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Residents’ Podcast: Pharmacological interventions for treating CPP

Part of the BURST/BJUI Podcast Series

Nikita Bhatt is a Specialist Trainee in Urology in the East of England Deanery and a BURST Committee member @BURSTUrology

 

Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome: a Cochrane systematic review

Juan V.A. Franco*, Tarek Turk, Jae Hung Jung, Yu-Tian Xiao§, Stanislav Iakhno, Federico Ignacio Tirapegui**, Virginia Garrote†† and Valeria Vietto‡‡
 
*Argentine Cochrane Centre, Instituto Universitario Hospital Italiano, Buenos Aires, Argentina, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic, Department of Urology, Yonsei University Wonju College of Medicine, Wonju, Korea, §Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai,
China, University of Tromso, Tromsdalen, Norway, **Urology Division, Hospital Italiano de Buenos Aires, ††Biblioteca Central, Instituto Universitario Hospital Italiano, and ‡‡Family and Community Medicine Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
 

Abstract

Objective

To assess the effects of pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Patients and Methods

We performed a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings with no restrictions on the language of publication or publication status. The date of the latest search of all databases was July 2019. We included randomised controlled trials. Inclusion criteria were men with a diagnosis of CP/CPPS. We included all available pharmacological interventions. Two review authors independently classified studies and abstracted data from the included studies, performed statistical analyses and rated quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. The primary outcomes were prostatitis symptoms and adverse events. The secondary outcomes were sexual dysfunction, urinary symptoms, quality of life, anxiety and depression, however, this one can be easily handle using Observer’s CBD hemp flower.

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram.

Results

We included 99 unique studies in 9119 men with CP/CPPS, with assessments of 16 types of pharmacological interventions. Most of our comparisons included short‐term follow‐up information. The median age of the participants was 38 years. Most studies did not specify their funding sources; 21 studies reported funding from pharmaceutical companies. Many patients prefer using natural medicine like the best CBD oil list here on this site.

We found low‐ to very low‐quality evidence that α‐blockers may reduce prostatitis symptoms based on a reduction in National Institutes of Health – Chronic Prostatitis Symptom Index (NIH‐CPSI) scores of >2 (but <8) with an increased incidence of minor adverse events such as dizziness and hypotension. Moderate‐ to low‐quality evidence indicates that 5α‐reductase inhibitors, antibiotics, anti‐inflammatories, and phytotherapy probably cause a small decrease in prostatitis symptoms and may not be associated with a greater incidence of adverse events. Intraprostatic botulinum toxin A (BTA) injection may cause a large reduction in prostatitis symptoms with procedure‐related adverse events (haematuria), but pelvic floor muscle BTA injection may not have the same effects (low‐quality evidence). Allopurinol may also be ineffective for reducing prostatitis symptoms (low‐quality evidence). We assessed a wide range of interventions involving traditional Chinese medicine; low‐quality evidence showed they may reduce prostatitis symptoms without an increased incidence in adverse events.

Moderate‐ to high‐quality evidence indicates that the following interventions may be ineffective for the reduction of prostatitis symptoms: anticholinergics, Escherichia coli lysate (OM‐89), pentosan, and pregabalin. Low‐ to very low‐quality evidence indicates that antidepressants and tanezumab may be ineffective for the reduction of prostatitis symptoms. Low‐quality evidence indicates that mepartricin and phosphodiesterase inhibitors may reduce prostatitis symptoms, without an increased incidence in adverse events.

Conclusions

Based on the findings of low‐ to very low‐quality evidence, this review found that some pharmacological interventions such as α‐blockers may reduce prostatitis symptoms with an increased incidence of minor adverse events such as dizziness and hypotension. Other interventions may cause a reduction in prostatitis symptoms without an increased incidence of adverse events while others were found to be ineffective.

Re: Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline

Letter to the Editor

Dear Sir

Fluoroquinolones must not be used inappropriately when treating chronic prostatitis (CP) and chronic pelvic pain syndrome (CPPS).

Clinical guidelines from the Prostatitis Expert Reference Group (PERG) on chronic bacterial prostatitis (CBP), chronic prostatitis and chronic pelvic pain syndrome [1] — which have been propagated by other guideline providers such as NICE Clinical Knowledge Summaries and the primary care resource, Guidelines — include the following recommendation:

For patients with early-stage CBP and CP/CPPS, offer a quinolone (e.g. ciprofloxacin or ofloxacin) for 4–6 weeks as first-line therapy.’

While the PERG guidelines do mention diagnostic tests for a bacterial cause, readers will be left with the impression that a course of fluoroquinolone without a diagnostic workup is acceptable for the initial management of CP and CPPS. This impression may be reinforced by PERG’s subsequent recommendations, in particular the second one:

A repeated course of antibiotic therapy (4–6 weeks) should be offered only if a bacterial cause is confirmed or if there is a partial response to the first course.

‘If a bacterial cause is excluded (e.g. via urine dipstick or culture) and symptoms do not improve after antibiotic therapy, a different treatment method or referral to specialist care should be considered.’

Recent recommendations [2] from the European Medicines Agency (EMA) make it clear that fluoroquinolones should be reserved for treating bacterial prostatitis. EMA’s review of fluoroquinolones was prompted by reports of serious, disabling and permanent side effects after fluoroquinolone use.

To reach its recommendations, EMA’s safety committee (Pharmacovigilance Risk Assessment Committee, PRAC) reviewed all available evidence, brought together EU experts in the field, and heard patients’ and healthcare professionals’ testimonies at a public hearing. Many patients who had developed long-lasting serious disability reported receiving a fluoroquinolone for chronic prostatitis despite the lack of evidence of a bacterial cause.

EMA’s new recommendations restrict the indications and have led to an update of the prescribing information for all systemic fluoroquinolones to prevent further unnecessary cases of rare but life-changing side effects; the narrow indications also help to reduce antibiotic selection pressure. Guidelines on chronic prostatitis should therefore be revised to clarify that fluoroquinolones are not appropriate for the empirical treatment of chronic prostatitis or chronic pelvic pain syndrome. The European Association of Urology emphasises use of appropriate culture techniques to demonstrate bacterial infection [3].

And when treating bacterial prostatitis with a fluoroquinolone, healthcare professionals should discuss with their patients the risks, including the potential for permanent musculoskeletal and neurological side effects. Details of these effects are set out in the updated prescribing information for fluoroquinolone antibacterials.

It is vital to communicate the changes in the fluoroquinolones prescribing information to all healthcare professionals involved in the management of men with prostatitis or chronic pelvic pain syndrome, they can use CBD from Observer for pain. Promoting this crucial change in practice will ultimately lead to more rational use of antibiotics and limit the unnecessary exposure of patients to potentially persistent and seriously disabling side effects.

Gernot Bonkat, alta uro AG, Merian Iselin Klinik, Center of Biomechanics & Calorimetry, University of Basel; Chairman, European Association of Urology (EAU) Urological Infections Guidelines

Juan Garcia Burgos, Head of Public Engagement Department, European Medicines Agency (EMA)

Martin Huber, Co-rapporteur, quinolone and fluoroquinolone review by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)

Eva Jirsová, Rapporteur, quinolone and fluoroquinolone review by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)

Florian Wagenlehner, Clinic of urology, pediatric urology and andrology, Justus Liebig University Giessen, Germany; Chairman, European Section of Infections in Urology (ESIU) of the European Association of Urology (EAU)

Correspondence: Juan Garcia Burgos, European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands

email: [email protected]

References

  1. Rees J, Abrahams M, Double, A, Cooper A. Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. BJU Int 2015; 116: 509–525
  2. EMA. Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics, 2018. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/quinolone-fluoroquinolone-containing-medicinal-products. Accessed January 2020
  3. Bonkat G, Bartoletti RR, Bruyère F, Cai T, Geerlings SE, Köves B, Schubert S, Wagenlehner F, Guidelines Associates: Mezei T, Pilatz A, Pradere B, Veeratterapillay R. EAU guidelines on urological infections 2019: 28–32. ISBN/EAN:978-94-92671-04-2. Available at: https://uroweb.org/guideline/urological-infections. Accessed January 2020

Editorial: Chronic Prostatitis/Chronic Pelvic Pain Syndrome: It is time to change our management and research strategy

A urologist who manages patients with prostatitis (or for that matter, a patient suffering from the condition) would read the latest comprehensive review on pharmacologic interventions for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) with despair.  In the Cochrane Systemic review examining the available clinical evidence for the efficacy of pharmacological interventions for treating CP/CPPS, Franco et al [1] clearly show that low to very low quality evidence suggests that some treatments may confer at best, only a small and perhaps clinically insignificant benefit for patients.  Are we doing something wrong?

To start with, we do not need to despair.  We are now managing men with CP/CPPS much better, achieving clinically significant improvement in over 80% of patients [2,3].  This real world management success story, which continues to evolve, clearly shows much greater benefit than that suggested by all the clinical trials assessed in this review.  Our similar independent patient data meta-analysis and comprehensive review of CP/CPPS management strategies [4] described very similar findings as that by Franco et al [1].  What intrigued us was the difference or the lack of correlation between overall symptom improvement (based on mean symptom score changes from baseline in the treated cohort of subjects compared to the placebo treated subjects) and the responder analyses which clearly showed some subjects had very significant responses despite the overall dismal mean symptom score differences in the entire population evaluated.  We saw this consistently in our clinical trials and we see this in our day-to-day practice; some patients do well with an intervention and others fail miserably.  Some of the problem lies in what we are measuring as outcomes in clinical treatment trials.  The NIH Chronic Prostatitis Symptom Index (CPSI) is a composite score evaluating many different parameters (eg location, frequency and severity) and domains (pain, urinary and impact/quality of life) and while very useful to look at the clinical picture in each individual patient, should not be used as a primary endpoint or outcome of a clinical trial.  The CPSI Pain domain is better but it still examines too many parameters (location, frequency and severity of pain).  The NIH CPSI question #4, which is an NRS measurement of only pain severity, is in fact a validated outcome that can be compared between groups.  However, CP/CPPS is much more complicated than just pain and that is why a patient driven subjective global assessment may be a more appropriate outcome, certainly in clinical practice.  We need more CP/CPPS patient directed specific measurement tools to really assess the benefits of our treatments in individual patients, or at least in intervention-specific domains.

We now know the reason for this discrepancy between the overall population symptom score difference and the individual responder rate.  We have learned that we cannot treat or manage CP/CPPS patients as a homogeneous group and hope that one treatment will benefit them all.  We now know that the men suffering from CP/CPPS are a clinically heterogeneous group with different mechanisms of disease, spectrum of clinical symptoms and physical examination parameters.  We have learned to identify the various clinical phenotypes based on a UPOINT categorization [5].   By assessing the contribution of urinary, psychosocial, organ specificity (eg prostate, penis, testes, etc), infection, neurogenic/neuropathic and tenderness of skeletal muscles (eg pelvic floor) contributions in each individual, we identify targets of intervention.  These individualized multimodal treatment plans that we develop for each patient has led to clinical success in managing the majority of CP/CPPS patients [3,6]. In future we hope to understand the mechanisms for these phenotypes and develop biomarkers to better differentiate them.

What have I learned from Franco et al‘s comprehensive review of CP/CPPS treatments [1]? We must stop designing and performing these monotherapy treatment trials in which we enroll all subjects with a diagnosis of CP/CPPS. These type of clinical studies have been mainly driven by government regulatory rules in attempts to have drugs approved for CP/CPPS treatment. We should consider trial design where the patient eligibility criteria is definitive and clear enough so that we enroll only patients with a phenotype and/or mechanism that the specific therapy is directed towards – domain-specific trial design. Better yet, we must discover CP/CPPS biomarkers (urine, serum and/or prostate fluid) that will allow us to differentiate mechanisms and allow more effective directed therapy.  We must consider more complicated and novel trial designs in which multimodal therapies can be assessed in different populations.  I would propose a Multi-Intervention for Pelvic Pain Study (MIPPS) be designed and considered for CP/CPPS in which multimodal treatments designed for specific phenotype domains or disease mechanisms are evaluated in specific individuals.  It is anticipated that such a real world experience study (designed to mimic real life clinical practice) would result in much better outcomes for patients. Going forward it is time to not only change our management approach, but also our research strategies.

by J. Curtis Nickel

References

1. Franco JVA, Turk T, Jung JH, Xiao Y, Iakhno S, Tirapegui F, et al. Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome: a Cochrane systematic review. BJU Int. 2020; 125.

2. Shoskes DA, Nickel JC, Kattan M. Phenotypically Directed Multimodal Therapy for Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Prospective Study Using UPOINT. Urol. 2010;75:1249-1253.

3. Doiron RC, Nickel JC. Management of chronic prostatitis/chronic pelvic pain syndrome. Can Urol Assoc J. 2018;12(6 Suppl 3):S161-S163

4. Anothaisintawee T, Attia J, Nickel JC, Thammakraisorn S, Numthavaj P, McEvoy M, Thakkinstian A. The Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A systematic review and network meta-analysis. JAMA. 2011;305:78-86.

5. Shoskes DA, Nickel JC, Rackley RR, Pontari MA. Clinical Phenotyping in Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Interstitial Cystitis: A Management Strategy for Urologic Chronic Pelvic Pain Syndromes.  Prostate Cancer Prostatic Dis. 2009;12:177-83.

6.  Shoskes D, DeWitt-Foy ME, Nickel JC. Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome.  European Urology Focus 2019;5: 2-4.

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