Emerging treatments

Aripiprazole

Aripiprazole is a dopamine D2 partial agonist with weak 5-HT1A partial agonism and 5-HT2A receptor antagonism. Dopamine-modulating drugs such as aripiprazole have been postulated to lead to clinical improvement in fatigue and cognitive symptoms in ME/CFS. A retrospective study that reviewed the medical records of 101 people with ME/CFS reported effects with use of low-dose aripiprazole.[230] The majority (74%) had improvements in one or more symptoms including fatigue, brain fog, unrefreshing sleep, and post-exertional malaise. There was no change for 12%, and 14% had worsening of symptoms. Randomised double-blind placebo-controlled studies have not yet been performed.

Oxaloacetate

Oxaloacetate is a metabolic intermediate in many processes that occur in animals including the Krebs cycle and gluconeogenesis. An open-label non-randomised dose-escalating 'proof of concept' trial with anhydrous enol-oxaloacetate capsules enrolled 76 people with ME/CFS. Improvements on Chalder Fatigue Scale were compared with a historical ME/CFS group: 22.5% of the 76 patients reported an improvement in physical and mental fatigue after 6 weeks compared with 5.9% in the historical control group.[231] However, for methodological reasons, the study design limits the ability to interpret the trial.  

Cyclophosphamide

Cyclophosphamide has been investigated in an open-label phase 2 trial of 40 patients with ME/CFS. Although the results were promising, caution is required in interpreting the data due to the lack of control group, and further evidence from randomised controlled trials (RCTs) is required to elucidate the safety and efficacy profile of this treatment.[232]

KPAX002

An investigational combination of methylphenidate and mitochondrial support nutrients, KPAX002 improved Checklist Individual Strength by 34% at 12 weeks (P <0.0001).[233] Over 50% reported some improvement of fatigue and concentration.

Rintatolimod

Rintatolimod (polyI:polyC12U), an investigational immunomodulatory poly I:C double-stranded RNA drug that has toll-like receptor 3 agonist properties, has low-quality evidence for improvement of exercise in patients with ME/CFS.[234][235][236][237]​ However, one post-hoc subset analysis suggests that patients who have had ME/CFS for 2-8 years may have a significantly better response than those with longer-duration disease.[238] Time on the treadmill was increased 27.8% with rintatolimod compared with 4.2% with placebo, while those with <2 year or >8 year duration had no response to drug (9.8%) or placebo (5.1%).[238] These results indicate the need for early diagnosis and initiation of immunomodulatory therapy. All patients had post-exertional malaise lasting >24 hours, which reinforces the need for careful inclusion criteria to select ME/CFS patients for clinical trials, and to exclude chronic idiopathic fatigue and other conditions in the differential diagnosis.

Naltrexone

There is anecdotal support for the use of low-dose naltrexone (an opioid antagonist) for the management of chronic pain and hyperalgesia associated with ME/CFS, although RCT evidence specific to ME/CFS is lacking. For ME/CFS, low-dose naltrexone is sometimes prescribed off-label by specialists. Low-dose naltrexone appears to be effective for chronic pain associated with certain inflammatory conditions, including inflammatory bowel disease and multiple sclerosis.[239] It is also sometimes prescribed off-label for fibromyalgia, and there is some preliminary evidence that this approach is effective and well tolerated, although larger-scale evidence is lacking.[240][241] RCT evidence is needed to elucidate the safety and efficacy of low-dose naltrexone for ME/CFS; further research may also determine whether low-dose naltrexone helps with other features of ME/CFS such as cognition and fatigue.

Other drug therapies

Antivirals (alone or with intravenous immunoglobulin), intravenous immunoglobulin alone, clonidine, citalopram (in patients without depression), hydrocortisone, fludrocortisone, methylphenidate, melatonin, galantamine, nicotinamide adenine dinucleotide alone and combined with coenzyme Q10, staphylococcal toxoid, the interleukin-1 receptor inhibitor anakinra, guanidinoacetic acid, subcutaneous human placental extract, valganciclovir, valaciclovir, inosine pranobex, and various complementary medicines have been studied in ME/CFS, but results have been equivocal, or they have shown limited or no effect.[12][40][53][54][242][243][244][245][246][247][248][249][250][251][252][253][254][255][256][257][258][259][260][261][262][263] These studies may provide misleading results due to small sample sizes and poor study designs; therefore, results should be in interpreted with caution.

Low-intensity behavioural treatments

Low-intensity alternative delivery methods for evidence-based care (e.g., telephone, internet, brief primary care visits, and guided self-instruction of cognitive behavioural therapy [CBT] programmes) suggest comparable improvements in physical functioning, fatigue, and patient satisfaction to usual care.[264][265] In a study in adults, home-delivered (in-person nurse visit or telephone coaching) 'pragmatic rehabilitation' intervention for 20 weeks improved self-reported fatigue compared with either supportive listening or treatment as usual.[266] However, no between-group differences were found at 70-week follow-up. One randomised trial conducted in primary care found that a 2-session fatigue self-management intervention improved self-reported fatigue compared with either 2-session symptom monitoring or usual care. However, high dropout rates limit interpretation of the study.[267] Future research will need to explore the effectiveness of different treatment delivery modalities to help improve access to behavioural interventions.

Alternative and complementary approaches

Vitamin D, essential fatty acid and magnesium supplements, polynutrients, traditional Chinese medicines, isometric yoga, phototherapy, tryptophan depletion, Qigong therapy, and homeopathic interventions have been equivocal, or they have shown limited or no effect. These interventions are generally not recommended in ME/CFS as they lack sufficient evidence. Furthermore, these studies may provide misleading results due to small sample sizes and poor study designs; therefore, results should be interpreted with caution.[225][253][268][269][270][271][272][273][274][275][276]

Use of this content is subject to our disclaimer