Approach

The primary goals of management are to provide a supportive healthcare environment with a team of occupational therapists, physiotherapists, and other appropriate therapists who will manage symptoms and improve functional capacity.

Primary care clinicians play a key role in management of patients with ME/CFS, typically retaining responsibility for long-term care and monitoring, in partnership with the ME/CFS specialist team in secondary care. A key role of the primary care clinician is to liaise with other health, social care, and educational professionals in response to specific evolving patient needs, and to facilitate access to resources in the community (e.g., physiotherapy, occupational therapy, dietetic support, and district nursing staff visits) as guided by disease severity and individual need.[10] The National Institute for Health and Care Excellence (NICE) recommends that adults with ME/CFS receive a review of their care and support plan in primary care at least once a year; review at least every 6 months is recommended for children and young people with ME/CFS. More frequent primary care reviews should be arranged as needed, with the interval dependent on the severity and complexity of symptoms, and the effectiveness of symptom management.[8] Referral to the person's named contact in the ME/CFS secondary care team is required if new or deteriorating aspects of their condition develop.[8] A possible strategy may be to provide counsel to patients every 3 months and to reassess any other health issues and treatable diseases.

General considerations

The primary goals of treatment are to manage symptoms and improve functional capacity; with symptom-oriented support, patients may experience improvements over time, or they may learn to better manage the effects of illness.[10] The evidence base for ME/CFS treatments is limited.[183]​ There are no curative medications or treatments for ME/CFS. No drug therapies have been licensed for ME/CFS, and there is no evidence showing that any single drug therapy regimen is more effective than another.[183]

After infectious and medical causes have been excluded, a treatment plan can be developed with the patient. Initial treatment should be individualised based on the spectrum of most severe complaints. One approach is to focus on the most severe symptoms and address each one at a time through a series of scheduled visits.

Initial treatment begins with rehabilitation and supportive care. Treatments for ME/CFS are palliative and restorative; there are no curative treatments. Time and patience are required to assist the newly diagnosed patient in developing the skills needed to cope with this debilitating condition. A supportive family, medical team, and home environment will facilitate adaptation to a new diagnosis of ME/CFS and its management.

Some patients with ME/CFS may already be established on a complicated and extensive treatment regimen. A general treatment strategy may involve a stepwise process of simplifying the treatment regimen across time (e.g., gradually reducing the number of medications). Treatment interventions tend to be multidimensional and tailored to each person’s circumstances. The focus of treatment should be oriented towards symptom management and functional improvement, and away from repeated, extensive diagnostic procedures, or ongoing referrals to additional specialists.

The provision of reliable educational materials may be useful, and can help with empowering the patient for self-management. NHS: ME/CFS Opens in new window

Treatment controversies and uncertainties: graded exercise therapy (GET)

Historically, treatment has been complicated by strong differences in opinion between people with ME/CFS and their support groups compared with medical specialists, as well as differences in opinion among specialists.[184][185]​​​​ Further complexity has arisen owing to a historical lack of consensus about ME/CFS diagnostic criteria and about treatment approaches across Europe and around the world.[186]

Although previous randomised controlled trials (RCTs) have reported benefits to structured GET in the management of ME/CFS, a re-analysis by Cochrane in 2019 highlighted the presence of methodological flaws. Concerns about the potential for iatrogenic harm with GET have been noted, owing to inadequate reporting of harms within RCTs.[187][188][189]​​​​​​​

​The possibility of iatrogenic harm with GET is supported by results of 2-day maximal exercise stress tests, where ME/CFS patients do well on the first day, but have reduced cardiopulmonary function on the second day, followed by exacerbation of fatigue and other ME/CFS symptoms.[111][164]​​​​​​ Graded exercise may be particularly counter-productive in severe and/or bed-bound ME/CFS because the treatment may induce post-exertional malaise (PEM) and prolonged exercise-induced exacerbations.

Dissenting opinion about the safety and efficacy of GET has led to uncertainty among clinicians as to how best to support patients in safely managing their activity and exercise levels. Fundamental gaps in the evidence regarding GET in ME/CFS remain, and a full update of the Cochrane review is currently in progress.[190]

Based on these concerns, GET is no longer recommended as a treatment for ME/CFS by the NICE guidelines, or by the US Centers for Disease Control and Prevention (CDC).[8][191]​​​​ With respect to this decision, the NICE guideline development committee cites reports of harm in the qualitative evidence, as well as the committee's experience of the effects when people exceed their energy limit.[8]​ 

Many patients and clinicians now favour an alternative approach to managing activity levels in ME/CFS, referred to as ‘energy management’ or ‘pacing’, which involves carefully planning activities and rest to avoid overexertion (PEM). Note that energy management is intended as a possible coping strategy for people with ME/CFS, rather than as a curative therapy. The evidence for energy management is largely anecdotal, based on patient experience and clinical observation. This approach is supported by NICE in the UK, as well as by the CDC and the National Institutes of Health (NIH) in the US, and the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE).[8][10]​​[145][192]​ NICE emphasises the importance in the absence of clinical consensus to provide clarity of information and clear guidance around energy management, physical activity, and exercise to people with ME/CFS; this topic aligns with this pragmatic approach.[8]  

Note: NICE defines graded exercise therapy as "establishing a baseline of achievable exercise or physical activity and then making fixed incremental increases in the time spent being physically active. It is a therapy based on the deconditioning and exercise avoidance theories of ME/CFS." In practice, some patients with ME/CFS may tolerate a carefully individualised activity plan developed in collaboration with knowledgeable and experienced professionals: for example, those who feel ready to progress their physical activity beyond their current levels, and/or those who would like to incorporate physical activity or exercise into managing their ME/CS.[23] The activity plan must aim to minimise the negative effects of exertion on impaired aerobic and cognitive function. See the section Multidisciplinary support.

Multidisciplinary support

NICE guidance suggests that good care for people with ME/CFS results from access to an integrated team of health and social care professionals trained and experienced in managing ME/CFS.[8]​ According to the NICE guidelines, it is necessary to undertake a thorough assessment of the person with ME/CFS to inform a care and support plan to improve health outcomes. This may include support for activities of daily living, developing self-management strategies, guidance on managing potential relapse, and encouraging flexible work commitments. It is essential that service providers are proactive and recommend flexibility for those with severe or very severe ME/CFS: specifically, by offering home visits or online or phone consultations, and by supporting applications for disability aids and appliances.[8]

NICE recommends referring people with ME/CFS to a physiotherapist or occupational therapist working in an ME/CFS specialist team if they:[8] 

  • have difficulties caused by reduced physical activity or mobility, or

  • feel ready to progress their physical activity beyond their current activities of daily living, or

  • would like to incorporate a physical activity or exercise programme into managing their ME/CFS.

Mobility support

As the primary physician it is important to promptly encourage assessment and access to occupational therapy for home adaptation for people with moderate to very severe ME/CFS. These aids may include, but are not limited to:

  • Disability parking

  • Wheelchairs

  • Motorised scooters

  • Shower chairs

  • Stairlifts

In addition, physiotherapy may support physical symptoms of ME/CFS. Physiotherapy is offered as a management approach and is not a proven treatment option. Furthermore, physiotherapy is to be closely monitored and guided by a physiotherapist with interest or training in ME/CFS and tailored to the individual concerns of the patient.

Structured GET is not recommended, owing to the potential for iatrogenic harm.[8] However, patients with ME/CFS may tolerate an individualised activity plan developed in collaboration with knowledgeable and experienced professionals.[23]​ The activity plan must aim to minimise the negative effects of exertion on impaired aerobic and cognitive function.

Energy management/pacing

The concept of an 'energy envelope', as outlined by NICE guidelines, provides people with ME/CFS with a strategy to manage their exertional tolerance.[8][10]​​​​ The energy envelope refers to the amount of energy that the patient has available to perform all of their daily activities.[183] The size of the energy envelope needs to be defined on a daily basis because resources and tolerance can vary from day to day and depending on other life stressors. Exceeding the energy envelope depletes these reserves and leads to post-exertional worsening of symptoms and of cognitive and physical functioning. The patient and practitioner can work together to recognise personal energy limits and set reasonable limits on activities. 

'Pacing' refers to a self-management strategy whereby individuals divide activities into smaller parts with interspersed rest intervals in order to remain within the limits of the envelope.[23][183][193]​​​​​​ As a general guide, patients are encouraged to keep their heart rate at less than 70% of the age-predicted maximum. Planned organisation of efforts is important to avoid doing harm by exceeding the limitations of the energy envelope.[194] While pacing may introduce a coping strategy for some patients, this is not a therapy and may not improve or alleviate the symptoms of ME/CFS, and should be undertaken with the guidance of a physician or nurse practitioner. Successful pacing is believed to be the most beneficial management strategy for ME/CFS according to NICE, the CDC, and the NIH.[8]​​[145]​​​​[192] The aim is to optimise the patient’s ability to maintain activities of daily living and community/society participation. 

It is important to highlight that structured GET is not recommended to accompany pacing strategies.[8]​ However, patients with ME/CFS may tolerate an individualised activity plan developed in collaboration with knowledgeable and experienced professionals.[23]​ The activity plan must aim to minimise the negative effects of exertion on impaired aerobic and cognitive function.

Environmental modifications

People with ME/CFS commonly report sensitivities to light, noise, and odours, and are often diagnosed with comorbid multiple chemical sensitivities. Therefore, it may be pertinent to discuss encouraging the following to limit impact of the environment on symptoms:

  • A perfume- and chemical-free environment

  • Use of eye masks and ear plugs

Psychosocial interventions

Cognitive behavioural therapy (CBT) may be offered to adults, children, and young people with ME/CFS who would like to use it to support them in managing their symptoms.[8] Mindfulness is an alternative psychosocial approach recommended for symptom relief in ME/CFS by European ME/CFS guidance.[10]

Protocols for techniques including CBT or a mindfulness approach are not standardised as there are significant differences in outcomes between different countries and different studies depending on their inclusion criteria. Studies of CBT in people with ME/CFS report significant improvements in mental health scores, fatigue scores, and 6-minute walking, but effect sizes were low and were not corrected for multiple comparisons.[195]​​​​[196]​​​​ Internet-supported CBT is an emerging approach that has shown initially promising results, and that may help facilitate access for people with difficulties attending face-to-face appointments.[197]

It is important to highlight that the offer of psychosocial interventions does not reflect the belief that ME/CFS is of psychological aetiology; psychosocial interventions should be offered with considerable care to avoid distress.[198]​ 

Rather, these techniques have been beneficial in people suffering other chronic diseases. For example, in patients who have been chronically ill, mindfulness skills have a positive effect on depression, mood, and activity level.[199] This approach facilitates the person with ME/CFS to identify unhelpful negative emotion-provoking thoughts, dysfunctional behaviours, and cognitive patterns, and uses a goal-oriented, systematic procedure to enhance self-esteem. CBT may help in dealing with a new diagnosis of ME/CFS, improve coping strategies, and assist with rehabilitation. CBT should be offered not as a 'cure' for ME/CFS but to support people to manage their symptoms and to refine self-management strategies to improve functioning and quality of life.[8] In routine medical practice CBT has not yielded clinically significant long-term benefits in ME/CFS.[196]

​Family sessions can help educate and inform spouses, children, parents, and other significant people about the disabling nature of ME/CFS.[200] NICE stipulates that CBT should only be delivered by a healthcare professional with appropriate training and experience in CBT for ME/CFS, and under the clinical supervision of someone with expertise in CBT for ME/CFS.[8]​ Although referral to mental health services with expertise in CBT has been recommended regardless of ME/CFS severity, this is limited by a lack of availability in some settings of a qualified CBT psychologist, social worker, nurse, or other practitioner with ME/CFS training.

CBT may also be helpful in the treatment of comorbid depression and/or anxiety and insomnia. See the section Management of common symptoms/comorbidities below.

Further resources providing psychosocial support may be available through ME/CFS support groups. Successful support groups have effective leadership and positive programming that avoids simply exchanging complaints.

Management of common symptoms/comorbidities

Evidence regarding the management of common symptoms and comorbidities is limited, and there are few randomised double-blind placebo-controlled studies of treatments for ME/CFS to direct logical treatment.[183] Choice of drug should be based on the side-effect profile of the drug and the patient's initial response to treatment. Please note that drug treatments are sometimes used off-label and should be managed carefully to prevent synergistic or other adverse events; specialist advice (from a clinician experienced in managing ME/CFS) is recommended. Given that some patients with ME/CFS may have hypersensitivity to medication adverse effects, starting drug treatment at a low sub-therapeutic dose, and gradually increasing to therapeutic levels over time as tolerated, is usually recommended.[201]

The most recent update to the NICE guidelines for ME/CFS emphasises that no medicines or supplements are to be offered as a cure for ME/CFS; several pharmaceutical agents have been removed from the guideline compared with its previous iteration.[8]

Fatigue, PEM, and cognitive disturbance

According to the CDC, NICE, and the Mayo Clinic, pacing provides the most beneficial approach to reducing the burden of fatigue and PEM in ME/CFS.[8][192][202]​​​​​​​ Other supportive measures may include:

  • Assistive devices and home health aides

  • School/work flexibility

Sleep alteration

Sleep difficulties are a major problem, and initial management is to address sleep hygiene. NICE guidance recommends personalised sleep management advice for people with ME/CFS.[8] If this is ineffective, evaluate for underlying causes of sleep problems. In the general adult population, CBT for insomnia (CBT-I) is typically recommended as the first-line management option for chronic insomnia.[203] Normalisation of the sleep/wake rhythm begins by stopping daytime napping and proceeds to improving the quality of sleep through relaxation therapy. Instruction is provided to prevent relapse.

See Insomnia.

Pain

Rehabilitation and allied health services may provide non-pharmacotherapeutic approaches to pain including acupuncture and massage if touch is tolerated by the patient.[10]

NICE guidance for ME/CFS refers to the treatment of headache and neuropathic pain, detailing a choice of aspirin, paracetamol, or non-steroidal anti-inflammatory drugs (NSAIDs) (for headache), and amitriptyline, duloxetine, gabapentin, or pregabalin (for other pain in ME/CFS).[8] NICE made the recommendation not to recommend any pharmacological interventions specific to pain in ME/CFS, citing a lack of evidence. The options above referred to by NICE are consistent with those recommended for pain in ME/CFS in European guidance by EUROMENE.[10] However, it is important to highlight that there is limited evidence for these pharmacotherapeutic agents for the treatment of pain in ME/CFS through RCTs. Note that pain medications improve pain but do not treat systemic hyperalgesia.

Referral to specialist pain services may be required if pain does not respond to initial management.[8] If the initial treatment is not tolerated, pharmacological recommendations for the management of pain in fibromyalgia may be used to guide treatment, in conjunction with specialist pain/ME/CFS/fibromyalgia services.[204][205]​​​​​

See Fibromyalgia.

The following should not be offered according to NICE guidelines: cannabis sativa extract, capsaicin transdermal patch, lacosamide, lamotrigine, levetiracetam, morphine, oxcarbazepine, topiramate, tramadol (long-term use), venlafaxine.[206]​ 

Orthostatic intolerance

Orthostatic intolerance even without postural orthostatic tachycardia is a major limiting condition that can be treated with compression stockings, positional changes, and salt loading.[10][207]​​​​​​ Advice on diet, daily activities, and activity support should be tailored to the individual, taking into account their other ME/CFS symptoms.[8]​ There may be a role for fludrocortisone, pyridostigmine, or other drugs used for orthostatic instability in ME/CFS.[10][208]​​​ NICE advises that pharmacotherapy for orthostatic intolerance in people with ME/CFS should only be prescribed or overseen by a clinician with expertise in orthostatic intolerance; this is because pharmacotherapy may worsen other symptoms in people with ME/CFS.[8]​ Referral to secondary care is warranted if symptoms are severe or worsening, or there are concerns that another condition may be the cause.[8]​ 

See Postural orthostatic tachycardia syndrome.

Gastrointestinal symptoms

Symptoms akin to irritable bowel syndrome and food intolerances are commonly reported in ME/CFS.[10] Monitor patients for malnutrition and unintentional weight loss or gain.[8] Dietary modification and food avoidance practices may be recommended in specific circumstances with support from a dietician.[10] However, it should be highlighted that RCTs examining the effects of dietary interventions in ME/CFS have yielded inconsistent results.[209] Dietary management is not offered as a cure or treatment but rather as part of a management plan with the aim of minimising the effects of diet on gastrointestinal manifestations. 

The NICE guidelines for ME/CFS encourage referring people with ME/CFS for a dietetic assessment and creation of a management plan by a dietitian with a special interest in ME/CFS, if they are:[8] 

  • Losing weight and at risk of malnutrition

  • Gaining weight

  • Following a restrictive diet

In the event that food avoidance practices and dietary management is not successful, pharmacological interventions may be utilised to improve gastrointestinal symptoms.

See Irritable bowel syndrome.

Co-existing depression or anxiety

​For comorbid anxiety or depression, CBT ± antidepressants may be helpful, in keeping with the management of depression and anxiety for the general population.[210][211]​​​​​ There is no evidence to suggest that antidepressants help with PEM, cognitive dysfunction, orthostatic intolerance, or other cardinal features of ME/CFS. Choice of antidepressant drug for comorbid depression or anxiety should be based on the treatment history, the adverse-effect profile of the drug, and the patient's initial response to treatment.

A suicide evaluation is standard practice for all patients who appear to be clinically depressed or highly stressed. In one UK-based study, suicide-specific mortality was found to be significantly increased in patients with ME/CFS compared with the general population, indicating the need for physician awareness and compassionate care.[212]

Possible adverse effects of standard treatments for depression include sedation, orthostatic hypotension, and increased appetite and weight gain, which may worsen fatigue and autonomic lability in some patients. Based on clinical experience, difficulties in achieving necessary amounts of exercise mean that people with ME/CFS may experience exaggerated adverse effects such as weight gain that may promote iatrogenic type 2 diabetes and metabolic syndrome with associated long-term health consequences.

Improvements with drug therapy may take several weeks, but more severe levels of depression may predict a slower treatment response.[213]​ 

See Depression in adults, Depression in children, Generalised anxiety disorder, and Suicide risk mitigation.

Further-line treatments

In the event that a person with ME/CFS desires pharmacological intervention when rehabilitation and support strategies have been unsuccessful, pharmacological interventions targeting fatigue and cognitive disturbances may be considered by a specialist in ME/CFS following risk-benefit analysis.

The NICE guidelines for ME/CFS highlight that the evidence for these agents is limited and of very low quality. Ultimately, NICE has recommended that many of these pharmaceuticals should not be used for the treatment of ME/CFS.[8]​ 

It is essential to highlight that no pharmacological interventions can be offered as a treatment or cure for ME/CFS; however, based on clinical experience, they may provide some relief.

Given that some patients with ME/CFS may have hypersensitivity to medication adverse effects, starting drug treatment at a low sub-therapeutic dose, and gradually increasing to therapeutic levels over time as tolerated, is usually recommended.[201]

Further-line pharmaceutical agents that are sometimes prescribed in secondary care for cognitive disturbances and fatigue (based on very low-quality evidence) include modafinil, amantadine, and methylphenidate.[214][215]​​​​[216][217][218]​​​​​ Note that amantadine in particular is associated with several adverse events, and may be poorly tolerated.[217]

Further-line agents that are sometimes prescribed for sleep disturbance include trazodone, low-dose tricyclic antidepressants, and cyclobenzaprine. Evidence on these drugs specific to ME/CFS is lacking.[219][220][221][222]

Treatments of uncertain efficacy

Few medications have had beneficial effects on PEM, fatigue, cognitive dysfunction, or long-term sleep disruption in ME/CFS.[223] Pain medications improve pain but do not treat systemic hyperalgesia. No drug therapies have been licensed for ME/CFS. Palliative treatments are instead directed at specific symptoms.

Systematic reviews have examined randomised clinical trials evaluating pharmacological and non-pharmacological treatments for ME/CFS, although in the absence of more definitive studies comparing participants meeting different case definitions, it is difficult to draw clear conclusions from this research.[183][224]​ RCTs assessing anticholinergics, corticosteroids, and hormones targeted against cardinal symptoms of ME/CFS have produced equivocal findings.[225]

RCTs investigating other agents, including immunomodulators or anti-inflammatories, have demonstrated limited safety and efficacy in ME/CFS. Rituximab is a chimeric monoclonal antibody targeting the pan-B-cell antigen CD20.[226] Small randomised placebo-controlled and open studies showed improvement rates of 60% to 83% after 22-83 weeks of treatment compared with 7% to 10% in placebo groups.[31]​​​​[58][97][227] However, one large randomised placebo-controlled study showed no significant treatment benefit and a large placebo effect.[228][229]​ Rituximab can cause serious adverse events including febrile neutropenia, infusion-related reactions, and other events requiring hospitalisation. Routine use of rituximab is contraindicated in ME/CFS. 

The absence of effective therapies indicates a significant need for research to clarify that the emerging treatment aligns with the pathophysiology of ME/CFS. Randomised double-blind placebo-controlled studies will be needed to identify drugs that are beneficial in ME/CFS.

Addressing potential barriers to treatment

In the setting of treatment resistance, the diagnosis should be re-evaluated including the possibility of comorbid conditions.

Factors contributing to sub-optimal engagement with treatment recommendations may include severe fatigue, pain, difficulties in travelling to the physician, and severity of PEM following visits to the physician.

Family, financial, and other conflicts may interfere with the physician-patient relationship. Sleep disruption with reversal of day-night cycles may confound travel plans and appointments. Furthermore, concomitant problems such as irritable bowel syndrome with uncontrolled explosive diarrhoea can be an embarrassment that keeps the person housebound.

Social withdrawal with depression should be addressed, and all such patients asked about suicidal ideation. Management of depression as described above may be of value in these situations. Pain medications can help.

Patients with severe or very severe ME/CFS may be bed-bound and require home visits and in-home therapy sessions because severe pain and discomfort will prevent them from travelling. It is essential that service providers are proactive and recommend flexibility for those with severe or very severe ME/CFS: specifically, by offering home visits or online or phone consultations, and by supporting applications for disability aids and appliances.[8]

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