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Fibromyalgia Syndrome – FMS Part 2

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Effect of a Novel Medical Food Containting Spent Hops and Pomegranate and Prune Extracts to Address Symptoms Associated with Fibromyalgia

Musculoskeletal pain syndromes, such as fibromyalgia (FM), are often characterized by an increased sensitivity to chemicals and toxins, including heavy metals—which have been shown to trigger or exacerbate debilitating symptoms. Theoretically, impaired detoxification may play a role in FM and related syndromes. An increased toxic burden can lead to oxidative stress, neuropathic pain, increased cytokine induction, and mitochondrial dysfunction, all of which have been associated with FM.

Preliminary in vitro studies conducted at MetaProteomics®—the proteomics research arm of Metagenics, Inc.—identified key botanicals that positively influence upstream signaling pathways and enzymes in heavy metal metabolism (e.g., GST, NQO-1, Nrf-2, HO-1, metallothionein). These botanicals were then combined with nutrients and macronutrients that support hepatic detoxification function in a low-allergen-potential, rice protein-based medical food for clinical testing.

Researchers at the Functional Medicine Research CenterSM, the clinical research arm of Metagenics, Inc., conducted a preliminary study to determine the effects of an intervention with this medical food and a modified elimination diet on functioning in FM patients with dental amalgams that may be associated with increased toxic burden and symptomatology.

This preliminary research suggested a positive influence on creatinine-adjusted mercury clearance and genetic expression of metallothionein, as well as an improvement in scores for FM surveys of functionality and quality of life. This medical food and a modified elimination diet may offer a promising approach for investigational use in patients presenting with musculoskeletal pain of unknown etiology.ADDRESSING CHRONIC MUSCULOSKELETAL PAIN OF UNKNOWN ETIOLOGY
Some reports suggest that 30% to 80% of patients may have conditions for which no physiological or organic cause can be found during routine investigation.1 This includes chronic musculoskeletal pain syndromes such as FM—with associated symptoms that fail to demonstrate consistent relationships to routine biological markers used in clinical practice.2 While generally not life-threatening, these conditions significantly impact the quality of life of a sizeable population.
FM is primarily characterized by widespread, nonarticular musculoskeletal pain and generalized tender points, and may be accompanied by symptoms that include fatigue, sleep dysfunction, stiffness, depression, anxiety, cognitive disturbance, memory impairment, and intolerance to exercise.3-8 FM is difficult to distinguish from other pain syndromes with similar symptoms and has a high degree of comorbid disorders—particularly with chronic fatigue and immunodeficiency syndrome (CFS/CFIDS), migraines, and multiple chemical sensitivities (MCS).6-11COMMON THERAPY SHORTFALLS—ADVERSE EVENTS & LACK OF RELIABILITY

While there are many theories regarding the etiology of FM, few therapies have resulted in demonstrable, predictable improvement. In fact, an effective treatment—defined as > 50% of patient population receiving benefit—has yet to be found.4 An estimated 40% to 50% of FM patients are on multiple pain-related pharmacotherapies; no combination of these therapies, however, have been tested.7,11

The failure of common anti-inflammatory approaches—which carry the risk of adverse effects with long-term use—supports a lack of findings of underlying joint damage or inflammatory signs associated with rheumatological disorders.4 Other commonly relied upon approaches target relief for pain and other symptoms attributed to neuropathic origin (e.g., serotonin, norepinephrine, GABA), and a few target inhibition of pain receptors in the central nervous system.4,5,7,12,13

While some approaches may attenuate pain and/or improve mental well-being or sleep patterns, they fail to address the underlying causes of FM and carry a risk of well-known adverse effects.7 Most importantly, however, they fail to offer reliable treatment responses or long-term evidence of efficacy for improving functionality and/or quality of life.4,5 And, to date, there are no specific therapeutic recommendations for non-responders.12

Because single modality therapies offer limited benefit, multiple modalities are often suggested for these challenging cases.14 Clinicians typically rely on a multi-disciplinary approach to FM that may include pharmaceuticals, cognitive behavioral therapy, and self-management techniques, such as stress management, diet, and exercise, including flexibility or strength training.4,5 Other suggested and commonly applied therapies for FM include chiropractic, massage therapy, acupuncture, and weight loss programs.5,14

While pain is the main symptom of FM, clinical experience demonstrates the use of questionnaires that evaluate other aspects, including fatigue and functioning, when assessing response to FM therapies.5,12,13,15,16A FUNCTIONAL MEDICINE APPROACH TO FM
Pharmaceutical interventions typically focus on individual
symptoms, while FM is often multiple symptoms. In fact, literature suggests that a “diversity of biology” may be related to FM.The syndrome has also been recommended for classification as “multiplicitous” rather than defining its common comorbidities.12

The functional medicine model postulates that complex diseases can be better understood by exploring dysfunction in basic physiological processes. An understanding of these disturbances—and the therapies used to help restore balance—may provide valuable tools in understanding complex chronic disease. Neuroendocrine aberration, sleep disruption, sympathetic nervous system disruption, neurochemical abnormalities, traumatic and immunological processes, static problems, and HPA axis imbalance and psychological conditions (e.g., depression, anxiety, stress) have all been implicated in the etiology of FM.3,11,13,17,18HEPATIC DETOXIFICATION MAY OFFER SYMPTOM RELIEF

One dysfunction that may provide insight to FM etiology is the dysregulation of basic detoxification processes. Some literature suggests an association between impaired detoxification and certain diseases, including FM and CFS. Accumulated data suggest that the ability to remove toxins may play a role in the etiology or exacerbation of a range of chronic diseases and conditions.19

Clinical and case management studies with programs that include support for hepatic detoxification at the Functional Medicine Research Center have shown therapeutic value in reducing symptomatology associated with CFS, and have also been utilized for patients presenting with chronic musculoskeletal pain—with or without a formal diagnosis of FM.

Hepatic detoxification occurs in 2 primary phases:

  • Phase I bioactivation generates a reactive site on the molecule, similar to that of reactive oxygen species, enabling it to bind to other molecules such as DNA and proteins.
  • Phase II conjugation reactions—which include glucuronidation, sulfation, glutathione conjugation, amino acid conjugation, methylation, and acetylation—convert the potentially more toxic, reactive intermediate generated in Phase I into
    a non-toxic molecule ready for excretion.

Current research suggests that the body’s detoxification system is a nutrient-supported process that requires macronutrients (to help reduce dietary obstacles to detoxification) and targeted micronutrients (to help replenish nutritive cofactors in Phase I and Phase II detoxification pathways).

Therefore, simple juice or water fasting is no longer a preferred method. In fact, prolonged fasting may weaken muscles and deplete energy stores—already compromised in FM—due to protein losses and severely reduced caloric intake.

Chemical & Heavy Metal Sensitivity. It has been suggested that
certain environmental factors may trigger development of FM and related conditions in genetically predisposed individuals, and chemical and environmental sensitivities are common in these disorders.3,8-10,14,17,19,20 In fact, 47% to 67% of FM patients report increased symptoms, primarily pain, following specific environmental chemical exposures.8,10

This increase in pain transmission has been postulated to be a result of central nervous system malfunction, which has been linked to chemical insensitivities along with pain attributed to neurogenic inflammation and immune activation.3,6,10 Cytokine release due to immune activation has been recognized to cause functional symptoms associated with FM, such as sleep disturbances, cognitive dysfunction, fatigue, stress, and anxiety.20,21

Elevated levels of cytokines (e.g., TNF-∂, IL-1, IL-6, IL-8, IL-10) have been observed in FM studies.9,11,20,21

Even short-term stress of a chemical exposure has been suggested to
lead to chronic pathology.9 And a growing body of peer-reviewed scientific evidence suggests an association between long-term exposure to heavy metals with an increasing number of adverse health effects. Metal sensitivity may be determined by individual genetic predisposition. Monozygous twins with CFS, for example, have been shown to display an identical pattern of metal sensitivity; these findings are also supported by animal studies.19

Chronic exposure to corrosion products of dental metals (e.g., mercury)
or to metals in general has been suggested in some literature to trigger symptoms in those who are sensitive; and a greater number of dental amalgams has been associated with a greater mercury concentration in blood and urine.19,22,23 While amalgam removal is generally not advocated in the U.S., a few studies have demonstrated relief of fatigue and FM symptoms after extraction.19,24-26

In addition to fatigue, mercury (in dental amalgams or otherwise)
has also been associated with porphyrin disturbances, allergic and autoimmune symptoms, and symptoms of neurotoxicity, such as depression and impairment of vision, manual dexterity, and memory.23-28

Subjects with FM and other myalgic syndromes have demonstrated increased sensitivity not only to mercury, but also nickel, gold, cadmium, palladium, aluminum, lead, platinum, and silicon.19,25,29

The Role of Metallothionein. The cellular protein metallothionein (MT) transports zinc and copper and plays a crucial role in the chain of activities leading to the excretion of toxic metals. The body’s natural chelating agent, MT efficiently binds to several toxic metals for delivery to the liver or kidneys for conjugation and excretion. MT further serves to prevent the reaction of these metals with other biomolecules, thereby attenuating their toxicity and the release of gaseous mediators such as hydroxyl radicals and nitric oxide.30-36 Increased production of reactive oxygen species (ROS) and reduced oxidative capacity has been identified in FM and related conditions. One theory is that elevated nitric oxide stimulates nociceptors and may be the etiology of associated muscle and joint pain symptoms.4,9,37

MT is induced by inflammation and other stress responses, including the stress of exposure to heavy metals.33,35,36 One study with MT-deficient
mice demonstrated nonspecific chronic inflammation after repeated exposure to cadmium.35 Some evidence suggests that MT may help modulate the immune system.33NUTRIGENOMIC AGENTS FOR SYMPTOM RELIEF
Key Nutrients. The novel medical food is specifically formulated for FM patients who may benefit from additional nutritional support to address altered pain signaling and neuromuscular function, as well as Phase II hepatic detoxification and other metabolic functions. These ingredients have demonstrated safety for long-term use in individuals for chronic exposure to toxins—helping lessen that exposure and facilitate elimination.

  • Essential amino acids. In addition to muscle tissue abnormalities and dysfunction, lower plasma levels of branched-chain amino acids (BCAAs) have been recorded in FM.18,38 To provide a more complete protein source, the low-allergen-potential rice protein base is fortified with additional amino acids L-lysine, L-threonine, L-DL- methionine, L-glycine, L-glutamine, and L-cysteine to aid in:
    • Energy production. Amino acids provide the primary
      energy source for skeletal muscles. Lower levels of ATP and mitochondrial metabolism dysfunction have been reported in FM, which may contribute to fatigue symptoms.4,9
    • Phase II sulfation. Research suggests that sulfur-containing amino acids (e.g., methionine, cysteine) positively influence synthesis of SAM-e, glutathione S-transferase (GST), taurine, and N-acetylcysteine.14,39 Individuals with mercury exposure may also benefit from protein supplementation, since mercury exposure has been associated with cysteine depletion.40
    •  Phase II enzyme conjugation. Glycine is a unique amino acid used in the synthesis of GST (which can be depleted by heavy metals) and is a cofactor in Phase II amino acid conjugation reactions.41 GST also supports a major detoxification pathway for heavy metals, which bind to GST’s sulfhydryl group.42,43
  • Antioxidant nutrients. Vitamins A, C, E, and beta-carotene possess antioxidant activity and reduce the potential for damage caused by intermediate metabolites and other oxidative molecules generated during Phase I activity.44 Lower levels of antioxidants have been associated with FM, and antioxidant therapies have been suggested to offer positive effects on mitochondrial performance.9,37,45
  • Pantothenic acid. Vitamin B5 is provided to help facilitate the production of ATP, which is necessary for adequate biotransformation of toxins into non-toxic molecules.46
  • Zinc. This important mineral has been shown to reduce oxidative stress uring heavy metal detoxification, whereas low zinc intake may increase their toxic effects.47 Proprietary and third-party laboratory research suggest that zinc induces genetic expression of metallothionein. A recent study suggests that reduced magnesium and zinc levels may contribute to pathophysiology of FM, particularly tender points and fatigue.48
  • Watercress. Glucosinolates found in watercress (Nasturtium officinale) are precursors of phenythyl isothicynate (PEITC) and sulphoraphane, which have been demonstrated in third-party studies to effectively inhibit the overinduction of specific cytochrome P450 enzymes and enhances GST and NQO-1 induction.49-51

Novel Active Botanicals. Research suggests the role of gene polymorphisms in the etiology of FM.3 Preliminary laboratory studies conducted at MetaProteomics—the proteomics research arm of Metagenics, Inc.—demonstrated that the key botanicals and zinc in the novel medical food positively modified upstream signaling pathways. Individual active ingredients have been shown in vitro to induce genetic expression of metallothionein (MT mRNA) and beneficially influence Phase II enzymes (GST, NQO-1) and activators (Nrf-2, HO-1) associated with the antioxidant response element (ARE) and metal response element (MRE)—transcriptional elements that induce toxic element metabolism and hepatic detoxification. (In accordance with scientific literature, those compounds considered active were shown to demonstrate ≥ 20% activity induction over the control compound.)52

  • Spent Hops. Hops (Humulus lupulus) have been used in traditional medicine for centuries to reduce anxiety and aid relaxation and sleep. Emerging research has shown that an active constituent of spent hops demonstrates antioxidant protection against ROS. Spent hops have also been the subject of preliminary ex vivo (human cell line) and in vivo (animal and human) studies and shown to reduce pain-associated markers in a manner that suggests potential investigation for use in pain-associated disorders.53,54
    • Preliminary in vitro findings:
      Spent hops was shown to induce MT mRNA expression, HO-1 and NQO-1 activity, and Nrf-2 translocation.52
  • Prune Skin Extract (Prunus domestica). Prunes are a rich source of antioxidant compounds that have been studied for application in a number of conditions characterized by oxidative stress.55,56
    • Preliminary in vitro findings:
      Prune skin extract was shown to induce NQO-1 activity.52
  • Pomegranate Extract (Punica granatum). This antioxidant-rich fruit contains ellagic acid, which has also been demonstrated in published studies to beneficially modulate Phase I biotransformation and enhances Phase II GST and NQO-1 enzyme induction.57-59 It also scavenges superoxide radicals and hydroxyl radicals, reducing hepatic oxidative stress.59,60
    • Preliminary in vitro findings:
      Pomegranate extract induced GST activity.52

Table 1. Preliminary in vitro research at MetaProteomics demonstrated active induction of MRE and ARE transcriptional elements with spent hops, prune extract, and pomegranate extract. Zinc, which has shown positive modulation of detoxification activities in numerous third-party studies, was used for comparison during this proprietary in vitro research.

Researchers at the Functional Medicine Research Center (FMRC), the clinical research arm of Metagenics, Inc., conducted preliminary clinical research
to determine the effects of a lifestyle intervention with the novel medical food and modified elimination diet on indicators of quality of life in FM patients. They also wanted to evaluate the effects of the program on markers of heavy metal metabolism in subjects with dental amalgams, suggested by some research to be a potential indicator of increased toxic burden.61

Methodology. An 8-week pilot study—a 4-week control phase
followed by a 4-week intervention phase—was conducted
with 8 female subjects who met the following criteria:

  • Diagnosis of FM
  • Frequent musculoskeletal pain over last 3 months
  • Tenderness in at least 11 of 18 tender point sites on digital exam (as defined established American College of Rheumatology criteria)62
  • 4 or more current dental amalgams

The control phase consisted of 4 weeks of a Standard American Diet
(high in animal fats and processed foods) and twice daily supplemen-tation with a dietary supplement providing primarily macronutrients.  The treatment phase consisted of 4 weeks of a modified elimination diet and twice daily supplementation with the novel medical food, provided in a powdered form for administration as a beverage.

Note: Seafood was excluded from the diets in both phases due to its potential mercury content to avoid unnecessary influence on study results.

Results. The intervention demonstrated a trend toward greater effects on subjective measures of quality of life and biomarkers of detoxification and heavy metal excretion. Results are presented as a mean of visits 5-7 versus baseline measurements (visit 1), unless otherwise noted.

Efficacy endpoints evaluated during the study included the Fibromyalgia Impact Questionnaire (FIQ), the Medical Symptoms Questionnaire (MSQ), the FibroQuest questionnaire, urinary creatinine-adjusted mercury excretion, and genetic expression of metallothionein (MT mRNA).

  • FIQ Score. Because pain is highly variable in FM, FIQ is deemed the most common measure of function and is used extensively as an index of therapeutic efficacy (available at www.myalgia.com/FIQ/FIQ_B. htm). It includes 10 subscales that assess physical function, common FM symptoms, and general well-being over the previous 7 days.5,16
    • Intervention demonstrated a 21% mean improvement in FIQ total score.
    • A reduction of 20 points or more has been suggested as an indicator of clinically significant outcomes in FM patients.5 (See Subgroup Analyses below.)
  • MSQ Score. This subjective measure of physical and mental well-being can be used to assess general health and is not specific to any single condition. Functional medicine practitioners often use this questionnaire to identify patients who may benefit from hepatic detoxification programs.
    • Intervention showed a mean improvement of 21% in MSQ score.
    • A reduced MSQ score suggests fewer symptoms and better overall quality of life.
  • FibroQuest Score. FibroQuest is a clinically validated FM symptoms  survey. Lower scores generally mean greater functional ability and  improved quality of life.15
    • Intervention showed a mean reduction of 16% vs. baseline.
    • Intervention demonstrated a significant reduction in mean FibroQuest subscales scores for pain and stiffness in comparison to mean measures for the control phase (visits 2-4).
  • Mercury Excretion. With dental amalgams as a key selection criterion, this measure was important for evaluation in the study. Comparisons were made with creatinine-adjusted urinary mercury excretion.
    • Intervention showed a significant increase of 74% in mercury excretion (p=0.0234) vs. baseline.
    • Those who had a clinically significant response and/or a greater number of dental amalgams typically showed larger increases. (See Subgroup Analyses below.)
  • Metallothionein mRNA Expression. Changes in genetic expression of metallothionein (MT mRNA) were measured in whole blood by qPCR technology and compared by fold induction (baseline value=1). Results here are presented as final measure for each phase (control=visit 4; intervention=visit 7) vs. baseline (visit 1).
    • Intervention showed a 54% increase in MT mRNA expression vs. baseline, suggesting an enhanced ability to detoxify heavy metals.
    • Control showed only a 7% in MT mRNA expression vs. baseline.
    • Those with a greater number of dental amalgams demonstrated a larger increase in MT mRNA expression (See Subgroup Analyses below.)

Researchers identified 2 important subgroups for separate analyses. As mentioned, half of the subjects (n=4) individually demonstrated what can be considered clinically significant responses (CSR) to the intervention based on a mean reduction of their total FIQ scores ≥ 20 points. A separate analysis was conducted on half of the subjects (n=4) representing the highest concentration of dental amalgams (HDA), suggesting a greater potential for sensitivity to mercury and/or other heavy metals if genetically predisposed.
Results are presented as a mean of visits 5-7 vs. baseline for subgroups and compared with mean intervention results for all subjects (ALL).

  • FIQ Score. Subgroups displayed greater score improvements (CSR 55%, HDA 50%, ALL 21%).
  • MSQ Score. Subgroups demonstrated greater reductions in this score as well (CSR 51%, HDA 37%, ALL 21%).
  • FibroQuest Score. Subgroups showed much greater improvements in total score (CSR 40%, HDA 32%, ALL 11%). Subgroups also displayed 2-3 times greater improvements on key subscales.
  • Mercury Excretion. While both subgroups showed above average increases, those with more dental amalgams demonstrated the greatest increase (CSR 87%, HDA 112%, ALL 74%).

Results for MT mRNA are presented as final measure for all subjects and subgroups (visit 7) vs. baseline (visit 1).

  • Metallothionein mRNA Expression. Likewise, the heavy dental amalgam subgroup showed the greatest evidence of induced MT mRNA expression (CSR 24%, HDA 59%, ALL 54%).

Note: These subgroup analyses were intended for investigational purposes only to help identify potential mechanisms of action that may have contributed to greater reduction in symptomatology. Results were not statistically significant. Researchers, however, were encouraged by preliminary correlations they hope to confirm in future studies.

Safety & Tolerance. The medical food, formulated with ingredients generally recognized as safe (GRAS), was well tolerated. During the 8-week study, 6 of 8 subjects experienced headaches and mild gastric discomfort, which is consistent with modified elimination diets designed to facilitate toxin clearance (e.g., minor gas, temporary bowel habit changes, caffeine clearance headaches). Vital signs and blood tests were also conducted as safety measures. No severe or serious adverse events occurred during this pilot study.Conclusions. Single modality treatments for FM have shown limited benefits, and many researchers in published literature have suggested multi-modality treatment programs.14 This novel medical food was formulated as a multi-mechanistic approach to address not only the pain associated with FM, but other associated symptoms that have been linked to impaired detoxification. The intervention in this pilot study showed a greater mean improvement in all 3 self-reported measures of quality of life, which suggested potential relief from pain and stiffness that impact functionality and daily living. These preliminary results also suggested a trend toward improved heavy metal metabolism based on increases in key observational biomarkers.

Because FM, CFS, and MCS patients rarely have consistent clinical presentations, comparison of improvement between subject groups in clinical trials is difficult. And no approach to date has offered what might be defined as an effective mode of treatment for all patients presenting with FM-like symptoms.4 For example, a placebo-controlled, multi-center clinical trial (n=150) of a popular approach for FM demonstrated an 18% mean improvement in FIQ total score.12,13 Although the preliminary study at the FMRC did not include a population of considerable size to demonstrate similar statistical significance, FMRC researchers were encouraged by the overall mean improvement in total FIQ score of 21%.

The control phase also delivered favorable responses. The macronutrient supplement in powder form demonstrates how a healthy source of low- allergen-potential rice protein, carbohydrates, and fats contribute to overall nutriture and the body’s ability to produce energy, handle stress and immune challenges, and process toxins. It also provides small measures of sesamin, glutamine, and glycine to support bifunctional detoxification, as well as fiber to facilitate waste removal.

The statistically significant changes in protocol comparisons of the intervention vs. the control phase suggest that the modified elimination diet and medical food provided measurable therapeutic value. Further studies are recommended to confirm these and other correlations and trends suggested by this preliminary research. The FMRC continues to monitor FM patients
in investigational case management studies for future summaries of clinical outcomes.

For patients presenting with musculoskeletal pain of unknown etiology and potential indicators of environmental sensitivity or toxic burden, this program may offer a safer primary approach—or a complementary addition to a comprehensive program—to help relieve debilitating symptoms that impact quality of life.

Depending on individual presenting symptoms and response to this medical food program, clinicians may also consider incorporating recommendations for exercise, stress management, and/or nutritional support for neurotransmitter function or healthy sleep.

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Health practitioners who have years of experience in the natural medicine field. We provide health supplements and vitamins to support healthy living. Our articles are researched and talk about the products we carry.

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