“Problem of pain”: Further questions for the utility of vitamin D for chronic pain after gastrointestinal surgery

Abstract

This letter to the editor provides a short review on the number of different disease states that have been linked with at least a factorial relation with deficiency in vitamin D (defined at less than 50 nmol/L or 20 ng/mL serum levels) and tries to raise some question in regards to the recent publication within the journal. This letter also highlights some of the recent work within the neurology literature which demonstrates that supratherapeutic levels of vitamin D might provide benefit for patients suffering with different disease states, with the D-Lay MS randomized clinical trial utilizing 100000 international units every 2 weeks and some of the migraine literature supporting a higher target between 50 ng/mL to 100 ng/mL which might provide benefit for patients suffering from migraines. The letter concludes with a key question for further research asking about whether in gastrointestinal surgery should a normal vitamin D level, defined as 50 nmol/L (20 ng/mL) or greater, be targeted or if there might be a role for supratherapeutic dosing within gastrointestinal surgery.

Key Words: Vitamin D-OH25; Vitamin D; Literature; Supratherapeutic dosing; Optimal dosing; Post-operative pain; Gastrointestinal surgery

Core Tip: There are a number of different disease states that also have been associated with vitamin D, further investigation like that in these other disease states into the use of high than normal vitamin D-OH 25 serum targets or supra therapeutic dosing should be investigated.

TO THE EDITOR

I would love to commend the authors for their excellent review on the “Role of vitamin D in the management of chronic pain after gastrointestinal surgery”[1]. This review targeted both the deficiency and its effects on the health of the patient in the pre-, peri-, and post operative periods including the role that vitamin D plays in immunomodulation, infection prevention, wound healing, and tissue regeneration[1]. One key idea that the authors touched upon in the section: “clinical evidence: Vitamin D status and postsurgical pain outcomes” was that patients with a vitamin D level (vitamin D-OH 25 based on the source article) of less than 50 nmol/L (20 ng/mL) had increased opioid use and heightened pain sensitivity, demonstrating a potential role that vitamin D has in the pain related outcomes for these patients[1].

In the psychiatry and neurology literature, there are numerous studies that have found that lower levels of vitamin D and deficient vitamin D levels can cause patients to be more predisposed to post stroke depression[2], pediatric onset multiple sclerosis[3], Multiple sclerosis relapses even when on highly effective immunosuppressive agents[4], depression[5], anxiety[6], and fibromyalgia[7]. In a meta-analysis of 7 studies containing 3537 participants, the researchers found that stroke patients with vitamin D deficiency had an increased risk of post stroke depression as compared with those stroke patients with normal vitamin D levels[2]. In a mendelian randomization study of 16820 participants, they demonstrated evidence supporting independent and causal effects of decreased vitamin D levels, based on genetic varients, and increased body mass index on susceptibility to pediatric-onset MS[3]. In an observational study of 118 patients with relapsing remitting MS treated with natulizumab, they found that those patients with low vitamin D had a statistically significant difference in their relapse rates, with the vitamin D deficient patients more likely to have relapses[4]. In a literature review, the researchers found numerous empiric studies that demonstrated that lower vitamin D-OH25 levels were associated with either the development or worsening of depression[5]. In a literature review, the researchers found that in the epidemiological studies, there was an inverse relationship between vitamin D levels and levels of anxiety and in a randomized control trial that the administration of 1600 mg of vitamin D for 6 months improved anxiety symptom[6]. In a systematic literature review on vitamin D levels and vitamin D supplementation on Fibromyalgia patients, the researchers found that patients with fibromyalgia have low levels of vitamin D compared to healthy controls[7]. In each of these disease states it has been found that patients with a normal vitamin D level of 50 nmol/L (20 ng/mL) were less likely to develop these different disease states, nevertheless, it was unclear if there was any benefit for increased supplementation beyond that point[2-7].

Nevertheless, in the immunologically based disease of Multiple Sclerosis, a recent trial showed that high dose vitamin D at supratherapeutic levels provided benefits in the prevention of further worsening of the disease state[8]. The D-lay trial was a randomized placebo-controlled trial of 303 participants which looked at supratherapeutic doses of vitamin D (100000 International Units every 2 weeks) and its effects on disease activity, defined as occurrence of a relapse and/or magnetic resonance imaging (MRI) activity (new and/or contrast-enhancing lesions) over 24 months of follow-up[8]. This trial demonstrated that patients on supratherapeutic doses of vitamin D had statistically significant reduction in relapse and/or MRI activity over the trial period[8].

In addition, in some of the migraine literature there, patients with higher than just sufficient levels of vitamin D (50-100 ng/mL) were demonstrated to have better outcomes[9,10]. In one study, an observational study of 70 patients with migraine headaches where blood values of baseline 25-hydroxyvitamin D were measured using ELISA techniques, they found that this high level was associated with 80%-83% lower odds of developing migraine headaches as compared to those who were deficient (less than 20 ng/mL or 50 nmol/L) reflecting that for each 5 ng/mL increase in the serum Vitamin D-OH 25 level there is a 19%-22% odds decrease for the development of migraine headaches[9]. Therefore, in addition to the future directions posed by the authorial team, an additional question should be investigated: What serum range of 25-hydroxyvitamin D optimizes post-surgical pain relief while minimizing toxicity?