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Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-controlled trial among adult ethnic minorities in Norway Kirsten V. Knutsen a,⇑, Ahmed A. Madar b, Mette Brekke a, Haakon E. Meyer b,c, Bård Natvig a, Ibrahimu Mdala a, Per Lagerløv a a
Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway Department of Community Medicine, Institute of Health and Society, University of Oslo, Norway c Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway b
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 26 June 2014 Received in revised form 4 September 2014 Accepted 16 September 2014 Available online xxxx Keywords: Vitamin D Pain Headache Musculoskeletal pain Visual analogue scale HIT-6 Randomized controlled trial
a b s t r a c t Immigrants from South Asia, the Middle East, and Africa living in Northern Europe frequently have low vitamin D levels and more pain compared to the native Western population. The aim of this study was to examine whether daily vitamin D3 (25 lg/d or 10 lg/d) supplementation for 16 weeks would improve musculoskeletal pain or headache compared to placebo. This randomized, double-blind, placebocontrolled, parallel-group trial recruited 251 participants aged 18 to 50 years, and 215 (86%) attended the follow-up visit. The pain measures were occurrence, anatomical localization, and degree of musculoskeletal pain, as measured by visual analogue scale (VAS) score during the past 2 weeks. Headache was measured with VAS and the Headache Impact Test (HIT-6) questionnaire. At baseline, females reported more pain sites (4.7) than males (3.4), and only 7% reported no pain in the past 2 weeks. During the past 4 weeks, 63% reported headache with a high mean HIT-6 score of 60 (SD 7). At follow-up, vitamin D level, measured as serum 25(OH)D3, increased from 27 nmol/L to 52 nmol/L and from 27 nmol/L to 43 nmol/L in the 25-lg and 10-lg supplementation groups, respectively, whereas serum 25(OH)D3 did not change in the placebo group. Pain scores and headache scores were improved at follow-up compared with baseline. The use of vitamin D supplements, however, showed no significant effect on the occurrence, anatomical localization, and degree of pain or headache compared to placebo. Ó 2014 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
1. Introduction Musculoskeletal pain and headache are common symptoms worldwide, with complex and partly unknown etiology. Vitamin D deficiency has been associated with headache and musculoskeletal pain, even though the mechanisms underlying these associations remain unclear [7,12,20,24,28]. Vitamin D receptors are located in various cells and vitamin D seems to be involved in the regulation of inflammatory processes [14,21,29]. Children with nutritional rickets tend to have musculoskeletal pain that resolves with vitamin D treatment, whereas the symptoms among adolescents with rickets are less pronounced and more diffuse [5,35]. In adults, osteomalacia due to vitamin D deficiency can also result in musculoskeletal pain [14]. ⇑ Corresponding author. Tel.: +47 22850582; fax: +47 22850590. E-mail address: [email protected] (K.V. Knutsen).
Immigrants from South Asia, the Middle East, or Africa living in Northern Europe tend to have low vitamin D levels, due to a diet low in vitamin D and low sun exposure, and they report more pain than native Western populations [6,15,24]. Headache was found to be more prevalent among patients in general practice with 25(OH)D levels < 50 nmol/L than among those with levels above 50 nmol/L [19]. In a study from Norway, tension-type headache was associated with low 25(OH)D level, while migraine was not [18]. Observational studies are not suitable to evaluate whether a person‘s health would benefit from vitamin D supplementation, and health benefits found in such studies have seldom been reproduced in randomized trials [4]. Intervention studies on vitamin D supplementation have been limited by methodological shortcomings [13,23,34]. A Cochrane Review investigating the utility of vitamin D treatment for chronic pain identified only 4 studies eligible for inclusion (n = 294), of which only one study reported a beneficial effect [33]. If shown to have a beneficial effect on pain, vitamin
http://dx.doi.org/10.1016/j.pain.2014.09.024 0304-3959/Ó 2014 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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D would constitute a safe and cheap treatment. However, to date, too few randomized controlled trials have been conducted to support this conclusion [33]. This double-blinded, randomized-controlled study aimed to examine whether supplements with daily vitamin D3 (25 lg/d or 10 lg/d) would reduce musculoskeletal pain or headache compared to placebo among an adult ethnic minority population with presumed low level of vitamin D.
2. Materials and methods 2.1. Study design, setting and participants This study was a block randomized, double-blinded, placebocontrolled, parallel-group trial with 3 equally sized groups. It was conducted in local immigrants’ activity centers in Oslo, Norway and surrounding areas (at latitude 60°N) between January and June 2011. Further details of the study methods have been described elsewhere (ClinicalTrials.gov Identifier: NCT01263288) [20]. The study participants came from an assumed healthy population, male and female, aged 18–50 years, who were born in – or had parents born in – the Middle East, Africa, or South Asia. They were recruited through local immigrant organizations. The exclusion criteria were: regular use of vitamin D-containing supplements, ongoing treatment for vitamin D deficiency, use of strong pain killers or medication interfering with vitamin D metabolism (e.g., thiazides, antiepileptic drugs, prednisolone, or hormone replacement therapy), pregnancy, breastfeeding, kidney disease, cancer, tuberculosis, sarcoidosis, osteoporosis, or a recent fracture. 2.2. Intervention, randomization, and blinding Participants who provided consent to participate and fulfilled the eligibility criteria were randomly assigned to 1 of 3 intervention groups receiving 1 tablet daily over 16 weeks, containing either (1) 25 lg of vitamin D3, (2) 10 lg of vitamin D3, or (3) placebo. In the study we included one intervention group with 10 lg vitamin D3/day because this was the recommended daily intake according to official Norwegian guidelines when the study was performed, and one intervention group with 25 lg vitamin D3/day, a dose approved as a dietary supplement by authorities in Europe (United Kingdom and Denmark). Each participant received a box with 120 tablets (112 tablets correspond to 16 weeks of use). Participants were advised to take 2 tablets the following day if they had forgotten to take a tablet the previous day and to maintain their usual dietary pattern during the study. To maximize adherence, the participants received brief reminders via mobile phone text messages twice a week. The participants were advised to contact the study staff by telephone if they had any questions related to the study. The tablets were identical in color, size, taste, and packaging. Group allocations were unknown to participants, research staff, investigators, and data collectors. Randomly varying the block size between 3 and 6 ensured a good balance of gender and different ethnicity in each group. 2.3. Main outcome variable The main outcome variable was difference in change in the predefined pain parameters between the combined intervention groups (25 lg or 10 lg of vitamin D3) and placebo after 16 weeks of intervention. Level and location of pain were recorded at baseline and follow-up by the research staff using an interview-administered questionnaire. Occurrence, anatomical localization, and degree of pain during the preceding 2 weeks were assessed. The participants localized
their pain during the interview by marking a blank body mannequin, with words, or by pointing at the painful part of the body. Localization of musculoskeletal pain was divided into 10 anatomical areas; head, neck, shoulders/upper arm, elbows/forearm, hands/ wrists, upper back, lower back, hips/thighs, knees/lower leg, and ankles/feet. Our questionnaire included the anatomical areas used in the Standardized Nordic Questionnaire [22] in the Oslo Health Study (http://www.fhi.no) and in the Ullensaker Study [17]. A visual analogue scale (VAS; range 0–100) was used for assessment of pain, and the participant marked the pain intensity for each of the 10 anatomical areas. The VAS with the text ‘‘no pain’’ at on one end and ‘‘worst imaginable pain’’ at the other end was turned toward the participant. VAS total is the sum of all VAS scores in the 10 anatomical areas. The Headache Impact Test (HIT-6) questionnaire was developed to measure headache severity and the subjective impact on quality of life in areas such as: pain, social participation, general activity, vitality, psychological distress, and intellectual activity. The questions were answered with: ‘‘never,’’ ‘‘seldom,’’ ‘‘sometimes,’’ ‘‘very often,’’ and ‘‘always,’’ yielding a total score between 36 and 78. The participants with no headache the last 4 weeks were given the lowest score, 36 (‘‘never’’). The HIT-6 questionnaire has been validated in both the general population and clinical samples across different diagnostic groups of headache [27]. It has been translated and validated in a number of languages, including Norwegian [10]. Additional outcomes were: use of pain killers the last 2 weeks and C-reactive protein (CRP), including high-sensitivity CRP. 2.4. Blood sampling and laboratory assays Blood samples from nonfasting participants were collected at baseline and at follow-up examination after 16 weeks. Blood for analyses of serum (25[OH]D3, 25[OH]D2, CRP) and plasma parathyroid hormone (PTH) was collected and handled in separate tubes and stored at 20 °C the same day and within 1–2 weeks frozen at 80 °C. The samples were analyzed in one batch at Fürst Medical Laboratory, Oslo, Norway (http://www.furst.no/), accredited by the International Organization for Standardization, and part of a vitamin D quality assessment scheme, DEQAS. Serum 25-hydroxyvitamin D (25[OH]D) was measured using high-pressure liquid chromatography–tandem mass spectrometry, able to measure both serum 25(OH)D2 and serum 25(OH)D3. Serum 25(OH)D2 was negligible in this population, and serum 25(OH)D3 was used for analysis. Plasma PTH was analyzed with chemiluminescence (Advia Centaur XP; Siemens Healthcare, USA). CRP, including high-sensitivity CRP for CRP values 30 at baseline, we found no significant effect of the intervention (data not shown). 3.5. Harms Reported adverse events were few, mild, and equally distributed between the placebo and supplementation groups, and the symptoms were considered unrelated to the intervention (8, 6, and 7 participants in the 25-lg vitamin D group, 10-lg vitamin D group, and placebo group, respectively). At follow-up, 3 participants (2 in the 25-lg vitamin D group and 1 in the placebo group) reported a brief admission to a hospital in the study period, but the symptoms were unrelated to the intervention. 4. Discussion The adult, healthy study participants from ethnic minorities with low vitamin D levels reported frequent headache and musculoskeletal pain at baseline. Participants in both intervention and placebo groups reported significantly less pain at the end of the trial. The use of vitamin D supplements, however, showed no significant effect on the occurrence, anatomical localization, and degree of pain or headache compared to placebo.
4.1. Strength and weaknesses The study complied with CONSORT guidelines (http:// www.consort-statement.org) for randomized trials, and had a high retention to follow-up (86%). The trial was performed during winter and spring, a time with minimal impact of sun exposure at our latitude and impact of skin type (not recorded in this study). The blood samples were analyzed in a single batch. Our study focused on symptoms in a presumed healthy ethnic minority population, excluding defined illnesses. More women than men were recruited, rendering gender comparisons less efficient. Even though 16 weeks of supplementation with vitamin D raised the serum levels in the intervention groups, not all participants attained a serum level of 25(OH)D3 P 50 nmol/L at the end of trial. Power calculations to determine the sample size were based on expected changes in muscle strength (results reported elsewhere) and not in symptom reduction [20]. 4.2. Comparison with other studies 4.2.1. Baseline characteristics and associations Our population showed a high percentage (92%) of vitamin D deficiency (serum 25(OH)D < 50 nmol/L), with a mean concentration of serum 25(OH)D3 of 26 nmol/L. Additionally, our results showed no significant baseline associations between pain experiences and vitamin D level. A prospective case–control study from Kuwait similarly showed no differences in mean vitamin D values of patients with musculoskeletal pain (serum 25[OH]D = 26 nmol/ L) and healthy controls without pain (serum 25[OH]D = 28 nmol/L) [1]. However, a cross-sectional study with 3075 men from 8 centers in Europe, in which 41% of the study subjects were pain free, showed an increase in the odds of having low serum 25(OH)D if the participants had musculoskeletal pain [26]. In a population study among white British adult men and women (n = 9377), low serum 25(OH)D status was found to be associated with widespread pain in women only [3]. Our findings indicated significant gender differences at baseline; specifically, women reported pain more frequently than men, yet no significant baseline associations existed between low serum 25(OH)D and pain, even when examined for each gender separately. In a review of 13 studies (1996–2012) investigating the association between musculoskeletal pain and vitamin D levels, Al-Jarallah et al. found inconsistent results across studies, warranting the need for further research [1]. Our study population reported a high frequency of headache, and participants with headache had a high mean HIT-6 score of 60. A mean HIT-6 score of 60 or above reflects headaches with a severe impact on a person’s life [27]. Coeytaux and Linville found similar HIT-6 scores in their primary care population among patients who reported headache 15 times or more per month [9].
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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Table 2 Effect of vitamin D3 supplementation (25 lg and 10 lg combined) on pain and headache disability scores and inflammation parameters at the end of intervention compared to placebo.
n (%)
After 16 weeksa Effect (95% CI) of vitamin P-value D3 compared to placebob n (%) OR
144 71
135 (94%) 67 (94%)
107 (74%) 54 (76%)
1.07 (0.34–3.43) –
0.91
1.15 (0.34–3.96) –
0.82
Pain killers past 2 weeks Vitamin D3 Placebo
144 71
55 (38%) 37 (52%)
55 (38%) 24 (34%)
1.98 (0.99–3.95) –
0.05
2.10 (1.03–4.30) –
0.04
Headache past 2 weeks Vitamin D3 Placebo
144 71
77 (54%) 41 (58%)
50 (35%) 27 (38%)
1.00 (0.51–1.96) –
1.00
1.01 (0.50–2.04) –
0.97
Headache past 4 weeks Vitamin D3 Placebo
144 71
88 (61%) 44 (62%)
62 (43%) 32 (45%)
0.97 (0.50–1.91) –
0.94
0.99 (0.49–1.99) –
0.97
Mean (95% CI)
Mean (95% CI)
IRR
144 71
4.3 (3.8–4.8) 4.7 (4.1–5.3)
2.7 (2.3–3.2) 2.8 (2.2–3.4)
1.08 (0.86–1.35) –
Mean (95% CI)
Mean (95% CI)
b
Vitamin D3 Placebo
144 71
223 (191–255) 140 (115–165) 252 (205–299) 143 (107–179)
27 ( 17–71) –
VAS headache Vitamin D3 Placebo
144 71
25 (21–30) 28 (21–35)
18 (13–22) 21 (14–28)
–
HIT-6 score past 4 weeks Vitamin D3 Placebo
144 71
50 (48–52) 51 (48–55)
46 (44–48) 47 (44–50)
0.3 ( 3.5–4.0) –
CRP w/hs CRP Vitamin D3 Placebo
143 71
4.3 (3.3–5.2) 4.6 (2.7–6.5)
4.6 (3.7–5.5) 4.7 (3.3–6.0)
–
n
Pain past 2 weeks Vitamin D3 Placebo
Number of pain sites Vitamin D3 Placebo VAS Totale
Baselinea
c
Adjusted effect (95% CI) of P-valuec vitamin D3 compared to placebod Adj OR
IRR 0.52
1.10 (0.88–1.37) –
0.42
b
1.0 ( 10.0–8.0)
0.23
31 ( 14–75) –
0.83
0.7 ( 9.7–8.3)
0.18
0.88
–
0.3 ( 2.2–1.5)
0.89
0.4 ( 3.3–4.1) –
0.74
0.2 ( 2.1–1.6)
0.82
0.80
–
CI, confidence interval; OR, odds ratio (supplementation is compared to placebo and an OR >1.00 indicates more pain in the supplementation groups than placebo); IRR, incidence rate ratio (the change in the dependent variable in terms of a percentage increase or decrease); b, beta. a Proportions and means of pain scores at baseline and follow-up among those 215 participants who came to follow-up. b Effect of intervention at follow-up. c A 1% significant level has been chosen because of multiple testing. d Effect of intervention with P-value adjusted for gender, age, and baseline level of vitamin D3. e Visual analogue scale (VAS) total, sum of VAS of 10 anatomical areas (range score 0–1000).
Of interest, one-third of their participants had not informed their doctors of their headache. This might reflect that frequent occurrence of headache is considered normal also in a presumed healthy population. In the Tromsø study, Kjærgaard et al. found that nonmigraine headaches were associated with low levels of serum 25(OH)D, but migraine headaches were not [18]. We found no association with levels of serum 25(OH)D and headache scores in the present study. 4.2.2. Effect of vitamin D supplementation The 2012 Cochrane review concluded that the current evidence base for the use of vitamin D in adults with chronic pain is poor, consistent with findings from the 2010 report [33]. This conclusion was largely due to low quality and insufficient number of randomized controlled trials in this area of research. A few randomized controlled studies focusing on the effect of vitamin D on pain have since been published. In 2013, Sandoughi et al. found no effect of 8 weeks vitamin D supplementation on nonspecific low back pain compared to placebo among patients (n = 53) in Iran with low serum 25(OH)D levels at baseline, although both groups had a significant reduction in VAS scores at follow-up [30]. Similarly, McAlindon et al. showed no effect of 2 years of vitamin D supplementation compared to placebo to reduce knee pain in patients (n = 146) with osteoarthritis, even when the dose of vitamin D was sufficient to elevate 25(OH)D to levels above 90 nmol/L [25]. These results are in line
with our findings, despite different pain measurements. However, Sanghi et al. detected a small but significant effect of vitamin D treatment compared to placebo in patients with knee osteoarthritis (n = 107) after 1 year of treatment [31]. Wepner et al. showed a reduction in VAS score in patients with fibromyalgia syndrome among those treated with vitamin D supplementation for 20 weeks compared to the placebo group, but the number of participants was low (n = 30) [36]. In our study, we were not able to identify any reduction in occurrence and pain intensity at different anatomical sites as a result of vitamin D supplementation. Our study included a relatively large number of participants, and we had a high retention to follow-up. However, not all participants in the supplement groups might have been exposed to sufficient serum 25(OH)D levels within a sufficient period of time to affect pain score outcomes. A total of 57% in the 25-lg supplementation group and only 38% in the 10-lg supplementation group reached 25(OH)D levels P 50 nmol/L. Yet a longer study period might have contributed to a greater loss to follow-up and some impact of sun exposure (vitamin D-producing ultraviolet B rays), blurring the differences between groups. A higher vitamin D supplementation dose might also have increased the serum 25(OH)D during the study. However, we did not find that the 25-lg supplementation group had a greater effect on pain scores than placebo, and further, we found no association between pain scores and level of serum 25(OH)D at follow-up. Thus, our data do not encourage
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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K.V. Knutsen et al. / PAIN xxx (2014) xxx–xxx Table 3 Effect of vitamin D3 supplementation (25 lg and 10 lg combined) on localized pain and VAS score at the end of intervention compared to placebo. Pain localization
n
Proportion with pain a
Local VAS score a
Baselinea
After 16 weeksa
P-valuec Adj
Mean (95% CI)
Effect (95% CI) of vitamin D3 compared to placebob b
Mean (95% CI) 0.51
29 (24–34) 33 (26–40)
16 (12–21) 15 (10–21)
5.66 ( 3.62–14.93) –
0.23
1.76 (0.84–3.70) –
0.14
31 (26–37) 38 (30–45)
22 (17–26) 18 (12–24)
10.09 (0.69–19.50) –
0.04
16 (11%) 6 (9%)
1.49 (0.48–4.56) –
0.49
11 (7–15) 14 (8–21)
6 (3–9) 3 (0.5–6)
5.48 ( 1.57–12.53) –
0.13
37 (26%) 25 (35%)
20 (14%) 13 (18%)
1.06 (0.46–2.42) –
0.89
13 (9–17) 19 (12–25)
6 (4–9) 8 (4–14)
2.53 ( 4.59–9.64) –
0.49
144 71
55 (38%) 34 (48%)
33 (23%) 20 (28%)
1.20 (0.61–2.38) –
0.60
21 (16–26) 26 (19–34)
12 (8–16) 14 (8–20)
3.04 ( 5.08–11.15) –
0.46
Lower back Vitamin D3 Placebo
144 71
81 (56%) 36 (51%)
52 (36%) 23 (32%)
1.13 (0.58–2.20) –
0.73
29 (24–34) 30 (22–38)
18 (13–23) 18 (12–25)
2.17 ( 6.70–11.04) –
0.63
Hips/thighs Vitamin D3 Placebo
144 71
47 (33%) 24 (34%)
27 (19%) 13 (18%)
1.21 (0.56–2.61) –
0.62
18 (13–22) 17 (11–24)
10 (6–13) 11 (5–17)
0.25 ( 8.65–9.14) –
0.96
Knees/lower leg Vitamin D3 Placebo
144 71
71 (49%) 38 (54%)
54 (38%) 27 (38%)
1.29 (0.64–2.59) –
0.48
29 (23–34) 30 (22–38)
19 (15–23) 21 (14–28)
1.80 ( 7.23–10.82) –
0.70
Ankles/feet Vitamin D3 Placebo
144 71
47 (33%) 20 (28%)
35 (24%) 16 (23%)
1.06 (0.52–2.16) –
0.88
17 (12–22) 17 (10–23)
13 (9–17) 13 (7–19)
0.33 ( 7.26–7.92) –
0.93
Baseline
After 16 weeks
n (%) 144 71
c
P-value Adj
n (%)
Effect (95% CI) of vitamin D3 compared to placebob OR
81 (56%) 45 (63%)
46 (32%) 25 (35%)
1.29 (0.60–2.76) –
Shoulder/upper arm Vitamin D3 144 Placebo 71
83 (58%) 50 (70%)
54 (38%) 27 (38%)
Elbows/forearm Vitamin D3 Placebo
144 71
35 (24%) 18 (25%)
Hands/wrists Vitamin D3 Placebo
144 71
Upper back Vitamin D3 Placebo
Neck Vitamin D3 Placebo
VAS, visual analogue scale; CI, confidence interval; OR, odds ratio (supplementation is compared to placebo and an OR >1.00 indicates more pain in the supplementation groups than placebo); b, Beta. a Proportions and means of pain scores at baseline and follow-up among those 215 participants who came to follow-up. b Effect of intervention at follow-up, adjusted for gender, age, and baseline level of vitamin D3. c A 1% significant level has been chosen because of multiple testing.
speculation of a possible effect of vitamin D supplementation on pain using moderate dosages. McAlindon et al. demonstrated that higher doses of vitamin D supplements had no significant effect on pain scores [25]. Research indicates a link between vitamin D and inflammation [4]. Although Chandler et al. found no effect of 3 months of vitamin D supplementation on CRP in healthy African Americans, participants with 25(OH)D < 50 nmol/L had higher CRP levels [8]. We focused on CRP as a possible marker of inflammation as a cause of pain. However, in our healthy population of immigrants with low levels of vitamin D, we found no correlation between serum 25(OH)D levels and serum CRP at baseline, and supplementation with vitamin D did not decrease levels of CRP. However, caution should be exercised in extrapolating these findings to patients with severe inflammatory conditions. Some other studies among patients have found a reduction in inflammatory biomarkers with vitamin D supplementation [11,16]. Interestingly, there were significant decreases in pain scores at follow-up compared to baseline, also in the placebo group. Findings might attribute to a placebo effect of participation in a research trial, taking a tablet every day, and receiving mobile phone text messages twice a week to prompt compliance. External factors affecting both supplement groups and placebo group equally during the 16 weeks trial cannot be ruled out. One such factor might be the change in daylight time from winter to spring, thereby increasing the level of melatonin. Melatonin has been shown to modulate pain by reducing nociception [2]. Directing
attention to musculoskeletal pain symptoms, by questionnaire at the first visit, in our research trial may have produced a higher pain score at baseline than reported at follow-up, independent of the actual intervention. Steingrimsdottir et al. also found higher complaint levels at intake than later assessments among healthy service-sector workers [32]. Regression to the mean may also account for these findings. 4.3. Conclusion Daily supplementation of vitamin D3 (25 lg or 10 lg) for 16 weeks compared to placebo did not reduce scores for musculoskeletal pain or headache among a healthy population of adult immigrants from the Middle East, Africa, or South Asia residing in Norway. Conflict of interest The authors declare no conflict of interest. Acknowledgements The authors thank Eva Kristensen and Morten Ariansen for their help with data collection, Anne Karen Jenum for the biobank support, Marie Buchmann and Anne-Lise Sund at Fürst Medical Laboratory for facilitating the laboratory analyses, and Svein Gjelstad for his assistance in data management. Finally, we extend
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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our gratitude to the study participants who participated in this 16-week trial and those organizations who allowed us to use their venues for recruitment and data collection. The research was funded by the University of Oslo. The study was also supported by the Norwegian Women’s Public Health Association, Fürst Medical Laboratory, and by Nycomed Pharma AS. None of the supporting bodies had any influence on the performance of the trial, analyses of data, writing, or the publication of the results. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.pain.2014.09.024. References [1] Al-Jarallah K, Shehab D, Abraham M, Mojiminiyi OA, Abdella NA. Musculoskeletal pain: should physicians test for vitamin D level? Int J Rheum Dis 2013;16:193–7. [2] Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, Granados-Soto V. Melatonin: a hormone that modulates pain. Life Sci 2009;84:489–98. [3] Atherton K, Berry DJ, Parsons T, Macfarlane GJ, Power C, Hypponen E. Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey. Ann Rheum Dis 2009;68:817–22. [4] Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diab Endocrinol 2014;2:76–89. [5] Beck-Nielsen SS, Jensen TK, Gram J, Brixen K, Brock-Jacobsen B. Nutritional rickets in Denmark: a retrospective review of children’s medical records from 1985 to 2005. Eur J Pediatr 2009;168:941–9. [6] Brekke M, Hjortdahl P. Musculo-skeletal pain among 40- and 45-year olds in Oslo: differences between two socioeconomically contrasting areas, and their possible explanations. Int J Equity Health 2004;3:10. [7] Caillet P, Jaglal SB, Laforest L, Chapurlat R, Rabilloud M, Ducher M, Schott AM. Impact of vitamin D supplementation on health-care use in a 25hydroxyvitamin D-tested population in France: a population-based descriptive cohort study. Public Health Nutr 2014;31:1–11. [8] Chandler PD, Scott JB, Drake BF, Ng K, Manson JE, Rifai N, Chan AT, Bennett GG, Hollis BW, Giovannucci EL, Emmons KM, Fuchs CS. Impact of vitamin D supplementation on inflammatory markers in African–Americans: results of a four-arm, randomized, placebo-controlled trial. Cancer Prev Res (Phila) 2014;7:218–25. [9] Coeytaux RR, Linville JC. Chronic daily headache in a primary care population: prevalence and headache impact test scores. Headache 2007;47:7–12. [10] Gandek B, Alacoque J, Uzun V, Andrew-Hobbs M, Davis K. Translating the Short-Form Headache Impact Test (HIT-6) in 27 countries: methodological and conceptual issues. Qual Life Res 2003;12:975–9. [11] Grossmann RE, Zughaier SM, Liu S, Lyles RH, Tangpricha V. Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation. Eur J Clin Nutr 2012;66:1072–4. [12] Harari M, Dramsdahl E, Shany S, Baumfeld Y, Ingber A, Novack V, Sukenik S. Increased vitamin D serum levels correlate with clinical improvement of rheumatic diseases after Dead Sea climatotherapy. Isr Med Assoc J 2011;13:212–5. [13] Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 2014;72:48–54. [14] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. [15] Holvik K, Meyer HE, Haug E, Brunvand L. Prevalence and predictors of vitamin D deficiency in five immigrant groups living in Oslo, Norway: the Oslo Immigrant Health Study. Eur J Clin Nutr 2005;59:57–63.
[16] Hopkins MH, Owen J, Ahearn T, Fedirko V, Flanders WD, Jones DP, Bostick RM. Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: a randomized, controlled clinical trial. Cancer Prev Res (Phila) 2011;4:1645–54. [17] Kamaleri Y, Natvig B, Ihlebaek CM, Benth JS, Bruusgaard D. Change in the number of musculoskeletal pain sites: a 14-year prospective study. PAINÒ 2009;141:25–30. [18] Kjærgaard M, Eggen AE, Mathiesen EB, Jorde R. Association between headache and serum 25-hydroxyvitamin D; the Tromsø study: Tromsø 6. Headache 2012;52:1499–505. [19] Knutsen KV, Brekke M, Gjelstad S, Lagerlov P. Vitamin D status in patients with musculoskeletal pain, fatigue and headache: a cross-sectional descriptive study in a multi-ethnic general practice in Norway. Scand J Prim Health Care 2010;28:166–71. [20] Knutsen KV, Madar AA, Lagerlov P, Brekke M, Raastad T, Stene LC, Meyer HE. Does vitamin D improve muscle strength in adults? a randomized, doubleblind, placebo-controlled trial among ethnic min Norway. J Clin Endocrinol Metab 2014;99:194–202. [21] Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 2011;51:311–36. [22] Kuorinka I, Jonsson B, Kilbom A, Vinterberg H, Biering-Sorensen F, Andersson G, Jorgensen K. Standardised Nordic questionnaires for the analysis of musculoskeletal symptoms. Appl Ergon 1987;18:233–7. [23] Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrinology 2012;4:95–100. [24] Macfarlane GJ, Palmer B, Roy D, Afzal C, Silman AJ, O’Neill T. An excess of widespread pain among South Asians: are low levels of vitamin D implicated? Ann Rheum Dis 2005;64:1217–9. [25] McAlindon T, LaValley M, Schneider E, Nuite M, Lee JY, Price LL, Lo G, DawsonHughes B. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial. JAMA 2013;309:155–62. [26] McBeth J, Pye SR, O’Neill TW, Macfarlane GJ, Tajar A, Bartfai G, Boonen S, Bouillon R, Casanueva F, Finn JD, Forti G, Giwercman A, Han TS, Huhtaniemi IT, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Wu FC. Musculoskeletal pain is associated with very low levels of vitamin D in men: results from the European Male Ageing Study. Ann Rheum Dis 2010;69:1448–52. [27] Nachit-Ouinekh F, Dartigues JF, Henry P, Becg JP, Chastan G, Lemaire N, El Hasnaoui A. Use of the Headache Impact Test (HIT-6) in general practice: relationship with quality of life and severity. Eur J Neurol 2005;12:189–93. [28] Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463–70. [29] Pojednic RM, Ceglia L. The emerging biomolecular role of vitamin D in skeletal muscle. Exerc Sport Sci Rev 2014;42:76–81. [30] Sandoughi M, Zakeri Z, Mirhosainee Z, Mohammadi M, Shahbakhsh S. The effect of vitamin D on nonspecific low back pain. Int J Rheum Dis 2013. http:// dx.doi.org/10.1111/1756-185X.12172 [Epub ahead of print]. [31] Sanghi D, Mishra A, Sharma AC, Singh A, Natu SM, Agarwal S, Srivastava RN. Does vitamin D improve osteoarthritis of the knee: a randomized controlled pilot trial. Clin Orthop Relat Res 2013;471:3556–62. [32] Steingrimsdottir OA, Vollestad NK, Roe C, Knardahl S. Variation in reporting of pain and other subjective health complaints in a working population and limitations of single sample measurements. PAINÒ 2004;110:130–9. [33] Straube S, Derry S, Moore RA, McQuay HJ. Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database Syst Rev 2010:CD007771. [34] Straube S, Moore RA, Derry S, McQuay HJ. Vitamin D and chronic pain. PAINÒ 2009;141:10–3. [35] Torun E, Genc H, Gonullu E, Akovali B, Ozgen IT. The clinical and biochemical presentation of vitamin D deficiency and insufficiency in children and adolescents. J Pediatr Endocrinol Metab 2013;26:469–75. [36] Wepner F, Scheuer R, Schuetz-Wieser B, Machacek P, Pieler-Bruha E, Cross HS, Hahne J, Friedrich M. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. PAINÒ 2014;155:261–8.
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Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-controlled trial among adult ethnic minorities in Norway Kirsten V. Knutsen a,⇑, Ahmed A. Madar b, Mette Brekke a, Haakon E. Meyer b,c, Bård Natvig a, Ibrahimu Mdala a, Per Lagerløv a a
Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway Department of Community Medicine, Institute of Health and Society, University of Oslo, Norway c Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway b
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 26 June 2014 Received in revised form 4 September 2014 Accepted 16 September 2014 Available online xxxx Keywords: Vitamin D Pain Headache Musculoskeletal pain Visual analogue scale HIT-6 Randomized controlled trial
a b s t r a c t Immigrants from South Asia, the Middle East, and Africa living in Northern Europe frequently have low vitamin D levels and more pain compared to the native Western population. The aim of this study was to examine whether daily vitamin D3 (25 lg/d or 10 lg/d) supplementation for 16 weeks would improve musculoskeletal pain or headache compared to placebo. This randomized, double-blind, placebocontrolled, parallel-group trial recruited 251 participants aged 18 to 50 years, and 215 (86%) attended the follow-up visit. The pain measures were occurrence, anatomical localization, and degree of musculoskeletal pain, as measured by visual analogue scale (VAS) score during the past 2 weeks. Headache was measured with VAS and the Headache Impact Test (HIT-6) questionnaire. At baseline, females reported more pain sites (4.7) than males (3.4), and only 7% reported no pain in the past 2 weeks. During the past 4 weeks, 63% reported headache with a high mean HIT-6 score of 60 (SD 7). At follow-up, vitamin D level, measured as serum 25(OH)D3, increased from 27 nmol/L to 52 nmol/L and from 27 nmol/L to 43 nmol/L in the 25-lg and 10-lg supplementation groups, respectively, whereas serum 25(OH)D3 did not change in the placebo group. Pain scores and headache scores were improved at follow-up compared with baseline. The use of vitamin D supplements, however, showed no significant effect on the occurrence, anatomical localization, and degree of pain or headache compared to placebo. Ó 2014 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
1. Introduction Musculoskeletal pain and headache are common symptoms worldwide, with complex and partly unknown etiology. Vitamin D deficiency has been associated with headache and musculoskeletal pain, even though the mechanisms underlying these associations remain unclear [7,12,20,24,28]. Vitamin D receptors are located in various cells and vitamin D seems to be involved in the regulation of inflammatory processes [14,21,29]. Children with nutritional rickets tend to have musculoskeletal pain that resolves with vitamin D treatment, whereas the symptoms among adolescents with rickets are less pronounced and more diffuse [5,35]. In adults, osteomalacia due to vitamin D deficiency can also result in musculoskeletal pain [14]. ⇑ Corresponding author. Tel.: +47 22850582; fax: +47 22850590. E-mail address: [email protected] (K.V. Knutsen).
Immigrants from South Asia, the Middle East, or Africa living in Northern Europe tend to have low vitamin D levels, due to a diet low in vitamin D and low sun exposure, and they report more pain than native Western populations [6,15,24]. Headache was found to be more prevalent among patients in general practice with 25(OH)D levels < 50 nmol/L than among those with levels above 50 nmol/L [19]. In a study from Norway, tension-type headache was associated with low 25(OH)D level, while migraine was not [18]. Observational studies are not suitable to evaluate whether a person‘s health would benefit from vitamin D supplementation, and health benefits found in such studies have seldom been reproduced in randomized trials [4]. Intervention studies on vitamin D supplementation have been limited by methodological shortcomings [13,23,34]. A Cochrane Review investigating the utility of vitamin D treatment for chronic pain identified only 4 studies eligible for inclusion (n = 294), of which only one study reported a beneficial effect [33]. If shown to have a beneficial effect on pain, vitamin
http://dx.doi.org/10.1016/j.pain.2014.09.024 0304-3959/Ó 2014 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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D would constitute a safe and cheap treatment. However, to date, too few randomized controlled trials have been conducted to support this conclusion [33]. This double-blinded, randomized-controlled study aimed to examine whether supplements with daily vitamin D3 (25 lg/d or 10 lg/d) would reduce musculoskeletal pain or headache compared to placebo among an adult ethnic minority population with presumed low level of vitamin D.
2. Materials and methods 2.1. Study design, setting and participants This study was a block randomized, double-blinded, placebocontrolled, parallel-group trial with 3 equally sized groups. It was conducted in local immigrants’ activity centers in Oslo, Norway and surrounding areas (at latitude 60°N) between January and June 2011. Further details of the study methods have been described elsewhere (ClinicalTrials.gov Identifier: NCT01263288) [20]. The study participants came from an assumed healthy population, male and female, aged 18–50 years, who were born in – or had parents born in – the Middle East, Africa, or South Asia. They were recruited through local immigrant organizations. The exclusion criteria were: regular use of vitamin D-containing supplements, ongoing treatment for vitamin D deficiency, use of strong pain killers or medication interfering with vitamin D metabolism (e.g., thiazides, antiepileptic drugs, prednisolone, or hormone replacement therapy), pregnancy, breastfeeding, kidney disease, cancer, tuberculosis, sarcoidosis, osteoporosis, or a recent fracture. 2.2. Intervention, randomization, and blinding Participants who provided consent to participate and fulfilled the eligibility criteria were randomly assigned to 1 of 3 intervention groups receiving 1 tablet daily over 16 weeks, containing either (1) 25 lg of vitamin D3, (2) 10 lg of vitamin D3, or (3) placebo. In the study we included one intervention group with 10 lg vitamin D3/day because this was the recommended daily intake according to official Norwegian guidelines when the study was performed, and one intervention group with 25 lg vitamin D3/day, a dose approved as a dietary supplement by authorities in Europe (United Kingdom and Denmark). Each participant received a box with 120 tablets (112 tablets correspond to 16 weeks of use). Participants were advised to take 2 tablets the following day if they had forgotten to take a tablet the previous day and to maintain their usual dietary pattern during the study. To maximize adherence, the participants received brief reminders via mobile phone text messages twice a week. The participants were advised to contact the study staff by telephone if they had any questions related to the study. The tablets were identical in color, size, taste, and packaging. Group allocations were unknown to participants, research staff, investigators, and data collectors. Randomly varying the block size between 3 and 6 ensured a good balance of gender and different ethnicity in each group. 2.3. Main outcome variable The main outcome variable was difference in change in the predefined pain parameters between the combined intervention groups (25 lg or 10 lg of vitamin D3) and placebo after 16 weeks of intervention. Level and location of pain were recorded at baseline and follow-up by the research staff using an interview-administered questionnaire. Occurrence, anatomical localization, and degree of pain during the preceding 2 weeks were assessed. The participants localized
their pain during the interview by marking a blank body mannequin, with words, or by pointing at the painful part of the body. Localization of musculoskeletal pain was divided into 10 anatomical areas; head, neck, shoulders/upper arm, elbows/forearm, hands/ wrists, upper back, lower back, hips/thighs, knees/lower leg, and ankles/feet. Our questionnaire included the anatomical areas used in the Standardized Nordic Questionnaire [22] in the Oslo Health Study (http://www.fhi.no) and in the Ullensaker Study [17]. A visual analogue scale (VAS; range 0–100) was used for assessment of pain, and the participant marked the pain intensity for each of the 10 anatomical areas. The VAS with the text ‘‘no pain’’ at on one end and ‘‘worst imaginable pain’’ at the other end was turned toward the participant. VAS total is the sum of all VAS scores in the 10 anatomical areas. The Headache Impact Test (HIT-6) questionnaire was developed to measure headache severity and the subjective impact on quality of life in areas such as: pain, social participation, general activity, vitality, psychological distress, and intellectual activity. The questions were answered with: ‘‘never,’’ ‘‘seldom,’’ ‘‘sometimes,’’ ‘‘very often,’’ and ‘‘always,’’ yielding a total score between 36 and 78. The participants with no headache the last 4 weeks were given the lowest score, 36 (‘‘never’’). The HIT-6 questionnaire has been validated in both the general population and clinical samples across different diagnostic groups of headache [27]. It has been translated and validated in a number of languages, including Norwegian [10]. Additional outcomes were: use of pain killers the last 2 weeks and C-reactive protein (CRP), including high-sensitivity CRP. 2.4. Blood sampling and laboratory assays Blood samples from nonfasting participants were collected at baseline and at follow-up examination after 16 weeks. Blood for analyses of serum (25[OH]D3, 25[OH]D2, CRP) and plasma parathyroid hormone (PTH) was collected and handled in separate tubes and stored at 20 °C the same day and within 1–2 weeks frozen at 80 °C. The samples were analyzed in one batch at Fürst Medical Laboratory, Oslo, Norway (http://www.furst.no/), accredited by the International Organization for Standardization, and part of a vitamin D quality assessment scheme, DEQAS. Serum 25-hydroxyvitamin D (25[OH]D) was measured using high-pressure liquid chromatography–tandem mass spectrometry, able to measure both serum 25(OH)D2 and serum 25(OH)D3. Serum 25(OH)D2 was negligible in this population, and serum 25(OH)D3 was used for analysis. Plasma PTH was analyzed with chemiluminescence (Advia Centaur XP; Siemens Healthcare, USA). CRP, including high-sensitivity CRP for CRP values 30 at baseline, we found no significant effect of the intervention (data not shown). 3.5. Harms Reported adverse events were few, mild, and equally distributed between the placebo and supplementation groups, and the symptoms were considered unrelated to the intervention (8, 6, and 7 participants in the 25-lg vitamin D group, 10-lg vitamin D group, and placebo group, respectively). At follow-up, 3 participants (2 in the 25-lg vitamin D group and 1 in the placebo group) reported a brief admission to a hospital in the study period, but the symptoms were unrelated to the intervention. 4. Discussion The adult, healthy study participants from ethnic minorities with low vitamin D levels reported frequent headache and musculoskeletal pain at baseline. Participants in both intervention and placebo groups reported significantly less pain at the end of the trial. The use of vitamin D supplements, however, showed no significant effect on the occurrence, anatomical localization, and degree of pain or headache compared to placebo.
4.1. Strength and weaknesses The study complied with CONSORT guidelines (http:// www.consort-statement.org) for randomized trials, and had a high retention to follow-up (86%). The trial was performed during winter and spring, a time with minimal impact of sun exposure at our latitude and impact of skin type (not recorded in this study). The blood samples were analyzed in a single batch. Our study focused on symptoms in a presumed healthy ethnic minority population, excluding defined illnesses. More women than men were recruited, rendering gender comparisons less efficient. Even though 16 weeks of supplementation with vitamin D raised the serum levels in the intervention groups, not all participants attained a serum level of 25(OH)D3 P 50 nmol/L at the end of trial. Power calculations to determine the sample size were based on expected changes in muscle strength (results reported elsewhere) and not in symptom reduction [20]. 4.2. Comparison with other studies 4.2.1. Baseline characteristics and associations Our population showed a high percentage (92%) of vitamin D deficiency (serum 25(OH)D < 50 nmol/L), with a mean concentration of serum 25(OH)D3 of 26 nmol/L. Additionally, our results showed no significant baseline associations between pain experiences and vitamin D level. A prospective case–control study from Kuwait similarly showed no differences in mean vitamin D values of patients with musculoskeletal pain (serum 25[OH]D = 26 nmol/ L) and healthy controls without pain (serum 25[OH]D = 28 nmol/L) [1]. However, a cross-sectional study with 3075 men from 8 centers in Europe, in which 41% of the study subjects were pain free, showed an increase in the odds of having low serum 25(OH)D if the participants had musculoskeletal pain [26]. In a population study among white British adult men and women (n = 9377), low serum 25(OH)D status was found to be associated with widespread pain in women only [3]. Our findings indicated significant gender differences at baseline; specifically, women reported pain more frequently than men, yet no significant baseline associations existed between low serum 25(OH)D and pain, even when examined for each gender separately. In a review of 13 studies (1996–2012) investigating the association between musculoskeletal pain and vitamin D levels, Al-Jarallah et al. found inconsistent results across studies, warranting the need for further research [1]. Our study population reported a high frequency of headache, and participants with headache had a high mean HIT-6 score of 60. A mean HIT-6 score of 60 or above reflects headaches with a severe impact on a person’s life [27]. Coeytaux and Linville found similar HIT-6 scores in their primary care population among patients who reported headache 15 times or more per month [9].
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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Table 2 Effect of vitamin D3 supplementation (25 lg and 10 lg combined) on pain and headache disability scores and inflammation parameters at the end of intervention compared to placebo.
n (%)
After 16 weeksa Effect (95% CI) of vitamin P-value D3 compared to placebob n (%) OR
144 71
135 (94%) 67 (94%)
107 (74%) 54 (76%)
1.07 (0.34–3.43) –
0.91
1.15 (0.34–3.96) –
0.82
Pain killers past 2 weeks Vitamin D3 Placebo
144 71
55 (38%) 37 (52%)
55 (38%) 24 (34%)
1.98 (0.99–3.95) –
0.05
2.10 (1.03–4.30) –
0.04
Headache past 2 weeks Vitamin D3 Placebo
144 71
77 (54%) 41 (58%)
50 (35%) 27 (38%)
1.00 (0.51–1.96) –
1.00
1.01 (0.50–2.04) –
0.97
Headache past 4 weeks Vitamin D3 Placebo
144 71
88 (61%) 44 (62%)
62 (43%) 32 (45%)
0.97 (0.50–1.91) –
0.94
0.99 (0.49–1.99) –
0.97
Mean (95% CI)
Mean (95% CI)
IRR
144 71
4.3 (3.8–4.8) 4.7 (4.1–5.3)
2.7 (2.3–3.2) 2.8 (2.2–3.4)
1.08 (0.86–1.35) –
Mean (95% CI)
Mean (95% CI)
b
Vitamin D3 Placebo
144 71
223 (191–255) 140 (115–165) 252 (205–299) 143 (107–179)
27 ( 17–71) –
VAS headache Vitamin D3 Placebo
144 71
25 (21–30) 28 (21–35)
18 (13–22) 21 (14–28)
–
HIT-6 score past 4 weeks Vitamin D3 Placebo
144 71
50 (48–52) 51 (48–55)
46 (44–48) 47 (44–50)
0.3 ( 3.5–4.0) –
CRP w/hs CRP Vitamin D3 Placebo
143 71
4.3 (3.3–5.2) 4.6 (2.7–6.5)
4.6 (3.7–5.5) 4.7 (3.3–6.0)
–
n
Pain past 2 weeks Vitamin D3 Placebo
Number of pain sites Vitamin D3 Placebo VAS Totale
Baselinea
c
Adjusted effect (95% CI) of P-valuec vitamin D3 compared to placebod Adj OR
IRR 0.52
1.10 (0.88–1.37) –
0.42
b
1.0 ( 10.0–8.0)
0.23
31 ( 14–75) –
0.83
0.7 ( 9.7–8.3)
0.18
0.88
–
0.3 ( 2.2–1.5)
0.89
0.4 ( 3.3–4.1) –
0.74
0.2 ( 2.1–1.6)
0.82
0.80
–
CI, confidence interval; OR, odds ratio (supplementation is compared to placebo and an OR >1.00 indicates more pain in the supplementation groups than placebo); IRR, incidence rate ratio (the change in the dependent variable in terms of a percentage increase or decrease); b, beta. a Proportions and means of pain scores at baseline and follow-up among those 215 participants who came to follow-up. b Effect of intervention at follow-up. c A 1% significant level has been chosen because of multiple testing. d Effect of intervention with P-value adjusted for gender, age, and baseline level of vitamin D3. e Visual analogue scale (VAS) total, sum of VAS of 10 anatomical areas (range score 0–1000).
Of interest, one-third of their participants had not informed their doctors of their headache. This might reflect that frequent occurrence of headache is considered normal also in a presumed healthy population. In the Tromsø study, Kjærgaard et al. found that nonmigraine headaches were associated with low levels of serum 25(OH)D, but migraine headaches were not [18]. We found no association with levels of serum 25(OH)D and headache scores in the present study. 4.2.2. Effect of vitamin D supplementation The 2012 Cochrane review concluded that the current evidence base for the use of vitamin D in adults with chronic pain is poor, consistent with findings from the 2010 report [33]. This conclusion was largely due to low quality and insufficient number of randomized controlled trials in this area of research. A few randomized controlled studies focusing on the effect of vitamin D on pain have since been published. In 2013, Sandoughi et al. found no effect of 8 weeks vitamin D supplementation on nonspecific low back pain compared to placebo among patients (n = 53) in Iran with low serum 25(OH)D levels at baseline, although both groups had a significant reduction in VAS scores at follow-up [30]. Similarly, McAlindon et al. showed no effect of 2 years of vitamin D supplementation compared to placebo to reduce knee pain in patients (n = 146) with osteoarthritis, even when the dose of vitamin D was sufficient to elevate 25(OH)D to levels above 90 nmol/L [25]. These results are in line
with our findings, despite different pain measurements. However, Sanghi et al. detected a small but significant effect of vitamin D treatment compared to placebo in patients with knee osteoarthritis (n = 107) after 1 year of treatment [31]. Wepner et al. showed a reduction in VAS score in patients with fibromyalgia syndrome among those treated with vitamin D supplementation for 20 weeks compared to the placebo group, but the number of participants was low (n = 30) [36]. In our study, we were not able to identify any reduction in occurrence and pain intensity at different anatomical sites as a result of vitamin D supplementation. Our study included a relatively large number of participants, and we had a high retention to follow-up. However, not all participants in the supplement groups might have been exposed to sufficient serum 25(OH)D levels within a sufficient period of time to affect pain score outcomes. A total of 57% in the 25-lg supplementation group and only 38% in the 10-lg supplementation group reached 25(OH)D levels P 50 nmol/L. Yet a longer study period might have contributed to a greater loss to follow-up and some impact of sun exposure (vitamin D-producing ultraviolet B rays), blurring the differences between groups. A higher vitamin D supplementation dose might also have increased the serum 25(OH)D during the study. However, we did not find that the 25-lg supplementation group had a greater effect on pain scores than placebo, and further, we found no association between pain scores and level of serum 25(OH)D at follow-up. Thus, our data do not encourage
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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K.V. Knutsen et al. / PAIN xxx (2014) xxx–xxx Table 3 Effect of vitamin D3 supplementation (25 lg and 10 lg combined) on localized pain and VAS score at the end of intervention compared to placebo. Pain localization
n
Proportion with pain a
Local VAS score a
Baselinea
After 16 weeksa
P-valuec Adj
Mean (95% CI)
Effect (95% CI) of vitamin D3 compared to placebob b
Mean (95% CI) 0.51
29 (24–34) 33 (26–40)
16 (12–21) 15 (10–21)
5.66 ( 3.62–14.93) –
0.23
1.76 (0.84–3.70) –
0.14
31 (26–37) 38 (30–45)
22 (17–26) 18 (12–24)
10.09 (0.69–19.50) –
0.04
16 (11%) 6 (9%)
1.49 (0.48–4.56) –
0.49
11 (7–15) 14 (8–21)
6 (3–9) 3 (0.5–6)
5.48 ( 1.57–12.53) –
0.13
37 (26%) 25 (35%)
20 (14%) 13 (18%)
1.06 (0.46–2.42) –
0.89
13 (9–17) 19 (12–25)
6 (4–9) 8 (4–14)
2.53 ( 4.59–9.64) –
0.49
144 71
55 (38%) 34 (48%)
33 (23%) 20 (28%)
1.20 (0.61–2.38) –
0.60
21 (16–26) 26 (19–34)
12 (8–16) 14 (8–20)
3.04 ( 5.08–11.15) –
0.46
Lower back Vitamin D3 Placebo
144 71
81 (56%) 36 (51%)
52 (36%) 23 (32%)
1.13 (0.58–2.20) –
0.73
29 (24–34) 30 (22–38)
18 (13–23) 18 (12–25)
2.17 ( 6.70–11.04) –
0.63
Hips/thighs Vitamin D3 Placebo
144 71
47 (33%) 24 (34%)
27 (19%) 13 (18%)
1.21 (0.56–2.61) –
0.62
18 (13–22) 17 (11–24)
10 (6–13) 11 (5–17)
0.25 ( 8.65–9.14) –
0.96
Knees/lower leg Vitamin D3 Placebo
144 71
71 (49%) 38 (54%)
54 (38%) 27 (38%)
1.29 (0.64–2.59) –
0.48
29 (23–34) 30 (22–38)
19 (15–23) 21 (14–28)
1.80 ( 7.23–10.82) –
0.70
Ankles/feet Vitamin D3 Placebo
144 71
47 (33%) 20 (28%)
35 (24%) 16 (23%)
1.06 (0.52–2.16) –
0.88
17 (12–22) 17 (10–23)
13 (9–17) 13 (7–19)
0.33 ( 7.26–7.92) –
0.93
Baseline
After 16 weeks
n (%) 144 71
c
P-value Adj
n (%)
Effect (95% CI) of vitamin D3 compared to placebob OR
81 (56%) 45 (63%)
46 (32%) 25 (35%)
1.29 (0.60–2.76) –
Shoulder/upper arm Vitamin D3 144 Placebo 71
83 (58%) 50 (70%)
54 (38%) 27 (38%)
Elbows/forearm Vitamin D3 Placebo
144 71
35 (24%) 18 (25%)
Hands/wrists Vitamin D3 Placebo
144 71
Upper back Vitamin D3 Placebo
Neck Vitamin D3 Placebo
VAS, visual analogue scale; CI, confidence interval; OR, odds ratio (supplementation is compared to placebo and an OR >1.00 indicates more pain in the supplementation groups than placebo); b, Beta. a Proportions and means of pain scores at baseline and follow-up among those 215 participants who came to follow-up. b Effect of intervention at follow-up, adjusted for gender, age, and baseline level of vitamin D3. c A 1% significant level has been chosen because of multiple testing.
speculation of a possible effect of vitamin D supplementation on pain using moderate dosages. McAlindon et al. demonstrated that higher doses of vitamin D supplements had no significant effect on pain scores [25]. Research indicates a link between vitamin D and inflammation [4]. Although Chandler et al. found no effect of 3 months of vitamin D supplementation on CRP in healthy African Americans, participants with 25(OH)D < 50 nmol/L had higher CRP levels [8]. We focused on CRP as a possible marker of inflammation as a cause of pain. However, in our healthy population of immigrants with low levels of vitamin D, we found no correlation between serum 25(OH)D levels and serum CRP at baseline, and supplementation with vitamin D did not decrease levels of CRP. However, caution should be exercised in extrapolating these findings to patients with severe inflammatory conditions. Some other studies among patients have found a reduction in inflammatory biomarkers with vitamin D supplementation [11,16]. Interestingly, there were significant decreases in pain scores at follow-up compared to baseline, also in the placebo group. Findings might attribute to a placebo effect of participation in a research trial, taking a tablet every day, and receiving mobile phone text messages twice a week to prompt compliance. External factors affecting both supplement groups and placebo group equally during the 16 weeks trial cannot be ruled out. One such factor might be the change in daylight time from winter to spring, thereby increasing the level of melatonin. Melatonin has been shown to modulate pain by reducing nociception [2]. Directing
attention to musculoskeletal pain symptoms, by questionnaire at the first visit, in our research trial may have produced a higher pain score at baseline than reported at follow-up, independent of the actual intervention. Steingrimsdottir et al. also found higher complaint levels at intake than later assessments among healthy service-sector workers [32]. Regression to the mean may also account for these findings. 4.3. Conclusion Daily supplementation of vitamin D3 (25 lg or 10 lg) for 16 weeks compared to placebo did not reduce scores for musculoskeletal pain or headache among a healthy population of adult immigrants from the Middle East, Africa, or South Asia residing in Norway. Conflict of interest The authors declare no conflict of interest. Acknowledgements The authors thank Eva Kristensen and Morten Ariansen for their help with data collection, Anne Karen Jenum for the biobank support, Marie Buchmann and Anne-Lise Sund at Fürst Medical Laboratory for facilitating the laboratory analyses, and Svein Gjelstad for his assistance in data management. Finally, we extend
Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
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our gratitude to the study participants who participated in this 16-week trial and those organizations who allowed us to use their venues for recruitment and data collection. The research was funded by the University of Oslo. The study was also supported by the Norwegian Women’s Public Health Association, Fürst Medical Laboratory, and by Nycomed Pharma AS. None of the supporting bodies had any influence on the performance of the trial, analyses of data, writing, or the publication of the results. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.pain.2014.09.024. References [1] Al-Jarallah K, Shehab D, Abraham M, Mojiminiyi OA, Abdella NA. Musculoskeletal pain: should physicians test for vitamin D level? Int J Rheum Dis 2013;16:193–7. [2] Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, Granados-Soto V. Melatonin: a hormone that modulates pain. Life Sci 2009;84:489–98. [3] Atherton K, Berry DJ, Parsons T, Macfarlane GJ, Power C, Hypponen E. Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey. Ann Rheum Dis 2009;68:817–22. [4] Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diab Endocrinol 2014;2:76–89. [5] Beck-Nielsen SS, Jensen TK, Gram J, Brixen K, Brock-Jacobsen B. Nutritional rickets in Denmark: a retrospective review of children’s medical records from 1985 to 2005. Eur J Pediatr 2009;168:941–9. [6] Brekke M, Hjortdahl P. Musculo-skeletal pain among 40- and 45-year olds in Oslo: differences between two socioeconomically contrasting areas, and their possible explanations. Int J Equity Health 2004;3:10. [7] Caillet P, Jaglal SB, Laforest L, Chapurlat R, Rabilloud M, Ducher M, Schott AM. Impact of vitamin D supplementation on health-care use in a 25hydroxyvitamin D-tested population in France: a population-based descriptive cohort study. Public Health Nutr 2014;31:1–11. [8] Chandler PD, Scott JB, Drake BF, Ng K, Manson JE, Rifai N, Chan AT, Bennett GG, Hollis BW, Giovannucci EL, Emmons KM, Fuchs CS. Impact of vitamin D supplementation on inflammatory markers in African–Americans: results of a four-arm, randomized, placebo-controlled trial. Cancer Prev Res (Phila) 2014;7:218–25. [9] Coeytaux RR, Linville JC. Chronic daily headache in a primary care population: prevalence and headache impact test scores. Headache 2007;47:7–12. [10] Gandek B, Alacoque J, Uzun V, Andrew-Hobbs M, Davis K. Translating the Short-Form Headache Impact Test (HIT-6) in 27 countries: methodological and conceptual issues. Qual Life Res 2003;12:975–9. [11] Grossmann RE, Zughaier SM, Liu S, Lyles RH, Tangpricha V. Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation. Eur J Clin Nutr 2012;66:1072–4. [12] Harari M, Dramsdahl E, Shany S, Baumfeld Y, Ingber A, Novack V, Sukenik S. Increased vitamin D serum levels correlate with clinical improvement of rheumatic diseases after Dead Sea climatotherapy. Isr Med Assoc J 2011;13:212–5. [13] Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 2014;72:48–54. [14] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. [15] Holvik K, Meyer HE, Haug E, Brunvand L. Prevalence and predictors of vitamin D deficiency in five immigrant groups living in Oslo, Norway: the Oslo Immigrant Health Study. Eur J Clin Nutr 2005;59:57–63.
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Please cite this article in press as: Knutsen KV et al. Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind, placebo-conÒ trolled trial among adult ethnic minorities in Norway. PAIN (2014), http://dx.doi.org/10.1016/j.pain.2014.09.024
