US Pharm. 2022;47(3):25-33.

ABSTRACT: About one in five U.S. adults experiences pain daily or on most days, and for patients struggling with pain, the toll on their health and well-being is detrimental and can be debilitating. Appropriate pain management has been a growing concern since the rise of the opioid epidemic. When prescription pharmacologic agents do not alleviate their pain or are not easily accessible, patients seek alternative therapies. Vitamins and minerals are one option that has gained traction and has attracted researchers’ interest. Although evidence supporting the use of these agents is limited, pharmacists are in a position to help patients make educated decisions on the use of vitamins and minerals.

In the United States, chronic pain is one of the leading conditions for which people seek medical treatment, and the toll on their health and well-being is detrimental and can be debilitating. Based on the 2019 National Health Interview Survey, about one in five adults in the U.S. experiences pain on most days or every day.¹ Appropriate pain management has been a growing concern since the rise of the opioid epidemic. When prescription pharmacologic agents do not alleviate their pain or are not easily accessible, patients seek alternative therapies.  In 2011, chronic pain was reported to have an annual economic burden of $560 billion to $635 billion, of which direct healthcare costs comprised only $261 billion to $300 billion.²

The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”³ As the definition implies, pain is relative to the individual afflicted; the optimal treatment depends on the pain classification. There are four common pain-classification schemes based on the pathophysiologic mechanism (nociceptive or neuropathic), duration (acute or chronic), etiology (malignant or nonmalignant), or anatomical location.⁴ The goal of treatment for any type of pain is to improve quality of life, functioning, and comfort.

Over the past 3 decades, the approach to pain and its management has been a key focus area.⁵ In the 1990s, the inadequate assessment and treatment of pain was recognized as a health emergency and eventually labeled as “the 5th vital sign.” In the effort to improve pain control and in the wake of new pharmaceutical formulations, liberal opioid prescribing eventually led to a national opioid crisis. In response, research and guidelines have aimed to identify alternative pain-management modalities.^5,6 Most recent guidelines and best-practice reports have recommended individualized, multimodal, and multidisciplinary pain management encompassing medications, restorative therapies, interventional procedures, behavioral-health approaches, and complementary and integrative medicine. One limitation of these documents, however, is the lack of discussion of the role that vitamins and minerals may play in pain management. According to a survey conducted in 2002, more than one-third of Americans use complementary and alternative medicine.⁷ Given that pharmacists are often the only healthcare professionals available to answer consumers’ questions about OTC medications, it is important to understand the possible role of these agents in pain management.

Neuropathic Pain

The IASP defines neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system.”⁸ This condition encompasses a number of etiologies, including diabetes, cancer, chronic alcohol consumption, herpes zoster infection, traumatic nerve injury, drug toxicity, and central processes including cerebrovascular accidents, spinal cord injuries, and multiple sclerosis.⁹ Broadly, current pharmacologic treatment strategies include serotonin-norepinephrine reuptake inhibitors such as venlafaxine and duloxetine, tricyclic antidepressants, and the anticonvulsants gabapentin and pregabalin as first-line therapies. However, given the complex nature of neuropathic pain, its spectrum of symptoms, and its prevalence in up to 10% of the population (according to validated questionnaires), there is a growing demand for new treatments.⁹ Research into vitamin supplementation—with or without a preexisting deficiency—has been gaining traction.

Vitamin B₁₂

In humans, vitamin B₁₂ functions mainly as a cofactor for the methyltransferase enzyme known as methionine synthase.¹⁰ This allows for the formation of methionine, which is later converted to S-adenosyl methionine (SAMe). SAMe is responsible for donating methyl groups to the formation of myelin sheaths around neurons. Animal models have exhibited several mechanisms through which vitamin B₁₂ is proposed to alleviate neuropathic pain in humans (TABLE 1). A recent systematic review of 325 articles found that the strongest areas of research on the use of vitamin B₁₂ in treating peripheral polyneuropathy are postherpetic neuralgia (PHN), diabetic neuropathy, and alcohol-related neuropathy.⁹ This study found no articles that disproved the utility of vitamin B₁₂ for neuropathic pain.

Diabetic Neuropathy: Hyperglycemia (and hyperlipidemia) cause the increased production of reactive oxygen species (ROS), advanced glycation end products, and insoluble sugars such as sorbitol.¹¹ All of these end products induce cellular damage and a proinflammatory environment, particularly affecting the peripheral neurons. Although there is a positive trend in the use of vitamin B₁₂ for diabetic neuropathy, evidence is insufficient because most of the research trials lacked adequate follow-up periods or sample sizes and did not have a placebo arm for comparison. Additionally, many of these studies focused on the adjunctive use of vitamin B₁₂ with gabapentinoids and other B vitamins, thereby limiting the assessment of vitamin B₁₂ on its own.

PHN: PHN is a lingering pain that persists beyond 4 months following a rash induced by herpes zoster.¹² Inflammation caused by the virus triggers fibrosis of nerves and spontaneous activity capable of maintaining pain in the absence of ongoing tissue damage. Five randomized, controlled trials included in a systematic review found that vitamin B₁₂ was helpful—whether as monotherapy or adjunctively—for PHN regardless of where the pain manifested.⁹

Alcohol-Related Neuropathy: Vitamin deficiencies resulting from chronic alcoholism lead to complications in the demyelination of peripheral neurons and to slow nerve conduction caused by alcohol-induced neurotoxicity.¹³ Symptoms are usually symmetrical and distal, including paresthesia, cramps, weakness, and pain. Vitamin supplementation in this case would help reverse those complications. It has been found that the addition of vitamin B₁₂ may provide a benefit in pain improvement.⁹

Zinc

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood, but the mechanism appears to involve axonal degradation from chronic exposure to chemotherapeutic agents.¹⁴ One possible cause may be an increase in ROS from the chemotherapeutic agents, so researchers are investigating the use of antioxidants to treat or prevent CIPN. The questionnaire-based Diet, Exercise, Lifestyle, and Cancer Prognosis (DELCaP) study found a correlation between multivitamin use and reduced incidence of CIPN in stage I–III breast cancer patients who received doxorubicin, cyclophosphamide, and paclitaxel, but there was no statistically significant risk reduction with individual supplement use.¹⁵ A study in mouse models with paclitaxel-induced CIPN demonstrated dose-dependent reduction of local allodynia following intraplantar zinc administration for up to 4 days.¹⁶ This study found that exogenous zinc inhibited TRPV1 (transient receptor potential cation channel subfamily V member 1; a nonselective cation transport protein), thereby preventing paclitaxel-induced sensitization of peripheral nociceptors. The Pathways study found that women who initiated zinc and other antioxidants after diagnosis were two to three times more likely to report CIPN at 6-month follow-up.¹⁷ Further research is needed on the use of zinc for CIPN treatment before any changes to recommendations are made.

Vitamin E

Vitamin E, the primary fat-soluble antioxidant, is being studied relative to the role of ROS in neuropathic pain. A 2006 study using rat models concluded that vitamin E administration—as either a high-dose single injection (0.1, 1, or 5 g/kg with no equivalent human dose owing to variations in metabolic rates between species) or repetitive daily low-dose injections (50 or 100 mg/kg, equating to 3 g in a 60-kg human)—reduced behaviors associated with mechanical allodynia.¹⁸ Similar to the results of the DELCaP study, a phase III clinical trial in patients receiving neurotoxic chemotherapy found no difference in CIPN incidence regardless of whether vitamin E was administered.¹⁴ The researchers found a slight positive effect on neuropathy duration in patients who took 400 mg of vitamin E twice daily; however, they noted that the dose may have been too low to achieve a statistically significant benefit. A randomized trial that examined vitamin E supplementation versus placebo as an adjunct to standard pain management for diabetic neuropathy concluded that vitamin E was effective in reducing some pain, but no improvement was seen in overall quality-of-life scores.¹⁹

CHRONIC PAIN

According to the IASP, chronic pain is “pain that persists or recurs for longer than 3 months.”²⁰ The principles informing the treatment of neuropathic pain and chronic pain are subject to overlapping, as forms of neuropathic pain can become chronic afflictions. The preferred first-line treatment options are nonpharmacologic therapies (diet, exercise, and behavioral) and nonopioid prescription medications; however, given the nature of chronic pain, many of the affected patients have been prescribed opioids.²¹ Because chronic pain is the leading cause of disability in U.S. adults, there has been a significant push for alternative treatments, including research into vitamins and minerals.²²

Vitamin C

Vitamin C deficiency (plasma concentrations <11 mcmol/L) manifests as scurvy-related myalgia and arthralgia in the knees, wrists, and ankles due to bleeding within these areas.²³ Deficiency of this vitamin is rare in developed countries (<6% in the U.S.), but the populations primarily affected are hospitalized elderly patients, cancer patients, and critically ill patients. The use of vitamin C has been shown to be effective in several aspects of pain management.

Complex Regional Pain Syndrome (CRPS): Many randomized, controlled trials have demonstrated that vitamin C supplementation reduced the incidence of CRPS in wrist- and ankle-surgery patients, with the most efficacious dosage being 0.5 g or more per day.^23,24 The same dosage was also administered prophylactically for osteoarthritis in joint-replacement patients, who were then found to have no incidence of CRPS.

Rheumatoid Arthritis and Osteoarthritis: It has been noted that patients with rheumatoid arthritis present with average vitamin C levels less than half the level in healthy controls.²³ One study reported a total reduction of pain in a single rheumatoid arthritis patient following twice-weekly infusions of high-dose vitamin C, and a study in osteoarthritis patients given 1 g of oral calcium ascorbate per day found that the reduction in pain was less than half of that reported for nonsteroidal anti-inflammatory drugs.²³ These data may also suggest more efficacy with parenteral versus oral administration in patients with arthritis.

Orthopedic Pain: Vitamin C exhibits regulatory effects on bone and collagen formation.²³ A study of 16 patients with Paget’s disease showed a reduction in bone pain following administration of 3 g of oral vitamin C per day for 2 weeks. However, the pain reduction was not greater than that observed with typical calcitonin treatment for the disease.

PHN: Serum levels of vitamin C are much lower in shingles patients than in healthy persons, and this has been found to increase the risk of PHN.²³ Randomized, controlled trials have shown a reduced incidence of PHN and decreased long-term pain following parenteral vitamin C administration.

Cancer Pain: Cancer patients typically have increased vitamin C requirements and lower circulating levels than healthy individuals.²³ Questionnaire-based studies examining quality of life showed significant improvements (>30%) due to decreased pain following vitamin C administered orally or parenterally.

Decreased Opioid Requirements: Patients receiving opioids have been found to exhibit decreased withdrawal symptoms with coadministration of vitamin C.²³ Several studies have also observed that these patients required fewer morphine equivalents of opioids compared with patients who did not receive vitamin C coadministration.

Vitamin D

Vitamin D deficiency is associated with several etiologies of chronic pain, including type 1 diabetes, hypertension, metabolic syndrome, ischemic heart disease, falls, broken bones, depression, and cancer.²⁵ More recent studies have also linked vitamin D deficiency to sickle cell disease, aromatase inhibitor–induced arthralgia, headache, PHN, pain in patients taking high doses of opioids, and various types of musculoskeletal and orthopedic pain. In these conditions, higher reported levels of pain and opioid use occurred in patients with deficient circulating levels of vitamin D.^25,26 In addition to its bone-regulation and hormonal effects, vitamin D regulates the inflammatory responses mediated by the adaptive immune system.²⁶ Similar to vitamin C supplementation, administration of vitamin D in these cases prevents pain associated with a deficiency of the vitamin (<30 nmol/L) and has little effect in patients with adequate levels. Current evidence is insufficient to change recommendations regarding vitamin D supplementation, and more research should be conducted.

Magnesium

Magnesium is an antagonist of N-methyl-D-aspartate voltage-gated receptors that exhibits antinociceptive effects by preventing and attenuating hypersensitivity to pain.^27,28 It is also known to reduce neuromuscular excitability by antagonizing the effects of calcium on acetylcholine release.²¹ Further research must be conducted before changes to recommendations should be considered, but promising trends have been noted in the use of magnesium for the following conditions.

Perioperative Pain: In a systematic review of 27 randomized, controlled trials, data trends suggested that systemic administration of magnesium during general anesthesia may lessen postoperative pain without increasing the risk of adverse effects.²⁷ The usual regimen is a loading dose of 30 mg/kg to 50 mg/kg followed by a maintenance dose of 6 mg/kg to 20 mg/kg per hour. Magnesium has also been associated with increased hemodynamic stability during surgery as well as reduced anesthetic and opioid use. It has been found to be largely ineffective for attenuating pain associated with cesarean delivery, hysterectomy, inguinal hernia repair, and varicose vein surgery; however, it is worth noting that the studies reporting these results used a single dose rather than a loading dose plus continuous infusion.²⁸

Migraine: Hypomagnesemia has been observed in patients who develop migraines, but the etiology of this condition is not fully understood.²⁷ Magnesium supplementation has yielded inconsistent results in preventing and treating migraines. This may be due to differences in magnesium formulation, dosing, and administration as well as migraine subtype.

Fibromyalgia: Patients with fibromyalgia have been found to have lower magnesium levels and magnesium intake.²⁷ Magnesium supplementation has been suggested to be beneficial because it reduces levels of substance P, which correlates to a decrease in fibromyalgia pain.

PHN: IV magnesium sulfate administered at 30 mg/kg over 30 minutes was shown to lessen or completely resolve pain in patients with PHN.²⁸ Studies have suggested that it is as effective as ketamine for reducing pain associated with PHN, but more research should be conducted before it is recommended as a treatment option.²⁷

CIPN: A 2004 study reported that infusions of calcium and magnesium (Ca²⁺/Mg²⁺) before and after administration of oxaliplatin could prevent the development of CIPN.^27,28 Metanalyses and systematic reviews have yielded inconsistent results, and although their effectiveness remains inconclusive, these infusions have been adopted into clinical practice anyway.

CONCLUSION

Pain is a complex and multifaceted health condition that has variable effects on different individuals. Although a number of pharmacologic therapies are available to help manage pain, no uniform regimen works for all patients. Vitamins and minerals may be an alternative option for pain relief, particularly for neuropathic and chronic pain. Although evidence supporting the use of vitamins and minerals is limited, pharmacists are well positioned to help patients make educated decisions on the use of these nutrients.

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