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\begin{document}

\title{Fibromyalgia: could hyperbaric oxygen therapy make the difference? Our
experience.}



\author[1]{Andrea Neville Cracchiolo}%
\author[1]{Daniela Maria Palma}%
\author[1]{Fabio Genco}%
\author[1]{Marco Palmeri}%
\author[1]{Alessandra Teresi}%
\author[1]{LEILA ZUMMO}%
\author[2]{Carmelo Gigliuto}%
\author[3]{Erik Flavio Giuseppe Saporito}%
\author[4]{Angela Ferruzza}%
\author[5]{Tommaso Piccoli}%
\affil[1]{ARNAS Civico Di Cristina Benfratelli}%
\affil[2]{Umberto I di Siracusa Hospital}%
\affil[3]{Cannizzaro Hospital}%
\affil[4]{Villa Sofia Cervello United Hospitals}%
\affil[5]{Policlinico di Palermo}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\textbf{Introduction}

Fibromyalgia (FM) is defined as a ``syndrome of central sensitisation
with dysfunction of the neuronal circuits involved in the perception,
transmission and processing of nociceptive afferents, with pain
predominantly expressed in the musculoskeletal
system''\textsuperscript{1}. It is an incurable syndrome of unknown
origin with signs and symptoms often similar and overlapping with those
of other syndromes. This condition, unfortunately with high frequency,
delays its diagnosis. The pathogenetic mechanism underlying the clinical
picture is alteration of the nociceptive system.

Several hypotheses have been proposed concerning the pathogenesis of FM
and the management of FM patients requires a multidisciplinary approach.

Accumulating evidence suggests that hyperbaric oxygen therapy (HBOT) is
a non-invasive modality with lasting efficacy to treat
FM\textsuperscript{2}. HBOT is defined by the Undersea and Hyperbaric
Medical Society (UHMS) as a treatment in which a patient intermittently
breathes 100\% oxygen while the treatment chamber is pressurised to
above sea level pressure (1 atmosphere absolute, 1 ATA = 760
mmHg)\textsuperscript{3}. HBOT is able to induce many interesting
effects on plasma oxygen concentration. Based on Henry's Law, increased
pressure will cause more gas to go into solution, and therefore,more
oxygen will be transported in the plasma. As a result a lot of oxygen
becomes available for the microcirculation, resulting in significant
improvement of all metabolic parameters, which have also been shown in
several works to influence neurological functions\textsuperscript{4}. We
report about a case of woman affected by FM and treated with HBOT as
adjuvant, experimental and non conventional therapy.

\textbf{Case Presentation}

In January 2021 a 54-year-old Caucasian woman with a negative medical
past history reported pain in her left arm 24 hours after receiving the
first dose of the Pfizer SARS-Covid 19 vaccine. Localised pain in the
injection zone (the triceps muscle of the left arm) was accompanied by
the onset of high fever (40\selectlanguage{ngerman}°C), intense headache with vomiting and
abdominal pain. After 48 hours there was defervescence with return to
normo-thermia but progressive appearance of fatigue. Subsequently
patient report a relief of pain in the left arm with progressive
development of constant, severe and persistent pain in occipital and
back neck area, low back and legs with a marked sense of heaviness in
the lower limbs. The patient also complained of progressive difficulty
in walking, for which the use of nordic walking sticks was necessary.
Furthermore, she reported stiffening of the facial muscles with pain
defined as intense, mental fogginess, severe short-term memory
involvement and progressive depression, symptoms that had undoubtedly
caused a significant impairment in her quality of life.

The patient underwent routine blood sample tests (blood count, ESR, PCR,
protein electrophoresis, AST, ALT, gamma GT), as well as more specific
immuno-enzymatic tests (serum kappa and lambda chains, IgG, IgA, IgM,
anti-nuclear antibodies, ENA, ANA with subclasses). The exams showed no
values outside the standard range. Only a slight increase in ESR and a
reduction in 25-OH-vitamin D levels was shown. The patient also
performed total body CTs, spine MRI, femoral and lumbar bone
densitometry from which no structural morphological alteration was
highlighted except for an initial picture of osteoporosis. The exclusion
of inflammatory disease, although some rheumatic diseases could coexist,
suggested a possible diagnosis of FM and thus rheumatologists have
sought its diagnostic criteria\textsuperscript{5}. The persistence of
pain was well over 3 months (the patient reported the onset of symptoms
about 18 months ago).

The following questionnaires were administered: Widespread Pain Index
(WPI), Symptom Severity Scale (SSS), Revised Fibromyalgia Impact
Questionnaire (FIQR), Pittsburgh Sleep Quality Index (PHQI), Generalized
Anxiety Disorder Screener (GAD-7), Functional Assessment of Chronic
Illness Therapy Fatigue (FACIT-F). The scores reported from each
individual questionnaires carried out before the start of HBOT were as
follows: WPI=18, SSS=10, FIQR=96, PHQI=17, GAD-7=14, FACIT=12.

Thus she started a multidisciplinary therapeutic course based on
antalgic therapy, physiotherapy, psychological support, relaxation
techniques and healthy nutrition.

Among the various therapies, HBOT was indicated as an experimental
non-conventional treatment. The patient underwent forty sessions of HBOT
at 2.4 ATA (absolute atmospheres), total oxygen time 60 minutes per
session, once a day, five times a week, performed at the multi-place
chamber (Sistemi Iperbarici Integrati-Camera Iperbarica Mod 2000) of the
Hyperbaric Medicine Centre of ARNAS Ospedale Civico Di Cristina
Benfratelli, Palermo, Italy. Therapy started in the first week of
September and ended in mid-November 2022. Throughout each session, the
patient showed stable vital parameters (blood pressure, heart rate,
oxygen saturation and body temperature). Blood tests, markers of
flogosis and haematochemical examinations carried out at mid term and at
the end showed no change in values outside the normal range.

The patient underwent 40 sessions of HBOT. The clinical improvement
achieved was evident and affected all symptom areas reported before
treatment. In particular, there was a complete recovery of mobility with
the avoidance of walking sticks, an increase in muscular strength
evidenced by the ability to climb several flights of stairs and to walk
long distances independently. The patient reported a drastic reduction
in pain symptoms evident from the moment she woke up in the morning, a
significant improvement in sleep quality, previously reported as light,
non-restorative and with multiple breaks. The highly debilitating sense
of fatigue was reported after treatment as markedly reduced and in any
case easily manageable. In addition, a significant change in cognitive
abilities was reported, with disappearance of mental fogginess and
recovery of short-term memory. In summary, there was a significant
improvement in quality of life with the disappearance of the depression
into which the patient had plunged, a condition confirmed by
psychological advice at the end of the hyperbaric treatment. The scores
reported by each individual test at the end of HBOT are shown below:
WPI=6, SSS=3, FIQR=13, PHQI=2, GAD-7=3, FACIT=42.

\textbf{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 symptoms\textsuperscript{6}. FM affects more
frequently female and it is estimated that between 2\% and 8\% of the
world's population is afflicted\textsuperscript{7}. The age range in
which FM generally appears is between 30 to 35 years\textsuperscript{8}.
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 individuals\textsuperscript{9}.

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 1970s\textsuperscript{10}.
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
patients\textsuperscript{11}.

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 vulnerable\textsuperscript{12}. 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
FM\textsuperscript{13}.

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
pathways\textsuperscript{14}. 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 talk\textsuperscript{15}. 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
pattern\textsuperscript{16-17}.

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
dopamine\textsuperscript{18-19}. As noted above Substance P reaches
three times higher levels in the cerebral spinal fluid of FM patients
than in the healthy population\textsuperscript{20}.

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
patient\textsuperscript{21}. 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)\textsuperscript{22}to the critical review published
by the same author in 2016\textsuperscript{5}which 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) \selectlanguage{english}[?] 7 and Symptom Severity Scale (SSS) \selectlanguage{english}[?] 5
or WPI of 4-6 and SSS \selectlanguage{english}[?]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
ACR\textsuperscript{23}.

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 higher\textsuperscript{24}. 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 2004\textsuperscript{25}. 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 FIQR\textsuperscript{26}. 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 function\textsuperscript{27}. Furthermore, in animal
models HBOT is able to reduce lipo-peroxidation and pro-oxidative
processes\textsuperscript{28}. Research in animal models has revealed
that muscle tissue ischemia is a severe activator of unmyelinated muscle
nociceptors, which can facilitate central
sensitisation\textsuperscript{29}. 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 patients\textsuperscript{30}. 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
opioids\textsuperscript{31}. Furthermore, Guggino et
al\textsuperscript{32} 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'' \textsuperscript{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
\textsuperscript{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
\textsuperscript{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.

\textbf{Conclusion}

We report on our experience with the use of HBOT in the treatment of a
patient suffering from FM. FM is a very invalidating disease often
afflicting young people. The impaired quality of life of these patients
has serious ripercussions on public economy. HBOT is a asafe therapy to
experiment with FM because it could improve the quality of life of these
patients and reduce its economic impact on society. Further studies are
needed to improve our understanding of the mechanisms underlying the
effects of HBOT and clarify its role in the treatment of these chronic
disorders.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest.

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