Thursday, December 13, 2012
Various studies have reported beneficial effects of vitamin D supplements on chronically painful musculoskeletal conditions, although higher quality evidence from randomized controlled trials (RCTs) is relatively rare. A new RCT examined vitamin D for nonspecific persistent musculoskeletal pain and found important benefits after only 6 weeks of therapy.
Ferdinand Schreuder, MD, from The Netherlands, and colleagues conducted a semi-crossover randomized placebo-controlled trial in 84 non-Western immigrants with nonspecific musculoskeletal pain persisting >3 months. Patients were immigrants born in the Middle East, Turkey, northern Africa, and Somalia, and their offspring who were currently living in The Netherlands. This was a population known to have deficient vitamin D levels and also prone to developing difficult-to-treat musculoskeletal pain complaints.
The 84 selected patients were 42 years of age on average, 76% were female, and pain was moderate to severe (mean average pain score was 63.0 on 100 mm VAS, mean highest score was 86.0). More than half of the patients had nonspecific widespread pain, while others had pain in arms, legs and/or joints. At baseline, mean vitamin D levels — measured as 25(OH)D — were highly deficient at 8.0 ± 4.0 ng/mL.
At the start of the trial patients were randomized to receive either placebo (N=40) or vitamin D (single-dose 150,000 IU oral vitamin D3; N=44), and results were first assessed at week 6. At that time, patients in the original vitamin D group were randomized a second time to either continue vitamin D or to receive placebo, whereas patients in the original placebo group were all switched to vitamin D. Results were assessed again at week 12, and patients and investigators were blinded throughout as to group assignment.
Therefore, after eliminating subjects lost to followup, at week 6 there was a vitamin D group (N=43) and a placebo group (N=36). At week 12, there were 3 groups for assessment:
- Vitamin D–Vitamin D = subjects who received vitamin D throughout the 12 weeks (N=23).
- Vitamin D–Placebo = subjects receiving vitamin D initially, then switched at 6 weeks to placebo (N=16).
- Placebo–Vitamin D = subjects receiving placebo initially, then switched at 6 weeks to vitamin D (N=30)
The primary outcome was self-assessed change in pain on a 5-point Likert scale after the first 6 weeks of treatment. Secondary outcomes included reported change in ability to climb stairs at 6 and 12 weeks (also Likert scale), and pain at 12 weeks (Likert scale). Likert scales asked patients to categorize their pain or stair-climbing ability as being either (a) much less/much better, (b) less/better, (c) equal or no change, (d) more/worse, or (e) much more/much worse.
The researchers also assessed pain specifically in the neck/shoulders, low back, arms, legs, and joints on visual analog scales (VAS, 100mm). During the study, patients were allowed to continue their medical care as usual, including physiotherapy and/or medications.
Writing in the November/December 2012 edition of the Annals of Family Medicine, Schrueder et al. reported the following results:
- At week 6, the vitamin D group reported significant improvements in pain — ie, much less or less pain — compared with the placebo group (34.9% vs 19.5%, respectively; P=0.04). And, at that time, the two groups were equivalent in the use of pain medication or physiotherapy.
- Also at week 6, a lower proportion of the vitamin D group reported worsening pain — eg, more or much more pain — than patients receiving placebo (25.6% vs 44.4% respectively, P=0.04).
- Furthermore, at week 6, the vitamin D group reported significant improvements (ie, much better or better) in their ability to climb stairs, connoting leg-muscle strength, compared with the placebo group (21.0% vs 8.4% respectively, P=0.008), and the vitamin D group was less likely to have deterioration in this ability than the placebo group.
- Patients receiving vitamin D for the full 12 weeks — Vitamin D–Vitamin D group — were more likely to report improvements in pain and leg strength than those taking vitamin D for only 6 weeks, although this trend was not statistically significant.
- The various assessments using 100mm VAS measurements of pain in specific body regions did not reach statistical significance, but this was likely due to study limitations (discussed below).
- There were no adverse effects of vitamin D supplementation found during or after the trial.
The authors conclude that, using a randomized placebo-controlled design, vitamin D supplementation demonstrated significantly positive effects on pain within 6 weeks in a population of non-Western immigrants in the Netherlands. Additionally, there were benefits of vitamin D for musculoskeletal strength, as evidenced by stair climbing ability. Further investigations should involve greater numbers of subjects and higher doses of vitamin D.
COMMENTARY: We have repeatedly advocated for vitamin D supplementation as adjunctive therapy for aiding persons with various chronic pain conditions, particularly those that are musculoskeletal-related. See research reports here and ongoing UPDATES series here.
At the same time, we have been critical of the low quality of research in this area, which more often than not consists of small observational studies or anecdotal case reports. So, this present randomized controlled trial by Schreuder and colleagues could be an important contribution to the literature on this subject; however, this trial is disappointing in a number of respects.
The researchers pursued a design that was complex in both execution and analysis, and they probably could have used a more parsimonious approach. For example, they could have kept just two groups for assessment at both 6 and 12 weeks — a treatment group (receiving vitamin D) and a placebo control group. Instead, at 6 weeks they re-randomized half the subjects and switched the placebo group to vitamin D, ending up with 3 smaller groups at 12 weeks.
The researchers’ explanation for this was that they wanted all patients to receive some vitamin D supplementation and to compare subjects receiving continuous vitamin D dosing over the entire trial with those who received only 6-weeks dosing, either during the first half or the second half of the trial. As a result, however, there was no control group receiving placebo during all 12 weeks of the trial for comparison purposes at the end of the study.
Another problem of this approach was that it diminished group sizes to a point where there was insufficient statistical power at 12 weeks to adequately detect significant differences between groups. The researchers had calculated that they would need 38 patients per group to detect an absolute improvement of 30% (40% in vitamin D group minus 10% in placebo group) with 80% power at a 5% significance level (P=0.05). At week 6 there were barely sufficient numbers of subjects remaining for adequate assessment and by week 12, when group sizes ranged from 16 to 30, there was a greatly increased likelihood of Type II (false-negative) errors.
The lack of statistically significant findings at 12 weeks on Likert scales, as well as on VAS scores, may reflect this lack of statistical power. The researchers attribute the nonsignificant VAS findings as possibly due to “greater validity of the verbal Likert scales than the abstract VAS scores in our probably less educated population.” However, this seems like a rather cursory explanation and they offer little further discussion of this shortcoming in the research design, other than to admit that the small numbers of patients probably defeated reliable and valid analyses of the many variables measured at week 12.
As another important consideration, the vitamin D dosing protocol in this trial was probably inadequate in several respects. Although single high-dose administration of vitamin D — 150,000 IU D3 in this trial — may be convenient and improve patient adherence, there is little evidence in the literature that this is suitable for raising 25(OH)D levels to desired ranges and maintaining them over time.
Generally, less than 25% of a dose of vitamin D from any source — sun exposure, diet, supplements — is actually used and the rest is excreted within several days [for a complete discussion with references, see article PDF here]. Of the relatively small portion that is put to use, some of it contributes to stores of vitamin D — maintained in adipose tissue, skeletal muscle, and many organs —and the rest is immediately metabolized to 25(OH)D and then to the active metabolite 1,25(OH)D. When there is a continuous daily supply of exogenous vitamin D, an equilibrium is reached that maintains a balance between storage, removal from tissue stores, metabolism, and clearance. If vitamin D intake is diminished or stopped — or only administered once in high dose — reabsorption of vitamin D from the tissue-storage reservoirs can be used to sustain conversion to 25(OH)D during a period of time; however, an initially abundant supply of vitamin D does not deter its complete depletion during periods of lean or no intake.
A normal level of 25(OH)D in healthy persons is ≈30 ng/mL (although some newer guidance claims ≥20 ng/mL as an acceptable threshold). However, in persons with chronic musculoskeletal pain, levels up to 50 ng/mL or more have been found necessary and appropriate for helping to ameliorate their conditions.
In this present trial, patients who had received 150,000 IU Vitamin D3 at the outset reached a mean 25(OH)D level of 25 ng/mL at 6 weeks. This was a large, significant increase from the mean 8 ng/mL at baseline, but still insufficient for persons with pain. Furthermore, the 25(OH)D level declined by 12 weeks to 16 ng/mL on average in those not receiving a second dose at 6 weeks.
Schreuder et al. concede that their supplementation dose may have been too low to achieve desired impact, and the greater improvement among patients who received vitamin D for the full 12 weeks supports this contention. Still, it would have been more informative and a greater contribution to the research on vitamin D for pain if they had used a sufficient daily dose of D3 to raise 25(OH)D concentrations to more optimal levels.
Finally, two other important factors were not taken into account in this trial, as acknowledged by the researchers. For example, patients were not assessed for possible psychosocial influences on their pain — depression, somatization, other psychological disorder — which would not be ameliorated by vitamin D supplementation, but could have skewed outcomes. Also, there was no assessment of parathyroid hormone (PTH) levels, which increase with deficient 25(OH)D and negatively affect skeletal muscles. While the researchers assert that PTH testing is unimportant for clinical practice, its measurement in this trial might have been helpful for better defining potential benefits of vitamin D supplementation.
So, a most remarkable aspect of this study is that, even though patients probably received fundamentally inadequate vitamin D supplementation and for a relatively brief period of time, there were still strongly beneficial outcomes. From the available data, we calculated an NNT≈6 for improvement in pain and NNT≈8 for stair climbing after only 6 weeks of therapy. That is, 1 of every 6 persons treated with vitamin D rather than placebo would have some pain relief, and 1 of 8 would have greater leg strength for climbing stairs. While these are relatively small effect sizes, they are significant enough to realize meaningful differences in everyday clinical practice, and effects might be improved dramatically with more adequate, daily dosing of oral vitamin D3 and for an extended period of time.
REFERENCE: Schreuder F, Bernsen RMD, van der Wouden JC. Vitamin D Supplementation for Nonspecific Musculoskeletal Pain in Non-Western Immigrants: A Randomized Controlled Trial. Ann Fam Med. 2012(Nov/Dec);10(6): 547-555 [access article here].