Chronic Prostatitis/Chronic Pelvic Pain at AUA 2009
Treatment news from this year’s AUA meeting in Chicago last April held promise for men with chronic prostatitis/chronic pelvic pain (CP/CPPS). Meanwhile, basic and clinical research moved us closer to understanding the condition, although its cause is by no means clear.
Researchers announced the results of a large clinical trial of pregabalin (Lyrica) for longstanding CP/CPPS. The study is the next to last clinical trial conducted by the NIH-sponsored Chronic Prostatitis Collaborative Research Network (CPCRN). (The last, on physical therapy, is finishing up.) Although the treatment wasn’t better than placebo based on the major outcome measurement, it was significantly better based on other measurements, especially measurements of pain. The results for pain show this drug may be a good option for men who have suffered for a long time with the condition. Another intriguing trial also showed very encouraging results for pain with the drug memantine (Namenda). It is used for Alzheimer’s disease in the United States, but like some anesthetics, it is an NMDA receptor blocker and is, in fact, based on a Bulgarian folk remedy for pain. The drug is derived from the snowdrop plant. Interestingly, most other studies of potential treatments showed effects mainly on pain rather than on other components of the condition, such as urinary symptoms.
Certainly CP/CPPS is not the same in all men. Some have associated conditions, such as fibromyalgia or irritable bowel syndrome, and some don’t, so one-size-fits-all treatment can’t make everyone feel better. That’s why some CP/CPPS experts have proposed a classification system for the condition that could help individualize treatment and also help researchers do a better job at conducting and analyzing clinical trials.
This year, the pendulum seemed to swing back to considering CP/CPPS and IC to be different conditions because different brain areas are active with pain in each. That could help us learn how to better distinguish the two conditions in men and get them appropriate treatment. The finding also demonstrates that the nervous system plays a role, but whether nervous system abnormalities cause the condition isn’t clear. Men with CP/CPPS don’t test positive for urinary tract infection (part of the CP/CPPS definition), but some have speculated that unusual bacteria in the prostate may produce symptoms by spurring inflammation. Analysis of bacterial genetic material in prostatic fluid, however, showed that no particular bacteria or group of them had any relationship with symptoms. Some basic research did seem to point to an immune system abnormality, although much more research needs to be done. What did seem clear from a study of two different ethnic groups of teens with symptoms is that CP/CPPS is not a cultural phenomenon.
Below, you can read the details of the relevant studies presented at the meeting.
Lyrica Yields Improvements, Especially in Pain, for Longstanding CP/CPPS
A Randomized Placebo-Controlled Multicenter Trial of Pregabalin for the Treatment of Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Michel A Pontari, Philadelphia, PA; John N Krieger, Seattle, WA; Mark S Litwin, Los Angeles, CA; Paige C White, Jackson, MS; Rodney U Anderson, Palo Alto, CA; Mary McNaughton-Collins, Boston, MA; J Curtis Nickel, Kingston, ONCanada; Daniel A Shoskes, Cleveland, OH; Richard B Alexander, Baltimore, MD; Robert B Nadler, Chicago, IL; Michael P O’Leary, Boston, MA; Scott Zeitlin, Los Angeles, CA; Shannon Chuai, J. Richard Landis, Philadelphia, PA; John W Kusek, Leroy M Nyberg, Bethesda, MD; Anthony J Schaeffer, Chicago, IL; The Chronic Prostatitis Collaborative Research Network(CPCRN)
This large (324 patients) randomized, placebo-controlled trial of treatment with pregabalin (Lyrica) for CP/CPPS showed significant overall improvements and less pain, although there was no improvement in the main outcome measure. That was a drop of 6 points in the NIH Chronic Prostatitis Symptom Index (CPSI) score, which is considered to be meaningful to patients. Men who got the active treatment took 150 mg/day at the start, increasing the dose at two-week intervals to 600 mg/day. After 6 weeks, 47.2% of men taking pregabalin reported at least a 6-point decrease in total NIH-CPSI score, compared with 35.8% of men assigned to placebo, which was not a statistically significant difference. However, the differences in total scores between the groups and in various subscores were. In addition, significantly more men taking pregabalin said they were moderately or markedly improved (31% vs 19%). The pregabalin group also showed significantly more improvement than the placebo group in total scores on the McGill Pain Questionnaire and in the sensory and mood subscores. Anxiety and depression scores and sexual function scores, however, did not differ significantly between the groups. The investigators called the differences in the secondary outcome measurements impressive and said that the results suggest that pregabalin may prove to be an effective treatment for some men with longstanding CP/CPPS.
Memory Drug Eases Pelvic Pain
Memantine in the Alleviation of Symptoms of Chronic Pelvic Pain Syndrome: A Randomized, Double-Blind Placebo-Controlled Trial
Jordan D Dimitrakov, Boston, MA; Jean Chitalov, Ivan Dechev, Plovdiv, Bulgaria
The drug memantine (Namenda) eased pelvic pain effectively in men with CP/CPPS. Although the drug is used to improve memory in Alzheimer’s disease patients in the United States, its origin is as a folk remedy for pain in Bulgaria. The drug is derived from the snowdrop plant, which grows there. Like some anesthetics, memantine is an N-methyl-D-aspartate (NMDA)-receptor blocker. The trial included 170 men with CP/CPPS randomized to treatment with the drug or placebo. After six months of treatment, 77% of the men taking memantine reported significant improvement in pain, their overall rating of their condition, and their quality of life, compared with only 16 percent of those taking placebo. After 12 months, pain scores in those taking placebo had dropped only 2 points, whereas they dropped 7 points for those taking memantine. The drug did not improve urinary function, however. Side effects were minimal.
Heat Eases Pain and Other Symptoms
Effect of the Combination Treatment of URO-DrTM and Medical Therapy for Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Prospective Study.
Tag Keun Yoo, Kyung Tae Moon, Seung Wook Lee, Seoul, Republic of Korea; Hong Sup Kim, Hong Chung, Chungju, Republic of Korea; Jong Yun Kim, Gangneung, Republic of Korea
These researchers looked at the effects of internal heating with a portable, transrectal heat therapy device, the URO-Dr. The 120 patients in the study got either medical therapy, Uro-Dr treatment, or both. Significantly more of those who got the combination said they were improved compared with the other groups. They also had lower pain scores and total NIH-CPSI scores than those who got medical therapy alone. The temperature achieved in the prostate with this instrument, however, may not be higher than that achieved with a hot bath, so patients may be able to take advantage of heat therapy this way.
Radiofrequency Stimulation of the Pelvic Floor Eases Pain
A Prospective, Randomized, Placebo Controlled Study of Radiofrequency Therapy for the Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Mi Mi Oh, Ansansi, Republic of Korea; Myeong Heon Jin, Du Geon Moon, Sang Gan Nam, Seoul, Republic of Korea; Jae Hyun Bae, Hong Seok Park, Ansansi, Republic of Korea
Radiofrequency stimulation of the pelvic floor eased symptoms in this placebo-controlled study. The researchers used a radiofrequency instrument placed on the perineum to stimulate the pelvic floor at a frequency of 0.5 MHz twice a week for four weeks. Twenty men got active treatment and 10 sham treatment. At the end of the month, mean symptom scores decreased significantly in the treatment group compared with the placebo group. Treatment had the greatest effect on pain-related symptoms.
Shockwave Treatment May Ease Pain
Extracorporeal Shock Wave Treatment for Non-Inflammatory Chronic Pelvic Pain Syndrome: A Prospective, Randomized, Sham-Controlled Study
Xiaoyong Zeng, Zhangqun Ye, Weimin Yang, Zhiqiang Chen, Guanghui Du, Wuhan, China
Usually used to break up urinary tract stones, extracorporeal shockwave treatment (ESWT) is also known to ease pain. This study hinted that it may be useful for CP/CPPS pain. Forty men with CP/CPPS got ESWT, and 20 got a sham treatment in 10 sessions over two weeks. Total NIH-CPSI scores improved significantly in both groups, as did pain and quality of life, but not urination. The total scores and pain scores stayed lower in the active treatment group after four weeks but rose again in the sham treatment group. After treatment and four weeks later, the active treatment group had significantly more perceptible improvement (6 points on the NIH-CPSI) and clinically significant improvement (12 points) than the sham group. No side effects or adverse events occurred. Larger trials are needed to assess the effects of this treatment, said the researchers.
Classification System May Lead to Better Treatment, Research
Clinical Phenotyping of Chronic Prostatitis/Chronic Pelvic Pain Syndrome Patients and Correlation with Symptom Severity
Daniel A Shoskes, Cleveland, OH; J Curtis Nickel, Kingston, ON, Canada; Robert Dolinga, Dona Prots, Cleveland, OH
Each CP/CPPS and IC patient is unique, so these doctors are working on a “phenotyping” system that would characterize the condition in each patient and point to appropriate, individualized therapy. The system, called UPOINT, has six “domains” (like a snowflake’s six arms): urinary (voiding symptoms), psychosocial (identifiable psychopathology), organ-specific (prostate/bladder centric), infection (history of bacteriuria/prostate localization), neurologic/systemic (for example, associated fibromyalgia), and tenderness (of pelvic muscles). Applying the system to 90 CP/CPPS showed these percentages of CP/CPPS patients positive for each domain: urinary 52%, psychosocial 34%, organ-specific 61%, infection 16%, neurologic/systemic 37%, and tenderness 53%. The more positive domains patients had, the more severe their symptoms were. Patients who had symptoms longer also had more positive domains. Patients positive for the neurologic/systemic and tenderness domains had worse symptoms. These two domains, along with the psychosocial domain, related most strongly to quality of life. More comprehensive phenotyping studies and biomarker development will further expand the domains. A lack of phenotyping like this, argued these authors, explains the consistent failure to develop a standard treatment strategy. The system could help clinicians and researchers formulate individualized, dynamic ones.
Brain Activity Different in CP/CPPS, IC Pain
Brain Activity for Spontaneous Fluctuations of Pain in Urologic Pelvic Pain Syndrome
Anthony J Schaeffer, Elle L Parks, A. Vania Apkarian, Chicago, IL
Pain affects different areas of the brain in CP/CPPS and IC, found these researchers. That implies the two conditions are different and can be distinguished in men. Patients with each pain condition underwent functional magnetic resonance imaging (fMRI) of the brain while they were having pain and continuously rating the fluctuations in their pain. Brain activity maps showed that the regions most active during pain were in the insula in CP/CPPS patients and in the cingulate and somatosensory regions in IC patients. These maps are also different from those of patients with other chronic pain conditions, such as chronic back pain. The brain regions affected in CP/CPPS and IC affect decision making under stress, so the investigators used some standard psychologic tests and found that decision making and emotional recognition skills were impaired in CP/CPPS and IC patients in pain.
Checking for “Inflammation” Is No Help
Clinical impact of leukocytes in chronic abacterial prostatitis
David T Duong, Rodney U. Anderson, Stanford, CA
The presence of white blood cells in prostatic fluid implies inflammation in men with CP/CPPS, but is it relevant clinically? To find out, these urologists looked at white blood cell counts and compared them with scores on the NIH-CPSI and the Stanford Pelvic Pain Symptom Survey (PPSS) questionnaires for 114 patients who had had other therapies fail. These men had gone to Stanford for treatment with pelvic floor therapy and cognitive relaxation training. Forty-four men showed white blood cells in prostatic fluid (category IIIA prostatitis), and 58 did not (category IIIB). The men were evenly matched in age and degree of symptoms overall. There was no significant difference between the IIIA and IIIB patients in terms of severity of symptoms on the NIH-CPSI except for quality of life and no significant difference in the severity of symptoms on the PPSS. Furthermore, there was no difference between IIIA and IIIB patients in terms of improvement in symptoms after therapy. (NIH-CPSI scores improved 7 points for IIIA patients and 8 points for IIIB patients and PPSS scores 10 points each.) White blood cells didn’t correlate with age, disease duration, or symptom severity and did not predict which patients benefited from this type of therapy, so doing tests to detect white blood cells does not appear to be clinically useful, the investigators concluded.
New Pain Index Useful for CP/CPPS and IC
Validation of a Genitourinary Pain Index for Use in Men and Women
J Quentin Clemens, Ann Arbor, MI; Elizabeth A Calhoun, Chicago, IL; Mark S Litwin, Los Angeles, CA; Mary McNaughton-Collins, Boston, MA; Evelyn M. Crowley, J Richard Landis, Philadelphia, PA; Urologic Pelvic Pain Collaborative Research Network
Having one pain questionnaire for research on the urologic chronic pelvic pain syndromes, interstitial cystitis and CP/CPPS, should aid research to measure the degree of symptoms in both men and women and to help separate IC from CP/CPPS in men. These investigators adapted the NIH-CPSI for all the patients by adding two questions about bladder discomfort for men and changing the male-specific questions to female for women. Then they tested the questionnaire and found that, in men, it discriminated between CP/CPPS and IC, some other urologic conditions, or no other conditions. In women it distinguished between IC and incontinence or neither of these conditions. In addition, the scores showed differences in how the patients were faring. A drop of seven points helped show who responded to therapy and who didn’t.
CP/CPPS May Be Autoimmune
Evaluation of infiltrating T cells and T-regulatory cells in prostate cancer and chronic abacterial prostatitis
Nieroshan Rajarubendra, Martin Elmes, Damien M Bolton, Ian D Davis, Melbourne, Australia
Based on the idea that CP/CPPS and other prostate conditions may be related to overactivity of the immune system, these researchers looked at the levels of a type of white blood cell called regulatory T cells (Tregs) in the blood of CP/CPPS and prostate cancer patients. These regulatory cells are crucial in controlling autoimmune responses and maintaining immune system balance. Overactivity of the immune system may be involved in CP/CPPS through changes in numbers of these cells or their function, whereas very local suppression of the immune system may be involved in prostate cancer. Levels of Tregs in the blood and tissue of CP/CPPS patients turned out to be low, whereas levels in men with prostate cancer were high. This supports the idea that CP/CPPS may result from autoimmunity related to low levels of Tregs in tissue.
Bacteria Don’t Correlate with CP/CPPS
Failure to Detect Unique Uncultured Bacteria in Urine and Prostate Fluid of CPPS Patients Using rRNA Probes
Daniel A Shoskes, Cleveland, OH; Sina Karimpour, Daniel Frank, Norman Pace, Boulder, CO
Antibiotics are no better than placebo at resolving symptoms of CP/CPPS, so it is not thought to be caused by infection. But two-thirds of CP/CPPS patients do have bacteria in their prostatic fluid, and most of the bacteria are not normal disease-causing bacteria. That led some to theorize that these unusual bacteria might trigger inflammation and cause CP/CPPS symptoms, so these researchers used molecular techniques to detect bacterial genetic material in the urine and prostatic fluid of 50 men with the condition. The men were not taking any antibiotics, and all had symptoms. Ten men had inflammatory CP/CPPS (with white blood cells in prostatic fluid), and 40 did not. Standard culture techniques grew bacteria from 52% (26) of the prostatic fluid specimens. Based on analysis of genetic material, all the samples had bacteria, but at very low levels. Most of the genes were from known Staphylococcus and Streptococcus species. There was no correlation between the inflammation apparent in prostatic fluid and the bacteria the researchers found. Failure to find any common pattern of bacteria supports the idea that prostatic bacteria do not play a role in the maintaining CP/CPPS symptoms and should not be a target for therapy if there is no proven urinary tract infection, concluded the investigators.
Chronic Prostatitis Is Not Cultural
Are Prostatitis Symptoms in Adolescent Men Determined by Culture?
Dean A Tripp, J Curtis Nickel, Jennifer Pikard, Annie Hsieh, Jessica Ginting, Kingston, ON, Canada
Is prostatitis common just in white, middle aged, Western men? To find out, these researchers determined the prevalence and impact of chronic prostatitis-like symptoms in 264 white Canadian and 166 African Kenyan teenagers. Each group answered questions about demographics and two questionnaires, the NIH-CPSI and the Patient Health Questionnaire. Based on the NIH-CPSI case definition, the prevalences of at least mild chronic prostatitis symptoms in white Canadian and African Kenyan teens were 8.3% and 13.3%, respectively. The prevalences of moderate symptoms were 3% and 5.4%, respectively. To rule out possible confounding of the definition by sexually transmitted disease, the researchers excluded urinary symptoms from the total score. That yielded prevalences of at least mild symptoms in 6.8% of the white Canadian teens and 9% of the African Kenyan teens. In both groups, pain, urinary symptoms, and depression correlated significantly with diminished quality of life. For white Canadian teens, depressive symptoms, pain, and urinary symptoms correlated with poorer quality of life. For the African Kenyan teens, living in a rural school district, depressive symptoms, and pain correlated with poorer quality of life, but urinary symptoms did not. Among the white Canadian teens, only “catastrophizing” (helplessness and hopelessness about the condition) was related to diminished quality of life when pain, urinary symptoms, and depression were also part of the analysis. Chronic prostatitis-like symptoms are common, have a significant impact on quality of life, and do not appear to be related to age, ethnicity, or culture, concluded the researchers.
Pain, Mental Quality of Life Worsens with Time
Comparison of Symptoms in Newly-Diagnosed vs Chronic-Refractory Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS)
J Curtis Nickel, Kingston, ON, Canada; Richard B Alexander, Baltimore, MD; Rodney U Anderson, Stanford, CA; Richard Berger, Seattle, WA; William L Duncan, Jackson, MS; John N Krieger, Seattle, WA; Mark S Litwin, Los Angeles, CA; Mary McNaughton-Collins, Boston, MA; Michel A Pontari, Philadelphia, PA; Anthony J Schaeffer, Chicago, IL; Daniel A Shoskes, Cleveland, OH; J Richard Landis, Philadelphia, PA; John W Kusek, Leroy M Nyberg, Bethesda, MD; Shannon Chuai, Philadelphia, PA; The Chronic Prostatitis Collaborative Research Network
Because patients with fairly new CP/CPPS were in one clinical trial, whereas those with chronic, hard-to-treat CP/CPPS were in another, the researchers had an opportunity to compare the groups and draw some conclusions about progression of the condition. The men with chronic CP/CPPS had had their symptoms for much longer (about 10 years vs about 2 years), were older (47 vs 40), had higher NIH-CPSI total scores (26.1 vs 24.4), higher pain subscores (8.9 vs 4.6), poorer mental quality of life (42.1 vs 44.5 on the mental component of the SF 12 questionnaire), and more anxiety and depression (14.6 vs 12.8 on an anxiety/depression questionnaire). There were no differences between the groups in terms of urinary symptoms, physical quality of life, or sexual functioning. Early therapy might help prevent the apparent cognitive progression, concluded the investigators.
Some Older Men with LUTS May Have CP/CPPS
Prostatitis-like Symptoms in Elderly Male Patients with Lower Urinary Tract Symptoms as Evaluated Using the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI)
Munekado Kojima, Yasufumi Yada, Yosimasa Hayase, Nagoya, Japan
About 12% of older men with lower urinary tract symptoms (LUTS) have prostatitis-like symptoms. That’s what investigators at a clinic in Japan found by having their senior patients (mean age 66.1 years) with LUTS fill out the NIH-CPSI and the International Prostate Symptom Index (IPSS) questionnaires. Men were deemed to have prostatitis-like symptoms if they complained of perineal and/or ejaculatory pain or discomfort and their total pain score was 4 or more on the NIH-CPSI. There were no differences in age, peak urine flow rates, bladder capacity, or prostate volume between those who had and didn’t have the prostatitis-like symptoms. But the men with prostatitis-like symptoms had higher scores on the IPSS questionnaire (often used to assess enlarged prostate symptoms), especially on questions related to incomplete emptying, urgency, and hesitancy. Quality of life was also lower in men with prostatitis-like symptoms. The researchers speculated that painful symptoms may share some common cause with LUTS in men.