DAKOTA L. TAYLOR, BS, LAT, ATC
Vitamin D can modulate the effects of ultraviolet radiation-induced β-endorphin and its actions on the central nervous system.
Patients who are vitamin D deficient consume higher doses and larger quantities of opioids. These patients are also more at risk of developing opioid use disorder.
Vitamin D can modulate the pain pathway, and vitamin D supplementation has been shown to decrease pain levels.
Vitamin D is a fat-soluble vitamin, produced in the skin by ultraviolet radiation (UVR), that has long been associated with calcium homeostasis and bone health. Increasing evidence supports the notion that vitamin D plays a larger role in human health than previously thought, specifically, in the detection of pain and opioid use (1). With opioid overdose deaths increasing, this relationship should be further explored to help identify potential solutions to mitigate this ever-growing crisis.
Tanning Addiction: The link
Addictive-like behaviors have been observed and reported in relation to UVR exposure (2). Harrington et al,, found that 41% of frequent indoor tanners surveyed using a modified CAGE questionnaire met the proposed criteria for tanning addictive behaviors (3). In a subsequent study, the researchers compared regional cerebral blood flow (rCBF) in frequent salon bed tanners subjected to a session of UVR and a session of sham UVR. They found that during the UVR session, participants experienced an increased rCBF to the dorsal striatum, anterior insula, and medial orbitofrontal cortex, which are all areas of the brain associated with experiencing reward (4). A study by Kaur et al. compared the effects of administrating naltrexone vs placebo in individuals who tanned frequently with those who tanned infrequently (5). Both groups had reduced preference for UV stimulus at higher naltrexone doses and half of the frequent tanners experienced withdrawal symptoms at higher naltrexone doses, eventually leading to the withdrawal of two subjects and the early termination of the study.
A likely explanation for these rewarding experiences is the release of skin β-endorphin, an endogenous opioid, upon exposure to UVR (6). In mice exposed to prolonged UVR, opioid-dependent symptoms were observed, along with increases in serum β-endorphin, associated with an elevated threshold for pain with a reversal in naloxone administration and absence in β-endorphin knock-out mice (7). Moreover, naloxone administration also led to observable withdrawal symptoms indicating physiologic dependence.
Opioids and Vitamin D
There is a current theory relating to an evolutionary advantage that aims to explain the increased release of β-endorphin with UVR exposure. It postulates that the resulting feelings of euphoria and analgesia help promote continued individual exposure to UVR to ensure appropriate levels of vitamin D (1). It is also logical to suspect a link between adequate or elevated vitamin D levels and the suppression of β-endorphin, providing a regulated negative feedback loop. Consequentially, this theory is supported in an animal study on vitamin D receptor (VDR) activation in mice. In these mice, receptor activation suppressed opioid-induced c-fos transcription in the nucleus accumbens, an area of the brain highly associated with reward and addiction. Additionally, receptor activation was associated with decreased UVR-induced endogenous analgesia and reward (1). They found that vitamin D deficiency increases sensitivity to morphine reward and exacerbates opioid dependence, leading to the conclusion that vitamin D regulates nociception and opioid analgesia (1).
This incidence is also applicable to human subjects. An observational study involving 100 palliative cancer patients in Sweden found that patients who were vitamin D deficient experienced significantly more pain and required higher doses of opioids to manage their pain (8). A subsequent retrospective study looked at perioperative vitamin D levels measured within three months of surgery in over 5,000 subjects. The study concluded that patients who were vitamin D deficient required higher doses and more days of opioid coverage compared to those who were vitamin D sufficient (9). Additionally, this study considered vitamin D levels and opioid use disorder (OUD), and showed that out of 11,713 patients, with presurgical history of OUD, those who were vitamin D deficient showed a significantly increased risk for OUD.
Pain and Vitamin D
In addition to its actions attenuating opioid use, several studies have also shown the direct action of vitamin D on the pain pathway. A systematic review demonstrated various locations of the VDR, including the skin, dorsal root ganglia (DRG), spinal cord, and brain, all relevant areas involved in nociception (10). The review also illustrates points of interaction between vitamin D and the VDR within the pain pathway. These interactions include modulating transient receptor potential (TRP) channels in the skin, up-regulation of nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF) in DRG neurons, and inhibition of epidermal growth factor receptor (EGFR) which has been shown to be increased in chronic and neuropathic pain. Similarly, Long et al. demonstrated that vitamin D is a partial agonist of the TRP vanilloid subfamily member 1 (TRPV1) channel and can act as a competitive antagonist in the presence of a full agonist such as capsaicin, the molecule responsible for the spice and burn of chili peppers (11). Table 1 shows the results of multiple studies where individuals deficient in vitamin D were treated with supplementation resulting in significant improvements in pain (10).
Evidence supports that addiction to tanning has a physiological basis with a proposed evolutionary link between addictive UVR exposure and vitamin D metabolism in the skin. Additionally, evidence supports the complex role of vitamin D in both nociception and opioid action in both endogenous and exogenous forms. Whether acting directly upon opioid metabolism or indirectly through its modulation of pain, vitamin D has been shown to reduce the need for opioids in both chronic pain and postoperative scenarios. Because of this, vitamin D supplementation should be considered to help reduce opioid use in patients. This measure could help reduce the amount of opioid naïve individuals who develop OUD and the divergence of opioids into the community. Further research involving, specifically, surgical patients and their preoperative vitamin D status with postoperative opioid habits would be prudent. A follow-up study involving supplementation of vitamin D vs placebo for patients who are deficient may also be warranted if significant differences are shown.
1. Kemény LV, Robinson KC, Hermann AL, et al. Vitamin D deficiency exacerbates UV/endorphin and opioid addiction. Science Advances. 2021. doi: 10.1126/sciadv.abe4577.
2. Kourosh AS, Harrington CR, Adinoff B. Tanning as a behavioral addiction. Am J Drug Alcohol Abuse. 2010;36(5):284-290. doi: 10.3109/00952990.2010.491883.
3. Harrington CR, Beswick TC, Leitenberger J, Minhajuddin A, Jacobe HT, Adinoff B. Addictive-like behaviours to ultraviolet light among frequent indoor tanners. Clin Exp Dermatol. 2011;36(1):33-38. doi: 10.1111/j.1365-2230.2010.03882.x.
4. Harrington CR, Beswick TC, Graves M, et al. Activation of the mesostriatal reward pathway with exposure to ultraviolet radiation (UVR) vs. sham UVR in frequent tanners: a pilot study. Addict Biol. 2012;17(3):680-686. doi: 10.1111/j.1369-1600.2010.00312.x.
5. Kaur M, Liguori A, Lang W, Rapp SR, Fleischer AB, Feldman SR. Induction of withdrawal-like symptoms in a small randomized, controlled trial of opioid blockade in frequent tanners. J Am Acad Dermatol. 2006;54(4):709-711. doi: 10.1016/j.jaad.2005.11.1059.
6. Jussila A, Huotari-Orava R, Ylianttila L, Partonen T, Snellman E. Narrow-band ultraviolet B radiation induces the expression of β-endorphin in human skin in vivo. J Photochem Photobiol B. 2016;155:104-108. doi: 10.1016/j.jphotobiol.2016.01.007.
7. Fell GL, Robinson KC, Mao J, Woolf CJ, Fisher DE. Skin β-endorphin mediates addiction to ultraviolet light. Cell. 2014;157(7):1527-1534. doi: 10.1016/j.cell.2014.04.032.
8. Bergman P, Sperneder S, Höijer J, Bergqvist J, Björkhem-Bergman L. Low vitamin D levels are associated with higher opioid dose in palliative cancer patients--results from an observational study in Sweden. PLoS One. 2015;10(5):e0128223. doi: 10.1371/journal.pone.0128223.
9. Kim Y, Zhang F, Su K, et al. Perioperative Serum 25-Hydroxyvitamin D Levels as a Predictor of Postoperative Opioid Use and Opioid Use Disorder: a Cohort Study. J Gen Intern Med. 2020;35(9):2545-2552. doi: 10.1007/s11606-020-06001-y.
10. Habib AM, Nagi K, Thillaiappan NB, Sukumaran V, Akhtar S. Vitamin D and Its Potential Interplay With Pain Signaling Pathways. Front Immunol. 2020;11:820. doi: 10.3389/fimmu.2020.00820.
11. Long W, Fatehi M, Soni S, et al. Vitamin D is an endogenous partial agonist of the transient receptor potential vanilloid 1 channel. J Physiol. 2020;598(19):4321-4338. doi: 10.1113/JP279961.