Vitamin D is a hormone synthesized in the skin in the presence of sunlight. Like other hormones, vitamin D plays a role in a wide range of processes in the body. Here we review the possible role of vitamin D in nociceptive and inflammatory pain. In observational studies, low vitamin D levels have been associated with increased pain and higher opioid doses. Recent interventional studies have shown promising effects of vitamin D supplementation on cancer pain and muscular pain—but only in patients with insufficient levels of vitamin D when starting intervention. Possible mechanisms for vitamin D in pain management are the anti-inflammatory effects mediated by reduced cytokine and prostaglandin release and effects on T-cell responses. The recent finding of vitamin D-mediated inhibition of Prostaglandin E2 (PGE2) is especially interesting and exhibits a credible mechanistic explanation. Having reviewed current literature, we suggest that patients with deficient levels defined as 25-hydroxyvitamin D (25-OHD) levels 50 nmol/L probably have little benefit from supplementation. Our conclusion is that vitamin D may constitute a safe, simple and potentially beneficial way to reduce pain among patients with vitamin D deficiency, but that more randomized and placebo-controlled studies are needed before any firm conclusions can be drawn.

The cytosolic sulfotransferases (SULTs) catalyze the sulfate conjugation of nucleophilic substrates, and the cofactor for sulfonation, 3′-phosphoadenosine-5′-phosphosulfate (PAPS), is biosynthesized from sulfate and ATP. The phenotype of male knockout mice for the NaS1 sodium sulfate cotransporter includes hyposulfatemia and increased hepatic expression of mouse cytoplasmic sulfotransferase Sult2a and Sult3a1. Here we report that in 8-week-old female NaS1-null mice, hepatic Sult2a1 mRNA levels were ∼51-fold higher than they were in a wild-type liver but expression of no other Sult was affected. To address whether hyposulfatemia-inducible Sult2a1 expression might be due to reduced PAPS levels, we stably knocked down PAPS synthases 1 and 2 in HepG2 cells (shPAPSS1/2 cells). When a reporter plasmid containing at least 233 nucleotides (nt) of Sult2a1 5′-flanking sequence was transfected into shPAPSS1/2 cells, reporter activity was significantly increased relative to the activity that was seen for reporters containing 179 or fewer nucleotides. Mutation of an IR0 (inverted repeat of AGGTCA, with 0 intervening bases) nuclear receptor motif at nt −191 to 180 significantly attenuated the PAPSS1/2 knockdown-mediated increase. PAPSS1/2 knockdown significantly activated farnesoid X receptor (FXR), retinoid-related orphan receptor, and pregnane X receptor responsive reporters, and treatment with the FXR agonist GW4064 [3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole] increased Sult2a1 promoter activity when the IR0 was intact. Transfection of shPAPSS1/2 cells with FXR small interfering RNA (siRNA) significantly reduced the Sult2a1 promoter activity. The impact of PAPSS1/2 knockdown on Sult2a1 promoter activity was recapitulated by knocking down endogenous SULT2A1 expression in HepG2 cells. We propose that hyposulfatemia leads to hepatic PAPS depletion, which causes loss of SULT2A1 activity and results in accumulation of nonsulfated bile acids and FXR activation.

Background: The aim of this study was to elucidate whether palliative cancer patients benefit from antibiotic treatment in the last two weeks of life when an infection is suspected. Method: We reviewed medical records from 160 deceased palliative cancer patients that had been included in previous studies on vitamin D and infections. Patients treated with antibiotics during the last two weeks of life were identified and net effects of treatment (symptom relief) and possible adverse events were extracted from medical records. Results: Seventy-nine patients (49%) had been treated with antibiotics during the last two weeks in life. In 37% (n = 29), the treatment resulted in evident symptom relief and among these 50% had a positive bacterial culture, 43% had a negative culture and in 7% no culture was taken. Among the patients with no or unknown effect of antibiotics, 50% had a positive culture. When the indication for antibiotic treatment was to avoid or treat sepsis, symptom relief was achieved in 50% of the patients (n = 19). Only 4% (n = 3) of the patients experienced adverse events of the treatment (diarrhea, nausea). Conclusions: Treating infections with antibiotics in the last weeks of life may improve the quality of life for palliative cancer patients, especially if sepsis is suspected or confirmed. According to our results, the beneficial effects outweigh the potentially negative outcomes.

Vitamin D deficiency is common among palliative cancer patients and has been connected to an increased risk for pain, depressions and infections. Therefore we wanted to test the hypothesis that low 25-hydroxyvitamin D (25OHD) levels are associated with higher opioid dose, higher infectious burden and impaired quality of life in palliative cancer patients. The secondary aim was to investigate the association between 25OHD-levels and survival time. In this prospective, observational study in palliative cancer-patients (n = 100) we performed univariate and multiple linear regression analysis to assess the association of 25OHD levels with opioid dose, infectious burden (antibiotic consumption), quality of life (Edmonton Symptom Assessment Scale, ESAS) and survival time, controlling for potential confounding factors. The median 25OHD level was 40 nmol/L (range 8-154 nmol/L). There was a significant association between 25OHD levels and opioid dose, beta coefficient -0.67; p=0.02; i.e. a low 25OHD level was associated with a higher opioid dose. This association remained significant after adjustment for stage of the cancer disease in a multivariate analysis, beta coefficient -0.66; p = 0.04. There was no association between 25OHD levels and antibiotic use or quality of life. Univariate cox regression analysis showed a weak correlation between survival time and 25OHD levels (p<0.05). However, decreased albumin levels and increased CRP levels were superior markers to predict survival time; p<0.001 for both analyses. Low 25OHD-levels are associated with increased opioid consumption in palliative cancer patients. Future interventional studies are needed to investigate if pain can be reduced by vitamin D supplementation in these patients. In addition, this study confirms previous findings that low albumin and increased CRP levels are useful markers for survival time in palliative cancer patients.

Fatigue is one of the most distressing symptoms experienced by cancer patients. The suggested biological mechanism for cancer related fatigue (CRF) includes immune activation triggered by tumor tissue or by anticancer treatment but other mechanisms have also been proposed. Previous large meta-analysis of interventions on fatigue focuses mostly on patients early in the disease trajectory, with only one tenth of included studies performed in palliative cohorts. The aim of this narrative review is therefore to present a background on CRF with focus on the palliative setting. A summary of recent randomized, controlled trials on pharmacological interventions on CRF in palliative care is presented, including studies on psychostimulants, corticosteroids, testosterone and melatonin. Interestingly, in several of these studies there was a positive and similar effect on fatigue in both the intervention and the placebo arm—indicating an important placebo effect for any pharmacological treatment. In addition, studies on dietary supplements and on pharmacological complementary medicines are discussed. To conclude, the evidence is still weak for using pharmacological treatments on CRF in palliative care patients—although methylphenidate and corticosteroids might be considered.