Vitamin D and Pain: Making Sense of It All

By Nancy J. Selfridge, MD. Dr. Selfridge is Associate Professor, Integrated Medicine, Ross University School of Medicine, Freeport, Grand Bahama; she reports no financial relationship to this field of study.

An association between bone disease due to vitamin D deficiency (i.e., osteomalacia and pain) has long been established. However, despite epidemiologic studies associating painful conditions with season and latitude, research on vitamin D and pain is confusing.

Clinical Studies

In 1991, Gloth et al reported hyperesthesia in five patients with pain aggravated by light touch and minimal movement. These symptoms resolved in all patients after vitamin D therapy was instituted but returned when therapy was discontinued, prompting the authors to question whether vitamin D deficiency is associated with a pain syndrome.1 Supporting this view is a study conducted at an inner city clinic in Minnesota by Plotnikoff et al, which showed the presence of hypovitaminosis D in 93% of the adults and children presenting with chronic pain.2 This report sparked a passionate editorial debate about vitamin D deficiency and pain, unfolding over the following year in the Mayo Clinic Proceedings.

A 2009 review identified 22 studies that reported mean 25-OH vitamin D levels and/or investigated the results of vitamin D treatment in patients with chronic pain. These included five randomized double-blind trials of vitamin D treatment, two randomized but not double-blind studies, and several observational studies and case series reports with and without evaluation of vitamin D treatment. The authors concluded from their analyses of these studies that there is no convincing evidence of a link between chronic pain and vitamin D.3 The same authors published in January 2010 a Cochrane review of vitamin D for the treatment of chronic painful conditions and once again concluded that the evidence base for the use of vitamin D for chronic pain in adults is poor.4

Discussion

There are several problems with the existing research on vitamin D and pain. It is admittedly seductive to think about a link between the two because of the attractiveness of having a simple, inexpensive, low-risk, and natural treatment for a condition that is so costly and creates so much human suffering. However, chronic pain is complex and vitamin D is not well understood as a drug, nor is it actually a vitamin per se. For example, we talk about "vitamin D deficiency," but rarely (if ever) "drug deficiency," and there are no natural food sources that are high in vitamin D. Furthermore, when attempting to draw conclusions from these studies, a number of questions need to be addressed, e.g., the form of vitamin D administered, whether appropriate dissolution studies were conducted with the product to determine oral bioavailability, whether patients were grouped into those with peripheral pain, visceral pain, and neuropathic pain, and whether any patients in the study were using drugs that reduce the absorption of fat-soluble vitamins.

Cholecalciferol, which is made in human skin by the sun or can be taken as an oral supplement, is the precursor for calcidiol (25-OH vitamin D). 25-OH vitamin D is the human substrate for calcitriol (1,25-OH2 vitamin D), a potent pleiotropic secosteroid hormone with multiple autocrine functions working primarily through effects on gene transcription in human tissues and organs. We know now that vitamin D insufficiency, defined by serum 25-OH vitamin D levels ≤ 30 ng/mL, is present in 90% of the dark skinned population and nearly 75% of the white population in the United States.5 Identifying a control group for studies evaluating pain as a possible symptom of vitamin D insufficiency might prove complicated. Using vitamin D as a therapeutic agent is also fraught with challenges. Oral cholecalciferol (D3), in the doses defined by our current RDAs (200-400 IU), is simply not enough to significantly alter serum levels in adults. Heaney et al have estimated that doses sufficient to provide enough substrate to fulfill all of the known human autocrine functions of vitamin D and to maintain D levels > 30 ng/mL in adults range from 3,000 to 5,000 IU daily.6 Patients who are large, obese, elderly, or dark skinned may require even more daily vitamin D to maintain blood levels > 30 ng/mL. However, the U.S. Institute of Medicine maintains an Upper Limit (UL) recommendation of 2,000 IU of D3 daily and states persistent concerns about vitamin D toxicity. It is likely that this UL continues to influence researchers in choosing doses of vitamin D for clinical trials. Thus, studies aimed at giving vitamin D for pain that ignore blood levels to check for repletion of D status simply do not consider what we now know about vitamin D physiology and pharmacokinetics.

Another problem may exist when vitamin D treatment is done using ergocalciferol (D2), which is a synthetic prescription product. Though this product does raise 25-OH vitamin D2 levels, this is not precisely the same vitamin D substrate that is made in human skin. While there is no evidence that D2 and D3 are not biologically equivalent, there is no evidence that they are biologically equivalent either. The two do appear to differ in their pharmacokinetics and potency.7 As yet, the mechanisms that underlie any association between low vitamin D status and pain remain unidentified. Nor do we know what blood level of 25-OH vitamin D would be necessary for a reduction in pain in most people if the two were convincingly linked. At least some of the biologic effects of vitamin D appear to have thresholds for optimum dose-response. For example, levels needed to prevent rickets (10 ng/mL) are lower than levels needed to significantly suppress parathyroid hormone (20 ng/mL) or to maximize intestinal calcium absorption (34 ng/mL).8 Thus, simply raising 25-OH vitamin D above deficiency levels of 10-20 ng/mL may not be enough to assess for a pain-alleviating effect.

Conclusion

For the time being, in clinical practice it may be helpful to look at pain as a possible harbinger of low vitamin D status, just as fatigue can be a harbinger of hypothyroidism. Most people with fatigue will not have hypothyroidism. However, this fact does not dissuade us from screening for hypothyroidism and correcting it if need be. Similarly, if low vitamin D status is found in patients with pain, correcting the D status may result in less pain, or for some, complete improvement. But correcting D status, or "repleting" vitamin D, is the prime directive, and research suggests that the benefits beyond possible pain relief may be substantial, including a reduction in risk of mortality.9 Until we have better guidelines to inform our standard of care, clinicians will have to monitor 25-OH vitamin D blood levels to ensure that patients achieve sufficiency (> 30 ng/mL, according to most vitamin D experts) and then maintain repletion throughout the year.

There thus remains a dire need for studies to convincingly link vitamin D levels to the different types of pain, and to discern a mechanism or mechanisms for vitamin D in chronic pain pathophysiology, as each type is associated with different neural pathways and mechanisms at the receptor level.

References

1. Gloth FM, et al. Can vitamin D deficiency produce an unusual pain syndrome? Arch Intern Med 1991;151:1662-1664.

2. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, non-specific musculoskeletal pain. Mayo Clin Proc 2003;78: 1463-1470.

3. Straube S, et al. Vitamin D and chronic pain. Pain 2009;141:10-13.

4. Straube S, et al. Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database Syst Rev 2010;(1):CD007771.

5. Adams JS, et al. Update in vitamin D. J Clin Endocrinol Metab 2010;95:471-478.

6. Heaney, RP. The vitamin D requirement in health and disease. J Steroid Biochem Mol Biol 2005;97:13-19.

7. Houghton LA, et al. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr 2006;84:694-697.

8. Cannell JJ, et al. Use of vitamin D in clinical practice. Altern Med Rev 2008;13:6-20.

9. Zitterman A, et al. Vitamin D deficiency and mortality. Curr Opin Clin Nutr Metab Care 2009;12:634-639.