fibromyalgia: a clinical approach

1

Nutrition interventions for managing fibromyalgia

Nina Bailey BSc, MSc, PhD RNutr

• The name fibromyalgia originates from the words fibro for fibrous tissues, such as tendons and ligaments, with my indicating muscles, and algia meaning pain

• Fibromyalgia syndrome (FMS) is a prevalent chronic pain syndrome characterised by widespread pain and other unspecific somatic symptoms including fatigue, sleep disturbances, cognitive dysfunction and depressive disorders

• FMS is more prevalent in women around 50 years old

• There are no diagnostic biochemical markers or instrumental tests on which to base a diagnosis

Wolfe F, Clauw DJ, Fitzcharles MA, et al. (2010) The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care and Research 62: 600–610

M. Niesters, A. Dahan Fibromyalgia Encyclopedia of the Neurological Sciences (Second Edition), 2014, 288–292

https://www.torbayandsouthdevon.nhs.uk/uploads/questionnaire-widespread-pain-index-and-symptom-severity-score.pdf

0=no problem1=slight or mild problems and generally mild or intermittent2=moderate, considerable problems, and often present and/or at a moderate level3=severe, pervasive, continuous, and life-disturbing problems

Considering somatic symptoms in general, indicate whether the patient has

0=no symptoms1=few symptoms2=a moderate number of symptoms3=a great deal of symptoms

The SS scale score is the sum of the severity of the three symptoms (fatigue, waking un-refreshed, and cognitive symptoms) plus the extent (severity) of somatic symptoms in general. The final score will be between 0 and 12

Symptom severity scale score: Indicate the level of severity over the last week for the following three symptoms: (1) fatigue; (2) waking un-refreshed; and (3) cognitive symptoms



Criteria

A patient satisfies diagnostic criteria for fibromyalgia if the following three conditions are met:

1.Widespread pain index ≥7 and symptom severity scale score≥5 or Widespread pain index 3–6 and symptom severity scale score≥9

2. Symptoms have been present at a similar level for at least 3 months

3. The patient does not have a disorder that would otherwise explain the pain

Classification criteria of fibromyalgia syndrome American College of Rheumatology, 2010



Who does fibromyalgia syndrome (FMS) affect? •The prevalence of FMS in the general population is estimated at 2% to 5% (of which 85% are females)•‘Typically’ develops between the age of 25 and 55•Although the exact causes of FMS are not fully understood, evidence suggests that both genetic and environmental factors are involved

Risk factors •Genes - first-degree relatives of individuals with FMS have an 8-fold greater risk of developing FMS•Stressors (mechanical or physical trauma or injury and psychosocial stressors)•Co-morbid conditions: FMS and ME/CFS often overlap but also have a host of other overlapping conditions associated with them that include other pain disorders, chronic headache, sleep problems, major depression, anxiety, nervous system disorders, restless leg symptom, digestive problems (IBS) and menstrual problems

•Patients with FMS and related conditions display diffuse hyperalgesia (heightened pain responses to normally painful stimuli) and/or allodynia (pain responses to normally non-painful stimuli)

•Such responses suggest that these individuals have specific issues with pain or sensory processing rather than an abnormality confined to the region of the body where pain is experienced

Catechol-O-methyltransferase (COMT) catalyzes the transfer of a methyl group from S-adenosylmethionine (SAMe) to catecholamines, including the neurotransmitters dopamine, adrenaline and noradrenaline

Clinical symptoms in fibromyalgia are associated to COMT gene Val158Met polymorphism

rs4680(A) methionine = lower COMT enzymatic activity, therefore higher dopamine levels; lower pain threshold, enhanced vulnerability to stress

rs4680(G) valine = higher COMT enzymatic activity, therefore lower dopamine levels; higher pain threshold, better stress resiliency

FMS women with the homozygous met/met genotype evidenced more pain on days when pain attention was elevated relative to those with the homozygous val/val genotype

Inanir A, Karakus N, Ates O, Sezer S, Bozkurt N, Inanir S, Yigit S Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) geneVal158Met polymorphism. Xenobiotica. 2014 Oct;44(10):952-6.

Finan PH, Zautra AJ, Davis MC, Lemery-Chalfant K, Covault J, Tennen H. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain. 2011 Feb;152(2):300-7.

The COMT gene codes for the COMT enzyme, which breaks down dopamine in the brain's prefrontal cortex. The wild-type allele is a (G) coding for a valine amino acid; the (A) substitution polymorphism changes the amino acid to a methionine


Risk factors •Genes - first-degree relatives of individuals with FMS have an 8-fold greater risk of developing FMS•Stressors (mechanical or physical trauma or injury and psychosocial stressors)•Co-morbid conditions: FMS and ME/CFS often overlap but also have a host of other overlapping conditions associated with them that include other pain disorders, chronic headache, sleep problems, major depression, anxiety, nervous system disorders, restless leg symptom, digestive problems (IBS) and menstrual problems



Stressors capable of triggering fibromyalgia and related conditions

• Peripheral pain syndromes • Infections (e.g. parvovirus, Epstein-Barr virus, Lyme disease,

Helicobacter pylori) • Physical trauma (e.g. car accidents) • Psychological stress/distress (e.g. physical/mental abuse)• Certain catastrophic events (war, but not natural disasters)• Hormonal alterations (e.g. hypothyroidism) • Drugs/vaccines

Chronic inflammation (increase in pro-inflammatory cytokines), together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS/ME and FMS

Furthermore, the presence of blunted HPA-axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the HPA axis and cortisol in the pathogenesis of these syndromes


Risk factors Genes - first-degree relatives of individuals with FMS have an 8-fold greater risk of developing FMSStressors (mechanical or physical trauma or injury and psychosocial stressors)Co-morbid conditions: FMS and ME/CFS often overlap but also have a host of other overlapping conditions associated with them that include other pain disorders, chronic headache, sleep problems, major depression, anxiety, nervous system disorders, restless leg symptom, digestive problems (IBS) and menstrual problems



High levels of substances that facilitate the transmission of pain,

like substance P, glutamate and nerve growth factor, and brain

derived nerve growth factor have been observed in the cerebrospinal

fluid of fibromyalgia patients

Noradrenaline and serotonin (neurotransmitters involved in the

central inhibition of pain) are decreased, which may also explain

why FMS patients have a higher risk for the development of

depression and anxiety disorders

Littlejohn G. Neurogenic neuroinflammation in fbromyalgia dnd complex regional pain syndrome. Nat Rev Rheumatol. 2015 Nov;11(11):639-48.

Activation of the N-methyl-D-aspartate (NMDA) receptor (i.e. glutamate) results in increased sensitivity of spinal cord and brain pathways that process sensory information, particularly those which relate to pain

When pain turns from acute to chronic, it involves opening the NMDA pain receptor

•Patients with fibromyalgia have been shown to have an increased expression of NMDA receptors in their skin (Kim et al. 2006)

•Thus people with fibromyalgia appear to already have overly active NMDA pain receptors, making them more susceptible to the stimulation

•A 4-week exclusion of monosodium glutamate (MSG), aspartame, and other excitotoxins resulted in over 30% improvement in fibromyalgia symptoms in 84% of those who completed the diet (Holton et al. 2012)

Kim SH, Jang TJ, Moon IS. Increased expression of N-methyl-D-aspartate receptor subunit 2D in the skin of patients with fibromyalgia. Rheumatol. 2006 Apr;33(4):785-8.

Holton K.F., Taren D.L., Thomson C.A., Bennett R.M., Jones K.D. The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms. Clin. Exp. Rheumatol. 2012;30:10–17.

Serotonin

IDOIFN-γ , TNF-α ,

IL-1, IL-6

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

+

+

KMO

5-HTP

Neuronal damage Depression

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Sleep disturbanceIDO : indoleamine 2,3-dioxygenase KMO : kynurenine monooxygenase

Glutamate

McCrae CS, O'Shea AM, Boissoneault J, Vatthauer KE, Robinson ME, Staud R, Perlstein WM, Craggs JG. Fibromyalgia patients have reduced hippocampal volume compared with healthy controls. J Pain Res. 2015 Jan 30;8:47-52.

Hippocampal atrophy = fibro fog?

Abnormal glutamate excitatory neurotransmission and glucocorticoid dysfunction can lead to neuronal atrophy, through excitotoxicity, and disrupt neurogenesis in the hippocampus – with magnetic resonance imaging (MRI) scans having shown significant hippocampal atrophy in the brains of FMS patients compared to healthy controls

Hippocampal atrophy may play a role in memory and cognitive complaints among fibromyalgia patients

•Hippocampal atrophy resulting from FMS may, in turn, worsen or exacerbate FMS symptomatology

•FMS patients often report a subjective worsening of cognitive function characterised by short-term memory problems (‘fibro fog’)

•Hippocampal atrophy and dysfunction may “feed forward”, resulting in more severe pain, discomfort, and anxiety in FMS patients, due to its central role in limbic circuits and pain modulation networks

Adrenal fatigue - occurs when the amount of stress overextends the capacity of the body to compensate and recover from that stress or the combined stress

When cortisol crashes:

•Increases inflammatory cytokines (IL-6, TNFα)

•Activates microglial cells causing neuroinflammation

•Causes hippocampal degeneration/atrophy

•Increased susceptibility to infections (i.e., Candida!)

•Promotes autoimmune disease

Head KA, Kelly GS. Nutrients and botanicals for treatment of stress: adrenal fatigue, neurotransmitter imbalance, anxiety, and restless sleep. Altern Med Rev. 2009 Jun;14(2):114-40. Review.

https://drlam-6bmwcfqpiol3wo6jnjj0.netdna-ssl.com/images/infographic-four-phases-of-adrenal-exhaustion.jpg

Sufferers can have numerous abnormalities in their hormonal, metabolic and brain-chemical activity

These include levels of:

•serotonin and melatonin (both involved in the sleep cycle and mood)

•cortisol and noradrenaline (stress hormones)

•thyroid issues (hypothyroidism)

•growth hormones (involved in bone and muscle growth)

•substance P and glutamate (associated with pain perception)

•cytokines (involved in immune system response regulation andthe inflammatory process)

Fibromyalgia and cytokines

FMS isn’t generally classified as an autoimmune disease per se, but it shares many traits with autoimmune-like diseases in which the body is attacking itself, often as a result of chronic overproduction of inflammatory cytokines

•Features found in FMS (elevated numbers of B cells and cytokines and decreased numbers of T regulatory [Treg] cells) are associated commonly with autoimmune diseases

•Cytokines have effects on the HPA-axis, the sympathetic nervous system and T lymphocytes, which in turn might be associated with fibromyalgia

•Studies of cytokine levels in patients with fibromyalgia suggest that levels of the proinflammatory cytokines IL-1, IL-6 and IL-8 are elevated, whereas TNFα levels are normal, and levels of the antiinflammatory cytokines IL-4 and IL-10 are unchanged or reduced

•Treg are responsible for turning inflammation on and off and can help prevent an immune system from becoming overactive and eventually leading to autoimmune dysfunction

•The % of Treg that suppresses the immune response appear to be reduced in a number of stress-related diseases/conditions

https://igennus.com/practitioner-blog/nutrition-interventions-adhd-focus-treg/

Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH. Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology (Oxford). 2001 Jul;40(7):743-9.

Generaal, E. et al. Basal inflammation and innate immune response in chronic multisite musculoskeletal pain. Pain 155, 1605–1612 (2014).

IL-1β Hyperalgesia, fatigue, fever, sleep, myalgias, substance P anti-nociception (increases GABA and decreases NMDA); noradrenaline and adrenaline stimulate its release

TNFα Stress; regulates substance P expression, rapid eye movement sleep, allodynia; increases excitatory amino acids; noradrenaline and adrenaline stimulate its release

IL-1Ra Stress; inhibits IL-8 expression

IFNγ Stress, anxiety; lowers substance P; myalgias IL-2 Myalgia, cognitive dysfunction IL-4 Decreases the production of Th1 cells, macrophages, IFN-γIL-6 Stress, fatigue, hyperalgesia, depression; noradrenaline, adrenaline and substance P

stimulate its release; activates sympathetic nervous systemIL-8 Substance P stimulates production, mediates sympathetic pain IL-10 Blocks pain


Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH. Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology (Oxford). 2001 Jul;40(7):743-9.

Studies of cytokine levels in patients with fibromyalgia suggest that levels of the proinflammatory cytokines IL-1, IL-6 and IL-8 are elevated, whereas TNFα levels are normal, and levels of the antiinflammatory cytokines IL-4 and IL-10 are unchanged or reduced


FMS is common in patients with autoimmune disorders, such as systemic lupus erythematosus, Sjogren’s Syndrome, and rheumatoid arthritis and while the chemokine/cytokine patterns found in FMS patients may not be unique to FMS, it is worth considering that:

substance P induces IL-8 expression and the release of IL-6

because IL-8 promotes sympathetic pain and IL-6 induces hyperalgesia, fatigue and depression, it is hypothesised that they may play a role in modulating FMS symptoms

increased levels of inflammatory cytokines can induce glutathione depletion, which, in turn, may activate redox-sensitive transcription factors, such as NF-κB

elevated levels of cytokines activate microglia and astrocytes in the brain leading to further production of elevated cytokines and ROS/RNS causing mitochondrial and metabolic dysfunction contributing to fatigue

the subsequent ATP deficit together with inflammation and ROS/NOS are responsible for the landmark symptoms of ME/CFS/FMS, including post-exertional malaise

Morris G, Berk M, Walder K, Maes M. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses. BMC Med. 2015 Feb 6;13:28.

Morris G, Maes M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis. 2013 Dec;28(4):523-40.

CoQ10, mitochondrial function & ATP

• CoQ10 deficiency decreases the numbers of healthy mitochondria – reduced gene expression related to mitochondrial biogenesis– CoQ10 required for synthesise pyrimidine synthesis which is required for the

generation of mitochondrial DNA

• CoQ10 deficiency triggers the opening of the mitochondrial permeability transition pore (mPTP) leading to increased ROS

• Opening of mPTP causes the collapse of mitochondrial membrane potential and the production of ATP (mitochondria require a electrochemical gradient to provide the driving force for ATP production) and the induction of mitophagy

• Excessive mitophagy induces ATP-dependent apoptosis cell death thereby exacerbating ATP depletion with the potential to induce further production of pro-inflammatory cytokines

Rodríguez-Hernández A, Cordero MD, Salviati L, Artuch R, Pineda M, Briones P, Gómez Izquierdo L, Cotán D, Navas P, Sánchez-Alcázar JA. Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy. 2009 Jan;5(1):19-32.

Mitochondrial dysfunction and FMS

Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature.

Effects of coenzyme Q10 supplementation on inflammatory markers

Meta- analysis of nine RCTs involving 428 subjects (Zhai et al, 2017)

The results showed that compared with control group, CoQ10 supplementation significantly improved the serum level of CoQ10 and significantly decreased TNFα

No significant difference was observed between CoQ10 and placebo with regard to CRP or IL-6

CoQ10 supplementation may partly improve the process of inflammatory state

Meta-analysis of seventeen RCTs (Fan et al., 2017)

CoQ10 supplementation significantly reduced the levels of circulating CRP, IL-6 and TNFα

Changes of CRP were independent of baseline CRP, treatment duration, dosage, and patients characteristics

A higher baseline IL-6 level was significantly associated with greater effects of CoQ10 on IL-6 levels

Significant lowering effects of CoQ10 on CRP, IL-6 and TNFα - buy results should be interpreted with caution because of the evidence of heterogeneity and limited number of studiesFan L, Feng Y, Chen GC, Qin LQ, Fu CL, Chen LH Effects of coenzyme Q10 supplementation on inflammatory markers: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2017 May;119:128-136. Zhai J, Bo Y, Lu Y, Liu C, Zhang L. Effects of Coenzyme Q10 on Markers of Inflammation: A Systematic Review and Meta-Analysis. PLoS One. 2017 Jan 26;12(1):e0170172

The effect of CoQ10 supplementation in FMS

Miyamae T, Seki M, Naga T, Uchino S, Asazuma H, Yoshida T, Iizuka Y, Kikuchi M, Imagawa T, Natsumeda Y, Yokota S, Yamamoto Y. Increased oxidative stress and coenzyme Q10 deficiency in juvenile fibromyalgia: amelioration of hypercholesterolemia and fatigue by ubiquinol-10 supplementation. Redox Rep. 2013;18(1):12-9

Double-blind, placebo-controlled trial (FMS n=10) vs 67 healthy controls

•Plasma level of ubiquinol was significantly decreased and the ratio of ubiquinone to total coenzyme Q10 (%CoQ10) was significantly increased in juvenile FM relative to healthy controls, suggesting that FM is associated with coenzyme Q10 deficiency and increased oxidative stress

•Plasma level of free fatty acids was significantly higher and the content of polyunsaturated fatty acids (PUFA) in total free fatty acids was significantly lower in FMS than in controls, suggesting increased tissue oxidative damage in juvenile FMS

•Ubiquinol supplementation (100 mg/day for 12 weeks) resulted in an increase in coenzyme Q10 levels

•Ubiquinol supplementation also improved chronic fatigue scores as measured by the Chalder Fatigue Scale

Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):301-7.

Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, Gottfries CG. Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PLoS One. 2015 Apr 22;10(4):e0124648. doi: 10.1371/journal.pone.0124648. eCollection 2015.

Fibromyalgia, the homocysteine link and hypomethylation

Homocysteine is a natural by-product of the methylation cycle and can be remethylated to methionine or directed to the transsulfuration pathway

Increased concentrations of homocysteine have been found in the cerebrospinal fluid in patients with FMS and ME/CFS

A case of nutrient deficiencies?

Homocysteine neurotoxicity - the neurological pathologies associated with hyperhomocysteinaemia are hypothesised to be caused by oxidative stress, excitotoxicity via glutamate receptors, and via DNA hypomethylation

Homocystic acid is an oxidative product of homocysteine that functions as an excitatory neurotransmitter activating NMDA receptors and enhancing calcium influx which damages neurones, leading to cell death

Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006 May 29;580(13):2994-3005. Bukharaeva E, Shakirzyanova A, Khuzakhmetova V, Sitdikova G, Giniatullin R. Homocysteine aggravates ROS induced depression of transmitter release from motor nerveterminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia. Front Cell Neurosci. 2015 Oct 6;9:391.

Fibromyalgia, homocysteine and hypomethylation

Low levels of intrinsic factor blocks the absorption of B12, with high-risk factors for poor absorption including:

Digestive disorders such as coeliac disease, Crohn's disease, IBS & small intestinal bacterial overgrowth

Acid-reducing medications – (heartburn, GERD, acid reflux and peptic ulcers) such as proton pump inhibitors or H2 (histamine 2) receptor antagonists suppress the secretion of stomach acids but also block the secretion of intrinsic factor

Diabetes medications –Metformin, used to treat diabetes, are known to impair intestinal absorption

Ageing – the older we get the more likely we are to be deficient in B12

Vegetarian and vegan diets – B12 is only found naturally in animal foods

Pernicious anaemia – a blood disease that develops when the body lacks the intrinsic factor necessary to naturally absorb vitamin B12 from food

Methionine recycling

Methionine

SAM: universal methyl donorMethylates: neurotransmitters, proteins, RNA, DHA, catecholamines, phosphatidylcholine, melatonin, myelin, creatine

Homocysteine

SAM

SAH

Methionine synthase

5-methyl THF

THF

FOLIC ACID

CYCLE

Processes affectedNeurotransmitter function Fatty acid metabolismAllergic responsesMyelinationCellular energyCell membrane and proteinstructure and function

Cystathionine

Virus fightingInflammation regulationAntioxidant production

DetoxificationIntestinal integrity

Cysteine

Glutathione

Metallathionines Affects potent metal-

binding and redox capabilities

Cysteinesulflinic acid

Phenol sulfur-transferase

Phenol processing

DigestionDetoxification

Gut barrier

Sulfate

Sulphite

Taurine

Production of bile salts

SULPHATION

TRANSSULFURATION

METHYLATION

Magnesium

Magnesium, vitamin B6, zinc

Vitamin B6

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH ); tetrahydrofolate (THF)

Folate, VitaminsB6 & B12

Vitamin B6

Methionine is required for protein synthesis and provides a methyl group for >50 critical transmethylation reactions

Methionine recycling

Methionine

Homocysteine

SAM

SAH

Methionine synthase

5-methyl THF

THF

FOLIC ACID CYCLE

Disrupts gene expressionDecreased neurotransmitter functionDecreased myelinationDisrupted cellular energy transferDisrupted fatty acid metabolismIncreased allergic reactions

Cystathionine

Reduced detoxification of toxins and heavy metals

Cysteine

Glutathione

Metallathionines Affects potent metal-

binding and redox capabilities

Cysteinesulflinic acid

Phenol sulfur-transferase

Poor phenol processing

Poor digestion

Sulphate

Sulphite

Taurine

Production of bile salts

SULPHATION

TRANSSULFURATION

METHYLATION

Gut and blood brain barrier integrity compromised

Poor detoxification

Inactivates MAT and decreases

SAM synthesis

Villi flatten and lose function

Reduced antioxidant

function

Th1 decreasesTh2 increases

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH); methionine adenosyltransferase (MAT); tetrahydrofolate (THF)

Fibromyalgia and hypochlorhydria

• Helicobacter pylori infection/inflammation/IL-11– loss of parietal cells = hypochlorhydria/low intrinsic factor

Stomach acid:• Promotes protein digestion – feeds the amino acid pool

– Protein malabsorption issues – FMS patients appear to have low BCAA (leucine, isoleucine, and valine)

• Promotes gastric emptying– Gas, bloating/IBS/GERD

• Sterilises the stomach/ kills bacteria and yeast– Dysbiosis/candida

• Required for the absorption of certain micronutrients: calcium, magnesium, zinc, copper, iron, selenium, vitamin B12 (intrinsic factor)

Pimentel M, Wallace D, Hallegua D, Chow E, Kong Y, Park S, Lin HC A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing. Ann Rheum Dis. 2004 Apr;63(4):450-2.

Goebel A, Buhner S, Schedel R, Lochs H, Sprotte G. Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome. Rheumatology (Oxford). 2008 Aug;47(8):1223-7.

Kaufmann I, Eisner C, Richter P, Huge V, Beyer A, Chouker A, Schelling G, Thiel M. Lymphocyte subsets and the role of TH1/TH2 balance in stressed chronic pain patients. Neuroimmunomodulation. 2007;14(5):272-80.

http://www.rothwellness.com/wp-content/uploads/2015/04/leakygut.jpg

Dysbiosis, leaky gut and FMS

The pain intensity of patients with FMS has been reported to be correlated with the degree of small intestinal bacterial overgrowth (SIBO) - abnormal lactulose breath test

SIBO is often associated with an increased intestinal permeability (leaky gut)

Leaky gut leads to the exposure of immune cells to luminal antigens and consequent immune modulation

FMS is often associated with a reduction of cytotoxic T lymphocytes and a diminished Th1 response

Inflammation, leaky gut and FMS

FMS is an extremely heterogeneous entity and patients differ in their clinical symptoms, endocrine and immune parameters; however:

•NF-kB, proinflammatory cytokines and oxidative and nitrosative stress (ROS/RNS), can lead to a disruption of epithelial tight junctions in the intestine allowing translocation of gram-negative bacteria, containing lipopolysaccharides, into the circulation, stimulating TLR4 mediated pathways (hypersensitive microglia often appear in FM and ME/CFS)

•Prolonged and or excessive stimulation of membrane bound TLR4 results in the further production of pro-inflammatory cytokines and ROS/RNS

•Increasing levels of ROS/RNS damage mitochondrial lipids and proteins leading to dissipation of the mitochondrial membrane potential and inhibition of the electron transport chain

•This leads to compromised oxidative phosphorylation and to the further production of ROS, making another major contribution to the inflammatory milieu related to fatigue

Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature.

BBA Clin. 2014 Jun 1;1:12-23. Schulzke JD, Ploeger S, Amasheh M, Fromm A, Zeissig S, Troeger H, Richter J, Bojarski C, Schumann M, Fromm M. Epithelial tight junctions in intestinal inflammation. Ann N Y Acad Sci. 2009 May;1165:294-300.

Oxidative stress – cause or consequence?

Oxidative and nitrosative stress take part in the pathogenesis of pain

Superoxide radicals induce an alteration of nociceptions through peripheral and central nervous system sensitisation and are implicated in the activation of several cytokines including TNFα and IL-1β which are involved in inflammatory pain

Substance P, which is co-released with glutamate during nociception, has been shown to increase the permeability of the blood–brain barrier (normally protects the brain from high plasma concentrations of dietary glutamate )

The balance of oxidants/antioxidants has been demonstrated in FMS• Glutathione and catalase levels significantly lower• Significant correlation between serum nitric oxide level and pain• Significant correlation between glutathione level and morning stiffness

Cordero MD, Díaz-Parrado E, Carrión AM, Alfonsi S, Sánchez-Alcazar JA, Bullón P, Battino M, de Miguel M. Is inflammation a mitochondrial dysfunction-dependent event in fibromyalgia? Antioxid Redox Signal. 2013 Mar 1;18(7):800-7.

Sendur OF, Turan Y, Tastaban E, Yenisey C, Serter M.Serum antioxidants and nitric oxide levels in fibromyalgia: a controlled study. Rheumatol Int. 2009 Apr;29(6):629-33.

https://www.ncbi.nlm.nih.gov/pubmed/18853166

https://www.ncbi.nlm.nih.gov/pubmed/18853166

Candida, leaky gut and FMS• Candida problems arise when the benign yeast form of Candida

albicans mutates to its fungal form which produces toxins that create holes in the intestinal lining, leading to leaky gut syndrome and an inflammatory immune system response

Kumamoto C.A. Inflammation and gastrointestinal Candida colonization Curr Opin Microbiol. 2011 Aug; 14(4): 386–391.http://docmontagne.com/index.php/candida-leaky-gut/

• In addition to FMS, a wide range of disorders have been linked to Candida including autism, multiple sclerosis, depression, and CFS/ME

• Use of antibiotics, oral contraceptives, and anti-inflammatory steroids greatly increase susceptibility to Candida

The impact on thyroid health - the prevalence of FMS in patients with autoimmune thyroid disease has been estimated to be ~30%

Common deficiencies of micronutrients such as iron, selenium, vitamin A and zinc may interact with iodine nutrition and thyroid function

• Iron absorption is dependent on the presence of adequate stomach acid

• Iron is required for thyroid peroxidase activity involved in the addition of iodine to tyrosine, and thus the manufacture of T4 and T3

• Selenium is required for deiodinase enzyme activity (required for T4 to T3)

Iron deficiency goes hand in hand with low thyroid activity because low thyroid activity worsens iron deficiency

If you have thyroid issues, just taking iron may not be enough to replenish iron levels because people with low thyroid hormones have issues absorbing iron (they can’t make enough stomach acid)

If you don’t absorb iron then it lowers the ability to make thyroid hormone – and so you get a vicious cycle!

Zimmermann MB, Köhrle J. The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. Thyroid. 2002 Oct;12(10):867-78. Review.

Fibromyalgia and obesityEpidemiological studies suggest that ~40% FMS patients are obese and ~30% overweight

•Leptin is secreted by the White Adipose Tissue (WAT) and is hyperexpressed in obese patients•Leptin has a decreasing effect on pain threshold •Leptin may modulate the stress response and may increase nociception

Ursini F, Naty S, Grembiale RD. Fibromyalgia and obesity: the hidden link. Rheumatol Int. 2011 Nov;31(11):1403-8.

• Obesity leads to higher levels of proinflammatory cytokines and increased indoleamine 2,3-dioxygenase (IDO) activity

• Circulating kynurenine concentration and kynurenine/tryptophan ratio are enhanced in obesity

Serotonin

IDOIFN-γ , TNF-α ,

IL-1, IL-6

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

+

+

KMO

5-HTP

Neuronal damage Depression

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Sleep disturbanceIDO : indoleamine 2,3-dioxygenase KMO : kynurenine monooxygenase

Glutamate

• The traditional drugs of choice, including NSAIDS, antidepressants, muscle relaxants, tranquilisers and pain medications, may provide short-term relief for some individuals but do not address the cause and their side-effects may potentially cause more symptoms than they help

• However, multimodal pain management including intensive physical therapy, exercise, counselling and sleep hygiene have been shown to be somewhat effective in managing fibromyalgia-related symptoms

• What about dietary interventions?

Foods to avoid: – Highly processed/highly refined foods– Additives and artificial sweeteners – Sugar/refined carbohydrates– Monosodium glutamate (MSG) and aspartame

Fibromyalgia interventions

Tests?

• Homocysteine• Stool test• Stress/cortisol test• Organic acids• Food allergy• Omega-3/6• Vitamin D

Managing fibromyalgia

Gut support

Mitochondrial support

Methylation support

Thyroid support

Adrenal support

‘Anti-inflammatory’ diet protocol

Increase antioxidants

Address gut health

Issue: disrupted gut function leads to excess inflammation in the gut lining and changes in the normal gut flora (dysbiosis/candida)Solution: Restore normal gut flora with supplemental probiotics: Lactobacillus rhamnosus - helps repair leaky gut, reduces vaginal discharge and candida cell numbersLactobacillus reuteri reduces vaginal discharge and candida cell numbersBifidobacterium longum - ferments sugars into lactic acid that increase the acidity of the intestine and inhibit the reproduction of many harmful microbes (candida prefers an alkaline environment)Bacteroides fragilis induces Tregs Lactobacillus fermentum - antimicrobials that inhibits the growth of some harmful pathogensSaccharomyces Boulardii yeast & colostrumInclude natural probiotics (lactobacilli and bifidus bacteria) derived from food such as: kefir (goat’s milk and fermented kefir grains), sauerkraut (fermented cabbage), miso and tempeh (both from fermented soya beans), kimchi (Asian form of pickled sauerkraut)L-glutamine (L-alanyl-L-glutamine) fuels gut cells and boosts immunityInulin from chicory root (prebiotics- bacteria food!)

Issue: overuse of Antibiotics, NSAIDS,Consequence: disrupted gut function leads to excess inflammation in the gut lining and changes in the normal gut flora (dysbiosis/candida)Solution: Increase nutrients known to support gut heath, mucus production, support

tight junctions and secretory immunoglobulin type A (SIgA) levels

L-glutamine (L-alanyl-L-glutamine) fuels gut cells (preferred fuel source) and boosts immunityPau d'arco is a great antifungal Coconut oil/MCTsProtein powder (provides essential amino acids) - protein requirements increase during times of increased stress/illness/inflammationN-acetyl glucosamine is anti-inflammatory and helps protect the lining of the stomach and intestinesIncrease natural stomach acid production by drinking water with a slice of lemon, a squeeze of lemon juice or a teaspoon of apple cider vinegar / betaine HCl supplements/high dose ascorbic acidGarlic (Allicin MAX) for Helicobacter pyloriMushrooms rich in beta glucans such as reishi, shiitake and maitakeBone broth / gelatine / collagenVitamins D3 and A -SigAAloe vera/liquorice/quercetinDigestive enzymes

Issue: Western-style diet (highly processed refined foods, high fat and high added sugar)Consequence: Lack of nutrients required to maintain a healthy gut flora result in dysbiosisSolution: Adopt a whole-food diet (exclude processed/refined foods) that provides the nutrients required to feed healthy gut flora, boost immunity and support liver function (detox)Choose foods with a low glycaemic index (GI) that release natural sugar slowly.

Issue: Stressful lifestyleConsequence: Chronic long-term stress increases inflammation and suppresses immune functionSolution: Take actions to reduce stress:Adopt breathing techniquesIncrease physical activity ‘Mindful’ meditation

Issue: Compromised nutrient absorption (i.e. iron deficiency) Another problem with leaky gut is that it can cause malabsorption of vital minerals and nutrients including zinc, iron and vitamin B12.Solution: Supplement with digestive enzymesEat a good supply of raw foods as these will be naturally rich in digestive enzymes (normally lost via cooking and heating) and boost immunity and support liver function (detox)

Olive oil

Fruit

Vegetables

Oily fish

Nuts & seeds

Legumes & cereals

Monounsaturated fat (oleic acid)

Antioxidants (i.e. polyphenols)

Vitamin A,B,C & E

Vitamin D

Omega-3 fatty acids(ALA, EPA & DHA)

Minerals (i.e. selenium, iron &

iodine)

Amino acids (i.e. taurine, tyrosine &

tryptophan)

Moderate red wine

Lean meat

Moderate dairy

Neuronal survivalEnergy metabolismNeurotrophinsNeurotransmissionMembrane fluidityCell membrane integrity Glucose transportNutrient synthesisNutrient metabolismGene expressionMethylationCerebral blood flow

Blood pressureOxidative damageNeuronal cell deathNeuroinflammationFree radicals

Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.

Focus on clean eating / maintain a healthy weight

Adrenal support Avoid sugar/ artificial sweeteners Avoid caffeine Focus on a ‘clean diet’ High-protein, low carbohydrate breakfast Eat every 3-4 hours to maintain optimal blood sugar levels Rest!

B-Complex Vitamin C Magnesium Liquorice root Ashwagandha Siberian ginseng Rhodiola rosea DHEA

Increase glutathione levels

Up-regulate glutathione-related enzymes including glutathione reductase (GR) and glutathioneS-transferase (GST) - anthocyanins are members of the flavonoid group of phytochemicals, a group predominant in teas, honey, wine, fruits, vegetables, nuts, olive oil & cocoa

Cruciferous vegetables such as broccoli, kale and cabbage contain antioxidants that increase the production of detoxifying enzymes in the body

Sulphur-rich foods such as onions and garlic, cauliflower, eggs, Brussels sprouts & broccoli

Cysteine-rich foods: soya beans, egg white, oats & tofu, providing the body with the balance of nutrients that make (glutathione = L-cysteine + L-glutamic acid + glycine)

The health promoting effects of Longvida curcumin in healthy individuals

Longvida curcumin Lowered β-amyloid protein: a marker of brain ageing, especially in relation to

Alzheimer’s disease Lowered triglycerides: related to increased risk of poor cardiovascular

health Soluble intercellular adhesion molecule (sICAM): linked to

atherosclerosis Salivary amylase: a marker of sympathetic nervous system stress Alanine aminotransferase (ALT): a marker of liver injury

Longvida curcumin Increased Catalase activity: an antioxidant enzyme Antioxidant status: linked to lower levels of damaging free radicals

DiSilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J. 2012 Sep 26;11:79. doi: 10.1186/1475-2891-11-79.

In a 30 day, randomised placebo-controlled trial, daily supplementation with 400mg Longvida curcumin in healthy, middle-aged individuals (40-60 years) led to significant (p<0.05) improvements (versus placebo) in the following markers:

Supporting antioxidant defences

Alpha lipoic acid is an endogenous antioxidant and essential cofactor for many enzyme complexes that interrupt cellular oxidative processes

Increases acetylcholine production by activation of choline acetyl-transferase Increases glucose uptake Acts as a metal chelator Down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF-α and inducible nitric oxide synthase Scavenges lipid peroxidation products such as 4-hydroxynonenal (HNE) and acrolein

Vitamin EAntioxidant protection Vitamin C Further supports detoxification, provides antioxidant protection against free radicals Reduces tiredness and fatigueNecessary for the proper functioning of the CNS and psychological functioning

(lui, 2007; Moreira et al., 2007; Maczurek et al., 2008; Salinthone et al., 2008)

•Magnesium blocks the NMDA receptor and must be removed in order for excitation to occur

•Zinc is co-released with glutamate into the synaptic cleft, and is thought to negatively modulate the excitatory response

•A deficiency in vitamin B6 can lead to higher levels of glutamate and reduced levels of GABA inhibition, thereby facilitating excitotoxicity

•Thus, low magnesium, zinc and or vitamin B6 levels could support excitotoxicity

Magnesium, B6 and zinc modulate glutamatergic neurotransmission and key role in regulating the NMDA receptor, the main glutamate receptor implicated in excitotoxicity

Holton K. The role of diet in the treatment of fibromyalgia.Pain Manag. 2016 May;6(4):317-20

Holton KF, Taren DL, Thomson CA, Bennett RM, Jones KD. The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms. Clin Exp Rheumatol. 2012 Nov-Dec;30(6 Suppl 74):10-7.

Zinc •Essential to the production of neurotransmitters•Enhances neurotransmission via interaction with receptors, transporters and ion channels in the neurone and synapse•Low zinc status is linked to cognitive impairment via epigenetic changes of the brain-derived neurotrophic factor (BDNF) gene

Selenium•Up-regulates glutathione production•Main component of antioxidant enzymes•Supports proper adrenal function – commonly disrupted by high stress and poor diet – leads to poor sleep, memory problems and fatigue • Low selenium status is a risk factor for cognitive declineBerr C, Arnaud J, Akbaraly TN. Selenium and cognitive impairment: a brief-review based on results from the EVA study. Biofactors. 2012 Mar-Apr;38(2):139-44.

Hu YD, Pang W, He CC, Lu H, Liu W, Wang ZY, Liu YQ, Huang CY, Jiang YG. The cognitive impairment induced by zinc deficiency in rats aged 0 2 months related to BDNF DNA ∼methylation changes in the hippocampus. Nutr Neurosci. 2016 Jun 22:1-7.

Pharmepa RESTORE provides 1000 mg pure 90% concentration, rTG EPA wild anchovy oil, in just two easy-to-swallow capsules

Pharmepa RESTORE provides a loading dose of super strength EPA and is ideal for people who have never supplemented with pure EPA or those who have taken a break from omega-3 EPA supplementation

Pharmepa MAINTAIN combines 80% concentrated rTG EPA (750mg) plus DHA (250mg) wild anchovy oil with GLA and triterpenes from organic virgin evening primrose oil and vitamins D3 & E

Pharmepa MAINTAIN protects the structure and function of our cells and helps maintain an optimal AA to EPA ratio, omega-6 to omega-3 ratio and omega-3 index

Pharmepa MAINTAIN is suitable for long-term use after supplementing with pure EPA

•Magnesium blocks the NMDA receptor and must be removed in order for excitation to occur

•Zinc is co-released with glutamate into the synaptic cleft, and is thought to negatively modulate the excitatory response

•A deficiency in vitamin B6 can lead to higher levels of glutamate and reduced levels of GABA inhibition, thereby facilitating excitotoxicity

•Thus, low magnesium, zinc and or vitamin B6 levels could support excitotoxicity

Magnesium, B6 and zinc modulate glutamatergic neurotransmission and have a key role in regulating the NMDA receptor, the main glutamate receptor implicated in excitotoxicity

Holton K. The role of diet in the treatment of fibromyalgia.Pain Manag. 2016 May;6(4):317-20

Holton KF, Taren DL, Thomson CA, Bennett RM, Jones KD. The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms. Clin Exp Rheumatol. 2012 Nov-Dec;30(6 Suppl 74):10-7.

• YNERGISTIC ACTIONS between Mg and B6 for enhanced absorption

• SUSTAINED RELEASE tablets and split dosing for enhanced absorption & optimal tissue distribution

• CONSISTENT PRODUCT QUALITY GUARANTEED GMP manufactured - quality standards that medicines manufacturers must meet in their production processes to ensure products are of consistent high quality

• SUITABLE FOR VEGETARIANS & VEGANS

• PIONEERING EFFECTIVE FORMULATION based on cutting edge research, specialist delivery technologies and innovation in raw ingredients

Key product features:• HIGHLY BIOAVAILABLE Neurobalance™ delivers maximum levels of key nutrients:

Chelated zinc as super absorbable zinc L-methionine Fully reacted magnesium citrate provides high levels of super absorbable elemental magnesium Vitamin B6 as pyridoxal-5-phosphate with cofactor activity

Serving size: 1 capsule Per serving % RI*Longvida® optimised curcumin extract from turmeric root (min. 20% curcuminoids)

500 mg n/a

DIRECTIONS FOR USEAdults: take 1 capsule daily with food. For intensive support, take 2 capsules daily as a split dose. Do not exceed the dose unless advised by a healthcare practitioner.

NUTRITIONAL INFORMATION

INGREDIENTS: Longvida® optimised curcumin extract; capsule shell (emulsifier: hydroxypropyl methylcellulose); stearic acid; soy lecithin; maltodextrin; ascorbyl palmitate; silicon dioxide.

Free from: dairy, gluten, lactose, soya protein, wheat, yeast, artificial colours and flavours; not tested on animals; non-GMO; suitable for vegetarians & vegans; halal & kosher.

* % Reference Intake

Product information

Serving size: 2 tablets Per serving %Reference Intake

Vitamin C (ascorbic acid) 240 mg 300

Vitamin B3 (nicotinamide) 48 mg NE 300

Zinc citrate 20 mg 200

Vitamin B5 (pantothenic acid) 18 mg 300

Vitamin B6 (pyridoxal 5-phosphate) 8 mg 570

Iron (ferrous bisglycinate chelate) 7 mg 50

Vitamin B1 (thiamine HCl) 5.5 mg 500

Vitamin B2 (riboflavin 5-phosphate) 4.2 mg 300

Vitamin E D-alpha tocopherol (natural) 2 mg a-TE 16.6

Boron (disodium tetraborate) 2 mg n/a

Manganese bisglycinate 2 mg 100

Copper bisglycinate 1 mg 100

Vitamin A (beta carotene) 800 mg 100

Folate ([6S]-5-methyltetrahydrofolate) 200 mg 100

Selenomethionine 110 mg 200

Iodine (kelp) 150 mg 100

Vitamin B7 (biotin) 100 mg 200

Chromium picolinate 50 mg 125

Molybdenum 50 mg 100

Vitamin K2 (menaquinone) 37.5 mg 50

Vitamin B12 (methylcobalamin) 20 mg 800

Vitamin D3 (cholecalciferol) 10 mg (400 iu) 200

MULTIVITAMIN & MINERALS™ provides 22 key essential vitamins & minerals in superior body-ready and active forms for enhanced absorption and utilisation. Our sustained slow release system optimises blood nutrient levels for longer-lasting action.

VESIsorbTM Oil-based

Time (hours)

VESIsorbTM

Therapeutic level

VESIsorbTM delivered CoQ10 is absorbed FASTER, reaching concentrations that are STRONGER and stays in the body LONGER than generic delivery methods

Fully reduced form of CoQ10VESIsorb® technology for enhanced bioavailability and tissue distribution100 mg therapeutic dose

Oil-based

Cmax

Tmax

MindCare LIFTNutritional information Per capsule % reference

intakeMagnesium glycinateof which magnesium

334 mg60 mg 16

5-HTP 100 mg n/aVitamin B3 (niacin) 48 mg 300Vitamin C (ascorbic acid) 40 mg 50Zinc (citrate) 20 mg 200Vitamin B5 (pantothenic acid) 12 mg 200Vitamin B6(pyridoxal-5-phosphate)

7.98 mg 570

Vitamin B1 (thiamine) 3.3 mg 300Vitamin B2 (riboflavin) 2.8 mg 200Vitamin B7 (biotin) 150 mg 300Folate ([6S]-5-methyltetrahydrofolate)

100 mg 50

Selenium 82.5 mg 150Vitamin B12 (methylcobalamin) 20 mg 800

Nutritional information Per capsule % reference intake

Omega-3 rTG concentrated fish oilof which: EPA (eicosapentaenoic acid) DHA (docosahexaenoic acid)

893 mg

410 mg250 mg

n/a

Vitamin E (d-alpha tocopherol) 6mg 50Vitamin D3 25 mg 500

Education Technical

Sophie TullyNutrition Education Manager

[email protected]

Dr Nina Bailey Head of Nutrition

[email protected] @DrNinaBailey

mailto:[email protected]

fibromyalgia: a clinical approach

Health & Medicine