Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Clinical Snapshot
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), previously called chronic fatigue syndrome, is a chronic, multisystem disease defined by profound, unexplained fatigue that causes substantial impairment in daily function and persists beyond 6 months.[1] Its defining, cardinal feature is post-exertional malaise (PEM) — a delayed, disproportionate worsening of symptoms after physical, cognitive, or even emotional exertion that would have been trivial before the illness, often described by patients as a crash. PEM, not fatigue alone, is what separates ME/CFS from ordinary tiredness or deconditioning, and recognizing it is the single most important diagnostic and counselling principle in this chapter.[2] The underlying mechanism is incompletely understood, but converging evidence points to chronic immune activation resembling a persistent infection-like sickness response, disrupted energy metabolism, and autonomic nervous system dysregulation, often following a viral or other infectious trigger — a pattern now recognized on a large scale with post-COVID-19/long-COVID illness.[3] No laboratory test or imaging study confirms the diagnosis, and no medication is approved to treat or cure it: care is symptom-targeted, individualized, and organized first and foremost around protecting the patient from PEM.
Recognize the Condition
Post-exertional malaise (PEM)
PEM is an exacerbation of some or all of a patient's baseline symptoms — flu-like malaise, pain, cognitive dysfunction, nausea or gastrointestinal discomfort, weakness or instability, lightheadedness, sensory sensitivity, and worsened sleep — triggered by physical, cognitive, or emotional exertion that would not have caused a problem before the illness. It is typically delayed (onset hours to a day or more after the triggering activity), disproportionate to the activity itself, and can last hours to days, weeks, or even months to resolve. A patient does not need to undergo formal exercise testing to establish PEM — the history alone, ideally supported by a symptom or activity diary, is sufficient and preferred, since exercise testing can itself trigger a severe, prolonged crash.[1]
Core symptom domains
- Profound fatigue that is new or has a definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially relieved by rest.
- Unrefreshing sleep — among the most consistently reported symptoms; patients wake unrefreshed regardless of how many hours they slept.
- Cognitive impairment (often called brain fog) — slowed information processing, short-term memory difficulty, trouble concentrating or finding words, and difficulty performing simple multi-step tasks.
- Orthostatic intolerance — lightheadedness, palpitations, nausea, or worsened cognitive symptoms that appear or worsen with standing or sitting upright and improve with lying down; a subset of patients meet formal criteria for postural orthostatic tachycardia syndrome (POTS).
- Widespread pain — myalgia, arthralgia without joint swelling, headache, and heightened sensitivity to touch, light, sound, or temperature.
- Sore throat, tender cervical or axillary lymph nodes, and feverishness can accompany PEM flares even without evidence of active infection.
Functional severity spectrum
Mild
Reduced capacity for occupational, educational, social, or personal activity relative to the patient's own baseline, but the patient remains mobile, can manage self-care, and can continue some work, school, or social activity with rest breaks and accommodation.
Moderate
Reduced mobility and substantially restricted activity; usually unable to sustain regular employment or full-time study; requires rest during the day and periodic use of aids (e.g., a cane or wheelchair for longer distances).
Severe
Mostly housebound; unable to perform most activities of daily living without help, with marked sensory sensitivity and minimal tolerance for physical or cognitive activity.
Very severe
Bedbound and dependent on others for most or all self-care, often with extreme sensory hypersensitivity that limits even light, sound, or conversation; requires a specialist or complex-care team approach.
Risk Factors
- A preceding infection is the most commonly recognized trigger — implicated pathogens include Epstein-Barr virus, enteroviruses, human cytomegalovirus, human herpesvirus-6, and SARS-CoV-2 (COVID-19); ME/CFS-like illness following COVID-19 is now a well-recognized presentation of long COVID.[3]
- A major physical stressor, surgery, or significant psychologically stressful life event preceding symptom onset in some patients.
- Family history of ME/CFS or related conditions, consistent with a proposed genetic contribution to immune regulation and stress response.
- Environmental exposure to toxins, chemicals, pesticides, or heavy metals has been proposed as a contributing factor in some cases.
- Diagnosed more frequently in women than men, though ME/CFS occurs across all ages, sexes, and socioeconomic groups and is substantially underdiagnosed, particularly in men.
- Presence of a hypermobility spectrum disorder or joint hypermobility (e.g., Ehlers-Danlos syndrome) is associated with a higher likelihood of comorbid ME/CFS and orthostatic intolerance.
Red Flags & Refer
ME/CFS itself is a diagnosis of exclusion made after a careful history, exam, and targeted investigations — escalate promptly rather than attributing the following to the underlying condition:
- Severe orthostatic intolerance causing recurrent falls or syncope, which needs prompt evaluation and may require cardiology referral rather than routine primary-care management.
- Signs pointing to a treatable alternative or comorbid diagnosis being missed — new focal neurologic findings, unexplained weight loss, lymphadenopathy, persistent fevers, or laboratory abnormalities inconsistent with ME/CFS.
- Severe, unremitting pain or a profound, progressive decline in function (new inability to manage self-care, or a transition toward being bedbound) requiring specialist reassessment rather than escalating the same symptomatic measures.
- Suicidal ideation — the chronic disease burden, functional loss, and the condition's long history of being dismissed or disbelieved place patients with ME/CFS at meaningful risk; screen directly and refer urgently for mental health assessment when present.
- Inability to maintain adequate oral intake or hydration in a severely or very severely affected patient — needs urgent medical assessment, not routine follow-up.
Assessment & Diagnosis
ME/CFS is a clinical diagnosis made from the history and examination, supported by targeted investigations used to exclude other chronic active illnesses that can cause similar fatigue — it is not confirmed by any single test. A confident diagnosis cannot be made before symptoms have been present for 6 months, but evaluation to rule out treatable causes should proceed during that interval rather than being deferred, and a well-controlled comorbid medical condition does not by itself preclude a diagnosis of ME/CFS if the patient otherwise meets the criteria.[1]
2015 National Academy of Medicine (Institute of Medicine) core diagnostic criteria
This is the most widely used diagnostic framework; the 2003 Canadian Consensus Criteria are a more detailed alternative sometimes preferred in research settings for their greater specificity against primary psychiatric conditions, but both frameworks share the same core requirement — PEM must be present.
| Criterion | Category | Description |
|---|---|---|
| Substantial activity reduction | Required | A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activity, persisting more than 6 months, accompanied by fatigue that is often profound, of new or definite onset (not lifelong), not the result of ongoing excessive exertion, and not substantially relieved by rest. |
| Post-exertional malaise | Required | Exacerbation of some or all baseline symptoms after physical or cognitive exertion that would not have been a problem before illness onset; may be delayed and can last hours to months. A history of PEM is sufficient — formal exercise testing is not required and can itself provoke a severe crash. |
| Unrefreshing sleep | Required | Insomnia, disturbed sleep, daytime sleepiness, or sleep that does not restore energy or alertness. |
| Cognitive impairment | Plus at least 1 of these 2 | Difficulty with short-term memory, concentration, word-finding, information processing speed, or performing simple multi-step tasks. |
| Orthostatic intolerance | Plus at least 1 of these 2 | Worsening of symptoms with quiet upright posture, improved by lying down, demonstrated objectively (heart rate/blood pressure change on standing) or reported by the patient. |
History and examination
- Characterize fatigue onset (gradual versus sudden, especially following an identifiable infection), duration, and its relationship to activity — specifically screen for PEM using open-ended questions and, where useful, a symptom or activity diary rather than a single yes/no question.
- Screen every core symptom domain directly: unrefreshing sleep, cognitive impairment, orthostatic symptoms, and pain.
- Full physical examination focused on excluding an alternative explanation — thyroid exam, lymph node exam, cardiopulmonary exam, and a joint/skin exam for signs of an inflammatory or connective tissue disorder.
Investigations
Laboratory testing in ME/CFS is expected to be normal — its purpose is to exclude other explanations for chronic fatigue, not to confirm the diagnosis. A reasonable baseline panel includes complete blood count with differential, erythrocyte sedimentation rate or C-reactive protein, thyroid-stimulating hormone, fasting glucose, electrolytes, creatinine, urea, calcium, phosphorus, total protein, albumin, liver enzymes, anti-tissue transglutaminase (celiac screen), and urinalysis.[2] Viral titers and neuroimaging are not required and not generally helpful in routine practice and should not be ordered reflexively — reserve more extensive or specialist-directed testing (e.g., autoimmune serologies, sleep study, tilt-table testing) for when specific history or exam findings point toward it.
Orthostatic intolerance assessment
A simple in-office passive standing test (supine vital signs, then repeated at 1, 3, 5, and 10 minutes of quiet standing) or the NASA 10-minute lean test can identify orthostatic intolerance without needing formal tilt-table testing in most patients; a sustained heart rate increase of 30 beats per minute or more (40 or more in adolescents) without a drop in blood pressure within 10 minutes of standing supports a diagnosis of POTS. Refer for formal tilt-table testing or cardiology assessment when the bedside test is inconclusive or symptoms are severe.[4]
Comorbidities and treatable mimics to screen for
These conditions are common in patients with ME/CFS, can meaningfully worsen the overall symptom burden, and are often independently treatable — actively screen for them rather than attributing every symptom to ME/CFS itself.
- Fibromyalgia — widespread pain with characteristic tender points; frequently coexists with ME/CFS.
- Mast cell activation syndrome — flushing, hives, gastrointestinal symptoms, and reactions to foods, medications, or temperature change; consider a trial of antihistamines/mast cell stabilizers when suggestive symptoms are present.
- Hypermobility spectrum disorders, including Ehlers-Danlos syndrome — screen with the Beighton hypermobility score; associated with a higher rate of orthostatic intolerance.
- Obstructive sleep apnea, restless legs syndrome, and circadian/sleep-phase disorders — refer for a sleep study when suggestive features (snoring, witnessed apneas, an urge to move the legs at rest, or persistent excessive daytime sleepiness out of proportion to reported nighttime sleep) are present.
- Irritable bowel syndrome — a common comorbid gastrointestinal diagnosis.
- Hypothyroidism and other treatable endocrine or hematologic causes of fatigue, excluded by the baseline panel above.
- Depression and anxiety — common and important to identify and treat in their own right as comorbidities, but are not the cause of ME/CFS and should not be treated as a substitute diagnosis.
Treatment Targets
- Relieve the patient's most disruptive symptoms first, prioritized according to the patient's own goals.
- Prevent and minimize post-exertional malaise by teaching pacing within a sustainable personal energy envelope.
- Improve sleep quality and restore some sense of restorative sleep.
- Reduce orthostatic intolerance symptoms and the associated fall/syncope risk.
- Control pain to a tolerable level using the lowest effective intervention.
- Support cognitive function within the limits of the disease, without provoking cognitive PEM.
- Validate the patient's experience, maintain a supportive therapeutic relationship, and support overall quality of life and psychosocial function.
- Avoid deconditioning from excessive inactivity while never pushing exertion past the level that triggers PEM — both extremes are harmful.
Choose Initial Treatment
No disease-modifying therapy exists
There is no pharmacotherapy proven to treat or cure ME/CFS. Treatment is entirely symptom-targeted and individualized — start with whichever symptom domain (PEM/fatigue, orthostatic intolerance, sleep, pain, or cognitive impairment) is most disruptive to the patient, using the lowest effective dose given the frequent drug sensitivity seen in this population.[2]
Pacing is foundational for every patient
1st line, all patients teach activity pacing within the personal energy envelope before or alongside any drug therapy — this is not an adjunct, it is the central management strategy for preventing PEM.[5]
Graded exercise therapy is not recommended
Do not prescribe graded exercise therapy — a structured, fixed, progressive increase in activity — as treatment for ME/CFS. Current CDC and NICE guidance removed this recommendation because it can provoke severe, sometimes prolonged PEM in patients with genuine exertion intolerance; this is a deliberate and significant reversal of older teaching, not a minor refinement.[2][6]
Orthostatic intolerance
1st line start with non-pharmacologic measures (fluid and salt intake, compression garments) for every patient with orthostatic symptoms; add fludrocortisone or a low-dose beta-blocker (propranolol or bisoprolol) when non-pharmacologic measures alone are insufficient, then midodrine, pyridostigmine, or ivabradine as further add-on or alternative options.[4]
Sleep disturbance
1st line address sleep hygiene and rule out a specific sleep disorder before adding medication; reserve a short-term, smallest-effective-dose trial of a sedating antihistamine or prescription hypnotic for when hygiene measures alone are insufficient.
Pain
1st line simple analgesics (acetaminophen or an NSAID); 2nd line — use when simple analgesics are inadequate a trial of low-dose naltrexone or a low-dose tricyclic antidepressant.
Cognitive impairment and fatigue
1st line pace cognitive activity the same way as physical activity; special situation — occasional use only, not routine daily dosing a stimulant (modafinil or methylphenidate) for a specific planned activity, since evidence does not support benefit with regular use.
Non-Pharmacologic Treatment
Pacing and the energy envelope
Pacing means distributing activity throughout the day in small, manageable amounts separated by rest, and staying within the amount of energy the patient's body can currently tolerate (the energy envelope) rather than doing as much as possible on a good day. Patients who are able to stay within their personal energy envelope show meaningful improvements in physical functioning and fatigue severity.[5] Explicitly counsel patients to avoid the push-crash cycle — overexerting on a good day, crashing, resting until they feel better, then overexerting again — since this cycle perpetuates rather than resolves PEM. Cognitive activity should be paced the same way as physical activity, since cognitive exertion can trigger PEM just as physical exertion can. Occupational therapy or physiotherapy input from a clinician familiar with ME/CFS-specific pacing (not standard reconditioning) can help patients build and adjust an individualized activity plan.[5]
Why graded exercise therapy is avoided
Older guidance recommended graded exercise therapy — a fixed, progressive increase in activity regardless of symptoms — on the assumption that deconditioning, rather than organic exertion intolerance, explained the fatigue. Current CDC and NICE guidance no longer recommends this approach: patients with genuine PEM do not tolerate standard progressive-exercise prescriptions the way patients with other chronic illnesses do, and pushing through symptoms in this way can cause a severe, sometimes prolonged relapse rather than gradual improvement.[2][6] This is a genuine, significant change from older teaching and needs to be communicated clearly, since some patients will have previously been told to push through their symptoms.
Orthostatic intolerance measures
- Increase fluid intake to roughly 2 to 3 litres per day, spread across the day.
- Increase dietary sodium intake (discuss an appropriate target with the patient's prescriber, particularly if there is coexisting hypertension or renal or cardiac disease).
- Waist-high compression garments or an abdominal binder to reduce venous pooling.
- Elevate the legs when sitting, avoid prolonged standing and rapid position changes, and avoid hot environments and alcohol, which worsen orthostatic symptoms.
- Small, more frequent meals may reduce post-meal (postprandial) worsening of orthostatic symptoms.
Sleep
Address sleep problems early — they can worsen fatigue, memory, headache, and pain. Encourage consistent sleep-wake timing, a dark, cool bedroom, and avoiding screens before bed. Refer for a sleep study when there are features suggesting sleep apnea, restless legs syndrome, a circadian/sleep-phase disorder, or persistent excessive daytime sleepiness that is out of proportion to reported nighttime sleep.
Nutrition
No specific diet or supplement regimen has been shown to broadly benefit ME/CFS. Encourage a balanced diet with adequate protein, vegetables, and fruit; patients with significant functional limitation may need practical help with shopping, meal preparation, or access to prepared foods. Correct any specific nutritional deficiency that has developed because fatigue has limited a patient's ability to shop for or prepare balanced meals, and consider a general multivitamin for patients whose diet is not balanced. Vitamin D deficiency is common, related to reduced sun exposure in patients who are housebound or bedbound — check levels and supplement appropriately.[2]
Cognitive behavioural therapy
CBT may be offered to patients who want support coping with the impact of a chronic illness, but must never be positioned as a treatment that reverses or cures ME/CFS — doing so reinforces the historically harmful framing of this as a primarily psychological condition.[2]
Validating the patient's experience
ME/CFS has a long history of being dismissed, minimized, or attributed purely to psychological causes by clinicians. Actively acknowledging the reality and severity of the illness, providing a clear and reasonable explanation of the diagnosis, and creating a supportive environment where the patient feels believed are core, evidence-informed parts of management, not just bedside manner. Suggest patient support groups or peer communities for self-management support and validation from others living with the condition.
General counselling points
- Avoid polypharmacy — patients with ME/CFS frequently see multiple providers and can accumulate overlapping medications; review the full medication list at every visit.
- Consider that a medication's adverse effect can mimic or worsen an ME/CFS symptom (e.g., sedation, orthostatic hypotension, cognitive slowing) — evaluate new or worsening symptoms for a drug cause before assuming disease progression.
Special Populations
Breastfeeding
Continue effective non-pharmacologic measures. Sedating antihistamines, low-dose beta-blockers, and pyridostigmine are generally considered compatible with breastfeeding; reassess any other medication for infant exposure and reevaluate the overall regimen postpartum, since symptom severity commonly changes after delivery.
Pediatric and adolescent patients
ME/CFS occurs in children and adolescents and the same core diagnostic criteria apply, but presentation and impact differ — school attendance and participation are often the most affected domains, and pacing needs to explicitly account for the physical and cognitive demands of a school day. Involve the school in accommodation planning (reduced course load, rest breaks, flexible attendance) as a core part of management, and favour a multidisciplinary pediatric team for diagnosis and ongoing care given the developmental stakes of a prolonged, severe illness during childhood or adolescence.
Renal, hepatic, and drug-sensitive patients
Patients with ME/CFS frequently report unusual sensitivity to medications generally, independent of renal or hepatic function — start every new medication, for ME/CFS or any other indication, at a low dose and titrate slowly.[2] Adjust renally cleared agents (pyridostigmine, midodrine) for reduced kidney function, and use caution with hepatically metabolized agents (fludrocortisone, tricyclic antidepressants) in significant hepatic impairment.
Monitoring & Follow-Up
- Reassess the patient's own priority symptom(s) at each visit and track functional status over time, not just symptom presence or absence — a structured symptom or activity diary is useful for both PEM frequency/severity and overall trend.
- Ask specifically about medication tolerability at every visit given the frequent drug sensitivity in this population, and stop any medication not providing clear benefit.
- For patients on fludrocortisone or midodrine: monitor blood pressure (including for supine hypertension) and serum potassium periodically.
- For patients on a beta-blocker or ivabradine: monitor heart rate and blood pressure.
- Recheck vitamin D level after supplementation is started and periodically thereafter in housebound or bedbound patients.
- Screen for mood symptoms and suicidal ideation at intervals given the significant chronic disease burden, not only at diagnosis.
- Reassess comorbidities (fibromyalgia, mast cell activation syndrome, sleep apnea, hypermobility spectrum disorder, IBS) periodically, since these can independently change and affect overall symptom control.
- Review the complete medication list periodically to identify and address polypharmacy.
Common Errors to Avoid
- Prescribing graded exercise therapy or advising a patient to push through fatigue — current evidence indicates this can provoke a severe, sometimes prolonged PEM crash rather than gradual improvement.
- Dismissing symptoms as purely psychological or attributing them only to deconditioning, which delays legitimate workup and damages the therapeutic relationship.
- Ordering extensive or exotic testing (broad autoimmune panels, viral titers, routine neuroimaging) without a specific clinical indication, instead of the focused baseline panel used to exclude common treatable causes.
- Diagnosing ME/CFS before adequately excluding treatable causes of chronic fatigue, or, conversely, delaying diagnosis and management for the full 6 months when the criteria are already clearly met.
- Starting any new medication at a standard adult starting dose without first adjusting downward, given how frequently patients with ME/CFS report drug sensitivity.
- Missing a treatable comorbidity — sleep apnea, hypothyroidism, mast cell activation syndrome, or a hypermobility spectrum disorder — that could meaningfully improve symptoms if addressed on its own.
- Positioning cognitive behavioural therapy as a cure rather than a coping-support adjunct.
- Overlooking suicidal ideation screening in a population with a significant chronic disease burden and a history of having their symptoms dismissed.
- Treating rituximab or other unproven immunomodulatory therapy as an established ME/CFS treatment — a large randomized trial found no benefit and an increased risk of adverse effects, despite earlier small studies suggesting promise.
Clinical Decision Algorithm
Drug Tables
How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Patients with ME/CFS frequently report unusual drug sensitivity, so start low and titrate slowly. Select any drug name to open its complete Pharmasist Drug Database page.
Orthostatic intolerance / POTS agents
Start with non-pharmacologic measures for every patient (see Non-Pharmacologic Treatment). The Syncope chapter in this library covers the broader orthostatic-intolerance work-up in more depth and is a useful companion reference.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Fludrocortisone | Adults: 0.1 mg PO once daily, may increase to 0.2 mg once daily Pediatric/adolescent: Weight-based, specialist-directed dosing for adolescent POTS — not detailed here; involve pediatric cardiology | Hypokalemia, fluid retention/edema, hypertension, headache | Additive hypokalemia with other potassium-wasting diuretics; NSAIDs can blunt its effect and worsen fluid retention | Mineralocorticoid used off-label for orthostatic intolerance/POTS to expand plasma volume; monitor blood pressure and potassium. |
| Propranolol (low-dose, orthostatic intolerance) | Adults: 10 to 20 mg PO once daily, up to a maximum of 40 mg per day Pediatric/adolescent: Specialist-directed dosing only — not established for routine use | Bradycardia, fatigue, hypotension, bronchospasm, masking of hypoglycemia symptoms | Additive bradycardia with other rate-slowing agents (bisoprolol, ivabradine, pyridostigmine); avoid combining with a non-dihydropyridine calcium channel blocker | Low, POTS-specific dosing, well under standard antihypertensive or antianginal doses; avoid in reactive airway disease. |
| Bisoprolol (low-dose, orthostatic intolerance) | Adults: 2.5 to 5 mg PO once daily, up to a maximum of 5 mg per day Pediatric/adolescent: Specialist-directed dosing only — not established for routine use | Bradycardia, fatigue, hypotension | Additive bradycardia with other rate-slowing agents | Once-daily alternative beta-blocker when propranolol is not tolerated or preferred. |
| Midodrine | Adults: 2.5 to 10 mg PO three times daily while upright; up to 15 mg per dose in refractory cases under specialist direction Pediatric/adolescent: Specialist-directed dosing only — not established for routine use | Supine hypertension, scalp tingling/piloerection, urinary retention, goosebumps | Additive hypertension with other vasopressor/vasoconstrictor agents | Give only while the patient will remain upright; avoid dosing within 4 hours of lying down, including at bedtime, given supine hypertension risk. |
| Pyridostigmine | Adults: 30 to 60 mg PO up to 3 times daily Pediatric/adolescent: Specialist-directed dosing only — not established for routine use | Gastrointestinal cramping, diarrhea, increased salivation/sweating, muscle fasciculation | Additive bradycardia with beta-blockers; avoid with other cholinergic agents | Growing randomized-trial evidence supports a benefit on exercise capacity and post-exertional malaise specifically, beyond its traditional use for orthostatic intolerance. |
| Ivabradine | Adults: 2.5 to 7.5 mg PO twice daily Pediatric/adolescent: Not established for routine use — specialist-directed only | Bradycardia, visual phosphenes (luminous phenomena), atrial fibrillation | Avoid strong CYP3A4 inhibitors (e.g., certain azole antifungals, macrolides); additive bradycardia with beta-blockers | Off-label, specialist-directed option for a significant sinus tachycardia component when standard agents are inadequate or not tolerated. |
Evidence note: beta-blocker/pyridostigmine dosing and comparative efficacy is drawn from a randomized clinical trial in postural tachycardia syndrome[7], pyridostigmine's specific benefit for post-exertional malaise/exercise intolerance is drawn from a randomized, placebo-controlled trial in ME/CFS[8], and the overall approach is cross-checked against Canadian POTS management guidance[4].
Sleep agents
Reserve medication for after sleep hygiene measures alone have been tried (see Non-Pharmacologic Treatment).
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Diphenhydramine | Adults: 25 to 50 mg PO at bedtime, short-term use only Pediatric/adolescent: Not recommended as a routine sleep aid in children — address sleep hygiene and refer for a sleep study instead | Next-day sedation, anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention), paradoxical stimulation | Additive sedation with other CNS depressants; additive anticholinergic burden with tricyclic antidepressants | Short-term use only, after sleep hygiene measures alone are inadequate — not a long-term solution. |
| Doxylamine | Adults: 25 mg PO at bedtime, short-term use only Pediatric/adolescent: Not recommended as a routine sleep aid in children | Next-day sedation, anticholinergic effects | Additive sedation with other CNS depressants | Alternative sedating antihistamine for short-term use. |
| Zopiclone | Adults: 3.75 to 7.5 mg PO at bedtime, smallest effective dose, short-term Pediatric/adolescent: Not established for pediatric use | Bitter/metallic taste, next-day sedation, dependence with regular use | Additive sedation with other CNS depressants, including alcohol | Reserve for the smallest effective dose, short-term, when sleep hygiene and other measures are inadequate; review regularly given dependence potential with ongoing use. |
Pain agents
Start with simple analgesics; escalate only if inadequate.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Acetaminophen | Adults: 325 to 1000 mg PO every 4 to 6 hours as needed, maximum 4000 mg per day (lower with hepatic impairment or regular alcohol use) Pediatric: Weight-based dosing per standard pediatric acetaminophen guidance | Hepatotoxicity at supratherapeutic doses | Increased hepatotoxicity risk with regular alcohol use | Confirm the total daily dose across all combination products a patient may be using. |
| Ibuprofen | Adults: 200 to 400 mg PO every 4 to 6 hours as needed with food, maximum 1200 mg per day without medical direction Pediatric: Weight-based dosing per standard pediatric ibuprofen guidance | GI upset/ulceration, renal impairment, fluid retention, hypertension | Additive GI/renal risk with other NSAIDs or corticosteroids; can blunt the effect of fludrocortisone and antihypertensives | Use the lowest effective dose for the shortest effective duration; caution combining with orthostatic-intolerance agents that also affect fluid balance. |
| Naproxen | Adults: 250 to 500 mg PO twice daily with food Pediatric: Weight-based dosing per standard pediatric naproxen guidance | GI upset/ulceration, renal impairment, fluid retention | Additive GI/renal risk with other NSAIDs or corticosteroids | Longer-acting NSAID alternative to ibuprofen. |
| Naltrexone (low-dose) | Adults: Compounded oral solution starting 0.5 mg once daily at bedtime, titrated slowly to a target of 4.5 mg once daily at bedtime Pediatric/adolescent: Not established for routine use — specialist-directed only | Vivid dreams/sleep disturbance (usually early and transient), nausea, headache | Must not be combined with an opioid — precipitates withdrawal and blocks analgesia; caution with other hepatically metabolized drugs | Requires a compounding pharmacy for these low, non-commercial doses; titrate slowly. |
| Nortriptyline (low-dose) | Adults: 10 to 25 mg PO once daily at bedtime, titrated slowly as tolerated Pediatric/adolescent: Not established for routine use — specialist-directed only | Sedation, orthostatic hypotension, anticholinergic effects (dry mouth, constipation, urinary retention) | Avoid with an MAOI; additive sedation/anticholinergic burden with other CNS depressants or antihistamines; additive QT effects with other QT-prolonging drugs | Doses used for ME/CFS are markedly lower than standard antidepressant doses; patients with ME/CFS are especially prone to sedation and orthostatic hypotension from this class. |
| Amitriptyline (low-dose) | Adults: 10 to 25 mg PO once daily at bedtime, titrated slowly as tolerated Pediatric/adolescent: Not established for routine use — specialist-directed only | Sedation, orthostatic hypotension, anticholinergic effects | Avoid with an MAOI; additive sedation/anticholinergic burden with other CNS depressants | Alternative tricyclic; more sedating and more anticholinergic than nortriptyline — useful when sedation is also desired for sleep. |
Evidence note: low-dose naltrexone evidence in this table draws in part on interventional data from a long-COVID cohort[9], given the overlapping patient population and limited ME/CFS-specific trial data.
Cognitive impairment and fatigue agents — occasional use only
Evidence does not support benefit with regular, routine use of a stimulant; reserve for occasional use ahead of a specific planned activity.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Modafinil | Adults: 100 to 200 mg PO in the morning, occasional use only Pediatric/adolescent: Not established for this indication in children | Insomnia, headache, anxiety, nausea | Reduces efficacy of hormonal contraceptives; multiple CYP450 interactions | Trial evidence does not support a significant benefit on fatigue or quality of life with regular use — reserve for occasional, purposeful use ahead of a specific planned activity, not routine daily dosing. |
| Methylphenidate | Adults: 5 to 10 mg PO in the morning, and at midday if needed, occasional use only Pediatric/adolescent: Not established for this indication in children | Insomnia, decreased appetite, increased heart rate/blood pressure, anxiety | Additive cardiovascular stimulation with other stimulants or decongestants; avoid with an MAOI | Only a minority of patients respond meaningfully; avoid routine daily use given limited evidence and stimulant adverse-effect burden. |
Adjunct for acute PEM or sensory overload
Off-label, short-term use only.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Lorazepam (short-term, off-label) | Adults: 0.5 to 1 mg PO as needed, short-term/occasional use only Pediatric/adolescent: Not established for this indication in children | Sedation, drowsiness, confusion, respiratory depression (particularly combined with other CNS depressants) | Additive CNS/respiratory depression with opioids, alcohol, or other sedatives | Short-term use only for acute PEM-related distress or sensory overload; regular use carries dependence and withdrawal risk — this is not a maintenance therapy. |
Nutritional supplementation
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Vitamin D3 (cholecalciferol) | Adults: Per current age- and sex-appropriate supplementation guidance, adjusted to measured level Pediatric: Per current age-appropriate supplementation guidance | Hypercalcemia with excessive dosing | None significant at standard supplementation doses | Deficiency is common given reduced sun exposure in housebound or bedbound patients — check a level and supplement to correct rather than assuming a fixed dose. |
Not recommended — insufficient evidence: early small studies suggested possible benefit from rituximab, a B-cell-depleting monoclonal antibody, in ME/CFS. A subsequent large randomized, double-blind, placebo-controlled trial found no benefit and an increased risk of adverse effects. Do not offer rituximab for ME/CFS outside a formal research setting.[2]
References
- Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness — Committee on the Diagnostic Criteria for ME/CFS, Board on the Health of Select Populations, Institute of Medicine, National Academies Press. Washington, DC: National Academies Press; 2015
- Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Clinical Care and Diagnosis for Healthcare Providers — Centers for Disease Control and Prevention. CDC ME/CFS Healthcare Provider Toolkit, accessed 2026
- A Long COVID Definition: A Chronic, Systemic Disease State with Profound Consequences — National Academies of Sciences, Engineering, and Medicine, National Academies Press. Washington, DC: National Academies Press; 2024
- Diagnosis and management of postural orthostatic tachycardia syndrome — Canadian Medical Association Journal (Raj SR, Fedorowski A, Sheldon RS). CMAJ 2022;194(10):E378-E385
- Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document — Disability and Rehabilitation (Goudsmit EM, Nijs J, Jason LA, Wallman KE). Disabil Rehabil 2012;34(13):1140-1147
- Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management (NICE guideline NG206) — National Institute for Health and Care Excellence. NICE guideline NG206, published October 29, 2021, surveillance-reviewed January 2025
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