The Prostrate Placebo

I seem to be writing a lot about the urinary tract this month. Just coincidence, I assure you. As I slide into old age, medical issues that were once only of cursory interest for a young whippersnapper have increasing potential to be directly applicable to grumpy old geezers. Like benign prostatic hypertrophy (BPH). I am heading into an age where I may have to start paying attention to my prostate (not prostrate, as it is so often pronounced, although an infection of the former certainly can make you the latter), so articles that in former days I would have ignored, I read. JAMA this month has what should be the nail in the coffin of saw palmetto, demonstrating that the herb has no efficacy in the treatment of symptoms of BPH: Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.

It demonstrated that compared to placebo, saw palmetto did nothing. There have been multiple studies in the past with the more or less the usual arc of clinical studies of CAM products: better designed trials showing decreasing efficacy, until excellent studies show no effect. There is the usual meta analysis or two, where all the suboptimal studies are lumped together, the authors bemoan the quality of the data, and proceed to draw conclusions from the garbage anyway. GIGO.

The NEJM study from 2006 demonstrated that saw palmetto was no better than placebo but it was suggested that perhaps the dose of saw palmetto was not high enough or that the patients were not treated long enough to demonstrate an effect, and the JAMA study hoped to remedy that defect.There is, as is often the case, no good reason to suspect that saw palmetto would benefit or harm the prostate. Like many herbal preparations, it had widespread uses back in the day, when I had an onion tied to my belt, which was the style at the time. You couldn’t get white onions, because of the war. The only thing you could get was those big yellow ones.., but I digress:

“It is also an expectorant, and controls irritation of mucous tissues. It has proved useful in irritative cough, chronic bronchial coughs, whooping-cough, laryngitis, acute and chronic, acute catarrh, asthma, tubercular laryngitis, and in the cough of phthisis pulmonalis. Upon the digestive organs it acts kindly, improving the appetite, digestion, and assimilation. However, its most pronounced effects appear to be those exerted upon the urino-genital tracts of both male and female, and upon all the organs concerned in reproduction. It is said to enlarge wasted organs, as the breasts, ovaries, and testicles, while the paradoxical claim is also made that it reduces hypertrophy of the prostate. Possibly this may be explained by claiming that it tends toward the production of a normal condition, reducing parts when unhealthily enlarged, and increasing them when atrophied.”

At the turn of century Edwin M Hale, MD and homeopath, wrote a treatise on the topic, extolling its benefits on the prostate and other organs. You will be happy to know that if you have testicular atrophy from being an old masturbator, saw palmetto will help. For no good reason I can find, it became popular only for BPH. As best I can determine from the internet, there was a natural medicine fad in the early 1900’s, and saw palmetto became part of the fad. No clinical trials were responsible for the use. And, like acupuncture and homeopathy, there are many explanations for an efficacy that does not exist.

The JAMA study followed 369 men for 72 weeks. They received placebo or saw palmetto twice a day, and at weeks 24 and 48 the dose of each was increased.

They were followed for subjective complaints with the AUASI score, which is a 7 question self administered questionnaire:

Well validated as a tool for BPH symptoms, it relies overmuch on memory and is subject to wishful thinking on the part of the test taker. I doubt I could ever accurately remember my urinary patterns over the prior month without writing it down.

There were also objective endpoints like peak urine flow, PSA levels, and post void residual. Makes me wonder again what they want done when the radio advertisement says ‘Void were prohibited by law.’ Would saw palmetto make that easier? When it came to the subjective measurements, there was a slight, and similar, improvements in both groups. Objective, anatomic and physiologic endpoints were not affected. No surprise. So much for the powerful placebo.

Adverse effects were the same in both groups, with the only significant difference that the saw palmetto group had more physical injury and trauma. Was this the dreaded nocebo effect, or the random badness that occurs as a result of life? Probably the latter.

Based on the JAMA and NEJM trials, it is reasonable to conclude that saw palmetto has no efficacy in the treatment of symptoms due to BPH.

More interesting is what this article says about the so called placebo effect. This is yet another article that demonstrates that for hard endpoints, altering abnormal physiology or anatomy, placebo does nothing. I bet if we did brain scans of these patients they would show changes when the patient took the medications, and to that I would yawn. Do anything to anyone, give a placebo, tickle their feet, there will be changes in the brain. And while in some studies, increasing placebo amounts and frequency leads to increasing effects, in this study an increase in placebo dose led to no improvement in subjective outcomes.

More real world data to suggest that there are no real placebo effects.

Of course, I have bias. I have spent 30 years in acute care hospitals. My patients have derangements of anatomy and physiology that, if not corrected or at least ameliorated, lead to death or permanent morbidity. Placebo isn’t going to cure endocarditis, stop a gastric ulcer bleed, or reverse a stroke. And even if the patient feels better from the therapeutic relationship, if the anatomic/pathophysiologic abnormalities continue unabated, the patient is toast.

I am not even certain it can be said that placebos cure gastric ulcers. There is little on the natural history of ulcers in the flexible endoscopy age. The only reference I could find suggests that patients who have ulcers found with x-ray screening (not a reliable way to diagnose ulcers and probably under-represented the incidence) and who are not treated had a 24% cure rate at 6 months and a 29% relapse rate at 24 months. Most of the placebo trials followed patients around 4 weeks and had a higher cure rate in the placebo wing than seen in the natural history report, but the two are not directly comparable. Given the propensity of untreated ulcers to come and go and the unreliability of symptoms for diagnosis, unless there was a study that had a treatment, a placebo, and a no intervention arm, I do not think it is reasonable to conclude that placebos ‘cure’ ulcers. Especially given the NEJM review that suggested that placebo is usually no more effective than a no treatment/waiting arm.

Perhaps it is me. I do have some intellectual blind spots, like the anthropic principal. Every time I come across it in a cosmology book, I think that it is inane. I lack the imagination, or perhaps I am not stoned enough, to recognize its significance. So too with the placebo effect.

Placebo effects are probably more like quantum mechanics. The single slit experiment gives key insights into the fundamental nature of reality, but in the macroscopic world of day to day life my electrons move about just fine to heat my house and run my computer. No need to worry about probability functions, I can throw potatoes at a slit all day and never see a interference pattern. So too with the placebo effect. Most of the practical effect is lost in the noise of the complexity of illness, especially in the acute care hospital where I spend most of my time.

As Harriet quotes Dr. Benedetti

the take-home message for clinicians, for physicians, for all health professionals is that their words, behaviors, attitudes are very important, and move a lot of molecules in the patient’s brain. So, what they say, what they do in routine clinical practice is very, very important, because the brain of the patient changes sometimes… there is a reduction in anxiety; but we know that there is a real change…in the patient’s brain which is due to… the ‘ritual of the therapeutic act.’

I do not disagree with that. I consciously try to accentuate just those interactions with every patient, because I know my job as a physician is more than ‘Me find bug, Me kill bug. Me go home’. But I do not think it is important for modifying any disease process I am involved with. Grooming each other has salubrious effects in monkeys, and as best I can tell, the placebo is no more than evolutionarily advanced nit picking.

Large swaths of the world rely on native healers and the only tool in their armamentarium is the “ritual of the therapeutic act.” And across the world and throughout time, people have suffered and died in droves. You may argue that is not a fair comparison, people suffered from poor hygiene, no vaccines, malnutrition and no health infrastructure. But the US has a group whose health care is only placebo, relying entirely on the ritual of the therapeutic act, and despite being surrounded by the benefits of western societal infrastructure, they die faster and younger: Christian Scientists.

At the end of the day, the practice of medicine is practical endeavor. I am a builder, not an architect. I have to try to make my patients better objectively and subjectively, and the placebo is a tool that has little utility in my toolbox. When my prostate grows to the size of a tennis ball, I am going to go looking for a therapy that will shrink it, not fool me into thinking I can write my name in the snow a little better.

Posted in: Clinical Trials, Herbs & Supplements, Science and Medicine

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