Ten consecutive subjects with chronic fatigue syndrome from a secondary care setting who fulfilled the exclusion and inclusion criteria were recruited in this study. The Centres for Disease Control and Prevention criteria were used to diagnose Chronic Fatigue syndrome[10]. Subjects having severe fatigue of at least 10 out of 11 on the Chalder Fatigue Scale (binary scored) were enrolled[11].

The exclusion criteria were: any co-morbid psychiatric disorder classified according to Diagnostic and Statistical Manual of Mental Disorders (fourth edition) (DSM IV) criteria (APA 1984), subjects taking more than 10 gm of chocolate per day, use of any prescription medication including benzodiazepine or antidepressant drugs, over the counter medications including herbal remedies two months before study entry, and an inability to attend the hospital for screening tests or follow-up visits.

All participants gave their written informed consent prior to participating in the study. The study was approved by the Hull and East Riding Local Research Ethics Committee. Block randomisation was performed. Subjects had 8 weeks of the initial intervention and then 8 weeks of the crossover intervention separated by a 2 week wash out between the 2 arms. Severity of fatigue and handicap was analysed using using validated self-report questionnaires (Chalder Fatigue Scale (Likert Scored), the London Handicap Scale (LHS) and the Hospital Anxiety and Depression Scale before and after each phase of the trial [11–13].

The active product was polyphenol rich chocolate containing 85% cocoa solids (derived from a high cocoa liquor content) compared with chocolate containing cocoa butter alone that contained no non-fat cocoa solids (cocoa liquor) (simulated iso-calorific chocolate). Chocolate containing cocoa butter alone was dyed to the same colour as the high cocoa liquor/polyphenol rich chocolate (with a recipe specially prepared by Nestlé PLC York. UK). Individual 15 g foil wrapped bars were provided and subjects were asked to consume 1 bar three times daily. Subjects were reviewed by the dietician during screening, before and after each intervention to assess whether they were taking more than 10 g of chocolate per day prior to recruitment, as well as to advise them not to consume extra chocolate during the study period. Apart from this, subjects were advised not to change their diet. A taste trial was performed prior to the study to confirm that subjects could not distinguish between the two treatments.

Analysis of the chocolate was performed by Nestlé PLC York. The simulated iso-calorific chocolate with the dye contained 547 Kilocalories/100 g where as the dark chocolate with cocoa powder contained 545 kilocalories/100 g (''Genesis for Windows, Esha Research'' software). The glycaemic index of dark chocolate was 41 where as for simulated iso-calorific chocolate was 40. The composition of high cocoa liquor/polyphenol rich chocolate and the simulated iso-calorific chocolate is given in Table 1, and the polyphenol content of each shown in Table 2. The total percentage of non-fat cocoa solids (cocoa liquor) in polyphenol rich chocolate was 33.17%. Micro analyses were carried out on a cross section of samples resulting in no salmonella or enterobacter laceae.

Table 1 Composition of high cocoa liquor/polyphenol rich chocolate and simulated iso-calorific chocolate (cocoa liquor free/low polyphenol) Full size table

Table 2 Polyphenol analysis* high cocoa liquor/polyphenol rich chocolate and simulated iso-calorific chocolate (cocoa liquor free/low polyphenol) Full size table

Statistical Methods

We calculated sample size according to previous published data on the fatigue scale in chronic fatigue syndrome[14]. With a confidence interval of 1-alpha (2 sided), and a standard deviation of 2.25, for 80% power that gave a number of 10 subjects to be studied to show a 4 point difference between the two treatments including a drop out rate of 2 subjects. Statistical analysis was performed using SPSS for Windows NT, version 9.0 (SPSS Inc., Chicago, Illinois). Data was analyzed on an 'intention to treat' basis with the Wilcoxon Signed Rank sum test before and after intervention. An arbitrary level of 5% statistical significance was assumed (two tailed). Successful demonstration of efficacy for the trial was defined as a statistically significant superiority over cocoa absent chocolate in the primary outcome variable, fatigue.