Discussion
FM is characterised by chronic pain at multiple specifical anatomical
sites lasting for more than 3 months and is usually accompanied by
clinical manifestations such as fatigue, muscle and joint stiffness,
sleep disturbance, irritative bowel syndrome, low energy, cognitive
dysfunction and depressive symptoms6. FM affects more
frequently female and it is estimated that between 2% and 8% of the
world’s population is afflicted7. The age range in
which FM generally appears is between 30 to 35 years8.
The quality of life in people with FM is severely impaired and the risk
of suicide associated with depression and global worsening of the mental
state are quite common in these individuals9.
The hypothesis that reduced oxygen availability could be the cause of
the structural and functional degeneration affecting the muscles of FM
patients dates back to the first half of the
1970s10.
Several works have shown that in FM patients, there is a reduction in
oxygen availability, either absolute or linked to a low tissue
extraction fraction, resulting in hypoperfusion/ischemia, which in turn
could play a key role in the onset of muscle pain, an element that
dramatically characterises the clinical picture of fibromyalgia
patients11.
Subsequently, research produced in order to define the pathogenesis of
FM piled up and several ideas were proposed. Enviromental, psychosocial
and genetic aspects have been implicated as being responsible for
reduced resilience to adverse stressful events, a condition that would
seem to make these individuals more vulnerable12. It
has been hypothesised that environmental factors such as adverse events
occurring early in lifetime, psychosocial stress, trauma and medical
diseases (as Lyme disease, Epstein Barr Virus infection, viral
hepatitis, Q fever) can trigger the development of
FM13.
Another work involves thalamic mast cells that seem to play a role in
the onset of inflammation and pain through the release of
pro-inflammatory mediators (interleukin, TNF-alpha) and the stimulation
of thalamic nociceptor neurons by direct and indirect
pathways14. Trauma and infection often precede the
onset of FM, suggesting a potential role for immune-mediated pathways.
Another fascinating theory being evaluated suggests changes in the serum
levels of certain neurotransmitters (serine and glutamate) linked in
turn to altered gut-brain cross
talk15. Several
works have shown that a reduced level of biogenic amine, an impaired
regulation of the hypothalamus-pituitary axis combined with an increased
concentration of excitatory neuro-molecules (in particular Substance P)
may play a central role in the onset of the clinical
pattern16-17.
To date, the dysfunction of the neurocircuits involved in the
perception, transmission and processing of nociceptive afferents is
considered a key element in the onset of FM symptoms, and indeed several
works have shown that impairments in the neurotransmission system are
able to affect pain perception, fatigue, sleep disturbances, anxiety
symptoms and depression. FM patients show high levels of norepinephrine
and glutamate, low levels of serotonin and
dopamine18-19. As noted above Substance P reaches
three times higher levels in the cerebral spinal fluid of FM patients
than in the healthy population20.
The extreme variety of symptoms and associated comorbidities make the
diagnosis of FM problematic. It is pretty frequent to observe the
association between FM and other diseases such as osteoarthritis,
rheumatoid arthritis and lupus. Many physicians are unfamiliar with the
diagnostic criteria, have no clinical experience with these patients and
are unaware of potential treatment options. These factors, as described
by Choy et al., lead to a diagnosis that often takes more than 2 years
and involves an average of 3.7 physicians per
patient21. It is clear that early diagnosis of FM is
essential in order to avoid aggravation of initial symptoms and the
development of vicious circles such as pain with immobility and/or pain
with mood disorders, conditions that can further complicate the
management of these patients. The diagnostic criteria for FM have
evolved progressively from the seminal work of the American College of
Rheumatology
(ACR)22to the
critical review published by the same author in 20165which is currently considered the reference point for the diagnosis of
FM. Briefly, the diagnosis is based on the finding of the following
clinical symptoms:
- Widespread Pain Index (WPI) ≥ 7 and Symptom Severity Scale
(SSS) ≥ 5 or WPI of 4-6 and SSS
≥9
- Generalised pain, present in at least 4 of the 5 topographically
defined areas
- Symptoms must have been generally present for at least 3 months
The anatomo-topographical areas considered are defined as right and left
upper area, right and left lower area and axial area. Some authors
recently stated that patients should be screened for WPI and that those
with positive WPI should be further screened for the presence of the
main symptoms of FM in accordance with the 2016 criteria of the
ACR23.
Unfortunately, to date there is no generally accepted and effective
cure, the treatment is multidisciplinary and, consequently, the
different pieces of the therapeutic puzzle employed focus on controlling
and managing the pain symptoms. Therapy is based on the combined use of
different categories of drugs (antidepressants, anticonvulsants, muscle
relaxants, analgesics, hypnotics, antipsychotics, cannabis and
cannabinoids) along with non-pharmacological therapies such as fitness,
psychotherapy, spa therapy, tai chi, qigong, yoga, mindfulness,
hypnosis, acupuncture, thermal and electrical energy. In fact, their
combined use has been shown to alleviate pain with variable and
time-limited efficacy.
HBOT is a procedure in which patients breathe 100 % oxygen inside a
pressurised multiplace hyperbaric chamber at a level above sea level.
The Undersea and Hyperbaric Medical Society (UHMS) has determined that
HBOT can only be defined as such if the pressure achieved in the
hyperbaric chamber is 1.4 ATA or higher24. In clinical
setting, applied pressures usually range from 2 to 3 ATA. Under
hyperbaric conditions, in patients with healthy lungs and normal
arterial flow, alveolar partial pressure of oxygen (PaO2) is acutely
elevated in proportion to atmospheric pressure, and at 2 ATA, PaO2 and
tissue oxygen pressure increase to 1500 mmHg and 200 mmHg, respectively.
HBOT is based on several physiological principles relating to the
response of gases to pressure and, more precisely, the response of
oxygen to pressure. Indeed, the concentration of dissolved oxygen in the
plasma can be strongly influenced by HBOT. In line with Henry’s law, an
increase in pressure causes more gas to go into solution and hence more
oxygen to be carried into the plasma. The rise in partial pressure
increases the driving force of diffusion and thus increases the
diffusion range, as defined by Fick’s law. Furthermore, it is the oxygen
dissolved in the plasma that is more bioavailable to the tissue. At 3
ATA, HBOT increases the level of oxygen dissolved in plasma from 0.3
ml/dL to 6 ml/dL assuring the amount of oxygen needed for metabolism
independently of the amount chemically bound to haemoglobin.
Although to date there aren’t official guidelines supporting the use of
HBOT in the treatment of FM patients, the first report on its use in FM
is from 200425.
Since then, a large number of papers have been conducted to validate the
effectiveness of HBOT as a treatment option in FM sufferers, and to
clarify the molecular mechanisms by which HBOT is able to produce
positive effects.
HBOT represents a non invasive potential therapeutic option, as it is
able to reduce the oxidative stress occurring in hypoxic tissues.
Indeed, numerous data show an alteration in the pro- and anti-oxidative
balance in FM patients characterised by a reduced function of super
oxide dismutase (SOD), nicotinamide adenine dinucleotide phosphate
oxidase (NADPH) and catalase (CAT) data that correlate well with the
severity of pain and fatigue assessed by FIQR26. HBOT
is able to deactivate caspase 3 and caspase 9 and increases the
expression of the Bcl-2 gene, which consequently increases regulated
apoptosis. This finding suggests that the increased oxygen availability
produced by HBOT reduces mitochondrial apoptosis and preserves
mitochondrial
function27.
Furthermore, in animal models HBOT is able to reduce lipo-peroxidation
and pro-oxidative processes28. Research in animal
models has revealed that muscle tissue ischemia is a severe activator of
unmyelinated muscle nociceptors, which can facilitate central
sensitisation29. Reduced oxygen availability in the
muscle tissue of FM patients influences structural and functional
changes, which in turn play a role in the sensitisation of central and
peripheral pain receptors, with altered central pain perception and
processing. This finding also supports the therapeutic role that HBOT
may play in these
patients30.
Moreover, HBOT has anti-inflammatory action, promotes neuroplasticity,
optimises mitochondrial functioning and stimulates nitric oxide, actions
that may reduce hyperalgesia and facilitate the release of endogenous
opioids31. Furthermore, Guggino et
al32 reported how the immune system may play a role in
the pathogenesis of FM and outlined the therapeutic impact of HBOT by
describing changes in the production of proinflammatory cytokines (IL-
1RA, IL-6, IL-8) by CD4 T-cell subpopulations. These results support the
idea that HBOT is an effective, safe and rapid means of treating the
various symptoms of FM.
Criticism of this treatment is related to the overproduction of oxygen
free radicals that could be responsible for an exaggerated pro-oxidative
response. In our clinical experience, the oxidative stress produced by
weighted use according to HBOT guidelines did not lead to adverse
effects. A possible explanation could be the so-called
“hyperoxic-hypoxic paradox” 33. Let us try to
elucidate its meaning concisely. Cellular respiration is a complex
biochemical process based at the mitochondrial level and involving the
complete oxidation of a glucose molecule with formation of CO2, H2O and
production of adenosine tri-phosphate (ATP) molecules. Hypoxia results
in reduced production of ATP. It is also one of the most strong inducers
of gene expression capable of influencing changes in metabolic
structure, regenerative processes, including angiogenesis, as well as
mobilisation migration and differentiation of stem
cells 34.
Variations in oxygen levels in hyperoxic-hypoxic sense are detected by
chemoreceptors and are able to induce metabolic changes by molecular
mechanisms. Of more interest is that at the cellular level, is
fluctuations in free oxygen that are recognised and interpreted as a
reduction in oxygen availability rather than absolute oxygen values. In
patients undergoing HBOT there is a fluctuation in oxygen concentration,
which in hyperbarism rises from 21% to 100% and then returns to basal
levels at the end of treatment. The adaptive response to repeated
hyperoxia leads to an up-regulation in scavengers production with a
concomitant increase in ROS production. The return to physiological
oxygenation levels (ambient air) is characterised by a low
ROS/Scavengers ratio and this is related to the different half-lives
that ROS and Scavengers have (the former having a half-life that is
about half that of the latter). This up regulation of scavengers could
play a protective role by counterbalancing the overproduction of oxygen
free radicals. Thus, repeated
exposure to hyperoxia mimics at the molecular level the hypoxic scenario
by triggering the transcriptional cascade underlying the molecular
effects induced by HBOT. However, to date HBOT has produced positive
effects in several clinical trials, with an overall increase in
neurological functions affected by FM 35-36.
It is evident that the results of a case report have limitations related
to the individual experience reported, which clearly cannot be
considered reproducible with absolute reliability on large populations.
In this perspective, one must consider the enormous difficulty with
which researchers manage to produce clinical trials that enrol large
populations of patients, and this is unfortunately linked to several
factors such as the lack of knowledge that many doctors have about the
indications for HBOT, the low level of information that they have about
the powerful role that HBOT may plays as adjuvant in the treatment of
this kind of patients, the scarce territorial spread of hyperbaric
chambers, and the difficulties linked to managing the economic costs
that hyperbaric treatment requires, especially for a pathology such as
FM that is not supported by any guidelines to date. Since the conclusion
of the hyperbaric treatment, the patient has been following the
multi-structurated therapy proposed by the rheumatology and report that
she is feeling well, no longer reporting the alterations in the
psycho-neuro-sensory and functional spheres that had severly impaired
her quality of life before HBOT.