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Anti-Inflammatory Therapies for Chronic Prostatitis

      Abstract

      Anti-inflammatory therapy is very commonly prescribed in men with chronic nonbacterial prostatitis, or chronic pelvic pain syndrome. This practice is based on clinical experience rather than clinical trial data. This paper reviews the evidence to support the use of anti-inflammatory therapy in chronic prostatitis, and presents some considerations for future research.

      Keywords

      1. Introduction

      Prostatitis has traditionally been classified into four clinical entities: (i) acute bacterial prostatitis; (ii) chronic bacterial prostatitis; (iii) nonbacterial prostatitis; and (iv) prostatodynia. In 1995, a new classification system was proposed during a meeting of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the US National Institutes of Health (NIH) [

      National Institutes of Health Summary Statement. National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Workshop on Chronic Prostatitis. Bethesda, MD, 1995.

      ]. Nonbacterial prostatitis and prostatodynia are now included in the NIH category III: chronic nonbacterial prostatitis (CP)/chronic pelvic pain syndrome (CPPS), which distinguishes further between inflammatory CPPS (IIIA) and non-inflammatory CPPS (IIIB). This classification is based on the presence or absence of white blood cells (WBCs) in the expressed prostatic secretions (EPSs) or post-prostatic massage urine (VB3) or semen. For the first time, evaluation of WBCs in semen has been integrated into the diagnostic evaluation as a marker of inflammation. Men with CP/CPPS routinely receive anti-inflammatory therapy. This treatment approach is instituted regardless of the presence of inflammation and therefore deserves further discussion.

      2. Diagnostic issues

      The evidence of WBCs in EPS, VB3 or semen is suggestive for infection, but the microbial etiology in CPPS is far from clear. Despite this, antimicrobial agents are the first-line treatment agents used by most urologists and physicians for chronic prostatitis syndromes [
      • Moon T.D.
      Questionnaire survey of urologists and primary care physicians’ diagnostic and treatment practices for prostatitis.
      ,
      • Nickel J.C.
      • Nigro M.
      • Valiquette L.
      • Anderson P.
      • Patrick A.
      • Mahoney J.
      • et al.
      Diagnosis and treatment of prostatitis in Canada.
      ,
      • McNaughton Collins M.
      • Fowler Jr, F.J.
      • Elliott D.B.
      • Albertsen P.C.
      • Barry M.J.
      Diagnosing and treating chronic prostatitis: do urologists use the four-glass test?.
      ]. Anti-inflammatory treatment is regarded as “useful” for symptom relief [

      Meares EMJ. Prostatitis and related disorders. In: Walsh PC, Retik AB, Vaughan Jr ED, Wein AJ, editors. Campbell’s urology, 7th ed. Philadelphia: Saunders; 1998.

      ,
      • Nickel J.C.
      Prostatitis: evolving management strategies.
      ], but there is a paucity of evidence in the form of well designed, randomised, placebo-controlled studies to support this therapeutic approach. The issues surrounding anti-inflammatory therapy lie within the diagnostic approach. Although the NIH prostatitis classification is widely accepted, some problems have to be taken into consideration.

      2.1 The four-glass test

      Urologists frequently diagnose chronic prostatitis but rarely perform the four-glass diagnostic test recommended in published urologic reports. In a US national survey, 80% of practising urologists responded that they “rarely” or “never” performed the Meares–Stamey four-glass diagnostic test, and only 4% answered “almost always” [
      • McNaughton Collins M.
      • Fowler Jr, F.J.
      • Elliott D.B.
      • Albertsen P.C.
      • Barry M.J.
      Diagnosing and treating chronic prostatitis: do urologists use the four-glass test?.
      ]. The reasons given for not performing the test related to the assumption that the test is not highly sensitive nor specific or that it is not routine for many clinical laboratories. Other reasons for not performing the test include the view that the interpretation of the results can be ambiguous with a poor therapeutic predictive value, and that the test is relatively expensive, uncomfortable for patients and time consuming for physicians [
      • de la Rosette J.J.
      • Hubregtse M.R.
      • Karthaus H.F.
      • Debruyne F.M.
      Results of a questionnaire among Dutch urologists and general practitioners concerning diagnostics and treatment of patients with prostatitis syndromes.
      ,
      • Nickel J.C.
      Prostatitis: myths and realities.
      ]. Therefore, a correct diagnosis in accordance to the NIH prostatitis classification is difficult to make. Although the management of patients with CP/CPPS often relies on empirical treatment strategies, the distinction between inflammatory and non-inflammatory CPPS is crucial in order to evaluate an evidence-based use of anti-inflammatory therapy.

      2.2 Diagnostic yield

      The NIH consensus classification of prostatitis considers symptomatic patients without bacteriuria but with evidence of inflammation in the EPS, VB3 or semen to have the inflammatory CPPS [
      • Krieger J.N.
      • Nyberg Jr, L.
      • Nickel J.C.
      NIH consensus definition and classification of prostatitis.
      ]. Patients without inflammation in any of these specimens are considered to have non-inflammatory CPPS. Krieger has shown that adopting the strict criteria of the NIH consensus approach to the diagnosis of inflammation increases diagnostic yield compared to the traditional classification limited to examination of the EPS. Examining EPS only missed inflammation in almost half of the patients with inflammatory CPPS [
      • Krieger J.N.
      • Jacobs R.R.
      • Ross S.O.
      Does the chronic prostatitis/pelvic pain syndrome differ from nonbacterial prostatitis and prostatodynia?.
      ]. The study also suggests that using a counting chamber to determine leukocyte concentrations (per mm3) is more accurate than the traditional cover slip counts of WBC per high power field (HPF). However, this technique has not been shown to significantly affect categorization of patients with CPPS into IIIA or IIIB. This is because category IIIA includes patients with any WBCs in their EPS or semen, and IIIB includes patients with no inflammation, i.e. no WBCs. A standard evaluation for WBC utilizing a glass slide and cover slip is as accurate as a counting chamber in terms of differentiating the absence (WBC=0) and the presence of leukocytes (WBC≥1).
      Since the Meares–Stamey four-glass urine test seems to be rarely used by urologists, it has to be assumed that the criteria of the NIH consensus classification are even less frequently adopted. Thus, the actual incidence of inflammation in patients with CPPS is probably underestimated. Today, few data are available regarding the rational use of anti-inflammatory therapy for CPPS. A better diagnostic approach is therefore required in order to better characterise this form of treatment, and such precision is necessary in research studies.

      3. What is the evidence?

      Nonsteroidal anti-inflammatory agents are often recommended in the treatment of CP/CPPS. The inflammatory process involves a series of events that can be elicited by numerous stimuli (e.g. infectious agents, antigen–antibody interactions, physical injury). Prostaglandins are released whenever cells are damaged, appearing in inflammatory exudates. The nonsteroidal anti-inflammatory drugs inhibit the enzyme cyclooxygenase, which is responsible for the biosynthesis of prostaglandins in cells. Therapeutic doses of these agents reduce the prostaglandin content in human semen and urine. Although the prostaglandins E1 and E2 cause oedema, it is not clear if they can increase vascular permeability and promote the migration of leukocytes into an inflamed area. It has been proposed that anti-inflammatory agents can directly inhibit the activation and function of neutrophils, thus inhibiting more enzymes than just cyclooxygenase [

      Insel PA. Analgesic–antipyretics and anti-inflammatory agents: drugs employed in the treatment of rheumatoid arthritis and gout. In: Gillman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman’s, The pharmacological basis of therapeutics, 8th ed. New York: Pergamon Press; 1990.

      ]. Clinical experience shows that some patients may benefit from nonsteroidal anti-inflammatory therapy. Since prostaglandins are also known to sensitise pain receptors, the inhibition of their biosynthesis may reduce hyperalgesia and pain. Thus, the use of nonsteroidal anti-inflammatory drugs may be justified because of their anti-inflammatory and analgesic properties.
      Allopurinol has been reported to have an ameliorative effect on nonbacterial prostatitis [
      • Persson B.E.
      • Ronquist G.
      • Ekblom M.
      Ameliorative effect of allopurinol on nonbacterial prostatitis: a parallel double-blind controlled study.
      ]. Its use is based on the hypothesis that urinary reflux into the prostatic ducts may produce pain and inflammation through the irritative effects of urinary urate, as this agent significantly reduces urate concentrations in urine and EPS compared to placebo. However, in this study no significant differences between the two groups regarding WBC counts were found and a further evaluation did not confirm the beneficial effects of allopurinol [
      • Nickel J.C.
      • Siemens D.R.
      • Lundie M.J.
      Allopurinol for prostatitis: where is the evidence?.
      ].
      Non-traditional dietary supplements are gaining popularity in the treatment of CPPS. In a double-blind, placebo-controlled trial, the bioflavonoid quercetin was found to significantly improve symptoms of patients with CPPS IIIA and IIIB [
      • Shoskes D.A.
      • Zeitlin S.I.
      • Shahed A.
      • Rajfer J.
      Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial.
      ]. Documented properties of quercetin include antioxidant activity, tyrosine kinase inhibition, nitric oxide inhibition, and anti-inflammatory activity, blocking mediators of inflammation such as chemokines and cytokines [
      • Shoskes D.A.
      Effect of bioflavonoids quercetin and curcumin on ischemic renal injury: a new class of renoprotective agents.
      ,
      • Sato M.
      • Miyazaki T.
      • Kambe F.
      • Maeda K.
      • Seo H.
      Quercetin, a bioflavonoid, inhibits the induction of interleukin 8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha in cultured human synovial cells.
      ]. Although the exact mechanism of action of quercetin is not known, large decreases in prostatic fluid isoprostane levels, a presumed marker of oxidative stress in the prostate, were found.
      The pollen extract Cernilton was found to be effective in the treatment of CPPS by reducing symptoms [
      • Buck A.C.
      • Rees R.W.
      • Ebeling L.
      Treatment of chronic prostatitis and prostatodynia with pollen extract.
      ,
      • Rugendorff E.W.
      • Weidner W.
      • Ebeling L.
      • Buck A.C.
      Results of treatment with pollen extract (Cernilton N) in chronic prostatitis and prostatodynia.
      ]. In vitro experiments suggest that Cernilton could be either a potent cyclooxygenase inhibitor blocking the synthesis of prostaglandins or a smooth muscle relaxant.
      Since the presence of WBCs is only one aspect of the inflammatory reaction, an interesting approach is the study of mediators of inflammation such as cytokines. Several studies suggest that cytokines may play an important role in CPPS [
      • Hochreiter W.W.
      • Nadler R.B.
      • Koch A.E.
      • Campbell P.L.
      • Ludwig M.
      • Weidner W.
      • et al.
      Evaluation of the cytokines interleukin 8 and epithelial neutrophil activating peptide 78 as indicators of inflammation in prostatic secretions.
      ,
      • Alexander R.B.
      • Ponniah S.
      • Hasday J.
      • Hebel J.R.
      Elevated levels of proinflammatory cytokines in the semen of patients with chronic prostatitis/chronic pelvic pain syndrome.
      ,
      • Nadler R.B.
      • Koch A.E.
      • Calhoun E.A.
      • Campbell P.L.
      • Pruden D.L.
      • Bennett C.L.
      • et al.
      IL-1beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis.
      ]. IL-1β and TNF-α were detectable in EPS and semen and appeared to be higher in men with CPPS IIIA than in those with CPPS IIIB. However, there was no correlation between the concentration of these cytokines and number of WBCs [
      • Alexander R.B.
      • Ponniah S.
      • Hasday J.
      • Hebel J.R.
      Elevated levels of proinflammatory cytokines in the semen of patients with chronic prostatitis/chronic pelvic pain syndrome.
      ,
      • Nadler R.B.
      • Koch A.E.
      • Calhoun E.A.
      • Campbell P.L.
      • Pruden D.L.
      • Bennett C.L.
      • et al.
      IL-1beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis.
      ]. The pro-inflammatory cytokines IL-8 and ENA-78 were found to be elevated in prostatic secretions of men with ≥10 WBC/HPF in their EPS compared to men with ≤10 WBC/HPF in the EPS [
      • Hochreiter W.W.
      • Nadler R.B.
      • Koch A.E.
      • Campbell P.L.
      • Ludwig M.
      • Weidner W.
      • et al.
      Evaluation of the cytokines interleukin 8 and epithelial neutrophil activating peptide 78 as indicators of inflammation in prostatic secretions.
      ]. These data suggest that cytokines might be useful as novel clinical parameters for the identification, characterisation, and potential management of men with CPPS, differing from traditional methods based on WBC counts. Anti-TNF agents have been shown to be effective in patients with rheumatic diseases and the first trials in CPPS are underway.

      4. Conclusions

      Anti-inflammatory therapy in CPPS remains a challenge. Due to their mechanism of action, traditional nonsteroidal anti-inflammatory drugs seem to be useful in terms of inhibition of the inflammatory process and pain management. Their use is recommended by the NIH International Prostatitis Collaborative Network Research Guidelines as rank 3 following antimicrobials and α-blockers in the prioritization of treatments for chronic prostatitis [
      • Nickel J.C.
      • Nyberg L.M.
      • Hennenfent M.
      Research guidelines for chronic prostatitis: consensus report from the first National Institutes of Health International Prostatitis Collaborative Network.
      ]. There is evidence that alternative treatments, i.e. phytotherapies, may be reasonable alternative approaches. Evaluation of the complex cytokine network in chronic prostatitis has only commenced recently. This field seems to be promising in the management of patients with CPPS.Open discussion following the presentation by Dr. Werner HochreiterDr. Anthony Schaeffer: Does the group feel that there should be some evidence of inflammation, presumably found by looking at the prostatic fluid, before one embarks on anti-inflammatory therapy? Or can patients be treated empirically without any assessment of inflammation?Dr. Jeannette Potts: Aside from the prostatic inflammation, if you are doing a thorough pelvic floor examination, you would screen for musculoskeletal inflammation.Dr. Curtis Nickel: Our study showed that the Cox-2 inhibitors as a monotherapy produced a moderate improvement in patients with chronic pelvic pain syndrome. It was only a 6-week pilot study, but it did have 160 patients. The secondary analysis showed exactly the opposite of what we expected in our hypothesis, in that a patient with category IIIB did better than one with category IIIA prostatitis. So in fact, we are not able to say that differentiating IIIA from IIIB is a rationale for prescribing NSAIDs or Cox-2 inhibitors.Dr. Schaeffer: We could say that anti-inflammatories should be used in the context of some evidence of inflammation as characterized by white cells, muscle discomfort, or pain.Dr. Hochreiter: Irrespective of whether it is IIIA or IIIB, we can recommend nonsteroidal drugs because they have an analgesic effect.Dr. Schaeffer: And you could add that it should be limited therapy.Dr. Truls Bjerklund Johansen: I would be happy to prescribe anti-inflammatory drugs on symptoms only. But I feel that antimicrobials should not be used unless there is evidence of infection, because I might do some harm to the patient, to his flora and to the environment.Dr. Schaeffer: I think the only rationale might be for a 2-week trial in a patient who has no common organisms by culture but you give him the benefit of the doubt that there may be some uncommon pathogens present that might be producing symptoms.

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