Efficacy And Safety Of Hyperbaric Oxygen Therapy For Fibromyalgia: A Systematic Review And Meta-analysis Part 2

Fatigue

Three studies 34 37 showed that HBOT could reduce fatigue in FM patients, while Curtis et al32 reported that  HBOT had no significant effect on fatigue in FM. Studies have shown that HBOT reduced fatigue in chronic fatigue syndrome,45 which was attributed to its ability to reduce reactive oxygen species and acid-lactic acid levels, as well as muscle fatigue after exercise.46 HBOT alleviated fatigue in FM patients, possibly because HBOT increased oxygen supply to the musculoskeletal system, thereby activating cellular activity and promoting the metabolism of fatigue-related substances.47 Clinical studies have shown that increased plasma proinflammatory cytokine levels trigger symptoms such as fatigue, fever, sleep, pain and myalgia in FM patients.48 HBOT can improve FM symptoms by reducing the upregulation of proinflammatory cytokines in FM. Atzen et al37 proposed that the fatigue of FM was only improved after 20 treatments, indicating that the number of treatments would affect the efficacy of HBOT. In Curtis et al’s study,32 the lack of an effect of HBOT on fatigue may be attributed to baseline differences in the small sample size. In addition, Casale et al35 found that HBO did not directly increase FM muscle strength or alter muscle fiber content to alleviate fatigue but increased the ability of the central motor command to generate the same effort with fewer recruited fibers.

Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.

Click on COVID fatigue

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Patient global

Only one study32 reported PGIC, which assessed global response to treatment and has been associated with clinical symptoms in patients with FM. Curtis32 reported that patients with FM had a different degree of symptom improvement after HBOT and at a 3-month follow-up. After HBOT treatment, ‘almost the same’ was the most common impression of global symptoms in FM patients (44.4%). However, at the 3-month follow-up, ‘a great deal better' was the most common impression of global symptoms in FM patients (41.7%). This showed that HBOT   may be effective for a long time.

Sleep disturbance

Three studies reported sleep quality. Guggino et al34  reported that HBOT did not improve the total sleep time of FM patients but improved their sleep quality. Curtis et al32 proposed that HBOT improved sustained sleep quality in FM at a 3-month follow-up assessment. However, Atzeni et al37 indicated that HBOT did not significantly improve the sleep quality of FM. This inconsistency may be related to the different number of HBOT sessions, which needs further study.

AEs of HBOT

Five studies reported the side effects of HBOT for FM  (as shown in Table 1). AEs occurred in 44 of 185 patients  (23.8%). Twelve patients (6.5%) withdrew because they could not tolerate adverse reactions. Of these AEs, there were 30 cases of mild barotrauma, 4 cases of new-onset myopia, 1 case of headache, 7 cases of dizziness, claustrophobia, inability to adjust ear pressure by ‘ear pumping’ and 2 cases of side effects (not reported). The predominant AE was mild barotrauma that could be resolved spontaneously and did not prevent patients from completing the treatment regimen. No serious side effects, complications, or deaths were reported.

Grade analysis of the evidence

The quality of pain relief was ‘moderate’. Although there was a serious risk of bias and inconsistency, there was no serious directness or imprecision. In addition, the outcome of pain relief has a large effect. The GRADE evidence profile is shown in Table 3.

DISCUSSION

In this study, we focused on the efficacy of HBOT on the inner core outcomes of FM. Pain relief was the primary outcome and could be meta-analyzed (three RCTs). Tenderness, fatigue, multidimensional function, patient global, sleep disturbance, and AEs were secondary outcome measures and were analyzed descriptively because of the limited number of studies or limited available data that could be combined. After a systematic review, we found that HBOT could relieve the pain of FM patients compared with the control intervention (SMD=−1.56, 95%CI (−2.18 to –0.93), p<0.001, I 2 =51%). In addition, most of the included studies have shown that HBOT could significantly improve tender points, fatigue, quality of life, patient global, and sleep disturbance in patients with FM. However, Curtis et al32 found that HBOT had no positive effect on fatigue reduction of FM, and Atzeni et al37 indicated that HBOT did not significantly improve the quality of life of FM. This inconsistency might be due to baseline differences in small sample sizes or the insufficient number of HBOT sessions. Of the 185 patients with FM who received HBOT, 44 patients had adverse reactions during HBOT treatment (23.8%) and 12 patients withdrew (6.5%) because they could not tolerate the side effects. However, in one retrospective study of 1.5 million cases of treatment with HBOT, the AE rate was only 0.68%.49 We speculated that patients with FM might have a lower pain threshold and may be more sensitive to discomfort than patients with other diseases. Mild barotrauma was the most common complication of HBOT for  FM. Patients may experience pressure, difficulty in ear balance, earache, and discomfort during compression.50 However, mild barotrauma can be resolved spontaneously does not prevent patients from completing the treatment, and can usually be prevented by appropriate screening.51 Oliaei et al52 found that most complications of HBOT occurred when the pressure applied exceeded  2.0 ATA. The articles included in this study mostly used hyperbaric oxygen chambers of 2–2.5 ATA for the treatment of FM, which may lead to side effects. A randomized controlled study 33 confirmed that low-pressure HBOT (1.45 ATA) was effective in the treatment of FM without  AEs. Therefore, a pressure lower than 2.0 ATA may be a good choice for patients with FM to avoid side effects.  Further studies are needed to explore the efficacy and safety of low-pressure HBOT for FM. In addition, contraindications for HBOT should be strictly screened before treatment, and the appropriate pressure and duration of treatment should be determined according to the patient’s tolerance.

Patients with FM in the control group received conventional treatment or nothing in the included studies. Yildiz et al., 40 Efrati et al. 39 and Guggino et al34 did not give any treatment to the patients in the control group, while Hadanny et al., 38 Izquierdo-Alventosa et al. 33 and Curtis et al. 32 performed conventional treatment for the patients in the control group. The conventional treatment that  FM received included psychotherapy, medications, physical activity, nutrition therapy, massage, acupuncture, behavioral therapy, and cognitive therapy. Therefore, HBOT may be effective both as an adjunctive therapy and as an independent treatment. Most of the included studies used the same HBOT protocol, which was 100% oxygen at 2–2.5 ATA, 90 minutes per session, 5 days per week. Only a study by Izquierdo-Alventosa et al33 used 1.45 ATA to avoid the side effects of HBOT. The length of treatment in the included studies ranged from three to twelve weeks, of which the study by Yildiz et al40 lasted 3weeks, the study by  Hadanny et al38 lasted 12 weeks, three non-comparative   studies35–37 lasted 4weeks and the rest of the studies lasted  8weeks. A rodent study found that the anti-injury effects of HBOT were apparent immediately after treatment and lasted for up to 5hours.19 In a rat neuropathic pain model, 2weeks of HBOT resulted in a significant improvement in pain levels during and after treatment.53 Atzeni et al37 proposed that 2–4 weeks of HBOT treatment significantly improved pain and anxiety symptoms in FM, while fatigue only improved after 4 weeks. In addition, sleep quality and depressive symptoms were not positively affected in  FM after 4 weeks of HBOT. In this review, only Curtis et al32 mentioned a follow-up measurement (3 months) and found that HBOT can continuously improve patient global, psychological symptoms, and sleep quality in FM.  Another study16 showed that HBOT for 10 days had a rapid onset, dose-dependent and long-lasting analgesic effect in patients with idiopathic trigeminal neuralgia documented a reduction in the dosage of carbamazepine analgesics and lower pain VAS. Therefore, long-term treatment with HBOT may be beneficial to improve symptoms of FM or prolong efficacy. However, the prolonged treatment window of patients is likely to cause side effects. Studies have shown that human lenses exposed to 2.0–2.5  ATA and 100% oxygen for 90 minutes once a day will lead to the development of myopia and cataracts after 150–850 courses of HBOT.54 However, when exposed to 2.5 ATA and 100% oxygen for 90min once a day for 48 courses, the above side effects rarely occur. 55 It is challenging to establish the effect and optimal dose-response curves of  HBOT in FM considering both safety and efficacy.

There is growing evidence that HBOT is a non-invasive way to treat chronic pain diseases with long-lasting efficacy and minor adverse effects.13 In murine models of pain, HBOT has been shown to inhibit pain sensation, which may be due to the nitric oxide-dependent release of opiate peptides and could be restrained by an antagonist, naltrexone.56 57 This effect works in the central system but also involves HBO activating µ-opioid and  K-opioid receptors in the spinal cord and releasing neuronal dynorphins.58 In murine models of arthritis,  HBOT has also been shown to affect inflammatory pain by reducing mechanical hypersensitivity and inflammation.59 Patients with FM often experience degenerative changes in muscle, abnormal oxygen pressure, and lower muscle blood flow due to hypoxia.16 60 Local ischemia causes mitochondria to produce higher levels of free radicals to induce apoptosis, reduce ATP synthesis, and increase lactate concentration in the muscle, thus ultimately leading to muscle weakness and pain.61 62 HBOT improves muscle oxygenation in FM, which can reduce the tissue lactate concentration and help maintain ATP levels, thus possibly preventing tissue damage in ischaemic tissue.63 It raises the oxygen concentration in all tissues far above physiological levels to cause hyperoxia, which breaks the hypoxic-pain cycle in patients with  FM.63 In addition, the high excitability of pain processing pathways in the brain and low activity of pain inhibition pathways may cause excessive pain in FM.64 Studies have shown that patients with FM have higher activity in the somatosensory cortex and lower activity in the frontal, medial frontal, cingulate gyrus and cerebellar cortex than healthy subjects.65 HBOT has been shown to increase neurotrophic and nitric oxide levels, reduce oxidative stress, promote cell metabolism by enhancing the mitochondrial function of neurons and glial cells, and may even promote the production of endogenous neural stem cells.66 The specific mechanism of HBOT on FM needs to be further investigated.

The quality of evidence (pain relief of HBOT for FM) assessed using the GRADE system was moderate. There are inherently ethical and logistical difficulties in handling sham control in HBOT experiments. In two RCTs,33 38 the researchers did not use the sham control/placebo in the control group, which may lower the quality of the evidence. The heterogeneity of the outcome may be caused by the population and HBOT regimen. However, the large effect (SMD >0.8) may increase the quality of the evidence. Therefore, we have a moderate degree of confidence in our estimated effect. The true value may be close to the estimated value, but there is still a chance that they could be very different.

There are some limitations in this systematic review. The main limitation is that the small number of RCTs included may lead to an overall risk of bias or insufficient evidence. Second, HBOT protocols (the length of treatment and pressure parameters) have clinical heterogeneity, which may introduce bias to the results. Third, we only retrieved data from Chinese and English databases, which may limit the data availability or cause language bias. Finally, due to the small number of included studies and heterogeneity, we did not conduct a subgroup analysis. Therefore, we cannot evaluate the efficacy of different HBOT regimens.

In conclusion, this study shows that HBOT may have a good effect in improving pain, tender points, fatigue, multidimensional function, patient global, and sleep disturbance in FM, with reversible side effects. Low pressure (less than 2.0 ATA) may be beneficial to reduce AEs in patients with FM. Further high-quality and large sample RCTs should be carried out to further evaluate its efficacy and safety.

Contributors Conceptualisation: CH, XC, JY. Funding Acquisition: CH. Formal Analysis: XC. Investigation: CH. Writing-Original Draft Preparation: XC, JY, MZ, HM. Writing–Review & Editing: all the authors. Guarantor: CH. All the authors fulfill the ICMJE criteria for authorship.

Funding Key Research and Development Project of Sichuan Provincial Science and Technology Department (No. 2018SZ0082); 1·3·5 Project for Disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan  University (No. 2021HXFH063)

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting, or dissemination plans of this research.

Patient consent for publication Not applicable.

Ethics approval Not applicable.

Provenance and peer review Not commissioned; externally peer-reviewed.

Data availability statement Data are available upon reasonable request.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names, and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Open access This is an open-access article distributed by the  Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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