Researchers
Arne Wyns, Jolien Hendrix, Elke De Bruyne, Lode Godderis, Jente Van Campenhout, Jo Nijs, Yanthe Buntinx, Huan-Yu Xiong, David Rice, Daniel Chiang, and Andrea Polli.
Institution
Pain in Motion (PiM) International Research Group, Vrije Universiteit Brussel, Belgium
Publication
Int. J. Mol. Sci. 2026, 27, 826
Funding
ME Research UK and the European College for Lymphatic Therapy in the Netherlands. It is worth noting that while this study is not directly funded by ME Research UK, the group used samples obtained during their previous ME Research UK-funded project.
Key findings
- People with ME/CFS and comorbid fibromyalgia (ME/CFS/FM) reported significantly worse symptom outcomes compared with healthy controls.
- People with ME/CFS/FM had a significantly higher pain sensitivity compared to their matched counterparts.
- Findings suggest that the endogenous opioid system, a system central to pain regulation, may be dysregulated in people with ME/CFS/FM.
- More research is needed to validate the findings of this study in larger sample sizes, and to consider how the results tie into the complex disease mechanisms underlying ME/CFS/FM.
About the study
Dysregulation of the endogenous opioid system, a system central to pain regulation, may be involved in the disease mechanisms underlying ME/CFS and fibromyalgia, two illnesses characterised by overlapping symptoms including chronic pain and fatigue.
Therefore, the team of researchers at Vrije Universiteit Brussel, who have previously completed several ME Research UK-funded studies looking at areas including the role of brain-derived neurotrophic factor genetics, epigenetics and protein expression in people with both ME/CFS and fibromyalgia (ME/CFS/FM), set out to investigate whether changes in gene activity that do not alter the DNA sequence itself (epigenetic modifications) could lead to dysregulation of the endogenous opioid system. They also wanted to assess whether this dysregulation might be linked to poorer clinical outcomes – such as higher fatigue and increased pain sensitivity – for people with ME/CFS/FM.
Specifically, the research team hypothesised that “The opioid system of patients with ME/CFS and FM is dysregulated and that OPRM1 epigenetic regulation, at least partially, drives this dysregulation and may account for poorer clinical outcomes”
Notably, OPRM1 is a gene which makes a receptor – the ‘mu opioid receptor’ – which is crucial for pain regulation.
What did they do?
In this study, 28 people with “a clear diagnosis of ME/CFS, according to the Centre for Disease Control and Prevention Criteria (the IOM 2015 Diagnostic Criteria), and FM, according to the American College of Rheumatology Criteria (ACR-2011)” alongside 26 matched healthy controls, attended hospital appointments for study assessment on two separate mornings, four days apart. Data collection was performed at the Department of Internal Medicine and Endocrinology of the University Hospital Brussels from August 2015 to March 2017.
At each visit, information relating to the characteristics (such as age and body mass index), general health, and physical activity of the participants was collected using questionnaires. Pain sensitivity was also assessed, and blood samples were taken.
The researchers then used complex methods to prepare the blood samples for epigenetic analysis, and looked at whether there were differences in findings between the participants with ME/CFS/FM and the healthy controls.
What did they find?
Results were complex but, in short, there were significant differences between participants with ME/CFS/FM and healthy controls:
- People with ME/CFS/FM reported significantly worse symptom outcomes compared with healthy controls.
- People with ME/CFS/FM also had a significantly higher pain sensitivity compared to their matched counterparts.
- Participants with ME/CFS/FM showed significantly higher methylation in the OPRM1 promoter region.
Importantly, the findings suggest that the opioid system may indeed be dysregulated in people with ME/CFS/FM.
Limitations
There are several limitations of the study noted by the research team, including:
- The sample size may not have been optimal for the research question, and therefore the results should, according to the authors, be interpreted with “the necessary caution”.
- The methods used provided a “snapshot” of methylation in the OPRM1 promoter region, rather than the whole picture. In the paper the team note that going forward, research should consider “mapping the epigenome on a larger scale“.
Conclusions
The results of this study support dysregulation of the opioid system in people with ME/CFS/FM compared with healthy controls. However, more research is needed to validate the findings of this study in larger sample sizes, and to consider how the results tie into the complex disease mechanisms underlying ME/CFS/FM.
Importantly, the team noted that “To progress in unravelling these mechanisms, we must emphasize the heterogeneous socioeconomic, psychological, and biological nature of the conditions”. ME Research UK adds that in future, it would also be useful to look at whether the dysregulation can be observed in those with ME/CFS, and in those with FM, separately.
