Hey Neuropath,

Great post!  It's good to hear you've finally had a CH pain free response to vitamin D3 therapy. 

After 11 years of providing information outreach on the benefits of following the anti-inflammatory regimen treatment protocol to control and prevent CH to thousands of CHers and reading their feedback comments, there are a few reasons why some CHers don't respond to vitamin D3 therapy or loading doses of 50,000 IU/day.

The first and most common reason CHers don't respond to this treatment protocol is the 25(OH)D3 response simply isn't high enough.  While 80% of CHers respond to the basic protocol taking 10,000 IU/day vitamin D3 and all the cofactors with a significant reduction in CH frequency or a complete cessation of CH symptoms at an average 25(OH)D3 serum concentration of 80 ng/mL (200 nmol/L), some CHers require a 25(OH)D3 serum concentration much higher over 100 ng/mL (250 nmol/L).  This is why the second set of lab assays for 25(OH)D3. calcium and PTH are so important.

The following chart illustrates the normal distribution curves for the baseline assays for 25(OH)D3 before start of treatment and  after ≥ 30 days of treatment for 313 CHers starting this treatment protocol.

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Here, under the green 25(OH)D3 response curve, you can see where some CHers required a 25(OH)D3 serum concentration up to 150 ng/mL (375 nmol/L) in order to achieve a significant reduction in CH frequency or a complete cessation of CH symptoms.

The corrective action in this case is simple.  If you're still getting hit after 30 days of treatment and the results from your 30 day assays of 25(OH)D3, calcium and PTH indicate calcium is within its normal reference range, load vitamin D3 at 50,000 IU/day for four days and increase the maintenance dose to 15,000 IU/day.  Four days of loading should increase 25(OH)D3 serum concentration by 20 ng/mL (50 nmol/L) and this maintenance dose should keep you at this level.

The second most common reason some CHer don't respond is they didn't take all of the cofactors.  These cofactors are essential for effective vitamin D3 hydroxylation/metabolism to 25(OH)D3 and on to 1,25(OH)2D3.  The first of these two enzymatic processes take place in the liver where the enzyme 25-Hydroxylase adds a hydroxyl group [OH] to the vitamin D3 molecule at the 25th position resulting in 25(OH)D3.  As only a small fraction of serum vitamin D3 is hydroxylated during each pass through the liver, it can take upwards of two weeks to completely hydroxylate each dose of vitamin D3 to 25(OH)D3

The second hydroxylation takes place in the kidneys where  the enzyme 1-alpha-Hydroxylase adds a second hydroxyl group to the 1st position on the 25(OH)D3 molecule to create 1,25(OH)2D3, the genetically active metabolite.  It's this serum bound vitamin D3 metabolite that's responsible for pulling calcium from the gut to maintain calcium serum concentrations in the bloodstream in a very narrow range and also to build bone mineral density. 

These same two enzymatic processes also take place at the cellular level in neurons and glia within the trigeminal ganglia.  It's here where vitamin D3 does its magic in preventing CH. The vitamin D3 cofactors: magnesium, zinc, boron, vitamin A and vitamin K2 must also be present at the cellular level to support the expression/synthesis of the enzymes needed to hydroxylate vitamin D3 to its genetically active metabolite.  Without these enzymes, this process cannot occur and vitamin D3 will be ineffective in preventing CH.

The corrective action is review the cofactors and make sure you're taking all of them.

Another less common reason why some CHers don't respond to this treatment protocol even when they're taking all the cofactors is an enzyme imbalance caused when the cofactors are not taken up sufficiently by neurons and glia within the trigeminal ganglia. This happens with roughly 2% of CHers starting this treatment protocol, but it's temporary and lasts for a week to 10 days then usually clears as sufficient cofactors build at the cellular level..

When this condition happens, the genes responsible for expressing/synthesizing one or both the two essential enzymes 25-Hydroxylase and 1-alpha-Hydroxylade, cannot synthesize enough of them.  As vitamin D3 and 25(OH)D3 are still entering the neurons and glia and they're not being hydroxylated to 1,25(OH)2D3, a third enzyme, 24-hydoroxylase, comes into play to prevent too much vitamin D3 and 25(OH)D3 from accumulating.  24-Hydroxylase is part of the body's vitamin D3 self regulating/protection system that prevents too much vitamin D3 from accumulating. 

Once vitamin D3 is hydroxylated at the 24th position to make 24(OH)D3 and 25(OH)D3 is hydroxylated at the 24th postion to make 24,25(OH)2D3, both of these two metabolites are broken down rapidly and eliminated from the cell. Any 1,25(OH)2D3 is also hydroxylated at the 24th position to make 1,24,25(OH)3D2 and it is also broken down and eliminated. 

When this happens, there is insufficient 1,25(OH)2D3 to initiate the genetic expression that down-regulates the synthesis of Calcitonin Gene-Related Peptide (CGRP), Substance P (SP), Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase-Activating Peptide (PACAP).  These four neuropeptides are responsible for triggering the neurogenic inflammation and pain we know as CH.

The corrective action here is to stop taking vitamin D3 for a week, but continue taking all the cofactors.  You can also reduce the vitmin D3 intake to less than 10,000 IU/day and keep taking all the cofactors.  Both options allow for the buildup of the needed enzymes to meet the demands of hydroxylating vitamin D3 to 1,25(OH)2D3.

Take care and please keep us posted.

V/R, Batch

Hey Eric,

Thanks for the update and sorry for the delay in responding.  I spent the month of June in Pelican, AK fishing for King lmon and Halibut.  The payback in honey-do for being gone from home that long has been onerous.

What you're experiencing is actually quite common.  The main reason CHers on the anti-inflammatory regimen fall out of remission is an immune system response to allergens.  I've had it happen to me with a 25(OH)D3 serum concentration of 150 ng/mL (375 nmol/L).  This is where the immune system's Mast Cells degranulate (spill their contents of inflammatory mediators) as illustrated in the following graphic.  As you can see, histamine is the leading culprit.

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Histamine to a CHer is like Kryptonite to Superman.  None of the interventions work and that includes vitamin D3 if the allergen load is high.  That makes an antihistamine the first order of business.

In the past I've suggested a first-generation antihistamine like Benadryl (Diphenhydramine HCL) as it crosses the blood brain Barrier to block histamine H1 receptors throughout the brain and trigeminal ganglia.  Blocking the histamine H1 receptors helps down-regulate expression of the four primary neuropeptides (CGRP, SP, VIP and PACAP) that are responsible for the neurogenic inflammation and pain we know as CH.  An effective antihistamine enables vitamin D3 to do its thing through genetic expression to control and prevent CH.

As Benadryl can make us drowsy, in March, I started suggesting a clutch of supplements with antihistamine properties I call the Antihistamine Full Monty as an alternative.  Rationale - Just as effective as Benadryl, but with none of drowsy side effects.  The Antihistamine Full Monty is taken on top of the basic anti-inflammatory regimen shown below.

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The Antihistamine Full Monty includes 3 grams/day each as a loading dose of Turmeric (Curcumin), Resveratrol, Quercetin and Omega-3 Fish Oil.  It also includes 5mg/day Melatonin taken at bedtime and 8 grams/day Vitamin C. 

I buy Vitamin C (Ascorbic Acid) from amazon in 1 Kg bags and stir 2 level teaspoon measures in 8 to 12 oz of water and take sips all day until it's gone by bedtime.  It tastes like unsweetened lemonade and the bulk powdered form is the least expensive form of Vitamin C.  The rationale for this much Vitamin C is it has a serum half-life of 30 minutes as our kidneys filter it rapidly.  Accordingly, taking sips of this Vitamin C solution throughout the day helps maintain a constant serum concentration.

Most of us taking the Antihistamine Full Monty stay at the loading dose of the first four supplements for a week to 10 days or until a CH pain free response then taper the dose to two grams/day for a week then down to one gram/day.  I've been on the Antihistamine Full Monty at one gram/day for the first four supplements since April.  Dealer's choice on the Melatonin but I still take 8 grams/day vitamin C.  Linus Pauling took 18 grams/day vitamin c and lived to 93.  Watch his video on  Preventing Illnesses and Diseases with Vitamin C.

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If there has been no response to the Antihistamine Full Monty, there are two additional supplements you can try. 200 mcg/day Selenium and 1000 mg/day N-Acetyl Systeine (NAC).  Selenium  plays critical roles in reproduction, thyroid hormone metabolism, DNA synthesis, as well as protection from oxidative damage and infection.  Selenium is also one of the Cofactors in the Coimbra protocol for MS.    NAC has many benefits but the big three for CHers are:  antioxidant, antiviral and anti[inflammatory.

Hope all this helps.  Take care and please keep us posted.

V/R, Batch