Introduction

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The UK Department of Health and the Medical Control Agency have recently published recommendations to restrict the dose of vitamin B-6 available generally to 10 mg and to limit the dose sold by a pharmacist to less than 50 mg.¹ Vitamin B-6 is often used to treat premenstrual syndrome without clear evidence of its efficacy, hence it is timely to re-evaluate vitamin B-6 in the treatment of premenstrual syndrome.

Premenstrual syndrome exists when women complain of regularly recurring psychological or somatic symptoms, or both, which occur specifically during the luteal phase of the menstrual cycle and which are relieved by the onset of, or during, menstruation. Symptoms can be severe enough to disrupt every day life.² Mild physiological symptoms occur in approximately 95% of all women of reproductive age. Approximately 5% of symptomatic women complain of such severe symptoms that their lives are completely disrupted.³

Somatic symptoms of premenstrual syndrome include bloating, weight gain, mastalgia, abdominal discomfort and pain, lack of energy, headache, and exacerbations of chronic illnesses such as asthma, allergies, epilepsy, or migraine. Commonly reported affective changes are dysphoria, irritability, anxiety, tension, aggression, feelings of being unable to cope, and a sense of loss of control.⁴

Since the original description of the syndrome in 1931⁵ numerous hypotheses have been advanced to explain premenstrual syndrome, but to date the pathogenesis remains unclear and speculative.⁶ This uncertainty reflects the many treatments available⁷; one reviewer suggested that there were as many as 327 different treatments for premenstrual syndrome.⁶ Most interventions, however, have been on the basis of informal observations, retrospective data collection, or inadequately controlled trials.

The recommended dietary allowance for vitamin B-6 is around 2.0 mg/day, depending on age and protein intake,⁸ and deficiency of vitamin B-6 is rare.⁹ Excessive ingestion (2000-6000 mg) of vitamin B-6 causes peripheral neuropathy,^10-17 and doses of 200 mg/day may cause similar, although probably reversible, effects.¹⁸

Because the efficacy of vitamin B-6 has not yet been proved, and in light of recent government recommendations, we undertook a systematic review of published and unpublished randomised controlled trials where efficacy of vitamin B-6 was compared with placebo in women with premenstrual syndrome.

	Methods

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Trials
We found reports of published and unpublished clinical trials by searching medical databases for trials of vitamin B-6 (pyridoxine) in the management of premenstrual syndrome (MeSH terms used were premenstrual syndrome and pyridoxine, together with title and abstract searches for keywords vitamin and pyridoxine, premenstrual syndrome, PMT, LLPDD, and PMDD). We also contacted relevant pharmaceutical companies manufacturing vitamin B-6 preparations. The trials were identified by searching Embase (1988 to 1996), Medline (1966 to 1998), Psychlit (1974 to 1997), Cinahl (1982 to 1997), and the database of the Cochrane Controlled Trials Register. We searched references cited in all included and excluded trials to identify any missing studies. All languages were included. Trials investigating the effect of vitamin B-6 on premenstrual symptoms were included if they were randomised, placebo controlled, double blind, parallel, or crossover studies (where the first treatment period could be treated as a parallel trial) for which data could be acquired. We also included studies investigating the effect of multivitamin supplements on premenstrual symptoms, when the vitamin preparation contained 50 mg or more of vitamin B-6.

Data extraction and outcome measures
We extracted the data from each trial that met the inclusion criteria. When there were insufficient data presented for inclusion, we contacted authors for further details. Data on the dosage and preparation of vitamin B-6 were collected. The main outcome measure was an improvement in overall premenstrual symptoms. Combined or overall symptoms was chosen in an attempt to overcome the clinical heterogeneity concerned with the measurement and scoring of premenstrual symptoms. As a secondary outcome we recorded the improvement in depressive premenstrual symptoms when suitable information was presented. Where possible we also recorded the number of women withdrawing from treatment and those complaining of side effects.

Quality assessment
We assessed the quality of each trial with two different methods. Firstly, we assessed the methodology of each trial with a scale developed by Jadad and colleagues.¹⁹ This scale assesses the randomisation and double blinding and reports of dropouts and withdrawals. Secondly, we developed a second quality scale to assess the trials for study design, reproducibility, and statistical analysis. The eight point scale measured: preliminary diagnosis of premenstrual syndrome for all participants in the trial; confirmation that no other vitamin supplements or oral contraceptives were being concurrently taken; the randomisation procedure described in detail; a power calculation to justify participant numbers, or >65 participants in each arm of the study; a single clearly stated dose of vitamin B-6 only; reproducible measurement of premenstrual symptoms such as use of visual analogue scales or Moos' menstrual distress questionnaire; clear presentation of results; and a description of the number and reason for trial withdrawals. One point was awarded for each category. Each trial was independently scored by KMW and PWD, and any areas of disagreement arbitrated by PMSO. A predetermined criterion for the recognition of the highest quality trials was established. A score of 3 or more was required in the Jadad score (as recommended by Jadad and colleagues¹⁹) and a score of 6 or more was required in our eight item quality assessment.

Statistical analysis
Where dichotomous data were presented, odds ratios with 95% confidence intervals were generated for the primary and, where possible, secondary outcome in each trial.²⁰ We calculated odds ratios by categorising patients with a subjective improvement as "better," and those with no change or worse symptoms as "not better." Odds ratios of >1 indicated that an event was more likely to occur in the group receiving vitamin B-6 than in the group receiving placebo. We calculated an overall odds ratio with fixed and random effects models.²⁰ Homogeneity was tested for with a ² test, with P<0.05 indicating significant heterogeneity. For trials using continuous measures of premenstrual symptomology, we calculated a standardised mean difference (or effect size), and converted to an odds ratio using a relation given by Hasselblad and Hedges.²¹

	Results

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We identified 25 published trials. ^{2 18 23-45} Of these, four were excluded because they did not include a placebo group, ^{34 38 39 43} two were retrospective studies, ^{40 41} and nine presented quantitative data that could not be analysed, ^{2 18 23 27 35-37 42 45} leaving 10 placebo controlled trials. ^{24-26 28-44} Two of the trials had two separate dosing regimens and were effectively treated as four studies. Only one trial contained details of the method of randomisation.²⁵

Quality assessment of the trials
Three of the included trials met the Jadad scale cut off point of a score of 3. ^{25 26 33} However, only one of the trials included in the meta-analysis scored 6 on our eight point criteria for classification as a high quality trial.³¹ Unfortunately this trial had too few subjects to achieve sufficient power and had a low Jadad score. The overall methodology of the trials was poor, with none of the included trials justifying patient numbers with a power calculation. Three of the 10 studies reported the number of withdrawals from a trial, together with reasons, and side effects when taking either vitamin B-6 or placebo. ^{26 30 33}

	Discussion

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The conclusions that can be drawn from our systematic review are limited. Although the results from the available data suggest that vitamin B-6 is more effective than placebo, there is insufficient evidence of high enough quality to give a confident recommendation for using vitamin B-6 in the treatment of premenstrual syndrome. For example, the evidence from the overall analysis would be more compelling if there were large scale rigorous trials with sufficient power to detect a clinically significant effect. To detect a medium effect size (0.5) at a significance level of 0.05 and 80% power, approximately 65 subjects would be required in each arm, using a two tailed test. Only one of the nine studies included a sufficient number of patients,²⁶ and all the other trials had low statistical power (<70%). The methodologies of each trial varied considerably using differing dosage regimens and different outcome measures, which makes intercomparisons difficult. In addition, the possible inclusion of women taking oral contraceptives complicates the overall analysis of the effect of vitamin B-6 on premenstrual syndrome as the vitamin may be treating pill induced premenstrual symptoms or depression.

An overall odds ratio was calculated from the nine included trials. Of these trials, two ^{24 29} only studied the effect of vitamin B-6 on mastalgia and three ^{28 30 33} used the multivitamin preparation Optivite (Optimox, Torrance, CA, USA). We believed it was appropriate to include the trials of mastalgia, as breast pain and breast swelling are frequent premenstrual symptoms. As many as 60% of women with premenstrual syndrome report cyclical breast pain as a primary component.⁴⁶

View larger version (30K): [in this window] [in a new window]   Fig 1.   Odds ratios (95% confidence intervals) for proportion of patients showing improvement in overall premenstrual symptoms with vitamin B-6

View larger version (24K): [in this window] [in a new window]   Fig 2.   Odds ratios (95% confidence intervals) for proportion of patients showing improvement in depressive premenstrual symptoms with vitamin B-6

The odds ratios in the four included trials that used only vitamin B-6 and studied premenstrual symptomatology ^{25 26 31 32} were found to be heterogeneous. The combined odds ratio for the four trials was 2.15 (95% confidence interval 1.79 to 2.59; homogeneity test, P=0.035), and when one heterogeneous trial was excluded,²⁵ the recalculated odds ratio was 2.07 (1.72 to 2.50; homogeneity test, P=0.61).

The use of funnel plots in meta-analysis gives a simple graphical method of assessing bias. A regression analysis to assess quantitatively potential asymmetry of the funnel plot shown in figure 4 indicated no significant asymmetry.²² The size and quality of the included trials, however, makes any definite statement concerning bias inappropriate.

Depression
One of the rationales behind vitamin B-6 being recommended as a treatment for premenstrual syndrome was the observation that it could ease induced depression in several conditions^47-49 particularly that associated with contraceptive pills high in oestrogen and progesterone. ^{50 51} The combined odds ratio of the four trials (representing 541 patients) that presented data for depressive symptoms was 1.69 (1.39 to 2.06), and this was homogeneous. This indicates that vitamin B-6 is better than placebo in treating premenstrual depression. It is unlikely, however, that this is the central mode of action of vitamin B-6 in treating premenstrual syndrome, as the odds ratio for overall symptomatology is more favourable than when considering premenstrual depression alone.

View larger version (10K): [in this window] [in a new window]   Fig 3.   Dose response of vitamin B-6 against individual odds ratios for patients who showed improvement in premenstrual symptoms with vitamin B-6 (when two trials used same dose, data points offset for clarity)

View larger version (8K): [in this window] [in a new window]   Fig 4.   Funnel plot of included studies: precision of study (inverse of SE) against odds ratios

Dose response
The lack of a dose response (fig 3) indicates that the amount of vitamin B-6 given has no impact on the efficacy of its use as treatment for premenstrual syndrome, for either vitamin B-6 alone or when given in a multivitamin preparation. This result adds to the misgivings surrounding the use of vitamin B-6 as a treatment. The toxic effects of vitamin B-6 at doses higher than 200 mg/day are well characterised. As the recommended daily allowance of vitamin B-6 is around 2 mg,⁸ any effect of vitamin B-6 on premenstrual symptomatology would be pharmacological. However, there does remain some controversy as to the precise vitamin B-6 requirement in disease states, highlighted by the successful use of vitamin B-6 doses of around 100 mg/day in the management of carpal tunnel syndrome.⁵²

Multivitamins
The rationale for including multivitamin treatments in a review on vitamin B-6 is the very large amount of vitamin B-6 in the tablets used, 50 mg per tablet (600 mg/day), which represents over 25 times the recommended daily allowance.⁸ Figure 1 shows the results of the published trials on use of multivitamins in the treatment of premenstrual syndrome, with an overall odds ratio of 2.08 (1.55 to 2.78; homogeneity test, P=0.61). The lack of a dose response makes the daily consumption of more than 100 mg of vitamin B-6 inadvisable, and doses in excess of 200 mg/day cannot be recommended in the light of the proved toxic side effects of vitamin B-6, even in a multivitamin preparation.

Side effects
Only one patient of the 940 participating in these trials indicated the presence of any side effects that could be attributed to the neuropathy associated with pyridoxine toxicity.³³ This may be due to the comparatively low doses used and the short duration of the trials. The symptoms, however, may have been missed owing to the lack of assessment by a suitably qualified neurologist. Detailed animal studies on pyridoxine indicate that nerve damage can occur before manifestation of the gross symptoms such as ataxia and neuropathy. ^{11 12}

Conclusions
Conclusions from this meta-analysis are limited by the quality of the trials. No conclusive evidence of vitamin B-6 toxicity was reported, and there seems to be no dose related response to treatment. We conclude, therefore, that there is no rationale for giving daily doses of vitamin B-6 in excess of 100 mg. Such doses, and possibly doses of 50 mg/day, are likely to be of benefit in relieving premenstrual symptoms.