Mechanistic Rationale and Clinical Efficacy of Hyperbaric Oxygen Therapy in Chronic Neuropathic Pain: An Evidence-Based Narrative Review

Background Chronic neuropathic pain is a condition affecting an increasing proportion of the general population and its management requires a comprehensive, multidisciplinary program. A growing body of evidence supports the use of hyperbaric oxygen therapy (HBOT) in several chronic neuropathic pain conditions; however, its role and efficacy remain unclear. Purpose To summarize current evidence for the mechanistic rationale of HBOT in chronic neuropathic pain conditions and to evaluate its clinical efficacy. Methods This narrative review was conducted after searching the following databases (Medline, Embase, Cochrane, PsycINFO, the Web of Science, Scopus, ClinicalTrials. gov, WHO ICTRP, and ProQuest Digital Dissertation) from January 1946 to March 2020. Articles published in English that involved either animal or human studies with acute or chronic neuropathic pain evaluating any HBOT-related intervention were included. Results A total of 2971 citations were identified. A total of 29 studies were included in this review. The mechanisms of action for HBOT use in neuropathic conditions included the primary effects of hyperoxia and edema resolution, as well as the secondary effects pertinent to the production of oxygen and nitrogen reactive species (serving as pain signaling molecules), nitric oxide-dependent release of opioid peptides, and reduction of inflammatory mediators. A robust evidence for HBOT use in the clinical setting was associated with chronic regional pain syndrome and chronic primary bladder pain syndrome. Some evidence supported its use for chronic secondary (peripheral) neuropathic pain including radiation-induced plexus neuropathies, postherpetic neuralgia, and trigeminal neuralgia. Conclusions HBOT has been shown to have antinociceptive and analgesic effects in animal models of inflammatory, neuropathic, and chronic pain. Human studies demonstrated beneficial effects of HBOT in improving clinical outcomes such as pain scores, pain-related symptoms, and quality of life. A systematic methodology of HBOT application is necessary to confirm its safety and efficacy.


Introduction
Chronic neuropathic pain is a silent, global health epidemic requiring a novel approach to improve the treatment methodologies. It is estimated that 10-30% of adults live with a chronic pain condition and more than half of these patients report continuous moderate to severe pain and reduced quality of life resulting in job loss or reduced efficacy at workplace [1,2].
Neuropathic pain, as defined by the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group, is "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" [3]. Controversy in understanding chronic pain as a symptom or a disease has led to a new classification for chronic pain disorders [4], reclassifying some neuropathic pain conditions as chronic primary pain disorders [5] ( Table 1) and others as chronic secondary (central or peripheral) neuropathic pain disorders [3] (Table 2). Primary chronic pain disorders differ from the secondary ones in that they are independent of identified biological or psychological conditions.
Currently, the first-line management strategy for chronic neuropathic pain is based on multifaceted approach including tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and gabapentinoids, as well as topical and transdermal substances. e second-line therapy consists of a combination of first-line medications with tramadol or tapentadol. Serotonin-specific reuptake inhibitors/ anticonvulsants/N-methyl-D-aspartate receptor antagonists and interventional therapies are suggested as a third-line option. Neurostimulation is a fourth-line treatment. Lowdose opioids (no greater than 90 morphine equivalent units) are the fifth-line approach. Finally, a targeted drug delivery is considered as the last option for patients who are resistant to all other therapeutic interventions [6].
Given that the current pharmacological and interventional therapies are not devoid of significant adverse events, there is an urgent need for new, effective, noninvasive therapies.
A growing body of evidence supports the use of hyperbaric oxygen therapy (HBOT) in a number of neuropathic pain conditions with persistent efficacy and minimal adverse events.
HBOT was initially developed to treat decompression sickness, a complication of deep sea diving. In decompression sickness, a diver has surfaced before dissolved gases have time to equilibrate, producing space-occupying embolic nitrogen bubbles in the tissues and vasculature. HBOT provides patients with 100% oxygen at pressures two to three times greater than atmospheric pressure. According to Boyle's law, the increase of hydrostatic pressure in the hyperbaric chamber elevates the partial pressure of gases and causes a reduction in the volume of the gas-filled spaces, allowing them to dissolve into solution [7]. HBOT also increases partial pressure of oxygen in the alveoli and results in a corresponding increase in the amount of dissolved oxygen carried in blood. During HBOT, the arterial partial pressure of oxygen (PaO 2 ) may reach up to 1,900-2,100 mmHg, with dissolved oxygen (O 2 ) content increasing from 0.3 to 6.8 ml O 2 /100 ml of blood. is translates to a significant increase in partial pressure of O 2 in tissues with compromised circulation [8]. A list of current conditions approved for treatment with HBOT by the Undersea & Hyperbaric Medicine Society is reflected in Table 3 [9]. For the majority of indications, the HBOT treatments are administered daily for 90-120 minutes for a total of 20-40 consecutive sessions. HBOT is considered a safe, noninvasive therapy with very few side effects (Table 4) [10]. e only absolute contraindication for HBOT is an untreated pneumothorax.
HBOT is an effective treatment of neuropathic pain conditions due to its primary and secondary effects (Figure 1). e primary effects relate to significant increase in partial pressure of tissue O 2 (hyperoxia) [8]. Hyperoxia serves as a potential mechanism for treatment of pain conditions with evidence of deep tissue hypoxia, such as in the chronic regional pain syndrome (CRPS) [11,12]. Increased hydrostatic pressure is another primary effect of HBOT. It induces arteriolar vasoconstriction that reduces formation of tissue edema, without compromising the effect of hyperoxia [13]. e secondary effects of HBOT involve the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ese reactive species serve as signaling molecules implicated in pain perception, wound healing, angiogenesis, neovascularization, leukocyte function, growth factor, and progenitor stem cell release, as well as tissue homeostasis [8].
Another secondary effect of HBOT is related to reduction in inflammatory mediators. e objective of this review was to summarize evidence for the mechanistic rationale of HBOT in chronic neuropathic pain conditions and to evaluate its clinical efficacy in this patient population.

Methods
e methodology used was consistent with the PRISMA Extension for Scoping Reviews Checklist (PRISMA-ScR) [14]. e following databases were searched from January 1946 to March 21, 2020, via the Ovid search interface: Medline, Medline In-Process/ePubs, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and PsycINFO. e Web of Science (Clarivate) and Scopus databases, ClinicalTrials.gov (NIH), WHO ICTRP, and ProQuest Digital Dissertation were also included in our search strategy. Search strategy concept blocks were built on the topics of Hyperbaric Oxygen erapy and Neuropathic Pain, Hyperbaric Oxygen erapy and Chronic Primary Bladder Pain Syndrome, and Hyperbaric Oxygen erapy and Complex Regional Pain Syndrome (CRPS). e Medline search strategy is provided in detail in Supplementary Material. We included all articles published or translated in English that involved either animal or human studies with acute or chronic neuropathic pain evaluating any HBOT-related intervention. Study outcomes had to include an assessment of any pain-related or physiologic endpoints, either objective (e.g., cytokine blood levels, imaging, and tissue oxygenation) or subjective (e.g., questionnaires). In order to limit the scope of the review, we excluded studies examining chronic primary headache or orofacial pain (such as migraine, cluster, and tension headaches) and, within the secondary neuropathic pain, the painful diabetic neuropathy, because the abundant literature on these topics over the last four decades would deserve a separate review and is out of the scope of the current analysis. Study selection was performed by two reviewers (SS and JDB) using inclusion and exclusion criteria. e third reviewer (RK) was available to solve any disagreements related to selection process.

Results
A total of 2971 records were identified through database searching, while 505 references were identified with the search strategy. Furthermore, there were 802 additional 2 Pain Research and Management   Figure 2, PRISMA flow diagram).

HBOT in Animal Models of Neuropathic Pain.
Animal models for both neuropathic and inflammatory pain conditions demonstrate the antiallodynic and antinociceptive effects of HBOT through a wide range of treatment regimens. e most common animal model for neuropathic pain is a chronic constriction injury (CCI) to the sciatic nerve. In this model investigators tie four ligatures around the sciatic nerve to create intraneural edema and ischemia, neuronal apoptosis, and Wallerian degeneration [15]. Shortly after CCI, rats exhibit neuropathic pain behaviors including mechanical, chemical, and thermal hyperalgesia and allodynia persisting for up to two months [15]. Other painrelated characteristics including appetite suppression, nocifensive behaviors (scratching, biting, self-mutilation), Table 4: Side effects of hyperbaric oxygen therapy [10]. Middle ear barotrauma, sinus squeeze, claustrophobia, progressive myopia, pulmonary barotrauma, seizures Growth factor and progenitor stem cell production Edema Figure 1: HBOT mechanisms and effect on chronic neuropathic pain disorders. HBOT: hyperbaric oxygen therapy; ROS: reactive oxygen species; RNS: reactive nitrogen species; TNFα: tumor necrosis factor-alpha; IFNc: interferon-gamma; IL: interleukin. 4 Pain Research and Management and increased anxiety-and depression-like behaviors following CCI implicate cognitive and affective sequalae of this neuropathic pain model [16]. Table 5 summarizes 9 animal studies of neuropathic pain that all demonstrate the efficacy of HBOT, across a wide spectrum of treatment regimens, in reducing the thermal and mechanical hyperalgesia and allodynia induced by experimental nerve injury [17][18][19][20][21][22][23][24][25].
While some of these studies demonstrate sustained (up to one month) antiallodynic and antinociceptive effects with only one HBOT session, the majority of studies suggest a dose-response with sustained therapeutic benefit after multiple consecutive HBOTsessions. Suggested mechanisms for the therapeutic effects of HBOT in this animal model include inhibition or suppression of CCI-induced inflammation [17,18,22], neuronal apoptosis [21,25], and increased expression of endogenous opioids [20]. CCIinduced expression of nitric oxide synthase isoforms, which are involved in the modulation of periphery and central nociceptive pathways, are also attenuated following HBOT [23,24].
Animal studies have also suggested potential benefits of HBOT in chemotherapy-induced neuropathic pain. In one study [26], 7-day exposure to paclitaxel induced mechanical and cold allodynia in rats. After 1-4 treatments of HBOT, mechanical allodynia was completely reversed, while cold allodynia was not reliably reduced. Another study [27] examined the effects of HBOT as a treatment and prophylaxis in cisplatin-induced peripheral neuropathy. After twice-weekly intraperitoneal injections of cisplatin over a period of four weeks, mechanical allodynia was observed in rats following the first week of cisplatin exposure and persisting throughout the three following weeks. A 7-day HBOT treatment course following 4 weeks of cisplatin exposure did not improve the mechanical nociceptive threshold; however the 7-day HBOT treatment course before the 4 weeks of cisplatin exposure did significantly improve mechanical allodynia. In this "preconditioning" group, the antinociceptive benefit of HBOT was attributed to decreased apoptosis and inflammation. Immunohistochemical analysis of the sciatic nerve and associated ganglia demonstrated     decreased upregulation of caspase-3 expression (proapoptotic mediator) and an attenuated expression of TNF-α and inducible NOS expression when compared to the control group. In combination with the CCI-model of neuropathic pain, these animal studies further validated some of the proposed antiallodynic and antinociceptive mechanisms of HBOT.
Hyperoxygenation serves as a potential mechanism for treatment of neuropathic pain conditions that show evidence of deep tissue hypoxia, such as in chronic regional pain syndrome (CRPS) [11,12]. e deep tissue hypoxia hypothesis has been tested in the animal model of ischemia and reperfusion related chronic pain. Known as "chronic postischemia pain," a tourniquet is placed around a rat's ankle for 3 hours under general anesthesia and then released. After reperfusion, the hind paw exhibits an initial phase of hyperemia and edema lasting for 2-12 hours, followed by neuropathic pain (mechano-hyperalgesia, mechano-allodynia, and cold allodynia) that lasts for at least one month [28]. Using this ischemia-reperfusion model, Coderre et al. [11] discovered microvascular injury in the capillaries of deep muscles and nerves. eir findings implicated deep tissue and endoneurial ischemia and inflammation in the activation of both muscle nociceptors and ectopic sensory afferent axons [11]. e efficacy of HBOT, however, has not yet been tested in this animal model. e deep tissue hypoxia hypothesis for chronic pain also extends to the central nervous system. is is because regional, cerebral hypoperfusion and hypometabolism have been associated with chronic pain conditions, such as fibromyalgia and CRPS [29][30][31]. HBOT appears to correct or rectify these regional differences in brain perfusion and metabolism, inducing changes that are associated with reduction in pain symptoms and improved quality of life [32].
Increased hydrostatic pressure is another primary effect of HBOT. HBOT induces arteriolar vasoconstriction by subsequently reducing tissue edema formation, without compromising the supernormal tissue pO 2 [13]. is mechanism may contribute to a reduction in symptoms in patients with chronic pain conditions where tissue edema and inflammation are the primary components [33]. An animal model of inflammatory pain and edema has tested this theory. A subcutaneous injection of 1% carrageenan substance into rats' hind paws induced both mechanical hyperalgesia and edema providing a close clinical surrogate to inflammatory pain in humans [28]. Mechanical hyperalgesia or hypersensitivity was measured using the "mechanical paw withdrawal threshold (MPWT)," whereby von Frey filaments of increasing diameter (increasing force) poked the animals' hind paws through a mesh cage. Compared to sham group, HBOT-treated rats exhibited decreased mechanical hyperalgesia/hypersensitivity (a higher MPWT) almost immediately following treatment.
ere was also evidence for the decreased edema formation after HBOT; however, it lagged slightly behind the antinociceptive effect [28].
Secondary effects of HBOT that may underlie the treatment of chronic pain disorders involve the production of ROS and RNS. In animal models for neuropathic pain, the therapeutic effect for HBOT involves a reduction or attenuation of CCI-induced nitric oxide synthase expression [23,24]. However, in experimental models of abdominal pain the opposite is shown [29,31].
Zelinski et al. [29] sought to elucidate the mechanism underlying the antinociceptive effect of HBOT in their animal model of chronic pain. Following intraperitoneal injection of 0.6% glacial acetic acid, mice exhibited abdominal constrictions (lengthwise stretches of the torso with concave arching of the back), presumed to be a pain response that was quantifiable (number of constrictions). HBOT showed a profound reduction in abdominal constrictions compared to those in the untreated mice [29].
In search of a mechanistic explanation for the antinociceptive effect of HBOT in this model the group hypothesized a neural nitric oxide-(NO-) dependent mechanism as it was known that HBOT increased cerebral blood flow and RNS production through neural NO synthase (nNOS) activation in the cerebral cortex [30]. ey discovered that central administration (intracerebroventricular or intrathecal) of NOS enzyme inhibitors and antisense oligodeoxynucleotides against nNOS attenuated HBOT-mediated analgesia in mice. A similar attenuation was noted in nNOS knockout mice and with naltrexone (opioid antagonist) administration [29,31]. While both neuropathic and abdominal/inflammatory models of pain demonstrate the release of endogenous opioids as a therapeutic mechanism, the pro-or antinociceptive role of NOS and RNS remains controversial [34] and may vary at different locations within the central and peripheral nervous system as well as with different etiology of chronic pain.

HBOT in Human Studies of Neuropathic Pain
3.2.1. HBOT in Complex Regional Pain Syndrome. A total of 5 case reports and one RCT described effects of HBOT in CRPS patients (Tables 6 and 7).
CRPS is a chronic primary pain syndrome characterized by spontaneous and/or evoked pain disproportionate to the typical course of pain produced from a similar inciting event.
e pain distribution is not limited to specific nerve territory or dermatome and often has a distal spread. It can be accompanied by sensory (hyperalgesia/allodynia), vasomotor, sudomotor/edema, and motor/trophic changes [47]. CRPS is caused by a multifactorial process involving both peripheral and central mechanisms as well as sensitization. Inflammatory and immune-related factors, altered sympathetic nervous system function, ischemic reperfusion injury, and oxidative stress are among the many possible mechanisms implicated in CRPS [48,49]. In addition to anti-inflammatory activity [17,28], four possible mechanisms are proposed to account for the improvement in symptoms and quality of life that is seen following HBOT in CRPS patients.

HBOT and Reduction of Deep Tissue Hypoxia.
Bellingham et al. [12] demonstrated that deep tissue oxygen saturation (StO 2 ) was significantly lower in the affected limb of patients with CRPS compared to either the nonaffected  [50], the "deep tissue hypoxia" theory is an attractive mechanism for the proposed benefit of HBOT, although the changes in StO 2 before and after HBOT have not been documented in patients with CRPS. Improved tissue oxygenation was the suspected mechanism in the first report of HBOT benefit in a CRPS patient. A case study from 1995 [35] reported a 44-year-old woman with CRPS treated with emergent HBOT for acute smoke inhalation for 46 minutes at 2.8 ATA. 15 minutes after the start of the therapy the patient "reported relief of pain in her foot" that appeared "less cyanotic and warmer to the touch." e foot color remained pink for 8 hours and painless for 18 hours after the first HBOT session. e patient was offered a second 90-minute HBOT session at 2.0 ATA with mild symptom improvement (the foot remained pink for 1 hour and painless for 2 hours after HBOT) and one additional session at 2.4 ATA, with marked and long-lasting relief (the foot was pink and painless for 30 hours after HBOT). While no precise methodology for assessment was reported, the clinical findings were thought to be related to improved perfusion and oxygenation with the corresponding improvement in pain control.

HBOT and Reduction of Tissue Edema.
A second potential mechanism of HBOT is related to decreased tissue edema, which is a common feature of CRPS. It is well described that HBOT causes vasoconstriction and decreases edema [13,33]. It is suggested that the hyperoxic environment leads to increased oxidation of NO radicals produced by the endothelium and a loss of the vasorelaxant effect [51], alterations in other vasodilator compounds (i.e., prostaglandins) [52], and stimulation of central vasoregulation via the sympathetic nervous system [53]. Indeed, an RCT of patients with CRPS [33] demonstrated improved range of motion and decreased edema following HBOT. In this double-blind RCT, 71 patients with posttraumatic wrist CRPS were randomized to a treatment group (37 patients), receiving 15 HBOT sessions, 90 minutes each at 2.4 ATA, or a control group (34 patients) that received 15 placebo sessions in the hyperbaric chamber, 90-minute each breathing normal air at 2.4 ATA. In addition to HBOT, all patients received paracetamol 500 mg three times a day but did not receive any physical therapy during the study. Assessments included evaluation of visual analogue pain scores, range of motion (goniometric assessment of wrist flexion and    14 Pain Research and Management extension), and edema (wrist circumference) at baseline, at the end of the 15 HBOT sessions, and at 45-day follow-up. e HBOT group reported significantly lower pain scores, improved range of motion, and decreased edema, both at the end of HBOTand at the follow-up sessions, while the control group did not have any improvement. e authors concluded that HBOT was effective in decreasing pain and swelling and increasing wrist range of motion in patients with CRPS. Given that the sham control was also exposed to higher pressure (breathing air at 2.4 ATA), this study implicates the therapeutic benefits of hyperoxia rather than just increased atmospheric pressure environment, although it should be noted that even the control group experienced higher levels of oxygenation at 2.4 ATA.

Role of HBOT in Acute and Chronic CRPS.
Another possible mechanism for HBOT in CRPS is in preventing progression of the disease from the early acute and dystrophic stages to the irreversible/atrophic stage that is characterized by stiffness and flexion contractures. A critique of the previous RCT [33] was that the population studied were young and otherwise healthy soldiers receiving HBOT within 1.5 months of the original injury. It was postulated that because HBOT stimulates the activity of osteoblasts and decreases formation of fibrosis [54], it interrupts the basic vicious cycle of CRPS pathophysiology.
Williams et al. [36] described a case report of a 48-yearold diabetic man who developed complications after elective subtalar arthrodesis for chronic ankle instability. Following two irrigations and debridement for infection, the patient received 19 sessions (90 min at 2.2 ATA) of HBOT for wound healing enhancement, starting 3 weeks after the first surgery. One month after HBOT the wound was completely healed, but the patient started to develop neuropathic pain and other symptoms pertinent to CRPS. e authors concluded that HBOT, even if initiated early after a traumatic extremity injury, did not confer any protection against the possibility to developing CRPS. Two case reports described potential benefits of HBOT in patients with chronic CRPS [37,38]. A 41-year-old male with a 1-year history of left-foot CRPS following ankle fracture demonstrated less pain, decreased swelling, less allodynia, improvement in skin color, and a range of motion of the lower limb after 3 weeks of HBOT [37]. Furthermore, his mood and walking ability as well as interactions with other people and enjoyment of life markedly improved. Another case report [38] described a 50-year-old female with an 8-year complicated history of CRPS following the left fifth proximal phalanx fracture, in which multiple conventional and nonconventional therapies failed. e disease was partially controlled with a high dose of prednisone (85 mg/ day). After 40 HBOT sessions, 90 minutes each at 2.4 ATA, the prednisone dose was reduced to 9 mg/day, with marked improvement in symptoms. Five months after the HBOT sessions, the patient had a mild flare of symptoms and received a second HBOT course of 33 sessions, 90 minutes each at 2.0 ATA, again with marked improvement, and further decrease in prednisone to 5 mg/day. e patients also experienced significant reduction of steroid related complications including diabetes, hypertension, dyslipidemia, insomnia, skin integrity, infections, and bruising. Even though these case reports are promising, it is paramount to acquire more robust evidence to advocate for HBOT as a standard treatment in patients with acute and chronic CRPS.

Cerebral Targets for HBOT in CRPS.
A fourth potential mechanism for HBOT benefit is through central or cerebral effects. A study by Barad et al. [55] discovered decreased gray matter changes in the limbic system (posterior mid-cingulate cortex, bilateral pregenual anterior cingulate cortex, and orbitofrontal cortex) and left posterior insula and increased gray matter in the dorsal putamen and hypothalamus that is involved in the processing of pain in patients with CRPS. Duration of illness and increased pain intensity were correlated with gray matter atrophy in the dorsolateral prefrontal cortex and gray matter hypertrophy in the hippocampus and amygdala. While brain changes have not been demonstrated in HBOT with CRPS patients, preliminary data from the fibromyalgia population demonstrate a rectification of imbalanced brain activity after treatments with HBOT [32,56].

HBOT in Chronic Primary Bladder Pain Syndrome.
e reports of HBOT in chronic primary bladder pain syndrome are reflected in Tables 6 and 7.
Also known as interstitial cystitis, bladder pain syndrome (BPS) is characterized by chronic pelvic pain or discomfort, associated with at least one urinary symptom, such as persistent urge to void, increased frequency, and nocturia [57,58]. Under the ICD-11 classification BPS is considered as a chronic primary pain disorder [5]. Ophoven et al. [39,40] sought to determine the feasibility and efficacy of HBOT in BPS based on observations of decreased pelvic pain in patients undergoing HBOT for radiation cystitis. Following a feasibility study [39], van Ophoven et al. conducted a randomized, sham controlled, double-blind trial [40] whereby 14 patients (experimental group) received 30 HBOT treatments at 2.4 ATA for 90 minutes and 6 patients (control group) received a sham treatment breathing room air at 1.3-1.4 ATA. Pain intensity measured by visual analogue scores (VAS) decreased significantly in the experimental group compared to the control group at 3-month follow-up. A prospective cohort study by Tanaka et al. [41] evaluated 11 patients with BPS symptoms who received 10-20 HBOT treatments for 60 minutes each at 2.0 ATA. Seven "responders" demonstrated a significant improvement in pain scores at 12-month follow-up. A pilot study by Wenzler et al. [42] evaluated 9 patients with interstitial cystitis receiving 30 HBOT sessions of 90 minutes at 2.2 ATA. Five "responders" had considerable reduction in VAS at the 12-month follow-up. Histological findings from patients with BPS demonstrated decreased microvascular density in the suburothelial plexus which was indicative of reduced edema and decreased vascular congestion. Consequently, HBOT-mediated neoangiogenesis and increased tissue oxygenation may serve as two proposed mechanisms for improved pain relief in patients with BPS.

Radiation-Induced Plexus
Neuropathies. Efficacy of HBOT in radiotherapy induced brachial and sacral plexus neuropathy has been evaluated in three clinical studies (Tables 6 and 7).
Pritchard et al. [43] reported the use of HBOT as an adjunctive therapy for radiation-induced brachial plexopathy (RIBP), an intractable neuropathic pain resulting in severe motor dysfunction [68]. 34 patients with RIBP were randomized to either experimental (100% O 2 at 2.4 ATA) or control (41% O 2 at 2.4 ATA) groups for 30 sessions of 90 minutes. Clinical and neurologic assessments including warm sensory threshold (measuring the function of small sensory fibers) and pain and quality of life questionnaires were conducted after the end of the HBOT treatment period and at 1-and 2-year follow-up. No differences in clinical outcomes either between or within the groups were found for up to 1-year follow-up. However, 2 patients in the HBOT group exhibited normalization of the warm sensory threshold, and 2 other patients experienced normalization of chronic arm lymphedema. While the authors concluded that "there is currently no basis for recommending HBOT as a proven treatment for RIBP," it should be noted that statistical analysis was performed for just a single primary endpoint, "warm sensory threshold," and no formal analysis was done for secondary endpoints, including pain. Additionally, while there was no "within-group" benefit, it should be noted that the control group was breathing 41% O 2 at 2.4 ATA, which corresponds to approximately 100% oxygen at 1 ATA. Indeed, breathing 100% oxygen at sea level is considered a therapy by itself, since the increase in blood oxygen content could exert beneficial effects [69].
A case report by Videtic and Venkatesan [44] noted the beneficial effects of HBOT on sacral plexopathy causing severe pelvic pain in a 55-year-old woman. While the HBOT indication was for sacral osteoradionecrosis due to radiotherapy for bladder leiomyosarcoma, severe pain was a main symptom. Her pain was not responding to opioid analgesics, anti-inflammatories, dexamethasone, and amitriptyline. e patient received 30 sessions of HBOT at 2.5 ATA with a gradual but constant decrease on opioid requirement. 12month follow-up consultation revealed no pain and no pain medications apart from minimal dose of amitriptyline. Another case report [45] described a brachial plexopathy in a 45-year-old man who underwent radiotherapy for neck carcinoma. He developed severe left shoulder/arm pain and decreased range of motion (ROM) after 15 months and RIBP diagnosis was confirmed by brachial plexus magnetic resonance imaging (MRI). He received dexamethasone for 2 weeks and underwent 30 HBOT sessions at 2.4 ATA, 120 minutes each. At 2-month and 13-month follow-up the patient regained full ROM in his left arm and reported no pain.
ese clinical findings were corroborated by a significant decrease of abnormal enhancement on follow-up MRI at 6 months. e authors hypothesized that the potential benefit could be related to longer HBOT sessions (120 minutes) as well as an early diagnosis and treatment. e results of these case studies suggest a potential benefit of HBOT for radiation-induced neuropathic pain and merit further investigations.

Postherpetic Neuralgia. Postherpetic neuralgia (PHN)
consists of a persistent irritation and intermittent neuropathic pain, usually associated with allodynia and itching [70], that persist after a primary herpes zoster infection. Peng et al. [46] randomized 68 patients who developed acute herpes zoster infection within 2 weeks to either intervention group (receiving HBOT 30 sessions, twice daily, 80 minutes each at 2.2 ATA, in addition to medical therapy) or control group, receiving optimal medical therapy (antiviral [acyclovir], nerve nutritive [mecobalamin], pain relief [tramadol], and antidepressant [nortriptyline]). Effectiveness of HBOT was assessed by objective measures including period of blister resolution, scar formation time and percentage of patients developing PHN, and subjective assessments with questionnaires reflecting pain and depression. Based on these assessments, all patients were categorized into three different "therapeutic efficacy" classes, namely, healed, improved, or ineffective. Overall, the calculated therapeutic efficacy in the HBOT group was significantly higher than in the control group (97 vs 81%). e HBOT group exhibited a significant reduction in persistent PHN development when compared to control group (11 vs 31%) and in scar formation time (11 vs 14 days). Pain and depression scores decreased in both groups; however, they were significantly lower in the HBOT group compared to controls. e authors concluded that "the combination of HBOT and conventional pharmacological therapy was more effective than pharmacological treatment alone." A critical appraisal [71] highlighted that the study outcomes were measured when by natural history one would expect the infection to have resolved anyway (within 5 weeks period) and that the numerical differences in pain scores between the two groups were lacking clinical significance. It is clear that further studies with long-term follow-up are needed to determine the efficacy of HBOT in patients with chronic PHN.

Trigeminal Neuralgia.
Trigeminal neuralgia (TN) is defined as a neuropathic facial pain condition, characterized by unilateral paroxysmal pain, evoked by trigger factors [72,73]. Under the new ICD-11, TN overlaps two different categories and is considered an example of "multiple parenting," since it can be classified as both a chronic primary pain (subcategory of chronic primary headache/orofacial pain) and a chronic secondary peripheral neuropathic pain [4]. Multiple clinical studies of HBOT have been conducted in patients with chronic migraine and cluster headaches [74]; however, they are beyond the scope of this review. Nonetheless, TN plays a special role in both mechanistic rationale and clinical efficacy of HBOT in patients with neuropathic pain.
Many animal models for TN involve constriction, compression, or ligation of neural structures [18,75,76] to produce mechanical or thermal allodynia. ese models are either identical or parallel to those used in elucidating the mechanism by which HBOT exerts antinociceptive effects in animals as discussed earlier in the "animal models" section ( Table 5). Gu et al. [18] evaluated the effect of HBOT following chronic constriction injury of the sciatic nerve in rats and also conducted a trial in humans with idiopathic TN. In the animal model, they demonstrated that repetitive HBOT produced a rapid, dose-dependent, and long-lasting inhibition of thermal hyperalgesia and mechanical allodynia. In the clinical study, 42 patients with TN, concurrently treated with carbamazepine, were randomized to a treatment group (22 patients) receiving 10 sessions of HBOT for 70 minutes at 1.8 ATA or to a sham group (20 patients) receiving the same treatment in a hyperbaric chamber breathing room air at atmospheric pressure. Effectiveness of HBOT was assessed by carbamazepine dose reduction and VAS score changes at the 6-month follow-up. After 10 HBOT sessions, the treatment group had a significant decrease in required carbamazepine dose that lasted up to 90 days. Carbamazepine dose was also significantly lower when compared to the sham group for up to 60 days after HBOT.
is was associated with significant reduction in VAS up to 6 months after HBOT.

Conclusions
ere is a growing body of evidence suggesting the potential benefits and therapeutic impact of HBOT in different chronic neuropathic pain conditions. e current literature confirms a wide heterogeneity in the HBOT treatment modalities in patients with different chronic neuropathic pain presentations suggesting that appropriate dose-response curve specifics should be considered for each condition. HBOT has been shown to reduce pain scores and improve pain-related symptoms and quality of life. Future research should focus on the identification of a subset of patients with chronic pain who can benefit from HBOT.

Data Availability
Data are available in Supplementary Materials and are anyway available upon request to the corresponding author.