A Program Consisting of a Phytonutrient-rich Medical Food and an Elimination Diet Ameliorated Fibromyalgia Symptoms and Promoted Toxicelement Detoxification in a Pilot Trial


Joseph J. Lamb, MD; Veera R. Konda, PhD; David W. Quig, PhD; Anuradha Desai, PhD; Deanna M. Minich, PhD; Lincoln Bouillon, MS, MBA; Jyh-Lurn Chang, PhD; Alex Hsi, MPH; Robert H. Lerman, MD, PhD; Jacob Kornberg, MD; Jeffrey S. Bland, PhD; Matthew L. Tripp, PhD



Background ? An effective treatment for fibromyalgia (FM) has yet to become available.

Objective ? To assess the efficacy of a lifestyle program consisting of a modified elimination diet and a supplemental medical food on clinical symptoms of FM assessed by the Fibromyalgia Impact Questionnaire (FIQ ), FibroQuest Symptoms Survey (FibroQuest), Medical Symptoms Questionnaire (MSQ ), metallothionein mRNA expression, and urinary toxic element excretion.

Methods ? Eight women (aged 48-74 years) were enrolled in an 8-week pilot trial employing a sequential design. During the initial 4-week Program A (control), participants consumed a modified US Department of Agriculture food pyramid diet and a rice protein powder supplement that provided basic macronutrient support. During the second 4-week Program B (intervention), participants consumed a modified elimination diet and a phytonutrient-rich medical food.

Results ? Compared to baseline, both programs showed trends toward lower mean FIQ total score, MSQ total score, and FibroQuest total score, FIQ stiffness score, and FibroQuest headaches score. Compared to Program A, Program B resulted in a significant decrease (P < .05) in the FIQ pain score and stiffness score. Participants also had better pain tolerance at five tender points during Program B than during Program A. Higher metallothionein mRNA expression was observed during Program B. An increase in creatinine-adjusted mercury excretion and suggestive increase in creatinine-adjusted arsenic excretion were noted when Program B was compared to baseline. Urinary mercury/arsenic concentrations were inversely associated with FIQ and FibroQuest scores.

Conclusions ? Program B was shown to be a safe and efficacious botanically derived medical food treatment program for the amelioration of FM symptoms. (Altern Ther Health Med. 2011;17(2):36-44.)

Joseph J. Lamb, MD, is director of Intramural Clinical Research; Veera R. Konda, PhD, is director of the Department of Molecular and Cellular Biology; Anuradha Desai, PhD, is principal scientist of the Department of Molecular and Cellular Biology; Deanna M. Minich, PhD, is vice president of Research & Development Communications; Lincoln Bouillon, MS, MBA, is senior manager of Clinical Research; Jyh-Lurn Chang, PhD, is senior medical writer; Alex Hsi, MPH, is a biostatistician; Robert H. Lerman, MD, PhD, is director of Medicine and Extramural Clinical Research; Jacob Kornberg, MD, is director of Professional & Clinical Services; Jeffrey S. Bland, PhD, is chief science officer and president; and Matthew L. Tripp, PhD, is vice president of Research & Development, all at MetaProteomics LLC, Gig Harbor, Washington. David W. Quig, PhD, is vice president of Scientific Support of Doctor?s Data Inc, St Charles, Illinois.

Corresponding author: Joseph J. Lamb, MD



Chronic conditions like fibromyalgia (FM), chronic fatigue syndrome, and multiple chemical sensitivity significantly affect the quality of life in a sizeable proportion of the population. FM, characterized by morning stiffness, fatigue, sleep disturbances, and widespread pain, is estimated to affect 3.4% of women and 0.5% of men in the United States.1 FM represents a significant financial burden for our health care system. A recent epidemiologic survey showed that the mean annual expenditures for FM patients, approximately $11 000, are comparable to those for rheumatoid arthritis patients.2 Twenty percent of these patients reported?short-term disability, and 65% had work absence days.2 Overall, FM patients average 39.7 doctor visits per year.3

No clear-cut pathophysiological mechanism has been identified for FM. It has been suggested that FM is caused by central nervous system malfunction leading to amplification of pain transmission and interpretation,4 possibly related to neurotransmitter imbalances.5 External stimuli, including infection, trauma, stress, and toxicity, may contribute to the development of these imbalances. Some have suggested that FM is a disorder of premature neurologic aging.6 The lack of a clear etiology challenges the allopathic acutecare model. All too often, acute-care medicine utilizes a reductionistic ?name it, and blame it? model. Diseases and particularly syndromes, defined by signs and symptoms, are generally assumed to have one cause and then treatments are selected. Hence, in the absence of a unique etiology and defined biomarkers, FM is generally diagnosed by exclusion. Indeed, in spite of the serious and pervasive disruption in a patient?s life, many practitioners and caregivers continue to consider FM an entirely psychosomatic illness.

Using a different heuristic, the functional medicine model postulates that complex diseases?FM, as a specific example?often can be better addressed by restoring balance to basic dysfunctional physiological processes. This approach provides valuable tools to the researcher and clinician in the assessment of complex chronic diseases such as FM. While it is generally assumed that FM has none of the common inflammatory characteristics associated with other rheumatologic conditions such as rheumatoid arthritis and systemic lupus erythematosus, recent literature suggests that FM may be associated with subtle signs of inflammation and immune dysregulation.7 Two additional dysfunctions that contribute to an understanding of the pathophysiology of FM are oxidoreductive imbalances resulting in oxidative stress and the dysregulation of basic detoxification processes. The reduced ability to excrete toxins may play a role in the etiology or exacerbation of a range of chronic diseases and conditions.8 Lyon et al have suggested that hepatic detoxification and reduction of toxic element burden may offer symptom relief.9

In addressing the imbalances that underlie FM, we chose to focus on the homeodynamics of the body?s natural defenses against toxic elements. A key component in toxic element excretion is metallothionein, a protein rich in the constituent amino acid cysteine (~30%), which has the ability to bind toxic elements including mercury, cadmium, lead, and arsenic.10,11 By binding and sequestering these toxic elements, metallothionein prevents their biochemical interaction with other biomolecules and reduces the production of reactive oxygen species,10,12 thereby attenuating their toxicity,13 which may be associated with FM symptoms.14 Promoter regions of the genes encoding several Phase II biotransformation enzymes and metallothionein contain several response elements including the xenobiotic response element, the antioxidant response element, and the metal response element.15 Signal transduction of external stimuli activates the response elements and upregulates gene expression with resultant induction of metallothionein and phase II biotransformation enzymes. Preliminary work in our facility has demonstrated that certain phytonutrients?such as rho iso-alpha acids and spent hops (Humulus lupulus), pomegranate rind extract (Punica granatum), prune skin extract (Prunus domestica), and watercress whole plant extract (Nasturitum officinalis)?upregulate expression of mRNAs for glutathione S-transferase, NADPH quinone reductase, and heme oxygenase-1, and spent hops upregulates expression of mRNA for metallothionein in vitro (unpublished data).

Few therapies have resulted in demonstrable, predictable improvement.16 Goldenberg et al have proposed that the approach should be multimodal and include nonpharmacologic components, including diet and lifestyle changes.17 Bland et al have previously shown that a medical food-supplemented detoxification program could improve chronic health problems.18 Here, we hypothesized that a lifestyle program consisting of a modified elimination diet and a novel phytonutrient-rich medical food may potentially be a safe and efficient way to increase the excretion of toxic elements and to address symptoms of FM. We conducted a pilot study to assess the efficacy of this program on clinical symptoms and markers of biotransformation and detoxification in subjects with FM. The primary endpoints were the Fibromyalgia Impact Questionnaire (FIQ ),19 the Medical Symptom Questionnaire (MSQ ), and the FibroQuest Symptoms Survey (FibroQuest).20 These questionnaires have been used to track subjective responses of patients to treatment in both clinical and research settings. Secondary endpoints included the response of tender points, whole blood metallothionein mRNA expression levels, and urinary excretion of toxic elements.



This was an 8-week pilot study that compared two novel lifestyle programs for the management of FM and toxic element elimination in eight adult women. Entrance criteria included the diagnosis of FM based on American College of Rheumatology classification criteria21? ie, 3 or more months of widespread pain, the presence of tenderness in at least 11 of the 18 specified tender points, and the presence of four or more current dental amalgams. Major exclusion criteria included (1) history of significant liver, kidney or heart disease, uncontrolled hypertension, HIV infection or AIDS, and serious mental illness; (2) use of prescription and nonprescription medication and/or nutritional supplements/medical foods for the support of detoxification in the past 3 months; (3) changes in exercise routine in the past 2 weeks; (4) pregnancy or lactation; and (5) allergy to one or more of the ingredients in the investigational products. The study was conducted in accordance with the Declaration of Helsinki and approved by the Copernicus Institutional Review Board. Informed written consent was obtained from each participant before enrollment in the study.

Trial Design

The study was conducted at the Functional Medicine Research Center in Gig Harbor, Washington, from September to November of 2008. The control arm (Program A) consisted of 4 weeks of a standard American diet (seafood excluded) with food choices compliant with the US Department of Agriculture (USDA) food pyramid guidelines plus twice daily supplementation with a rice protein powder supplement that provided basic macronutrient support. The treatment arm (Program B) consisted?of 4 weeks of a hypoallergenic, modified elimination diet (seafood excluded) plus twice daily supplementation with a phytonutrientrich medical food.Participants were asked to discontinue all seafood 1 week prior to the study and make no changes to any current prescription or nonprescription medications or nutritional supplements throughout the study (Figure 1). Each participant completed Program A before beginning Program B with no washout period. In addition to the onsite screening visit, participants returned to the clinic seven times throughout the study, during which fasting blood and 24-hour urine samples were collected. At each visit, the study clinician assessed tender points and grip strength; reviewed patient FIQ, MSQ, and FibroQuest scores; assessed safety and tolerability; and reviewed compliance to study product and dietary guidelines.

Measurement for Tender Points and Grip Strength

The same study clinician performed tender point measurement at nine bilateral tender point sites. The clinician used a modified dolorimeter (Chatillon, Kew Gardens, New York) to apply pressure on each location loading at approximately 1 kg per second and stopped when the patient indicated pain or at 4 kg of force maximum. The numeric value of each result was the amount of force tolerated by the participant. The clinician also performed the grip strength test, an indicator of overall strength. An adjustable dynamometer (Asimow Engineering, Santa Monica, California) was used to measure the maximum force that a participant was able to exert with her hands. The test was performed three times individually for each hand alternating between dominant and nondominant hand in succession. The scale for measurements ranged from 0 to 90 kg.


Laboratory Analysis

For metallothionein mRNA expression, RNA was first extracted from whole blood using the RiboPure Blood RNA Isolation Kit (Ambion, Austin, Texas) per manufacturer instruction. RNA was converted to first strand cDNA by use of the RETROscript First Strand Synthesis Kit (Ambion) and primed with oligo-dT according to the manufacturer?s specifications. A Taqman gene expression assay to quantify GAPDH expression, which was used as an endogenous control, was obtained from Applied Biosystems (Foster City, California; assay ID Hs99999905_m1). Forward and reverse primers and HPLCpurified Taqman probes labeled with 5?-FAM and 3?-TAMRA were obtained from Operon Biotechnologies, Inc (Huntsville, Alabama). Primers and probes for Taqman-based assays targeting human metallothioneins have been previously described.22 Twostep Taqman-based RT-qPCR was performed. The cDNA equivalent of 20 ng starting RNA was then included in qPCR reactions. Reactions to detect metallothionein expression contained 1X Taqman Master Mix (Applied Biosystems), forward and reverse primers at 400 nM, and Taqman probe at 200 nM. Reactions to detect GAPDH expression contained 1X Taqman Master Mix and 1X gene-specific assay reagents as recommended by the manufacturer. All reactions were run in triplicate. Reactions that did not contain template cDNA were included as negative controls. Reaction plates were processed on an Applied Biosystems 7900HT Sequence Detection System. The AmpliTaq Gold polymerase was activated at 95o C for 10 minutes, followed by 40 cycles consisting of denaturation for 15 seconds at 95o C and annealing and extension for 60 seconds at 60?C. Amplification data was analyzed with the ABI Prism SDS 2.1 software (Applied Biosystems). Relative quantification of gene expression was performed by the ??Ct method,23 with GAPDH expression serving as an endogenous control to normalize expression within each sample.

Urinary toxic element concentrations were measured using a commercially available method, ICP-MS (Doctor?s Data, Inc, St Charles, Illinois). Safety measures were also assessed by tracking adverse events, vital signs, and performing safety blood tests.

Statistical Analysis

All eight women completed the study and were included in the analyses. Each questionnaire was collected three times during each treatment period, and the mean score at each period was calculated. The mean scores were compared between the two treatment programs as well as between each individual program and the baseline mean scores using two-sided paired t-tests. Tender points, grip strength, and urinary toxic element excretion were analyzed with the same methods. The metallothionein mRNA expression was presented as fold induction over time relative to baseline expression. All data are expressed as mean ?SEM.


Fibromyalgia Questionnaires

The eight enrolled participants were white females between the ages of 48 and 74 years (55.6 ? 9.4) with BMI ranging from 20.4 to 44.8 (32.9?9.5). Table 1 presents the scores of the subjective questionnaires from each participant at baseline and during both treatment periods. Compared to baseline scores, both Programs A and B showed trends toward lower mean FIQ total score, MSQ total score, FibroQuest total score, FIQ stiffness score, and FibroQuest headaches score, but only the MSQ total score in Program A was statistically significantly lower than baseline. Comparing the two programs, Program B resulted in lower mean FIQ total score, MSQ total score, FibroQuest total score, FIQ pain score, and FIQ stiffness score than Program A but only reaching statistical significance (P<.05) in FIQ pain and stiffness scores. There was a nonsignificant increase in FibroQuest headaches score in Program B compared to Program A.



Noting the review by Rooks24 and with the suggestion that a treatment leading to a reduction in FIQ total score by 20% or more to be clinically significant,25 we performed an analysis of four ?responders? who met the criterion (Figure 2). There were suggestive trends that Program B resulted in stronger decrease in all questionnaire scores than Program A.



Tender Points and Grip Strength

Compared to baseline, there was better pain tolerance at four tender points (left occiput, left low cervical, right trapezius, and right greater trochanter) during Program A and eight tender points (left epicondyles, right knee, low cervical on both sides, right trapezius, supraspinatus on both sides, and right greater trochanter) during Program B (Table 2). Comparing both programs, participants during Program B had better pain tolerance at five tender points (left epicondyles, both knees, left supraspinatus, and left gluteal) and worse pain tolerance at the second rib on the right side. Grip strength on either side was not changed throughout the study.



Urinary Excretion of Toxic Elements

Compared to baseline, the mean creatinine-adjusted urinary mercury excretion was significantly increased during Program A and Program B (Figure 3A). Our data suggested that the mercury excretion was higher in Program B than in Program A, although it did not reach statistical significance. There was a trend toward increase (P=.056) in the mean creatinine-adjusted urinary arsenic excretion during Program B but not Program A in comparison to baseline; the difference between programs was not significant (Figure 3B). Creatinine-adjusted cadmium levels remained similar to baseline after either treatment program. Compared to baseline, creatinine-adjusted lead levels decreased significantly during Program B (P=.037) but not Program A; the difference between programs was not significant. Using 24-hour excretion data, similar findings were found for all four elements (data not shown). Data from responders suggested that during Program B their mean mercury excretion was higher than that in all participants (1.83 ?g/g creatinine and 1.73 ?g/g creatinine, respectively; Figure 3A). Similar observation was found for mean arsenic excretion (18.43 ?g/g creatinine and 16.08 ?g/g creatinine, respectively; Figure 3B). Data of other toxic elements?did not show changes over time or between two programs, either in all participants or in responders only.


When evaluating the association between questionnaire scores and the creatinine-adjusted urinary heavy metal excretion, we found that the urinary mercury concentration was inversely correlated with the FIQ pain score (R = -0.306; P = .02), and the urinary arsenic concentration was inversely correlated with FIQ total score (R = -0.360; P = .007), FibroQuest total score (R = -0.312; P?= .022), and FIQ pain score (R=-0.394; P?= .003). Urinary cadmium and lead concentrations were not associated with any questionnaire score except that cadmium was positively associated with MSQ total score (R=0.331; P?= .014).

Metallothionein mRNA Expression

Compared to the baseline, the metallothionein mRNA expression measured at the end of Program A (the end of week 4) increased by 7%. The expression measured at the end of Program B (the end of week 8) increased by 54% (Figure 4).



Both programs were well tolerated. During the 8 weeks, six of eight participants experienced a total of 20 mild adverse events (AEs) and one moderate AE (10 during Program A and 11 during Program B), with symptomatology consistent with detoxification or deemed to be unlikely associated with consumption of either product. Reported symptoms included constipation, diarrhea, gastrointestinal hypermotility, lethargy, hypersensitivity, upper respiratory tract infection, urinary tract infection, muscle spasms, myalgia, headache, nocturia, pruritis, and rash. One of 21 AEs was deemed to be possibly related to use of the rice protein powder supplement. No AEs were deemed to be related to use of phytonutrient-rich medical food. No severe or serious AEs occurred during the study.


Simms et al compared a variety of parameters designed to assess clinical outcome in FM patients, including sleep patterns, tender points, and a global assessment of physical functioning.26 Their results suggest that, despite the clinical importance of pain as a cardinal feature of FM, improvement in pain alone did not discriminate as well as did a combination of outcome measures. Thus, questionnaires evaluating different aspects of fatigue and functioning should be included with tender point analysis when assessing response to therapy for FM. In this 8-week pilot trial in which eight FM patients underwent two lifestyle programs, we found that the 4-week regimen of modified elimination diet supplemented with a phytonutrient-rich medical food (Program B) reduced symptom scores on multiple FM questionnaires, increased urinary mercury and arsenic excretion, increased pain tolerance at eight tender points, and increased metallothionein mRNA expression. In comparison,?Program B was more effective than the standard American diet supplemented with a rice protein powder supplement (Program A) in reducing FIQ pain and stiffness scores, increasing urinary mercury and arsenic excretion, increasing metallothionein mRNA expression, and reducing tender point sensitivity.

FM is a complicated syndrome, and a reductionistic allopathic medicine approach is unlikely to find a unifying etiology as causative in all patients who experience the illness. This has been acknowledged in the direction that clinical research studies have taken in their focus on the symptoms experienced by these participants. Marcus concludes in his recent review, ?Fibromyalgia is a common, disabling, chronic pain condition that predominately affects women. Symptoms can be effectively treated using both drug and nondrug therapies,? and further, ?The strongest evidence suggests effective treatment of fibromyalgia with duloxetine and milnacipran. Studies also report efficacy with gabapentin, pramipexole, pregabalin, tramadol, and IV tropisetron.?27 The broad spectrum of pharmacological choices suggests that the focus on symptom management rather than pathophysiologically centered therapy is the standard approach. Indeed, Lawson states that ?the primary focus of RCTs has often been toward pain management; however, marked efficacy (a ?50% decrease in pain) was limited to subgroups of patients, while the majority only gained marginal benefits. These findings suggest that a single drug class may not be sufficient to manage the condition.?28

Much attention has been given to the recent FDA approval of pregabalin (Lyrica, Pfizer, New York, New York) for the treatment of FM. One trial conducted to support this approval was the Fibromyalgia Relapse Evaluation and Efficacy for Durability of Meaningful Relief (FREEDOM) trial.29 In this trial, 1051 people were enrolled in the initial 6-week open-label run-in treatment with increasing doses of pregabalin; only 566 (53.8%) of participants responded (?50% reduction in pain scored on a visual analog scale) and were randomized to the second phase of a double-blind withdrawal trial. During the open-label period, 178 participants (17%) discontinued due to treatment-related adverse events. The primary outcome was time to loss of therapeutic response postrandomization. While a statistically greater number of pregabalin patients did not lose therapeutic response, it is hard to imagine that participants remained truly blinded with the difference in AEs associated with the two treatments. As such, placebo patients were likely to realize that they had been randomized to placebo instead of the active substance with which they had been previously treated. Though it is inherently difficult to compare exploratory work to large clinical trials with different designs, we did find that half of the participants in our trial responded (ie, ?20% reduction in total FIQ score, a less rigid criterion) during the active treatment phase, yet no differences in adverse event occurrence were noted between Program A and Program B.

The functional medicine model, with its exploration of contributing pathophysiological imbalances, provides an etiologic understanding of FM. We focused on specific imbalances related to hepatic biotransformation and detoxification in general and specifically of toxic elements, which are the principles behind the design of the Program B intervention in this trial. Our findings of increased urinary mercury and arsenic excretion correlated with reductions in FIQ pain and stiffness scores confirm Program B?s ability to intervene in addressing pathophysiology and not simply symptomatology.

Granted, nutraceuticals and pharmaceuticals may serve different roles in the treatment of FM. Nonetheless, the modified elimination diet supplemented with a phytonutrient-rich medical food offers multiple unique advantages for use in this population of patients. The medical food used in Program B provides specific nutrients that may be lacking in the diet of FM patients and those patients who may benefit from additional support of hepatic detoxification and elimination of toxic elements. In addition to rho isoalpha acids and spent hops, pomegranate rind extract, prune skin extract, and watercress whole plant extract, the medical food also includes low allergy potential rice protein concentrate with added limiting amino acids L-lysine and L-threonine to increase the biological value of the protein. Other ingredients include glycine, taurine, sodium sulfate, and catechins from decaffeinated green tea to support hepatic detoxification.

Even though our intervention led to favorable outcomes related to FM symptom reduction and toxic element excretion, we recognize several limitations of this pilot study. With only eight participants in this trial, small sample size and interindividual differences are likely to limit the statistical power to detect treatment effects. The generalization of the study finding to a large population should be conducted with caution, as the selected sample may not be representative. Each intervention lasted 4 weeks; future studies are required to assess the intermediate- and long-term effects of treatment. The study?s sequential treatment design did not randomize individuals to either the treatment or the control arm.

In studies without a washout period between treatments, the effect of the first treatment period may carry over to the second treatment period. In our study, participants were not aware of which treatment program represented the active phase; they were only informed that the study was to compare two different programs. Clinically, it is often noted that there is a honeymoon or placebo effect with the introduction of new therapies. Wash-in periods or control interventions allow for this effect, as these effects are generally transitory. No loss of benefit was noted during Program A, and benefit was maintained and extended during Program B. During the first diet period (Program A), participants were instructed to follow a standard American diet based upon the USDA food pyramid recommendations. For many participants, this resulted in the elimination of refined carbohydrates, saturated fats, and partially hydrogenated trans-fatty acids while a quality source of rice protein was added through the use of a nutritional supplement. These changes represent a modification of the baseline diets with proinflammatory characteristics and may well have had therapeutic benefit, thus masking a possible honeymoon effect. Regardless of the explanation for benefit gained during Program A, Program B was therapeutically stronger.

In conclusion, the 4-week modified elimination diet supplemented with a phytonutrient-rich medical food has been demonstrated to?be an efficacious, whole food?based dietary program for the treatment of fibromyalgia, with a uniquely benign side effect profile. Further studies are planned in our research center to expand this work to larger and more diverse populations.


Author Disclosure Statement

The study was conducted by MetaProteomics LLC and financially supported by MetaProteomics LLC and Doctor?s Data, Inc. MetaProteomics is a subsidiary of Metagenics Inc that manufacturers the study dietary supplement UltraClear MACRO and medical food UltraClear RENEW for licensed health care professionals.


We thank Cynthia Baxter, Meraf Eyassu, Kim Koch, and Leslie Pilkington for expert technical assistance.




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