Sunday, January 17, 2010

Vitamin D for Pain: Update of Research Evidence

Vitamin DIn summer 2008 Pain Treatment Topics published ground-breaking research reviews focusing extensively on the potential benefits of vitamin D for patients with chronic pain conditions, particularly musculoskeletal and back pain [see reports here]. What has happened since that time? This blogpost summarizes relevant research on the subject published during the past year.

In a review last fall, practitioners from the University of Miami School of Medicine reiterated how research evidence has expanded our perspectives on the importance of adequate vitamin D for overall health [Stechschulte et al. 2009]. They note that, in addition to traditionally reducing the risk for bone disease, vitamin D has demonstrated benefits in reducing falls and decreasing musculoskeletal pain, as well as stemming autoimmune diseases, cancers, heart disease, cognitive declines, and overall mortality. On this basis, improving the vitamin D status in all patients has become an essential aspect of healthcare, especially since deficiency or insufficiency can be safely prevented or corrected via inexpensive supplementation.

During the past year research of varying quality has reported on the relationship of vitamin D and pain; although, none of the newer evidence refutes the findings in our earlier reports. Overall, the conclusion still appears to be that vitamin D inadequacies are prevalent in persons with various chronic pain syndromes and, with sufficient vitamin D supplementation, the pain-relieving effects are sometimes quite dramatic. In those cases where pain is unrelieved or only partially resolved there seems to be no harm done, and most likely some healthful effects are achieved in other ways by more adequate vitamin D levels. Following are brief summaries of the research reports organized by topic areas (references with links are at the end of this blogpost).
  • Back Pain — A quite noteworthy report during the past year was a case presentation by Schwalfenberg [2009] of 6 patients who achieved relief from severe chronic back pain or pain associated with failed back surgery after vitamin D supplementation. Complete resolution of pain was achieved in 4 of the 6 patients within 3 to 6 weeks of beginning supplements, and the remaining 2 patients had significant improvement allowing them to reduce use of analgesics. Of great interest, patients responded best to vitamin D3 supplementation between 4,000 and 5,000 IU/day, which suggests that our prior recommendation of 2,000+ IU of D3/day may have been overly conservative for many patients with pain. Furthermore, Schwalfenberg noted that each 100 IU of vitamin D3 supplementation appears to raise 25(OH)D levels by 1 ng/mL (2.5 nmol/L), which is consistent with our own reported findings; however, we also noted that the increase is not linear and the trend in 25(OH)D production in response to vitamin D3 supplementation is more curvilinear [see, Leavitt 2008, p. 21]. POSTSCRIPT 5/9/10: This ratio of increase (1 ng/mL for each 100 IU D3) does not appear to apply to single megadoses of supplementation. For example, a 50,000 IU dose does not increase 25(OH)D by 500 ng/mL. Rather, the increase is vastly lower with such megadoses and there appears to be a self-limiting mechanism at work that needs further elaboration by research.

  • Chronic Pain — In a brief, but negative report on vitamin D for pain, Straube and colleagues conducted a literature search to extract and examine relevant research studies of vitamin D for chronic musculoskeletal pain [Straube et al. 2009]. They identified 22 relevant studies of which only 13 reported on followup treatment with vitamin D supplements for the pain conditions. Based on outcomes of these trials, the investigators conclude that “the presently available evidence does not allow us to conclude that vitamin D is relevant to chronic pain.” However, there are several deficiencies in their approach: First, their search was limited to Medline (PubMed) and cannot be considered exhaustive; Second, 7 of the 13 studies examining treatment effects actually found that vitamin D was of significant benefit in resolving pain; Third, the studies examined were highly heterogenous, involving varying pain conditions, different forms of vitamin D supplementation, and disparate qualities of evidence — so a meta-analysis of data was no doubt impractical and the broadly negative conclusion of the authors is suspect. In fact, they concede that, “There may not be quite enough evidence for a conclusively negative answer”; yet, despite this candid disclaimer, their report has been erroneously cited in subsequent literature as exemplifying the ineffectiveness of vitamin D for ameliorating chronic pain.

    In another report, this same group of investigators conducted a systematic review examining the relationship between vitamin D and chronic musculoskeletal pain in immigrant and ethnic minority populations. They found that vitamin D levels were low and often deficient in these populations; however, they believed there was insufficient evidence to reach a verdict on the value of treating chronic pain in immigrant/ethnic minority patients with vitamin D preparations because the studies were few, small, and of low quality. As above, however, their literature search was limited to Medline, and they retrieved only 7 relevant studies, 4 of which included 12 or fewer subjects.

  • Rheumatoid Arthritis — American researchers investigated the prevalence of vitamin D insufficiency and associations of this with rheumatoid arthritis status in a population of African Americans (n = 266) [Craig et al. 2009]. Half of the subjects had 25(OH)D insufficiency (less than 15 ng/mL) with the greatest inadequacies during winter months, as might be expected. Low vitamin D concentrations were associated with greater pain, more swollen joints, and higher Disease Activity Scores, but in further (multivariate) analyses these factors primarily related to differences in season, age, and gender rather than to vitamin D status. This study was complicated by the facts that patients were concurrently receiving various remedial pharmacotherapies for rheumatoid arthritis and vitamin D supplementation as a modifier of pain symptoms was not examined.

  • Fibromyalgia — Israeli researchers examined the association between low levels of vitamin D and fibromyalgia syndrome in 68 premenopausal women with fibromyalgia compared with 82 age-matched premenopausal women without the disorder [Tandeter et al. 2009]. No statistically significant differences were found between the groups in 25(OH)D levels. This is in contrast to earlier investigations in Middle East populations that found a significantly greater prevalence of low 25(OH)D concentrations in women with fibromyalgia as compared with age-matched female controls (43% vs 19%). Of interest in the Tandeter et al. study, although Israel is a sunny country, the researchers found a very high overall prevalence of 25(OH)D deficiency (48% had levels less than 20 ng/ml). Despite this, they did not report on relationships between severity of fibromyalgia symptoms and 25(OH)D status or effects of vitamin D supplementation in women with fibromyalgia, so no comment can be made about its potential benefits.

    Another study from the Middle East examined the prevalence of vitamin D deficiency among 139 patients who were diagnosed with fibromyalgia and/or non-specific musculoskeletal pain [Badsha et al. 2009]. Average age was 40 years, 95% were female, and 74% had 25(OH)D levels less than 20 ng/mL. Following treatment with vitamin D supplementation clinical improvements were reportedly observed in 90% of patients.

  • PHN-Shingles — In a review article, the author suggests that many of the mechanisms relating to painful post-herpetic neuralgia (PHN, or shingles) remain uncertain [Bartley 2009]. In the central nervous system the glia, their receptors, and signalling factors are known to have a major influence on neural function. In the peripheral nervous system, glial (Schwann) cell activation in response to infection and trauma releases a number of neuro-excitatory substances. Drugs useful in the amelioration of glial cell activation such as naloxone, naltrexone, minocycline, and others could be useful in PHN. The author also notes that high-dose topical vitamin D might offer particular promise because vitamin D has the ability to reduce both glial inflammation and excitatory neurotransmitters, such as nitric oxide.

  • Cancer Pain — Vitamin D inadequacy may contribute to musculoskeletal symptoms and bone loss observed in women administered chemotherapy for cancer. In an investigation of women with breast cancer, 63% exhibited vitamin D deficiency (less than 20 ng/ml) or insufficiency (20-31 ng/ml) at baseline [Kahn et al. 2010]. Desirable 25(OH)D levels (greater than 40 ng/ml) were achieved in all 42 subjects who received 12 weeks of supplementation with 50,000 IU vitamin D3 weekly, with no adverse effects. After 16 weeks of letrozole (aromatase inhibitor) therapy, significantly more women with serum 25(OH)D concentrations above 66 ng/ml (median level) reported no disability from joint pain as compared with women who had lesser levels of vitamin D status.

    Similar to the above study, researchers at the University of Nebraska Medical center examined the relationship between musculoskeletal pain symptoms and 25(OH)D serum levels in 29 breast cancer survivors on aromatase inhibitor therapy [Waltman et al. 2009]. Most of the women (85%) had levels below 30 ng/mL (mean 25.6 ng/mL), despite taking vitamin D supplements, and there was a significant correlation of increased neck and back pain intensity with decreased 25(OH)D levels. The authors did not report on possible beneficial effects of increasing the vitamin D supplementation.

    In a different study of women with bone metastases from breast cancer (n=40), all patients were being treated with bisphosphonates and received 10,000 IU of vitamin D3 and 1000 mg of calcium supplementation each day for 4 months [Amir et al. 2009]. No significant changes in bone resorption markers were seen; although treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There was a significant reduction in the number of sites of pain, but no change in global pain scores.

  • Osteomalacic Myopathy — A retrospective study conducted in Saudi Arabia examined 47 female patients (mean age 23.5 years) to describe features of myopathy associated with vitamin D deficiency [Al-Said et al. 2009]. Clinical, biochemical, radiological, and electrophysiological findings were collected before and after vitamin D treatment. All patients had presented with progressive proximal muscle weakness lasting 6 to 24 months (mean 14), and weakness was severe in 6 patients leading to wheelchair-bound states. Associated musculoskeletal pain involving the back, hips, and/or lower limbs was common (66% of patients). All patients had metabolic and radiological profiles suggestive of osteomalacia, yet this was the referral diagnosis in only 11 patients and the remaining 36 patients (77%) had been misdiagnosed. According to the researchers, remarkable recovery was documented in all patients following oral vitamin D3 and calcium supplementation (dosing details unavailable).

  • Prevalence Studies — Researchers from the UK reported on the association between vitamin D status and chronic widespread pain (CWP) in a large nationwide sample of 45-year-old white adults (n=6,824) [Atherton et al. 2009]. CWP, which was consistent with American College of Rheumatology criteria as being a component of fibromyalgia, was present in 11.1% of men and 12.5% of women. Overall, women with CWP had mean 25(OH)D concentrations of roughly 19 ng/mL, compared with 21 ng/mL in women without CWP. In men, comparable concentrations were 21 ng/mL and 21.4 ng/mL, respectively. The prevalence of CWP varied by 25(OH)D concentration in women but not in men, and this was not accounted for by differences in lifestyle, social factors, anxiety, depression, or diet. Of interest, average vitamin D concentrations in all subjects — men and women, with and without CWP — were similar and fell below the usually accepted optimal range of 30 to 50 ng/mL. However, nearly 1 in 5 women with CWP did have vitamin D concentrations within the optimal range, which suggests that they may have needed vitamin D levels above what is usually considered an “adequate” threshold — it is presently unknown why some persons are more adversely affected by vitamin D levels in certain ranges than others. Another interesting finding was an association of CWP with a body mass index (BMI) curve that was U-shaped; there was a higher CWP prevalence in both underweight and obese subjects, and these two groups also had the lowest 25(OH)D concentrations. These relationships seem worthy of further investigation. Unfortunately, the researchers did not report on effects of vitamin D supplementation for any subjects with CWP to observe possible pain relief benefits.

    In the United States, vitamin D deficiencies are increasing, according to a large-scale comparison of data from 1988-1994 and 2001-2004 (total n=32,000) [Ginde et al. 2009]. Between those time periods, average 25(OH)D serum levels decreased by 20% (from 30 ng/mL to 24 ng/mL), severe deficiencies of less than 10 ng/mL increased 3-fold (from 2% to 6% of the population), and at the latter time point in the study 3 out of 4 persons had vitamin D levels below the minimally desirable 30 ng/mL level. This seems to suggest that in everyday clinical practice it might be assumed that 75% of patients could benefit from vitamin D supplementation.
COMMENTARY: It appears that practitioners are generally becoming more alert to the vitamin D needs of their patients for good health; although, there is still an under-appreciation of the potential linkages between inadequate serum concentrations of 25(OH)D and certain chronic pain syndromes. Serum 25(OH)D assays are routinely ordered in many clinical settings and, if the results are within reportedly normal ranges, vitamin D inadequacy is dismissed as a contributing factor. Yet, there are several cautions for consideration:

  1. Concerns have been expressed about the reliability and precision of some 25(OH)D assays, which also can be relatively expensive.

  2. Reference ranges portrayed by some testing laboratories as “normal” may not be seasonally adjusted or pertinent for the particular patient population.

  3. In any event, research evidence suggests that particular serum 25(OH)D concentrations alone are not prognostic of pain or its degree and duration [see Leavitt 2008, pp 26-30].

  4. A “normal” 25(OH)D level for a person without pain may be inadequate for a person with pain; although, the research has yet to define reasons for this or threshold values.
When vitamin D supplementation is deemed necessary another common practice seems to be the prescribing of very large doses taken once weekly for a period of weeks; yet, there does not appear to be robust evidence supporting this practice. In fact, at least one investigation during this past year found that daily doses at a moderately high level are more efficient in raising 25(OH)D concentrations than very large doses administered less frequently [Pekkarinen et al. 2009]; for example, 5,000 IU of D3/day could be more advantageous than 50,000 IU D3 once a week. This seems logical, based on physiological understandings of how the body naturally acquires, processes, and stores vitamin D.

Finally, our research update above may not be all-encompassing, as an exhaustive search of all possible literature databases was not conducted. Even so, it is disappointing that so many of the past and newer reports reveal the high prevalence of inadequate vitamin D levels in patients with pain, but do not go the next step by measuring responses to different formulations, doses, and durations of vitamin D supplementation. Clearly, further and better-quality clinical trials of vitamin D as therapy for chronic pain conditions are needed. However, based on the preponderance of available evidence at hand, we would still advise healthcare providers to consider vitamin D supplementation as an adjunctive therapy for patients with pain. As we have noted previously, this has a favorable potential benefit to cost ratio with minimal, if any, risks and should be considered early in the course of pain management.
ADDENDUM:
First, an excellent review article was just published in the British Medical Journal on vitamin D in general (Pearce SHS, Cheetham TD. Diagnosis and management of vitamin D deficiency. BMJ. 2010; 340:142-147 [
article here]). Comments to the article note that higher-dose vitamin D supplements, even 1000 IU D3 tablets, are presently unapproved or difficult to come by in the United Kingdom.

Second, a fairly recent trial report noted that large doses of vitamin D3 (550,000 IU at start then 50,000 IU D3 monthly) safely raised deficient 25(OH)D to desirable levels within 1 month in a group of elderly persons; 50,000 IU D3 once monthly (without the start-up 500,000 IU loading dose) was equally effective but required 3 to 5 months to produce desired 25(OH)D levels (Bacon CJ, Gamble GD, Horne AM, et al. High-dose oral vitamin D3 supplementation in the elderly. Osteoporos Int. 2009;20(8):1407–1415 [
abstract]). However, while large, less frequent dosing might be viewed as overcoming problems of therapeutic compliance with a daily regimen, we still prefer steady daily dosing with more moderate amounts of D3, as we noted above, until more extensive research is available.
References:
> Al-Said YA, Al-Rached HS, Al-Qahtani HA, Jan MM. Severe proximal myopathy with remarkable recovery after vitamin D treatment. Can J Neurol Sci. 2009;36(3):336-339 [
abstract].
> Amir E, Simmons CE, Freedman OC, et al. A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases. Cancer. 2009 (Nov 13 - Epub ahead of print) [
abstract].
> Atherton K, Berry DJ, Parsons T, et al. Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey. Ann Rheum Dis. 2009 Jun;68(6):817-822 [
abstract]. Also published in an earlier Pain-Topics UPDATES blogpost as Vitamin D Deficits Engender More Pain in Women?
> Badsha H, Daher M, Ooi Kong K. Myalgias or non-specific muscle pain in Arab or Indo-Pakistani patients may indicate vitamin D deficiency. Clin Rheumatol. 2009;28(8):971-973 [
abstract].
> Bartley J. Post herpetic neuralgia, Schwann cell activation and vitamin D. Med Hypotheses. 2009;73(6):927-929 [
abstract].
> Craig SM, Yu F, Curtis JR, et al. Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J Rheumatol. 2009(Dec - Epub ahead of print) [
abstract].
> Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Int Med. 2009;169(6):626-632 [
abstract].
> Khan QJ, Reddy PS, Kimler BF, et al. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat. 2010;119(1):111-118 [
abstract].
> Leavitt SB. Vitamin D – a neglected ‘analgesic’ for chronic musculoskeletal pain. An evidence-based review & clinical practice guidance. Pain Treatment Topics. 2008(Jun) [
PDF here].
> Pekkarinen T, Valimaki VV, Aarum S, et al. The same annual dose of 292 000 IU of vitamin D(3) (cholecalciferol) on either daily or four monthly basis for elderly women: 1-year comparative study of the effects on serum 25(OH)D(3) concentrations and renal function. Clin Endocrinol (Oxf). 2009 (May 25 - Epub ahead of print) [
abstract]
> Schwalfenberg G. Improvement of chronic back pain or failed back surgery with vitamin D repletion: a case series. J Am Board Fam Med. 2009;22(1):69-74 [
free article here].
> Stechschulte SA, Kirsner RS, Federman DG. Vitamin D: bone and beyond, rationale and recommendations for supplementation. Am J Med. 2009;122(9):793-802 [
free article here].
> Straube S, Moore RA, Derry S, Hallier E, McQuay HJ. Vitamin d and chronic pain in immigrant and ethnic minority patients-investigation of the relationship and comparison with native Western populations. Int J Endocrinol. 2010 (Epub ahead of print) [
abstract]
> Straube S, Moore RA, Derry S, McQuay HJ. Vitamin D and chronic pain. Pain. 2009;141(1-2):10-13 [no abstract available].
> Tandeter H, Grynbaum M, Zuili I, Shany S, Shvartzman P. Serum 25-OH vitamin D levels in patients with fibromyalgia. Isr Med Assoc J. 2009;11(6):339-342 [
free article PDF]. Also see comment on this article at: Arnson Y, Amital D, Amital H. The diverse world of vitamin D: does it also modulate pain sensation? Isr Med Assoc J. 2009 Jun;11(6):371-372 [free article PDF].
> Waltman NL, Ott CD, Twiss JJ, Gross GJ, Lindsey AM. Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy. Cancer Nurs. 2009;32(2):143-50 [
abstract].