Researchers in a clinical trial at Rice University in Houston, Texas, along with two Israeli research institutes, have determined that after two months of hyperbaric oxygen therapy, the condition of every one of 48 female participants diagnosed with fibromyalgia who completed the program improved. Brain scans of the women before and after treatment corroborated the theory that abnormal responses in pain-related areas of the brain may be responsible for the syndrome, and that HBOT can actually catalyze healing of the malfunctioning areas of the brain.
Results of the study have been published in the open-access journal PLOS One in a research article entitled “Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome – Prospective Clinical Trial“ (Published: May 26, 2015 PLoS ONE 10(5): e0127012. doi:10.1371/journal.pone.0127012), coauthored by Shai Efrati, Ham Golan, Olga Volkov, Gregori Fishlev, Jacob Bergan and Mony Friedman of the Sackler School of Medicine at Tel Aviv University and the Assaf Harofeh Medical Center, Zerifin, Israel; Yair Bechor of the Institute of Hyperbaric Medicine at Assaf Harofeh; Yifat Faran of Ashkelon Academic College, Israel; Shir Daphna-Tekoah of Ashkelon Academic College and Kaplan Medical Center, Israel; Gal Sekler of Tel Aviv University; Jacob Ablin of the Tel Aviv Sourasky Medical Center and Tel Aviv University; and Dan Buskila of Ben-Gurion University of the Negev, Israel.
The scientists note that Fibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair quality of life of up to 24 percent of the population (although FMS incidence guesses are all over the lot and as low as 2 to 4 percent of adult Americans). Women disproportionately suffer from the disorder, with a lopsided 9:1 female-to-male incidence ratio. Whatever the total number of affected, FMS is now the second most common disorder, after osteoarthritis, observed by rheumatologists, its defining symptoms including chronic widespread pain, intense pain in response to tactile pressure (allodynia), prolonged muscle spasms, weakness in the limbs, nerve pain, muscle twitching, palpitations and diffuse tenderness, all accompanied by fatigue, sleep disturbance and cognitive impairments. The disease can later include problems with short- and long- term memory, short-term memory consolidation, impaired speed of information processing, reduced attention span and limited multi-tasking performance.
FMS is a persistent disorder with symptoms that devastatingly affect people’s lives, including limits on their ability to engage in everyday activities, limited ability to maintain outside work and difficulties maintaining normal relationships with family, friends and employers, which in turn can lead to occurrence of anxiety and depression in many FMS patients.
The study coauthors maintain that FMS is an important representative example of central nervous system sensitization and is associated with abnormal brain activity. Key symptoms include chronic widespread pain, allodynia and diffuse tenderness, along with fatigue and sleep disturbance. The goal of this prospective, active control, crossover clinical trial (ClinicalTrials.gov NCT01827683) was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on symptoms and brain activity in persons with FMS.
Patients were randomly assigned to treated and crossover groups: The treated group cohort were evaluated at before and after receiving HBOT. Patients in the crossover-control group were evaluated three times: at baseline, after a control period of no treatment, and after HBOT. Evaluations consisted of physical examination, including a tender point count and pain threshold testing, extensive evaluation of quality of life, and single photon emission computed tomography (SPECT) imaging for evaluation of brain activity.
The HBOT protocol involved 40 sessions, lasting 90 minutes each over five days a week intervals in 100 percent oxygen at 2ATA inside a hyperbaric chamber. Sixty female patients were originally enrolled between the ages of 21-67 years and who had been diagnosed with FMS at least two years earlier. The PLOS One article coauthors report that HBOT led to significant amelioration of all FMS symptoms in both trial groups, with significant improvement in life quality.
Those in the crossover-control group experienced no improvement in their conditions until, after the two-month control, they were given the same HBOT treatment as the first group and experienced the same relief, according to the researchers who note that SPECT imaging analysis revealed rectification of abnormal brain activity in the subjects, decrease of hyperactivity mainly in the posterior region and elevation of reduced activity mainly in frontal areas. No improvement in any of the parameters was observed following the control period.
The researchers noted the successful treatment enabled patients to drastically reduce or even eliminate their use of pain medications. The intake of the drugs eased the pain but did not reverse the condition, while HBOT did reverse the condition, the researchers wrote, concluding that their study provides evidence that HBOT can improve symptoms and life quality for FMS patients, and moreover it shows that HBOT can induce neuroplasticity and significantly rectify abnormal brain activity in pain related areas of FMS patients.
FMS is not completely understood, in part because there is no evidence of a single event that causes fibromyalgia. Rather, many physical and/or emotional stressors may trigger or aggravate symptoms, including certain infections such as viral illness or Lyme disease, as well as emotional or physical trauma. These vague and general characteristics have made establishing proper diagnostic criteria for FMS difficult. The American College of Rheumatology (ACR) introduced the first fibromyalgia classification in 1990, but over time those criteria have been challenged by conceptual and practical objections. For example, many physicians did not know how to evaluate the FMS “tender points.” Another reservation was that important aspects of FMS such as fatigue and cognitive symptoms were not included in the 1990 criteria, and some critics have questioned the validity of defining fibromyalgia as a unique syndrome because of overlap between its symptoms and those of other conditions such as chronic fatigue syndrome.
Toward resolution of the difficulties associated with the classification and diagnosis of FMS, researchers are proposing a new, simple practical criteria that does not require tender point examination but still correctly classifies almost 90 percent of cases diagnosed by the 1990 ACR classification criteria.
Partly due to these diagnostic and classificational controversies, there is no efficient cure for FMS and no consensus regarding treatment, which will depend on the classification of choice. Those who consider FMS a neurological disorder advocate pharmacotherapy, although all current treatments, such as prescribed medications, aerobic exercises and cognitive behavioral therapies, consist of symptom management. Integrated programs based on these treatments have been shown to alleviate pain and some other symptoms but with only limited effectiveness.
The intensity of pain sensation is determined by relevant sensors recording the pain’s location and processing of that information by the brain. Comparison between SPECT imaging of FMS patients and healthy subjects revealed elevated activity in the somatosensory cortex and reduced activity in the frontal, cingulate, medial temporal and cerebellar cortices. These results are consistent with earlier studies based on fMRI imaging. Other fMRI studies have found that depressive symptoms in FMS were associated with the pain response in areas of the brain that participate in interpretation and assignment of the pain sensation, but not in areas involved in sensory processing of the input signal — findings that might indicate amplified pain sensation in FMS patients as being largely associated with higher level processing of information in the brain. However, there is ongoing controversy, with many rheumatologists taking the opposite stand on this issue.
The study coauthors say their finding that pain amelioration in those patients who responded to the HBOT treatments goes hand-in-hand with changes in brain activity provide important validation to the idea that in many FMS patients the syndrome is associated with abnormal pain processing in the brain. This explanation is in opposition to the stand maintained by other rheumatologists who contend that FMS is a sort of peripheral small fiber inflammation. The researchers agree that it’s likely that the latter is the cause of FMS in some patients, but contend that claiming it is the only cause stands in contradiction to a wide body of literature, for example failing to explain why FMS appears in many patients following a traumatic brain injury.
They observe that evidence suggests that fibromyalgia pain results primarily from pain processing pathway abnormalities, that may be described as the volume of the neurons being set too high. This hyper-excitability of pain processing pathways and under-activity of inhibitory pain pathways in the brain result in the affected individual experiencing pain, and since some neuro-chemical abnormalities that occur in fibromyalgia can also regulate mood, sleep and energy, it may explain why mood, sleep and fatigue problems are commonly fibromyalgia co-morbidities.
Possible solution: Hyperbaric oxygen therapy (HBOT)
The scientists contend that clearly, new methods should be examined in an effort provide FMS patients some sustained relief. Their study was motivated by a hypothesis that hyperbaric oxygen therapy (HBOT) can rectify (Photo Courtesy of the Sagol Center for Hyperbaric Medicine and Research) abnormal brain function underlying the FMS symptoms based on new trials demonstrating that HBOT can induce neuroplasticity that leads to repair of chronically impaired brain functions and improved quality of life in post-stroke patients and mild Traumatic Brain Injury (mTBI) patients with prolonged post concussion syndrome (PCS), even years after the brain insult occurs. They suggest that it is therefore plausible that increasing oxygen concentration by HBOT can change brain metabolism and glial function to rectify the FMS-associated brain abnormal activity — it having already been demonstrated that hyperbaric oxygen exposure induces significant anti-inflammatory effect in different conditions and pathologies, and also demonstrated that repetitive HBOT may attenuate pain by reducing production of glial cells’ inflammatory mediators.
The current study’s goal was to provide firm evaluation of the HBOT effect on brain activity and well-being of FMS patients and to look for correspondence between changes in brain activity as assessed by SPECT imaging and improvements in the FMS symptoms. The coauthors maintain that What makes the results of this study particularly convincing, is the good correspondence between the physiological improvements and the changes in brain functionality as detected by the SPECT scans, as well as the good agreement with the abnormal brain activity of FMS patients.
“More than 90 percent of those diagnosed with the syndrome are women, says study lead author Eshel Ben-Jacob, an adjunct professor of biosciences at Rice University who developed the analytical method used to show the association between patients’ improvement and changes in their brains. Dr. Ben-Jacob is a senior investigator at Rice’s Center for Theoretical Biological Physics and a professor of physics and member of the Sagol School of Neuroscience at Tel Aviv University.
“Symptoms in about 70 percent of the women who took part have to do with the interpretation of pain in their brains,” Dr. Ben-Jacob notes in a release. “They’re the ones who showed the most improvement with hyperbaric oxygen treatment. We found significant changes in their brain activity.”
“Scientists have not pinned down the syndromes cause, although another recent PLOS One study identified a possible RNA-based biomarker for its diagnosis. A variety of treatments from drugs to lifestyle changes have been tried to relieve patients suffering, with limited success,” Dr. Ben-Jacob continues.
That study, entitled “Identification of a MicroRNA Signature for the Diagnosis of Fibromyalgia” (March 24, 2015 PLOS ONE 10(3): e0121903. doi:10.1371/journal.pone.0121903) is coauthored by Germán Cerdá-Olmedo , Armando Vicente Mena-Durán , Vicente Monsalve, and Elisa Oltra of the Facultad de Medicina, Universidad Católica de Valencia “San Vicente Mártir”, and the, Cátedra Umivale en innovación e investigación en patologías del trabajo, both in Valencia, Spain.
The Spanish researchers note that diagnosis of FMS is a challenging process hindered by symptom heterogeneity and clinical overlap with other disorders. The aim of their study was to identify changes in miRNA expression profiles (miRNome) of FMS patients toward development of a quantitative diagnostic method. In addition, they suggest that knowledge of FMS patient miRNomes should lead to a deeper understanding of the etiology and/or symptom severity of this complex disease. Their research leads them to propose a signature of five strikingly downregulated miRNAs (hsa-miR223-3p, hsa-miR451a, hsa-miR338-3p, hsa-miR143-3p and hsa-miR145-5p) to be used as biomarkers for FMS diagnosis, although they say validation in larger study groups is required before the results can be transferred to the clinic.
“Most people have never heard of fibromyalgia,” observes Dr. Ben Jacob. “And many who have, including some medical doctors, don’t admit that this is a real disorder. I learned from my M.D. friends that this is not the only case in which disorders that target mainly women raise skepticism in the medical community as to whether they’re real or not. However, these days there are increasing efforts to understand the effect of gender on body disorders.”
Patients who had fibromyalgia in addition to their post-concussion symptoms had complete resolution of the symptoms, says Dr. Shai Efrati, lead author of the PLOS One hyperbaric treatment study article, and head of the research and development unit at the Assaf Harofeh Medical Center and a member of the Sagol School of Neuroscience at Tel Aviv University. Dr. Efrati notes that his own mother suffers from FMS.
Photo Courtesy of the Sagol Center for Hyperbaric Medicine and Research
Hyperbaric oxygen chambers that expose patients to pure oxygen at higher-than-atmospheric pressures are commonly used to treat patients with embolisms, burns, carbon monoxide poisoning and decompression sickness (known to deep-sea divers as “the bends”), among many other conditions. (Photo Courtesy of the Sagol Center for Hyperbaric Medicine and Research)
One effect of exposure in these chambers is to push more oxygen into a patient’s bloodstream, and thereby delivered to the brain. Dr. Efrati’s earlier trials found HBOT induces neuroplasticity that results in repair of chronically impaired brain functions and improved quality of life for post-stroke and mild traumatic brain injury patients, even years after the initial injury.
Dr. Ben-Jacob says two patients in particular lobbied for organization of the study: an Oxford graduate student who developed fibromyalgia after suffering a traumatic brain injury in a train crash and a professor of sociology who specializes in post-traumatic stress disorders due to child abuse and who had suffered from fibromyalgia for many years. By the end of treatment both women showed remarkable improvement, Dr. Ben-Jacob reports.
Dr. Efrati notes that some patients will likely require follow-up sessions, observing that the abnormalities in brain regions responsible for chronic pain sensation in fibromyalgia patients can be triggered by different events, so accordingly long-term response may be different. “We have learned, for example, that when fibromyalgia is triggered by traumatic brain injury, we can expect complete resolution without any need for further treatment,” he says. “However, when the trigger is attributed to other causes, such as fever-related diseases, patients will probably need periodic maintenance therapy.”
Dr. Efrati says the study findings warrant further investigation, and that the results are of significant importance since, unlike current treatments offered for fibromyalgia patients, HBOT is not aiming for just symptomatic improvement, but for the actual cause of the brain pathology responsible for the syndrome. Ergo: it means that brain repair, including even neuronal regeneration, is possible even for chronic, long-lasting pain syndromes, and we can and should aim for that in any future treatment development.
The PLOS One research article can be found at:
Sagol School of Neuroscience
Assaf Harofeh Medical Center
Sagol Center for Hyperbaric Medicine and Research
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