Role of vitamin D in the management of chronic pain after gastrointestinal surgery

Abstract

Chronic postsurgical pain (CPSP) following gastrointestinal (GI) surgery is a common issue that poses significant challenges to patients’ recovery and quality of life. Given the importance of vitamin D in inflammation reduction, nerve repair, bone health, and immune regulation, its potential role in pain management has gained increasing attention. Preliminary evidence suggests that many patients who undergo GI surgery have lower perioperative vitamin D levels. Patients with vitamin D deficiency have increased opioid use and heightened pain sensitivity after colorectal cancer surgery. Patients with lower vitamin D levels experience greater pain three months after arthroscopic rotator cuff repair or video-assisted thoracoscopic surgery. However, research on the relationship between vitamin D and CPSP after GI surgery is limited. Larger, well-designed clinical trials are needed to determine the causal relationship between low vitamin D levels and CPSP, determine the optimal perioperative vitamin D levels, and provide more reliable evidence for clinical application. Moreover, vitamin D has positive effects on various systemic diseases and postoperative recovery, including immune regulation, infection prevention, wound healing, tissue regeneration, nutritional status, and metabolic health. These findings indicate that vitamin D has broad clinical application potential. We hope to provide a new insight into postoperative recovery and pain management strategies for GI surgeries.

Key Words: Vitamin D; Chronic postsurgical pain; Gastrointestinal surgery; Pain management; Postoperative recovery

Core Tip: Vitamin D may play a beneficial role in managing chronic pain following gastrointestinal surgery and postoperative recovery by modulating immune responses, aiding neural repair, and regulating gastrointestinal function. While preliminary evidence is promising, further large-scale clinical trials are essential to confirm its effects in these patients.

INTRODUCTION

Gastrointestinal (GI) surgeries, including gastrectomy, colectomy and bariatric procedures, are commonly performed to treat conditions such as cancer, inflammatory bowel disease, and obesity[1]. While these surgeries can be life-saving, up to 30% of patients experience chronic postsurgical pain (CPSP) lasting more than 3-6 months[2]. This pain is often caused by multiple factors, including surgical injury, inflammation and GI dysfunction[3,4]. Vitamin D has neuroprotective, anti-inflammatory, and gut microbiota modulatory properties[5]. Recent studies have highlighted vitamin D deficiency as a modifiable risk factor for CPSP[6,7]. Low levels of vitamin D have been associated with increased pain sensitivity in various conditions, such as fibromyalgia, neuropathy, and chronic musculoskeletal pain[8-11]. It is thought to be linked to the inflammatory and neurogenic effects of low vitamin D[8]. In the context of postoperative pain, vitamin D deficiency may exacerbate pain and hinder recovery[12].

To date, there has been limited research specifically establishing a link between vitamin D and chronic pain after GI surgery. This review examines the mechanisms of chronic pain after GI surgeries and the role of vitamin D in pain modulation. Given the similar mechanisms underlying CPSP across different surgeries such as nerve injury and inflammation, we extrapolate findings from other surgical fields to GI surgery.

VITAMIN D: PHYSIOLOGY AND RELEVANCE TO PAIN

Physiological effects of vitamin D

Vitamin D is a fat-soluble steroid that plays a critical role in numerous physiological processes. It is synthesized in the skin upon sunlight exposure and can also be obtained from dietary sources such as fatty fish, fortified foods, and supplements[13]. Once synthesized or ingested, vitamin D is converted into its active form, calcitriol (1,25-dihydroxyvitamin D), in the liver and kidneys. Calcitriol binds to vitamin D receptors (VDRs) in various cells, including immune cells, neurons, and GI cells. Upon activation, the VDR, a nuclear transcription factor, forms a heterodimer with the retinoid X receptor. This complex then binds to vitamin D response elements in target genes, modulating gene expression to regulate bone metabolism, immune responses, inflammatory pathways, neuronal health, and gut function[5,14].

Target systems of vitamin D

Vitamin D may improve chronic pain after GI surgery, mainly by regulating the immune system, nervous system, and digestive system.

Immune system: Vitamin D plays a key role in regulating the immune system by balancing proinflammatory and anti-inflammatory responses[15,16]. It inhibits proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6, which play crucial roles in pain pathways[17]. Moreover, vitamin D promotes the production of anti-inflammatory cytokines such as interleukin-10, helping to counteract excessive inflammation[18], a common trigger of chronic pain[17,18]. This balance is crucial in conditions where inflammation contributes to pain, such as autoimmune diseases and chronic pain conditions. By regulating the immune system to ensure a balance between proinflammatory and anti-inflammatory signals[15,16], vitamin D can help alleviate inflammation-related pain.

Nervous system: Vitamin D influences neuronal function by modulating the expression of nerve growth factor, which is essential for neuron growth, maintenance, and survival[19]. Additionally, VDRs are activated by vitamin D to regulate the calcium balance within neurons, which is essential for proper nerve function and pain perception. It also helps reduce neuroinflammation, which can contribute to neuropathic pain[18]. By suppressing neuroinflammation, vitamin D may alleviate pain associated with nerve damage or dysfunction[20], making it particularly beneficial for postoperative pain management. Finally, as a novel endogenous regulator, vitamin D also modulates the expression of pain-related genes, such as transient receptor potential vanilloid 1 channel (TRPV1) and glial cell line-derived neurotrophic factor[21,22]. By regulating the expression of these pain-related genes, vitamin D can effectively diminish pain sensitivity, thereby alleviating chronic pain[18].

Digestive system: Vitamin D plays a crucial role in regulating the gut-brain axis by modulating microbiome composition, influencing immune responses and supporting neuronal health[23]. This regulation is vital for GI function, especially in conditions such as visceral hypersensitivity, where abdominal organs become overly sensitive to stimuli[24]. Specifically, vitamin D may help alleviate the visceral pain commonly associated with irritable bowel syndrome (IBS) by enhancing intestinal integrity, promoting ion exchange, restoring epithelial function, and protecting against inflammatory damage[25].

Vitamin D and chronic pain: Mechanistic links

Vitamin D supplementation can relieve chronic pain[26]. Vitamin D plays a crucial role in chronic pain management because of its anti-inflammatory, neuroprotective, and microbiome-regulating effects[27,28].

Anti-inflammatory role in chronic pain: In the context of chronic pain, the nuclear factor kappa-B (NF-κB) signaling pathway is crucial for triggering the release of proinflammatory cytokines and sensitizing pain receptors[29]. By reducing NF-κB activity, vitamin D helps alleviate inflammation and decreases pain perception[30,31]. Preclinical animal studies have demonstrated that vitamin D can reduce visceral pain in patients with inflammatory bowel diseases[32-35]. These findings suggest that vitamin D may offer potential therapeutic benefits for individuals with chronic pain associated with inflammation.

Neuroprotection and pain alleviation: In a rat model of peroneal nerve injury, vitamin D promoted axonal sparing/regeneration and improved physiological maturation. Vitamin D can enhance myelination and nerve function[36]. By interacting with the VDR in dorsal root ganglia and spinal cord neurons[5], vitamin D helps maintain calcium balance in neurons and regulates pain-related genes such as TRPV1, thereby maintaining normal neuronal function, reducing pain sensitivity, and supporting the recovery of neurological function after injury or surgery[21,37].

Gut microbiota and pain: The gut microbiome plays crucial roles in systemic inflammation and pain signaling[38-40]. In humans, the gut microbiome has been implicated in the onset of postoperative pain. Concurrently, animal research has highlighted the pivotal role of the gut microbiome in neuropathic pain, which is mediated by immunomodulatory processes[41]. However, the composition of the gut microbiome changes after general anesthesia and surgery[41]. In individuals with vitamin D deficiency, the impact of microbial imbalance may be more pronounced[42,43]. Individuals with sufficient vitamin D levels are better equipped to maintain a balanced microbiome, potentially reducing the severity of pain after surgery or in conditions such as IBS[44]. A study showed that regulating the intestinal flora can help alleviate chronic pain in rats after spared nerve injury[45]. Vitamin D may prevent dysbiosis (an imbalance in gut bacteria) after GI surgery[46,47], thereby reducing inflammation and subsequent pain[48].

CHRONIC PAIN AFTER GI SURGERY: MECHANISMS AND RISK FACTORS

During GI surgery, various forms of surgical trauma, such as tissue manipulation, nerve damage, and inflammation, can lead to chronic pain[49]. This pain may persist long after healing, often due to scar tissue, adhesions, or nerve entrapment[50].

Preoperative factors

Preoperative factors may increase the risk of CPSP. Patients with chronic pain conditions, such as fibromyalgia or a history of abdominal pain, are more prone to experience ongoing pain[51]. High levels of psychological stress, anxiety, or depression can exacerbate pain perception and make postoperative pain management more challenging. Preoperative malnutrition can also impede wound healing[52]. Certain nutrient deficiencies, such as vitamin D deficiency, are particularly common in patients undergoing GI surgery, especially in those with Crohn’s disease or obesity[53-57]. Vitamin D plays a key role in immune function, tissue repair, and pain regulation[5]. Low levels of vitamin D (below 20 ng/mL) can increase inflammation, increase pain sensitivity and slow tissue repair, leading to increased pain and delayed recovery.

Surgical factors

Surgical procedures, especially laparoscopic surgeries, may inadvertently damage surrounding nerves, leading to persistent neuropathic pain or burning sensation. After surgery, scar tissue (adhesions) may form internally, causing organs or tissues that should remain separate to become attached. These adhesions can lead to lifelong complications, including adhesive small bowel obstruction (ASBO), chronic pain, infertility, and difficulties during reoperations[58]. Additionally, abdominal organs may become abnormally sensitive after surgery. This heightened sensitivity may manifest as increased pain from normal abdominal sensations, a condition known as visceral hypersensitivity[59]. This hypersensitivity is closely linked to GI dysfunction and clinical pain syndromes, such as postoperative ileus, ASBO-related pain, or visceral pain after colectomy[59-61].

Inflammation plays a key role in the development of CPSP. Even after surgery, inflammation may persist due to surgical trauma[62]. This ongoing inflammation can be triggered by the changes in the gut microbiota or immune system dysregulation, both of which can prolong pain[63]. Additionally, a prolonged immune response can cause tissue damage, exacerbate pain, and delay recovery[64].

CLINICAL EVIDENCE: VITAMIN D STATUS AND POSTSURGICAL PAIN OUTCOMES

Several studies have shown that chronic pain after GI surgery is associated with surgical injury, inflammation, and GI dysfunction (Table 1)[2,4,65-70]. Although there is no strong evidence linking vitamin D to this pain, many patients who undergo GI surgery have low vitamin D levels during the perioperative period[71-73]. In a prospective observational study involving 112 patients who underwent colorectal cancer surgery, patients with vitamin D levels less than 20 ng/mL had increased perioperative opioid use and heightened pain sensitivity compared with those with vitamin D levels ≥ 20 ng/mL[74]. In addition, a cohort study involving 89 patients who underwent arthroscopic rotator cuff repair surgery revealed that patients with lower vitamin D levels experienced greater pain three months after surgery[6]. In video-assisted thoracoscopic surgery, low vitamin D levels were associated with higher pain scores at three months after surgery[12]. These studies highlight that vitamin D deficiency may lead to higher rates of acute and chronic pain after surgery.

Table 1 Chronic postsurgical pain following gastrointestinal surgery[2,4,65-70].

GI surgery	Finding	Related factors	Ref.
Hernia repair surgery	Laparo-endoscopic hernia surgery leads to a lower incidence of chronic inguinal pain compared to Lichtenstein repair	Surgical injury (tissue injury, nerve damage)	Lillo-Albert et al[65]
Roux-en-Y gastric bypass	A substantial proportion of patients experienced chronic abdominal pain and symptoms 5 years after Roux-en-Y gastric bypass	Gastrointestinal dysfunction	Høgestøl et al[4]; Blom-Høgestøl et al[66]
Lower gastrointestinal tract surgery	In one study following 198 patients after for adhesive small bowel obstruction, 40% of patients developed chronic abdominal pain	Surgical injury; Inflammation	ten Broek et al[67]
Colorectal surgery	CPSP was reported by 32.1% of patients at 3 months and 21.8% at 6 months after colorectal surgery	Surgical injury	Jin et al[2]
Total pancreactectomy	Symptoms of chronic gastrointestinal dysmotility and chronic abdominal pain are common post-surgery	Gastrointestinal dysfunction	John et al[68]
Gastrointestinal laparotomy	The prevalence of chronic pain four years after surgery was 18%, with pain predominantly of a neuropathic nature	Surgical injury (nerve damage)	Bruce and Krukowski[69]
Bariatric surgery	Chronic abdominal pain was the most prevalent complication to bariatric surgery	Surgical injury; Gastrointestinal dysfunction	Simoni et al[70]

GI: Gastrointestinal; CPSP: Chronic postsurgical pain.

A meta-analysis of studies on bariatric bypass surgery revealed that vitamin D supplementation effectively reduced chronic axial back pain in patients after surgery[75]. However, a randomized clinical trial examining brain tumor surgery reported inconsistent results, suggesting that the effects of vitamin D supplements vary across different types of surgeries[76].

In summary, observational studies have shown that vitamin D deficiency may increase the risk of pain and opioid dependency after surgery[77], and vitamin D supplementation can help reduce pain and opioid consumption[78]. However, more research is needed to understand its effects on pain after GI surgery.

THE IMPORTANT ROLE OF VITAMIN D IN POSTOPERATIVE RECOVERY

Postoperative recovery represents a critical phase following surgery, during which the body initiates a complex series of physiological processes to repair and regenerate tissues. Notably, vitamin D has emerged as a promising candidate for optimizing these recovery processes.

Immune modulation

Vitamin D plays a pivotal role in modulating the immune system, particularly during the postoperative recovery phase. Studies have shown that vitamin D can enhance the function of immune cells, including macrophages and T cells, thereby reducing the risk of postoperative infections[79,80]. By upregulating the expression of antimicrobial peptides, vitamin D helps strengthen the body’s innate immune defenses, providing a robust shield against potential pathogens[81].

Infection prevention

Surgical procedures inherently carry a risk of infection, which can prolong the recovery period, complicate the rehabilitation process, and prolong the hospital stay. The anti-inflammatory and antimicrobial properties of vitamin D make it a valuable asset for preventing postoperative infections. Clinical studies have shown that supplementation with vitamin D may lower the incidence of surgical site infections and other postoperative complications[82].

Wound healing and tissue regeneration

Vitamin D is also involved in the process of wound healing and tissue regeneration[83]. It facilitates the differentiation of mesenchymal stem cells into osteoblasts and a variety of other cell types and is essential for the repair of bone and soft tissues[83,84]. Moreover, vitamin D helps increase collagen synthesis and reduce scar formation[85], thereby enhancing both aesthetic outcomes and functional performance.

Nutritional status and metabolic health

Patients often face nutritional stress, which can severely affect their recovery after surgery. Vitamin D helps improve nutritional status by enhancing calcium absorption and promoting bone mineralization[86,87]. Additionally, vitamin D may also affect metabolic processes[88], thus profoundly affecting the overall recovery process after GI surgery.

Accumulating evidence indicates that vitamin D has expansive roles in postoperative recovery, extending beyond its well-known benefits for bone health. It has the potential to modulate the immune system, prevent infections, facilitate wound healing, and support nutritional and metabolic health, making vitamin D a promising therapeutic agent for perioperative care.

CHALLENGES AND FUTURE DIRECTIONS

The use of vitamin D supplementation in surgery presents several challenges due to methodological heterogeneity across studies, which complicates the interpretation of findings. The main sources of variability include the type of surgery, pain assessment methods, timing of vitamin D measurement, and supplementation protocols.

For example, the type of surgery (e.g., orthopedic vs abdominal surgeries) can influence pain outcomes and the body’s response to vitamin D, and different methods of pain assessment, such as self-report scales and objective measurements, may lead to inconsistent results. The timing of vitamin D measurement, from pre-surgery to post-surgery, is also a critical factor, as surgical stress can cause fluctuations in vitamin D levels. Furthermore, supplementation protocols (dosage and duration) vary widely, hindering the ability to determine the optimal supplementation regimen.

Moreover, the pain mechanisms differ across surgeries, such as laparoscopic and open procedures, making it challenging to generalize the findings. Other factors, including obesity, malnutrition, and comorbidities, can also affect vitamin D levels and pain outcomes. To address these challenges, future research should focus on large-scale trials of patients with GI surgery who are vitamin D-deficient, explore the role of vitamin D in gut-nerve interactions and the microbiome’s impact on pain, and develop standardized clinical guidelines for vitamin D screening and supplementation during surgical care. These efforts will help provide more reliable, generalizable conclusions and improve clinical practices for surgical patients.

LIMITATIONS

The limitations of this study include the lack of clinical trials specifically examining the impact of vitamin D on postoperative pain in patients undergoing GI surgery. Most of the available studies are observational in nature and involve diverse patient populations, which may introduce potential biases and limit the generalizability of the findings. Furthermore, there is a significant gap in research that directly investigates the role of vitamin D in pain management within the context of GI surgery. These limitations underscore the necessity for more focused and targeted research in GI surgery settings to better understand the value of vitamin D in this specific patient group.

CONCLUSION

Chronic pain after GI surgery is influenced by various factors, including surgical trauma, inflammation, pre-existing health conditions, and nutritional status. Vitamin D may improve CPSP and promote postoperative recovery after GI surgery through immune regulation, neuroprotection and regulation of GI function (Figure 1). However, further research is needed to determine the optimal methods for integrating vitamin D into postoperative recovery and pain management strategies.

Figure 1 Relationships between gastrointestinal surgery, chronic postsurgical pain and vitamin D.