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. 2018 Mar 21;21(11):2022–2037. doi: 10.1017/S1368980018000551

The association between vitamin D concentration and pain: a systematic review and meta-analysis

Zhenqiang Wu 1, Zarintaj Malihi 1, Alistair W Stewart 1, Carlene MM Lawes 1, Robert Scragg 1,*
PMCID: PMC10260782  PMID: 29559013

Abstract

Objective

Pain-related conditions, such as chronic widespread pain and fibromyalgia, are major burdens for individuals and the health system. Evidence from previous research on the association between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and pain is conflicting. Thus, we aimed to determine if there is an association between mean 25(OH)D concentration (primary aim), or proportion of hypovitaminosis D (secondary aim), and pain conditions in observational studies.

Design

Published observational research on 25(OH)D concentration and pain-related conditions was systematically searched for in electronic sources (MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials) and a random-effects meta-analysis was conducted on included studies.

Results

Eighty-one observational studies with a total of 50 834 participants were identified. Compared with controls, mean 25(OH)D concentration was significantly lower in patients with arthritis (mean difference (MD): −12·34 nmol/l; P<0·001), muscle pain (MD: −8·97 nmol/l; P=0·003) and chronic widespread pain (MD: −7·77 nmol/l; P<0·001), but not in patients with headache or migraine (MD: −2·53 nmol/l; P=0·06). The odds of vitamin D deficiency was increased for arthritis, muscle pain and chronic widespread pain, but not for headache or migraine, compared with controls. Sensitivity analyses revealed similar results.

Conclusions

A significantly lower 25(OH)D concentration was observed in patients with arthritis, muscle pain and chronic widespread pain, compared with those without. These results suggest that low 25(OH)D concentrations may be associated with pain conditions.

Keywords: Vitamin D, Pain, Systematic review, Meta-analysis, Observational studies

Pain is defined by the International Association for the Study of Pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’( 1 ). Pain, and conditions with pain as a prominent symptom, including chronic widespread pain, musculoskeletal pain (e.g. lower-back pain), arthritis and headache, are the most common reason for primary care and medical consultations( 2 – 4 ). The prevalence of chronic pain ranges from 8 to 60 % and over, depending on the population studied( 5 ). Recent reviews of painful conditions have reported that the prevalence of fibromyalgia varies from 2 to 8 % in the general population( 6 ); while the global prevalence of lower-back pain is 9·4 %( 7 ), of rheumatoid arthritis is 0·24 %( 8 ) and of current migraine is more than 10 % in adults( 4 ). Painful conditions can seriously influence quality of life, lead to work disability, and result in major economic burdens for both individuals and the health system( 2 , 4 , 5 , 8 – 12 ).

Vitamin D comprises a group of fat-soluble secosteroids( 13 ) and the receptor of vitamin D has been identified in muscle tissue( 14 ). Although the optimal level of serum 25-hydroxyvitamin D (25(OH)D) is a topic of ongoing research, vitamin D deficiency is typically defined as 25(OH)D<50 nmol/l( 15 ). Vitamin D deficiency is very common in both developed( 16 ) and developing countries( 17 ). There is increasing evidence from observational studies that vitamin D deficiency is associated with a wide range of acute and chronic diseases( 18 ), including diseases with pain as a prominent symptom( 19 ). Previous research has provided inconsistent findings on the association between vitamin D status and pain. A meta-analysis of seven observational studies with 2420 statin-treated patients found that 25(OH)D levels were lower in those with myalgia than in those without( 20 ). However, it used a fixed-effects model, not justified by the high heterogeneity of the results (I 2=94 %), which when repeated with a random-effects model was no longer significant (mean difference (MD): −3·52; 95 % CI −8·55, 1·51 ng/ml; P=0·17). Another meta-analysis of twelve observational studies with 1854 participants reported inconsistent results, with significantly increased odds of vitamin D deficiency associated with chronic widespread pain, but no difference in mean 25(OH)D levels between people with and without chronic widespread pain( 21 ). Moreover, these previous meta-analyses have not reported the association between 25(OH)D concentration and other pain-related conditions, such as arthritis and headache. In addition, recent reviews of randomized controlled trials have reported inconsistent conclusions about whether vitamin D supplementation improves chronic pain, with two being qualitative reviews( 22 , 23 ) and only one using quantitative methods( 24 ).

Given the limited evidence and inconsistent conclusions from previous reviews and meta-analyses, which for observational studies only searched up to September 2014( 20 , 21 ), we conducted an updated meta-analysis of all observational studies reporting data on 25(OH)D levels and pain, including studies of non-statin users and participants with different pain conditions, to determine if there is an association between these two variables.

Methods

Search strategy

Two trained researchers (Z.W., Z.M.) independently searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (up to April 2017) using the following key words: Vitamin D, Vitamin D2, Vitamin D3, Cholecalciferol, Ergocalciferol, 25-hydroxyvitamin D, Pain, Myalgia, Myopathy, Myalgic, Headache, Migraine, Arthritis and Sciatica, for original publications pertinent to vitamin D levels and pain (search strategy listed in the online supplementary material, Supplement 1). In addition, we manually searched the reference lists of eligible articles and previous reviews for additional studies.

Aims

Two aims were predefined in the meta-analysis. The primary aim was the difference in mean circulating 25(OH)D concentration (nmol/l) between participants with and without pain-related conditions. The secondary aim was the difference in proportions of hypovitaminosis D in the participants with and without painful conditions. For the latter, we used the original definition of hypovitaminosis D from each paper (eight studies with a threshold of 75 nmol/l; thirty-four studies with 50 nmol/l; two studies with 25 nmol/l; six studies with other definitions, which were 20 nmol/l, 30 nmol/l, 37·5 nmol/l, 80 nmol/l and 100 nmol/l).

Eligibility criteria

We included observational studies in the current meta-analysis if the study: (i) was a cohort, case–control or cross-sectional study; (ii) enrolled adult participants (≥18 years old); (iii) described specific information on pain, such as a pain definition or category; and (iv) reported the 25(OH)D level and/or the proportion of hypovitaminosis D in participants with and without pain. There was no language or ethnicity restriction. In addition, the studies which selected controls with pain conditions were excluded.

Data extraction

Reviewers (Z.W., Z.M.) independently identified the included articles by screening title, abstract and full text (κ coefficient=0·73), and the main data were extracted based on a standardized data collection form developed for the study. Any inconsistencies were resolved by consensus and discussion.

Quality assessment of individual studies

The quality of each included study was assessed using the Newcastle–Ottawa scale( 25 ). Specifically, there were five items for cross-sectional studies, and eight items for cohort and case–control studies. We used the same score to categorize the quality of studies as reported previously( 26 ): 5 as very good, 4 as good, 3 as satisfactory and 0–2 as unsatisfactory in cross-sectional studies; similarly, 7–8 as very good, 5–6 as good, 4 as satisfactory and 0–3 as unsatisfactory in case–control or cohort studies.

Synthesis and analysis

Mean and sd of serum 25(OH)D levels, and number of participants with and without pain, were collected for the continuous exposure measurement. All 25(OH)D levels were transformed to nmol/l in the meta-analysis. Digitizer software (GetData Graph Digitizer version 2.26; www.getdata-graph-digitizer.com/) was used to extract the data from graphs, and Wan et al.’s( 27 ) methods were used to estimate the mean and sd by reported median and range, or median and interquartile range. Sample size and the proportion with hypovitaminosis D were collected for the dichotomous exposure measurement.

Weighted MD and 95 % CI were calculated for continuous exposure, and OR and 95 % CI were calculated for dichotomous exposure, to allow the combining of different study designs in the synthesis analysis. Heterogeneity was measured using Cochran’s Q test and the I 2 statistic (I 2>50 % denotes large or extreme heterogeneity). Random-effects models were used in the meta-analysis( 28 ). Predefined analyses were performed to detect the relationship of 25(OH)D with pain by different painful conditions (arthritis, muscle pain, chronic widespread pain, and headache or migraine), type of study design, statin user and different cut-off points of vitamin D deficiency (25 nmol/l, 50 nmol/l and 75 nmol/l). Interactions were tested between different subgroups using a standard method( 29 ). In addition, we also conducted meta-regression to examine other sources of heterogeneity (e.g. year, sample size, mean age, female proportion, type of study). Sensitivity analyses were also conducted by individually excluding each study in turn, and by collectively excluding low-quality studies or those that used other definitions of vitamin D deficiency (as listed above). We generated funnel plots for visual assessment of publication bias, as well as performed the Egger test( 30 ). All tests were two-tailed and P≤0·05 was considered statistically significant. We conducted the meta-analysis using the Stata statistical software package version 13.1 and Review Manager software (Revman version 5.2).

Results

Included studies

A total of 2340 unique articles were identified by searching the three electronic databases and by applying snowballing techniques. After reviewing titles and abstracts, 2155 publications were excluded. The full texts of the remaining 185 studies were assessed for their eligibility and a further 107 were excluded because they did not meet the eligibility criteria (see Supplement 1). The remaining seventy-eight publications, which reported eighty-one observational studies with data on vitamin D concentration and pain, were included in the current meta-analysis (Fig. 1).

Fig. 1.

Fig. 1

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(colour online) PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram of study selection

The eighty-one observational studies involved nineteen cross-sectional studies( 31 – 48 ), fifty-six case–control studies( 49 – 102 ) and six cohort studies( 103 – 108 ). Together, these studies included 50 834 participants, 21 723 of whom were reported as pain subjects, with a median mean age of 49·4 (median sd 10·3) years and median female proportion of 80·5 % (range: 0–100 %); and 29 111 participants who were community- or hospital-based controls without pain-related conditions, with a median mean age of 50·0 (median sd 10·3) years and median female proportion of 78·4 % (range: 0–100 %). The pain conditions or symptoms reported in these studies included arthritis, muscle pain, chronic widespread pain, and headache or migraine. Characteristics of included studies are shown in Table 1.

Table 1.

Characteristics of studies included in the current meta-analysis on the association between vitamin D concentration and pain

No. of subjects Age (years) Female
Total With pain Without pain With pain Without pain With pain Without pain
Study Country Population Pain measurement n n n Mean or median sd or IQR or range Mean or median sd or IQR or range n % n % Type of study
Cross-sectional studies
Macfarlane et al. (2005( 31 ) UK Females aged 18–36 years Widespread pain 109 8 101 NA NA 8 100·0 101 100·0 Community-based
Duell et al. (2008)( 32 ) USA Hyperlipidaemia patients with statin therapy Statin-related myalgia 99 38 61 59·3 10·4 58·4 12·3 26 68·4 30 49·2 Hospital-based
Hicks et al. (2008)( 33 ) Italy People living in the Chianti geographic area Pain at lower extremities and back 958 420 538 NA NA 302 71·9 227 42·2 Community-based
Ahmed et al. (2009)( 34 ) USA Hyperlipidaemia outpatients with statin therapy Statin-related myalgia 621 128 493 60 11 58 12 76 59·4 219 44·4 Hospital-based
Golan et al. (2009)( 35 ) Israel Patients with haemodialysis Chronic pain 100 51 49 64·0 12·5 65·0 15·2 32 62·7 23 46·9 Hospital-based
Linde et al. (2010)( 36 ) USA Patients with statin therapy Statin-related myalgia 64 39 25 59·5 10 59·3 13·8 18 46·2 9 36·0 Hospital-based
McBeth et al. (2010)( 37 ) European Males aged 40–79 years CWP and other pain 3075 1813 1262 NA NA 0 0·0 0 0·0 Community-based
Backes et al. (2011)( 38 ) USA Patients with statin therapy Statin-related myalgia 129 57 72 62·4 10·5 58·3 13 31 54·4 28 38·9 Hospital-based
Kjaergaard et al. (2012)( 39 ) * Norway Smokers aged 30–87 years Headache 2339 907 1432 52·1 10·8 57·1 11·6 606 66·8 686 47·9 Community-based
Kjaergaard et al. (2012)( 39 ) * Norway Non-smokers aged 30–87 years Headache 9275 3154 6121 53·7 12·1 59·8 12·5 2006 63·6 2820 46·1 Community-based
Riphagen et al. (2012)( 40 ) Netherlands Outpatients with statin therapy Statin-related myalgia 75 22 53 NA NA NA NA Hospital based
e Silva et al.( 41 ) Twenty-three countries Postmenopausal women aged 60–85 years Back pain 9276 6284 2992 NA NA 6284 100·0 2992 100·0 Community-based
Eisen et al. (2014)( 42 ) Israel Clinics patients with statin therapy Statin-related myalgia 272 106 166 66·3 10·2 69·3 10·0 57 53·8 113 68·1 Hospital-based
Madani et al. (2014)( 43 ) Iran Female nurses Non-specific MSK pain 200 178 22 NA NA 178 100·0 22 100·0 Community-based
Alipour et al. (2015)( 44 ) Iran Adults aged >60 years and without cancer, depression, osteoarthritis, RA Chronic pain 857 666 191 69·4 7·3 68·7 7·4 NA NA Community-based
Hirani et al. (2015) ( 45 ) Australia Male aged ≥70 years Chronic pain 1616 480 1136 NA NA 0 0·0 0 0·0 Community-based
Morioka et al. (2015)( 46 ) USA Adults aged >40 years (NHANES) MSK pain 5247 1429 3818 NA NA NA NA Community-based
Tasoglu et al. (2015)( 47 ) Turkey Male patients with statin therapy Statin-related myalgia 40 17 23 49·1 7·9 50·6 9·0 0 0·0 0 0·0 Hospital-based
Virtanen et al. (2017)( 48 ) Finland Middle-aged males Headache 2601 250 2351 NA NA 0 0·0 0 0·0 Community-based
Case–control studies
Pietschmann et al. (1989)( 49 ) Austria Patients with RA and healthy controls RA 59 29 30 53† 45–59 52† 42–68 21 72·4 20 66·7 Hospital-based
Muller et al. (1995)( 50 ) Denmark Patients with RA or osteoarthritis and healthy controls RA or osteoarthritis 113 41 72 NA 45–65∥ 29 70·7 36 50 Hospital-based
Al-Allaf et al. (2003)( 51 ) UK Premenopausal women with FM and age- & sex-matched controls FM 77 40 37 42·5 3·6 42·5 4·3 40 100·0 37 100·0 Hospital-based
Benson et al. (2006)( 52 ) Australia Patients with muscle pain and age- & sex-matched controls Muscle pain 16 8 8 47·6 16·1 44·4 12·2 7 87·5 7 87·5 Hospital-based
Cutolo et al. (2006)( 53 ) * Italy Female patients with RA and age- & sex-matched healthy controls RA 88 53 35 58·5 8·0 59·9 5·3 53 100·0 35 100·0 Hospital-based
Cutolo et al. (2006)( 53 ) * Estonia Female patients with RA and age- & sex-matched healthy controls RA 94 64 30 56·3 18·4 51·1 20·8 64 100·0 30 100·0 Hospital-based
Lotfi et al. (2007)( 54 ) Egypt Female patients with LBP and age- & sex-matched health controls Chronic LBP 80 60 20 32·8 7·1 33·6 8·6 60 100·0 20 100·0 Hospital-based
Tandeter et al. (2009)( 55 ) Israel Premenopausal women with FM and age- & sex-matched women FM 150 68 82 43·8 7·6 40·4 9·9 68 100·0 82 100·0 Hospital-based
de Rezende Pena et al. (2010)( 56 ) Brazil Female patients with FM and age- & sex-matched controls FM 179 87 92 44·9 8·6 32·0 10·5 87 100·0 92 100·0 Hospital-based
Heidari et al. (2010)( 57 ) Iran Outpatients with non-specific skeletal pain and controls Non-specific skeletal pain 478 276 202 44·3 15 46·4 14·2 NA NA Hospital-based
Turhanoglu et al. (2011)( 58 ) Turkey Patients with RA and healthy controls RA 105 65 40 46·3 11·9 44·8 10·6 NA NA Hospital-based
Attar (2012)( 59 ) Saudi Arabia Patients with RA and age- & sex-matched healthy controls RA 200 100 100 47 13 47 15 90 90·0 89 89·0 Hospital-based
Baykal et al. (2012)( 60 ) Turkey Patients with RA and age- & sex-matched healthy controls RA 100 55 45 45‡ 28–68 NA 40 72·7 33 73·3 Hospital-based
Dong et al. (2012)( 61 ) China Female patients with RA and healthy controls RA 130 72 58 59·5 5·3 58·8 5·1 72 100·0 58 100·0 Hospital-based
Heidari et al. (2012)( 62 ) Iran Patients with inflammatory arthritis (RA and UIA) and controls Inflammatory arthritis (RA and UIA) 386 147 239 47·1 14·9 49·4 14·5 NA NA Hospital-based
Kostoglou-Athanassiou et al. (2012)( 63 ) Greece Patients with RA and age- & sex-matched controls RA 88 44 44 NA NA NA NA Hospital-based
Al-Jarallah et al. (2013)( 64 ) Kuwait Rheumatology/rehabilitation clinics patients with MSK pain and age- & sex-matched healthy controls MSK pain 206 124 82 41·7 13·9 43·7 7·4 118 95·2 79 96·3 Hospital-based
Atwa et al. (2013)( 65 ) Saudi Arabia Patients with RA and age-matched healthy controls RA 95 55 40 45·6 12·4 45·0 8·0 43 78·2 20 50·0 Hospital-based
Azali et al. (2013)( 66 ) Sweden Patients with IIM and sex- & month of blood sample-matched healthy controls IIM 439 149 290 56§ 18–72 41§ 18–70 97 65·1 192 66·2 Hospital-based
Olama et al. (2013)( 67 ) Egypt Female patients with FM and age- & sex-matched healthy controls FM 100 50 50 32·3 9·4 33·1 9·7 50 100·0 50 100·0 Hospital-based
Orgaz-Molina et al. (2013)( 68 ) Spain Psoriasis patients with arthritis and age- & sex-matched psoriasis without arthritis Arthritis 122 61 61 44·9 10·9 45·6 11·7 28 45·9 28 45·9 Hospital-based
Rkain et al. (2013)( 69 ) Morocco Postmenopausal women with chronic LBP and age-, sex- & BMI-matched healthy controls Chronic LBP 149 105 44 56·5 5·6 56·8 7·4 105 100·0 44 100·0 Hospital-based
Yazmalar et al. (2013)( 70 ) Turkey Patients with RA or osteoarthritis and healthy controls RA or osteoarthritis 215 145 70 47·0 9·1 41·4 4·2 99 68·3 26 37·1 Hospital-based
Baykara et al. (2014)( 71 ) Turkey Patients with chronic non-specific LBP and heathy controls Chronic non-specific LBP 90 60 30 30·6 7·8 31·0 6·7 37 61·7 19 63·3 Hospital-based
Celikbilek et al. (2014)( 72 ) Turkey Patients with migraine and age- & sex-matched healthy people Migraine 101 52 49 35·9 9·1 34·2 10·2 48 92·3 42 85·7 Hospital-based
Chen et al. (2014)( 73 ) China Patients with RA and age- & sex-matched healthy controls RA 220 110 110 59·5 11·4 56·9 10·5 75 68·2 71 64·5 Hospital-based
Cote et al. (2014)( 74 ) USA Patients with RA and age- & sex-matched non-RA controls RA 1611 270 1341 NA NA 225 83·3 1125 83·9 Community-based
Heidari et al. (2014)( 75 ) Iran Patients with unexplained arthralgia and controls Arthralgia 453 167 286 38 13·3 42·6 14·4 135 80·8 221 77·3 Hospital-based
Hiraki et al. (2014)( 76 ) * USA Female patients with RA and age-, sex-, date of blood draw- & hormonal factors-matched controls from NHS RA 477 120 357 56·0 7·1 56·0 7·1 120 100·0 357 100·0 Community-based
Hiraki et al. (2014)( 76 ) * USA Female patients with RA and age-, sex-, date of blood draw- & hormonal factors-matched controls from NHSII RA 179 46 133 44·4 4·4 44·5 5·3 46 100·0 133 100·0 Community-based
Hong et al. (2014)( 77 ) China Patients with RA and age- & sex-matched healthy controls RA 210 130 80 54 14 54 13 95 73·1 57 71·3 Hospital-based
Mateos et al. (2014)( 78 ) Spain Female patients with FM and age-, sex- & enrolled year-matched healthy controls FM 410 205 205 51·5 9·6 51·3 9·9 205 100·0 205 100·0 Hospital-based
Sezgin Ozcan et al. (2014)( 79 ) Turkey Female patients with FM and age- & sex-matched healthy controls FM 90 60 30 41·9 9·8 38·8 12·7 60 100·0 30 100·0 Hospital-based
Sharma et al. (2014)( 80 ) India Patients with RA and age- & sex-matched healthy controls RA 160 80 80 40·98 12·53 42·64 12·67 NA NA Hospital-based
Zandifar et al. (2014)( 81 ) Iran Patients with migraine and age- & sex-matched healthy controls Migraine 215 105 110 33·6 9·9 32·5 9·5 80 76·2 89 80·9 Hospital-based
Brance et al. (2015)( 82 ) Argentina Female patients with RA and age-, sex- & BMI-matched healthy controls RA 75 34 41 52·2 11·1 54·8 10·9 34 100·0 41 100·0 Hospital-based
Cen et al. (2015)( 83 ) China Patients with RA and normal controls RA 166 116 50 50·1 10·9 48·1 10·3 93 80·2 40 80·0 Hospital-based
Gullo et al. (2015)( 84 ) Italy Patients with RA and age- & sex-matched controls RA 68 27 41 47·5 12·5 46·4 4·1 19 70·4 28 68·3 Hospital-based
Lodh et al. (2015)( 85 ) India Patients with chronic LBP and controls Chronic LBP 400 200 200 46·2 15·7 NA 146 73 NA Hospital-based
Matsumoto et al. (2015)( 86 ) Japan Outpatients with RA and age- & sex-matched controls RA 367 181 186 61† 51–69 60† 51–66 151 83·4 155 83·3 Hospital-based
Park et al. (2015)( 87 ) South Korea Patients with EIA and age- & sex-matched healthy controls EIA 202 101 101 56·5 12·2 56·6 12·1 86 85·1 86 85·1 Hospital-based
Petho et al. (2015)( 88 ) Hungary Male patients with psoriasis arthritis and age- & sex-matched healthy controls Psoriatic arthritis 106 53 53 54·7‡ 31–84 54·7‡ 31–84 0 0·0 0 0·0 Hospital-based
Yagiz et al. (2015)( 89 ) Turkey Patients with RA and healthy controls RA 154 92 62 49·6 13·9 43·9 8·0 83 90·2 35 56·5 Hospital-based
Askari et al. (2016)( 90 ) Iran Patients with keen osteoarthritis and sex-matched healthy controls Osteoarthritis 393 131 262 52·0 8·0 55·0 9·0 107 81·7 214 81·7 Hospital-based
Elbassiony et al. (2016)( 91 ) Egypt Consecutive patients with RA and age- & sex-matched healthy controls RA 300 150 150 44·2 11·6 46·4 12·9 97 64·7 97 64·7 Hospital-based
Gamal et al. (2016)( 92 ) Egypt Patients with RA and age- & sex-matched healthy controls RA 80 55 25 42·2 10·6 41·2 15·8 47 85·5 20 80·0 Hospital-based
Gheita et al. (2016)( 93 ) Egypt Patients with RA and age- & sex-matched healthy controls RA 125 63 62 41·6 9·7 39·7 9·8 49 77·8 49 79·0 Hospital-based
Kasapoğlu Aksoy et al. (2017)( 94 ) Turkey Patients with FM and age- & sex-matched healthy controls FM 100 53 47 46·4 9·8 44·4 7·6 51 96·2 41 87·2 Hospital-based
Liao et al. (2016)( 95 ) China Female patients with RA and healthy controls RA 114 82 32 54·0 14·0 53·0 14·0 82 100·0 32 100·0 Hospital-based
Maafi et al. (2016)( 96 ) Iran Female patients with FM and healthy controls FM 142 74 68 38·0 9·8 32·6 10·1 74 100·0 68 100·0 Hospital-based
Okyay et al. (2016)( 97 ) Turkey Female patients with FM and healthy controls FM 159 79 80 37·0 9·0 35·8 10·7 79 100·0 80 100·0 Hospital-based
Thorneby et al. (2016)( 98 ) Sweden Patients with chronic LBP and age- & sex-matched controls Chronic LBP 88 44 44 55·0 16·0 55·0 15·0 26 59·1 26 59·1 Community-based
Wang et al. (2016)( 99 ) China Patients with RA and age- & sex-matched healthy controls RA 214 154 60 53·5 12·4 51·4 10·3 88 57·1 35 58·3 Hospital-based
Yildirim et al. (2016)( 100 ) Turkey Patients with FM and age- & sex-matched healthy controls FM 198 99 99 49·4 9·2 50·8 8·8 80 80·8 77 77·8 Hospital-based
Brennan-Speranzaa et al. (2017)( 101 ) Australia Patients with keen osteoarthritis and age-matched controls Osteoarthritis 29 19 10 66·1 5·2 64·7 7·6 10 52·6 7 70·0 Hospital-based
Wong et al. (2017)( 102 ) Malaysia Female patients with RA and age-matched healthy controls RA 106 77 29 54·1 6·9 52·6 5·4 77 100·0 29 100·0 Hospital-based
Cohort studies
Laroche et al. (2014)( 103 ) France Early-stage breast cancer and no pain at the start of AI treatment Joint pain, diffuse pain, neuropathic pain and mixed pain 134 77 57 61 7 62·4 7·2 77 100·0 57 100·0 Hospital-based
Mergenhagen et al. (2014)( 104 ) USA Patients with statin therapy Statin-related myalgia 450 50 400 65·5‡ 43–91 68·9‡ 39–96 5 10·0 16 4·0 Hospital-based
Shantha et al. (2014)( 105 ) USA Patients with statin therapy Statin-related myalgia 1160 276 884 63·5 10·1 61·8 13·9 92 33·3 349 39·5 Community-based
Singer et al. (2014)( 106 ) USA Postmenopausal women with non-metastatic, hormone receptor-positive breast cancer, prescribed adjuvant AI therapy MSK symptoms 52 28 24 59·8‡ 44–76 61·5‡ 45–76 28 100·0 24 100·0 Hospital-based
Ovesjo et al. (2016)( 107 ) Sweden Patients with statin therapy Myopathy 127 16 111 65§ 39–86 65§ 32–86 12 75·0 55 49·5 Hospital-based
Calza et al. (2017)( 108 ) Italy HIV patients with statin therapy Myalgia 487 42 445 58·6 19·6 52·5 20·2 7 16·7 83 18·7 Hospital-based
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IQR, interquartile range; RA, rheumatoid arthritis; NHANES, National Health and Nutrition Examination Survey; FM, fibromyalgia; LBP, lower-back pain; UIA, undifferentiated inflammatory arthritis; MSK, musculoskeletal; IIM, idiopathic inflammatory myopathies; NHS, Nurses’ Health Study; NHSII, Nurses’ Health Study II; EIA, early inflammatory arthritis; AI, aromatase inhibitor; CWP, chronic widespread pain; NA, not available.

*

One publication reported two studies.

†

Median and IQR.

‡

Mean and range.

§

Median and range.

∥

Original article reported age range only.

Quality assessment in included studies

According to the Newcastle–Ottawa scale, sixty-two of the eighty-one observational studies were very good or good quality( 33 – 35 , 37 , 39 – 43 , 45 , 48 , 49 , 51 , 54 – 57 , 59 , 60 , 62 , 64 – 70 , 72 – 74 , 76 – 82 , 84 , 86 – 100 , 102 – 108 ), sixteen were satisfactory( 31 , 44 , 46 , 47 , 50 , 52 , 53 , 58 , 61 , 63 , 71 , 75 , 83 , 85 , 101 ) and the remaining three were unsatisfactory( 32 , 36 , 38 ). Specifically, the quality for cross-sectional studies was good for twelve, satisfactory for four and unsatisfactory for three; for case–control studies, nine were very good, thirty-five were good and twelve were satisfactory; and for cohort studies, three were very good and three good. For the unsatisfactory studies, most of them did not have enough information to evaluate the representativeness for the target population. In addition, all the pain-related outcome measurements were based on questionnaire or self-report, and only a few of them validated the pain measurements. The quality assessment scores are shown in Supplement 2, Supplemental Table 1 (see online supplementary material).

Pooled results

Vitamin D concentration and pain

For the primary aim, seventy-three studies, containing 13 294 participants with pain and 21 078 without pain conditions, reported serum 25(OH)D levels( 32 , 34 – 40 , 42 – 45 , 47 – 50 , 52 – 75 , 77 – 102 , 104 – 108 ). Two publications reported the vitamin D concentration and pain conditions on different subgroups (smokers and non-smokers( 39 ) or Italian and Estonian( 53 )), which are reported separately as four different studies in the current meta-analysis (Supplement 2, Supplemental Table 2).

Table 2.

Association between 25-hydroxyvitamin D concentration and painful conditions

No. of participants Effect estimate
Category Subgroup No. of included studies With pain Without pain MD 95 % CI P value Test of subgroup differences, P value
Pain conditions Arthritis 33 3018 3925 −12·34 −17·97, −6·71 <0·001 0·004
Muscle pain 22 1723 3784 −8·97 −14·92, −3·02 0·003
Chronic widespread pain 13 4085 3306 −7·77 −11·97, −3·57 <0·001
Headache or migraine 5 4468 10 063 −2·53 −5·13, 0·07 0·06
Study design Cross-sectional 15 7906 13 457 −3·10 −4·98, −1·21 0·001 <0·001
Case–control 53 4976 5757 −11·09 −15·25, −6·93 <0·001
Cohort 5 412 1864 −23·55 −30·68, −16·41 <0·001
Statin use Yes 11 791 2733 −11·15 −20·49, −1·80 0·02 0·85
No 62 12 503 18 345 −10·17 −13·17, −7·17 <0·001
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MD, mean difference.

Compared with controls, mean 25(OH)D concentration was significantly lower in patients with arthritis (MD=−12·34 nmol/l; P<0·001), muscle pain (MD=−8·97 nmol/l; P=0·003) and chronic widespread pain (MD=−7·77 nmol/l; P<0·001), but not in patients with headache or migraine (MD=−2·53 nmol/l; P=0·06; Table 2). These mean differences by disease condition were significantly different (P=0·004). Because of this interaction, forest plots are shown by pain condition rather than for all conditions combined (Fig. 2). Additionally, among age- and sex-matched case–control studies, similar lower vitamin D levels also were observed in patients with arthritis (MD=−12·03 nmol/l; P<0·001) and muscle pain (MD=−11·49 nmol/l, P<0·01).

Fig. 2.

Fig. 2

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(colour online) Meta-analysis of the difference in mean serum vitamin D concentration (nmol/l) between participants with and without pain-related conditions. The study-specific mean difference (MD) and 95 % CI are represented by the square and horizontal line, respectively; the centre of the diamond represents the pooled MD and its width represents the pooled 95 % CI. IV denotes inverse variance; random denotes random-effects model

In addition, interaction tests were conducted by type of study design and statin use (Table 2; Supplement 2, Supplemental Figs 1 and 2). There was a significant interaction between the three types of study design (P<0·001). For each study design, pain patients had significantly lower 25(OH)D concentration compared with those without pain, but the effect was strongest in cohort studies (MD=−23·55 nmol/l; P<0·001), moderate in case–control studies (MD=−11·09 nmol/l; P<0·001) and weakest in cross-sectional studies (MD=−3·10 nmol/l; P=0·001). However, there was no interaction between studies of statin users and non-statin users (interaction test P=0·85).

To investigate the impact of other covariables (year, sample size, mean age, female proportion, ratio of participants with and without pain, type of study) on the study-level estimate of the MD in 25(OH)D concentration, we performed random-effects meta-regression analyses. We did not observe any significant association for the above covariables and MD in 25(OH)D levels in both the univariate and multivariate meta-regression analyses (Supplement 2, Supplemental Table 3).

Table 3.

Association between hypovitaminosis D and painful conditions

No. of participants Effect estimate
Category Subgroup No. of included studies With pain Without pain OR 95 % CI P value Test of subgroup differences, P value
Pain conditions Arthritis 21 2148 3411 2·17 1·56, 3·00 <0·001 0·06
Muscle pain 16 1052 1712 2·03 1·24, 3·33 0·005
Chronic widespread pain 12 10 722 9124 1·51 1·24, 1·85 <0·001
Headache or migraine 1 105 110 0·89 0·45, 1·76 0·73
Study design Cross-sectional 11 10 500 9550 1·42 1·17, 1·73 <0·001 0·07
Case–control 36 3406 4615 2·08 1·59, 2·73 <0·001
Cohort 3 121 192 2·32 0·76, 7·10 0·14
Statin use Yes 7 659 1539 1·88 1·15, 3·10 0·01 0·94
No 44 13 368 12 818 1·92 1·58, 2·33 <0·001
Cut-off point (nmol/l) 25 2 428 639 1·26 0·93, 1·72 0·13 0·06
50 34 9398 7573 2·08 1·59, 2·71 <0·001
75 8 1999 4142 1·64 1·04, 2·57 0·03
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Vitamin D deficiency and pain

For the secondary aim, fifty studies reported the proportion of vitamin D deficiency among 14 027 patients with pain conditions and 14 357 without( 31 – 34 , 36 – 38 , 41 – 43 , 46 , 51 , 52 , 54 – 57 , 59 , 61 , 62 , 65 – 69 , 74 – 77 , 79 – 83 , 87 – 89 , 91 – 99 , 103 , 106 , 107 ). One publication( 76 ) reported results from two studies which are included separately in the current meta-analysis (Supplement 2, Supplementary Table 4). To maintain consistency with the primary aim analyses (Table 2), the secondary aim of vitamin D deficiency was also analysed by pain condition, study design, statin use and cut-off point for vitamin D deficiency (Table 3 and Fig. 3). The odds of vitamin D deficiency was increased for arthritis, muscle pain and chronic widespread pain, but not for headache or migraine; and also increased for each of the study designs (cross-sectional, case–control and cohort) and for statin users and non-users separately (Supplement 2, Supplemental Figs 3 and 4). There was a significant interaction associated with the 25(OH)D cut-off point (P=0·06), with studies that used cut-offs below 50 or 75 nmol/l reporting significantly increased odds of vitamin D deficiency in patients with pain, but not at a very low cut-off of <25 nmol/l, although there were only two studies in the latter group (Table 3; Supplement 2, Supplemental Fig. 5). Meta-regression analyses did not find any other covariables that were significantly associated with the log(OR) of vitamin D deficiency (Supplement 2, Supplemental Table 5).

Fig. 3.

Fig. 3

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(colour online) Meta-analysis of the difference in the proportion of vitamin D deficiency between participants with and without pain-related conditions. The study-specific OR and 95 % CI are represented by the square and horizontal line, respectively; the centre of the diamond represents the pooled OR and its width represents the pooled 95 % CI. M-H denotes Mantel–Haenszel; random denotes random-effects model

Sensitivity analysis and publication bias

For the primary and secondary aims, sensitivity analyses found similar summary measures to those shown in Figs 2 and 3 when studies were individually excluded (see Supplement 2, Supplemental Tables 6 and 7). In addition, after excluding studies with poor quality, we observed similarly lower 25(OH)D levels in arthritis, muscle pain and chronic widespread pain patients than in their controls (see Supplement 2, Supplemental Table 6). There was no convincing evidence of publication bias from funnel plots (Supplement 2, Supplemental Figs 6 and 7), nor from the Egger’s test for the primary and secondary aims (25(OH)D concentration: P values for publication bias were 0·49, 0·10, 0·17 and 0·66 for arthritis, muscle pain, chronic widespread pain, and headache or migraine conditions, respectively; while for the proportion of vitamin D deficiency: P values were 0·13, 0·64 and 0·06 for arthritis, muscle pain and chronic widespread pain conditions, respectively).

Discussion

Our results show lower mean 25(OH)D concentration among patients with widespread chronic pain, muscle pain and arthritis than among their controls (Fig. 2). This result was consistent with the increased odds of hypovitaminosis D associated with these three conditions (Fig. 3). In addition, our study found that the weighted MD in 25(OH)D concentration between patients with pain and control groups is large (arthritis: 12·34 nmol/l or 20 % difference; muscle pain: 8·97 nmol/l or 14 % difference; chronic widespread pain: 7·77 nmol/l or 11·7 % difference) compared with disease-related differences in previous studies, such as those which have reported a 3 nmol/l (5 %)( 109 ) and a 7 nmol/l (11 %) difference( 110 ) between diabetes cases and controls. Overall, these results suggest that low vitamin D status may be associated with the development of painful conditions, with the overall quality of the evidence being rated as moderate according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria( 111 ) because of the high heterogeneity, although there was no evidence of publication bias, the quality of studies was good and the association was strong (Supplement 2, Supplemental Tables 8 and 9).

Our findings are consistent with previous meta-analyses which found significantly lower 25(OH)D levels in patients on statin therapy with myalgia compared with those without( 20 ) and a positive association between hypovitaminosis D and chronic widespread pain( 21 ). However, by including a further sixty-two studies in our meta-analysis (three studies that were included in the previous meta-analysis were excluded because of controls with pain conditions or no available data), we have extended previous meta-analyses to show that 25(OH)D levels are also lower in patients with pain not caused by statin therapy – for both the 25(OH)D concentration and hypovitaminosis D aims (Tables 2 and 3). The evidence for the primary aim from the five cohort studies( 104 – 108 ), which shows that low vitamin D levels at baseline predicted increased incidence of pain-related conditions (Table 2), supports a possible causal association. In addition, in analyses based on painful conditions, lower mean 25(OH)D levels were found in patients with arthritis, muscle pain and chronic widespread pain (compared with those without pain) for both primary and secondary aims, but not in patients with headache or migraine (Table 2). The latter finding could be due to chance because of the small number of studies (three cross-sectional comparisons from two publications, and two case–control studies) and further research is required to clarify this.

The strengths of the current meta-analysis include: (i) two aims that were predefined at the start of the study; (ii) a search of three electronic databases (MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials), which reduces the possibility of missing relevant articles; (iii) assessment for publication bias by both funnel plots and Egger’s test; (iv) inclusion of broader pain conditions, particularly studies of patients with pain who were not on statins; and (v) evaluation of the quality of included studies by the Newcastle–Ottawa scale.

Nevertheless, there are several limitations of the current meta-analysis. Most of the included studies were case–control or cross-sectional in design, which could have resulted in reverse causation between pain and lower vitamin D levels. Some studies reported medians, and not means and sd, and information may have been lost in the transfer process. In addition, the included studies lack or have limited adjustment for potential confounders, so the unadjusted association must be interpreted with caution as the spurious associations can be result from potential confounders.

Of major importance is the high heterogeneity observed in the meta-analysis. We tried to identify the sources of this using subgroup, meta-regression and sensitivity analyses, but it remained even when analysing studies by type of pain condition or study design. The high heterogeneity could partly be due to the higher heterogeneity often seen in meta-analyses of observational studies where there is variable control of confounding, compared with randomized controlled trials where effects from standard interventions congregate more closely; and also due to the relatively large number of studies (up to thirty-three) included in the pooled analyses which increases the opportunity for heterogeneity. In our view, this does not lessen the validity of our findings as the results of individual studies almost all go in the same direction (Supplement 2, Supplemental Figs 1 and 2). Further, we used a random-effects model which allows for between-study variation of effect in its calculations.

In addition, the definition of pain varied in each individual publication, so that combining them may also have contributed to the heterogeneity of our results. Therefore, more objective outcome measurements, such as consumption of analgesics as reported in previous studies which have found increased opioid use in people with vitamin D deficiency( 46 , 112 ), or use of validated questionnaires to assess pain severity and function( 113 ), would help to clarify the association between vitamin D levels and pain in future studies.

Conclusion

In conclusion, our meta-analysis of eighty-one observational studies suggests that low vitamin D concentration is associated with arthritis, muscle pain and chronic widespread pain. Further well-designed randomized controlled trials should be conducted to confirm the relationship between vitamin D levels and painful conditions.

Acknowledgements

Financial support: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Conflict of interest: The authors declare no conflicts of interest related to this study. Authorship: Z.W. conceived the idea, carried out the meta-analyses and drafted the text; Z.M. edited the manuscript and assisted with searching and extracting data; A.W.S. edited the manuscript and advised on statistical methods; C.M.M.L. edited the manuscript; R.S. contributed to the manuscript and provided critical revision to the study. Ethics of human subject participation: Not applicable.

Supplementary material

For supplementary material accompanying this paper visit https://doi.org/10.1017/S1368980018000551.

S1368980018000551sup001.docx (3.8MB, docx)

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