not me- aerobic exercise, in which patients gradually perform more
diated by a change in physical activity (Wiborg et al., 2010). intense exercise. In a Cochrane review and meta-analysis on
This raises the following question: perhaps a change in activ- effectiveness of GET in treating CFS/ME (Edmonds et al.,
ity regulation is more important in facilitating improvement 2004), five studies (Fulcher and White, 1997; Powell et al.,
in relatively active CFS patients than an increase in physical 2001; Wallman et al., 2004; Moss-Morris et al., 2005;
activity. Furthermore, a smaller group of CFS patients with a Wearden et al., 2010) examined the effects of exercise ther-
passive activity pattern (who show extremely low levels of apy. Patients in the studies met either the 1991 Oxford
physical activity) might benefit from a persistent increase in criteria (Fulcher and White, 1997; Wearden et al., 1998; Pow-
physical activity. Unfortunately, the number of patients in ell et al., 2001) or the 1994 CDC/Fukuda definition (Wallman
this group was too small to properly assess the effect of this et al., 2004; Moss-Morris et al., 2005) for CFS. At 12 weeks, ex-
treatment. ercise therapy was slightly more beneficial for patients with
According to a 2014 systematic review, the lack of changes depression than for controls (Fulcher and White, 1997;
in objectively measured physical activity challenges the va- Wearden et al., 1998; Wallman et al., 2004).
lidity of the cognitive behavioural model of CFS/ME, because Graded exercise works best for CFS/ME when combined
it suggests that patients still avoided post-exertional symp- with CBT and psychoeducation therapy, but it may not work
tom exacerbations and adapted to the illness rather than re- for all CFS/ME patients. In fact, over-exercising may intensify
covering from it (Adamowicz et al., 2014). To date, the symptoms, and some patients experience profound fatigue
effectiveness of CBT for the severely ill ME/CFS patients has after even moderate exercise. Two systematic reviews cau-
not been assessed, and in practice, these patients may be ex- tiously conclude that some CFS/ME patients may benefit
cluded from trials because they need to attend a clinic (Cham- from GET, although there are limitations regarding the evi-
bers et al., 2006). dence and the generalisability of the findings (Edmonds
Around 25–40% of CFS patients can be expected to have et al., 2004; Chambers et al., 2006).
comorbid anxiety and depression. Moss-Morris’s working A 2012 systematic review concluded that despite the con-
group (Moss-Morris et al., 2005) carried out a study with sistently positive outcomes of GET trials for CFS/ME, exercise
the following two hypotheses; GET would lead to a reduc- therapy is not a cure and that full recovery from CFS/ME is
tion in fatigue and disability (i) through an increase in rare (Van Cauwenbergh et al., 2012). A 2004 Cochrane sys-
physiological fitness and (ii) by decreasing patients’ tenden- tematic review of five eligible studies of GET found statisti-
cies to focus on their symptoms and increasing their belief cally significant improvements in self-reported fatigue
that exercise can help control their symptoms. The study severity and physical functioning. This benefit was sustained
included patients with and without comorbid psychopa- after 6 months but was no longer significant compared with
thology; all met the 1994 CDC/Fukuda definition for CFS, the control group who did not receive GET. Functional work
and those with anxiety and depression were diagnosed capacity did not significantly improve. The authors stated
using the self-reported HADS. Between 50–55% of CFS pa- that the evidence base and the accuracy of the results are lim-
tients versus 24% of controls reported that they felt much ited, and called for higher quality studies in subgroups of
better after the 12 weeks of exercise therapy. Furthermore, CFS/ME patients and settings that measured additional out-
around 40% of patients in this study had a probable comor- comes such as adverse effects, quality of life and cost effec-
bid anxiety or depression, suggesting that graded exercise tiveness over longer periods of time (Edmonds et al., 2004).
could be more effective in these patients. A 2006 systematic review of five eligible studies of GET
A study including 45 CFS/ME patients found that the ef- found an overall reduction in symptoms and an improve-
fectiveness of psychodynamic counselling for treating ment in physical functioning, but GET was not shown to re-
CFS/ME was comparable with that of CBT (Chisholm et al., store the ability to work. Withdrawals were recorded in
2001; Ridsdale et al., 2001). Children have been successfully some GET studies but were difficult to interpret due to the
treated using antidepressants and therapy (Patel et al., 2003). poor reporting of adverse effects. The protocols for many clin-
ical studies may have biased sample selection towards inclu-
Graded exercise therapy (GET) sion of patients with less severe symptoms. In general, most
The assessment of the effectiveness of GET and the analysis of the studies cited here recruited patients who were able to
of the Cochrane database used the 1991 Oxford criteria attend the place where the study was being carried out, but
(Larun et al., 2015). It is known that depressed patients im- excluded severely ill ME/CFS patients (homebound or
prove with activity. As defined in the 2003 Canadian bedbound) whose condition did not allow them to go. This
Criteria, CFS/ME is a physical illness with post-exertional is why patient selection shifts towards inclusion of patients
malaise as a core symptom of the illness. Because patients with less severe symptoms.
with depression were included in the 1991 Oxford criteria, The authors noted the need for research to define fully the
the studies erroneously concluded that CFS patients were characteristics of patients who would benefit from specific in-
improving with GET. CFS/ME patients have demonstrated terventions, and also to develop clinically relevant objective
post-exertional malaise on 2 day following CPET testing. outcome measures (Chambers et al., 2006). A New Zealand
Exercise capacity varies greatly among CFS/ME patients, study suggested that GET may result in self-reported improve-
and some may not be able to increase their aerobic intensity ment, in part by reducing the degree to which patients focus
(Bested and Marshall, 2015). on their symptoms (Moss-Morris et al., 2005). Nijs et al. (Vrije
Nonetheless, a number of studies using both the 1991 Universiteit Brussels, Belgium) noted that, in order to avoid
Oxford criteria and 1994 CDC/Fukuda definition have detrimental effects of GET, care must be taken to avoid symp-
reported the benefits of a GET programme, particularly tom exacerbation while tailoring the programme to
British Journal of Pharmacology (2017) •• ••–•• 13You can also read
