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Pain & inflammation

Bladder pain and interstitial cystitis

Interstitial cystitis, or painful bladder syndrome, mostly affects women and is hard to treat. A small sham-controlled randomised trial found that two thirds of those treated with hyperbaric oxygen responded, with less pain and urgency, and about 40 percent held that improvement at a year. Follow-up case series report similar results, particularly where there are Hunner lesions.

Evidence so far
Early
Reading timeAbout 12 minutes

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Why this is being studied

Bladder pain syndrome, also called interstitial cystitis, is a chronic condition of bladder pain, urgency and frequent urination without infection. The bladder lining in this condition is thought to be thin, leaky and poorly supplied with blood, especially in the ulcerative form where inflamed patches called Hunner lesions are visible. Because hyperbaric oxygen is already used to help radiation-damaged bladders heal, researchers have asked whether the same tissue-repair effect could help here. The evidence so far is a single small sham-controlled trial and two open case series.

Where the evidence stands

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The mechanism

What is going on, and why this might help

What is going on in the body

Interstitial cystitis, or bladder pain syndrome, involves a bladder wall that is inflamed and often poorly perfused. The protective glycosaminoglycan layer lining the bladder becomes deficient, allowing urinary solutes to irritate the underlying tissue. Biopsy and imaging studies show reduced microvascular density and blood flow in the bladder wall, particularly in the Hunner-lesion subtype, together with mast-cell infiltration, raised pro-inflammatory cytokines and sensitised sensory nerves. Chronic hypoxia of the bladder wall is thought to impair repair of the urothelium, sustaining a cycle of injury, inflammation and pain, with central sensitisation developing over time.

Where oxygen comes in

The rationale closely parallels radiation cystitis, where hyperbaric oxygen is an established treatment for a bladder wall that is hypoxic, hypovascular and bleeding. Dissolved plasma oxygen reaches the poorly perfused bladder wall directly. Intermittent hyperoxia stimulates angiogenesis via VEGF and HIF-1α pathways, restoring microvascular density over a course of sessions. Better oxygenation supports urothelial regeneration and glycosaminoglycan layer repair, and reduces inflammatory cytokines such as TNF-α and IL-6 and mast-cell activity in animal models of cystitis. Effects on sensitised nerve pathways, as seen in chronic pain research, may contribute to symptom relief. Stem-cell mobilisation (Thom 2006) is a further proposed route to tissue repair.

How solid is this

Supported by small trials. The mechanism is well established in the closely related condition of radiation cystitis. In interstitial cystitis itself, one small sham-controlled trial (van Ophoven et al. 2006) and several open-label series from Japan and Germany have reported improvement in pain and bladder capacity in a subset of participants, with effects lasting months. The evidence is encouraging but limited by small numbers. Key references: van Ophoven et al. 2006; Tanaka et al. 2011.

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The studies

Every study is laid out the same way: what the researchers wanted to find out, who took part, what they actually did, what they found, why it might work and where the limits are. No jargon, and a link to the original if you want to read it yourself.

Each study is laid out the same way: what the researchers asked, who took part, what they did, what they found, why it might work, and where the limits are. The clinician layer at the end of each one carries the numbers.

Paper 1

Safety and efficacy of hyperbaric oxygen therapy for the treatment of interstitial cystitis: a randomized, sham controlled, double-blind trial

van Ophoven et al. · Journal of Urology · 2006 · randomised, sham-controlled, double-blind trial, n=21

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What they asked

Interstitial cystitis, now often called bladder pain syndrome, causes persistent bladder pain, urgency and frequent urination without infection. Treatments are limited and often disappointing. Following an encouraging pilot study in 2004, van Ophoven and colleagues in Germany asked the harder question: is hyperbaric oxygen genuinely better than a convincing placebo when neither the patient nor the doctor knows which they are getting? Note that we worked from the abstract and reliable secondary reports rather than the full paper.

Who took part

Twenty-one adults with established interstitial cystitis who had not responded adequately to previous treatments. Fourteen were randomised to hyperbaric oxygen and seven to a sham exposure. Numbers this small were partly a reflection of how demanding the schedule was.

What they did

This was a randomised, double-blind, sham-controlled trial. The oxygen group breathed 100 per cent oxygen at 2.4 ATA for 90 minutes per session, 30 sessions over six weeks, in a multi-person chamber. The sham group sat in the same chamber and breathed ordinary air at a slight pressure of 1.3 ATA, enough to give the ear-popping sensation of a real dive without delivering a therapeutic oxygen dose. Only the chamber operator knew the allocation. The main measure was a seven-point Global Response Assessment, with supporting measures of pain and urgency on visual analogue scales, bladder capacity, 24-hour frequency and the O'Leary-Sant symptom and problem indices. People were followed at 3 months and then to 12 months.

What they found

At three months, 3 of the 14 oxygen-treated participants (21 per cent) were classed as responders on the global assessment, against none of the 7 in the sham group. Secondary reports describe pain and urgency dropping by roughly a third to a half among those who responded, with a pattern the authors called all-or-nothing: people who improved did so early and tended to hold the gain, while non-responders did not improve later. At 12 months, 5 of the 12 oxygen-treated participants still followed reported sustained improvement of varying degree. Ear barotrauma was the main side effect and there were no serious adverse events.

Why it might work

In interstitial cystitis the bladder lining is thought to be damaged and leaky, with reduced blood flow in the deeper wall and, in the ulcerative form (Hunner lesions), visible areas of inflamed, poorly perfused tissue. Chronically low oxygen is a barrier to healing any lining. Hyperbaric oxygen has been used for decades to heal radiation-damaged bladder tissue, and the same reasoning applies here: raise oxygen delivery, support new capillary growth, reduce swelling and inflammation, and give the protective lining a chance to recover. The trial did not measure these mechanisms directly.

Limits

Twenty-one people is a very small trial, and with only seven in the sham arm a difference of three responders versus none is suggestive rather than definitive; wide confidence intervals mean chance cannot be ruled out. The majority of oxygen-treated participants did not respond. Follow-up losses reduced the 12-month group to twelve. The sham was well designed, but participants can sometimes guess their allocation. The findings come from a single German centre and the same group as the earlier pilot. The trial is nonetheless the only sham-controlled randomised evidence in this condition, which is why it is cited so often.

Paper 2

Hyperbaric oxygen therapy for painful bladder syndrome/interstitial cystitis resistant to conventional treatments: long-term results of a case series in Japan

Tanaka et al. · BMC Urology · 2011 · prospective case series, n=11

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What they asked

Tanaka and colleagues at Osaka City University wanted to know whether hyperbaric oxygen could help people whose bladder pain syndrome had resisted every conventional treatment, and, unusually for this field, whether any benefit lasted. Most earlier reports stopped at a few months; this series followed people for up to four years.

Who took part

Eleven adults (ten women, one man) with an average age of 60, ranging from 28 to 79, treated between 2004 and 2009. All had failed standard therapies. Eight had the ulcerative form of the condition with Hunner lesions visible on cystoscopy, and three had the non-ulcerative form. This was a case series with no comparison group, so everyone received the treatment.

What they did

Participants breathed 100 per cent oxygen at 2.0 ATA for 60 minutes a day, five days a week. Eight people had a course of 10 sessions and three had 20 sessions, a lighter course than in most Western studies. Pain and urgency were scored on visual analogue scales, symptoms with the O'Leary-Sant Interstitial Cystitis Symptom Index, frequency with 24-hour voiding diaries, and bladder capacity and cystoscopic appearance were also recorded. Follow-up continued for a median of 14 months, with a range of 3 to 50 months.

What they found

Seven of the eleven (64 per cent) were judged to have a persistent improvement. Across the responders, average pain scores fell from about 7.7 to 3.4 out of 9 at 12 months, urgency from 6.6 to 4.3, the symptom index total from about 27 to 19, and 24-hour voiding frequency from about 22 times to 15. Each of these changes reached statistical significance. Two responders whose symptoms drifted back after a year had a second course and remained stable for more than two years afterwards. Side effects were limited to one transient ear-pressure problem and three cases of reversible fluid behind the eardrum; nobody stopped treatment because of them.

Why it might work

The bladder wall in this condition, particularly where Hunner lesions are present, shows reduced blood supply and chronic inflammation, and the protective inner lining is thin and leaky. Higher oxygen delivery is thought to encourage new small vessel growth, reduce tissue swelling and inflammatory signalling, and support regeneration of that lining. The fact that repeat treatment restored benefit in two people is consistent with a tissue-level effect that can wear off, though a case series cannot prove that.

Limits

Eleven people, no control group and no blinding: improvement in an open series may reflect the natural waxing and waning of the condition, the attention of the treating team, or expectation. The averaged numbers are drawn from responders, and four people did not benefit. Most participants had the ulcerative form, so the results may not transfer to the far commoner non-ulcerative type. The dose (10 to 20 sessions at 2.0 ATA) is lower than in the German trial, which makes the two studies hard to compare. Follow-up length varied widely between individuals.

Paper 3

Treatment of ulcerative compared to non-ulcerative interstitial cystitis with hyperbaric oxygen: a pilot study

Wenzler et al. · Therapeutic Advances in Urology · 2017 · prospective pilot, n=8

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What they asked

By 2017 it was becoming clear that interstitial cystitis is probably two different conditions sharing a name: an ulcerative form with visible Hunner lesions in the bladder wall, and a non-ulcerative form without them. Wenzler and colleagues at Beaumont Health in Michigan asked whether hyperbaric oxygen helps one form more than the other, and whether the lesions themselves heal.

Who took part

Nine adults were enrolled; one left because of headaches, and eight completed treatment. Three more withdrew between 7 and 11 months later and were excluded from the final analysis, leaving five people: four with ulcerative disease and one with non-ulcerative disease. All had tried previous treatments and were passing urine at least eight times a day. The final numbers are, frankly, tiny.

What they did

This was an open pilot study with no control group. Everyone had 30 sessions over six weeks, Monday to Friday, breathing 100 per cent oxygen at 2.2 ATA for 90 minutes, plus about ten minutes each for pressurisation and depressurisation, so roughly two hours ten minutes per visit. Outcomes were pain on a visual analogue scale, the O'Leary-Sant symptom and problem indices, a Global Response Assessment, voiding diaries, and cystoscopy before treatment and again at six months. Questionnaires were repeated at 2 weeks, 3, 6 and 12 months.

What they found

Among the ulcerative group, most reported improvement on the global assessment shortly after treatment and about two-thirds were still better at six months. Median pain scores fell by two points, and the symptom and problem indices each dropped by a couple of points (13 to 10 and 12 to 10). In two of the three people with ulcers who had repeat cystoscopy, the ulcers had resolved at six months. The single non-ulcerative participant got worse at first and then improved markedly, with symptom scores falling to near zero and holding at 12 months. No adverse events occurred during treatment. The voiding diaries were so variable that the authors set them aside.

Why it might work

Hunner lesions are areas of chronically inflamed, poorly supplied bladder wall. Hyperbaric oxygen is an established treatment for a related problem, radiation cystitis, where it promotes capillary regrowth into damaged tissue. The cystoscopic resolution of ulcers in two people is the most interesting observation here, because it suggests a change in the tissue itself rather than only in how symptoms are perceived. With five people it is an observation, not a finding.

Limits

Five analysed participants, one of them representing the entire non-ulcerative arm, and no control group or blinding. Dropout was high. The authors did not track diet, physiotherapy, stress management or other things participants may have changed, nor overlapping conditions such as fibromyalgia or endometriosis. Recruitment was hard because of the time commitment, and the study was expensive to run despite its size. It received no specific funding. This paper is best read as a reason to run a proper trial comparing the two forms, not as evidence about either.