Pharmacological interventions

National Guideline Centre (UK)

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Pharmacological interventions

Myalgic encephalomyelitis (or encephalopathy) / chronic fatigue syndrome: diagnosis and management

Evidence review F

NICE Guideline, No. 206

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2021 Oct.

ISBN-13: 978-1-4731-4221-3

1. Pharmacological interventions

1.1. Review question

What is the clinical and cost effectiveness of pharmacological interventions for people with ME/CFS? What are the experiences of people who have had interventions for ME/CFS?

1.1.1. Introduction

No drug treatment has been found to be a safe and effective cure for ME/CFS. Pharmacological interventions are however commonly used for symptomatic relief in people with ME/CFS, for example for pain and sleep, even though evidence from clinical trials in ME/CFS may be lacking. Approaches can also be used for co-morbid conditions such as irritable bowel syndrome, migraine-type headaches, postural orthostatic tachycardia syndrome or vitamin D deficiency. Many people report self-medicating with vitamins and supplements.

The committee evaluated evidence from clinical effectiveness studies and patient experience from a wide range of pharmacological management strategies to inform the recommendation in these areas.

The clinical and cost effectiveness methods and evidence found are outlined Evidence review G: Non pharmacological management as well as the methods and evidence found for the review on the experiences of people who have had interventions for ME/CFS.

1.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

A search was conducted for randomised trials comparing the effectiveness of pharmacological interventions for adults, children and young people who are diagnosed with ME/CFS. A variety of pharmacological interventions were identified; immunomodulatory drugs, antidepressants, corticosteroids, antihypertensive drugs, central nervous system stimulants, antiviral drugs, 5-HT3 antagonists, Galantamine hydrobromide, antihistamines, pro-inflammatory cytokine antagonists and Staphylococcus vaccine. The majority of the interventions are compared to placebo. The study populations were adults with mixed or unclear severity categories.

Thirty studies were included in the review;⁴^, ⁸^, ⁹^, ²²^, ²³^, ³⁴^, ³⁷^, ⁴⁴^, ⁴⁷^, ⁵²^, ⁵³^, ⁵⁶^, ⁶¹^, ⁶³^–⁶⁵^, ⁶⁸^, ⁷⁰^, ⁷⁷^, ⁷⁹^, ⁸⁴^, ⁸⁶^, ⁸⁸^, ⁹¹^, ⁹³^, ⁹⁷^, ⁹⁹^, ¹⁰³^, ¹⁰⁷^, ¹⁰⁹ these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below (Table 3 - Table 19).

See also the study selection flow chart, study evidence tables, forest plots and GRADE tables in the appendices.

There was a small amount of limited evidence for a number of different drugs. Network meta-analysis was considered for the comparison of drugs but was not pursued because of insufficient data available for the relevant outcomes. In addition there were substantial differences between the study interventions, comparators, populations and outcomes. There was a general lack of evidence of clinically important differences for any pairwise comparisons.

1.1.4.2. Excluded studies

See the excluded studies list in Appendix J.

1.1.5. Summary of studies included in the effectiveness evidence

It should be noted that post exertional malaise (PEM) is also referred to as post exertional symptom exacerbation (PESE). PESE is the committee’s preferred term.

Table 2

Summary of studies included in the evidence review.

1.1.6. Quality assessment of clinical studies included in the evidence review

Table 3

Clinical evidence summary: Immunomodulatory drugs (rituximab, rintatolimod, IV immunoglobulin G) versus placebo for ME/CFS.

Table 4

Clinical evidence summary: Antidepressants (duloxetine, fluoxetine, moclobemide) versus placebo for ME/CFS.

Table 5

Clinical evidence summary: Antidepressants (fluoxetine) versus graded exercise for ME/CFS.

Table 6

Clinical evidence summary: Antidepressants (fluoxetine) versus combined antidepressants (fluoxetine) & graded exercise for ME/CFS.

Table 7

Clinical evidence summary: Combined antidepressants (fluoxetine) & graded exercise versus placebo for ME/CFS.

Table 8

Clinical evidence summary: Combined antidepressants (fluoxetine) & graded exercise versus graded exercise for ME/CFS.

Table 9

Clinical evidence summary: Antidepressants (fluoxetine) versus antipsychotics (amisulpride) for ME/CFS.

Table 10

Clinical evidence summary: Corticosteroids (oral hydrocortisone or fludrocortisone, nasal flunisolide) versus placebo for ME/CFS.

Table 11

Clinical evidence summary: Central antihypertensive drugs (clonidine) versus placebo for ME/CFS.

Table 12

Clinical evidence summary: Central nervous system stimulants (methylphenidate, modafinil, dexamphetamine, lisdexamphetamine) versus placebo for ME/CFS.

Table 13

Clinical evidence summary: Antiviral drugs (IV acyclovir or oral valganciclovir) versus placebo for ME/CFS.

Table 14

Clinical evidence summary: 5-HT3 antagonists (ondansetron) versus placebo for ME/CFS.

Table 15

Clinical evidence summary: Galantamine hydrobromide versus placebo for ME/CFS.

Table 16

Clinical evidence summary: Antihistamines (terfenadine) versus placebo for ME/CFS.

Table 17

Clinical evidence summary: Pro-inflammatory cytokine antagonists (anakinra) versus placebo for ME/CFS.

Table 18

Clinical evidence summary: Staphylococcus vaccine (Staphypan Berna) versus placebo for ME/CFS.

Table 19

Clinical evidence summary: Central antihypertensive drugs (clonidine) versus placebo for ME/CFS (children and young people).

See Appendix F for full GRADE and/or GRADE-CERQual tables.

More information on the minimally important differences (MIDs) used and the interpretation can be found in Appendix K of this review and the Methods Chapter of this guideline.

1.1.7. Economic evidence

1.1.7.1. Included studies

No health economic studies were included.

1.1.7.2. Excluded studies

No relevant health economic studies were specifically excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G.

1.2. The committee’s discussion and interpretation of the evidence

The committee’s discussion on the evidence reviews for the clinical and cost-effectiveness of pharmacological interventions and the experiences of people who have had interventions for ME/CFS are included here. See Evidence review G – Non-pharmacological management for the full methods and results sections of the review on the experiences of people who have had interventions (pharmacological and non-pharmacological) for ME/CFS.

The committee discussed this evidence with the findings from the review on diagnosis (report D) and the reports on Children and Young people (Appendix 1) and people with severe ME/CFS (Appendix 2). Where relevant this is noted.

1.1.8. The outcomes that matter most – review of the clinical and cost effectiveness

Mortality, quality of life, general symptom scales, fatigue/fatigability, physical function, cognitive function, psychological status, pain, sleep quality, treatment-related adverse events, activity levels, return to school/work and exercise performance measures were considered by the committee to be critical outcomes for decision making.

Fatigue/fatigability, unrefreshing sleep and physical and cognitive dysfunction are recognised as key symptoms of ME/CFS. The worsening or improvement of these symptoms reflect the impact of an intervention or strategy. The committee agreed that pain though not key to the diagnosis of ME/CFS, is a common symptom in people with ME/CFS and should be considered by the committee in their decision making. The committee agreed that any decisions on interventions and strategies should be informed by treatment related adverse events as a possible indicator of harm.

Care needs, impact on families and carers and ability to resume occupation, school or study were considered important outcomes for decision making reflecting the effectiveness of an intervention.

The committee acknowledged the lack of existing objective outcome measures of effectiveness of interventions for ME/CFS and the limitations of subjective measures (see Professor Edwards expert testimony – Appendix 3: Expert testimonies). Only validated outcome measurement scales were included in the evidence review.

No evidence was identified for care needs or impact on families and carers.

1.1.9. The outcomes that matter most – qualitative review of experiences of interventions review of the clinical and cost effectiveness

Themes emerging from qualitative data regarding the experiences of people that have had interventions for ME/CFS. Themes were derived from the evidence identified and were not pre-specified by the committee.

Only findings that were relevant to the review question were included; findings related to people’s experiences of general ME/CFS services rather than specific interventions were not extracted.

1.1.10. The quality of the evidence – summary of quality in review of clinical and cost effectiveness

Evidence from 30 studies was identified for the following pharmacological interventions: immunomodulatory drugs (n=6), antidepressants (n=5), corticosteroids (n=4), antihypertensive drugs (n=2), central nervous system stimulants (n=5), antiviral drugs (n=2), 5-HT3 antagonists (n=1), galantamine hydrobromide (n=2), antihistamines (n=1), pro-inflammatory cytokine antagonists(n=1) and staphylococcus vaccine (n=1). No evidence was identified for sleep medication, pain relief, sodium valproate or low dose naltrexone.

The majority of the interventions were compared with placebo. The study populations were mostly adults all with mixed or unclear ME/CFS severity. One study comparing clonidine to placebo included young people (12-18 years).

Most of the evidence was of low and very low quality. The main reasons for downgrading were risk of bias, indirectness and imprecision. Several outcomes were at high risk of selection bias due to insufficient randomisation and allocation concealment methods reported in the studies. The majority of the studies were placebo-controlled and double blinded, but those that were not double blinded were at high risk of performance bias. This was particularly relevant for subjective outcomes and the committee considered this limitation when interpreting the evidence.

After considering the stakeholder comments the committee agreed to revisit the evidence for the intervention reviews, further scrutinising the information on PEM reported in the trials and the application of indirectness in the evidence. For outcomes that were reanalysed, this did not result in any changes to the overall quality rating of the evidence. Further information on this analysis is briefly summarised elsewhere in this section. Full details of the approach taken, the analysis, and the impact on the results and interpretation of the evidence are in Appendix G.

For most outcomes, meta-analysis was not appropriate due to important differences between the types of drugs or multiple relevant measures of the same outcome being reported within the same study. Most of the comparisons only included one study. Therefore, evidence for most outcomes was based on single studies, many of which included very small sample sizes. This resulted in imprecision around the point estimates.

Population indirectness

The committee discussed the CDC 1994 diagnostic criteria used in the studies to recruit eligible participants. The committee have identified PEM/PESE as an essential symptom that is central to the diagnosis of ME/CFS (see evidence report D: diagnosis) and the CDC 1994 criteria does not include this as a compulsory requirement. It should be noted that PESE is also referred to as post exertional malaise (PEM) in the criteria, PESE is the committee’s preferred term. The committee agreed that a population diagnosed with such criteria may not accurately represent the ME/CFS population and that people experiencing PEM/PESE are likely to respond differently to treatment than those who do not experience PEM/PESE. This raised concerns over the generalisability of findings to the ME/CFS population. It was therefore agreed to downgrade the evidence for population indirectness.

After considering the stakeholder comments the committee agreed to revisit the evidence for the intervention reviews further scrutinising the information on PEM reported in the trials and the application of indirectness in the evidence. As part of this they agreed that any evidence with a population ≥ 95% with PEM would be considered direct. Studies where < 95% of participants had PEM, or where the percentage of participants with PEM was not reported would be considered indirect. See Appendix G for full details of the approach taken, the analysis, and the impact on the results and interpretation of the evidence.

Evidence was not stratified by diagnostic criteria used, so theoretically, studies including potentially different populations could have been combined. In practice, for the majority of outcomes, meta-analysis was not appropriate due to important differences between the types of interventions, comparators, population strata, or multiple relevant measures of the same outcome being reported within the same study. Therefore, potentially different populations were rarely combined. Where they were combined, no serious heterogeneity was identified.

Evidence quality by intervention

Immunomodulatory drugs

Evidence from six randomised controlled trials were identified for immunomodulatory drugs compared to placebo; two rituximab, three IV immunoglobulin G and one rintatolimod. Most of the evidence was low and very low quality (apart from some moderate and high quality evidence for rituximab) and based on single small studies. No evidence was identified for mortality, cognitive function, pain, sleep quality, activity levels, care needs and impact on families and carers.

Antidepressants and antipsychotics

Evidence from five randomised controlled trials were identified for antidepressants. Three trials (single trials on the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine hydrochloride, the monoamine oxidase inhibitor (MAOI) moclobemide, and the selective serotonin reuptake inhibitor (SSRI) fluoxetine) were compared only to placebo. One trial had four arms comparing fluoxetine and exercise control, graded exercise and placebo, fluoxetine and graded exercise, and placebo and exercise control. One trial compared fluoxetine to amisulpride (an atypical antipsychotic). All the evidence very low quality and the majority was based on single small studies. No evidence was identified for mortality, cognitive function, sleep quality, activity levels, return to school/work, exercise performance measures, care needs and impact on families and carers.

Corticosteroids

Evidence from four randomised controlled trials were identified for corticosteroids (one nasal flunisolide, two oral fludrocortisone and one oral hydrocortisone) compared to placebo. Most of the evidence was very low quality and based on single small studies. No evidence was identified for mortality, physical function, activity levels, return to school/work, care needs and impact on families and carers.

Central antihypertensive drugs

Evidence from two randomised controlled trials compared clonidine to placebo. Most of the evidence was very low to low quality and based on single small studies. No evidence was identified for mortality, quality of life, psychological status, return to school/work, exercise performance measures, care needs and impact on families and carers.

Central nervous system (CNS) stimulants

Evidence from five randomised controlled trials identified for CNS stimulants (two methylphenidate, and one each of dexamphetamine, lisdexamphetamine, and Modafinil) compared to placebo. Most of the evidence was very low to low quality based on single small studies. No evidence was identified for mortality, physical function, activity levels, return to school/work, exercise performance measures, care needs and impact on families and carers.

Antiviral drugs

Evidence from two randomised controlled trials compared acyclovir (IV and oral) to placebo. All the evidence was very low quality and based on single small studies. No evidence was identified for mortality, quality of life, physical function, cognitive function, pain, sleep quality, return to school/work, exercise performance measures, care needs and impact on families and carers.

5-HT3 antagonists

Evidence from one randomised controlled trial compared ondansetron to placebo. All the evidence was very low quality. No evidence was identified for mortality, quality of life, physical function, psychological status, sleep quality, exercise performance measures, care needs and impact on families and carers were also considered to be important outcomes.

Galantamine hydrobromide

Evidence from two randomised controlled trials compared galantamine hydrobromide to placebo. All the evidence was very low quality and based on single small studies. No evidence was identified for mortality, quality of life, physical function, psychological status, activity levels, exercise performance measures, care needs and impact on families and carers were also considered to be important outcomes.

Antihistamines

Evidence from one randomised controlled trial compared terfenadine to placebo. All the evidence was very low quality. No evidence was identified for mortality, quality of life, general symptom scales, fatigue/fatigability, cognitive function, pain, sleep quality, treatment-related adverse events, activity levels, return to school/work, exercise performance measures, care needs and impact on families and carers.

Pro-inflammatory cytokine antagonists

Evidence from one randomised controlled trial compared anakinra to placebo. The evidence was very low to moderate quality. No evidence was identified for quality of life, cognitive function, sleep quality, activity levels, return to school/work, exercise performance measures, care needs and impact on families and carers.

Staphylococcus vaccine

Evidence from one randomised controlled trial compared staphylococcus vaccine to placebo. All the evidence was very low quality. No evidence was identified for mortality, quality of life, fatigue/fatigability, physical function, cognitive function, psychological status, sleep quality, activity levels, return to school/work, exercise performance measures, care needs and impact on families and carers.

1.1.11. The quality of the evidence - qualitative review of people’s experience of interventions

The majority of the studies included in the qualitative review reported experiences of non-pharmacological interventions. One study in adults, using a survey with open-ended questions, reported experiences of antidepressants. Two studies in children and young people, using semi-structured interviews, reported experiences of sickness or stomach acid relief medication or pharmacological interventions in general.

Confidence in the review findings was very low. The main reasons for downgrading were methodological limitations, relevance and adequacy. Issues regarding recruitment strategy and data analysis were the main contributory factors to concerns over methodological limitations in the study in adults. The main methodological limitations of the studies in children/young people included the role of the researcher and concerns regarding the richness of the data. The study in adults reported limited information on participant characteristics, so it was unclear how applicable the findings were to the wider ME/CFS population. There were also concerns regarding applicability of the findings reported in the studies on children/young people; the population in one study was limited to adolescents with ME/CFS who experienced eating difficulties and the population in the other study was limited to children/young people with comorbid depression. Findings were reported without elaboration or examples and were based on single studies, leading to concerns regarding adequacy.

1.1.12. Benefits and harms - Review of clinical and cost effectiveness

Immunomodulatory drugs

The evidence showed a clinical benefit of rituximab compared with placebo for the physical component of SF36 quality of life, however there was some uncertainty (imprecision) around the point estimate. The evidence showed no clinically important difference of rituximab for the mental component of SF36 quality of life, fatigue/fatigability, activity levels, and physical functioning. High and moderate quality evidence showed harm of rituximab for serious adverse events and adverse events of at least moderate severity, respectively. Serious adverse events included febrile neutropenia, infusion-related reactions, and other events also requiring hospitalisation, and were considered to be possibly or probably related to the study intervention.

The evidence showed a clinical benefit of intravenous immunoglobulin G (IV Ig) compared with placebo for symptom improvement and for return to work, however there was some uncertainty (imprecision) around the point estimate for symptom improvement. There was no clinically important difference of IV Ig for psychological status, or physical functioning. There was a clinically important difference in adverse events, with participants from one study receiving IVIG reporting fewer constitutional symptoms compared to those receiving placebo. In another study, there was no clinical difference in unspecified major adverse events between study arms.

There was no clinically important difference of rintatolimod for exercise performance (treadmill test). There was no clinical difference in serious adverse events with possible or probable relation to the intervention, between study arms.

The committee considered that the majority of the evidence for immunomodulatory drugs was of low and very low quality and based on single small studies and the committee was not confident about the effects for any of the treatments. The committee were aware from their clinical experience that immunomodulatory drugs can cause serious adverse events, and they acknowledged the high quality evidence of harm of rituximab. The committee were aware of anecdotal reports of some of these drugs working for some people with ME/CFS, however they decided that due to the limitations of the evidence, the lack of any clear benefit, and potential for serious harms, immunomodulatory drugs should not be used for the purposes of treating or curing ME/CFS.

PEM re-analysis

After further scrutinising the information on PEM reported in the trials, no new information on PEM was identified that required re-analysis. See Appendix G for full details of the approach taken, the analysis, and the impact on the results and interpretation of the evidence.

Antidepressants and antipsychotics

The evidence showed a clinical benefit of duloxetine (SNRI antidepressant) compared with placebo for the bodily pain sub scale of SF36 quality of life and the general fatigue sub scale of the MFI-20 fatigue scale, however there was some uncertainty (imprecision) around the point estimates. There was no clinical difference for the remainder of the SF36 or MFI-20 sub scales, the hospital anxiety and depression scale, the brief pain inventory, or general symptom scales (clinical global impression of severity and improvement) for duloxetine. Evidence showed a clinical benefit of fluoxetine (SSRI antidepressant) and moclobemide (MAOI antidepressant) for general symptom scales, however there was considerable uncertainty around the point estimates. There was no clinical difference of fluoxetine for fatigue, beck depression inventory and exercise performance. For moclobemide there was no clinical difference for physical functioning or profile of mood states. There was a harm of fluoxetine for adverse events (tremor/perspiration).

The committee considered that the majority of the evidence was of low and very low quality and based on single studies, and they were not confident about the effects. The committee noted the evidence suggesting harm of fluoxetine in the form of side effects was also broadly reflected in the qualitative review of people’s experiences of interventions, though this evidence was also of low quality (see Evidence review G for the full methods and results of this review, and section 1.1.13 below). The committee are also aware from their own experience that ME/CFS is commonly misdiagnosed as depression and that treatment with antidepressants is often given on the basis of these incorrect beliefs. The committee decided based on the lack of any clear benefit from the evidence and their own clinical experience that antidepressants should not be used for the purpose of ME/CFS. However, they acknowledged that people with ME/CFS can experience comorbid depression, and that antidepressants may be useful in some of these people as a treatment for depression (as for any other person with depression regardless of whether or not they have ME/CFS). The committee cross referred to the NICE guideline on depression.

The committee also reviewed the evidence for fluoxetine compared with amisulpride (atypical anti-psychotic) and graded exercise therapy. Evidence from one study showed a clinical benefit of amisulpride over fluoxetine for quality of life, general symptom scales and fatigue, but no clinically important difference for psychological status, or pain, There was no clinically important difference in adverse events (FIBSER global burden) between study arms. The committee considered the lack of robust evidence identified for anti-psychotics and their own experience of potential harms and decided that anti-psychotics should not be used for the purposes of treating or curing ME/CFS.

Very low quality evidence from one four armed study showed no clinically important difference in fatigue, psychological status or exercise performance between fluoxetine, graded exercise therapy, placebo and exercise control. The committee considered that there was insufficient evidence to conclude whether SSRIs were more effective than graded exercise therapy. The evidence for graded exercise therapy is discussed further in Evidence review G - non pharmacological management.

PEM re-analysis

Corticosteroids

Evidence for corticosteroids was mainly of very low quality. Evidence for hydrocortisone showed no clinical difference for any of the outcomes assessed for fatigue, psychological status, general symptom scales, and activity levels.. There was a clinically important harm of hydrocortisone in terms of adverse events, with participants in the hydrocortisone study arm experience more adverse reactions compared to those in the placebo arm.

Similarly, for fludrocortisone there was no clinical difference for any SF36 quality of life subscales, fatigue, physical functioning, psychological status, cognitive functioning, pain, sleep, activity levels, exercise performance, or general symptom scales. There was a clinically important difference in any adverse events and adverse events leading to study withdrawal, with participants receiving fludrocortisone experiencing fewer events, the latter of which was from one small study with considerable uncertainty (imprecision) around the point estimate.

There was no clinical difference for symptom severity and sleep for nasal flunisolide.

The committee raised concerns about the long-term safety of these drugs for people with ME/CFS, specifically disruption to the hypothalamic-pituitary-adrenal axis and weakening of muscle and bone. Taking into account the very low quality of the evidence and lack of any clear benefit, as well as their own clinical experience of the potential harms, the committee decided that corticosteroids should not be used as a curative treatment of ME/CFS. The committee was aware that fludrocortisone is sometimes given for orthostatic intolerance syndromes, such as postural hypotension or Postural Tachycardia Syndrome (POTS). They agreed that this recommendation would not prevent people with ME/CFS being offered fludrocortisone treatment for relevant comorbidities, but that it should not be offered for the purpose of treating or curing ME/CFS. See Evidence review G - non pharmacological management report for further recommendations and discussion on the management of orthostatic intolerance.

PEM re-analysis

Central antihypertensive drugs

Evidence from one small study showed a clinical benefit of clonidine compared with placebo for some measures of cognitive function, but no clinically important difference for others. There was considerable uncertainty (imprecision) around most of the effect estimates. The committee noted that the evidence of benefit for cognitive function was based on a small study whereby a single dose of the drug was administered and follow up was at thirty minutes and the committee was not confident in the effect.

Low to very low quality evidence from one study in young people showed no clinically importance difference in general symptom scales, fatigue, physical function, sleep quality or activity levels, and harm of clonidine for cognitive function, and pain. There was a harm of clonidine for adverse events, with participants receiving clonidine experiencing more self-reported adverse events. This was from one small study and there was uncertainty (imprecision) around the effect estimate.

The committee considered the limitations of the evidence, the evidence of potential harm as well as their own clinical knowledge regarding evidence for other relevant conditions and decided that that clonidine should not be used for the curative treatment of ME/CFS.

PEM re-analysis

Central nervous system (CNS) stimulants

Evidence showed a clinical benefit of amphetamines (dexamphetamine and lisdexamphetamine) compared with placebo for reducing fatigue on the fatigue severity scale, anxiety measured by the Hamilton anxiety scale, general symptom scales, pain and cognitive function, however there was uncertainty (imprecision) around the point estimates for most of these outcomes. There was no clinical difference for SF36 quality of life and sleep scales. The evidence showed harm of amphetamines for adverse events leading to discontinuation and other adverse events, including anorexia, dry mouth, headache and insomnia, however there was considerable uncertainty (imprecision) around the point estimates.

For methylphenidate there was no clinical difference for fatigue, psychological status, and SF36 quality of life. There was harm for serious adverse events, however the adverse event that occurred was not considered to be treatment-related (pyelonephritis), dry mouth, and abdominal pain. The remaining evidence on adverse events was mixed depending on the adverse event. There was a clinical difference in some adverse events (dizziness, chest pain and akathisia), with participants receiving methylphenidate experiencing fewer events, however there was uncertainty (imprecision) around these point estimates. There was no clinical difference between study arms for the adverse event, sleepiness.

Finally, short-term evidence from one study (20-day follow-up) showed a harm of modafinil for adverse events (none were serious and included headache and nausea) and some sub scales of SF36 quality of life. There was considerable uncertainty (imprecision) around all of these point estimates. There was no clinical difference for other SF36 sub scales and the Chalder fatigue scale.

The committee noted the very low quality of the evidence and was not confident in the effects for CNS stimulants. The committee discussed their experience of CNS stimulants and were concerned about possible harms. They noted that CNS stimulants could cause people with ME/CFS to push themselves outside of their energy limits which could have damaging effects. They also discussed side effects which could be particularly detrimental to people with ME/CFS, some of which were noted in the evidence (such as anorexia and insomnia). The committee considered the low to very low quality of the evidence, as well as their own clinical knowledge regarding evidence for other chronic conditions, and possible harms, and decided that CNS stimulants should not be used for the curative treatment of ME/CFS.

PEM re-analysis

Antiviral drugs

The evidence showed a clinical benefit of oral valganciclovir compared with placebo for fatigue (MFI-20), however there was some uncertainty (imprecision) around the effect estimate. There was no clinical difference between study arms in terms of treatment-related adverse events.

The evidence showed harm of intravenous (IV) acyclovir for profile of mood states and adverse events (reversible renal failure), although there was some uncertainty (imprecision) around the effect estimates. There was no clinically important difference of IV acyclovir for general symptom scales or activity levels.

The committee noted that evidence for antiviral drugs came from two small studies and was of very low quality, and they could not be confident of the effects. Evidence of harm came from a single study on IV acyclovir with a short follow up of 37 days. The committee discussed that antiviral drugs are used by some specialists and they were aware of anecdotal evidence of benefit in some people, but they recognised the absence of convincing clinical evidence and possible harms. Therefore, the committee recommended that antiviral drugs should not be used for purposes of treating or curing ME/CFS, however they acknowledged this recommendation should not stop antiviral drugs being used where a genuine indication exists, for example for the treatment of some viral infections.

After further scrutinising the information on PEM reported in the trials, the study on oral valganciclovir (Montoya 2013) that was previously downgraded for indirectness for using a diagnostic criteria that did not have PEM as a compulsory feature (1994 CDC criteria) reported that ≥95% of participants had PEM. As a result, the indirectness rating was changed from very serious to serious indirectness (the study remained downgraded by one increment for other population concerns relating to a requirement for viral onset of disease and elevated viral titres). Only two outcomes were reported in this trial: fatigue and adverse events. The overall quality rating remained very low for both outcomes and the committee’s interpretation of the evidence did not change.

For the other trial of antiviral drugs, no new information on PEM was identified that required re-analysis. See Appendix G for full details of the approach taken, the analysis, and the impact on the results and interpretation of the evidence.

Other drugs

The committee also reviewed evidence for antidepressants combined with graded exercise, 5HT3 antagonists, galantamine, antihistamines, proinflammatory cytokine antagonists and staphylococcus vaccine. Evidence for these comparisons was mostly low and very low quality and based on individual studies. Due to the significant limitations of the evidence the committee agreed that none of these drug treatments should be offered for the purpose of treating or curing ME/CFS, but they noted there may be other indications for the use of some of these medications (for example for management of specific symptoms or comorbidities).

PEM re-analysis

1.1.13. Benefits and harms - qualitative review of people’s experience of interventions

Evidence from one study showed that in people who did not attend specialist ME services, antidepressants were prescribed for ME/CFS symptoms by health care professionals and people experienced negative side effects, although these side effects were not described. There was very low confidence in this finding. See section 1.1.12 above for full discussion regarding antidepressants.

Evidence from one study in children/young people showed that some took prescribed sickness or stomach acid relief medication, which they found to be helpful. However, it was not common to have been offered medication to relieve their symptoms which frustrated some. There was very low confidence in this finding. Evidence from one study in children/young people showed that they generally did not mind taking medication providing they found it helpful. There was very low confidence in this finding. The committee considered that this qualitative evidence was too limited to support any recommendations.

1.1.14. Overall summary for pharmacological interventions for ME/CFS

Overall, the evidence for pharmacological interventions is limited and most was of low to very low quality and the committee was not confident in the effects. There is little evidence for most of the interventions identified and little evidence of clinical benefit and some evidence of harm. After discussing the clinical effectiveness of pharmacological interventions and people’s experiences and considering the reports from the young people (see Appendix 1: Children and Young people) and people with severe ME/CFS (see Appendix 2: People with severe ME/CFS) the committee agreed there is no current pharmacological cure for ME/CFS. The committee discussed the claims that have been made about cures for people with ME/CFS and lack of evidence for this. The committee were aware of interventions that are promoted as cures and there is often a financial cost to people with ME/CFS when these are pursued. To address this the committee made a recommendation to raise awareness that there is no current pharmacological cure for people with ME/CFS. In addition, the committee made a clear recommendation not to offer any medicines or supplements to cure ME/CFS.

The committee acknowledged that while there are not any current pharmacological cures for ME/CFS, people with ME/CFS have found some drugs when used appropriately with advice and support from health care professionals can be helpful in managing the symptoms of ME/CFS and they could be discussed on an individual basis.

1.1.15. Cost effectiveness and resource use

There were no published economic evaluations of pharmacological treatment of ME/CFS.

The annual cost of the drugs per patient that have been trialled range from only a few pounds to thousands of pounds a year.

Since there was no good quality evidence of clinical effectiveness for any of the drugs trialled, their cost effectiveness remains unproven.

Therefore, the committee did not recommend any drugs, other than those for the treatment of symptoms as recommended in other guidelines.

1.1.16. Other factors the committee took into account

The committee noted that no clinical or cost effectiveness evidence was identified for interventions evaluating some of the drugs that have been commonly used in people with ME/CFS, for example thyroxine. The committee was aware of people with ME/CFS who have been given thyroxine and other thyroid supplements as a treatment for ME/CFS fatigue and noted there is no evidence for it use in people with ME/CFS.

Medicines management

The committee highlighted that in their clinical experience people with ME/CFS may be more intolerant of drug treatment than people who do not have ME/CFS. The committee agreed it was important to raise awareness to clinicians of possible greater intolerance in this group in order to allow consideration when medications are being prescribed and taken, especially as people with ME/CFS may not initially know they are sensitive to medicines. Therefore, the committee made a recommendation to be aware that people with ME/CFS may be more intolerant of drug treatment. The committee discussed using a cautious approach to medicines prescribing, which includes starting the medicine at a lower dose than in usual clinical practice and monitoring how the person responds before adjusting the dose. The committee agreed that this type of approach would reduce the risk of harm and recommended that it be considered. The committee agreed it was important that medicines management was tailored to the person with ME/CFS and they could not provide detailed advice on how to manage intolerance.

The committee discussed medicines management for children and young people. Committee members who had experience of general paediatric services expressed that ME/CFS specialists were better placed to deliver care in this context than paediatricians. It was considered by the committee that prescribing should be initiated under the supervision of a paediatrician with expertise in ME/CFS and made a consensus based recommendation. It was acknowledged that the current availability of paediatric specialist care is limited. The committee considered whether a lack of access by GPs to specialist ME/CFS paediatricians may result in children and young people with ME/CFS being prevented from accessing medicines. However, it was agreed that telephone supervision/consultation and shared care protocols would help to overcome this. It was also agreed that continuation of prescribing by a specialist ME/CFS paediatrician may not be necessary and the committee noted that prescribing may be continued in primary care, depending on the preferences of the patient and their carers and local circumstances.

Appendices

Appendix A. Review protocols

Review protocol for pharmacological interventions (PDF, 315K)

Health economic review protocol (PDF, 201K)

Appendix B. Literature search strategies

This literature search strategy was used for the following review questions:

What is the clinical effectiveness, cost-effectiveness and acceptability (including patient experiences) of pharmacological interventions for people with ME/CFS?

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.⁵⁹

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy (PDF, 292K)

B.2. Health economics literature search strategy (PDF, 291K)

Appendix G. PEM reanalysis

G.1. PEM reanalysis – Methods and rationale

After considering the stakeholder comments the committee agreed to revisit the evidence for the intervention reviews further scrutinising the information on PEM reported in the trials and the application of indirectness in the evidence. In the original analysis studies were downgraded for indirectness if the diagnostic criteria used in the study did not have PEM as a compulsory feature.

We looked for any published information on the percentage of participants with PEM in the included trials, or subgroup analyses in study participants with PEM. The papers for all included studies were reviewed again, as well as any published supplements. The excluded studies list was also re-examined to ensure any relevant information relating to PEM in the included studies were not missed. Unpublished data was not accepted for this analysis.

The committee agreed that studies using criteria without PEM as a compulsory feature (e.g. 1994 CDC criteria, Oxford criteria) should not be downgraded if a high proportion of study participants had PEM and this was adequately described. In order to not downgrade the following criteria must be met:

≥95% of study participants are reported to have PEM (or a subgroup analysis where ≥95% participants are reported to have PEM)
AND
If another term is used other than PEM (e.g. post-exertional fatigue) there must be a clear description that indicates all of the following:
- Symptom worsening that follows minimal physical or mental activity that was previously tolerated
- Symptom worsening is typically delayed (12-24 hours after the activity)
- The impact is prolonged
OR
≥95% of study participants meet diagnostic criteria where PEM is compulsory (e.g. IOM 2015, NICE 2007, Carruthers 2003/Canadian criteria).

Only new or changed results are reported below. Results for outcomes where applying the above criteria did not change the indirectness rating are not shown. See original results in Section 1.1.4, Appendix E (forest plots), Appendix F (GRADE tables), and the committee’s discussion and interpretation of the evidence in Section 1.2 of this report. Additionally, results reported below have also been added throughout the report, alongside the original results.

G.2. PEM reanalysis – Summary of results

Immunomodulatory drugs

No new information on PEM identified that required re-analysis.

Antidepressants

No new information on PEM identified that required re-analysis.

Corticosteroids

No new information on PEM identified that required re-analysis.

Antihypertensive drugs

No new information on PEM identified that required re-analysis.

CNS stimulants

No new information on PEM identified that required re-analysis.

Antiviral drugs

For the comparison of oral valganciclovir vs placebo (1 study – Montoya 2013), the percentage of participants with PEM was reported (96.7% of participants had PEM). This study had previously been downgraded as the 1994 CDC criteria was used which does not have PEM as a compulsory feature.

Changing the indirectness rating resulted in a change from very serious indirectness to serious indirectness (the study remained downgraded due to other concerns about the population). The overall quality of the evidence remained very low for all outcomes.

Amended GRADE tables are presented below in section G.3. Also see original results in Section 1.1.4, Appendix E (forest plots), Appendix F (GRADE tables), and the committee’s discussion and interpretation of the evidence in Section 1.2 of this report.

For the remaining study in this category (IV acyclovir vs placebo) there was no new information on PEM identified that required re-analysis.

Other drugs

No new information on PEM identified that required re-analysis.

G.3. PEM reanalysis – Reporting of PEM

Table 39. Summary PEM reporting in each study (PDF, 172K)

G.4. PEM reanalysis – GRADE tables

Antiviral drugs (PDF, 139K)

Appendix H. Economic evidence study selection

Download PDF (241K)

Appendix I. Economic evidence tables

No economic evaluations were found.

Appendix J. Excluded studies

Table 40. Studies excluded from the clinical review (PDF, 166K)

Appendix K. MIDs for continuous outcomes

Table 41. MID for continuous outcomes (0.5 × SD): Immunomodulatory drugs versus placebo (PDF, 124K)

Table 42. MID for continuous outcomes (0.5 × SD): Antidepressants versus placebo (PDF, 136K)

Table 43. MID for continuous outcomes (0.5 × SD): Antidepressants versus graded exercise (PDF, 122K)

Table 44. MID for continuous outcomes (0.5 × SD): Antidepressants versus combined antidepressants and graded exercise (PDF, 122K)

Table 45. MID for continuous outcomes (0.5 × SD): Combined antidepressants and graded exercise versus placebo (PDF, 122K)

Table 46. MID for continuous outcomes (0.5 × SD): Combined antidepressants and graded exercise versus graded exercise (PDF, 121K)

Table 47. MID for continuous outcomes (0.5 × SD): Antidepressants versus antipsychotics (PDF, 122K)

Table 48. MID for continuous outcomes (0.5 × SD): Corticosteroids versus placebo (PDF, 161K)

Table 49. MID for continuous outcomes (0.5 × SD): Antihypertensive drugs versus placebo (PDF, 126K)

Table 50. MID for continuous outcomes (0.5 × SD): Central nervous system stimulants versus placebo (PDF, 135K)

Table 51. MID for continuous outcomes (0.5 × SD): Antiviral drugs versus placebo (PDF, 131K)

Table 52. MID for continuous outcomes (0.5 × SD): 5-HT3 antagonists versus placebo (PDF, 122K)

Table 53. MID for continuous outcomes (0.5 × SD): Galantamine hydrobromide versus placebo (PDF, 122K)

Table 54. MID for continuous outcomes (0.5 × SD): Antihistamines versus placebo (PDF, 121K)

Table 55. MID for continuous outcomes (0.5 × SD): Pro-inflammatory cytokine antagonists versus placebo (PDF, 131K)

Table 56. MID for continuous outcomes (0.5 × SD): Staphylococcus vaccine versus placebo (PDF, 121K)

Table 57. MID for continuous outcomes (0.5 × SD): Children and young people: Sympathomimetic/central antihypertensive drugs versus placebo (PDF, 121K)

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Final

Evidence reviews underpinning recommendations and research recommendations in the NICE guideline

These evidence reviews were developed by the National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK579665PMID: 35467812

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National Guideline Centre (UK). Pharmacological interventions: Myalgic encephalomyelitis (or encephalopathy) / chronic fatigue syndrome: diagnosis and management: Evidence review F. London: National Institute for Health and Care Excellence (NICE); 2021 Oct. (NICE Guideline, No. 206.)
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Pharmacological interventions

1. Pharmacological interventions

1.1. Review question

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

1.1.4.2. Excluded studies

1.1.5. Summary of studies included in the effectiveness evidence

1.1.6. Quality assessment of clinical studies included in the evidence review

1.1.7. Economic evidence

1.1.7.1. Included studies

1.1.7.2. Excluded studies

1.2. The committee’s discussion and interpretation of the evidence

1.1.8. The outcomes that matter most – review of the clinical and cost effectiveness

1.1.9. The outcomes that matter most – qualitative review of experiences of interventions review of the clinical and cost effectiveness

1.1.10. The quality of the evidence – summary of quality in review of clinical and cost effectiveness

Population indirectness

Evidence quality by intervention

Immunomodulatory drugs

Antidepressants and antipsychotics

Corticosteroids

Central antihypertensive drugs

Central nervous system (CNS) stimulants

Antiviral drugs

5-HT3 antagonists

Galantamine hydrobromide

Antihistamines

Pro-inflammatory cytokine antagonists

Staphylococcus vaccine

1.1.11. The quality of the evidence - qualitative review of people’s experience of interventions

1.1.12. Benefits and harms - Review of clinical and cost effectiveness

Immunomodulatory drugs

PEM re-analysis

Antidepressants and antipsychotics

PEM re-analysis

Corticosteroids

PEM re-analysis

Central antihypertensive drugs

PEM re-analysis

Central nervous system (CNS) stimulants

PEM re-analysis

Antiviral drugs

Other drugs

PEM re-analysis

1.1.13. Benefits and harms - qualitative review of people’s experience of interventions

1.1.14. Overall summary for pharmacological interventions for ME/CFS

1.1.15. Cost effectiveness and resource use

1.1.16. Other factors the committee took into account

Medicines management

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

Appendix C. Effectiveness evidence study selection

Appendix D. Effectiveness evidence

Appendix E. Forest plots

Appendix F. GRADE and/or GRADE-CERQual tables

Appendix G. PEM reanalysis

G.1. PEM reanalysis – Methods and rationale

G.2. PEM reanalysis – Summary of results

Immunomodulatory drugs

Antidepressants

Corticosteroids

Antihypertensive drugs

CNS stimulants

Antiviral drugs

Other drugs

G.3. PEM reanalysis – Reporting of PEM

G.4. PEM reanalysis – GRADE tables

Appendix H. Economic evidence study selection

Appendix I. Economic evidence tables

Appendix J. Excluded studies

Appendix K. MIDs for continuous outcomes

References

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