Vitamin d and chronic pain

Sebastian Straube, R. Andrew Moore *, Sheena Derry, Henry J. McQuay Pain Research and Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Level 6 West Wing, Oxford OX3 9DU, UK vitamin D levels and, secondly, a demonstrable benefit of vitaminD treatment.
A number of studies have suggested a link between low levels of vitamin D and higher incidence of chronic pain There is a well-established link between low vitamin D and pain due toosteomalacia. There is no clear biological mechanism of how low We searched Medline (PubMed) using various search terms for vitamin D might be causally related to other types of chronic pain, vitamin D (vitamin D; vitamin D2; vitamin D3; 1-alpha-hydroxyvi- though vitamin D is thought to be involved in regulating inflamma- tamin D3; 1-alpha hydroxycalciferol; 1,25-dihydroxyvitamin D3; tory cytokine synthesis , and might be implicated in some hydroxyvitamin D; alfacalcidol; calcidiol; calcitriol; calcifediol; Associations of pain with latitude and season of the year offer calciferol; ergocalciferol; cholecalciferol; and spelling variations circumstantial evidence that vitamin D may be involved. These thereof) and ‘‘pain*”. The last search was conducted on 8 Septem- associations have been suggested for such diverse types of pain ber 2008. The limits in PubMed were set to ‘‘humans”. Bibliogra- as headache, abdominal pain, knee pain and back pain; but the evi- phies of review articles were also searched for additional dence is far from convincing This paper undertakes an relevant publications. Full publications in any language were in- assessment of the relationship between vitamin D and chronic cluded; case reports or studies in children were excluded. Studies pain. Before vitamin D supplementation can be advocated for involving patients with osteomalacia were included only if they re- chronic pain, evidence for health benefits and adverse effects needs ported on pain. Clinical studies were accepted provided they re- ported on populations with chronic pain conditions and gave Vitamin D and its roles in health and disease have been of inter- mean or median values for 25-OH vitamin D levels in these popu- est in the scientific community and the general media lations and investigated pain outcomes after vitamin D treatment, Many tissues express vitamin D receptors, and it is not surprising that a physiological role beyond the skeleton has been proposed.
We extracted data regarding study design, study location, con- Vitamin D deficiency has been implicated in conditions like auto- dition and population, patient characteristics, mean or median 25- immune and cardiovascular diseases, cancers, and chronic pain OH vitamin D levels, types and doses of vitamin D preparations . A recent meta-analysis even suggested reduced all-cause- used, concurrent other therapy, study duration, pain outcomes, mortality with vitamin D supplementation This contrasts with and adverse events. We defined chronic pain in the broadest pos- antioxidant vitamins A and E, where a review suggested a possible sible sense in order to be inclusive and uncover any possible asso- ciation. We defined an improvement of chronic pain with vitamin Some experts advocate limited and sensible sun exposure and D treatment as a statistically significant improvement compared vitamin D supplementation in order to ensure adequate blood with placebo, or an improvement over time (significant, or in more levels. Excessive dietary supplementation can lead to vitamin D than half the cases). Guidelines for quality of reporting of meta- intoxication and excessive sun exposure increases the risk of analyses were followed where appropriate Lat–Long Finder skin cancers, already a substantial health problem. Although cases of vitamin D intoxication have been reported infrequently, they the latitude of the study locations.
could become more common with widespread use of vitamin Dsupplements.
If there is a link between vitamin D deficiency and chronic pain, a systematic review of the evidence would be expected to uncover We identified 22 relevant studies that reported mean 25-OH two things: firstly, an inverse association between pain and 25-OH vitamin D levels and/or investigated the results of vitamin D treat-ment in patients with chronic pain conditions. Five were random-ised double blind trials of vitamin D treatment .
* Corresponding author. Tel.: +44 1865 231512; fax: +44 1865 234539.
Eight studies with weaker designs more prone to bias also evalu- ated vitamin D treatment; two were randomised but not double (R. Andrew Moore), (S. Derry), (H.J. McQuay).
0304-3959/$34.00 Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2008.11.010 S. Straube et al. / PAIN 141 (2009) 10–13 als with no significant improvement in pain with vitamin D. Only one of these randomised trials measured 25-OH vitamin D, for men and women and was treated as two data sets. These 23 demonstrating both deficiency at baseline and significant change data sets ranged in size from 5 to 3459 patients. The total number with treatment. By contrast, six of eight treatment studies that of patients in ‘‘pain” and ‘‘control” groups was 8644; 58% were wo- were not double blind showed significant improvement in pain men. Few studies actually measured vitamin D status, and there with vitamin D (457 of 504 patients, 93%). Only three of these trials was no common definition of what constituted deficiency.
measured vitamin status. There was no apparent correla- The expected dependence of 25-OH vitamin D level on latitude tion between significant improvement in pain with vitamin D and was confirmed, with lower average levels at higher latitude, a particular preparation, dose, or condition ( though with considerable variability between populations Three observational studies explored differences in 25-OH vita- 4. Conclusion and design of future studies min D levels between patients with and without chronic musculo-skeletal or widespread pain. Two very small studies (104 patients in There is no convincing evidence of a link between chronic pain total) claimed significantly reduced 25-OH vitamin D levels prevalence or incidence and latitude. In Greece, there was only a in pain subjects compared with controls. In a large study a sig- weak correlation of daily headache with latitude, though a similar nificant association between 25-OH vitamin D levels and increased size of correlation was also found with temperature Lower pain was found in only one of the several analyses for 3495 women, prevalence of knee and back pain in southern China compared but not for 3365 men. Another study investigated 25-OH vita- with northern China was complicated by rural versus urban life- min D levels in patients with diffuse musculoskeletal pain and used style A suggested seasonal variation in the presentation of patients with osteoarthritis as a ‘‘control” group. It found no differ- abdominal pain (higher in winter months) was less apparent at ence in 25-OH vitamin D levels between these two populations; be- southern latitudes . If vitamin D were important, we would cause the control group also consisted of patients with a chronically expect to see substantial evidence of higher chronic pain painful condition, both groups of patients from this study are trea- incidence at higher latitudes, as with the incidence of multiple ted as ‘‘pain” populations for the purpose of this review.
Characteristics of treatment studies are in . Vitamin D There was no persuasive evidence of lower levels of 25-OH vita- treatments involved monthly equivalent doses between 1200 and min D in chronic pain than in control populations 400,000 IU. Fourteen studies were in musculoskeletal pain There was a striking contrast in treatment effects between ran- domised, double blind trials that minimised bias and those with pain or fibromyalgia one in diabetic subjects with designs known to be subject to bias. In the former, only 10% of pa- neuropathic pain one addressing an unusual hyperaesthetic tients were in trials showing a benefit of vitamin D treatment; in pain syndrome and one with various conditions Patients the latter, 93% were in trials showing a benefit of vitamin D in these studies may have had ill-defined subclinical or overt osteomalacia, as is not infrequently the case with vitamin D defi- Is this enough to conclude that vitamin D is not linked to ciency. Duration of treatment was from a few days to 12 months, chronic pain? There may not be quite enough evidence for a con- though most studies lasted two months or more. It was rare for clusively negative answer, but we have been here before. Examples studies to report on adverse events.
include TENS for postoperative pain, where randomised trials were Treatment studies involved 733 patients. Randomised double overwhelmingly negative and non-randomised, overwhelmingly blind trials involved 229 patients, of whom only 22 (10%) were positive , or hyperbaric oxygen for multiple sclerosis, where in a trial with a significant improvement in pain with vitamin D, the early observational and non-randomised studies suggested and then only on a pain mobility measure; 207 patients were in tri- substantial benefits, but where a dozen subsequent RCTs foundnone .
The presently available evidence does not allow us to conclude that vitamin D is relevant to chronic pain. To overturn this verdictwill demand substantially better evidence, specifically large, doubleblind RCTs, stratified by baseline vitamin D level, with definedtreatments, possibly with outcome analysed by post-treatment25-OH vitamin D level, and ideally conducted in different painfulconditions, and over a sensible period of time. Vitamin D treat-ments can be of low intensity (typically 1000 IU per day, or30,000 IU per month), or of high intensity (150,000–400,000 IUper month). There may be a threshold and not a simple dose re-sponse; non-linearity may be expected because vitamin D acts ongene transcription. Given the limited level of knowledge, a placebogroup is essential to underline causation and effect. Trials shoulduse standardized, validated pain outcomes (such as the number ofpatients achieving at least 50% pain relief), and also report on ad-verse events.
There is a beguiling attraction in a link between low levels of vitamin D and chronic pain, because it offers a simple treatmentwith known and probably limited adverse effects, and with afavourable public perception of vitamin treatment. The RCTs wehave are too small, and supporting studies are insufficient to sup-port the hypothesis that vitamin D supplementation is a useful Fig. 1. 25-OH vitamin D levels in pain subjects (white circles) and non-pain treatment for chronic pain. We need to better understand how controls (black circles) according to latitude (northern or southern hemisphere).
Vitamin D could generate or maintain pain, especially musculo- The size of the symbol is proportional to the size of the study populations (insetscale).
skeletal pain (other than osteomalacia, which is known to be due S. Straube et al. / PAIN 141 (2009) 10–13 Table 1Characteristics of treatment studies. M = male, F = female, IU = international units, Ca = calcium, signif. = significant, mcg = micrograms; 25-OHD = 25-hydroxyvitamin D; 1-alpha-OHD = 1-alpha-hydroxyvitamin D; 1,25-(OH)2D = 1,25-dihydroxyvitamin D.
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