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
pru.ox.ac.uk (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.
both groups overtime, no greatdifference betweengroups
S. Straube et al. / PAIN 141 (2009) 10–13
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