Evidence browser

Pain and SensitizationSleepCognitive Impairment

Possible Application of Melatonin in Long COVID.

Cardinali, Daniel P, Brown, Gregory M, Pandi-Perumal, Seithikurippu R·Biomolecules·2022

This review examines whether melatonin, a natural hormone that regulates sleep, might help people with long COVID who experience symptoms similar to ME/CFS—such as brain fog, fatigue, and muscle pain. Melatonin has several properties that could potentially help: it reduces inflammation, fights harmful molecules in the body, supports immune function, and protects nerve cells. The authors suggest melatonin might be worth studying further as a treatment for the lingering cognitive and pain symptoms some long COVID patients experience.

E3 PreliminaryCohortPEM unclearObservational

Clinical effects of wasabi extract containing 6-MSITC on myalgic encephalomyelitis/chronic fatigue syndrome: an open-label trial.

Oka, Takakazu, Yamada, Yu, Lkhagvasuren, Battuvshin et al.·BioPsychoSocial medicine·2022

Researchers tested whether wasabi extract—specifically a compound called 6-MSITC that has anti-inflammatory properties—could help people with ME/CFS. Fifteen patients took the supplement daily for 12 weeks, and many reported improvements in headaches, muscle pain, brain fog, and cognitive problems like word-finding difficulties. The study found measurable improvements in pain sensitivity and thinking speed, though overall fatigue scores did not change significantly.

Pain and SensitizationCognitive Impairment

E3 PreliminaryCohortPEM unclearCross-Sectional

Experiences of pain in paediatric chronic fatigue syndrome/myalgic encephalomyelitis: a single-centre qualitative study.

Serafimova, Teona, Ascough, Caitlin, Parslow, Roxanne Morin et al.·BMJ paediatrics open·2022

This study explored how children with ME/CFS experience pain by interviewing 13 young people (average age 15). Researchers found that pain is very common, highly varied, and significantly impacts daily life—affecting physical activity, eating, schooling, and mental health. Most importantly, the children reported that current treatments don't work well, highlighting an urgent need for better pain management options.

Migraine Is More Than Just Headache: Is the Link to Chronic Fatigue and Mood Disorders Simply Due to Shared Biological Systems?

Karsan, Nazia, Goadsby, Peter J·Frontiers in human neuroscience·2021

This review examines why migraine sufferers often experience fatigue, mood changes, and cognitive difficulties—symptoms that can occur hours or days before a headache arrives. Rather than being separate diseases, the authors suggest these symptoms may stem from shared brain chemistry problems in people with migraines, similar to what happens in ME/CFS and depression. The study proposes that migraine is fundamentally a disorder of how the brain processes sensory information, not just a headache condition.

E3 PreliminaryMechanismPEM not requiredMechanistic

Does muscular or mental fatigue have an influence on the nociceptive flexion reflex? A randomized cross-over study in healthy people.

Dhondt, Evy, Danneels, Lieven, Rijckaert, Johan et al.·European journal of pain (London, England)·2021

This study tested whether being physically or mentally tired changes how the body's spinal cord responds to pain signals. Researchers measured a reflex that happens in the spinal cord when stimulated with electrical pulses to a nerve in the leg, both before and after participants either rested, did tiring leg exercises, or completed a difficult mental task. They found that low-to-moderate levels of fatigue—whether physical or mental—did not change this spinal reflex, suggesting the body's pain-dampening systems stay stable even when tired.

E3 PreliminaryCohortPEM unclearObservational

An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue.

Teitelbaum, Jacob, Goudie, Sarah·Pharmaceuticals (Basel, Switzerland)·2021

This study tested a special form of red ginseng called HRG80 in people with ME/CFS, fibromyalgia, and post-COVID fatigue. Over one month, 188 patients took daily ginseng supplements and reported their symptoms. About 60% of participants felt better, with improvements in energy, mental clarity, sleep, and stamina.

Pain and SensitizationSleepCognitive Impairment

E3 PreliminaryMechanismPEM unclearCross-Sectional

Orthostatic stress testing in myalgic encephalomyelitis/chronic fatigue syndrome patients with or without concomitant fibromyalgia: effects on pressure pain thresholds and temporal summation.

van Campen, C Linda M C, Rowe, Peter C, Verheugt, Freek W A et al.·Clinical and experimental rheumatology·2021

This study tested how standing up quickly (which can trigger ME/CFS symptoms) affects pain sensitivity in ME/CFS patients. Researchers measured how much pressure patients could tolerate on their finger and shoulder before and after a tilt test. They found that ME/CFS patients became more pain-sensitive after the tilt test, meaning their bodies responded to pain more strongly than healthy people, and this effect was even more pronounced in those who also had fibromyalgia.

E3 PreliminaryReviewPEM not requiredReview-Narrative

[Endometriosis and chronic overlapping pain conditions].

Häuser, Winfried·Schmerz (Berlin, Germany)·2021

This review examines how endometriosis (a painful condition affecting the reproductive system) often occurs alongside other chronic pain conditions like fibromyalgia, ME/CFS, migraines, and others. The authors explain that these conditions share common underlying causes—such as childhood stress or trauma—and similar ways the nervous system processes pain signals. They recommend that doctors screen endometriosis patients for these overlapping conditions and use medications like amitriptyline or duloxetine combined with physical therapy and psychological support, rather than repeated surgeries.

E3 PreliminaryMechanismPEM unclearCross-Sectional

DNA Methylation and Brain-Derived Neurotrophic Factor Expression Account for Symptoms and Widespread Hyperalgesia in Patients With Chronic Fatigue Syndrome and Comorbid Fibromyalgia.

Polli, Andrea, Ghosh, Manosij, Bakusic, Jelena et al.·Arthritis & rheumatology (Hoboken, N.J.)·2020

This study found that people with ME/CFS and fibromyalgia have unusual patterns in how their genes are regulated, specifically involving a molecule called BDNF that affects pain and nerve function. Researchers measured genetic markers and protein levels in blood samples and found that changes in how BDNF genes are 'switched on and off' may explain why patients experience severe fatigue, pain, and widespread body aches.

The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms.

Hendrix, Jolien, Nijs, Jo, Ickmans, Kelly et al.·Antioxidants (Basel, Switzerland)·2020

This review examines how physical activity, pain, and a harmful process called oxidative stress (cellular damage from unstable molecules) interact in both healthy people and those with chronic pain conditions. The authors found that the relationships between these three factors are complicated and depend on the type of exercise and which person is being studied. They suggest that the nervous system's automatic functions and changes in how genes are expressed may help explain why these connections work differently in different people.

E3 PreliminaryReviewPEM not requiredReview-Narrative

Chronic Fatigue Syndrome and chronic pain conditions - vitally protective systems gone wrong.

Pedersen, Maria·Scandinavian journal of pain·2019

This review explains that ME/CFS and chronic pain conditions share important similarities—both involve protective body signals that were helpful in the short term but become problematic when they persist long-term. The authors suggest that our brain's tendency to anticipate and predict threats may play a role in keeping these conditions going, which helps explain why treatments focusing on stress relief and changing thought patterns can sometimes help patients improve.

An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens.

Paredes, Stephania, Cantillo, Santiago, Candido, Kenneth D et al.·International journal of molecular sciences·2019

This review article explains how a brain chemical called serotonin affects pain perception, and how female hormones (estrogens) can influence serotonin levels. The authors examine the connection between serotonin, hormones, and several pain conditions including irritable bowel syndrome, fibromyalgia, and migraines. They suggest that targeting serotonin and hormone pathways might offer new treatment options for pain in the future.

E3 PreliminaryTrialPEM not requiredRCT

Treatment for Gulf War Illness (GWI) with KPAX002 (methylphenidate hydrochloride + GWI nutrient formula) in subjects meeting the Kansas case definition: A prospective, open-label trial.

Holodniy, Mark, Kaiser, Jon D·Journal of psychiatric research·2019

Researchers tested a combination treatment called KPAX002—containing a stimulant medication (methylphenidate) plus vitamins and nutrients meant to support energy production in cells—in 17 people with Gulf War Illness. After 12 weeks, patients reported about 25% improvement in their overall symptoms, including better fatigue, brain fog, sleep, and pain. The treatment was generally safe and well-tolerated, though a larger, more rigorous study is needed to confirm these results.

Pain and SensitizationSleepCognitive Impairment

Pain and SensitizationCognitive Impairment

The link between idiopathic intracranial hypertension, fibromyalgia, and chronic fatigue syndrome: exploration of a shared pathophysiology.

Hulens, Mieke, Rasschaert, Ricky, Vansant, Greet et al.·Journal of pain research·2018

This review paper proposes that ME/CFS, fibromyalgia, and a condition called idiopathic intracranial hypertension (IICH—where pressure builds up around the brain) may share similar underlying causes. All three conditions cause widespread pain, fatigue, cognitive problems, and other symptoms that could potentially be explained by increased pressure in the fluid surrounding the brain and spinal cord.

HPV vaccination syndrome: A clinical mirage, or a new tragic fibromyalgia model.

Martínez-Lavín, Manuel·Reumatologia clinica·2018

Some people have reported developing chronic pain and autonomic symptoms (problems with heart rate, blood pressure, and sweating) after receiving the HPV vaccine. This article reviews whether this connection is real and suggests that if it exists, these cases might share similarities with fibromyalgia—a condition involving widespread pain and nervous system dysfunction. The authors propose that understanding fibromyalgia's mechanisms could help diagnose and treat patients who develop symptoms after HPV vaccination.

E3 PreliminaryDiagnosticPEM not requiredMethods-Paper

Clinical Criteria of Central Sensitization in Chronic Pelvic and Perineal Pain (Convergences PP Criteria): Elaboration of a Clinical Evaluation Tool Based on Formal Expert Consensus.

Levesque, Amélie, Riant, Thibault, Ploteau, Stéphane et al.·Pain medicine (Malden, Mass.)·2018

This study created a simple checklist to help doctors identify when chronic pelvic pain is caused by the nervous system becoming overly sensitive, rather than from a structural injury or disease they can see on tests. Experts agreed on 10 key signs to look for, including pain that changes in intensity, pain triggered by normal activities, and having other conditions like fibromyalgia or chronic fatigue syndrome alongside pelvic pain.

E3 PreliminaryReviewPEM not requiredReview-Narrative

Frontline Temporomandibular Joint/Orofacial Pain Therapy for Every Dental Practice.

Germain, Lisa, Malcmacher, Louis·Compendium of continuing education in dentistry (Jamesburg, N.J. : 1995)·2017

This article explains how dentists can help patients with temporomandibular joint (jaw joint) and orofacial pain using straightforward, conservative treatment approaches. The authors note that jaw pain often occurs alongside other pain conditions, including chronic fatigue syndrome (ME/CFS), and suggest that dentists with proper training can be a first line of care for these patients.

E3 PreliminaryDiagnosticPEM not requiredMethods-Paper

Development of the Sensory Hypersensitivity Scale (SHS): a self-report tool for assessing sensitivity to sensory stimuli.

Dixon, Eric A, Benham, Grant, Sturgeon, John A et al.·Journal of behavioral medicine·2016

Researchers created a new questionnaire called the Sensory Hypersensitivity Scale (SHS) to measure how sensitive people are to everyday sensations like touch, sound, taste, and temperature. The tool was tested on over 1,200 people and worked well at identifying those with heightened sensory sensitivity. People with fibromyalgia scored higher on the scale than those with other types of chronic pain, suggesting the tool could help identify central sensitization—a condition where the nervous system amplifies pain signals.

E3 PreliminaryCohortPEM not requiredCross-Sectional

HPV vaccination syndrome. A questionnaire-based study.

Martínez-Lavín, Manuel, Martínez-Martínez, Laura-Aline, Reyes-Loyola, Paola·Clinical rheumatology·2015

This study looked at people who developed long-lasting pain, fatigue, and heart/blood pressure problems shortly after receiving the HPV vaccine. Researchers used three validated questionnaires to assess 45 people from 13 countries. Most reported muscle pain, tiredness, and dizziness, and after an average of 4 years, 93% still had severe symptoms preventing them from working or going to school.