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Remy provides the second in a series of blogs on using nimidopine – a calcium channel blocking drug – in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). As described in Dr. Katherine Downing-Orr’s 2010 book, “Beating Chronic Fatigue Your step by step guide to complete recovery“, nimodipine, a calcium channel blocker, played a key role in Dr. Mason Brown’s protocol for chronic fatigue syndrome (ME/CFS). 

The Nimodipine Way? A Review of “Beating Chronic Fatigue: Your Step-by-Step Guide to Complete Recovery”

Calcium Channel Blockers in ME/CFS and FM

Using calcium channel blockers (CCBs) to treat the symptoms of ME/CFS is nothing new.  In reality, doctors have been using CCBs to treat the vascular symptoms of ME/CFS (like headaches) for many years.   But the benefits of the CCBs as a class go far beyond the vascular system to include many other commonplace ME/CFS symptoms.  Beyond that, the effects of a specific CCB, nimodipine, may provide even greater benefits for our population due to its ability to cross the blood-brain barrier.

What are calcium channels anyway?

By definition, ion channels are pores in the cell membrane that allow specific ions (atoms or molecules) to pass through into the cell.

Calcium exercise

Among many other things, calcium ions also play a critical role in exercise. (from Wikimedia – https://commons.wikimedia.org/wiki/File:Anaerobic_exercise.svg)

Different types of ions use different channels to perform their intended cellular functions.  Calcium ions, logically, use calcium channels and are one of the most important regulators of crucial cellular functions including muscle activity. Proper calcium functioning is vital for cell survival and disruption to these processes can be catastrophic.  As a result, many degenerative diseases feature disrupted calcium homeostasis (steady state), and the importance of calcium to the proper working of the body really cannot be overemphasized.

For proper functioning, calcium levels should be higher in concentration (by about 10,000x) outside the cell in the blood and the extracellular fluid than in the cell. This concentration gradient is vital for the proper functioning of muscles, glial cells and neurotransmission.  Calcium ions are further involved in the regulation of neurotransmitters and hormones, enzymes, transport, glycolysis, respiration, membrane potential and intracellular communication.  Regardless of the original insult to the system, disruption in calcium channel functioning is often the final common pathway that will ultimately lead to the death of the cell.

Generally, CCBs function by reducing the crossing of calcium ions from the blood into the cells.  The lowering of intracellular calcium has many important therapeutic effects, including the relaxation of blood vessels, which improves blood flow and oxygen delivery to the organs.  This is the traditional reason for prescribing CCBs to patients with high blood pressure.  But the main benefits in ME/CFS go well beyond the relief of hypertension.

Immune System Effects

The role CCBs play in modulating the immune system is clear. They can suppress the activation of different types of immune cells including T-cells and macrophages. The late immunologist, Dr. Robert Keller, noted CCB activity inhibits T-cell activation. Beyond that, research has demonstrated that CCBs have some systemic antiviral activity against common viral infections like influenza and all the way to HIV and hepatitis.

Researchers from Griffith University have recently shown that calcium handling is dysregulated in patients with ME/CFS.  They are currently studying potential drugs that are able to activate the TRPM3 channel in similar fashion to pregnenolone, including the CCB, nifedipine.

Effects on the Mitochondria

Calcium affects mitochondrial function as well, with high intracellular calcium levels causing conformational changes which inhibit mitochondrial functioning leading to mitochondrial dysfunction. Unlike other mitochondrial issues, however, this isn’t due to genetic mitochondrial disorder, it’s simply caused by increased levels of intracellular calcium.  More importantly, it can be reversed by lowering the calcium levels.

Effects on Microglial Cells

Dr Jarred Younger has studied microglial cells in patients with ME/CFS and hypothesizes that activated microglial cells in the brain could be responsible for producing some of the common symptoms of the disease.  While Younger has not specifically mentioned CCBs in his work, other researchers have found that CCBs that cross the blood-brain barrier can inhibit the inflammatory activity of activated microglial cells.  Nimodipine, in particular, can even promote remyelination in oligodendrocytes, which has important ramifications for multiple sclerosis (MS) sufferers.

Effects in MCAS

Mast cell activation disorder is specifically characterized by high levels of intracellular calcium and reducing this level may help improve allergic symptoms.  Calcium channel blockers have also been shown to reduce the symptoms of urticaria and hives in several studies, beyond what antihistamines could do alone.

Effects on Chronic Pain

Calcium channel

Crystalline structure of the N-type calcium channel believed involved in chronic pain. (from https://commons.wikimedia.org/wiki/File:Crystal_Structure_of_N-Type_Channel.png)

CCBs can also improve the pain of fibromyalgia.  Dr. Jay Goldstein noted a decrease in the number of tender points after administration of a CCB in his practice.  More current research also demonstrates how a specific type of calcium channel, the N-type, contributes to the experience of chronic pain.

N-type calcium channels have been identified as future key targets in controlling certain types of pain.  Pain is a result of a cascade of signals involving the calcium channels.  The influx of calcium ions triggers the release of neurotransmitters which then potentiate the pain signal to the brain where it is perceived as pain.   Therefore, blocking this cascade with CCBs has the potential to dramatically improve pain levels in ME/CFS and fibromyalgia.

Beyond general, body-wide pain, CCBs are often prescribed to help control headaches, particularly migraine headaches.  Migraine is thought to be initiated by cerebral vasospasm, which is then followed by vasodilation outside of the head.  Cerebral blood flow has been shown in studies to be decreased, which then leads to low levels of oxygen in the brain.  Calcium channel blockers can help prevent this cascade of events from happening as readily.

Other Important Benefits

Some clinicians, like Goldstein, report that CCBs may also help to increase exercise capacity in ME/CFS.  CCBs have also been shown to improve vagal tone in patients following a heart attack.

Some ME/CFS specialists have noticed increases in cognition, presumably as a result of improved blood flow and increased oxygenation, as well as an improvement in mood disorders like depression and a decreased number of panic attacks.

Nimodipine vs Other Calcium Channel Blockers For ME/CFS and Fibromyalgia?

There are two common classes of CCBs, known as the dihydropyridine and the non-dihydropyridine types.  Verapamil is a well-known example of the non-dihydropyridine type whereas nimodipine is a dihydropyridine type of CCB.  This distinction is important because the dihydropyridine type of CCB has a greater effect on the blood vessels in the body as a whole, whereas non-dihydropyridine drugs are more targeted on the heart muscle, helping to make it easier to pump blood through the body.

The evidence for using a specific calcium channel blocker, nimodipine, may be even more robust than for calcium channel blockers as a whole.  Dr. David Mason-Brown considers nimodipine (along with ginkgo biloba and other supplements) to be the most important treatment for normalizing brain circulation in ME/CFS.

nimodipine blood-brain barrier

One of nimodipine’s advantages is its ability to cross the blood-brain barrier.

Nimodipine is somewhat uniquely able to cross the blood-brain barrier and enter the cerebrospinal fluid, making it specifically suited to treating cases of reduced cerebral blood flow.  In fact, the most common use for nimodipine in the US is to help increase blood flow to the brain after a stroke or cerebral aneurysm.  This also means that nimodipine has less of an effect on the overall blood pressure than other CCBs, which is good for anyone suffering with low blood pressure or orthostatic hypotension.

The late Dr. Ismael Mena, one of the authors of the 2011 ME/CFS ICC criteria, used nuclear medicine imaging to measure functional brain flow in patients with brain degenerative diseases.  He found that 71% of ME/CFS patients have low blood flow in the temporal lobe of the brain.  After treatment with CCBs, patients showed improvements in cerebral blood flow.

Excess production of platelet activating factor increases the viscosity of the blood.  Nimodipine normalizes blood flow by countering this effect.

Using Nimodipine in ME/CFS and FM

As the late Kristina Downing-Orr details in her book, Beating Chronic Fatigue, nimodipine forms the cornerstone of their medical protocol for reversing ME/CFS.  Working with Dr. David Mason Brown, Downing-Orr developed a protocol for using very low doses, slowly ramped up, to increase brain circulation and remove the toxins that have built up as a result of the low circulation.  This protocol starts with a very low dose of nimodipine, 7.5 mg, and then slowly ramps up over 33 weeks to a maximum of 120 mg.

Other practitioners, such as Jay Goldstein, also trialed nimodipine with patients, but if a positive response was not seen immediately, they did not continue the trial. Goldstein rated nimodipine the third best of his top 23 drugs for ME/CFS.  Most practitioners now feel that either the slow-titration or slow-response protocols are more useful, however, as it may take time to observe the beneficial effects of improved brain circulation.

Because this is an off-label use of the drug, there are as many plans and protocols to dose nimodipine as there are practitioners.  Some practitioners use the slow titration method Downing-Orr recommended, but others use faster protocols.

In the US, there is currently only one dose strength available, the 30 mg softgel, which complicates matters quite a lot when trying to start at the very low dose.  There is a liquid form of nimodipine, designed to be used with a nasogastric tube that may be an option.  It may also be possible to use a pin to open up the softgel and empty the contents into an oral syringe for dispensing that way.

Nimodipine is very expensive in the US if it is not covered by insurance.  Cash prices currently are approaching $300/ 90 softgels.  It may also be possible to use an online pharmacy to purchase nimodipine tablets that can be easily split as many will accept a US prescription.  Typically, the cost will also be much lower as well.  Pharmacychecker.com displays prices ranging from approximately $100-200/ 100 pills.

If lower dose options are not available, patients will have to start at the 30 mg dose and titrate up from there.  Many practitioners, including the group that produced the Canadian Consensus document, take this approach anyway, so it’s really up to the patient and their prescriber which way to begin.

The risk of starting at a higher dose is, of course, the risk of having more side effects as brain circulation improves and toxins are released from the brain faster than the body can process them.  In that case, most practitioners would recommend decreasing the dose, or skipping doses until the symptoms are manageable again.

As with any treatment, this will not work for everyone (though some estimate it will help more than 60% of patients) and some patients may get worse before they improve.  This risk is always an important one to consider, as some patients may not find it an acceptable one until there are studies showing certain positive effects in our population.

Calcium channel blockers are a diverse class of medications with similar, yet also widely ranging effects.  There are so many different variations of this drug that it isn’t really possible to generalize a reaction to one to a similar reaction to the entire class.

That said, nimodipine is considered a low-risk drug, and side effects are typically mild.  Susan Parker reports in her very useful document, “Nimodipine Use in ME/CFS:  A Comprehensive Guide”, that only 4 out of 100 patients experienced side effects with nimodipine, a rate that was less than the placebo.  Parker also reports that there are no signs of drug accumulation, toxicity or liver injury, dependence, increased risk of cancer or GI bleeding as a result of nimodipine use, which is obviously in direct contrast to most pain-relieving drugs.

My Personal Experience

I started using nimodipine several months ago to try to treat vascular spasms that were causing ocular migraines and making my high pass IV ozone treatments difficult due to the reduced flow of blood during the spasm.  I had no preconceived notions of benefit, other than hopefully easing my ozone treatments.

I first tried to take a small dose by freezing the softgel and cutting it into quarters, but this was mostly unsuccessful as the inside of the capsule did not freeze solid and made quite a mess.  I tend not to be terribly sensitive, so I went ahead and trialed a full 30 mg capsule and immediately noticed a great reduction in the coat-hanger type pain across my shoulders that had plagued me for years.

This effect was somewhat short-lived, as nimodipine has a short half-life, but was thankfully repeated when I took another dose.  Fairly quickly I worked up to 120 mg/day and have stayed there ever since.

I have POTS, though I am not currently symptomatic, but I did not notice any increase in orthostatic hypotension or a decrease in my blood pressure overall.  Others have noted that nimodipine can actually increase blood pressure.

This reduction in pain has made such an enormous difference in my daily life.  I never expected my fibromyalgia type pain to decrease from nimodipine, but that is exactly what happened.  It works better for me than any OTC or prescription pain med ever has, and without most of the most significant side effects associated with long-term use of those drugs.  Suffice it to say, I’m a fan.  It hasn’t cured me, but I never expected that, and in terms of symptom relief, it is by far the best medication I have tried (and I have tried a lot!).

Most of the research I could find on nimodipine and calcium channel blockers in ME/CFS and other related conditions seems to be quite old now.  Most of the resources online are out-of-date and many of the leading researchers into this treatment have now passed away or retired.  But I’m hoping for a resurgence of interest in this drug and further research on how its use may benefit our population in the future.

Health Rising Resources

The Nimodipine Way? A Review of “Beating Chronic Fatigue: Your Step-by-Step Guide to Complete Recovery”

Nimodipine For Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia

Susan Parker’s Comprehensive Overview (2014) 

N I M O D I P I N E use in M.E. / CFS: A comprehensive guide.

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