Food Supplements in the Treatment of Primary Fibromyalgia: A Double-blind, Crossover Trial of Anthocyanidins and Placebo


Purpose: To determine whether anthocyanidins when administered as a food supplement are effective in the treatment of primary fibromyalgia.

Design: Double-blind, randomized, crossover trial comparing 3 doses of anthocyanidins and placebo.

Materials and Methods: Twelve patients with moderate to severe primary fibromyalgia were treated with anthocyanidins, 120, 80, 40 mg day-1 and placebo, each for 3 months after a one-month baseline observation period. All treatments were administered orally as identical capsules. Primary variables to assess the effectiveness of treatments were the severity of symptoms of pain, fatigue and sleep disturbance recorded by the patient on daily diary cards, the patient's assessment of the effectiveness of each treatment and the patient's treatment preference. Secondary variables were the investigator's assessment of symptom severity, and patient scores from a General Health Questionnaire (GHQ28).

Results: Ten subjects completed the trial. Two withdrew, one owing to suspected adverse effects of treatment and one owing to concurrent illness. Friedman 2-way ANOVA test showed significant treatment effects on sleep disturbance recorded by the patient (p = 0.01), fatigue as assessed by the investigator (p = 0.01) and on the scores using the GHQ28 (p = 0.03).

Conclusions: This trial of anthocyanidins in the treatment of primary fibromyalgia has shown small but statistically significant benefits at a dose of 80 mg day-1, the dose that is recommended for these substances to be used as a food supplement. It may therefore be worthwhile patients suffering from this difficult chronic condition undergoing an individual therapeutic trial. A minimum of 3 months' treatment is recommended. Further trials of anthocyanidins in a larger number of patients should probably be undertaken.

Keywords: anthocyanidins, clinical trials, depression, dietary supplements, double-blind method, fibromyalgia, placebos, irritable bowel syndrome, IgA.


Fibromyalgia is a condition characterized by chronic, widespread, musculo-skeletal pain, fatigue and multiple tender points. The criteria required for diagnosis as proposed by the American College of Rheumatology [ 1] are widespread pain of at least 3 months' duration in combination with pain on digital palpation at 11 or more of the 18 specific tender point sites (Fig. 1). Pain is considered widespread if there is pain in both sides of the body and above and below the waist.

There is no definitive treatment for fibromyalgia although many patients are treated with a combination of standard analgesics and low dose anti-depressants. It is uncertain whether the claimed benefits of the tricyclic anti-depressants such as amitryptiline result from anti-depressant activity or their other effects on serotonin metabolism. It has been shown that there are decreased serum levels of serotonin and tryptophan and an increased density of serotonin receptors in patients with fibromyalgia [ 2, 3]. Amitryptiline is widely used in treatment but many of the placebo-controlled trials reported to demonstrate benefit have relied on improvement in pre-study outcome measures rather than comparisons with placebo [ 4, 5]. A review of 3 trials using selective serotonin reuptake inhibitors (SSRIs), concluded that it is unclear from the available evidence whether SSRIs are beneficial for fibromyalgia [ 6]. A placebo-controlled trial of 5-hydroxytryptophan reported that all clinical parameters improved but again this was based on within-group comparisons with baseline rather than between group tests [ 7]. A trial of ondansetron, a 5-hydroxytryptamine Type 3 receptor antagonist, also reported improvements in pain and tender points but only on a within-group analysis [ 8]. In a review of 24 controlled clinical trials the authors identified significant potential sources of bias, inadequate randomization, inadequate blinding, errors in outcome measurement and inappropriate analysis of data [ 9].

In the absence of clear guidelines for optimal treatment, many patients turn to alternative remedies, including homeopathy, food and herbal supplements. Magnesium supplements are recommended particularly in combination with malic acid [ 10]. However, a double-blind, placebo-controlled trial of magnesium (300 mg day-1) + malic acid (1200 mg day-1) failed to show any treatment effect but higher doses given on an open basis were reported to do so [ 11].

A group of food supplements that are sometimes recommended are the anthocyanidins. Anthocyanidins are members of the flavonoid group of plant-derived chemicals. Flavonoids are non-nutritive compounds of plants that have been intensively investigated in recent years for their possible protective effects against chronic disease [ 12]. In vitro studies show that they have considerable antioxidative activity mainly based on the scavenging of oxygen radicals [ 13]. Flavonoids and anthocyanidins are commonly found in European fruits and vegetables. In addition, black tea and red wine may have a high content of these compounds. The anthocyanidin pigments impart red, blue and violet colours in nature, and the sources of the anthocyanidins used in this trial were grape seed (Vitis vinifera), bilberries (Vaccinium myrtillus) and cranberries (Vaccinium macrocarpon). The product used is manufactured and sold by Lamberts Healthcare Ltd, 1 Lamberts Road, Tunbridge Wells, Kent TN2 3BE, UK under the name of Colladeen Trademark.

Anthocyanidins are recommended for the treatment of circulatory disorders, to increase intracellular vitamin C levels, to support collagen structures as well as to prevent the destruction of collagen. As it is possible that some of the problems found in fibromyalgia may derive from poor peripheral circulation and problems with collagen it was thought that a pilot study of these substances was justified, particularly in the light of significant anecdotal evidence from patients on the use of these plant compounds.

The primary aim of this trial was to determine whether the anthocyanidins could improve the main symptoms associated with fibromyalgia, pain, fatigue and sleep disturbance.


Adult patients over the age of 16 years, who had been diagnosed with fibromyalgia by a consultant rheumatologist or a general practitioner, were invited to take part in the study. Women who were pregnant or breast-feeding and those of childbearing potential who were not taking adequate contraceptive precautions were excluded. After an initial visit those who agreed to participate were asked to record on a daily diary card the severity of pain, fatigue and sleep disturbance for a period of 4 weeks, the baseline period. At the end of the baseline period, provided they showed evidence on the diary cards of symptoms of pain and fatigue on most days, they were invited to enter into the treatment period of the investigation. Twelve patients who met the entry criteria were recruited and entered the baseline period. One patient was diagnosed during the baseline period as having low thyroid function, and was withdrawn and replaced. Twelve patients entered the first treatment period. They were all female of mean age 45.6 + or - 5.9 years and the diagnosis had been made 4.2 +/- 2.3 years previously.

Trial Design
The trial was a double-blind, placebo-controlled, cross over trial in which the selected fibromyalgia patients all received four treatments. The treatment order was randomized in blocks of four, each treatment being given for a period of 12 weeks. The total trial period was 52 weeks with 4 treatment periods each of 12 weeks preceded by a 4-week baseline period. Patients were seen by the investigator every 4 weeks. Details of the treatment order are shown in Table 1.

Subjective and Clinical Assessments
Daily symptom diary. Throughout the period of the trial patients kept a daily diary card on which they recorded the severity of the symptoms of pain, fatigue and sleep disturbance.

Pain and fatigue were recorded on a 5-point scale.

0 = no symptoms
1 = mild severity
2 = moderate severity
3 = severe
4 = very severe.
Sleep was also recorded on a 5-point scale.

0 = Slept well all night, awoke refreshed.
1 = Sleep slightly disturbed by fibromyalgia. Awoke feeling slightly tired.
2 = Sleep moderately disturbed by fibromyalgia. Awoke feeling moderately tired.
3 = Sleep severely disturbed by fibromyalgia. Awoke feeling very tired.
4 = Sleep very severely affected by fibromyalgia. Awoke feeling very tired with no benefit from night's rest.
Overall efficacy. At the end of each 12-week treatment period patients were asked whether the treatment they had been taking for the previous 12 weeks had been: very effective, moderately effective, slightly effective, had no effect, made condition worse. At the end of the trial patients were asked which if any of the treatments they considered to be the most effective.

Unusual Events
At each 4-week visit patients were asked if they had experienced any unusual events during the previous 4 weeks. Any such event was recorded by the investigator with details of timing, severity, whether it was resolved or continuing, the severity, whether any action had been necessary and the likely relationship to the test treatment.

Assessment of Overall Health
At the beginning and end of the baseline period and at the end of each treatment period patients completed a General Health Questionnaire (GHQ 28), NFER-Nelson, 2 Oxford Road East, Windsor, Berks SL4 1DF, UK. This is a scaled version of a questionnaire developed originally to identify diagnosable psychiatric disorder [ 14]. It consists of 28 questions divided into 4 sections: A = somatic symptoms, B = anxiety and insomnia, C = social dysfunction, D = severe depression. A maximum score is 28 and a score of 5 or greater indicates a clinical disorder. Scores in the range 6-11 indicate cases of mild severity and 12-28 moderate to severe cases.

Clinical Assessments
At each 4-week visit one of two of the investigators (AME/LB) made an assessment of the severity of pain, fatigue and sleep disturbance experienced by the patient during the previous 4 weeks using similar scoring systems and scales to those used by the patient. This assessment was made after questioning the patient and reviewing the diary cards.

At the end of the treatment period patients were tested for the presence of the specific tender sites associated with primary fibromyalgia.

Other Investigations
Sputum samples were taken for the measurement of salivary immunoglobulin A (IgA).

Intervention Treatments
The four treatments that were compared were:

( 1) Anthocyanidins 120 mg day-1

( 2) Anthocyanidins 80 mg day-1

( 3) Anthocyanidins 40 mg day-1

( 4) Placebo.

The placebo was the excipients in which the anthocyanidins were suspended. All treatments were provided in identical capsules. The capsules were coated with iron oxide to disguise the contents. Patients took 3 capsules every day for the 52 weeks.

The 3 capsules taken each day were either:

All containing anthocyanidin 40 mg, or
Two containing anthocyanidin 40 mg, one containing placebo, or
One containing anthocyanidin 40 mg, two containing placebo, or
All containing placebo.
Other Medication
Patients were allowed to continue any treatment they were taking for fibromyalgia. As far as possible doses were kept constant throughout the trial. Any additional treatment needed to control symptoms was recorded.

Ethical Approval
The protocol was approved by the West Berkshire Ethical Review Committee and all patients read and signed an informed consent form.

Analytical Methods
The primary variables of treatment efficacy were the difference in severity of diary card symptom scores between the four treatments and the patient's opinion of each treatment and treatment preference. Secondary variables included the investigator's opinion of treatment and the difference in the scores recorded at the end of each treatment in the GHQ28. Mean diary card symptom scores were calculated for each patient for each of the 12 months of the treatment period. Comparisons were made between the mean monthly scores for each diary card symptom for the third month of each treatment period using a 2-way Friedman ANOVA test for non-parametric data with patient and treatment as factors. The third month only was used in order to avoid any carry-over effect of treatment as no wash-out period was included between treatments.

For the GHQ28 the total score was calculated for each patient at the end of each treatment period and mean scores derived for each treatment. Similarly, mean scores for the severity of each symptom during the third month of treatment, as assessed by the investigator, were calculated. Both these means and those of the GHQ28 were compared using 2-way Friedman ANOVA.

A value of p < 0.05 was considered to be statistically significant. Statistical tests were performed using Graphpad InStat version 3.00 Windows 95, GraphPad Software, San Diego, California, USA.


Twelve patients were entered into the treatment period. Ten patients completed the trial. Two patients withdrew, one because of an adverse event associated with the test capsules (severe indigestion) and one who was diagnosed with an overactive thyroid gland and diabetes and felt unable to continue. The data from a third patient were excluded from the analysis owing to her mislaying her diary cards for the final treatment period. The data from 9 subjects were therefore included in the analysis.

Table 2 shows the mean symptom scores for the baseline month and for the third month of each treatment recorded on the daily diary cards.

During the baseline month the mean scores for each symptom were between 2 and 3, a severity rating of moderate to severe. Four patients had mean scores of between 1 and 2 (mild to moderate), 2 had scores between 2 and 3 (moderate to severe) and 3 patients had scores between 3 and 4 (severe to very severe). The 2-way Friedman ANOVA test comparing the 4 treatments showed no treatment effect on pain (p = 0.39) or fatigue (p = 0.11), but did show an effect on sleep disturbance (p = 0.01). Wilcoxon-matched pairs, signed-rank tests comparing each dose of anthocyanidins with placebo showed significant effects at all doses. The difference in the mean scores and the 95% confidence intervals of the difference are given in Table 3. The largest effect was seen with the 80 mg day -1 dose difference in mean score: 0.40, 95% confidence interval (CI) -0.63 to -0.17, p = 0.004.

At the end of each treatment period patients were asked about the effectiveness of the treatment they had received. Statistical analysis does not show any difference between treatments.

At the end of the trial patients were asked which course of treatment they preferred. Two preferred 120 mg day -1, 2 preferred 80 mg day -1, 3 preferred 40 mg day -1, one preferred placebo and 2 had no preference. Again analysis shows no preference for any treatment.

General Health Questionnaires
The analysis of the scores derived from the General Health Questionnaires completed by each patient at the end of the baseline and each treatment is shown in Table 4.

The Friedman 2-way test comparing treatments gave a statistically significant treatment effect (p =0.03). Comparisons of the three active doses and placebo using Wilcoxon matched pairs, signed-rank tests showed that only the 80 mg day -1 dose was significantly different to placebo; mean difference -5.0, 95% CI -9.70 to -0.29, p = 0.02.

At the end of the baseline 8 patients had scores of less than 5, 2 had scores of between 6 and 11 and 2 had scores greater than 12. Scores mainly occurred in Section A (somatic symptoms). Three patients, patient numbers 1, 6 and 9, had relevant scores in Section D (severe depression), one on 5 occasions, one on 3 occasions and one on one occasion. Detailed discussion with the patients at this time confirmed the presence of depression. One patient became depressed during an exacerbation of her fibromyalgia but was well during the rest of the year. The two patients (numbers 6 and 9) who had scores in the depression scale on more than one occasion, both had severe fibromyalgia and both were trying to maintain demanding full-time employment and a normal domestic and family life. In the case of both these patients it is considered that it was the severity of the fibromyalgia which led to the depression rather than the other way round. When the work and domestic situations improved so did the depression.

Investigator Assessments
The results of the investigator assessments undertaken at the end of each treatment are shown in Table 5.

This shows a significant treatment effect on the severity of fatigue, p = 0.01. Wilcoxon-matched pairs, signed-rank tests were carried out comparing each dose with placebo and only the 80 mg day -l dose was significantly better than placebo; mean difference 1.00, 95% CI -1.77 to -0.23, p = 0.03.

Trigger Points, Irritable Bowel Syndrome, Secretory IgA
At the end of the trial 9 of the 10 patients who completed the trial were tested for the presence of trigger points. Seven patients had 11 or more positive trigger points of the 18 tested, and 2 had less than 11 (7 and 8) respectively.

Of the 10 patients who completed the additional health questionnaire, 9 had symptoms of irritable bowel syndrome.

Eight patients had measurements of secretory IgA in their saliva. The tests were undertaken by Diagnostech Ltd, York Chambers, York Street, Swansea SA1 3NJ, UK. They quote normal levels as 25-60 mg dl-1, borderline levels as 20-25 mg dl-1 and low levels as <20 mg dl-1. Of the 8 patients in whom this was determined, one had a level of >60 mg dl -1, 3 had levels in the borderline range (20,22and 22 mg dl-1) and 5 had low levels ( 5, 6, 7, 7and 12 mg dl-1).

Unusual Events
At each clinic visit patients were asked about any unusual events. The results are shown in Table 6.

It will be seen that all the active treatments were associated with some unusual events of which those occurring in the gastrointestinal tract predominated. One subject had to be withdrawn from the trial because of severe indigestion. In this patient the gastrointestinal side effects occurred while on the first treatment. This was stopped and the second treatment started after the symptoms had subsided. The side effects recurred. The code was broken and both the first and second treatments were found to be the active treatment.


This trial of anthocyanidins in the management of primary fibromyalgia showed a significant treatment effect compared to placebo in the primary variable of sleep disturbance as recorded by the patient, on a measurement of general health and on the severity of fatigue as assessed by the investigator. No effect was seen on the primary variables of pain and fatigue as recorded by the patient. In clinical terms the effect on sleep disturbance was small. At the dose which showed the greatest effect, 80 mg day-1, the mean severity score for the last month of treatment was 2.20, which represents moderately severe symptoms.

Food supplements are by definition supportive therapy, not subjected to the rigorous testing of efficacy and safety as required for conventional drug therapy, so perhaps it is unreasonable to judge them in those terms. Nevertheless, for chronic conditions such as fibromyalgia it is reasonable to expect any treatment trial to allow an evaluation of the size of beneficial effect that can be expected. In this trial we have evaluated effect on the key symptoms of fibromyalgia, generalized pain, fatigue and sleep disturbance, and have shown a small but potentially useful effect on two of them.

The scores recorded in the GHQ28 are of interest. Fibromyalgia is sometimes considered to be a manifestation of a depressive illness. There is no consistent evidence of this in this group of 12 subjects. Three subjects gave scores in the D section of the questionnaire (the part that refers to depression) but not on every occasion. In each case the underlying illness was having severe effects on the ability of these patients to meet either domestic or work requirements and it is considered that this resulted in depressive symptoms rather that depression being a primary cause. Two of these patients did require an increase in the dose of the anti-depressant treatment they were taking which may have accounted for the significant improvement seen at the 80 mg day-1 doses of anthocyanins. None of the other 9 patients had any evidence of a depressive illness. Where scores occurred above the threshold level of 5/6 these mainly occurred in Section A (somatic symptoms) and are accounted for by the underlying illness.

This small cohort of fibromyalgia patients did exhibit a high incidence of irritable bowel syndrome, 8 out of 9 subjects. In the original American paper that defined the criteria for fibromyalgia, 35.7% of fibromyalgia patients had irritable bowel syndrome compared to 13.3% in control subjects [ 1]. Other studies have reported the co-existence of fibromyalgia and irritable bowel syndrome as high as 70% [ 15, 16]. Also in the 9 patients in our study in whom secretory IgA levels were determined in the saliva, 5 had low levels, 3 borderline levels and 1 normal levels. Some of these patients also had evidence of food allergy or intolerance exacerbating their symptoms of irritable bowel syndrome. It is difficult to see how irritable bowel syndrome and fibromyalgia could be related but it would seem to be justified to extend these preliminary findings and to see whether better management of the irritable bowel, possibly with diet in responsive cases, can improve the fibromyalgia.

The recommended daily dose of anthocyanidins provided by the manufacturers as a food supplement at the time when this trial was planned was 40 mg day-1. This has subsequently been changed to 80 mg day-1. It is at this dose that the optimal and significant treatment effects are observed. It is possible that higher doses might have shown a greater effect but these were not considered justified at the time and are probably not justified if these substances are to be considered as food supplements rather than drugs. Patients reported gastrointestinal side effects and it was necessary to withdraw one patient because of severe indigestion.


This trial of anthocyanidins in the treatment of primary fibromyalgia has shown small but statistically significant benefits at a dose of 80 mg day-1, the dose that is recommended for these substances to be used as a food supplement. Many of the published trials of conventional drug therapy in fibromyalgia have problems in design or analysis making efficacy evaluation difficult. It may therefore be worthwhile for patients suffering from this difficult chronic condition to undergo an individual therapeutic trial. A minimum of 3 months' treatment is recommended. Further trials of anthocyanidins in larger numbers of patients should probably be undertaken.


The authors wish to thank Lamberts Healthcare Ltd for the supply of anthocyanidin capsules and placebo.

TABLE 1. Treatment code
Legend for Chart:

A - Patient No.
B - Period 1
C - Period 2
D - Period 3
E - Period 4


1 C A B D
2 A C D B
3 B D A C
4 D B C A
5 D A C B
6 B C A D
7 A B D C
8 C D B A
9 A C D B
10 B D A C
11 C A B D
12 D B C A

A: Anthocyanidins 120 mg day-1

C: Anthocyanidins 40 mg day-1

B: Anthocyanidins 80 mg day-1

D: Placebo
TABLE 2. Diary card symptom scores for baseline month and last month of each treatment (n = 9)
Legend for Chart:

A - Symptom
B - Baseline
C - Anthocyanidins 120 mg day-1
D - Anthocyanidins 80 mg day-1 Mean (SD)
E - Anthocyanidins 40 mg day-1
F - Placebo
G - Friedman 2-way ANOVA Fr statistic
H - Friedman 2-way ANOVA p


Pain 2.25 (0.79) 2.38 (0.95) 2.29 (0.81) 2.20 (0.89)
2.49 (0.77) 3.000 0.39

Fatigue 2.24 (0.69) 2.48 (0.91) 2.39 (0.81) 2.48 (0.59)
2.73 (0.75) 5.933 0.11

Sleep 2.17 (0.75) 2.33 (0.72) 2.20 (0.59) 2.29 (0.60)
2.60 (0.72) 11.318 0.01
TABLE 3. Comparison of treatments on sleep disturbance (Wilcoxon matched-pairs signed-ranks test)
Legend for Chart:

B - Mean difference
C - 95% confidence intervals of difference
D - p


Anthocyanidins 120 mg -0.27 -0.50 0.04
-- Placebo -0.04

Anthocyanidins 80 mg -0.40 -0.63 0.004
Placebo -0.17

Anthocyanidins 40 mg -0.32 -0.55 0.02
-- Placebo -0.08
TABLE 4. General Health Questionnaire (GHQ28). Mean scores at end of baseline and after each treatment (n = 9)
Legend for Chart:

B - Baseline
C - Anthocyanidins 120 mg day-1
D - Anthocyanidins 80 mg day-1 Mean (SD)
E - Anthocyanidins 40 mg day-1
F - Placebo
G - Friedman 2-way ANOVA Fr statistic
H - Friedman 2-way ANOVA p


Score 6.78 (7.59) 5.11 (5.57) 1.56 (2.40) 4.00 (3.87)
6.56 (6.71) 8.688 0.03
TABLE 5. Investigator assessments at end of baseline month and after last month of each treatment (n = 9)
Legend for Chart:

A - Symptom Mean (SD)
B - Baseline Mean (SD)
C - Anthocyanidins 120 mg day-1 Mean (SD)
D - Anthocyanidins 80 mg day-1 Mean (SD)
E - Anthocyanidins 40 mg day-1 Mean (SD)
F - Placebo Mean (SD)
G - Friedman 2-way ANOVA Fr statistic
H - Friedman 2-way ANOVA p


Pain 2.44 (0.88) 2.33 (1.0) 1.89 (0.78) 2.11 (1.05)
2.67 (1.00) 2.371 0.50

Fatigue 2.56 (0.88) 2.33 (1.00) 1.78 (0.67) 2.67 (0.71)
2.78 (0.83) 10.932 0.01

Sleep 2.33 (1.00) 1.78 (0.97) 1.78 (0.83) 2.22 (0.83)
2.56 (1.01) 5.308 0.15
TABLE 6. Unusual events recorded at investigator visits
Legend for Chart:

A - Event
B - 120 mg day-1
C - 80 mg day1
D - 40 mg day-1
E - Placebo


Indigestion 1 1

Nausea 1

Sinusitis and nausea 1

Gastric flu 1

Cold sweats, dizziness, nausea 1 1

Appendicitis 1

Dizzy spells 1

Skin rash 1

Urinary disturbance 2

Bad colds 1

Pain in head 1 1 1

Right leg heavy 1

Painful hands 1

Pain in legs 1

Fell downstairs 1

Total 6 5 7 2
Number of patients reporting at
least one event 5 3 6 2
DIAGRAM: FIG.1. Fibromyalgia syndrome diagnostic criteria.

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By A. M. Edwards, MA MB BCHIR MRCGP DIP PHARM MED, Department of Medical Specialties, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK; L. Blackburn, RGN, East Berkshire Community Trust, Ewhurst House, King Edward VII Hospital, Windsor SL4 3TS, UK; S. Christie, BSC (HONS), Hugh Sinclair Unit of Human Nutrition, Department of Food Science and Technology, The University of Reading, PO Box 226, Whiteknights, Reading RG6 6AP, UK; S. Townsend, RGN, Department of Rheumatology, Royal Berkshire & Battle Hospitals NHS Trust, Battle Hospital, Oxford Road, Reading RG30 1AG, UK and J. David, MB BCH FRCP, Department of Rheumatology, Royal Berkshire & Battle Hospitals NHS Trust, Battle Hospital, Oxford Road, Reading RG30 1AG, UK


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