Vitamin D supplementation reduces need for opioid pain relief in Cancer patients with vitamin D deficiency

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Patients with vitamin D deficiency who received vitamin D supplements had a reduced need for pain relief and lower levels of fatigue in palliative cancer treatment, a randomized and placebo-controlled study by researchers at Karolinska Institutet shows.

Among patients with cancer in the palliative phase, vitamin D deficiency is common.

Previous studies have shown that low levels of vitamin D in the blood may be associated with pain, sensitivity to infection, fatigue, depression, and lower self-rated quality of life.

A previous smaller study, which was not randomized or placebo-controlled, suggested that vitamin D supplementation could reduce opioid doses, reduce antibiotic use, and improve the quality of life in patients with advanced cancer.

244 cancer patients with palliative cancer, enrolled in ASIH, (advanced medical home care), took part in the current study in Stockholm during the years 2017-2020.

All study participants had a vitamin D deficiency at the start of the study. They received either 12 weeks of treatment with vitamin D at a relatively high dose (4000 IE/day) or a placebo.

The researchers then measured the change in opioid doses (as a measurement of pain) at 0, 4, 8, and 12 weeks after the start of the study.

“The results showed that vitamin D treatment was well tolerated and that the vitamin D-treated patients had a significantly slower increase in opioid doses than the placebo group during the study period. In addition, they experienced less cancer-related fatigue compared to the placebo group,” says Linda Björkhem-Bergman, senior physician at Stockholms Sjukhem and associate professor at the Department of Neurobiology, Healthcare Sciences, and Society, Karolinska Institutet.

On the other hand, there was no difference between the groups in terms of self-rated quality of life or antibiotic use.

“The effects were quite small, but statistically significant and may have clinical significance for patients with vitamin D deficiency who have cancer in the palliative phase.

This is the first time it has been shown that vitamin D treatment for palliative cancer patients can have an effect on both opioid-sensitive pain and fatigue,” says first author of the study Maria Helde Frankling, senior physician at ASIH and postdoc at the Department of Neurobiology, Healthcare Science and Society, Karolinska Institutet.

The study is one of the largest drug studies conducted within ASIH in Sweden. One weakness of the study is the large drop-out rate. Only 150 out of 244 patients were able to complete the 12-week study because many patients died of their cancer during the study.

Funding: The study was funded by Region Stockholm (ALF), the Swedish Cancer Society, Stockholms Sjukhems Foundation and was carried out with the support of ASIH Stockholm Södra and ASIH Stockholm Norr.


The newly proposed definition of pain by the International Association for the Study of Pain states—“An aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury1”. Pain represents the body’s alarm system and serves as an alert to danger.

Chronic pain is a complex disease in its own right for which currently available analgesics have been deemed woefully inadequate since ~20% of the sufferers derive no benefit. This is thought to be due to the complexity and plasticity of chronic pain, and the underpinning mechanisms are not clear as yet. About 50 million of the U.S. adult population suffer from chronic pain, and regardless of the reason, the current treatments primarily manage the condition rather than provide a cure (1).

Vitamin D, commonly identified as a fat-soluble vitamin, is known for its role in calcium homeostasis and bone metabolism. Recent studies have linked vitamin D status and its receptor activity with several health conditions, including development of chronic pain,1 the leading cause of disability and disease burden globally (2).

Studies on the association between vitamin D status and incidence of chronic pain have been contradictory (3, 4). There are potentially many reasons for the variations in the clinical trial studies. However, a recent well-controlled study in Europeans has shown that reduced vitamin D levels were significantly associated with painful diabetic peripheral neuropathy (5).

A strong correlation is also shown for hypovitaminosis D and bone pain (6). Indeed, several other studies have now reported a progressive exacerbation of pain with decreasing serum vitamin D levels and conversely, by increasing serum vitamin D levels through appropriate vitamin D supplementation, especially in vitamin D deficient patients, leads to an improvement in pain-relief (see Table 1).

However, the potential underlying mechanisms by which vitamin D might exert its analgesic effects are poorly understood. In this review, we discuss pathways involved in pain sensing and processing primarily at the level of DRG neurons and the potential interplay between vitamin D/VDR and known specific pain signaling pathways including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), epidermal growth factor receptor (EGFR), and opioid receptors. We also discuss how vitamin D might influence immune cells and pain sensitization as well as include a section on the increasingly important topic of vitamin D toxicity.

. . . .

Vitamin D Levels and OPIOID Use
Low serum vitamin D levels have been linked to the development of opioid side effects and dependency. Among opioid-dependent patients recruited from the methadone maintenance treatment (MMT), more than half recorded a low vitamin D status (182). This common association deserves attention since high prevalence of chronic pain has also been observed in drug-dependent populations (183, 184). Chronic muscle and joint pain are common features of opioid withdrawal and are usually attributed to the effect of methadone (185).

But, whether these conditions or other forms of chronic pain are affected by altered nutritional or metabolic factors related to vitamin D deficiency in drug-dependent populations is still unknown. Also, it should be noted that long-term therapy with some medications commonly used to treat chronic pain, such as steroids, antiepileptic drugs, and anticonvulsants can decrease levels of vitamin D (186–188). Therefore, it could be appropriate to recommend vitamin D supplements when levels are either deficient or insufficient with regards to the patient’s medical conditions, current medications and skin exposure to sunlight. Nonetheless, vitamin D supplementation was recently shown to improve cognitive function and mental health in patients undergoing the MMT program (189).

Moreover, it has been suggested, using animal models, that ultraviolet B (UVB) light exposure induces strong analgesic effects due to elevation of endogenous opioids in the skin (190). This elevation in the POMC-derived peptide, β-endorphin, generated in response to UV radiation (191–193) was suggested to produce an opioid receptor-mediated addiction that leads to an increase in the nociceptive thresholds with pain relieving actions. However, since UVB light is responsible for the formation of vitamin D (194), it would be of interest to know if vitamin D plays a role in releasing β-endorphins to develop such addiction and if signaling pathways involved in this addiction are similar to those involved in exogenous opioid addiction.

It is known that sustained activation of opioid receptors results in compensatory mechanisms that increase cAMP production (195), referred to as AC superactivation- one of the key mechanisms leading to the development of physical dependence (196–198) and tolerance to opioids (172, 199–202). However, since cholecalciferol supplementation was shown to dysregulate AC5 gene expression (64), it might also be believed to play a critical role in modulating the development of opioid dependence and tolerance by affecting the AC superactivation mechanism.

This correlation was partially proved by demonstrating the involvement of vitamin D deficiency in quickening the development of tolerance to opioid analgesics (153). In this study, rats raised for 3–4 weeks on a vitamin D-deficient rachitogenic diet developed tolerance to morphine faster than control rats, an effect that was prevented by cholecalciferol treatment.

Association between vitamin D levels and opioid use has also been investigated in human subjects. In an observational study, palliative cancer patients with 25-OHD levels <50 nmol/L required higher opioid (fentanyl) dose for pain relief compared to those with 25-OHD levels above 50 nmol/L (203). In a follow-up study, palliative cancer patients with 25-OHD levels <75 nmol/L were given vitamin D with a dose of 4,000 IU daily. After 1 month of supplementation, a decrease in fentanyl doses was observed compared to untreated controls (11). Together, these observations describe a significant correlation between low vitamin D levels and increased opioid consumption.

reference link: https://www.frontiersin.org/articles/10.3389/fimmu.2020.00820/full


Original Research: “‘Palliative-D’—Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial” by Maria Helde Frankling, Caritha Klasson, Carina Sandberg, Marie Nordström, Anna Warnqvist, Jenny Bergqvist, Peter Bergman, Linda Björkhem-Bergman. Cancers

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