Meta-analysis by shows Xiaflex (collagenase) with 34% improvement vs 18% placebo

[MikeSmith0]

Very odd numbers... but it is published in the Journal of Urology and Gelbard was one of the major researchers on collagenase.

Collagenase clostridium histolyticum OK in Peyronie's

Why on earth is the placebo giving 18% improvement when it's a tiny little needle with 1 injection?  Verapamil injections are 100x more aggressive (with a large needle) and I certainly got nothing out of those (as others on this board can also attest in their Verapamil experiences too).  I wonder if this actually means something & if it might be counter intuitive...There is no way that the placebo effect was psychological.  

The placebo was: 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride (saline) solution.  0.2-0.25 mL was injected...so the calcium chloride dihydrate is basically irrelevant.  Mostly, it was saline.  Interestingly, calcium chloride can cause "severe necrosis and sloughing" at its clinical dose of 100 mg/mL if injected into tissue instead of a vein.  But, I doubt 0.075 mg could do anything.

Maybe just injecting 1 small amount of saline into the scar on a regular interval will benefit people? The only thing that might be remotely relevant is the research on saline to reverse tissue damage (atrophy mostly - possibly tethering too though) from people who have had corticosteroids injected incorrectly.  Treatment of local, persistent cutaneous atrop... [Dermatol Surg. 2005] - PubMed - NCBI   So, maybe it actually does something here?   The 18% was not psychological.  People with Peyronies Disease don't improve that much in 6-9 months.  Something is going on...with ZERO side effects and almost no cost.

Basically, xiaflex will bring the a 40 degree curve down to 26 (for $40,000 and possible major side effects), and saline will bring it down 32.8 degrees - on average after 8 injections.  What would happen if the saline injections were doubled or tripled?  

[IhatePD]

MikeSmithO,

Am I correct that the Xiaflex injections were performed with a smaller gage needle?

If so, and this is just speculation, perhaps a larger needle gage causes the body to respond with the formation of more additional plaque than with a smaller needle?

If so, just double up the saline injections.  

[MikeSmith0]

Xiaflex injections were performed with the same gauge as the placebo (to keep the study controlled), but this was thinner than what is used in verapamil injections (25 gauge is recommended so the needle doesn't crack during the process of stabbing the plaque 100 times).  The other thing is, verapamil is a drug - saline is a natural substance in the body.  Maybe it helped bits of the plaque get freed up and go into solution so that macrophages could take care of it, without triggering the "penis is damaged" alarm to the immune system.  That's all collagenase does too really.

[Obsie]

Just a quick note about the placebo effect. It is a complex and not well understood process that affects various areas of the brain in measurable ways, for instance at the dopamine level.

Although there are many different types of placebo responses with considerable variability, there are countless examples of the reality of the effect and the contrary nocebo effect is also well documented. For example, some patients with acute pain due to cancer have reported significant pain relief after being injected saline solution in lieu of morphine.

The 18% improvement reported for placebo is in concordance with other studies on different drugs for other diseases. In fact, a drug is considered efficient when it outperforms the placebo, which is the case here. It does not mean at all that saline solutions should be considered a valid treatment for Peyronies Disease, as it is a totally neutral compound with no effects whatsoever on the body.

[MikeSmith0]

Just a quick note about the placebo effect. It is a complex and not well understood process that affects various areas of the brain in measurable ways, for instance at the dopamine level.

Although there are many different types of placebo responses with considerable variability, there are countless examples of the reality of the effect and the contrary nocebo effect is also well documented. For example, some patients with acute pain due to cancer have reported significant pain relief after being injected saline solution in lieu of morphine.

The 18% improvement reported for placebo is in concordance with other studies on different drugs for other diseases. In fact, a drug is considered efficient when it outperforms the placebo, which is the case here. It does not mean at all that saline solutions should be considered a valid treatment for Peyronies Disease, as it is a totally neutral compound with no effects whatsoever on the body.

Saline restores damaged tissue after atrophy from bad corticosteroid injections.  So, it's not totally neutral "with no effects whatosever on the body" .  I provided citations in my first post.

Pain is one thing... the brain controls pain.   You can affect pain through tricking the brain.  Scar tissue and penile curve isn't controlled by the brain...especially not in a 6-9 month period.   Btw, one study had the placebo helping up to 24%.  

[Obsie]

Mike,
The way our brain works is still not very well understood, and placebo effects concern not only pain relief but also other areas. If you take a holistic approach in which you consider body and mind as one thing, instead of thinking of them as two entities like western science wants to see it, you will realize that physical elements such as scar tissue can be controlled by the brain, not consciously of course. I personnally do not believe in God, but the powers of prayer have been demonstrated.
Some people are totally cured of chronic or fatal diseases for no particular reason except that they believed "someone" would cure them.  An exemple : Cancer cells totally eradicated in the uterus of a middle aged woman with survival chances estimated to be zero within one year, with a certainty of 100%. Which means she could not possibly be cured, and treatment was stopped. How can she be still alive? What happened to her cells? It is scientifically not explained. Of course some people believe genetics or other factors play a role wich might be true, but it is also true that the psychological orientation of a person helps cure, sometimes totally. This is what we call the placebo effect : believing that something can cure you.
I do not see why Peyronies Disease  would be different. I once worked with a famous oncologist who told me " if curing a patient involves painting my face in red, because they believe it plays a role, I will paint my face in red".
As for saline solution, there are different factors but if you believe it will cure you, then it will possibly cure you

[MikeSmith0]

Well, not cure...but 18-24% isn't bad.  So far, everything else has not worked, despite the placebo effect (traction, VED, pentox, etc).  Also, the placebo effect is most prevalent in areas more closely related to psych.  Pain, depression, allergies, chronic fatigue, and things like that are cited (wikipedia, which i normally never use as a source, has a huge list).  I wasn't able to find anything related to wound healing (burn healing, scar tissue, etc).  I could draw a hypothetical psychological path for every single one of those conditions to the brain (whether it is dopamine or internal opiate receptors or similar - these conditions all trace back to the brain).

Maybe if the placebo somehow activated the immune system to take a second look at the scar tissue...it could be plausible.  Placebos have worked for immunologic issues like MS and Herpes.  The brain does affect the immune system, which is the only path I can think that would be involved with resolving Peyronies Disease.

The thing is, the placebo effect is notorious for wearing off over time.  The study was pretty long to have such an enduring placebo effect.  The placebo effects last longer in pain syndromes, and only certain subsets of the population are amenable to it (the most obvious group with cognitive dysnfunciton, alzhimers patients, do not show placebo effects).

Btw, for ages, "sugar pills" or pills filled with lactose were used as placebos - but now many will argue that sugar and lactose are both biologically active and inappropriate to use most of the time.  

The dermatologists who discovered saline infiltration for restoring normal tissue after steroid damage may have thought he was using a placebo, but now it is accepted practice.  I don't know...it's just a rather small gap between active drug and placebo...and we're not talking about pain or depression or heavily brain based outcomes.

[james1947]

MikeSmith0

Here is my theory, I have expressed it already a few times on the forum.
The injections (Xiaflex & Placebo) were accompanied two days later by strong stretching of the penis, in many cases hearing "pop" noises.
I think that the results are very much doctors connected, some injected in the plaque and had very positive results after the stretching with both groups. Some doctors had bad results with both. Those things we will never know, because Auxilium will not tell us.
18-24% improvement with a very low cost saline injection sound excellent to me. Much better than $40,000 for 34%  

James

[Obsie]

Mike,
I agree, well summed up.
placebo effect does not work only with pain. In asthmatic patients, bronchiodilatation was created with a placebo product. In cancer treatment, studies have found a tumor decrease to some extent.

Let me point you to the following study : Placebo Effects in Oncology

I will quote the interesting part :

Objective response rates in the placebo arms were low but were different from zero in five trials, ranging from 2% to 7%.  In a placebo-controlled trial for renal cancer, Gleave et al. described objective responses in six (6.6%) of 90 patients in the placebo arm with three partial and three complete responses, lasting 2–13 months; by comparison, the response rate was only 4.4% in the interferon γ treatment arm. Rare tumor responses to placebo were also reported in trials for cancers of the lung,, colon, liver, and prostate .

And, my personal favorite, the toxicity of placebo effect:

Side effects of treatment in the placebo arms were reported in most of the trials included in our review. They were usually moderate, but in one study they were a reason for withdrawal of eight (12%) of 66 patients receiving placebo. In the study of renal cell cancer, five (6%) of 90 patients receiving placebo experienced grade III toxicity. Side effects were very similar from one trial to another—nausea and vomiting, abdominal pain, lethargy, dry mouth, diarrhea, and so on—and were present in about 10%–60% of patients. There was an association between the type of and incidence of side effects in the treatment and placebo arms among the randomized trials. These side effects may have been disease-related, or similar to those that are associated with active treatment and were anticipated by patients receiving placebos.

The study concludes that there are rare or limited improvements of patients with cancer who are receiving placebos in randomized trials.

Talking about Peyronies Disease, the placebo effect is difficult to discuss in the absence of double blind trial. For instance, how to do a double blind trial with extenders? When it comes to fibrosis or formation of scar tissue, though, we know that placebo effect works as well or as little as some popular cures, such as onion extract, which does not produce statistically different results when compared to placebo. It means not only that placebo is really useful in deciding whether a treatment is working or not, but that there is a placebo effect which achieves fibrotic reduction in scars.

Interestingly the placebo effect works even when the patient knows it is a placebo.

So, there is a rather small gap indeed. Problem : most of the times the scientific community has no idea how small it is. Which is why medicine is more an art than a science.  

[funnyfarm]

I am virtually certain the mind body connection is valid, and our thoughts are a major factor in our healing or lack thereof.

Regarding the Xiaflex results I think doctors and patients wanted to believe the drug was working and therefore may have unconsciously taken measurements in a manner that made them look better following treatment, vs baseline.  

The bottom line is no one would want to subject themselves to these traumatic injections and see no improvement, or worse increased curvature.  So both the patient and doctor inadvertently convince themselves it is working to backwards rationalize accepting the pain, effort, and risk.