ME/CFS and Long COVID: Treatment Algorithm
A practical, evidence-graded path for adults with ME/CFS or long COVID: confirm and exclude, protect the energy envelope, then treat the dominant symptom clusters. Options run from guideline-backed to anecdotal but worth a careful trial in selected patients. No treatment is TGA-approved for either condition.
At a glance
- First, do no harm: screen every patient for post-exertional malaise (PEM). If present, avoid fixed graded exercise; pace instead.
- Exclude the treatables: anaemia, iron deficiency, thyroid, coeliac, sleep apnoea, depression, medicines, POTS. One afternoon of bloods and a 10-minute stand test.
- Treat by cluster: orthostatic intolerance, sleep, pain, cognition, breathing, smell, mast-cell-type symptoms, gut.
- One change at a time, start low, review at 4–8 weeks with the same outcome measures, and stop what doesn’t help.
- Severe and very severe ME/CFS (housebound or bedbound) need home visits, sensory reduction and careful nutrition, not clinic-style plans.
Most of what helps is unglamorous: pacing, salt and fluids, sleep, and stopping the things that make it worse.
Evidence grades used here. A strong: guidelines plus consistent randomised trials. B moderate: at least one decent RCT or strong evidence in a closely related condition. C weak or mixed: small or conflicting trials. D anecdotal or mechanistic: case series or expert experience; a reasonable trial in selected patients with clear stop rules. X avoid: harmful or shown not to work.
Step 0 · Confirm and exclude
- ME/CFS (NICE 2021; IOM 2015): substantially reduced activity with debilitating fatigue for at least 3 months (NICE suspects it at 6 weeks and diagnoses at 3 months; IOM uses 6 months), PEM, unrefreshing sleep, plus cognitive problems and/or orthostatic intolerance.
- Long COVID (WHO): symptoms 3 months after probable or confirmed COVID-19, lasting at least 2 months, not explained by another diagnosis. Many meet ME/CFS criteria; many don’t.
- Screen for PEM: “What happens the day after you do more than usual?” Delayed worsening (12–72 hours) lasting days is the key feature. The DePaul Symptom Questionnaire PEM items help.
- Baseline tests: FBC, iron studies (ferritin), B12, folate, UEC, LFT, calcium, glucose or HbA1c, TSH, CRP or ESR, CK, coeliac serology, vitamin D, urinalysis. Consider morning cortisol, HIV, hepatitis and syphilis by risk, pregnancy test, and ECG.
- Bedside: 10-minute active stand test (lying then standing heart rate and BP), STOP-BANG for sleep apnoea, PHQ-9 and GAD-7, medication review (sedatives, beta blockers, antihistamines, opioids).
- Red flags needing other workup: weight loss, fevers or night sweats, focal neurology, chest pain, haemoptysis, persistent lymphadenopathy, desaturation on exertion, abnormal bloods.
- Long COVID specifics: exertional breathlessness or desaturation needs a chest X-ray and lung function; chest pain or palpitations need ECG ± troponin and echo; consider pulmonary embolism, myocarditis, new diabetes and thyroiditis.
Step 1 · Core management for everyone
These apply whatever the cluster. They carry the most consensus and the least risk.
- B · ModerateEducation, validation and a diagnosisName it, explain PEM and the energy envelope, and set realistic goals. Being believed is itself therapeutic.
- Evidence
- Guideline consensus (NICE 2021, CDC, WHO); strong patient-reported benefit
- How
- Plain-language handout (/me/, /long-covid/); a named GP; a written plan
- Watch for
- Language that implies laziness or “just anxiety”.
- B · ModeratePacing within the energy envelopePlan, prioritise and break up activity; rest before crashing; stay within what’s sustainable on a bad day.
- Evidence
- Recommended by NICE 2021 and most patient bodies; trial evidence is limited, but harm from boom-bust cycles is well described
- How
- Activity diary, heart rate monitor (some aim to stay under about 55–60% of age-predicted maximum), step counts, scheduled rests
- Watch for
- Pacing that becomes avoidance of all activity in people without PEM.
- B · ModerateSymptom-titrated activity (only if no PEM)Long COVID without PEM: gentle, gradual rehab, adjusted to symptoms rather than fixed increments.
- Evidence
- Rehabilitation trials in long COVID show benefit in people without PEM
- How
- Physio or exercise physiologist; recumbent options first if orthostatic
- Watch for
- Any delayed crash: drop back and reassess for PEM.
- X · AvoidGraded exercise therapy with fixed increments (in ME/CFS)Pushing through symptoms on a fixed schedule.
- Evidence
- NICE 2021 advises against it; surveys report harm in many patients with PEM
- How
- Don’t
- Watch for
- If used historically, ask about relapse.
- B · ModerateCBT as support, not cureFor coping, distress, sleep and mood. Not to “change illness beliefs” or as a cure.
- Evidence
- Helps distress and coping (NICE 2021 supports this framing)
- How
- Psychologist via a GP Mental Health Treatment Plan
- Watch for
- Programs that promise recovery through thinking differently.
- A · StrongTreat what’s treatableIron if ferritin is low, B12 or vitamin D if deficient, thyroid, CPAP for sleep apnoea, depression, anaemia.
- Evidence
- Strong evidence for each underlying condition
- How
- Usual treatment; recheck in 3 months
- Watch for
- Over-replacement (iron overload, high-dose vitamin D).
- B · ModeratePractical supportsWorkplace or study adjustments, carers, mobility aids, disability and income support.
- Evidence
- Consensus; large real-world impact
- How
- Letters for work or uni, Centrelink, NDIS for severe long-term disability, aids such as shower chairs and wheelchairs for longer trips
- Watch for
- Under-recognising how disabling severe ME/CFS is.
Step 2a · Orthostatic intolerance and POTS
Common in both. Check a 10-minute stand test. See the POTS deep dive for detail.
- B · ModerateFluids, salt and compression2–3 L of fluid a day, extra salt where safe, waist-high or abdominal compression.
- Evidence
- Physiological rationale and small trials; guideline-recommended for POTS
- How
- Salt tablets or electrolyte drinks; bolus 500 mL water before getting up
- Watch for
- Hypertension, kidney or heart disease.
- C · Weak / mixedLow-dose propranololBlunts the standing heart rate.
- Evidence
- Small RCT: low dose (10 mg) improved symptoms more than higher dose (Raj 2009)
- How
- 10 mg once or twice daily
- Watch for
- Asthma, low BP, fatigue, low mood.
- C · Weak / mixedIvabradineSlows the sinus node without lowering BP.
- Evidence
- Small trials lowered heart rate; a larger RCT lowered heart rate but didn’t improve symptoms
- How
- 2.5–5 mg twice daily (off label)
- Watch for
- Visual phosphenes, bradycardia; contraception needed.
- C · Weak / mixedFludrocortisone or midodrineExpand volume or tighten vessels for low-BP-type symptoms.
- Evidence
- Small studies, mostly in orthostatic hypotension or POTS
- How
- Fludrocortisone 50–100 µg; midodrine 2.5–10 mg three times daily, not within 4 hours of bed
- Watch for
- Low potassium, oedema, supine hypertension.
- D · Anecdotal or mechanisticPyridostigmineBoosts autonomic signalling.
- Evidence
- Case series and small studies
- How
- 30 mg twice to three times daily, titrate
- Watch for
- Cramps, diarrhoea, increased secretions.
Step 2b · Sleep
Unrefreshing sleep is near-universal. Treat sleep disorders first.
- A · StrongExclude and treat sleep apnoea and restless legsSTOP-BANG, sleep study if indicated; ferritin for restless legs.
- Evidence
- Strong evidence for CPAP and iron in RLS
- How
- Home sleep study; iron if ferritin under about 75
- Watch for
- Sedatives worsening untreated apnoea.
- B · ModerateRegular sleep window and adapted CBT-IFixed wake time, wind-down routine, limit long daytime naps but allow planned rest.
- Evidence
- CBT-I is first line for insomnia; strict sleep restriction may need adapting in ME/CFS
- How
- Psychologist or online CBT-I programs
- Watch for
- Over-strict sleep restriction triggering crashes.
- C · Weak / mixedMelatoninFor delayed sleep onset.
- Evidence
- Helps sleep onset in general populations; small studies in ME/CFS
- How
- 1–2 mg 1–2 hours before bed
- Watch for
- Morning grogginess.
- C · Weak / mixedLow-dose amitriptylineWhen sleep and pain coexist.
- Evidence
- Good evidence in fibromyalgia for sleep and pain; small effects
- How
- 5–10 mg at night, up to 25–30 mg
- Watch for
- Morning hangover, dry mouth, constipation, orthostatic worsening.
Step 2c · Pain
Myalgia, headache and neuropathic-type pain overlap with fibromyalgia. Borrow fibromyalgia evidence.
- B · ModerateDuloxetine or amitriptylineCentral pain modulation.
- Evidence
- Moderate evidence in fibromyalgia (Cochrane); benefit for a minority
- How
- Duloxetine 30 mg, then 60 mg; amitriptyline as above
- Watch for
- Nausea, sweating, orthostatic effects.
- C · Weak / mixedPregabalinFor neuropathic-type pain.
- Evidence
- Modest benefit in fibromyalgia; frequent side effects
- How
- Start 25–75 mg at night
- Watch for
- Dizziness, sedation, weight gain, cognitive dulling; misuse.
- C · Weak / mixedLow-dose naltrexone (LDN)Thought to modulate microglia and pain signalling.
- Evidence
- Small RCTs in fibromyalgia (mixed, mostly small benefit); open-label long COVID studies positive; larger RCTs under way
- How
- Compounded 1.5 mg at night, rising to 3–4.5 mg over weeks
- Watch for
- Vivid dreams, insomnia; not with opioids.
- X · AvoidOpioids for chronic symptomsLong-term opioids for widespread pain.
- Evidence
- No benefit for central pain; risks of dependence and worse pain
- How
- Avoid
- Watch for
Step 2d · Cognition (“brain fog”)
Pace cognitive load like physical load.
- B · ModerateCognitive pacing and aidsShort tasks, breaks, lists, alarms, reduced multitasking.
- Evidence
- Consensus and occupational therapy experience
- How
- OT; written plans; quiet workspace
- Watch for
- D · Anecdotal or mechanisticGuanfacine plus N-acetylcysteinePrefrontal noradrenergic support plus antioxidant.
- Evidence
- Case series in long COVID brain fog (Yale, 2023)
- How
- Guanfacine 1 mg at night, rising to 2 mg; NAC 600 mg daily
- Watch for
- Low BP, sedation.
- D · Anecdotal or mechanisticStimulants or modafinilFor marked fatigue or cognitive slowing.
- Evidence
- Small, mixed trials in ME/CFS; may cause crashes by masking limits
- How
- Low dose, cautious trial with clear goals
- Watch for
- Overdoing it then crashing; insomnia; misuse.
- D · Anecdotal or mechanisticLow-dose aripiprazoleProposed to modulate neuroinflammation.
- Evidence
- Retrospective series only (Crosby 2021)
- How
- 0.25–2 mg daily
- Watch for
- Akathisia, insomnia.
Step 2e · Mast-cell-type symptoms
Flushing, itch, hives, food reactions, gut upset, palpitations. Don’t label MCAS without evidence; treat symptoms.
- D · Anecdotal or mechanisticH1 plus H2 antihistaminese.g. fexofenadine or cetirizine plus famotidine.
- Evidence
- Observational long COVID reports of improvement (Glynne 2022); no RCTs
- How
- Fexofenadine 180 mg daily (up to twice daily) plus famotidine 20 mg twice daily; trial 4–6 weeks
- Watch for
- Sedation (cetirizine), headache.
- D · Anecdotal or mechanisticKetotifen or sodium cromoglycateMast-cell stabilisers.
- Evidence
- Small studies in mastocytosis; anecdotal in long COVID
- How
- Specialist or compounded
- Watch for
- Weight gain, sedation (ketotifen).
- D · Anecdotal or mechanisticQuercetinFlavonoid with mast-cell-stabilising effects in the lab.
- Evidence
- Mechanistic and small studies only
- How
- 500 mg daily or twice daily
- Watch for
- Interactions; liver.
Step 2f · Breathing and smell (long COVID)
- B · ModerateBreathing retrainingFor dysfunctional breathing: nasal, slow, diaphragmatic.
- Evidence
- Physiotherapy evidence in dysfunctional breathing; long COVID pilot trials
- How
- Respiratory physio
- Watch for
- Exclude PE, lung and heart causes first.
- B · ModerateOlfactory trainingSniff 4 strong scents twice a day for 3–6 months.
- Evidence
- Supported by meta-analyses in post-viral smell loss
- How
- Rose, lemon, clove, eucalyptus
- Watch for
- Parosmia can be distressing; persist.
- C · Weak / mixedSteroid nasal spray or rinseFor smell loss with nasal inflammation.
- Evidence
- Mixed evidence
- How
- Mometasone daily; budesonide rinse via specialist
- Watch for
Step 2g · Gut
Many have IBS-type symptoms, reflux or nausea.
- B · ModerateTreat as for IBS or functional dyspepsiaSoluble fibre, low-FODMAP with a dietitian, antispasmodics, gut-brain modulators.
- Evidence
- Strong evidence in IBS; extrapolated
- How
- See /ibs/
- Watch for
- Weight loss or restrictive eating in severe illness.
Step 3 · Specialist, experimental or emerging
For selected patients, ideally in trials or with specialist input.
- C · Weak / mixedHyperbaric oxygen (long COVID)High-pressure oxygen sessions.
- Evidence
- One sham-controlled RCT (Israel, 2022) improved cognition and energy; needs replication
- How
- 40 sessions in specialist centres; costly
- Watch for
- Ear barotrauma; cost; access.
- C · Weak / mixedCoenzyme Q10 with NADHMitochondrial support.
- Evidence
- One small RCT in ME/CFS showed modest fatigue benefit; a long COVID CoQ10 RCT was negative
- How
- CoQ10 200 mg + NADH 20 mg daily
- Watch for
- Cost; interactions with warfarin.
- D · Anecdotal or mechanisticStellate ganglion blockProposed to reset autonomic signalling.
- Evidence
- Case series; controlled data lacking
- How
- Interventional pain specialist
- Watch for
- Procedural risks, cost.
- D · Anecdotal or mechanisticImmunoadsorption, IVIG, other immunotherapiesFor suspected autoimmunity.
- Evidence
- Small or negative trials; experimental
- How
- Trials only
- Watch for
- Cost, risk.
- B · ModerateMetformin during acute COVID (prevention)Taken for 2 weeks during acute infection.
- Evidence
- COVID-OUT RCT: about 41% fewer long COVID diagnoses in overweight or obese adults
- How
- 500 mg, titrated to 1,500 mg daily for 14 days (off label)
- Watch for
- Gut upset; not for long COVID once established.
- X · AvoidRituximabB-cell depletion.
- Evidence
- Large RCT (RituxME, 2019) showed no benefit in ME/CFS
- How
- Avoid
- Watch for
- X · AvoidExtended Paxlovid for established long COVID15–25-day courses.
- Evidence
- RCTs (STOP-PASC, others) showed no benefit
- How
- Avoid outside trials
- Watch for
- X · AvoidUnproven clinicsStem cells, IV vitamin infusions, chelation, ozone, “detox”.
- Evidence
- No evidence; cost and harm
- How
- Avoid
- Watch for
Severe and very severe ME/CFS
- Home visits or telehealth; reduce light, noise and touch; short, planned contacts.
- Watch nutrition and hydration, pressure care, bone health and orthostatic tolerance.
- Admissions need a plan: quiet single room, minimal handling, a support person.
- Coordinate care and disability support (NDIS, carers, equipment).
Measuring progress
- Pick 2–3 measures and repeat them at each review: Bell CFS disability scale, daily steps or upright time, DePaul PEM frequency, a single 0–10 fatigue score, sleep quality.
- Change one thing at a time; trial 4–8 weeks; stop what doesn’t help.
- Expect fluctuation. Many people improve slowly; some recover, especially in long COVID.
For patients: plain-English pages on ME/CFS, long COVID and POTS.
Common questions
Is graded exercise therapy recommended for ME/CFS?
No. NICE (2021) advises against graded exercise therapy with fixed increments for ME/CFS. People without post-exertional malaise, including many with long COVID, may benefit from symptom-titrated rehabilitation.
What is the first step in managing ME/CFS or long COVID?
Confirm the diagnosis, exclude treatable causes, screen for post-exertional malaise and teach pacing within the energy envelope. Then treat the dominant symptom clusters such as orthostatic intolerance, sleep and pain.
Is there a cure for long COVID?
Not yet. Many people improve over time. Treatments target symptoms; several promising ideas are still in trials, and some (like extended Paxlovid and rituximab in ME/CFS) have not worked in RCTs.
Evidence and references
- NICE NG206: ME/CFS diagnosis and management (2021)
- WHO clinical case definition of post COVID-19 condition (2021)
- Institute of Medicine: Beyond ME/CFS, redefining an illness (2015)
- Emerge Australia: resources for health professionals
- Raj SR et al. Propranolol decreases tachycardia and improves symptoms in POTS (Circulation 2009)
- Bramante CT et al. Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition (COVID-OUT, Lancet Infect Dis 2023)
- Geng LN et al. Nirmatrelvir-ritonavir and symptoms in adults with post-COVID-19 condition (STOP-PASC, JAMA Intern Med 2024)
- Fluge Ø et al. B-lymphocyte depletion in ME/CFS (RituxME, Ann Intern Med 2019)
- Zilberman-Itskovich S et al. Hyperbaric oxygen therapy improves neurocognitive functions in post-COVID condition (Sci Rep 2022)
- Castro-Marrero J et al. CoQ10 plus NADH supplementation in ME/CFS (2016)
- Glynne P et al. Long COVID following mild SARS-CoV-2 infection: antihistamine response (2022)
- Fesharaki-Zadeh A et al. Guanfacine and N-acetylcysteine for post-COVID cognitive deficits (2023)
- Cochrane: Low-dose naltrexone and other evidence summaries (search)
maladywise.com/algorithms/me-cfs-long-covid/