Dr Graham Exelby May 2024
This is part of a personal management protocol in POTS, Long Covid and other MCAS-associated conditions. There are no Cochrane Guidelines at this point, and all treatments are based on research from around the world.
As the DNA studies reap more information the mutations found in the threat receptors TLR 2, TLR3 and TLR4 mutations are likely to be critical in the individual patient response. The pathogenesis of the cognitive impairment, fatigue, sensitization and autonomic dysfunction is complex and discussed in other papers
When considering treatment in MCAS, especially in Long Covid, you may have to decide whether to target the TLR4, TLR2, TLR3 or Mast cells, or all, as all may be dysfunctional.
Management requires to stop the ongoing inflammatory processes. Each area of inflammation from the Covid and pre-Covid state needs to be identified and managed.
Then our protocol is to reduce the desensitization and reduce the inflammatory activation:
Personal Protocol
H1 blockade -mast cell stabilization.
Fexofenadine 180 bd or Cetrizazine 10mg bd or equivalents
Ketotifen (see below)
H2 blockade:
Famotidine 40 bd, but may need to be increased to 80mg bd. Famotidine is limited by arrythmias and QT prolongation. Extra magnesium is thought to counter these. Famotidine has been shown to modulate the TLR3 response and is often invaluable.
TLR4 modulation
Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune system, recognizing pathogen-associated molecular patterns and initiating inflammatory responses. When TLR4 is overactivated, it can contribute to excessive inflammation and the development of various inflammatory and autoimmune diseases. Modulating TLR4 signalling can have significant effects on immune responses and inflammation
Low Dose Naltrexone -improves glymphatic function (and probably Natural Killer cell function). If H1/H2 not tolerated, caution with Low Dose Naltrexone. A study by Wang et al. (9) demonstrated that naltrexone could attenuate TLR4 signalling in glial cells, leading to reduced neuroinflammation it blocks toll4, is an NLRP3 inhibitor and well as restoring TRPM3 function.
Nigella Sativa contains several active compounds, in particular thymoquinone, that have been found to modulate TLR4 signalling. Studies have shown that thymoquinone can down-regulate TLR4 expression and inhibit TLR4-mediated signalling pathways, reducing inflammation and oxidative stress. It increasingly looks to be a reasonable adjunct to above treatments, especially when D-Dimer remains elevated as it has anti-thrombotic activity, and may be a reasonable replacement when LDN is not tolerated.
Curcumin- Turmeric is widely studied for its health-promoting properties. It has been used in Traditional Chinese Medicine, as well as Ayurvedic medicine, for more than 2,000 years. Curcumin is turmeric’s most active component and provides numerous health benefits, including support for joint function and mobility, liver and gut health, cardiovascular function. Curcumin is also a potent antioxidant and has been found to modulate TLR4 signalling.
PPARg agonists eg pioglitazone and rosiglitazone, have been shown to inhibit TLR4 expression and signalling in various cell types. Other products with potential benefit includes Telmisartan.
Other products that can influence TLR signalling include:
Glutathione indirectly by regulating redox state and mitigating oxidative stress (5)
Nicotinamide mononucleotide (NMN) appears to indirectly influence TLR4 signalling and inflammation by increasing NAD+ levels and promoting sirtuin activation. Sirtuins especially SIRT1 and SIRT6 can modulate TLR signalling and related inflammation.(6)
Amitriptyline is a tricyclic antidepressant (TCA) commonly used to treat depression, neuropathic pain, and other chronic pain conditions. While the primary mechanism of action of amitriptyline is the inhibition of serotonin and norepinephrine reuptake, it has also been shown to have other effects, including anti-inflammatory and immunomodulatory properties. While there is no direct evidence of amitriptyline acting as a TLR4 modulator, it appears to have anti-inflammatory and immunomodulatory effects that could be indirectly related to TLR4 signalling. (7)(8)
Doxycycline- is a broad-spectrum antibiotic that has been used to treat various bacterial infections. However, in addition to its antimicrobial effects, doxycycline has been found to have immunomodulatory properties, including the ability to inhibit TLR4 signalling. Several studies have demonstrated that doxycycline can reduce the expression and activity of TLR4 and its downstream signalling molecules, such as NF-κB and MAPKs, in various cell types. This can lead to a decrease in the production of pro-inflammatory cytokines, such as TNF-α and IL-6, and an overall dampening of the immune response. Therefore, doxycycline has been proposed as a potential therapeutic option for diseases that involve dysregulated TLR4 signalling and excessive inflammation, such as sepsis, inflammatory bowel disease, and autoimmune disorders.
In the POTS patients, especially when it has been triggered by COVID, we have found there is a high percentage that have QT prolongation shown in lying and standing ECGs. This makes the use of H1/H2 blockade with antihistamines and famotidine potentially risky until the prolongation can be controlled (which can be with sympathetic overactivity control with Japanese [Kiiko-Matsumoto in our studies] style acupuncture. In this situation consideration should be given to TLR4 modulation (see below) and/or oral ketotifen.
Ketotifen- H1 antihistamine/H1 blocker and mast cell stabilizer
Ketotifen requires compounding as it is not available in oral form in Australia. As it has no effect on the QT prolongation it provides a useful part of the armoury to manage Long Covid/POTS/MCAS pathways.
Ketotifen reduces antigen-induced mast cell degranulation and decreases the release of histamine, tryptase, and various prostaglandins. Ketotifen also stabilizes calcium permeability in mast cell membranes(2) making it a valuable product in MCAS and Long Covid management. It is known to interact with several ion channels and receptors that are involved in mast cell activation and the release of inflammatory mediators. One such target is the Transient Receptor Potential Melastatin 3 (TRPM3) ion channel, which has been shown to play a role in the regulation of mast cell degranulation and histamine release.
The Transient Receptor Potential Melastatin 3 or TRPM3 is a calcium-permeable ion channel that is expressed in a variety of cells, including mast cells. It plays a role in various physiological processes, including calcium homeostasis, pain perception, and temperature sensing. The activation of TRPM3 leads to an influx of calcium ions into the cell, which can trigger the release of inflammatory mediators.
Ketotifen has been shown to inhibit TRPM3 activity, thus reducing the influx of calcium ions and ultimately leading to a decrease in mast cell degranulation and histamine release.In addition to TRPM3, ketotifen has also been shown to interact with other Transient Receptor Potential (TRP) channels, such as TRPV1 and TRPA1. These channels are also involved in the regulation of mast cell activation and the release of inflammatory mediators, and their inhibition by ketotifen can contribute to its overall anti-inflammatory effects.
At the clinical level, the inhibition of TRP channels by ketotifen has been implicated in its efficacy in the treatment of various allergic and inflammatory conditions, including MCAS. It also reduces TNFa, macrophage-derived chemokines and IL-8.(2)
Dosage:
Ketotifen can be used in children as well as adults. The typical dose for children is 0.5mg to 2mg daily to twice daily. The adult dosage is typically 2mg to 4mg daily to twice daily.(3)
Side effects:
The main side effect is drowsiness, which affects 10%-20% of patients. This side effect tends to diminish with time, typically in about 2 months. Most patients begin treatment with a bedtime dose then increase to twice daily once the drowsiness subsides. Weight gain may occur.
Use of the eye drops commonly triggered eye pain, sensitivity, photophobia, dry mouth. Similar reactions in both adults and young children, but percentage of adverse effects lower in children eg sedation 14% in adults, 6% in children.(4)
Low Dose Naltrexone (LDN)- dosage 0.5 to 4.5 mg daily
Naltrexone is a drug that was approved to help prevent narcotics and alcoholics from relapsing. As an opiate antagonist, naltrexone competes with opioid drugs for real estate on opiate and endorphin receptors. This helps patients feel less “high” from opioids or alcohol and reduce cravings. LDN is thought to work primarily through its interaction with opioid receptors, particularly the mu-opioid receptor, modulating the immune system and reducing inflammation.
There is some evidence suggesting that naltrexone, and potentially LDN, may modulate Toll-like receptor 4 (TLR4) signaling. TLR4 is a pattern recognition receptor that plays a key role in the innate immune system, recognizing pathogen-associated molecular patterns and initiating inflammatory responses. LDN has also been shown to repair TRMP3 function, and function as an NLRP3 inhibitor.
A study by Wang et al. (9) demonstrated that naltrexone could attenuate TLR4 signalling in glial cells, leading to reduced neuroinflammation. LDN has a unique action mechanism of suppressing microglial activity. Microglia are the central nervous system’s primary immune cells and are responsible for creating inflammation as a response to injury or pathogens. Microglia when activated secretes various factors, like prostaglandins, nitric oxide, pro-inflammatory cytokines, and excitatory amino acids. Thus LDN works by reducing inflammation in the brain caused by over-active microglia.
By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals. The anti-inflammatory effect of opioid antagonists may also extend to the periphery, as evidenced by suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages.
Some of the inflammatory conditions that have shown to benefit from LDN include multiple sclerosis (10), Fibromyalgia (11), Crohn’s Disease (12) (quoted 80% symptom improvement), Complex regional pain syndrome (13) (a disease that often shows evidence of both local and low-level systemic inflammation). It has been suggested LDN may also be helpful in rheumatoid arthritis, SLE, and Griffith University has confirmed its application in CFS/ME. It may have applications in cancer management. Overall, while the literature is quite small, there is a consistent theme of LDN efficacy in controlling diseases with inflammatory components.
When LDN is used within a specific dosage window (typically between 0.5 mg and 4.5 mg), its binding of opiate receptors on immune cells can have a temporary immunoregulatory effect. The increased levels of endorphins stimulate the immune system by binding to regulatory T cells, which promotes an increase in T-lymphocytes. This upregulation of T-lymphocytes reduces cytokine and antibody production, restoring a more normal balance.
LDN has anti-inflammatory effects. Recent studies have demonstrated this effect in patients with fibromyalgia, in which inflammation of the central nervous system is a common characteristic. When triggered by inflammation or infection, microglia and immune cells in the central nervous system increase their expression of TLR-4, which leads to an increase in the production of pro-inflammatory cytokines. As a TLR-4 antagonist, LDN blocks this cascade of inflammation.
Fibromyalgia (FMS), is a chronic fatigue and pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation as well as profound fatigue, cognitive disruption, and sleep difficulty. FMS is now known to be glial sensitivity and inflammation driven primarily by ILs 6, 8 and TNFa. Fibromyalgia does not respond to common anti-inflammatories but researchers also found that the patients who took LDN had a 15% reduction of fibromyalgia-associated pain and an 18% reduction in overall symptoms. The serum levels of several pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β, IL-2, IL-15, IL-17A, and tumour necrosis factor (TNF)-ɑ decreased significantly. Fibromyalgia is also known to be associated with TLR2/astrocyte/ glutamate dysfunction, along with ADHD, ASD, and migraine.
LDN needs to be compounded, and starting dose is typically 0.5 mg daily, increasing by 0.5 mg weekly to a maximum of 4.5 mg. We have found improvements in fatigue are usually seen between 2 and 3 mg daily. Current trial are showing improved results using a smaller dose more frequently, eg 1.5 mg three times daily, to counter its short halflife on 4 hours. Doses are still trial and error, and occasionally the LDN needs to be compounded to even lower strengths.
Because low-dose naltrexone blocks opioid receptors, you should not continue taking narcotic pain medication with LDN without consent of your medical provider. Otherwise, LDN has few side effects and is generally well tolerated by most patients. Most people notice an increase in dreaming and some people notice a bit of sleep disruption during the initial few days of treatment but this improves over time. Nausea, dizziness, drowsiness, anxiety, fatigue and loss of appetite can occur. From our clinic observations, care needs to be taken if patients react poorly to H1/H2 blockade, and in patients with liver enzyme mutations and even lower starting doses seem appropriate, this starting dose may need to be reduced to 0.1 mg daily.
Potential interactions can occur with opioid medications, as naltrexone is an opioid antagonist, and blocks the effects of them. It can lead to opioid withdrawal if used together. This includes codeine, morphine, oxycodone, hydroxycodone and may cause an increase in pain controlled by those medications. It may interact with buprenorphine, naloxone, and it has immunomodulatory effects, it may interact with other immunosuppressive medications potentially altering the medication’s effectiveness. This may include methotrexate, corticosteroids and cyclosporine. It’s use must be discussed with your medical advisor.
Other mast cell stabilizers, inhibitors and blockers
Lawrence Afrin (14) describes other various products useful in managing mast cell activation:
Inhibition of mediator release (mast cell stabilization)
Benzodiazepines to address end organ receptors as well as mast cells, added to potential improvement from reduced anxiety in some inflammatory bowel disease.
Tricyclics eg doxepin have H1 and H2 receptor blocking effects that can be added to traditional antihistamines.
SSRIs may benefit the associated depression but also can affect mast cells via surface serotonin reuptake transporters. However adding antihistamines to SSRIs brings the risk of serotonin syndrome.
Cromolyn (Intal) can stabilize mucosal mast cells- for dosage regime see page 199 of “Presentation,Diagnosis and Management of Mast Cell Activation Syndrome.”
Oral Ketotifen-originally marketed as an inhibitor of anaphylaxis, it inhibits release and/or activity of mast cell and basophil mediators including histamine, neutrophil and eosinophil chemotactic factors, arachidonic acid metabolites, prostaglandins and leukotrienes. Taken orally with a dose of 1 mg twice daily increasing weekly as tolerated.
Quercetin is a flavonoid that is poorly absorbed but is thought to inhibit lipooxygenase and cyclooxygenase reducing production of inflammatory mediators eg leukotrienes and histamine. It seems to have general anti-inflammatory effects and impedes PGD2-driven flushing. General dosing is 500 to 1000 mg twice daily. As it can inhibit COMT and increase symptoms, DNA should be sought first. Side effects may include headache and upset stomach. Preliminary evidence suggests that a by-product of quercetin can lead to a loss of protein function. Very high doses of quercetin may damage the kidneys. Care must be taken with medication interaction, especially anti-depressants. More details available on https://www.mountsinai.org/health-library/supplement/quercetin#:~:text=Quercetin%20is%20generally%20considered%20safe,quercetin%20may%20damage%20the%20kidneys.
Allergen-driven cross-linking of multiple IgE molecules bound to mast cell-surface IgE receptors is a major route of mast cell activation. Omalizumab (Xolair) is a humanized monoclonal antibody which reversibly binds the Fc portion of IgE hindering IgE binding with its mast cell-surface receptor.
Blockade of released mediators
Histamine H1 and H2 blockade to address end organ receptors as well as mast cells
Leukotrienes are synthesized and released by mast cells –Selective leukotriene receptor antagonists eg Singulair 10 mg 1-2 times daily may help- limited in hepatic involvement.
Bisphosphonates are helpful in excessive bone resorption. Zolendronic acid has demonstrated a significant reduction in breast cancer recurrence rate. It is interesting to deliberate on the mechanism for this as it is very likely it produces this response via the mast cells.
A note of caution when adding any supplements or medications:
It might be tempting to take as many things as possible to relieve yourself of your symptoms, but people with MCAS can react to all sorts of things, even herbs. Slow down and take it easy. Start with one supplement or herb at a time and see how it affects your body.
Living with a chronic illness like MCAS can make you feel pretty discouraged. But there are things you can control. With the addition of healthy lifestyle choices and medications, you can stabilize mast cells and bring balance to your immune system.
References:
1. Dong H, Zhang X, Wang Y, Zhou X, Qian Y, Zhang S. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation. Mol Neurobiol. 2017 Mar;54(2):997-1007. doi: 10.1007/s12035-016-9720-x. Epub 2016 Jan 21. PMID: 26797518
2. Ang DC, Hilligoss J, Stump T. Mast Cell Stabilizer (Ketotifen) in Fibromyalgia: Phase 1 Randomized Controlled Clinical Trial. Clin J Pain. 2015 Sep;31(9):836-842. doi: 10.1097/AJP.0000000000000169. PMID: 25370135; PMCID: PMC4417653.
3. Rosenberg,S. Ketotifen: How it Works and Its Uses in Your Practice. Oregon Association of Naturopathic Physicians. 2022. https://www.oanp.org/news
4. Aronson,J (Ed). Meyler's Side Effects of Drugs (Sixteenth Edition), 2016.
5. Vlahopoulos, S., Adamaki, M., Khoury, N., Zoumpourlis, V., & Boldogh, I. (2018). Roles of DNA repair enzyme OGG1 in innate immunity and its significance for lung cancer. Pharmacology & Therapeutics, 183, 34-46
6. Schug, T. T., Xu, Q., Gao, H., Peres-da-Silva, A., Draper, D. W., Fessler, M. B., ... & Li, X. (2010). Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Molecular and cellular biology, 30(19), 4712-4721
7. Obuchowicz, E., Bielecka-Wajdman, A. M., Paul-Samojedny, M., & Nowacka, M. (2014). Antidepressant drugs inhibit the production of IL-6 and IL-8 but not the production of IL-1β and TNF-α by astrocytes exposed to lipopolysaccharide. Pharmacological Reports, 66(4), 613-623
8. Zhang, J., Yang, L., Lin, N., Pan, X., Zhu, Y., & Chen, X. (2016). Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy. Experimental and Therapeutic Medicine, 12(4), 2281-2288
9. Wang, X., Zhang, Y., Peng, Y., Hutchinson, M. R., Rice, K. C., Yin, H., & Watkins, L. R. (2016). Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. British journal of pharmacology, 173(5), 856-869
10. Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010 Aug;68(2):145-50. doi: 10.1002/ana.22006. PMID: 20695007.
11. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38. doi: 10.1002/art.37734. PMID: 23359310.
12. Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, Zagon IS. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's disease: a randomized placebo-controlled trial. Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8. PMID: 21380937; PMCID: PMC3381945.
13. Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol. 2013 Jun;8(3):470-6. doi: 10.1007/s11481-013-9451-y. Epub 2013 Apr 2. PMID: 23546884; PMCID: PMC3661907.
14. Afrin, L. Presentation,Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Nova Science Publishers,Inc. https://experts.umn.edu/en/publications/presentation-diagnosis-and-management-of-mast-cell-activation-syn
15. Lynch MA. The multifaceted profile of activated microglia. Mol Neurobiol. 2009 Oct;40(2):139-56. doi: 10.1007/s12035-009-8077-9. Epub 2009 Jul 23. PMID: 19629762.
16. Parkitny,L, Younger,J.Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia. Biomedicines. 2017 doi: 10.3390/biomedicines5020016
17. Weinstock,L., Brook, J., Myers,T., Goodman,B.: Successful treatment of postural orthostatic
tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Rep 2018. doi:10.1136/bcr-2017-221405
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