The link below is an interesting article by Dr. Whitaker MD titled:

Facts About Vitamin and Mineral Supplements. 

It's a short read and well worth the time.  It starts with the following...

"I can’t tell you how many patients have told me that when they tried talking to their doctors about using vitamin and mineral supplements, they were met with condescension, laughter or belittlement.

So how do you get your doctor to work with you and help you incorporate vitamin and mineral supplements into your daily health regimen?

Here are some of the most common stumbling blocks patients encounter when discussing supplements with their physicians—and suggestions for countering them."

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Take care,

V/R, Batch

Hey Thierry,

Thanks for the vote of confidence...  I'm still getting calls from neurologists since AAN published the abstract from our online survey of CH'ers taking this regimen and the poster presentation I made at the 2014 AAN Annual Meeting in Philadelphia, PA.

Regarding a possible placebo effect in CH medications...  The raw efficacy of 60% for a sustained pain free end point response to the anti-inflammatory regimen in preventing CH is well beyond the highest possible placebo response in CH of 14 to 43%. 

The lowest value was reported using the strict endpoint; cessation of headache attacks.  Nilsson Remahl AI, Laudon Meyer E, Cordonnier C, Goadsby PJ. Placebo response in cluster headache trials: a review. Cephalalgia. 2003 Sep;23(7):504-10.

and we all know the good Dr. Goadsby is a straight shooter when it comes to CH...

I also did a little research into the above article and it appears 75% of the CH'ers surveyed in this study were episodic... 

As it is very easy for episodic CH'ers to confuse a pain free response to any CH preventative medication with end of cycle...  and given the fact that it's downright next to impossible to wish or will away CH pain... I suspect the actual placebo effect is somewhere South of the 14% listed in the study above and likely closer to 7%.

Take care,

V/R, Batch

Interesting comments...  There's no question in my mind that a placebo effect exists in CH pharmaceutical and nutraceutical intervention...  The only issue Mike pointed out in his bottom line...  How big is the placebo effect for CH?

I'll side with the 14% arrived at in the study titled: Placebo response in cluster headache trials: a review... as that value was reported using the strict endpoint; cessation of headache attacks...  That said, I still have reservations with the 14%...

The two studies they used to come up with the 14% figure included episodic CH'ers...  They represent a built-in confounding factor due to confusing a favorable response, in this case a cessation of headache attacks with end of cycle.

We recognized this confounding factor and attempted to qualify and quantify its effect in the online survey questionnaire by adding the following question for episodic CH'ers who experienced a favorable response to the anti-inflammatory regimen:

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If you throw out the first and last category due to possible errors in estimating when the response occurred and in estimating the episodic cycle length, then take the remaining last quartile... you get 17% as a reasonable, ball park estimate of the number of episodic CH'ers who could have possibly confused the favorable response with end of cycle...

My rationale for going through these mental gymnastics is simple...  the end of cycle confounding factor apples to the placebo effect just as it applies to the overall efficacy of any given pharmaceutical and nutraceutical method of CH intervention for episodic CH'ers...

Sooo... if you've followed me so far...  the 14% placebo effect in the above study is likely high...  If we use the ballpark estimate for the confounding factor of 17%, the likely placebo effect is somewhere between 11% and 12% for episodic CH'ers.

Take care,

V/R, Batch

Hey MiRose,

Welcome to CH.com.  Thank you for the kind words and for the wonderful back brief on your experience with the anti-inflammatory regimen.

Your last question, "But why isn't it 100% cure for everyone?" has been a motivating factor for me since the early days of this regimen in 2011 when the raw efficacy of this regimen in preventing CH, based on posted comments, was around 70%.

We've learned a lot about this regimen over the last four years and the most recent findings are proving to be significant game changers for the non-responders to this regimen.

The first finding came from Dr. Stasha Gominak, MD.  She's a neurologist in Tyler TX who developed a similar vitamin D3 regimen for her patients with sleep, chronic pain, and headache disorders over six years ago. 

Dr. Gominak recommends the same vitamin D3 dose and cofactors as used in the anti-inflammatory regimen, but adds a lab test for vitamin B12 as an indicator of overall status of the seven B vitamins and she adds a 3-month course of vitamin B 50.  I've incorporated her suggestions in the anti-inflammatory regimen as of April of 2014.

One of the latest finding involves the role of allergic reactions in CH and their impact on the efficacy of the anti-inflammatory regimen as a CH preventative.  It turns out that allergic reactions, primarily to pollen, result in a flood of histamine that triggers the obvious signs of an allergy.  What is significant is these allergic reactions are also occurring in the brain where they cannot be seen... except for their impact on the anti-inflammatory regimen...  in short, making it less effective or not effective at all in preventing CH.

The breakthrough came in an attempt to treat these allergies with Benadryl, (Diphenhydramine).  Benadryl is a first-generation antihistamine that passes through the blood brain barrier to block histamine receptors in brain cells.  Second- and third-generation antihistamines cannot do this.

I started using Benadryl last March when the Alder and Big Leaf Maple pollen was blowing around my home like a dust storm.  Up until that point I had my chronic CH well under control with the anti-inflammatory regimen at a dose of 10,000 IU/day vitamin D3.

All that changed in March.  Within 6 hours of the pollen fall, I noted a clear allergic reaction, 12 hours after the pollen fall started, I got hit with an eye watering KIP-6 CH... 

My usual response to a burn-through or break-through hit is to increase the vitamin D3 intake...  I did that and was up to 50,000 IU/day vitamin D3 plus extra magnesium, but that wasn't working... I was still getting whacked every two hours.

That's when the clue bird made a low pass and my Good Idea light came on bright and flashing...  "TREAT THE ALLERGY !!!"

After a little research, I selected Benadryl and a 25 mg tablet four times a day.  24 hours after starting the Benadryl, I was again CH pain free.  I've sense found that two tablets a day, (one every 12 hours) is more than sufficient to keep me pain free while taking the anti-inflammatory regimen.  I also found I could lower the vitamin D3 dose to 15,000 IU/day and still remain pain free.

I've tested this three times over the last two months by stopping the Benadryl...  As expected, if the pollen was still present, my CH returned, then stopped when I restarted the Benadryl.  As you noted... that helps rule out any placebo effect.

One of the presentations at the 2014 American Academy of Neurology Annual Meeting in Philadelphia was on the human microbiome...  essentially the friendly colonies of flora and fauna in the GI tract, their role in the immune system, and how to keep them happy and healthy.   

The researchers found they could reduce flare-ups in remitting recurring multiple sclerosis (RRMS) patients by administering probiotics...

This got me thinking why wouldn't this work for CH as well.  That led to some additional reading that resulted in the following:

Treating cluster headache (CH) patients with the anti-inflammatory regimen to prevent their CH represents a paradigm shift from the conventional Standards of Care recommended treatments for CH.   The standards of care recommended treatments address the neurological symptoms of CH as a trigeminal autonomic cephalalgia (TAC) with neurogenic origins in the hypothalamus and manifestations in the trigeminal nerves.  Acute treatments include oxygen therapy inhalation with non-rebreathing mask at flow rates of 15 to 25 liters/minute, followed by Sumatriptan Succinate (Imitrex).  Subcutaneous injections of Imitrex are effective in aborting CH in 5 to 10 minutes.  Imitrex nasal spray can be effective in 10 to 20 minutes.  Imitrex tablets are usually effective in 20 to 30 minutes.  Typical prophylactic treatments include a prednisone taper as a transitional preventative while titrating up with the longer-term preventative verapamil, a calcium channel blocker and in some cases, lithium.  Greater Occipital Nerve (GON) blocks and Sphenopalatine Ganglion (SPG) blocks have also proven to effective preventative treatments.

The anti-inflammatory regimen with vitamin D3 is a completely different treatment modality that addresses vitamin and mineral deficiencies as an underlying cause or contributor of CH.  That > 82% of over 600 CH’ers respond favorably to a daily regimen of vitamin D3, Omega-3 fatty acids and the vitamin D3 cofactors that support vitamin D3 pharmacokinetics, suggests CH is a genetotrophic disease. 

In 1956 Dr. Roger J. Williams, PhD., the biochemist who discovered the B-vitamin pantothenic acid, coined the term "genetotrophic disease" to describe diseases which resulted from genetically determined nutritional metabolic needs not being met by the individual and which result in poor gene expression. Motulsky has recently argued that many of the common degenerative diseases are the result of the imbalance nutritional intake with genetically determined needs for good health.

When you stop and think about it, there are a number of diseases that meet the definition of a genetotrophic disease such as Scurvy - lack of vitamin C, Rickets - lack of vitamin D3, Osteoporosis - lack of vitamin D3, Berberi - lack of vitamin B1 (thiamine)...

What is also clear, is the CH disorder is also associated with neurogenic inflammation in and around the trigeminal nerves and very possibly elsewhere throughout the brain.  As inflammation is the result of an immune system response to insult from a number of sources, CH could also be classified as a chronic neuroimmune disease.

Once you make that distinction,  CH falls in with more than 80 other autoimmune diseases like Multiple Sclerosis, Guillain-Barre syndrome, Rheumatoid arthritis, the irritable bowel diseases: Crohn’s, Ulcerative Colitis, Celiac and IBS.  The list goes on… 

That makes CH very likely an autoimmune disease with neurological manifestations that can be treated and prevented by genetic expression made possible with vitamin D3.

Accordingly, there is no question in my mind that the success of the anti-inflammatory regimen with vitamin D3 as a CH preventative represents an "out of the box" new insight into the pathogenesis of CH...  It just needs to be reverse engineered to look at causality.

I'm also firmly convinced that the mechanism of action for this regimen lies with the autocrine/paracrine signaling role vitamin D3 plays at the genetic level triggering genetic expression. 

This is where a 1,25(OH)2D3 molecule combines with one of the retinoid molecules (vitamin A), to form a dimer bridge that then attaches one end to a vitamin D receptor (VDR) and the other to a Retinoid X Receptor (RXR) in a vitamin D response element (VDRE) on a candidate gene.

When this happens, Dr. Robert Heaney explains it best by saying, "vitamin D3 unlocks the cells genetic library of instructions and the cell starts executing them" i.e., genetic expression.

During genetic expression, the cell starts performing one or more of the following activities:  it replicates, differentiates, starts producing or inhibiting the production of peptides and other active chemicals that signal or control other biological processes within the cell or nearby or the cell dies.

Research in this area reveals several studies that indicate there are vitamin D3 receptors and the enzymes needed to hydroxylate vitamin D3 to 25(OH)D and 1,25(OH)2D3 found in brain cells throughout the brain.  What is particularly interesting is the highest concentrations of these genetic expression precursors are found in the hypothalamus and trigeminal nerves…  With the hypothalamus involved, we're talking the neurogenic headwaters of CH pathogenesis.

If we follow this confluence of findings and add in calcitonin gene-related peptide (CGRP), which several studies have found is produced in the trigeminal ganglia and elevated in the bloodstream during the pain phase of CH and migraine... we have a possible trigger. 

Adding one more factoid that vitamin D3 has been shown to down regulate/suppress the production of CGRP, (quite possibly through genetic expression), we have a viable candidate mechanism of action for vitamin D3's capacity to prevent CH.

I say possible candidate, as a 2010 study identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D3...  Accordingly, there are thousands of other candidates for genetic expression made possible by vitamin D3... and any one or more of them could easily play a role in a mechanism of action inhibiting CH pathogenesis...

And so ends a long winded update... with more info on CH to ponder...

Take care,

V/R, Batch

Peter,

Good on you for getting your wife started on this regimen...

I've been on travel for the last week in Northern VA, and Lewes, DE and am having the same problem...  Pollen is still flying in this neck of the woods... 

As a result, I'm also taking 50 mg/day Benadryl, 25 mg every 12 hours...  I've also had to bump my vitamin D3 intake to 50,000 IU/day in order to stay pain free...  I take 25,000 IU in the a.m. and 25,000 IU in the evening along with all the rest of the supplements prior to bed.

There are enough studies available that indicate a couple weeks at 50,000 IU/day vitamin D3 to get the edge on any allergic reaction is very safe...  If your 25(OH)D was already at 80 ng/mL, a couple weeks at a vitamin D3 intake of 50,000 IU/day will elevate it up to around 150 ng/mL... but it will drop as soon as you return to your maintenance dose.

I'd also suggest you pop the vitamin D3 liquid softgels between your back teeth and swirl the contents around your mouth, cheeks, and under the tongue without swallowing for at least 5 minutes.  This will get most of the vitamin D3 directly into your blood stream and bypass the GI tract where absorption may be a problem.

The contents taste slightly sweet and gel caps turn into a gummy bear consistency then dissolve.

My rapid response (less than 2 hours) to this method and dose of vitamin D3 provides an interesting piece of data, and that is it may be the vitamin D3 entering target nerve cells in the hypothalamus and trigeminal ganglia that produces the preventative effect in stead of just the first vitamin D3 metabolite, 25(OH)D.

Take care and please keep us posted.

V/R, Batch