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Treating prostatitis: Any cause for optimism?

Posted By Nancy Ferrari On November 3, 2009 @ 2:49 pm In Men's Health,Prostate Health,Prostate Knowledge,Prostatitis | Comments Disabled

Michael P. O’Leary, M.D., M.P.H., looks at what may be ahead

Prostatitis gets little press, but it’s an all-too-common genitourinary condition in men. It accounts for about 1.8 million visits to the doctor’s office in the United States each year. Depending on how you define the term, 9% to 16% of men experience prostatitis. It’s also an “equal opportunity” disorder. Unlike benign prostatic hyperplasia (BPH) and prostate cancer, which predominantly affect older men, prostatitis affects men of all ages.

Despite its commonness, little is known about what sparks prostatitis or, more importantly, how to treat it. Frustrated patients visit one doctor after another in search of a remedy, but they usually leave disappointed. Relative to other prostate conditions, little research has been conducted on prostatitis. But a few bright spots may be emerging.

What is prostatitis?

The term prostatitis, which translates to inflammation of the prostate, refers to a loose assemblage of syndromes characterized by urinary problems — for example, burning or painful urination, urgency, and trouble voiding — difficult or painful ejaculation, and pain in the perineum or lower back. The National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, classifies prostatitis into four categories, each with its own treatment approach (see Table 1).

Table 1: Prostatitis: What’s your type?

Type Definition Symptoms Comments
Category I
(acute bacterial prostatitis)
Acute infection of the prostate Chills, fever, body aches, fatigue, pain in the lower back and genital area, urinary frequency and urgency (often at night), burning or painful urination and ejaculation Rare; responds well to antibiotics
Category II
(chronic bacterial prostatitis)
Low-grade or recurrent infection of the prostate Same as above, but symptoms are often less pronounced More common than Category I; usually treatable with antibiotics, although the infection can be persistent and require several courses of therapy
Category III
(chronic nonbacterial prostatitis/chronic pelvic pain syndrome)
No proven bacterial infectionCategory IIIA
(inflammatory): white blood cells in urine or prostate secretions

Category IIIB
(noninflammatory): no white blood cells found in urine or prostate secretions

Pain in the lower back and genital area, urinary frequency and urgency (often at night), burning or painful urination and ejaculation Represents about 90% of all cases of prostatitis; no known cause or clinically proven treatments
Category IV
(asymptomatic inflammatory prostatitis)
White blood cells are present, but condition is usually found during tests for another medical condition, such as infertility None Treatment usually unnecessary

Category I and Category II refer to acute and chronic bacterial prostatitis, respectively. They are both associated with an infection of the prostate. Acute prostatitis begins abruptly with high fever, chills, joint and muscle aches, and profound fatigue. In addition, you may have pain around the base of the penis and behind the scrotum, pain in the lower back, and the feeling of a full rectum. As the prostate swells, you may find it more difficult to urinate. Unlike the acute form, chronic bacterial prostatitis is a subtle, low-grade infection that can begin insidiously and persist for weeks or even months. Together, these conditions, which can be treated with antibiotics, account for about 5% to 10% of prostatitis cases.

Category III prostatitis, also known as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), accounts for almost all other cases of prostatitis. (Category IV is rare; it has no symptoms and usually requires no treatment.) It’s characterized by episodes of pain and discomfort that come and go unpredictably, as well as the urinary difficulties and sexual dysfunction mentioned above. Quality of life takes a beating, too. The pain can be disabling, causing a man to withdraw from activities and become depressed.

A major difficulty is that in most cases doctors are unable to definitively diagnose CP/CPPS or identify a causative agent. Not surprisingly, with so little to go on, treatment is empiric — guided by a doctor’s clinical experience and instincts rather than hard evidence of what actually works, which isn’t much. Patients often find that the “standard” treatments provide little or only temporary relief.

Figure 1: The NIH–Chronic Prostatitis Symptom Index

Pain or Discomfort

  1. In the last week, have you experienced any pain or discomfort in the following areas?
    a. Area between rectum and testicles (perineum) Yes (1) No (0)
    b. Testicles Yes (1) No (0)
    c. Tip of the penis (not related to urination) Yes (1) No (0)
    d. Below your waist, in your pubic or bladder area Yes (1) No (0)

 

  1. In the last week, have you experienced:
    a. Pain or burning during urination? Yes (1) No (0)
    b. Pain or discomfort during or after sexual climax (ejaculation)? Yes (1) No (0)

 

  1. How often have you had pain or discomfort in any of these areas over the last week?
    0 Never
    1 Rarely
    2 Sometimes
    3 Often
    4 Usually
    5 Always

 

  1. Which number best describes your average pain or discomfort on the days that you had it, over the last week?
    0 1 2 3 4 5 6 7 8 9 10 (0 = no pain, 10 = pain as bad as you can imagine)

Urination

  1. How often have you had a sensation of not emptying your bladder completely after you finished urinating, over the last week?
    0 Not at all
    1 Less than 1 time in 5
    2 Less than half the time
    3 About half the time
    4 More than half the time
    5 Almost always

 

  1. How often have you had to urinate again less than two hours after you finished urinating, over the last week?
    0 Not at all
    1 Less than 1 time in 5
    2 Less than half the time
    3 About half the time
    4 More than half the time
    5 Almost always

Impact of Symptoms

  1. How much have your symptoms kept you from doing the kinds of things you would usually do, over the last week?
    0 None
    1 Only a little
    2 Some
    3 A lot

 

  1. How much did you think about your symptoms, over the last week?
    0 None
    1 Only a little
    2 Some
    3 A lot

Quality of Life

  1. If you were to spend the rest of your life with your symptoms just the way they have been during the last week, how would you feel about that?
    0 Delighted
    1 Pleased
    2 Mostly satisfied
    3 Mixed (about equally satisfied and dissatisfied)
    4 Mostly dissatisfied
    5 Unhappy
    6 Terrible

Scoring the NIH–Chronic Prostatitis Symptom Index Domains

Pain: Total of items 1a, 1b, 1c, 1d, 2a, 2b, 3, and 4 = _____

Urinary Symptoms: Total of items 5 and 6 = _____

Quality of Life Impact: Total of items 7, 8, and 9 = _____

SOURCE: Litwin MS, et al. The National Institutes of Health Chronic Prostatitis Symptom Index: Development and Validation of a New Outcome Measure. Journal of Urology 1999;162:369–75. PMID: 10411041. Reprinted with permission.

The “three A’s”

Known as the “three A’s,” traditional treatments for chronic nonbacterial prostatitis/chronic pelvic pain syndrome are antibiotics, anti-inflammatory medications, and alpha blockers.

The use of antibiotics remains controversial. For starters, few men with CP/CPPS test positive for bacterial infection. This suggests that antibiotics aren’t likely to be helpful, and randomized clinical trials bear this out. (See “Ineffectiveness of antibiotics.”) Even so, many doctors still prescribe a single course of antibiotics lasting several weeks, arguing that a negative test for bacteria doesn’t mean that bacteria aren’t present. Also, some antibiotics have anti-inflammatory properties, but work differently from other anti-inflammatory medications. This means they may help some men even when symptoms aren’t caused by a bacterial infection.

Ineffectiveness of antibiotics

Alexander RB, Propert KJ, Schaeffer AJ, et al. Ciprofloxacin or Tamsulosin in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Double-Blind Trial. Annals of Internal Medicine 2004;141:581–89. PMID: 15492337.

Nickel JC, Downey J, Clark J, et al. Levofloxacin for Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Men: A Randomized, Placebo-Controlled Multicenter Trial. Urology 2003;62:614–17. PMID: 14550427.

Repeat courses of antibiotics probably aren’t helpful. Even though they generally have few side effects, they aren’t without risk. They can cause nausea, vomiting, and diarrhea; interfere with other medications; and trigger allergies.

Anti-inflammatory medications, notably aspirin or NSAIDs such as ibuprofen, help some men cope with the pain of CP/CPPS. Yet only one controlled study supports the use of NSAIDs as the primary treatment for CP/CPPS. Most doctors agree that if NSAIDs are used, they should be taken for a limited period of time, to control pain, and preferably with another medication, such as an alpha blocker.

Alpha blockers (see Table 2) are most commonly prescribed to treat high blood pressure and BPH. However, they may also be prescribed for CP/CPPS. That’s because the prostate and bladder are rich in alpha receptors. By blocking these cellular structures, alpha blockers help relax muscles in the prostate and urinary tract, allowing urine to flow more freely.

Table 2: Alpha blockers

Generic name (brand name)  Drug class  Comments 
doxazosin (Cardura) Nonselective alpha-1 blockers Block alpha receptors in the prostate and elsewhere in the body, including the heart and blood vessels (talk with your doctor if you have heart disease)
terazosin (Hytrin)
alfuzosin (Uroxatral) Selective alpha-1 blockers Act more selectively on alpha receptors in the prostate; have less effect on receptors elsewhere
tamsulosin (Flomax)
silodosin (Rapaflo)

Four randomized, placebo-controlled trials initially demonstrated the effectiveness of alpha blockers in easing the symptoms of CP/CPPS, based on the NIH–Chronic Prostatitis Symptom Index (see Figure 1, above). A 2003 study randomly assigned 86 men with CP/CPPS to receive either terazosin (Hytrin) or a placebo for 14 weeks. Of participants taking the drug, 60% had a greater than 50% drop in their average symptom score, compared with 37% for participants taking a placebo. A subsequent study by the same researchers concluded that the beneficial effect lasted up to 38 weeks.

Another 2003 study evaluated the effectiveness of alfuzosin (Uroxatral) in 37 men diagnosed with CP/CPPS who were randomly assigned to receive either the drug or a placebo. After six months, the men who took alfuzosin had a statistically significant drop in their symptom score compared with the men who took a placebo. At that point, therapy was discontinued, and over the next six months, the beneficial effect of alfuzosin wore off.

In 2004, researchers tested the alpha blocker tamsulosin (Flomax) in 58 men with CP/CPPS who randomly received either the drug or a placebo for six weeks. As a group, the men treated with tamsulosin experienced statistically significant improvement in their symptoms compared with the men who received the placebo. The effect was greater in men with moderate-to-severe CP/CPPS than in those with mild symptoms.

Another study compared tamsulosin, the antibiotic ciprofloxacin (Cipro), both drugs together, and a placebo. In contrast, this trial found no benefit from the alpha blocker. Researchers speculated that the lack of improvement was due to the fact that many participants had had symptoms for a long time and had previously tried several treatments, including alpha blocker therapy. (See “Alpha blocker research.”)

Alpha blocker research

Cheah PY, Liong ML, Yuen KH, et al. Terazosin Therapy for Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Placebo-Controlled Trial. Journal of Urology 2003;169:592–96. PMID: 12544314.

Cheah PY, Liong ML, Yuen KH, et al. Initial, Long-Term, and Durable Responses to Terazosin, Placebo, or Other Therapies for Chronic Prostatitis/Chronic Pelvic Pain Syndrome. Urology 2004;64:881–86. PMID: 15533470.

Mehik A, Alas P, Nickel JC, et al. Alfuzosin Treatment for Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Prospective, Randomized, Double-Blind, Placebo-Controlled Pilot Study. Urology 2003;62:425–29. PMID: 12946740.

Nickel JC, Narayan P, McKay J, Doyle C. Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome with Tamsulosin: A Randomized, Double-Blind Trial. Journal of Urology 2004;171:1594–97. PMID: 15017228.

Given the contradictory findings of the studies, as well as the fact that the studies were small, the Chronic Prostatitis Collaborative Research Network (CPCRN), which includes dozens of researchers, launched a larger randomized, placebo-controlled trial of alfuzosin. Two hundred and seventy-two men from the United States, Canada, and Malaysia enrolled in the trial. They were randomly assigned to take 10 milligrams (mg) of alfuzosin per day or a placebo for 12 weeks. Participants who had previously taken alfuzosin or another alpha blocker were excluded from the study. The result: alfuzosin was no better than a placebo in treating CP/CPPS. In both groups, 49.3% of the men had a decrease of at least four points in their total NIH–Chronic Prostatitis Symptom Index score. The findings were published in The New England Journal of Medicine in December 2008. (See “Alfuzosin for CP/CPPS?”)

Alfuzosin for CP/CPPS?

Nickel JC, Krieger JN, McNaughton-Collins M, et al. Alfuzosin and Symptoms of Chronic Prostatitis–Chronic Pelvic Pain Syndrome. New England Journal of Medicine 2008;359:2663–73. PMID: 19092152.

The news was surprising and disappointing to urologists and their patients. Experts had thought that alfuzosin would probably be the most effective of the alpha blockers in treating CP/CPPS. But doctors continue to prescribe the medication because they have so few pharmacological options to offer patients. That may change, however.

On the horizon

Researchers are assessing the effectiveness of two other drugs — silodosin (Rapaflo) and pregabalin (Lyrica) — for the treatment of CP/CPPS. And nontraditional techniques, including biofeedback, which involves becoming more aware of the body’s signals, and myofascial trigger release, a type of massage therapy, are bringing much-needed relief to some medically savvy men. But most patients know little about these options.

Harvard’s Dr. O’Leary is a urologist at Brigham and Women’s Hospital in Boston and a professor of surgery at Harvard Medical School. He is one of the world’s foremost authorities on CP/CPPS, and one of the researchers involved in the CPCRN, a consortium funded by the National Institute of Diabetes and Digestive and Kidney Diseases. In this interview, conducted in August 2009, Dr. O’Leary talks about clinical trials under way for CP/CPPS and explains why biofeedback and myofascial trigger release might be worth looking into.

Lots of physicians were surprised by the outcome of the alfuzosin study. We were not expecting a negative result. Was the study poorly designed?

I think it was a well-designed trial. I may be biased because I’m one of the authors of the study, but The New England Journal of Medicine doesn’t publish poorly designed trials. My explanation is that alfuzosin just doesn’t work. As you know, we found that the placebo was just as effective as the drug at relieving symptoms. We did assess a number of secondary outcomes, such as general pain, urinary urgency, anxiety and depression, and erectile function. But the only difference we found between the two groups was in ejaculatory function, which improved significantly in the alfuzosin group. Otherwise, it was a completely negative trial — and another trial suggesting that alpha blockers probably don’t work.

Are any other drug trials under way at the moment for prostatitis?

We’re doing one right now on a drug called silodosin (Rapaflo), which is another alpha blocker. It’s being funded by a pharmaceutical company, and I’m a little surprised that they decided to go through with it after they saw the negative results of the alfuzosin trial and some negative findings related to tamsulosin. But it’s a brand-new drug and we really don’t have a lot of data on it. That might be why they are moving ahead with it.

Has the trial started? How many men do they hope to enroll?

The trial started in the fall of 2008, and the researchers aim to enroll 150 men who have had pelvic pain for at least three months. As with the alfuzosin study, men who have previously taken alpha blockers aren’t eligible. And it’s also a multicenter, double-blind, placebo-controlled trial. Participants will receive either 4 or 8 mg of silodosin or a placebo daily for 12 weeks. After that, the researchers will look at changes in the total symptom score. They will also look at changes related to pain and urinary symptoms, but those are secondary outcomes. I’m not involved in the trial, but we have enrolled a few patients in it.*

*Editor’s note: The trial concluded in October 2009. As of February 2011, the findings had not yet been published.

It will be interesting to see what happens, given that the other large alpha blocker studies have been negative.

That’s true. But I should say that I still prescribe alfuzosin even though the placebo response rate was so high. After all, what have you got to lose? These men are in pain, and they don’t have many other options at the moment.

Are researchers studying any other drugs that might ease prostatitis symptoms?

Yes. There’s the pregabalin (Lyrica) trial. Pregabalin is used to treat fibromyalgia.

People with fibromyalgia experience pain and stiffness in tendons, ligaments, and muscles, perhaps because of overly active nerves. What does that have to do with prostatitis?

Many experts hypothesize that severe, abnormal tension and overly active nerves in the muscles of the pelvic floor [see Figure 2] could explain the pain, discomfort, and urinary problems associated with prostatitis. Given that pain and muscle stiffness are symptoms of both conditions, and that pregabalin is effective in treating fibromyalgia, it seemed worth trying in men with prostatitis.

Tell us about the trial. Any encouraging findings?

Like the other trials I’ve mentioned, it was a randomized, double-blind, placebo-controlled trial. We randomly assigned 324 men with pelvic pain for at least three of the previous six months to receive either pregabalin or a placebo daily for six weeks. The dose started at 150 mg, increased to 300 mg after two weeks, and then finally to 600 mg two weeks after that. The primary endpoint was a drop of at least six points in the total score on the NIH–Chronic Prostatitis Symptom Index. After six weeks, 47.2% of the men assigned to take the drug reported a drop of at least six points in their total symptom score compared with 35.8% of the men assigned to take the placebo. That’s not a statistically significant difference, so technically, the trial was negative.

But it was positive for a number of the secondary endpoints. For example, 31% of the men who took pregabalin reported that their condition had markedly or moderately improved from the start of the trial, compared with just 19% of the men in the placebo group. The pregabalin group also showed more improvement than the placebo group in terms of pain. That was really encouraging. It suggests that pregabalin may be effective in some men with prostatitis. This was another CPCRN study. The findings were presented at the American Urological Association’s annual meeting in April 2009.

Do you prescribe pregabalin to your patients?

You bet — you’ve got nothing to lose by trying it. Virtually every patient I see who’s already been to another physician has been given long courses of antibiotics; that just doesn’t work. So we try alpha blockers, and if they don’t work, we try pregabalin. I use pregabalin for patients who mainly experience pain because that was one of the secondary endpoints of the trial that was positive.

Do you have any trouble getting insurance companies to cover the cost?

Yes, absolutely. Pregabalin isn’t approved for the treatment of prostatitis, so insurance won’t cover it. It’s not cheap.* But most of the men I see are so miserable that they’re willing to try it and pay for it themselves.

*Editor’s note: In February 2011, the Web site www.drugstore.com charged nearly $95 for a 30-day supply of 150-mg pregabalin capsules. Rates may vary by merchant.

What about nonpharmacological therapies?

I don’t know very much about biofeedback. I have had some patients who’ve tried it. As far as I know, they’ve had no great successes in terms of controlling pain. But the patients who are dysfunctional voiders definitely benefit from a behavioral technique like biofeedback. The challenge is to find professionals who know how to do it properly.

There has been growing interest in myofascial trigger release, or the so-called Stanford protocol, since the publication of a case study analysis back in 2005 in The Journal of Urology, which just published results of another study on it in the August 2009 issue. It wasn’t a large study — only 47 participants — and women were included, because they can develop chronic pelvic pain syndrome, too. Participants were randomly assigned to have weekly sessions of either traditional massage or myofascial therapy for 10 weeks. Although their goal was to determine whether such a study would generate solid data that might be the basis for a larger trial, the researchers also made some interesting observations. For example, 57% of those who received myofascial therapy reported that they were “markedly improved” or “moderately improved” versus just 21% in the group that received ordinary massage. [See “Myofascial physical therapy for CP/CPPS.”]

I don’t know whether they’ll find funding for a full-scale trial of myofascial therapy, but these results were definitely encouraging. And I’ve had a number of patients who say the treatment is definitely beneficial.

Myofascial physical therapy for CP/CPPS

Anderson RU, Wise D, Sawyer T, Chan C. Integration of Myofascial Trigger Point Release and Paradoxical Relaxation Training Treatment of Chronic Pelvic Pain in Men. Journal of Urology 2005;174:155–60. PMID: 15947608.

FitzGerald MP, Anderson RU, Potts J, et al. Randomized Multicenter Feasibility Trial of Myofascial Physical Therapy for the Treatment of Urological Chronic Pelvic Pain Syndromes. Journal of Urology 2009;182:570–80. PMID: 19535099.

What criteria do you use to refer patients for myofascial therapy?

I’m willing to refer almost anyone who is suffering with chronic pelvic pain and hasn’t responded to standard pharmacological therapy — and that’s a lot of people. There simply isn’t much that works, so this is cause for optimism.

Originally published October 2009; last reviewed Feb. 23, 2011.


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