Introduction
Synthesis, Absorption, and Metabolism of Vitamin D
Chronic Pain
The Interface of Vitamin D and Chronic Pain
Vitamin D Deficiency
General Prevalence of and Risk Factors Associated With Vitamin D Deficiency
Defining Adequate of Vitamin D Levels
Clinical Supplementation with Vitamin D
Evidence from Recent Randomized Placebo-Controlled Trials of Vitamin D Supplementation in Patients with Chronic Pain
References | Condition or population | Patient characteristics (total number, sex, age), and treatment protocol | Aim of study and measurement of outcomes | Study duration | Pain outcomes | Improvement with vitamin D | Oxford grading and limitations of study |
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Warner and Arnspiger [91]; double-blind RCT | Diffuse musculoskeletal pain and 25(OH)D levels between 9 and 20 ng/ml | 50 participants, mean age 56.2 ± 9.3 years, 100% female. Participants were divided into 2 equal groups and were either supplemented with 50,000 IU ergocalciferol per week (n = 25) or placebo (n = 25). Vitamin D and placebo capsules (identical in appearance) were dispensed in identically appearing capsules | The aim of the study was to evaluate the effect of treatment with vitamin D on musculoskeletal pain. Outcomes assessed were pain measured by VAS and FPS | 3 months | There was no difference in the change in VAS and FPS from baseline to 3-month follow-up between the placebo and active TGs. There was no correlation between vitamin D level and pain on VAS (r 0.038) or FPS (r 0.293) at 3-month follow-up. At 3 months, the mean vitamin D level in the active TG was significantly higher than placebo (31.2 ± 6.1 vs. 19.3 ± 6.5 ng/mL, P < 0.001) | No | Oxford rating 5/5. Generally this was a high-quality study. It is possible that a therapeutic effect of pharmacologic doses of vitamin D was missed because of (a) the small size of the study; and (b) the normalization of vitamin D levels in 50% of the placebo group (presumably because the study took place during the warm months of the year) |
Di Munno et al. [96]; double-blind RCT | Polymyalgia rheumatica of recent onset receiving 6-methylprednisolone | 24 participants, mean age 67.9 years (range 51–82 years), 63% (15) female. Participants were divided into 2 equal groups and were either supplemented with 35 µg 25(OH)D3 per day (n = 12) or placebo (n = 12) for 25 days per month (monthly equivalent 35,000 IU). All participants received 500 mg calcium per day | The aim of the study was to demonstrate that in patients with polymyalgia rheumatica, possible further bone loss (induced by moderate doses of steroids) could be avoided by administration of 25(OH)D3 and calcium supplements. Pain on movement and subjective tenderness on palpation of affected areas were evaluated | 9 months | Subjective pain on movement (scale 0–4): significantly decreased in both groups over time, but there was no great difference between the groups | No | Oxford rating 2/5. Small number of participants in the study, and no statistics were given for between-groups comparison. The level of vitamin D was not measured during the study |
Wepner et al. [97]; double-blind RCT | Severe pain from FMS | 27 women and 3 men, who fulfilled the 2010 American College of Rheumatology criteria for FMS, with serum calcifediol levels below 80 nmol/L (32 ng/mL), were included and randomized to TG (n = 15) or CG (n = 15). The goal was to achieve serum calcifediol levels between 32 and 48 ng/mL for 20 weeks via oral supplementation with cholecalciferol. The CG received placebo medication. Depending on their serum calcifediol levels, the TG received 2400 IU (serum calcifediol levels <60 nmol/L) or 1200 IU (serum calcifediol levels 60–80 nmol/L) of cholecalciferol (vitamin D3) daily, dissolved in a triglyceride solution. The CG received the triglyceride solution without the cholecalciferol | The aims of the study were to establish the role of vitamin D in patients with FMS, and to determine whether serum calcifediol levels within the normal range could improve symptoms, particularly reduce pain, in patients with initially low calcifediol levels (vitamin D deficiency). Pain levels were measured using a VAS scale. Additional variables were evaluated using the SF-36, the Hospital Anxiety and Depression Scale, the FIQ, and the Somatization subscale of Symptom Checklist-90-Revised | Initial supplementation for 20 weeks. Re-evaluation was performed in both groups after further 24 weeks without cholecalciferol supplementation | A marked reduction in pain was noted over the treatment period in the TG. Variance analysis of the 2 groups at 4 time points showed a significant group effect in VAS scores. This also was correlated with scores on the physical role functioning scale of the SF-36. Optimization of calcifediol levels in FMS had a positive effect on the perception of pain | Yes | Oxford rating 5/5. A major limitation of the present study was the small number of participants and the highly selected patient population. Results cannot be therefore extrapolated to patients with chronic pain |
McAlindon et al. [93]; double-blind RCT | Symptomatic knee OA pain | 146 participants with symptomatic knee OA, mean age 62.4 years (SD, 8.5 years); 57 (61%) women, 115 (79%) white race. Participants were randomized to receive either placebo or oral cholecalciferol, 2000 IU daily, with dose escalation to elevate serum levels to more than 36 ng/mL | Primary outcomes were knee pain severity (WOMAC pain scale, 0–20: 0, no pain; 20, extreme pain), and cartilage volume loss measured by magnetic resonance imaging. Secondary end points included physical function, knee function (WOMAC function scale, 0–68: 0, no difficulty; 68, extreme difficulty), cartilage thickness, bone marrow lesions, and radiographic joint space width | Vitamin D supplementation for 2 years. Assessments occurred at a baseline visit, and at months 2, 4, 8, 12, 16, 20, and 24 | 85% of participants completed the study. Serum 25(OH)D levels increased by a mean 16.1 ng/mL (95% CI, 13.7–18.6) in the TG, and by a mean 2.1 mg/mL (95% CI, 0.5–3.7) in the placebo group (P < 0.001). Baseline knee pain was slightly worse in the TG (mean, 6.9; 95% CI, 6.0–7.7) than in the placebo group (mean, 5.8; 95% CI, 5.0–6.6; P = 0.08). Baseline knee function was significantly worse in the TG (mean, 22.7; 95% CI, 19.8–25.6) than in the placebo group (mean, 18.5; 95% CI, 15.8–21.2; P = 0.04). Knee pain decreased in both groups by a mean −2.31 (95% CI, −3.24 to −1.38) in the TG and −1.46 (95% CI, −2.33 to −0.60) in placebo group, with no significant differences at any time. The percentage of cartilage volume decreased by the same extent in both groups (mean, −4.30 [95% CI, −5.48 to −3.12] vs. mean, −4.25 [95% CI, −6.12 to −2.39]; P = 0.96). There were no differences in any of the secondary clinical end points. Vitamin D supplementation for 2 years at a dose sufficient to elevate 25(OH)D serum levels to more than 36 ng/mL when compared to placebo, did not reduce knee pain or cartilage volume loss in patients with symptomatic knee OA | No | Oxford rating 5/5. Baseline knee pain was slightly worse in the TG. Baseline knee function was significantly worse in the TG. A concern in inferring a negative result is the possibility of type 2 error |
Rastelli et al. [95]; double-blind RCT | AIMSS/joint pain and bone loss | 60 women were enrolled. Patients with early breast cancer and AIMSS were stratified according to their baseline 25(OH)D levels. Stratum A (20–29 ng/mL) received either HDD supplementation (50,000 IU capsules weekly for 8 weeks then monthly for 4 months, or placebo. Stratum B (10–19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo | The primary goal of the study was to compare the effectiveness of HDD in patients with breast cancer who develop AIMSS after starting anastrozole. A secondary goal of the study was to assess the efficacy of HDD in protecting bone health in breast cancer patients on anastrozole therapy. AIMSS was assessed by the BPI-SF, the FIQ, and the HAQ-DI at baseline, 2, 4, and 6 months. BMD was measured at baseline and at 6 months. The primary end point of the study was change-from-baseline musculoskeletal pain. The secondary end point was percent change in BMD at 6 months | Assessments occurred at a baseline and at 2, 4, and 6 months | Baseline characteristics were comparable between groups. At 2 months, FIQ pain (P = 0.0045), BPI worst pain (P = 0.04), BPI average pain (P = 0.0067), BPI pain severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than in Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improved AIMSS and might have a positive effect on bone health | Yes | Oxford rating 5/5. The positive effect of vitamin D supplementation was not maintained at 4 and 6 months once subjects were switched to 50,000 IU monthly. It was possible that high enough serum levels of vitamin D were not reached to maximize its therapeutic effect |
Sakalli et al. [98]; double-blind RCT | Pain in the elderly | Community-dwelling elderly subjects of 149 consecutive men and women over 65 years of age were included in the study. 29 were excluded because of contraindications or already receiving vitamin D intake. The remaining 120 cases were given 300,000 IU vitamin D via p.o. and parenteral routes and assessed after 4 weeks. Mean age of all participants was 70.1 ± 4.3 years and there were 57 female participants. There was no difference in age and gender between the groups (P > 0.05). The 120 cases were included and randomized into four groups, each containing 30 cases: 1st group took i.m. vitamin D; 2nd group took i.m. placebo; 3rd group took p.o. vitamin D; and 4th group took p.o. placebo | The aim of this study was to investigate the benefits of a single dose per os or parenterally administrated vitamin D on increasing the quality of life and functional mobility, and decreasing the pain in the elderly. The serum creatinine, calcium, phosphorous, ALT, ALP, 24-h urine calcium excretion, PTH, and vitamin D levels, as well as VAS for pain assessment, functional mobility with TUG and quality of life with SF-36 before and after the treatment were evaluated | Baseline measurements and assessed after 4 weeks | After treatment, the PTH level of first group was decreased (P = 0.0001) and vitamin D level increased (P = 0.0001) significantly. In the third group, the PTH level of first group was decreased (P = 0.0001) and the vitamin D level increased (P = 0.004) and the 24-h calcium excretion in urine (P = 0.015) increased significantly. When the pain, the functional mobility, and the quality of life were evaluated, in the first group, the TUG (P = 0.0001) and the VAS (P = 0.0001) decreased significantly, whereas the SF-36 subtitles increased significantly: physical functioning (P = 0.0001), role physical (P −0.006), bodily pain (P = 0.0001), general health (P = 0.007), social functioning (P = 0.05), and mental health (P = 0.048). In group two, the VAS (P = 0.001) decreased significantly; the role physical (P = 0.009), and role emotional (P = 0.034) increased significantly. In group three, the TUG (P = 0.0001) and the VAS (P = 0.002) decreased significantly, whereas the physical function (P = 0.0001) and role physical (P = 0.001) increased significantly. In group four, the VAS (P = 0.007) decreased significantly. Megadose vitamin D administration increases quality of life, decreases pain, and improves functional mobility when given via oral or intramuscular routes in the elderly | Yes | Oxford rating 3/5. The study did not describe how the study was double blind. The authors did not state the final number of participants in each group, but merely indicated that if participants did not attend the 2nd examination, they were excluded from the group. This could constitute a fair risk of bias. A major limitation of the study was the small number of participants and the short study duration. The total time spent under sun exposure could not be exactly recorded |
Schreuder et al. [92]; semi-crossover double-blind RCT | Nonspecific musculoskeletal pain | 84 non-Western immigrants were enrolled in the study, of which 64 were female. At baseline, patients were randomized to placebo or to vitamin D (150,000 IU vitamin D3 p.o.). At week 6, patients in the original vitamin D group were randomized a second time to receive vitamin D (again) or switched to placebo, whereas patients in the original placebo group were all switched to vitamin D | The main outcome was self-assessed change in pain and function after the first 6 weeks. Patients rated their pain levels in 4 areas of the body on questionnaires using a VAS (range, 0–100) and localized pain by marking a mannequin. At both week 6 and week 12, patients were asked about improvement or deterioration (compared with baseline) of their pain on a 5-point Likert scale, and about adverse effects. Self-reported improvement in ability to walk stairs at week 6 and week 12 was also assessed. Levels of 25(OH)D in serum were measured at baseline, and after 12 weeks | Baseline measurements and assessed after 6 weeks. | Patients in vitamin D group were significantly more likely than their counterparts in the placebo group to report pain relief 6 weeks after treatment (34.9 vs. 19.5%, P = 0.04). The former were also more likely to report an improved ability to walk stairs (21.0 vs. 8.4%, P = 0.008). Pain pattern was not correlated with the success of treatment. There was a small positive effect 6 weeks after high-dose vitamin D3 on persistent nonspecific musculoskeletal pain. In a non-significant trend, patients receiving vitamin D over 12 weeks were more likely to have an improvement than patients receiving it over 6 weeks | Yes | Oxford rating 5/5. Some limitations of the study were due to the type of intervention. Firstly, a single mega dose of vitamin D enabled maximal patient compliance, but duration of treatment might have been too short. Secondly, the heterogeneity of the enrolled patients might have played a role. A third limitation was lack of data concerning PTH. In the multivariate model, the power to assess multiple determinants was limited by the study size |
Sanghi et al. [94]; double-blind pilot RCT | Patients with knee OA or OA (with vitamin D insufficiency [25(OH)D ≤50 nmol/L] | 106 patients entered study (n = 53 in TG, n = 53 in placebo). 66 were women ranging in age from 40–74 years (mean 54.11 years). At baseline, the two groups were comparable. Anthropometric measurements, clinical assessment (height, BMI, WOMAC, and VAS), pill counts, and completion of questionnaires were recorded at all visits. Biochemical (blood) assessments were performed at 6 and 12 months. Patients were randomized to receive oral vitamin D or placebo. The TG received oral vitamin D 60,000 IU per day followed by vitamin D 60,000 IU once a month for 12 months | The primary outcome measures were pain and function. The secondary outcome measures were biochemical markers. Clinical symptoms related to knee OA were assessed with the WOMAC index (which assesses pain, stiffness, function, and interpretation response in terms of a 5-point scale). Knee pain also was assessed using the VAS | The patients were followed for 1 year with 5 follow-up visits. | At 12 months, knee pain had decreased in the vitamin D group by a mean −0.26 (95% CI, −2.82 to ± 1.43) on VAS, and by a mean −0.55 (95% CI, −0.07 to 1.02) on the WOMAC. In the placebo group, it increased by a mean 0.13 (95% CI, −0.03 to 0.29) on the VAS, and by a mean 1.16 (95% CI, 0.82–1.49) on the WOMAC (effect size = 0.37 and 0.78). Knee function improved in vitamin D group by a mean −1.36 (95% CI, −1.87 to −0.85) over the placebo group with a mean 0.69 (95% CI, −0.03 to 1.41; effect size = 0.06). There were significant biochemical changes in serum levels of total calcium, 25(OH)D and of alkaline phosphatase | Yes | Oxford rating 5/5. The effect sizes observed for pain and function were statistically significant but very small (less than 1 mm on VAS pain and 2 points on WOMAC). The clinical importance of these results is not clear. This was a pilot study of 1 year with relatively small sample size. No absolute differentiation of grade of knee OA was described |