Update on Prostatitis and Update on Prostatitis and TreatmentsTreatments

BAUN Benign Study DayBAUN Benign Study Day14/03/201214/03/2012

Mr Richard CettiMr Richard CettiSpecialist Registrar Urology, QA Specialist Registrar Urology, QA

PortsmouthPortsmouth

Prostatitis an Important Prostatitis an Important Problem!Problem!

Prevalence 2.2-13.8%Prevalence 2.2-13.8% Quality of lifeQuality of life

Economic CostsEconomic Costs

Prostatitis an Important Prostatitis an Important Problem!Problem!

‘‘Pain management is a necessity in the Pain management is a necessity in the work of each physician.’ work of each physician.’

F. Sauerbruch, 1936F. Sauerbruch, 1936

IntroductionIntroduction

PainPain Classification/TerminologyClassification/Terminology PresentationPresentation InvestigationInvestigation Treatment- historical, contemporary and Treatment- historical, contemporary and

the evidencethe evidence The FutureThe Future

PainPain-an unpleasant sensory and emotional experience-an unpleasant sensory and emotional experience

Hypogastric Nerve

Pelvic Nerves

Pudendal Nerve

BraiBrainn

Ascending Ascending SystSyst

Dorsal Dorsal HornHorn

PeripheryPeriphery

Skin

Viscus

Convergence Projection Theory (Ruch)

Chronic PainChronic Pain

Combination of:Combination of:- NeuroplasticityNeuroplasticity- Central processing alteredCentral processing altered- Trophic changes in subcutaneous tissue and Trophic changes in subcutaneous tissue and

musclemuscle All site normal sensations become painful All site normal sensations become painful

(allodynia).(allodynia). At site painful stimuli become more painful At site painful stimuli become more painful

(hyperalgesia).(hyperalgesia). Zone affected adjacent tissue (secondary Zone affected adjacent tissue (secondary

hyperalgesia).hyperalgesia).

Aetiology of Chronic Aetiology of Chronic ProstatitisProstatitis

Poorly understoodPoorly understood Multiple factors within and between patientsMultiple factors within and between patients Hypotheses:Hypotheses:- Presence of antibiotic resistant non-culturable micro-Presence of antibiotic resistant non-culturable micro-

organismsorganisms- Chemical irritationChemical irritation- Intra-ductal reflux and obstructionIntra-ductal reflux and obstruction- Dysfunctional high pressure voidingDysfunctional high pressure voiding- Neuropathic painNeuropathic pain- Pudendal nerve entrapmentPudendal nerve entrapment- AutoimmuneAutoimmune

ClassificationClassification

Classification- NIH/EAUClassification- NIH/EAU

Cat ICat I Acute bacterial prostatitisAcute bacterial prostatitis Cat IICat II Chronic bacterial prostatitisChronic bacterial prostatitis Cat IIICat III Prostate Pain Syndrome (CPPS)Prostate Pain Syndrome (CPPS) Cat IVCat IV Asymptomatic inflammatory Asymptomatic inflammatory

prostatitisprostatitis

Classification- NIH/EAUClassification- NIH/EAU

Cat ICat I Acute bacterial prostatitisAcute bacterial prostatitis Cat IICat II Chronic bacterial prostatitisChronic bacterial prostatitis

Cat IIICat III Prostate Pain Syndrome (CPPS)Prostate Pain Syndrome (CPPS)

Discomfort or pain in the pelvic region for at least Discomfort or pain in the pelvic region for at least 3 months with variable voiding and sexual 3 months with variable voiding and sexual symptoms, no demonstrable infection.symptoms, no demonstrable infection.

IIIa- inflammatory PPS- white cells in IIIa- inflammatory PPS- white cells in semen/eps/post eps urinesemen/eps/post eps urine

IIIb- non-inflammatoryIIIb- non-inflammatory Cat IVCat IV

EvaluationEvaluation

3 main factors:3 main factors:

SymptomsSymptoms WBC’sWBC’s

BacteriaBacteria

EvaluationEvaluation

HistoryHistory Focused ExaminationFocused Examination Condition Specific QuestionnairesCondition Specific Questionnaires Urinalysis and CultureUrinalysis and Culture Semen cultureSemen culture Optional: PSA, Urinary Cytology, US, Optional: PSA, Urinary Cytology, US,

Cystoscopy, Urodynamics, Cystoscopy, Urodynamics, Psychosocial evaluationPsychosocial evaluation

EvaluationEvaluation

HistoryHistory Focused ExaminationFocused Examination Condition Specific QuestionnairesCondition Specific Questionnaires Urinalysis and CultureUrinalysis and Culture Semen cultureSemen culture Optional: PSA, Urinary Cytology, US, Optional: PSA, Urinary Cytology, US,

Cystoscopy, Urodynamics, Cystoscopy, Urodynamics, Psychosocial evaluationPsychosocial evaluation

EvaluationEvaluation

HistoryHistory Focused ExaminationFocused Examination Condition Specific QuestionnairesCondition Specific Questionnaires Urinalysis and CultureUrinalysis and Culture Semen cultureSemen culture Optional: PSA, Urinary Cytology, US, Optional: PSA, Urinary Cytology, US,

Cystoscopy, Urodynamics, Cystoscopy, Urodynamics, Psychosocial evaluationPsychosocial evaluation

EvaluationEvaluation

HistoryHistory Focused ExaminationFocused Examination Condition Specific QuestionnairesCondition Specific Questionnaires Urinalysis and CultureUrinalysis and Culture Semen cultureSemen culture Optional: PSA, Urinary Cytology, US, Optional: PSA, Urinary Cytology, US,

Cystoscopy, Urodynamics, Cystoscopy, Urodynamics, Psychosocial evaluationPsychosocial evaluation

EvaluationEvaluationChronic Prostatitis Symptom Index

IPSS

EvaluationEvaluation

HistoryHistory Focused ExaminationFocused Examination Condition Specific QuestionnairesCondition Specific Questionnaires Urinalysis and CultureUrinalysis and Culture Semen cultureSemen culture Optional: PSA, Urinary Cytology, US, Optional: PSA, Urinary Cytology, US,

Cystoscopy, Urodynamics, Cystoscopy, Urodynamics, Psychosocial evaluationPsychosocial evaluation

EvaluationEvaluation

Meares-Stamey ‘4 Meares-Stamey ‘4 Glass Test’Glass Test’

- 11stst 10-15ml of voided 10-15ml of voided urine urine VB1VB1

- MSU 10-15ml urine MSU 10-15ml urine VB2VB2- Prostate Massage- Prostate Massage- EPSEPS- 11stst 10-15ml voided 10-15ml voided

urine post massage urine post massage VB3VB3

- Modified: VB1 and VB3Modified: VB1 and VB3

EvaluationEvaluation

HistoryHistory Focused ExaminationFocused Examination Condition Specific QuestionnairesCondition Specific Questionnaires Urinalysis and CultureUrinalysis and Culture Semen cultureSemen culture Optional: PSA, Urinary Cytology, US, Optional: PSA, Urinary Cytology, US,

Cystoscopy, Urodynamics, Cystoscopy, Urodynamics, Psychosocial evaluationPsychosocial evaluation

EvaluationEvaluation

HistoryHistory Focused ExaminationFocused Examination Condition Specific QuestionnairesCondition Specific Questionnaires Urinalysis and CultureUrinalysis and Culture Semen cultureSemen culture Optional: PSA, Urinary Cytology, US, Optional: PSA, Urinary Cytology, US,

Cystoscopy, Urodynamics, Cystoscopy, Urodynamics, Psychosocial evaluationPsychosocial evaluation

EvaluationEvaluation

‘‘Diagnosis of exclusion’Diagnosis of exclusion’

Treatment- Organcentric vs. Treatment- Organcentric vs. SnowflakeSnowflake

Traditional Organcentric Traditional Organcentric ModelModel

Pathogenesis Pathogenesis simplesimple

Traditional Organcentric Traditional Organcentric ModelModel

Pathogenesis Pathogenesis simplesimpleInfection

‘itis’

Inflammation

PAIN!

Traditional Organcentric Traditional Organcentric ModelModel

Pathogenesis Pathogenesis simplesimple

AntibioticsAntibiotics Anti-inflammatoriesAnti-inflammatories Alpha blockersAlpha blockers Treatment simple?Treatment simple?

Infection‘itis’

Inflammation

PAIN!

AntibioticsAntibiotics

Ciprofloxacin, ofloxacin, levofloxacinCiprofloxacin, ofloxacin, levofloxacin ~10% patients will have culturable bacteria.~10% patients will have culturable bacteria. J Urol. 2001 May;165(5):1539-44. Predictors of patient J Urol. 2001 May;165(5):1539-44. Predictors of patient

response to antibiotic therapy for the chronic response to antibiotic therapy for the chronic prostatitis/chronic pelvic pain syndrome: a prospective prostatitis/chronic pelvic pain syndrome: a prospective multicenter clinical trial. Nickel JC et al.multicenter clinical trial. Nickel JC et al.

However, 57% of patients on ofloxacin saw improvementHowever, 57% of patients on ofloxacin saw improvement Trial 2 weeks and continue for 6 if benefit.Trial 2 weeks and continue for 6 if benefit.

Alpha-blockersAlpha-blockers

Alfuzosin, Terazosin, TamsulosinAlfuzosin, Terazosin, Tamsulosin N Engl J Med. 2008 Dec 18;359(25):2663-73. Alfuzosin and N Engl J Med. 2008 Dec 18;359(25):2663-73. Alfuzosin and

symptoms of chronic prostatitis-chronic pelvic pain symptoms of chronic prostatitis-chronic pelvic pain syndrome Nickel JC et al.syndrome Nickel JC et al.

Multicenter, randomized, double-blind, placebo-controlled Multicenter, randomized, double-blind, placebo-controlled trial of alfuzosin.trial of alfuzosin.

272 men were randomly assigned to treatment for 12 272 men were randomly assigned to treatment for 12 weeks with either 10 mg of alfuzosin/day or placebo.weeks with either 10 mg of alfuzosin/day or placebo.

The primary outcome was a reduction of at least 4 points in The primary outcome was a reduction of at least 4 points in the CPSI score.the CPSI score.

PlaceboPlacebo

N=134N=134AlfuzosinAlfuzosin

N=138N=138

CPSI respondersCPSI responders 66(49%)66(49%) 68(49%)68(49%)

Anti-inflammatoriesAnti-inflammatories

Celecoxib, rofecoxibCelecoxib, rofecoxib J Urol. 2003 Apr;169(4):1401-5. A randomized, placebo J Urol. 2003 Apr;169(4):1401-5. A randomized, placebo

controlled, multicenter study to evaluate the safety and controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis. Nickel JC et al.nonbacterial prostatitis. Nickel JC et al.

Multicenter, randomized, double-blind, placebo-controlled Multicenter, randomized, double-blind, placebo-controlled trial of rofecoxib.trial of rofecoxib.

161 men were randomly assigned to treatment with either 161 men were randomly assigned to treatment with either 25-50 mg of rofecoxib/day or placebo.25-50 mg of rofecoxib/day or placebo.

Of the patients, 79% on 50 mg rofecoxib versus 59% on Of the patients, 79% on 50 mg rofecoxib versus 59% on placebo reported no or mild pain. But not statistically placebo reported no or mild pain. But not statistically significant.significant.

Neuropathic PainkillersNeuropathic Painkillers

Amitriptylline, PregabalinAmitriptylline, Pregabalin Arch Intern Med. 2010 Sep 27;170(17):1586-93. Pregabalin Arch Intern Med. 2010 Sep 27;170(17):1586-93. Pregabalin

for the treatment of men with chronic prostatitis/chronic for the treatment of men with chronic prostatitis/chronic pelvic pain syndrome: a randomized controlled trial. Pontari pelvic pain syndrome: a randomized controlled trial. Pontari MA et al.MA et al.

Multicenter, randomized, double-blind, placebo-controlled Multicenter, randomized, double-blind, placebo-controlled trial of pregabalin.trial of pregabalin.

218 men were randomly assigned to treatment for 6 weeks 218 men were randomly assigned to treatment for 6 weeks with either 150-600 mg of pregabalin/day or placebo.with either 150-600 mg of pregabalin/day or placebo.

The primary outcome was a reduction of at least 6 points in The primary outcome was a reduction of at least 6 points in the CPSI score.the CPSI score.

PlaceboPlacebo

N=106N=106PregabalinPregabalin

N=218N=218

CPSI RespondersCPSI Responders 38(36%)38(36%) 103(47.2%)103(47.2%)

So are we getting So are we getting desperate?desperate?

Laparoscopic prostatectomy for Laparoscopic prostatectomy for chronic prostatitischronic prostatitis

This study is currently recruiting This study is currently recruiting participants.participants.

Verified by the Krongrad Institute Oct 2008.Verified by the Krongrad Institute Oct 2008.

ClinicalTrials.gov identifier: NCT00775515ClinicalTrials.gov identifier: NCT00775515

UPOINTUPOINT

Urinary

Psychosocial

Organcentric

Infection

Neurogenic/Systemic

Tenderness

UPOINTUPOINT

Retrospective study of 90 CPPS patients Retrospective study of 90 CPPS patients seen by one Urologist over 12 monthsseen by one Urologist over 12 months

DomainDomain PercentagePercentage

UrinaryUrinary 5252

PsychosocialPsychosocial 3434

Organ SpecificOrgan Specific 6161

InfectionInfection 1616

Neurogenic/SystemicNeurogenic/Systemic 3737

TendernessTenderness 5353

The Future: Patient-centric treatment. The Future: Patient-centric treatment. ‘Phenotyping’‘Phenotyping’

Novel TherapiesNovel Therapies

CerniltonCernilton Eur Urol. 2009 Sep;56(3):544-51. A pollen extract Eur Urol. 2009 Sep;56(3):544-51. A pollen extract

(Cernilton) in patients with inflammatory chronic prostatitis-(Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome: a multicentre, randomised, chronic pelvic pain syndrome: a multicentre, randomised, prospective, double-blind, placebo-controlled phase 3 prospective, double-blind, placebo-controlled phase 3 study. Wagenlehner FM et al.study. Wagenlehner FM et al.

Multicentre, prospective, randomised, double-blind, Multicentre, prospective, randomised, double-blind, placebo-controlled trial in men with CP/CPPS (NIH IIIA)placebo-controlled trial in men with CP/CPPS (NIH IIIA)

Primary end-point, defined as a decrease of the CPSI total Primary end-point, defined as a decrease of the CPSI total score by at least 25% or at least 6 points.score by at least 25% or at least 6 points.

PlaceboPlacebo

N=69N=69CerniltonCernilton

N=70N=70

CPSI RespondersCPSI Responders 50%50% 71%71%

Take Home PointsTake Home Points

Poorly understood aetiology/pathogenesis.Poorly understood aetiology/pathogenesis. Heterogenous disease.Heterogenous disease. Established treatments perform poorly in RCT’s.Established treatments perform poorly in RCT’s. Phenotyping patient and treatment.Phenotyping patient and treatment.

‘‘Active exclusion, Active Inclusion’Active exclusion, Active Inclusion’

‘‘Active exclusion, Active Inclusion’Active exclusion, Active Inclusion’

‘‘Active exclusion, Active Inclusion’Active exclusion, Active Inclusion’