A pilot trial evaluating the effect of an inflammatory-modulating medical food in patients with Fibromyalgia.

http://www.acam.org

Dan Lukaczer, ND, Barbara Schiltz, RN, MS, CN, DeAnn J. Liska, PhD

Journal-Vol. 1, No. 3, Fall 2000

Editorial- Crime and Punishment

Original Papers:

A Pilot Trial Evaluating the Effect of an Inflammatory-Modulating Medical Food in Patients With Fibromyalgia
Dan Lukaczer, ND, Barbara Schiltz, RN, MS, CN, DeAnn J. Liska, PhD

ABSTRACT: Fibromyalgia is a complex syndrome characterized by reproducible tenderness on palpation at specific anatomical sites, generalized stiffness and aching, and a variety of other systemic complaints. This syndrome is common in the United States and is one of the most common reasons for rheumatological referrals. The etiology and pathogenesis of fibromyalgia are controversial. A variety of approaches have been used with a lack of consistent results. The data in this study suggest that a complex medical food designed for clinical management of inflammatory conditions may also have a beneficial effect for fibromyalgia patients. With this medical food, a significant improvement in mental functioning (P<.05) was observed as assessed by the Medical Outcomes Survey Short Form-36 questionnaire, a significant decrease in the Tender Point Index (P<.05), and a substantial improvement in grip strength and physical symptoms. Although more studies are needed to verify this preliminary observation, these data suggest that focused nutritional support, as seen with this inflammatory modulating medical food, may be a beneficial part of the clinical strategy for fibromyalgia. (Clinical Practice of Alternative Medicine 1(3):148-156, 2000)

The latter half of the 20th century has been characterized by an increasing prevalence of chronic disorders. Indeed, 7 of the 10 leading causes of death in the United States are chronic in nature, accounting for 72% of the deaths from all causes.1 Although certain chronic conditions such as chronic fatigue syndrome, multiple chemical sensitivity, and fibromyalgia (FM) are not life threatening, these conditions significantly affect the quality of life of a sizeable proportion of the population. Research on these conditions is complicated, however, by the fact that these patients rarely have consistent clinical presentations, making comparison of improvement difficult between subject groups in clinical trials. Moreover, studies have shown that a variety of biological markers routinely used in clinical practice have an inconsistent relationship to symptoms in these chronic health conditions.2 In fact, 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.3

Fibromyalgia exemplifies the challenge facing clinicians in the diagnosis and treatment of complex, chronic conditions. Patients with FM commonly report morning stiffness, fatigue, sleep disturbances, and widespread pain, which they often suffer over many years without a diagnosable or definable disease. No biological markers have been shown to differentiate this condition; therefore, FM is generally diagnosed by exclusion and often overlooked. For example, in one study patients saw an average of 3 to 4 doctors and presented with the same complaints before being diagnosed with FM.4 Overall, FM patients average 39.7 doctor visits per year.5 The prevalence of FM increases with age, with the highest incidence in individuals between 60 and 79 years old. Moreover, FM primarily afflicts women; 3.4% of the US female population is estimated to suffer from this condition.6,7 Fibromyalgia is significantly debilitating, and it is not uncommon for FM patients to report that they are unable to work.8 In spite of the serious and pervasive disruption in a patient's life, and the difficulty found in correlating FM symptoms to organic etiologies and underlying mechanisms, many physicians continue to consider this an entirely psychosomatic illness. Fibromyalgia is clinically differentiated by the relatively objective evaluation of pain at specific sites, which are called tender points.6 These tender points are located bilaterally in 9 distinct areas of the body, including the base of the skull, above and between the shoulder blades, below the elbows, the lower back, lateral hips, buttocks, posterior knees, and lateral chest. The American College of Rheumatology has defined FM as widespread pain and the presence of tenderness in 11 or more of 18 tender points.9 A patient presenting with FM may report peripheral arthralgias as well, which can be confused with rheumatoid arthritis.2 However, FM is commonly believed to be pain that is not associated with inflammation or joint dysfunction, whereas arthralgias are considered inflammatory and associated with joint dysfunction. Although many theories exist regarding the etiology of FM, few therapies have resulted in demonstrable, predictable improvement.

Without laboratory or biological correlation, a patient's response to therapy is often monitored by the number of tender points reported over the course of the therapeutic intervention. Although widespread pain and tenderness at specific anatomical sites is the accepted criterion for diagnosing FM, some researchers have questioned whether overall improvement can be determined by monitoring tender points. Simms et al10 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. These researchers' 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. This finding suggests that questionnaires evaluating different aspects of fatigue and functioning should be included with tender point analysis when assessing response to therapy for FM. The Medical Outcomes Survey Short Form-36 (SF-36) questionnaire is an instrument particularly suited for this type of analysis, because it has been widely used in clinical trials and in clinical practice to assess physical and mental health outcome.11-13 The Medical Symptoms Questionnaire (MSQ) has also been used as a tool for general evaluation of symptoms and functioning in clinical studies and in research trials with patients experiencing fatigue.14-16

Fibromyalgia has none of the common inflammatory characteristics associated with other rheumatological conditions such as rheumatoid arthritis and systemic lupus erythematosus; however, some recent literature suggests that the pathophysiology of FM may be associated with more subtle signs of inflammation and immune dysregulation.17 In addition, favorable anecdotal reports exist on the use of a recently developed inflammatory-modulating medical food in clinical management of FM patients. Due to these observations a preliminary assessment of the efficacy of this medical rice-based food designed for inflammatory conditions was undertaken for the clinical management of FM.

Methods

Subjects
Subjects were women between the ages of 29 and 65 years, with an average age of 47 years. Before initiating the study, subjects were evaluated with blood chemistry tests, medical history, and physician examination. The 21 subjects were selected on the basis of past diagnosis of FM, musculoskeletal pain lasting longer than 6 months, and complaints of unrestorative or disturbed sleep as assessed by an initial symptoms questionnaire. The questionnaire was completed to provide information on the history and onset of each subject's illness (Table 1). Subjects who had been diagnosed with a serious debilitating condition such as acquired immune deficiency syndrome, cancer, congestive heart failure, liver disease, chronic obstructive pulmonary disease, or advanced diabetes were excluded from the study. Each subject signed an informed consent prior to participation in the study.

Study Design and Dietary Intervention
The medical food used in this study was originally designed for nutritional support of conditions associated with chronic inflammation of the lungs, joints, and intestinal tract. The nutrient profile of this inflammatory-modulating medical food (UltraInflamX) is shown in Table 2. This medical food was designed as a low-allergy, rice-based product fortified with the following components: antioxidant vitamins and minerals to reduce free-radical generation from oxidative stress18,19; phytonutrients, such as rosemary and limonene, and sulfate-containing compounds, such as N-acetylcysteine and sodium sulfate, to support detoxification processes20-24; anti-inflammatory phytonutrients, such as curcumin and rosemary, to nutritionally support clinical management of inflammation symptoms25,26; and enhanced levels of vitamins and minerals, such as vitamin C, vitamin B3, vitamin B6, zinc, and magnesium, which are involved in fatty acid synthesis and promote balance in production of pro- and anti-inflammatory cytokines and prostaglandins.27-29 Dietary changes consisted of a modified elimination diet, ie, a diet free of substances likely to produce allergenic responses. Foods eliminated in this diet included dairy, eggs, gluten, corn, pork, and yeast.

Subjects were assigned to 1 of 2 protocols by date of initial appointment at the research clinic. Protocol A included the medical food nutritional supplement daily with no other dietary changes, and protocol B included the medical food nutritional supplement daily with dietary changes. The medical food was provided as a powdered drink mix supplement, which was prepared by the subjects at the time of use by mixing the recommended amount of powder (52 g) in either water or a juice. Taken alone with water twice a day, the drink provided a total of 400 daily calories. Both protocols were followed for a 6-week period. Subjects were instructed to make no changes during the course of the study-other than those noted above-in their supplementation, medication, or exercise routine. Compliance to the respective protocol, exercise, and medication were documented during each visit by verbal communication with the subject and by answers to a written questionnaire.

Clinical Assessment
Subjects were evaluated initially, after 3 weeks, and after 6 weeks by questionnaires, presence of tender points, and grip strength. Questionnaire evaluation included: the SF-36 questionnaire, a well-validated general quality of life instrument; the MSQ, which evaluates general health symptoms; and the Fibromyalgia Questionnaire, a written inventory to evaluate history of illness, medication use, sleep patterns, perceived pain, and compliance to the protocol. The SF-36 is a 36-item questionnaire that summarizes health outcome in 2 reliable, reproducible scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). These scores are converted to a scale of 0 to 100, in which 50 is the mean for the US population. Low scores on the MCS indicate frequent psychological distress, compromised social and role disability due to emotional problems, and/or generally poor health, whereas high scores indicate frequent positive affect, and absence of psychological distress and limitations in usual social and role activities. Similarly, low scores on the PCS indicate substantial limitations in self-care, physical, social, and role activities, severe bodily pain, frequent tiredness, and health generally rated as poor, whereas high scores indicate no physical limitations, high energy level, and health generally rated as excellent.

The MSQ is another clinical tool for the evaluation of general physical symptoms that patients find easy to fill out; practitioners find this questionnaire easy to score and evaluate. In contrast to the SF-36 questionnaire, in which a high score means high functioning and a low score means compromised functioning, a high score on the MSQ means a higher or more substantial amount of overall symptoms in terms of duration, frequency, and intensity. Scores on the MSQ that total above 75 are generally associated with substantial symptomatology and disability; scores below 30 generally indicate few symptoms or symptoms of low intensity. Tender points were assessed by the subjects at each visit and were reported using the Tender Point Index (TPI). Subjects were presented with a diagram that identified the 9 specific bilateral points and asked to circle areas in which they felt pain. The number of tender points circled was summed to determine the TPI; the maximum possible value for TPI was 18. Grip strength was assessed as the static grip force in kilograms with an adjustable handgrip dynomometer. The grip strength test was performed with the subject in a standing position and the arms in a neutral position. Subjects were asked to squeeze the handgrip dynomometer as hard as possible without moving the arm. Grip strength measurements for the left and right hand were performed at each office visit.

Data were analyzed by standard statistical methods using the Wilcoxon signed rank test for determination of significance. Percent change in MSQ was determined as follows: percent MSQ change = ([initial MSQ score-final MSQ score] / initial MSQ score) x 100.

Results
Fourteen of the subjects completed the entire trial, and 7 subjects chose to withdraw from the trial before its completion, as indicated in Figure 1. The results of the SF-36 questionnaire are shown in Figure 2. The initial MCS scores were 40±8.4 (n=8) and 45±8.9 (n=5) for subjects on protocol A and protocol B, respectively, which was below the US average of 50. However, at the end of the 6-week study, the average MCS score had increased to the US average for subjects on both protocols, which was 51±8.5 (n=8, P=.025) and 57±6.6 (n=5, P=.043) for subjects on protocol A and protocol B, respectively. (One subject on protocol B did not complete the questionnaire and, therefore, the data from this subject were not included in the analysis.) The improvement in mental well-being did not appear to be dependent on whether dietary changes accompanied the medical food, since both groups receiving the medical food, with and without dietary changes, showed significant improvement. The PCS score from the SF-36 questionnaire, which provides an independent assessment of physical functioning, also showed improvement for subjects on protocol A from 30±6.8 initially to 38±5.7 (n=8, P=.05) after the intervention. No significant improvement was noted in PCS for the protocol B group. However, this may have been due primarily to 1 subject, who reported an initial PCS score of 34 and a final score of 8.4. When the data from this subject were removed, the subjects on protocol B showed modest improvement in PCS scores as well, from 25±8.8 before the intervention to 31±6.3 (n=5, P=.08) after the intervention, which was not statistically significant.

The MSQ questionnaire results for each subject on protocol A and protocol B are indicated in Table 3 and Figure 3. As seen in Table 3, 12 of the subjects reported MSQ scores above 75 before the intervention, whereas only 3 subjects reported MSQ scores above 75 after the intervention. The MSQ scores decreased on average by 53% and 32% for subjects on protocol A and protocol B, respectively, with an overall average decrease of 43%. Only 1 subject reported an increase in symptoms. (One subject on protocol A did not provide complete questionnaire data, therefore, data from this subject were not included in the analysis.) Subjects were also asked about sleep symptoms on the Fibromyalgia Questionnaire. At initiation of the trial, all 8 subjects on protocol A, and 4 of the 6 subjects on protocol B indicated that they were experiencing problems sleeping, which included problems falling asleep as well as waking numerous times during the night. At conclusion of the study, 6 of the 8 subjects on protocol A noted that their sleeping problems were resolved. The 4 subjects on protocol B who indicated problems sleeping did not indicate that these problems were resolved; however, these subjects noted a decrease in the number of times waking from an average of 3.5 times per night to 2.2 times per night.

As indicated in Table 4, improvement in grip strength was observed in subjects on both protocols as well. Right-hand grip strength improved from low average to midrange average, and poor to midrange average in the protocol A and protocol B groups, respectively. Left-hand grip strength improved from poor in both groups initially to within average range; however, less difference was observed in the left-hand grip strength overall. Figure 4 shows the grip strength average of the right and left hand for each subject before intervention, after 3 weeks on the respective protocol, and after the 6-week intervention with protocol A or protocol B. Although improvement was observed in grip strength for both groups, the protocol A subjects appeared to show improvement by the 3-week visit and sustained that improvement through the 6-week visit. In contrast, the protocol B subjects showed no difference at the 3-week visit but showed improvement at the 6-week visit. The TPI also showed improvement after the intervention for subjects on both protocols, as shown in Figure 5. However, the improvement in TPI was most evident with the subjects on protocol A, in which the subjects reported a significant (P=.0425) decrease in TPI from 13.3±3.49 before intervention to 8.5±4.77 after the intervention. The subjects on protocol B reported a modest improvement in TPI from 11.2±4.02 initially to 10.6±4.72 after the intervention, which was not statistically significant.

Discussion
Fibromyalgia is a complex syndrome characterized by reproducible tenderness at specific anatomical sites, and is one of the most common reasons for rheumatological referrals.6 Its etiology and pathogenesis are controversial, and no clinical management approach has shown consistent results. The data in this study suggest that an approach using an inflammatory-modulating medical food, which was designed to nutritionally support clinical management of chronic inflammatory conditions, may also provide benefit as nutritional support for FM patients. Fibromyalgia has not generally been assumed to be an inflammatory condition. However, clinical observations have suggested that patients presenting with FM concurrent with inflammation show favorable response to the medical food with respect to their symptoms. The use of this medical food resulted in a significant decrease in TPI (P<.05), a significant improvement in the mental functioning section of the SF-36 (P<.05), and a substantial improvement in grip strength and physical symptoms. These preliminary favorable findings in FM patients raise questions regarding the etiology and underlying mechanism(s) of FM. In general, anti-inflammatory pharmaceutical approaches, such as nonsteroidal anti-inflammatories, have shown minimal positive response in clinical trials on FM, and generally result in no significant improvement compared with placebo effects.30 In contrast, evidence has been reported to support an inflammatory component in FM. For example, Maes et al17 investigated biological markers of the inflammatory system in 21 FM patients and 33 non-FM controls. These researchers reported an alteration in the expression of some markers of the inflammatory response system in FM patients, which suggested an activation of the inflammatory system in these patients. However, the clinical utility of this observation has not been explored; the clinical consensus remains that a simple anti-inflammatory approach does not appear to be clinically effective for FM.

Some subclinical inflammatory mechanisms may be part of the FM etiology, but these mechanisms have not been clearly elucidated. If this is the case, supplementing with phytochemicals and nutrients that have a modulating effect on subclinical inflammatory processes may be of benefit. For example, subclinical inflammation may be modulated through the application of phytonutrients, such as curcumin, which inhibit synthesis of interleukin-1 and tumor necrosis factor, and inhibit lipoxygenase and cyclooxygenase.31,32 Ginger has shown efficacy in inflammation and may have a similar and/or complementary role as well.33 Moreover, inflammation has been associated with oxidative stress resulting in excessive production of reactive oxygen species. Fibromyalgia has also been postulated to involve some degree of cellular hypoxia with mitochondrial uncoupling and concurrent generation of excessive reactive oxygen species.34 Because the medical food used in this study contained a broad array of antioxidant support, improvement due to protection against excessive damage and injury from oxidative stress may have been observed.18 Many phytonutrients, such as rutin and quercetin, appear to act synergistically with respect to their antioxidant activities; therefore, these may have provided additional support for the nutritional management of FM symptoms.35,36

Fibromyalgia is a multifactorial syndrome that seriously compromises patients' quality of life. For example, FM patients have been reported to score lower on the SF-36, a quality-of-life instrument.13 Moreover, there is strong comorbidity between FM and major depression, and an increased incidence of depressive symptoms in FM patients.37 A striking finding in this study was the significant improvement in the mental functioning section of the SF-36 for FM patients after intervention with the medical food. The SF-36 has been shown to predict the course of depression over a 2-year course in clinical trials.12 In a similar study, in which the clinical affect of a rice macronutrient "placebo" powder mix and elimination diet was compared to that of a rice-based detoxification support medical food and elimination diet in FM patients, no changes were observed in either the PCS or MCS. This observation suggested that the micronutrients and/or the specific macronutrient ingredients other than the rice-based ingredients of the inflammatory-modulating medical food may be responsible for the observed improvement in MCS. Moreover, many patients with chronic conditions such as FM respond with moderate, variable improvement, and a noticeable percentage of these patients fail to respond when they are put on a dietary program that eliminates only common food allergens.

It was surprising in this study, however, that though both groups showed improvement, the group without dietary changes showed greater improvement. Since most subjects reported seeing several doctors over many years for their condition, it is possible that many of these patients had already attempted an allergen-free diet without success. Dietary changes are difficult to make, and if those changes do not appear to be working, the disappointment may be even more frustrating. Asking individuals to repeat a dietary therapy they have already found unsuccessful may be emotionally difficult and taxing. Therefore, the slightly decreased improvement on protocol B, which included dietary changes, could be due to the added complication of this approach and the associated mental frustration. Certainly, dietary changes should be considered in individuals who have not attempted such a therapy; however, this should be assessed carefully since dietary changes may not be effective. Although extensive clinical trials are required to fully assess and document the success of this medical food with FM, it is the observations of the individual's response in the clinic that matter most to clinicians and patients. An interesting case experience from this trial is that of a 51-year-old woman who was diagnosed with FM over 10 years before presentation. She was forced to quit her job and had been working on a part-time basis. She had consulted with 10 doctors regarding her illness and had taken a variety of anti-inflammatory and antidepressant medications, but continued to have chronic myalgia pain, sore throats, headaches, and fatigue. She complained of sleep disturbances and stated that she woke up 2 or 3 times a night. She reported chronic pain in all standard trigger point areas, stating that she was almost never pain free. Her initial MSQ score was 140; she was assigned to protocol A, receiving the inflammatory-modulating medical food with no dietary changes for 6 weeks.

At her 3-week follow-up visit, the patient reported having some difficulty with the taste of the product and was, therefore, taking only half of the prescribed dose of the medical food. She was provided with more instructions for alternative blending recipes and was encouraged to increase to the full dose. At the 6-week follow-up visit, she was taking the full dose successfully and reported that she could now awaken with no pain. Furthermore, she had noticed substantial improvement in sore throat, headache, and fatigue symptoms, and was also experiencing improved sleep, only waking on average one time per night. Perhaps most importantly, she reported that she was pain free over half of her waking hours, a significant improvement from the constant pain she experienced just 6 weeks earlier.

Summary
The data presented in this report represent a pilot study on the use of a complex medical food containing a variety of inflammatory-modulating pharmacological activities on symptoms of FM. With this medical food, a significant improvement was observed in mental functioning (P<.05) as assessed by the SF-36 questionnaire and a significant decrease in TPI (P<.05), as well as a substantial but not statistically significant improvement in grip strength and physical symptoms. Although the mechanisms underlying these observations are not understood, a number of activities may act synergistically to produce the noted improvements in FM patients treated with this inflammatory-modulating medical food. More studies are needed to verify this preliminary observation with FM. The complex nature and clinical challenge presented by the FM patient exemplifies the axiom that the whole is greater than the sum of its parts.

Acknowledgments The authors thank Kim Jordan and Julie Triggs for clinical assistance; Tracey Irving for preparation of the medical food supplement; Laura Nichols, Nancy Chatfield, and Mabel Lorenzi-Alb? for assistance in preparation of the manuscript. The authors also thank Dr Gary Darland and Dr Robert Lerman for technical review of the manuscript, and Dr Jeffrey S. Bland for critical comments and support of this project.

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