Evaluation of Botox Treatment on Chronical Scrotal Pain

Chronic Pain Clinical Trial

Official title:

Evaluation of Botox Treatment in Patients With Chronic Scrotal Pain: a Randomized Double Blinded Control Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05112081
• Other study ID #: E-BTX-CSP
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: June 1, 2022
• Est. completion date: June 30, 2026

Study information

• Verified date: April 2022
• Source: Odense University Hospital
• Contact: Nicolai S Schiellerup, MD
• Phone: +45 61692160
• Email: Nicolai.Skov.Schiellerup[@]rsyd.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of the study is to evaluate the effect of botox injections at the spermatic cord in patients with chronical scrotal pain.

A lot of patients experiences depressive symptoms and a lot feel isolated. The etiology if not fully understood and the condition poses a challenge for physicians.

The is no efficient minimal invasive treatment for these patients, and in severe cases patients are having there testicle removed.

By inject botox around the spermatic cord the investigators hope to relieve some of the pain in these patients and offer patients a new minimal invasive treatment.

The investigators aim to include 50 patients in this study, There will be randomised 1:1 to either the intervention arm (Botox) or control arm (sterile saline). Both patients and physicians will be blinded to the treatment.

Patients will undergo a thorough physical examination and will be asked to fill out questionaries to asses their quality of life.

After inclusion, patients will be followed closely for three months with physical examination and questionnaires.

After three months, patients in the control arm will have the opportunity to cross over to the intervention arm.

Data will be reported continuously.

Description:

Background:

Chronic scrotal pain (CSP) is a common condition with a prevalence of 2.5-4.8% in male outpatients. Up to 40% of these patients report depressive symptoms and many feel isolated.

CSP is defined as intermittent or constant unilateral or bilateral scrotal pain with a significant impact on the patients daily life. The etiology of CSP is not fully understood but can be related to surgical procedures such as vasectomy, inguinal hernia repair, scrotal surgery and abdominal and groin surgery, even though no apparent cause can be identified in 25-50% of the cases.

When no obvious source of pain is found the most common approach usually begins with conservative treatment including analgesia, antibiotics and in some cases anticonvulsants and antidepressants. When conservative treatment fails, a minimal invasive procedure with local anesthesia cord block is often used before more invasive treatments such as denervation, vasovasostomy, orchiectomy or epididymectomy.

Of the minimally invasive procedures, spermatic cord block has proven to significantly reduce pain briefly in patients with CSP. Because of these findings, it has been proposed that a longer-lasting effect could be obtained with the use of OnabotulinumtoxinA (BTX). BTX is widely used in pain management in many painful diseases such as chronic pain syndrome, myofascial syndrome, headaches, arthritis, and neuropathic pain.

BTX interfere with neural transmission by blocking the release of acetylcholine, the principal neurotransmitter at the neuromuscular junction, causing muscle paralysis. Function can be recovered by the sprouting of nerve terminals and formation of new synaptic contacts which usually takes two to three months.

The use of BTX in patients with CSP have had varying results. One open-label study by Khambati et al reported a significant reduction in pain measured by VAS-score at follow-up after one and three months, but pain and tenderness had returned to baseline after six months. The only randomized double-blinded study by Dockray et al. showed no significant reduction in pain measured by VAS-score at follow-up after one month.

The aim of this study is to investigate the effect of chemical denervation with BTX injections on pain in patients with CSP.

Methods

Study population and recruitment Patients with CSP will be included according to the inclusion and exclusion criteria's (table 1). The following variables will be considered: gender, age, length of symptoms, and questionnaires, e.g., quality-of-life questionnaire (EQ-5D-5L) and Chronic Prostatitis Symptom Index (NIH-CPSI).

Determination of sample size Given that the true success rate for BTX, regarding the primary endpoint, is at least 0.70, and the placebo success rate among controls is 0.20. The investigators will need to study 23 experimental patients and 23 control patients to be able to reject the null hypothesis that the failure rates for experimental and control subjects are equal with probability (power) 0.9. The type I error probability associated with this test of this null hypothesis is 0.05. Considering potential dropouts, the investigators will include 25 patients per group.

Investigations Patients with CSP will undergo a comprehensive workup: including a thorough medical and psychical history, physical examination (i.e. inspection and palpation of penis, testis, funiculus, groin including inguinal channel, abdomen, direct rectal exploration with evaluation of the pelvic muscles, hips and column), investigations of lower urinary tract symptoms (i.e. uroflowmetry and bladder diary), blood work (i.e. creatinine, hematocrit, white blood cells count and C-reactive protein), Doppler ultrasonography of the scrotum, urine analyze (i.e. urine culture, test for chlamydia and gonorrhea). In case of no apparent cause, conservative treatment will be initiated with paracetamol 1000 mg four times a day, ibuprofen 400 mg three times a day or Prostazocin 2.5 mg three times a day. If no pain relief occurs within 30 days, patients are offered funicle cord block with 10 ml lidocaine 20 mg/ml. In case of a significant decrease in scrotal pain measured by VAS, patients will be offered inclusion in the study according to the study inclusion criteria and after written informed consent is provided.

Prior to BTX cord block patients will answer the following questionnaires:

1. Visual analog score for pain (VAS)

2. Quality-of-life (EQ-5D-5L)

3. Chronic Prostatitis Symptom Index (NIH-CPSI)

4. ICD-10 depression questionnaire (MDI)

5. Likert global assessment scale (L-GAS)

6. International Index of Erectile Function questionnaire (IIEF) Questionnaires will be repeated after 1, 2, 3, 4, 8 and 12 weeks. Physical examination will be repeated after 4, 8 and 12 weeks. Patients will be randomized to the intervention or control group.

In both groups injection of either BTX or sterile saline will be given close to the superficial inguinal ring. The intervention group will receive a solution of 100 IU BTX with 10 ml sterile saline while the control arm will receive 10 ml sterile saline. At the 3 months' time point, patients will be unblinded to the treatment and patients in the control group will have the option of cross-over.

Data analysis Univariate analysis and multivariate analysis will be performed: T-tests will be used to compare means between groups and chi-squared tests to compare dichotomous variables, and to adjust for unequal distribution of parameters at baseline, multivariate regression models, linear models in case of an interval scaled outcome, and logistic regression in case of a dichotomous outcome will be performed.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: June 30, 2026
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Age of 18 - 70 years

2. Unilateral or bilateral scrotal pain > 3 months

3. No other identifiable cause of pain

4. Insufficient effect of conservative treatment

5. A positive effect of local anesthesia spermatic cord block

Exclusion Criteria:

1. Inability to provide informed consent

2. Interest in trying to conceive with partner in the following 6 months

3. Local infection near the proposed injection site

4. History with an allergic reaction to BTX and / or human serum albumin

5. History of motor neuron disease or hemostatic disorder

6. Active urogenital cancer

7. Current use of botox injections which would result in a total dose of botox higher than 300 IE in the span of 3 months

Related Conditions & MeSH terms

• Chronic Pain

Intervention

Drug:
• Botulinum toxin type A
The group will receive a solution of 100 units BTX with 10 ml sterile saline close to the superficial inguinal ring.

Other:
• Sterile saline
The group will receive a solution of 10 ml sterile saline close to the superficial inguinal ring.

Locations

Country	Name	City	State
Denmark	Odense University Hospital	Odense C	Fyn

Sponsors (1)

Lead Sponsor	Collaborator
Nicolai Skov Schiellerup

Country where clinical trial is conducted

Denmark, 

References & Publications (22)

Aljumaily A, Forbes E, Al-Khazraji HAJ, Gordon A, Lau S, Jarvi KA. Frequency and severity of chronic scrotal pain in Canadian men presenting to urologists for infertility investigations. Transl Androl Urol. 2017 Dec;6(6):1150-1154. doi: 10.21037/tau.2017.11.28. — View Citation

Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 2003 Jul-Aug;43 Suppl 1:S9-15. Review. — View Citation

Benson JS, Abern MR, Larsen S, Levine LA. Does a positive response to spermatic cord block predict response to microdenervation of the spermatic cord for chronic scrotal content pain? J Sex Med. 2013 Mar;10(3):876-82. doi: 10.1111/j.1743-6109.2012.02937.x. Epub 2012 Sep 27. — View Citation

Calixte N, Brahmbhatt J, Parekattil S. Genital pain: algorithm for management. Transl Androl Urol. 2017 Apr;6(2):252-257. doi: 10.21037/tau.2017.03.03. Review. — View Citation

Chancellor MB, Fowler CJ, Apostolidis A, de Groat WC, Smith CP, Somogyi GT, Aoki KR. Drug Insight: biological effects of botulinum toxin A in the lower urinary tract. Nat Clin Pract Urol. 2008 Jun;5(6):319-28. doi: 10.1038/ncpuro1124. Epub 2008 May 6. Review. — View Citation

Colhado OC, Boeing M, Ortega LB. Botulinum toxin in pain treatment. Rev Bras Anestesiol. 2009 May-Jun;59(3):366-81. Review. English, Portuguese. — View Citation

Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. — View Citation

Dockray J, Aljumaily A, Lau S, Jarvi KA. A Randomized, Double-Blind, Controlled Trial Shows that Onabotulinum Toxin A Nerve Blocks do Not Provide Improved Pain Control in Men with Chronic Scrotal Pain. J Urol. 2020 Apr;203(4):767-772. doi: 10.1097/JU.0000000000000658. Epub 2019 Oct 18. — View Citation

Heidenreich A, Olbert P, Engelmann UH. Management of chronic testalgia by microsurgical testicular denervation. Eur Urol. 2002 Apr;41(4):392-7. — View Citation

Jarvi KA, Wu C, Nickel JC, Domes T, Grantmyre J, Zini A. Canadian Urological Association best practice report on chronic scrotal pain. Can Urol Assoc J. 2018 Jun;12(6):161-172. doi: 10.5489/cuaj.5238. Epub 2018 Feb 23. — View Citation

Khambati A, Lau S, Gordon A, Jarvi KA. OnabotulinumtoxinA (Botox) nerve blocks provide durable pain relief for men with chronic scrotal pain: a pilot open-label trial. J Sex Med. 2014 Dec;11(12):3072-7. doi: 10.1111/jsm.12707. Epub 2014 Oct 6. — View Citation

Kumar R. Therapeutic use of botulinum toxin in pain treatment. Neuronal Signal. 2018 Aug 31;2(3):NS20180058. doi: 10.1042/NS20180058. eCollection 2018 Sep. Review. — View Citation

Lee CL, Kuo HC. Long-Term Efficacy and Safety of Repeated Intravescial OnabotulinumtoxinA Injections Plus Hydrodistention in the Treatment of Interstitial Cystitis/Bladder Pain Syndrome. Toxins (Basel). 2015 Oct 22;7(10):4283-93. doi: 10.3390/toxins7104283. — View Citation

Moore C, Rackley R, Goldman H. Urologic applications of botox. Curr Urol Rep. 2005 Nov;6(6):419-23. Review. — View Citation

Nigam PK, Nigam A. Botulinum toxin. Indian J Dermatol. 2010;55(1):8-14. doi: 10.4103/0019-5154.60343. — View Citation

Park J, Park HJ. Botulinum Toxin for the Treatment of Neuropathic Pain. Toxins (Basel). 2017 Aug 24;9(9). pii: E260. doi: 10.3390/toxins9090260. Review. — View Citation

Schover LR. Psychological factors in men with genital pain. Cleve Clin J Med. 1990 Nov-Dec;57(8):697-700. — View Citation

Sigalos JT, Pastuszak AW. Chronic orchialgia: epidemiology, diagnosis and evaluation. Transl Androl Urol. 2017 May;6(Suppl 1):S37-S43. doi: 10.21037/tau.2017.05.23. Review. — View Citation

Sim WS. Application of botulinum toxin in pain management. Korean J Pain. 2011 Mar;24(1):1-6. doi: 10.3344/kjp.2011.24.1.1. Epub 2011 Feb 25. — View Citation

Singh V, Sinha RJ. Idiopathic chronic orchialgia - a frustrating issue for the clinician and the patient. Indian J Surg. 2008 Jun;70(3):107-10. doi: 10.1007/s12262-008-0032-x. Epub 2008 Jul 24. — View Citation

Soares A, Andriolo RB, Atallah AN, da Silva EM. Botulinum toxin for myofascial pain syndromes in adults. Cochrane Database Syst Rev. 2014 Jul 25;(7):CD007533. doi: 10.1002/14651858.CD007533.pub3. Review. — View Citation

Wu C, Jarvi K. Management of chronic scrotal content pain. Can Urol Assoc J. 2018 Jun;12(6 Suppl 3):S164-S166. doi: 10.5489/cuaj.5326. Review. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect on pain 3 months after treatment	Pain is evaluated on a Visual Analog Scale (VAS) from 0-10, where 0 is no pain and 10 is the maximal pain a patient can report.; VAS prior to the treatment is compared to VAS 3 months after treatment.	3 months
Secondary	Duration of effect	Pain is evaluated on a Visual Analog Scale (VAS) from 0-10, where 0 is no pain and 10 is the maximal pain a patient can report.; Patients will evaluate pain by VAS after 1, 2, 3, 4, 8 and 12 weeks	3 months
Secondary	Changes in patient reported Quality of Life	Quality-of-life (EQ-5D-5L) Questionnaire containing 5 dimensions with a score scale from 0 - 5. A higher score correlates to a more negative impact on the patients life.; Questionnaire will be repeated after 1, 2, 3, 4, 8 and 12 weeks	3 months
Secondary	Changes in patient reported Quality of Life	Chronic Prostatitis Symptom Index (NIH-CPSI) The NIH-CPSI has a total score range from 0 to 43, and it includes three subscales addressing pain (score range 0-21).; A higher score correlates to a more negative impact on the patients life.; Questionnaire will be repeated after 1, 2, 3, 4, 8 and 12 weeks	3 months
Secondary	Changes in patient reported Quality of Life	ICD-10 depression questionnaire (MDI) Patients can score 0 - 5 in multiple questions. A higher score signifies deeper depression.; Questionnaire will be repeated after 1, 2, 3, 4, 8 and 12 weeks	3 months
Secondary	Changes in patient reported Quality of Life	Likert global assessment scale (L-GAS) The scale is a rating scale for evaluating the overall functioning of the treatment. Patients can answer 0 - 100, where 100 is full satisfaction with the treatment.; Questionnaire will be repeated after 1, 2, 3, 4, 8 and 12 weeks	3 months
Secondary	Changes in patient reported Quality of Life	International Index of Erectile Function questionnaire (IIEF) Patients can score 0 - 5 and NA (not applicable). A lower score correlates to a more negative impact on the patients life.; Questionnaire will be repeated after 1, 2, 3, 4, 8 and 12 weeks	3 months