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

Table 7

Effect of HBOT on neuropathic pain patient outcomes.

First author, year, pain model (n patients)	Outcomes	Timing of assessments and follow-up	Results		Remarks and safety
			Subjective clinical outcomes	Objective clinical outcomes
Kiralp, 2004, [33]CRPS (n = 71)	Clinical (pain (VAS), range of motion (ROM), edema (wrist circumference))	Before and after HBOT, 45 days F/U	Intervention: lower pain (); placebo: no improvements	Intervention: increased ROM and decreased edema (). Placebo: no improvements	Placebo received therapeutic oxygen dose
Peach, 1995, [35] CRPS (n = 1)	Clinical (pain, cyanosis)	Before and after each HBOT session	Decreased pain	Decreased cyanosis	HBOT started for another indication (CO poisoning)
William, 2009, [36] CRPS (n = 1)	Clinical (wound healing, pain)	Before and after HBOT	Increased pain, allodynia, new neuropathic features	Skin color, edema	(i) HBOT started for another indication (wound healing) did not prevent CRPS
					(ii) HBOT was not subsequentially used as treatment
Katznelson, 2016, [37] CRPS (n = 1)	Clinical (pain intensity (VAS), edema, skin discoloration, ROM); questionnaires (pain interference with everyday functioning (brief pain inventory (BPI)), mood and anxiety (hospital anxiety and depression scale (HADS)))	Before and after HBOT, 1- and 6-month F/U	Decreased pain (VAS from 7 to 3.2); marked BPI decrease (30% for general activity), HADS improvement (depression from 9 to 6, anxiety from 6 to 4)	Improvement of discoloration, swelling, ROM; Tinel’s sign disappeared; 6-minute walk test improvement (20%). Decreased medications to no medications required
Binkley, 2019, [38] CRPS (n = 1)	Clinical (pain (VAS), edema, skin discoloration, ROM, stiffness, tremor; steroids side effects); medication doses; quality of life (QoL)	Before and after both treatments, 3- and 6-month F/U	Improvement of all clinical findings. Improved QoL	Decreased steroid dose	Mild claustrophobia
van Ophoven, 2004, [39] IC (n = 6)	Clinical (pain (VAS), symptoms severity (O’Leary-Sant ICSI), including urgency, nocturia, frequency); well-being (PGAF); satisfaction with HBOT; bladder biopsy	Before and after HBOT, F/U: every 3 months for 15 months after HBOT	4 responders: decreased pain (from 2–9.7 to 0.3–3), decreased symptom severity ICSI (from 23–35 to 5–16 after HBOT and 8–24 at 15-month F/U). Improved well-being (PGAF) and ICSI satisfied; 2 nonresponders: no F/U. Nonsatisfied	(i) Improved ICSI; (ii) Biopsy: nonulcerative (early) IC: 1 responder vs 1 nonresponder. Ulcerative (late) IC: 3 responders vs 1 nonresponder	(i) No support to the hypothesis that HBOT benefits more late-IC than early-IC; (ii) 1 mild Eustachian disfunction
van Ophoven, 2006, [40] IC (n = 21)	Primary outcome: efficacy (global response assessment (GRA) questionnaire). Secondary outcomes: pain VAS, urgency (functional bladder capacity), frequency; symptoms severity (O'Leary-Sant ICSI); satisfaction	Before and after HBOT, 3- and 12-month F/U	Intervention: 3 responders (). At 12-month F/U, 3 patients (21.4%) reported treatment response. Decrease of baseline urgency intensity (from 60.2 +/- 15.0 to 49.9 +/- 35.2 mm, ), decrease of pain (from 4.3 +/- 2 to 3.1 +/- 2, ). Controls: no responders; no parameters improved compared to baseline	Intervention: ICSI decreased (from 25.7 to 19.9 points). Controls: no improvements	Conclusion: HBOT provides sustained decrease of IC symptoms with a discordant profile regarding the peak amelioration of symptoms compared to placebo
Tanaka, 2011, [41] IC (n = 11)	Efficacy (ICSI improvement > = 1), clinical (pain (VAS), urgency (VAS)); endoscopic findings	Before and after HBOT, 12-month F/U, variable F/U up to 50 months	7 responders, significant improvement in all measures (pain VAS from 7.7 ± 1.0 to 3.4 ± 2.5; urgency VAS from 6.6 ± 0.9 to 4.3 ± 2.4); sustained at F/U	(i) Improved ICSI (from 26.7 ± 7.0 to 18.7 ± 7.4 ()); (ii) Biopsy: 3 of the 4 nonresponders had nonulcerative IC	1 mild Eustachian disfunction, 3 mild exudative otitis media
Wenzler, 2017, [42] IC (n = 9)	Primary outcome: efficacy (GRA). Secondary: clinical symptoms (voiding diary, ICSI and ICPI questionnaires, VAS); cystoscopic appearance	Before HBOT, F/U after HBO: 2 weeks, months 3, 6, 12	5 responders, 1 nonresponder, 3 withdrew but considered nonresponder. Responders: GRA improved; VAS (1.5 points) improvement; voiding nonsignificant	(i) Improved ICSI, ICPI (1.5 points); (ii) Biopsy: 2 out of 3 ulcerative IC improved	(i) Nonulcerative IC (1 pt): marked improvement/resolution; ulcerative IC (4 pts): mild to moderate improvement; (ii) No adverse events
Pritchard, 2001, [43] RIBP (n = 34)	Primary endpoint: warm sensory threshold. Secondary: heat pain threshold, cool sensation threshold, routine neurophysiological tests, pain (McGill pain questionnaire), and QoL (MOS SF-36 questionnaire)	Before HBOT, 1-week F/U, 12-month F/U	No significant difference between groups	No significant difference between groups. Intervention: nonsignificant improvement of warm sensory threshold	(i) Placebo protocol is HBOT (therapeutic itself), not a real placebo.; (ii) Anecdotal evidence of improvement in longstanding arm lymphedema is an unexpected outcome of this study
Videtic, 1999, [44] sacral plexopathy (n = 1)	Clinical (pain), medication doses	Before and after HBOT, 12-month F/U	Marked pain improvement (from severe to none)	Marked reduction on medications (from high-dose multimodal to none)	HBOT started for another indication (ORN)
Stowe, 2020, [45] RIBP (n = 1)	Clinical (pain, ROM, neuroexam (sensory, motor)); imaging (brachial plexus MRI)	Before HBOT, F/U at 2, 6, and 13 months	Pain: from sever to none	(i) ROM: from decreased to full; (ii) Imaging: significantly decreased abnormal enhancement	Benefit could be related to a longer HBOT (120 min) compared to other literature (90 min) and to an early diagnosis and treatment
Peng, 2012, [46] PHN (n = 68)	Primary outcome: therapeutic efficacy (objective measures (period of blister resolution, scar formation time, and percentage of patients developing PHN), subjective assessments (pain-NPRS, depression questionnaire-HAMD))	Before and after HBOT, 6-month F/U	Intervention: therapeutic efficacy (97.2%), significantly higher than control group (81.5%) (). Significant reduction in persistent PHN development (HBOT 11.1% vs control 31.3%). Pain and depression scores decreased significantly in both groups but were significantly lower in the intervention group	Intervention: significant reduction in scar formation time (HBOT 11.1 days ± 4 vs control 14 days ± 4.3)	(i) Study outcomes were measured when by natural history one would expect the infection to have resolved (5 weeks); (ii) Small differences in pain after treatment could be not clinically significant; (ii) Although this is a positive study for HBOT in PHN, further studies are needed with chronic PHN (>3 months from onset) and longer follow-up periods
Gu, 2012, [18] TN (n = 42)	Primary outcome: changes in pain based on objective measure (changes in carbamazepine dose) and subjective assessments (pain VAS)	Before and after HBOT, 6-month F/U. 35 pts completed the study	Intervention group: VAS significantly decreased when comparing within-group to baseline and between-groups to the sham treatment, up to 6-month F/U	Intervention group: significant decrease in carbamazepine dose; significant lower dose for 60 days after HBOT than placebo; the lower dose was kept up to 90 days after HBOT	(i) A placebo effect was shown in the study (carbamazepine doses and VAS were decreased in the sham group, although the decrease was to a lesser degree than the treatment group); (ii) This study also implicates other cranial neuralgias as possible indications for HBOT

n = number; HBOT = hyperbaric oxygen therapy; CRPS = chronic regional pain syndrome; IC = interstitial cystitis; RIBP = radiation-induced brachial plexopathy; PHN = postherpetic neuralgia; TN = trigeminal neuralgia; VAS = visual analogue scale; ROM = range of motion; QoL = quality of life, ICSI = interstitial cystitis symptom index; ICPI = interstitial cystitis problem index; PGAF = patient global assessment form; MOS SF-36 = medical outcomes study, 36-Item Short Form Health Survey; MRI = magnetic resonance imaging; NPRS = numeric pain rating scale; HAMD= Hamilton depression rating scale; F/U = follow-up; ORN = osteoradio necrosis.