Ozone Therapy in Refractory Pelvic Pain Syndromes Secondary to Cancer Treatment: A New Approach Warranting Exploration

Abstract

Background:

Chronic pain secondary to treatment in cancer survivors without tumor evidence is not unusual. Its management often requires specific approaches that are different from those applied for cancer patients with advanced disease and short life expectancy. Some studies have described clinical benefit with ozone therapy (O₃T) in the management of pain and side effects secondary to cancer treatment.

Objective:

We present our preliminary experience with O₃T in the management of refractory pelvic pain syndromes secondary to cancer treatment.

Design:

Case series.

Subjects and Methods:

Six cancer patients (without tumor evidence) who had been treated previously with radiotherapy, chemotherapy, or endoscopic procedures and were suffering persistent or severe pelvic pain (median 14 months) received O₃T using ozone–oxygen gas mixture insufflation as a complementary therapy in addition to their scheduled conventional treatment.

Results:

All cases, except one, showed clinically relevant pain improvement. Visual analog scale score with the standard treatment was 7.8 ± 2.1 before O₃T, 4.3 ± 3.4 (p = 0.049) after one month, 3.3 ± 3.7 (p = 0.024) after two months, and 2.8 ± 3.8 (p = 0.020) after three months of O₃T. The median value of “pain symptom” according to the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events v. 5.0 showed a decrease from 3 (range: 2–3) to 1 (range: 0–3) (p = 0.046).

Conclusions:

Following unsuccessful conventional treatments, O₃T provided significant benefit in our patients with refractory pelvic pain secondary to cancer treatment. These results merit further evaluation in blinded, randomized clinical trials.

Introduction

Pain can be caused by the treatments themselves in 17% of cancer patients.¹ As survival is increased, the number of survivors with side effects and chronic pain induced by the cancer treatments is also increased.^1,2 A neuropathic pain mechanism may be involved in around 34% to 40% of these patients^1,3 and is associated with more difficult pain management, irruptive pain, higher opioid doses, lower performance status, poorer physical, cognitive, and social functions, and poorer quality of life.^3–5

The management of chronic pain in these patients requires approaches that differ from those in cancer patients with advanced tumor disease and short life expectancy. However, there is no broad consensus on the management of this problem because of the paucity of studies evaluating chronic pain in cancer survivors and the long-term safety and effectiveness of analgesic interventions.⁶

Ozone therapy (O₃T) consists of local and/or systemic administration of an ozone–oxygen gas mixture. We have previously described its value in the management of several cases of persistent radiation-induced toxicity such as hematuria,⁷ brain ischemia and hypometabolism,⁸ cutaneous fistula,⁹ delayed wound healing,¹⁰ and rectal bleeding¹¹ as well as a long-lasting effect.¹² Guidelines published by the American Society of Colon and Rectal Surgeons have described the use of O₃T as having grade of recommendation 1C for radiation-induced rectal bleeding.^11–13

Similarly, the beneficial effect of ozone has been described in treating neuropathic pain secondary to trigeminal neuralgia,¹⁴ zoster-associated pain,¹⁵ and in disc herniation, where a meta-analysis established a grade of recommendation 1B for paravertebral O₃T and grade 1C for intradiscal O₃T.¹⁶

In this report, we describe the clinical effects of O₃T as an adjuvant treatment in the management of cancer patients suffering from refractory pelvic pain syndromes secondary to cancer treatment. We focused on pain as the main symptom, although several other symptoms were also addressed.

Methods

Sixteen cancer patients were evaluated for compassionate ozone treatment at our Chronic Pain Unit between January 2017 and December 2018. Eight patients (50%) had pain as one of the main symptoms: seven had pelvic pain and six of them were treated with O₃T. The patients presented persistent pelvic pain and different side effects secondary to their cancer treatment. All patients had previously received pain management with pain reduction medications, and many had had several interventional techniques. No patient had evidence of tumor persistence before commencement of O₃T. Table 1 summarizes patient details and clinical course.

Table 1.

Clinical Characteristics and Patient-Reported Changes in Pain

Case number	Age, years	Sex	Diagnosis	VAS pre-O₃	VAS post-O₃^a	CTCAE pre-O₃	CTCAE post-O₃^a	Months with pain pre-O₃	Number of sessions	Previous treatments and clinical characteristics
Case 1	35	F	Uterine cervix carcinoma. Vaginal pain, post-RT. Associated to vaginal dryness and ulceration	7.5	0	2	0	4	12	Antibiotics and anti-inflammatory drugs had been used during several months.
Case 2	54	M	Prostate carcinoma. Bladder pain, post-RT. Associated to hematuria	10	10	3	3	15	15	Opioids, several drugs, and interventional approaches were unsuccessfully tried. Patient proposed cystectomy. RT-induced hematuria disappeared with O₃.
Case 3	61	M	Prostate carcinoma. Rectal pain, post-endoscopic treatment	4.5	2	3	1	13	36	RT-induced hematuria. After endoscopic procedure, hemorrhage disappeared but immediately appeared tenesmus and pain. Transdermal and sublingual fentanyl and other drugs were unsuccessfully tried.
Case 4	64	M	Follicular lymphoma Stage IV-A. Bladder pain, post-CT. Associated to vesical cystitis	10	1	3	0	30	33	Opioids, several drugs, and interventional approaches were unsuccessfully tried. Patient proposed cystectomy.
Case 5	60	F	Uterine cervix carcinoma. Vaginal and pelvic pain, post-RT + CT. Associated to vaginal necrosis and rectovaginal fistula	7	4	3	3	15	27	(1) Fentanyl, anti-inflammatory, metamizole (2) RT + CT. Partial relief with hyperbaric oxygen. Functional colostomy.
Case 6	71	F	Rectal adenocarcinoma. Rectal pain, post-S + RT + CT	8	0	2	0	9	32	Loperamide, anti-inflammatory drugs. Tenesmus and rectal pain. Subocclusive crises, several visits to Emergency Department.

			Mean ± SD or median (range)	7.8 ± 2.1	2.8 ± 3.8	3 (2–3)	1 (0–3)	14.3 ± 8.8	25.8 ± 10
			p	0.020^b		0.046^c

Data displayed in the table relate only to the pain symptom.

Reported changes in pain after three months of ozone therapy.

Paired Student's t-test.

Wilcoxon test.

F, female; M, male; S, surgery; RT, radiotherapy; CT, chemotherapy; VAS, visual analog scale; CTCAE, Common Terminology Criteria for Adverse Events v.5.0 (toxicity gradation system according to the U.S. National Cancer Institute); SD, standard deviation.

All patients provided informed written consent to the therapy, and all procedures conformed to the Declaration of Helsinki of 1975. Compassionate ozone treatment in these clinical conditions was evaluated by the Health Care Ethics Committee and included in the BCV-OZO-2019-01 study, which was approved by our Research Ethics Committee.

Pain before and after O₃T was scored on the visual analog scale (VAS) ranging from 0 (no pain) to 10 (worst imaginable pain). We also evaluated “pain as the main symptom” according to the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0, with a range from 0 (no symptoms) to 5 (death).

Ozone therapy

O₃T is an outpatient procedure. The O₃/O₂ gas mixture was accurately produced from clinical grade oxygen using a medical ozone generator (Ozonosan Alpha-plus^®; Dr. Hansler GmbH, Iffezheim, Germany). The gas mixture is prefiltered through a sterile 0.20 mm filter. We have presented details of the technique as applied in rectal insufflations¹¹ and bladder instillations.⁷

Rectal insufflations (using standard rectal cannulas) were applied in five patients (#2, #3, #4, #5, and #6). We followed the concept of “start slow go slow,”¹⁷ and we started with a volume insufflation of 180 mL of O₃/O₂ gas mixture at a concentration of 10 μg/mL (μg of O₃ per mL of O₂). Concentrations were increased by 5 μg/mL every two sessions until final concentration of 30 μg/mL. Volume was slowly increased as well, depending on patient tolerance of bowel distension (or bloating) up to a maximum volume of 300 mL, which was applied in two of the five patients (#2 and #4).

Additionally, bladder insufflation of O₃/O₂ gas or instillations of ozonated water (both via standard vesical cannulas) were applied in two patients (#2 and #4); vaginal insufflations and vaginal washing (by standard rectal cannulas) with ozonated water were applied in two patients (#1 and #5).

The required number of ozone sessions and the length of treatment can be highly heterogeneous in chronic and refractory symptoms. Our most relevant experience in cancer patients has been in the treatment of hemorrhagic radiation proctitis, which showed median duration of treatment: 10 months (range 1–19 months) and median number of sessions: 38 sessions (5–107 sessions), as it has been also described for treatment with hyperbaric chambers.^11,12 So, for patients with limited therapeutic options, in our Chronic Pain Unit, the end of O₃T depends on individual clinical evolution, and if it is observed: (1) no response in the initial two months, (2) a maintained plateau without further improvement, or (3) two to three sessions after full symptom recovery. Frequency of sessions was not constant. They were higher at the beginning (three sessions/week if possible), and they were progressively decreased following symptom improvement, from two sessions/week to one session every two to four weeks the last sessions. However, because of initial limitations in our facilities, patients #1 and #2 were only treated once per week.

Pain treatment before O₃T

Patient #1: antibiotics and different anti-inflammatory drugs were previously used over several months. Patient #2: prolonged release morphine sulfate 60 mg/12 hours, transmucosal fentanyl 400 μg as required, gabapentin 600 mg/8 hours, naproxen 500 mg/8 hours, and metamizole (dipyrone) 575 mg/8 hours. He also had used alprazolam, zopiclone, desvenlafaxine, trazodone, and indomethacin. Patient #3: transdermal fentanyl 37.5 μg/hour, transmucosal fentanyl 200 μg as required, paracetamol 1 g/8 hours, gabapentin 1200 mg/8 hours, clonazepam 1 mg/24 hours, and chlorpromazine 25 mg/12 hours. Patient #4: tramadol 250 mg/day, pregabalin 75 mg/24 hours, ibuprofen 600 mg/12 hours, dipyrone 575 mg/8 hours, hyoscine butylbromide 30 mg/day, clorazepate 20 mg/day, amitriptyline 10 mg/day, and intravesical hyaluronic acid. Additionally, different interventional procedures were unsuccessfully tried, following the American Urological Association guideline for interstitial cystitis¹⁸: third-line treatment by low-pressure hydrodistention under cystoscopy and fourth-line treatments by sacral nerve root stimulation, intradetrusor botulinum toxin A, and pudendal nerve block. Patient #5: hyperbaric oxygen at 1.45 atmospheres absolute (ATA), 25 sessions in eight weeks, with partial pain improvement. Initially, the patient was under transmucosal and transdermal fentanyl and different anti-inflammatory drugs were used without benefits. Patient #6: loperamide and different anti-inflammatory drugs were tried, unsuccessfully. The urgency of defecation got worse in frequency and in associated rectal pain during defecation. Opioid treatment was refused by the patient.

Statistical analyses

The SPSS software package (version 15 for Windows) was used for all statistical analyses. Pre- and post-O₃T comparisons of pelvic pain according to the VAS were by the paired Student t-test. Comparison of pelvic pain as the grade of toxicity according to the CTCAE v 5.0 was by the Wilcoxon test (CTCAE data were described as median and range from 25% to 75%). p-Values <0.05 were considered statistically significant.

Results

Patients were three males and three females, with median age 61 years (range 35–71 years). The median duration of pain management before commencement of O₃T was 14 months (range: 4–30 months). The median number of sessions of O₃T during the three months of treatment was 30 sessions (range 12–36 sessions).

VAS decreased in all patients, except patient #2. The mean score was 7.8 ± 2.1 at the beginning of O₃T, 4.3 ± 3.4 after the first month of treatment (p = 0.049), 3.3 ± 3.7 after the second month (p = 0.024), and 2.8 ± 3.8 (p = 0.020) after three months of O₃T. Furthermore, most patients were able to decrease or even discontinue analgesic intake requirements. The “pain symptom” evaluation according to the CTCAE v. 5.0 showed a decrease from a median value of 3 (range: 2–3) to 1 (range: 0–3) (p = 0.046). Figure 1 summarizes these data.

FIG. 1.

Clinical evolution of pain during ozone therapy. Patients underwent ozone therapy after a median of 14 months following unsuccessful pain treatments. Pain levels according to the VAS were 7.8 ± 2.1 before the commencement of ozone therapy, 4.3 ± 3.4 (p = 0.049) after one month, 3.3 ± 3.7 (p = 0.024) after two months, and 2.8 ± 3.8 (p = 0.020) after three months of ozone therapy. All patients (except one) reported a progressive and clinically relevant improvement in pain levels. The bars represent 95% confidence intervals. VAS, visual analog scale.

Discussion

This is the first report on the use of O₃T in the management of difficult chronic pelvic pain syndromes secondary to cancer treatments.

In this case series, all but one of the patients reported clinically significant pain relief with O₃T. Also, they had decreased, or even discontinued, analgesic requirements and recovered acceptable daily life activities. Additionally, most of the patients reported additional benefits with respect to other symptoms (vaginal dryness, rectal or vaginal wounds, hematuria, tenesmus, and the number of bowel movements per day). No adverse effects were noted, except occasional moderate discomfort at the site of the rectal tube placement and, frequently, slight intestinal bloating for some hours after each session. These effects have been reported previously.^11,19

Our patients were refractory to more conventional pain treatments, and most of them had tried, unsuccessfully, opioid drugs and several interventional therapies. Indeed, the two patients (#2 and #4) with pelvic pain secondary to cystitis requested cystectomy and had seriously contemplated suicide because of the pain. Patient #2 did not achieve pain alleviation with single-dose weekly ozone treatment, and eventually, a simple cystectomy was performed. It remains unclear if this patient could have had a better clinical evolution with a higher frequency of treatment (e.g., three sessions/week as with patient #4). Hence, an initial frequency of three sessions/week is highly recommended for future patients.

Oxidative stress, inflammation, and ischemia/hypoxia are the principal mechanisms involved in radiation-induced neuropathic pain,²⁰ chemotherapy-induced neuropathy,^21,22 and postoperative pain.²³ At appropriate doses and concentrations, ozone can induce an adaptive response, which can favorably modify those processes.^17,24–27

There are few clinical reports regarding O₃T for the management of side effects secondary to cancer treatments, and they were not focused on pain as the main symptom.^7–12,28,29 However, studies evaluating chronic pain in cancer survivors or the long-term safety and effectiveness of more conventional analgesic interventions are also very limited.⁶ So, further research is needed.

This study focused on the management of patients with difficult pain and symptoms, and it has several limitations: First, small number of patients. Second, different symptoms and diagnoses, although all of them were located in pelvis. Third, different etiology: radiation, chemotherapy, and resection procedures. Fourth, different chronic pain levels, as shown in Table 1, although acute pain level was ≥7.5 in all patients. Fifth, different previous pain treatments: several interventional techniques were tried in two patients, and opioids were rejected in other two patients. Sixth, different frequency and number of treatment sessions, as explained in the Methods section. Many of these limitations will be overcome in a related clinical trial in progress (EudraCT: 2019-000821-37 and NCT04299893).

Conclusions

This report suggests that persistent and refractory pelvic pain, secondary to cancer treatment, may be improved using O₃T. These results could support the complementary (or palliative) use of O₃T in similar intractable conditions. Blinded, randomized clinical trials are in progress.

Footnotes

Acknowledgment

The ozone therapy device Ozonosan Alpha-plus was provided by Dr. Renate Viebahn (Dr. Hänsler GmbH, Iffezheim, Germany). Preliminary data were presented at the Second International Traditional and Complementary Medicine Congress (Istanbul, Turkey, April 2019) organized with technical sponsorship of the World Health Organization.

Funding Information

No funding was received for this article.

Author Disclosure Statement

No competing financial interests exist.

References

Grond

, Zech

, Diefenbach

, et al.: Assessment of cancer pain: A prospective evaluation in 2266 cancer patients referred to a pain service. Pain, 1996; 64:107–114.

Vistad

, Cvancarova

, Kristensen

, et al.: A study of chronic pelvic pain after radiotherapy in survivors of locally advanced cervical cancer. J Cancer Surviv, 2011; 5:208–216.

Bennett

, Rayment

, Hjermstad

, et al.: Prevalence and aetiology of neuropathic pain in cancer patients: A systematic review. Pain, 2012; 153:359–365.

Rayment

, Hjermstad

, Aass

, et al.: Neuropathic cancer pain: Prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerised Symptom Assessment study. Palliat Med, 2013; 27:714–721.

Green

, Hart-Johnson

, Loeffler

: Cancer-related chronic pain: Examining quality of life in diverse cancer survivors. Cancer, 2011; 117:1994–2003.

Paice

, Portenoy

, Lacchetti

, et al.: Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol, 2016; 34:3325–3345.

Clavo

, Gutierrez

, Martin

, et al.: Intravesical ozone therapy for progressive radiation-induced hematuria. J Altern Complement Med, 2005; 11:539–541.

Clavo

, Suarez

, Aguilar

, et al.: Brain ischemia and hypometabolism treated by ozone therapy. Forsch Komplementmed, 2011; 18:283–287.

Clavo

, Santana-Rodriguez

, Lopez-Silva

, et al.: Persistent PORT-A-CATH(R)-related fistula and fibrosis in a breast cancer patient successfully treated with local ozone application. J Pain Symptom Manage, 2012; 43:e3–e6.

10.

Clavo

, Santana-Rodriguez

, Llontop

, et al.: Ozone therapy as adjuvant for cancer treatment: Is further research warranted?. Evid Based Complement Alternat Med, 2018; 2018:7931849.

11.

Clavo

, Ceballos

, Gutierrez

, et al.: Long-term control of refractory hemorrhagic radiation proctitis with ozone therapy. J Pain Symptom Manage, 2013; 46:106–112.

12.

Clavo

, Santana-Rodriguez

, Llontop

, et al.: Ozone therapy in the management of persistent radiation-induced rectal bleeding in prostate cancer patients. Evid Based Complement Alternat Med, 2015; 2015:480369.

13.

Paquette

, Vogel

, Abbas

, et al.: The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the treatment of chronic radiation proctitis. Dis Colon Rectum, 2018; 61:1135–1140.

14.

, Liu

, Chen

, et al.: Computed tomography-guided percutaneous ozone injection of the gasserian ganglion for the treatment of trigeminal neuralgia. J Pain Res, 2018; 11:255–263.

15.

Lin

, Zhang

, An

, et al.: The effect of ultrasound-guided percutaneous ozone injection around cervical dorsal root ganglion in zoster-associated pain: A retrospective study. J Pain Res, 2018; 11:2179–2188.

16.

Magalhaes

, Dotta

, Sasse

, et al.: Ozone therapy as a treatment for low back pain secondary to herniated disc: A systematic review and meta-analysis of randomized controlled trials. Pain Physician, 2012; 15:E115–E129.

17.

Bocci

, Zanardi

, Travagli

: Ozone acting on human blood yields a hormetic dose-response relationship. J Transl Med, 2011; 9:66.

18.

Hanno

, Erickson

, Moldwin

, et al.: Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol, 2015; 193:1545–1553.

19.

Viebahn-Hansler

, Leon Fernandez

, Fahmy

: Ozone in medicine: Clinical evaluation and evidence classification of the systemic ozone applications, major autohemotherapy and rectal insufflation, according to the requirements for evidence-based medicine. Ozone Sci Eng, 2016; 38:322–345.

20.

Delanian

, Lefaix

, Pradat

: Radiation-induced neuropathy in cancer survivors. Radiother Oncol, 2012; 105:273–282.

21.

Starobova

, Vetter

: Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci, 2017; 10:174.

22.

Areti

, Yerra

, Naidu

, et al.: Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy. Redox Biol, 2014; 2:289–295.

23.

Zorina-Lichtenwalter

, Parisien

, Diatchenko

: Genetic studies of human neuropathic pain conditions: A review. Pain, 2018; 159:583–594.

24.

Pecorelli

, Bocci

, Acquaviva

, et al.: NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells. Toxicol Appl Pharmacol, 2013; 267:30–40.

25.

Bocci

, Valacchi

: Nrf2 activation as target to implement therapeutic treatments. Front Chem, 2015; 3:4.

26.

Viebahn-Hansler

, Leon Fernandez

, Fahmy

: Ozone in medicine: The low-dose ozone concept—guidelines and treatment strategies. Ozone Sci Eng, 2012; 34:408–424.

27.

Clavo

, Rodriguez-Esparragon

, Rodriguez-Abreu

, et al.: Modulation of oxidative stress by ozone therapy in the prevention and treatment of chemotherapy-induced toxicity: Review and prospects. Antioxidants (Basel), 2019; 8.

28.

Menendez

, Cepero

, Borrego

: Ozone therapy in cancer treatment: State of the art. Ozone Sci Eng, 2008; 30:398–404.

29.

Waked

, Nagib

, Omar

MTA

: A single blinded randomized controlled clinical trial on the efficacy of ozone therapy on breast cancer-related lymphedema. Cancer Clin Oncol, 2013; 2:93–106.

Ozone Therapy in Refractory Pelvic Pain Syndromes Secondary to Cancer Treatment: A New Approach Warranting Exploration

Abstract

Background:

Objective:

Design:

Subjects and Methods:

Results:

Conclusions:

Introduction

Methods

Ozone therapy

Pain treatment before O3T

Statistical analyses

Results

Discussion

Conclusions

Footnotes

Acknowledgment

Funding Information

Author Disclosure Statement

References

Pain treatment before O₃T