Does vitamin D treat pain – still not absolutely, positively sure – meta-analysis April 2015

Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States

Pain and Therapy, April 2015, 29 Apr 2015
Elspeth E. Shipton, Edward A. Shipton shiptonea at xtra.co.nz

Introduction
A number of studies suggest a link between low levels of 25-hydroxy vitamin D and incidence of acute and chronic pain. Clinical studies of vitamin D supplementation in patients with known vitamin D deficiency have shown mixed results in improving pain scores.
Methods
In this article, vitamin D deficiency risk factors are observed and adequate levels of 25-hydroxy vitamin D defined. Clinical supplementation with vitamin D is explored, including the schedules used in published clinical trials. Evidence of the effectiveness of vitamin D supplementation for the treatment of chronic pain conditions from double-blind randomized controlled trials (RCTs) is examined.
Results
The scientific evidence for vitamin D as a treatment option for chronic pain is limited due to lack of RCTs. It cannot be stated conclusively that vitamin D deficiency is directly linked to the etiology or maintenance of chronic pain states.
Conclusion
There remains a growing body of both clinical and laboratory evidence pointing to a potential relationship between low levels of 25-hydroxy vitamin D and a variety of chronic pain states. More focused research involving large RCTs is necessary.

DISCUSSION

Evaluation of clinical studies regarding the use of vitamin D for the treatment of chronic pain was previously undertaken in 2008 [6]. The authors searched MEDLINE (PubMed) using various search terms for vitamin D and pain prior to September 2008. Twenty-two relevant studies were identified that reported mean 25(OH)D levels and/or investigated the results of vitamin D treatment in patients with chronic pain conditions.

• Only five of these studies were randomized double-blind trials of vitamin D treatment.
• Vitamin D treatments involved monthly equivalent doses between 1200 and 400,000 IU.
• Fourteen studies were in musculoskeletal pain,
• five in chronic widespread pain or fibromyalgia,
• one in diabetic subjects with neuropathic pain,
• one addressing an unusual hyperaesthetic pain syndrome, and
• one in various conditions.

Duration of treatment was from a few days to 12 months, although most studies lasted 2 months or more. Treatment studies involved 733 patients. Randomized double-blind trials involved 229 patients, of whom only 22 (10%) were in a trial with a significant improvement in pain with vitamin D, and then only on a pain mobility measure; 207 patients were involved in trials with no significant improvement in pain with vitamin D. There was also no apparent correlation between significant improvement in pain with vitamin D and with a particular preparation, dose, or condition. There was no persuasive evidence of lower levels of 25(OH)D in those with chronic pain than in the control populations. There was a striking contrast in treatment effects between randomized, doubleblind trials that minimized bias and those with designs known to be subject to bias. In the former, only 10% of patients were in trials showing a benefit of vitamin D treatment; in the latter, 93% were in trials showing a benefit of vitamin D treatment [6]. This study highlighted the need for further randomized double-blind placebo-controlled trials.

A Cochrane review of randomized doubleblind trials of vitamin D supplementation compared with placebo was published in 2010 [4]. The aim was to determine the efficacy of vitamin D in the treatment of chronic pain conditions. Only four studies (with a total of 294 participants) were included; eleven trials were excluded due to poor methodological design, or because not all participants received a clearly defined chronic pain diagnosis [4]. The studies included were similar in quality, used analogous chronic pain conditions with comparable outcome measures [91, 96, 99, 100]. Patients were supplemented with varying amounts and formulations of vitamin D for periods ranging from 16 weeks to 12 months. In summary, out of the four trials reviewed, the benefit of using vitamin D in chronic pain treatment was only shown in one trial. In the other three trials, there was no significant beneficial effect of vitamin D over placebo. Adverse effects of treatment were infrequent, and occurred at the same rates in vitamin D and placebo groups [96, 100].

Our study concurs with the results of the previous review on the subject published in 2009 and the Cochrane review published in 2010, in that there is insufficient high-quality evidence for a definitive effect of vitamin D in chronic pain. However, a trend appears in a positive direction indicating a beneficial effect of vitamin D over placebo in chronic pain.

The number of randomized placebo- controlled double-blind studies is increasing which is encouraging. Six of the RCTs included in our study were published since 2011. Although the search strategy of this comprehensive review was thorough, it is possible that some randomized clinical trials might not have been located. A positive publication bias cannot be excluded as journals are reluctant to publish negative results. The overall picture generated by a review of this type could thus be a false positive.

CONCLUSION

Studies using visual analog scale (VAS) pain scores as the primary or solitary outcome measure have shown mixed results in chronic pain patients when evaluating the impact of vitamin D supplementation in this condition [82, 91, 101-103]. Significant improvements in assessment of sleep, mood, pain levels, wellbeing, and various aspects of quality of life with vitamin D supplementation have been shown [82, 104-107]. Whilst there is a growing body of both clinical and laboratory evidence pointing to a potential relationship between low levels of 25(OH)D and chronic pain, it is not possible to state conclusively that vitamin D deficiency is directly linked to the etiology or maintenance of chronic pain states. The scientific evidence for the use of vitamin D as a treatment option for chronic pain is limited at present due to low-quality designs, and due to the lack of RCTs.

A number of questions remain with regard to supplementation of vitamin D in patients with chronic pain. Vitamin D metabolism and action needs to be further elucidated including extra- renal activation and catabolism, distribution and mobilization from body pools, and its interaction with relevant genetic polymorphisms [8]. There remains some debate over the precise definition of vitamin D deficiency or insufficiency based on the serum levels of 25(OH)D. The influence of age and body weight on the variability of the response of serum levels of 25(OH)D to intake needs to be clarified [8]. More focused research is necessary involving larger double-blind RCTs. These need to be stratified by baseline 25(OH)D levels, type of pain, and the use of adequate doses of vitamin D based on serum levels. More research is necessary to determine whether or not the effect of vitamin D supplementation is limited to patients who are vitamin D deficient. The optimal dose and length of time needed for supplementation need to be assessed as well.

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