Reduction of Pain , Fatigue , Gastrointestinal and Other Symptoms and Improvement in Quality of Life Indicators in Fibromyalgia Patients with Membrane Lipid Replacement Glycerolphospholipids and Controlled-Release Caffeine

Objectives: A preliminary, open label study was initiated to determine if oral wafers containing a combination of membrane glycerolphospholipids and controlled-release caffeine could reduce self-reported pain, fatigue, and gastrointestinal symptoms and improve quality of life (QOL) indicators in fibromyalgia patients. Methods: Pain, fatigue and other symptoms were determined using validated, patient survey forms completed over an 8-day test period and compared to baseline values. Participants included 21 patients (15 females and 6 males) of average age of 48.5 ± 9.8 years with a diagnosis of fibromyalgia. These patients consumed four daily chewable wafers containing glycerolphospholipids (4.8 g) and one controlled-released caffeine (184 mg) wafer that maintained caffeine levels at approximately one cup of coffee for over 8 h. Results: Participants in the study responded to the combination test supplement within days. By the end of the study there were significant overall improvements (36.1%, p < 0.001), reductions in pain (27.2%, p < 0.001), fatigue (37.8%, p < 0.001), gastrointestinal symptoms (54.7%, p < 0.001) and improved ability to complete tasks and participate in activities (quality of life indicators) (39.1%, p < 0.001). Regression analysis of the data using a generalized mixed-effects model and calculating R2 values indicated that reductions How to cite this paper: Nicolson, G.L., Settineri, R., Ferreira, G. and Breeding, P. (2018) Reduction of Pain, Fatigue, Gastrointestinal and Other Symptoms and Improvement in Quality of Life Indicators in Fibromyalgia Patients with Membrane Lipid Replacement Glycerolphospholipids and Controlled-Release Caffeine. International Journal of Clinical Medicine, 9, 560-579. https://doi.org/10.4236/ijcm.2018.97051 Received: June 25, 2018 Accepted: July 23, 2018 Published: July 26, 2018 Copyright © 2018 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access G. L. Nicolson et al. DOI: 10.4236/ijcm.2018.97051 561 International Journal of Clinical Medicine in pain, fatigue and gastrointestinal symptoms and improvements in quality of life indicators were consistent, and occurred with a low degree of variance. Males responded slightly better to the combination supplement than females but for most parameters these differences were not significant. Conclusions: The combination membrane lipid replacement glycerolphospholipid supplement with controlled-release caffeine was safe and effective and significantly reduced pain, fatigue and gastrointestinal symptoms as well as improved QOL indicators in fibromyalgia patients.


Introduction
Fibromyalgia is characterized by chronic, widespread pain, abnormal processing of pain and increased sensitivity to external stimuli, along with fatigue, gastrointestinal symptoms and changes in memory, mood and sleep [1] [2] [3]. In 2010 the American College of Rheumatology established diagnostic criteria for the diagnosis of fibromyalgia based on a pain index and symptom severity scale [2].
Using this diagnostic criteria it has been estimated that between 0.1% -3.3% of the populations in western countries and 2.0% of the population of the United States have fibromyalgia, with higher incidence rates in females compared to males [4].
In the last few years natural supplements have been used to reduce symptoms in patients with fibromyalgia, chronic fatigue and other chronic illnesses [5]; however, few if any of these natural supplements were considered effective [6].
Some symptoms, such as fatigue and pain, also occur naturally during aging, and they are important secondary conditions in many chronic diseases [7].
Pain and fatigue are related functionally to cellular energy systems found primarily in mitochondria and specifically in the electron transport chain of the mitochondrial inner membrane [8] [9]. Damage to mitochondrial membranes occurs in various diseases, mainly by oxidation of phospholipid components, and this can result in ion leakage across inner mitochondrial membranes and reductions in the ability of mitochondria to produce high-energy molecules [10] [11]. During aging and most chronic diseases the production of oxidative free radicals, such as Reactive Oxygen and Nitrogen species (ROS/RNS) and other molecules, can cause oxidative stress and cellular damage [10] [11] [12]. ROS/RNS damage often occurs to cellular membranes, and in particular, to the glycerolphospholipids of mitochondrial membranes [11] [12] [13] [14].
Membrane Lipid Replacement (MLR) therapy plus antioxidants has been used to replace damaged glycerolphospholipids in various clinical disorders and in aged individuals [8] [14] [15]. MLR results in the replacement of damaged cellu-International Journal of Clinical Medicine lar lipids with undamaged, unoxidized lipids to ensure proper function of cellular and organelle membranes. Combined with antioxidants, MLR supplements have proven to be effective in reducing ROS/RNS-associated changes in cellular activities and functions and for reducing symptom severity and providing host support in various clinical conditions [8] [14] [15] [16]. In fibromyalgia patients, the MLR supplement NTFactor Lipids  has been used to reduce fatigue [8] [16].
In a preliminary case report pain, fatigue and gastrointestinal symptoms were reduced in a small number of fibromyalgia patients (P.A. Breeding and G.L. Nicolson, in preparation) In fibromyalgia patients another natural approach to reducing the severity of symptoms has been to use low-dose caffeine (equivalent to one or less than one cup of coffee or about 40 -50 mg of caffeine) to moderate doses (equivalent to 1.5 -2.5 cups of coffee) of caffeine to reduce pain and fatigue [17]. In the study of Scott et al. [17] caffeine consumption had a modest but significant effect on chronic pain reduction compared to an absence of caffeine consumption, but among non-opioid users this effect was not significant [17]. Caffeine is one of the most widely consumed natural food supplements in the world, and it is present in numerous foods and beverages. Caffeine is generally considered safe at doses up to 400 mg per day for adults [18] [19].
Here we tested the results of a combination natural supplement that contained a formulation of MLR glycophospholipids (NTFactor Lipids  ) plus a low dose of controlled-released caffeine in chewable wafers in an open-label study format that used self-reported results on pain, fatigue, gastrointestinal symptoms and quality of life (QOL) indicators in a small group of fibromyalgia patinets.

Materials and Methods
An open label, Institutional Review Board approved, clinical trial was initiated to study the effects of an all-natural glycerolphospholipid chewable wafer supplement (Patented Energy TM with NTFactor Lipids  ) and a chewable wafer containing NTFactor Lipids  and 184 mg controlled-release caffeine (Brite-Alert TM ) on fibromyalgia signs and symptoms. The supplement products provided a total   [24]. Each question in the survey form was answered numerically based on a linear scale from 0 to 10. One question (Q38, based on time of day when subject is most symptomatic) was deleted from the analysis due to its non-numerical response. So that the general scale remained the same in the overall survey form, from lowest (0) to highest (10) severity of symptoms, the QOL portion of the survey form used this same format, which causes improvements in QOL to be shown by lower, not higher, scores.

Subjects
Participants (male and female) were recruited online using fibromyalgia support sites on social media (Facebook

Study Design
Male and Female subjects of age 18 -65 years with a confirmed diagnosis of fibromyalgia [2] and who signed an Informed Consent document and agreed to participate in the study were sent the test supplements. Each participant was instructed to take the test supplements in the morning and afternoon and complete the symptom survey form early in the evening on day 0 (the evening before starting the test supplements), day 1 (evening on the first day after taking the supplements), day 2 (evening on the second day after taking the supplements), day 4 (evening on the fourth day), day 6 (evening on the sixth day) and day 8 (evening on the eighth day). After the 8-day trial, the completed survey forms were returned by mail in a self-addressed mailer to the Lead Investigator. Participants were also advised not to change any of their daily medications, diet or routine during the study.

Statistics
Data were analyzed by analysis of variance (ANOVA), with significance defined as p < 0.05. Further data analysis was performed with regression analysis, with significance defined as p < 0.05. This was established using a generalized mixed-effects model and calculating R 2 as Marginal R 2 and Conditional R 2 values [25]. All of the statistical analyses were done indpendently by the Statistical Unit at Cornell University.

Subjects in the Study
Of the 30 participants recruited to this open-label pilot study, 21 subjects (15 females and 6 males) were fully compliant and completed the study. The main reason for subjects not completing the study was non-compliance with trial instructions. Either subjects did not sign the Informed Consent document, or they did not take all of the study supplements, or they failed to send back all of the fully completed symptom survey forms. Most of the subjects that withdrew from the study did so without taking the test supplements. However, one participant left the trial because of severe headaches, which had occurred intermittently before the trial; one participant left because of symptoms unrelated to the trial, and one left due to cardiovascular complaints that had also occurred before the trial.
In all of these cases the subjects reported that their symptoms that caused them to leave the study had occurred intermittently before starting the study.
The mean age of participants completing the study was 48.5 ± 9.8 years (16 females, 48.7 ± 10.2 years and 6 males, 48.0 ± 5.6 years, respectively). There was no significant difference in mean age between males and females or between participants completing the study and those that did not complete the study.

Effects of MLR Supplements on Fibromyalgia Symptoms and QOL
We examined the daily effects of the test supplements on self-reported symptom severity and QOL scores during the 8-day trial and found significant improvements in the individual scores on specific questions (Supplementary Table 1).
For example, the overall mean scores (Figure 1

Analysis of Data Based on Gender
We examined the trial data to see if there were any differences between the responses to the test supplements between females and males. Both females and males responded to the test supplements, but there were some differences

Model Analysis of the Data
We used the procedures of Nakagawa and Schielzeth [25]

Discussion
Oral supplements that contain membrane glycerolphospholipids have been used  [32]. Here fibromyalgia patients showed significant reductions in fatigue similar to those found in previous studies with fibromyalgia patients [27].
In addition to fatigue, in the present study we also examined subjects for reductions in widespread pain and gastrointestinal symptoms, common complaints of fibromyalgia patients, as well as changes in QOL indicators. We found significant reductions in pain (p < 0.001) and gastrointestinal symptoms (p < 0.001) as well as improvements in QOL indicators (p < 0.001). The changes in fatigue, pain, gastrointestinal symptoms and QOL indicators were found to be significant on each day of the study (p < 0.001). Although there were differences between the responses of males and females in the study, consistent with previously studies, these differences were generally not statistically significant. The formulation used in this clinical study contained controlled-release caffeine that delivered a modest dose of caffeine over eight hours. Caffeine in low to moderate doses has been used previously to reduce pain and other symptoms in patients with various diagnoses. Thirty clinical studies involving more than 10,000 patients have been conducted with combinations of drugs and caffeine to assess the value of caffeine as an added adjuvant [34]. For example, the pooled data on use of caffeine to increase the effectiveness of various analgesics compared to the analgesics alone have shown that caffeine can increase the overall relative potency by an estimated factor of 1.41 [34]. Vaeroy et al. [35] found that fibromyalgia patients benefited when a low dose of caffeine was added to a combination mixture of carisoprodol and paracetamol (acetaminophen) to reduce pain and other symptoms. When caffeine was in the mixture, the combination was more effective (p = 0.015) [35]. Here we did not compare caffeine alone to NTFactor Lipids alone or to the combination of NTFactor Lipids plus con-  [39]. Glycerolphospholipids and caffeine might act at these levels, and caffeine is known to be an important modulator of Ca 2+ release in muscles and neuroendocrine cells [40] [41]. A recent study from our group supports the notion that NTFactor Lipids may act not just by replacement of damaged membrane glycerolphospholipids, but also by modulating and restoring the function of ion channels, intracellular Ca 2+ and mitochondrial function [42]. The clinical trial results here are consistent with what has been described for the fibromyalgia syndrome etiology and the mechanism of action of NTFactor Lipids  and caffeine.

Conclusion
We tested the hypothesis that NTFactor Lipids  plus controlled-release, low-dose