Background

Chronic fatigue syndrome and myalgic encephalomyelitis are chronic multisystem disorders characterised by profound fatigue and postexertional malaise with multiple other symptoms varying among individuals, including widespread pain, immune dysfunction and autonomic and neurocognitive symptoms.1 The annual incidence is around 15–26 per 100 000 persons,2 3 with a prevalence between 0.2% and 0.4%,4 5 depending on the exact definition used and the country of study. The level of disability is greater than for most other chronic illnesses, and full recovery is rare.6–8 Much is unknown about the illness and even the names ascribed are controversial.1

There is a systematic lack of funding of research and specialist services for people with these conditions.9 10 Despite specialists, particularly in the USA, using a range of drugs in treatment,11 12 very few of these have been subjected to clinical trials, and the outcomes of the few that have been done have often been inconclusive.13 14 Reasons for failure to reach conclusions include difficulties in clinical trial design such as trials of short duration and small sample sizes; a lack of a single best clinical case definition and of a simple diagnostic marker1 and difficulties in measuring outcomes (such as no way of measuring fatigue objectively). Many of these issues are associated with poor funding opportunities.15

Naltrexone is a safe synthetic antiopioid with widespread action at opioid and non-opioid receptors.16 It is currently licensed for treatments of alcoholism and opioid addiction at 50 mg. At lower doses, 3–4.5 mg, it appears to work as an immune modulator,17 and can also suppress tumour growth.18 19 This usage is commonly described as low-dose naltrexone (LDN).20 Small-scale clinical trials of LDN in multiple sclerosis, HIV, fibromyalgia, Gulf War Illness and Crohn’s disease have shown proof-of-concept efficacy and/or low toxicity.21–28 Recent before-and-after cohort studies of patients with Crohn’s disease and rheumatoid arthritis in Norway showed reductions in prescriptions for disease-modifying medications after starting LDN.29 30 We know of no clinical trials of naltrexone in patients with chronic fatigue syndrome or myalgic encephalomyelitis, although some patients report benefits.31 We present a series of three case reports of this treatment as a prelude, we hope, to future clinical trials. The reports were compiled by those people whose case histories are described, two of whom are coauthors, using historic diaries and previous medical records, including any objective measures that were available.

Case presentation: case 1

A white British female, now aged 63 (the first author), developed viral meningitis with accompanying vomiting leading to severe dehydration in 1988 when aged 33. She had previously been well and working as a general practitioner. Viral meningitis was diagnosed by lumbar puncture and again 6 weeks later on repeat hospital admission. She remained extremely unwell, being bed bound and unable to self-care, with profound weakness and fatigue, general malaise, light and sound sensitivity, repeated dizziness causing collapse, persistent anxiety and widespread pain. Although she improved slowly over the next 5 years, she was only able to return to work on a limited basis, still suffering headaches, fatigue, postexertional malaise and frequent migraine attacks characterised by vomiting and visual disturbances.

Following gastroenteritis in 1999, she again became bed bound and unable to self-care. Improvement was slower than the initial illness, and after 5 years she was still dependent on carers and used a motorised wheelchair when outside. She developed multiple food intolerances, shown on blood tests and confirmed by repeated withdrawals and reintroductions of intolerant foods. She showed a more dramatic response to wheat, even small amounts, characterised by nausea, severe headache, rapid heart beat and collapse within 10 min of consumption, followed by a week of reduced energy and absolute constipation.

Investigations: case 1

Extensive investigations were performed during several hospital admissions following the initial meningitis, including extensive screening for infections, brain scan and electroencephalogram. These were all normal, and she was diagnosed with chronic fatigue syndrome by the hospital clinician in 1989. This diagnosis was confirmed in 2001 and 2003 by a rheumatologist and a psychiatrist, respectively; in the latter case confirming the diagnosis by reference to the 1994 Centres for Disease Control criteria for chronic fatigue syndrome.32 In 2001, she was diagnosed by a clinical neuropsychologist as having cognitive impairments characteristic of damage from viral meningitis. Although her IQ was in the very superior range, she was unable to complete the timed Stroop Neuropsychological screening test (less than second centile)33; the trail making test was below the 25th percentile34 and the Ray complex figure was below the 25th centile.35 These results showed respectively an inability to exclude irrelevant but superficially similar information, poor multitasking abilities and reduced visuospatial ability and memory. These results had improved only slightly by 2004, with further slight improvements by 2019; both the Ray complex figure and the Stroop test still scoring below the 25th centile for her age and educational level although the trail making test is now around the 50th centile.

An MRI scan of the brain in 1998 was normal, and an antigliadin antibody test for coeliac disease was negative in 2002. In 2009, she was shown to be deficient in vitamin D (25-hydroxyvitamin D₃ level of 22.7 nmol/L, current guidelines suggest above 50 nmol/L is sufficient).

Treatment: case 1

She tried various alternative treatments with little improvement. She improved slightly while taking antibiotic combinations including phenoxymethylpenicillin and azithromycin for a year in 2006 but relapsed rapidly on stopping them. She was started on oral vitamin D supplementation in 2009, although this did not improve her symptoms of fatigue. As she has had polymorphic light eruption since her midteens, she remains on colecalciferol 20 000 IU every 2 weeks and now has normal vitamin D levels.

In 2010, she was prescribed LDN, initially at 1.5 mg, slowly increasing the dose over 2 years. She noticed slightly increased energy and reduced food intolerances while taking 4.5 mg/day but needed to reduce the dose to 3 mg due to increased headaches. Ten months later, she started increasing the dose again without recurrence of symptoms, and subsequent stepped dose increases coincided with further improvements in energy, mood and pain. At 9 mg, the frequent episodes of abdominal pain subsided, and she started eating a full diet, including wheat and dairy. Her prescribing doctor suggested experimenting to find the optimum dose of LDN, and after increasing to 7.5 mg two times per day, she settled on 6 mg two times per day, which she has taken for the past 7 years.

Outcome and follow-up: case 1

Now aged 63, 30 years after the initial meningitis, she currently has a normal quality of life with no signs of ill health, although energy levels can reduce slightly during infections, prolonged overexertion or excessive mental effort. Such reductions can be delayed up to 48 hours after the initial overstimulation, suggestive of continuing mild postexertional malaise. Symptoms such as poor sleep and excessive pain are absent. Up until starting LDN, she was in receipt of the UK Government’s benefits of Disability Living Allowance at the higher rate for mobility (requiring the person to have severe walking difficulties) and middle rate for care (requiring frequent help during the day). These payments were reduced, and then finally stopped 3 years after starting LDN when it was clear she was stable and well, and could walk, and more recently, cycle, without problems. Prior to starting LDN, her intellectual and cognitive functioning was very limited. These abilities have returned apart from continuing cognitive impairments due to the meningitis.

Case presentation: case 2

A previously well white female living in the USA, developed a sudden onset of ill health when 29 years old in 1989. Symptoms included profound fatigue and weakness, flu-like symptoms, postexertional malaise, cognitive impairment, nausea, widespread pain and sleep disturbance. Possible precipitating factors included possible viral infection, early pregnancy and exposure to ticks within 6 weeks of onset. She was diagnosed with chronic fatigue immune dysfunction syndrome by a neurologist after 2 years of ill health and this diagnosis, and/or myalgic encephalomyelitis has been reconfirmed several times since. During subsequent years, she continued with symptoms of postexertional neuroimmune exhaustion (as defined in the International Consensus Criteria for myalgic encephalomyelitis (2011)),36 pain, periodic muscle weakness, flu-like symptoms, orthostatic intolerance and unrefreshing sleep despite seeing many specialists.

Treatment: case 2

Many therapies have been tried, including antiviral agents for reactivated Epstein-Barr virus, with limited success.

She was prescribed LDN in 2014 when 54 years old. Due to known immune hypersensitivity (urticaria), the dose was started very low, at 0.25 mg/day, and increased very slowly over 4 years to the present dose of 4 mg. Initially, her sleep was disturbed by vivid dreaming. At about 6 months, when on 1 mg/day, she noticed improved sleep and lower pain levels, and these symptoms continued to improve as the naltrexone dosage was increased

Outcome and follow-up: case 2

Although pain and sleep issues continue, these are at a lower level than prior to starting naltrexone. Her sleep journal prior to starting LDN showed she awoke every 90 min through the night. Monitoring after starting LDN shows that although she may not sleep through, she does not have repeated awakenings. She no longer requires acupuncture for symptomatic pain relief. However, her functional level did not improve with LDN. Now aged 59, she also continues with other symptoms of myalgic encephalomyelitis including postexertional neuroimmune exhaustion, periodic muscle weakness, orthostatic intolerance, symptomatic sinus tachycardia, urticarial rashes and susceptibility to bacterial infections. Due to these, she takes ivabradine 2.5 mg two times per day and cetirizine 10 mg/day. Despite these continuing symptoms, she feels LDN is of sufficient benefit to continue long term.

Case presentation: case 3

A white British male (the second author) sustained a head injury when 7 years old and was diagnosed with glandular fever when 10 years old. He developed severe tonsillitis in 1996 when 14 years old. His symptoms gradually worsened and he became bedridden and unable to self-care, suffering profound fatigue, headaches, excessive day and night sleeping and light and sound sensitivity. He was diagnosed with chronic fatigue syndrome by a hospital paediatrician in 1997. He gradually improved over the next 3 years with increased energy. By his mid-20s, he was able to work full time although with persistent tiredness and recurrent infections. He improved further by practising ‘pacing’, listening to body symptoms to control his activity and by changing jobs to one with flexible working hours, which he continues to this date. He continued to experience difficulty sleeping and recurrent colds, at least four per year, accompanied by energy dips and subsequent depression. He was diagnosed with nasal polyps, sinusitis and seasonal allergic rhinitis.

Treatment: case 3

In 2018, when aged 37, he started LDN, initially at 1 mg/day, increasing to 4.5 mg, which he still takes. He had no side effects starting the drug.

Outcome and follow-up: case 3

He noticed an improved sleep pattern, and now has fewer colds which are no longer associated with an energy dip or subsequent depression. Retrospective scoring of depression using the Hospital Anxiety and Depression Scale37 suggests his average mood improved from 13 (11–21 signifies depression) to 7 (0–7 signifies no abnormality), his anxiety scores being normal throughout. His functional level improved from being mild–moderately limited on a daily basis (60%–70% on a functional activity scale) to mild limitations (80%–90% on a functional activity scale38). The improvements are sufficiently marked that he intends to continue LDN long term.

For the past 4 years, he has followed a gluten and wheat-free diet and has been vegan for the past 18 months, partly due to cheese causing increased nasal symptoms. He has not tried altering his diet after starting naltrexone.