Mechanism, Dose, and Administration of Dexmedetomidine in Managing Visceral Pain Associated With Surgery: A Narrative Review

Introduction

Many individuals remain unaware of the intricate functions performed by their internal organs. Each organ has distinct physiological functions, and as long as life persists, these complex regulatory processes operate continuously [1]. Most internal organs in the human body are richly innervated, comprising both afferent and efferent nerve fibers [2,3]. In the event of an anomaly or perceived adverse condition, these organs can sense and recognize the disturbance, promptly making adaptive changes or issuing a series of early warning signals to alert the body, thereby triggering appropriate responses [4,5]. Visceral pain refers to discomfort originating from the internal organs, particularly those within the thoracic and abdominal cavities [6]. This type of pain can manifest as either acute or chronic and is characterized by its poorly localized nature [6]. It typically develops gradually and persists for extended periods. Unlike somatic/cutaneous pain, visceral pain lacks sharp sensations; it is insensate to cuts and burns but sensitive to traction, distension, and ischemic injuries [4,7]. Furthermore, it frequently presents with referred pain and pronounced autonomic reflexes [3]. Consequently, visceral pain is debilitating and often difficult to treat. Patients experiencing this type of pain endure varying degrees of discomfort, which can lead to psychological issues, escalate healthcare costs, and diminish overall quality of life [8].

In clinical practice, managing refractory visceral pain often necessitates a combination of pharmacological agents and therapeutic techniques [9–11]. The clinical challenge lies in the complex pathophysiology of visceral pain [6], which involves hypersensitivity to stimuli like distension and is often complicated by significant autonomic reflexes. Dexmedetomidine (DEX) is uniquely suited to this complexity, as its multifaceted pharmacological profile directly targets these underlying mechanisms. Recent studies have highlighted the potential of DEX, a highly selective alpha-2 adrenergic receptor (α2-ARs) agonist known for its sedative [12], analgesic, anxiolytic, anti-inflammatory [13], and intestinal barrier-protective properties [14,15], to alleviate visceral pain. Despite its growing recognition, a comprehensive synthesis of findings regarding the use of DEX in treating visceral pain remains lacking. This article reviews the mechanisms, dose, and modes of administration of DEX in managing visceral pain associated with surgery, and highlights the potential of DEX for clinical application and future research.

Overview of the Complexities of Visceral Pain

POTENTIAL MECHANISM OF DEX IN THE TREATMENT OF VISCERAL PAIN:

DEX is a highly selective α2-ARs agonist (α2: α1=1600: 1) with sedative, analgesic, anti-inflammatory, sympatholytic, and sleep-regulating properties [25]. The subtypes of α2-ARs, namely α2A, α2B and α2C, are related to the pharmacological action of DEX. For example, the α2A and α2C receptors are predominantly located in key neural nuclei of the CNS, particularly within the locus coeruleus [26]. The effects of DEX on visceral pain may be mediated through a multifactorial mechanism (Figure 1). For example, the sympatholytic effects of DEX may provide anxiolysis, sedation, and improved sleep quality, which contribute to pain relief post-surgery [27], with its anti-inflammatory effect concomitantly attenuating pain severity [28]. Sufficient perioperative evidence has indicated that DEX has clear advantages in reducing opioid drug use, prolonging analgesic duration, and reducing related adverse reactions. However, during its administration, it may cause bradycardia that requires atropine intervention [29,30]. Therefore, a cautious individualized treatment strategy should be adopted during its use, and the necessity of conducting large-scale clinical trials to evaluate its impact on long-term postoperative outcomes is highlighted. The following sections will discuss the potential role of DEX in the relief and management of visceral pain.

DIRECT ANALGESIC IMPACT OF DEX ON VISCERAL PAIN:

DEX exerts a direct analgesic effect on visceral pain through several mechanisms (Figure 1): (1) By suppressing the activity of Aδ and C fibers in the peripheral tissues adjacent to the surgical site, DEX reduces the activation of nociceptive neurons and the transmission of pain signals, thereby diminishing noxious signaling to the CNS; (2) By activating α2-ARs located in the locus coeruleus and spinal cord, DEX produces anxiolytic and antinociceptive effects, enhancing central analgesia [31,32], ultimately alleviating pain [33]; (3) DEX facilitates neuronal hyperpolarization and inhibits the release of substance P and other nociceptive peptides from the presynaptic membrane, thereby attenuating both peripheral and central sensitization of pain pathway [34,35]. Current evidence strongly supports these mechanisms (Figure 1A). Interestingly, a pioneering study conducted by Ulger et al [36] in 2009 showed that intravenously injected DEX (2.5 to 20 μg/kg) or clonidine (10 to 80 μg/kg) attenuated visceromotor response in a dose-dependent manner. The administration of yohimbine (1 mg/kg), a non-specific α2-ARs antagonist, negated the antinociceptive effects of DEX. Importantly, the authors confirmed that intravenous DEX administration induced antinociception for colorectal distension visceral pain, mediated partially by opioid receptors, not by peripheral α2-ARs.

Compared to the intravenous route, the intrathecal administration of DEX is more frequently used. To investigate the role of the dorsal horn of the spinal cord in pain transmission under DEX, DEX (50 μM diluted to 200 μL) was intrathecally administered via micropump infusion. Using paw withdrawal threshold for assessing pain response, the study demonstrated that DEX attenuates pain by activating α2-ARs, which leads to decreased levels of substance P and calcitonin gene-related peptide within the dorsal horn. Additionally, blockade of α2-ARs resulted in increased substance P and calcitonin gene-related peptide levels, correlating with heightened pain sensitivity [37]. These findings confirm that DEX alleviates visceral pain by down-regulating neurotransmitter release through α2-ARs stimulation. Other candidates in the dorsal horn also participate in the modulation of visceral pain.

Pain behaviors, such as abdominal withdrawal reflex and paw withdrawal latency, were assessed alongside potential molecular changes in the spinal cord. Results indicated that DEX inhibited acute inflammatory responses and reduced visceromotor responses to algesia, likely via Nrf2-mediated NF-κB activation signaling [38]. Similarly, when administered epidurally, DEX demonstrated preemptive analgesic effects, notably prolonging thermal withdrawal latency and the mechanical abdominal contraction response. The underlying mechanisms appear to involve the activation of Toll-like receptor 4 in the spinal dorsal horn, which subsequently inhibits the downstream IRF3/P65 signaling pathway [39].

DEX alone did not significantly reduce the incidence of visceral pain [40]. When combined with esketamine, it can lower visceral pain, suggesting that the effect of DEX as a single drug on the incidence is limited in specific scenarios. However, when used in combination, intraoperative neurological and psychiatric adverse reactions were more frequently observed and warrant careful attention [40]. It is noteworthy that DEX exhibits distinct safety profiles depending on the administration route and combination regimen. Interestingly, another clinical trial found that when 0.5 μg/kg DEX was used as an adjuvant in epidural anesthesia in combination with ropivacaine, it effectively reduced visceral traction responses without increasing related adverse reactions [41]. This divergence in safety profiles may be attributed to different administration routes and their corresponding mechanisms of action. When administered epidurally, DEX acts on α2-ARs located on both pre- and post-synaptic membranes of spinal cord neurons, hyperpolarizing neuronal membrane potentials via G-protein-mediated activation of potassium channels, leading to decreased sympathetic outflow and norepinephrine release, thus inhibiting pain transmission [42,43]. This localized mechanism explains why epidural administration of DEX can achieve satisfactory analgesic efficacy while simultaneously avoiding certain adverse events associated with systemic administration.

Collectively, the results from basic experiments and clinical studies demonstrated that DEX alleviates visceral pain through multiple pharmacological actions, whether administered systemically or intrathecally. It is important to note that while DEX provides multiple benefits as an adjuvant, its safety profile requires careful attention. During administration, excessive sedation should be avoided, with particular vigilance for cardiovascular adverse effects such as bradycardia and hypotension [33].

ANTI-INFLAMMATORY EFFECTS OF DEX ON VISCERAL PAIN:

Gut infection and/or inflammation are key risk factors for the development of gastrointestinal disorders. Inflammation significantly contributes to the manifestation of visceral pain, resulting in heightened hypersensitivity of visceromotor neurons even after the resolution of inflammation [44]. Irritable bowel syndrome and inflammatory bowel disease are characterized by visceral pain due to chronic or intermittent inflammation [45]. Anti-inflammatory therapies or antibiotics are effective in alleviating visceral pain [46]. Recent clinical and experimental studies have revealed that DEX exhibits pronounced anti-inflammatory effects (Figure 1B), positioning it as a promising therapeutic agent for managing visceral pain.

A chronic inflammatory visceral pain model was established in male Sprague–Dawley rats through intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid. Subdural administration of DEX (0.3 mL of 400 μg/mL) 15 minutes prior to behavioral testing significantly diminished abdominal withdrawal response to colorectal distension. A mechanistic study indicated that DEX alleviates inflammatory visceral pain by modulating the miR-34a-HDAC2 signaling pathway and reducing the production of proinflammatory cytokines – interleukin [IL]-6, tumor necrosis factor (TNF)-α, and IL-1β – thereby suppressing the visceral hyperirritable state [47]. To elucidate the precise mechanisms underlying systemic cytokine regulation during intravenous administration, an animal study was conducted using an endotoxin-induced sepsis model in male BALB/c mice. Preemptive use of DEX (40 μg/kg) significantly decreased the release of IL-6, TNF-α, and IL-1β, while also reducing cervical vagal nerve activity [48]. Furthermore, these beneficial effects were abolished in mice undergoing vagotomy or in those pretreated with an α7 nAChR antagonist, indicating that the cholinergic anti-inflammatory pathway, reliant on the vagal nerve and α7 nAChR, is essential for DEX’s anti-inflammatory efficacy [48]. This is supported by results from a rat model of severe acute pancreatitis [49]. The modulations via the cholinergic pathway are complex and involve multiple organs [50].

Notably, DEX produces anti-inflammatory effects in a multi-level ladder, from higher (brain area, eg, the locus coeruleus) to lower (the organ or tissue, eg, the gut). A study demonstrated that DEX inhibits the norepinephrine system in the locus coeruleus, significantly reducing the number of tyrosine hydroxylase-positive cells and lowering inflammatory cytokines (TNF-α and IL-1β) in both hippocampal tissue and serum in a C57BL/6J mouse model of intestinal ischemia-reperfusion injury [51]. This action alleviates cognitive impairment and visceral pain, making DEX a promising agent for managing visceral pain related to gut infection and inflammation. Additionally, intraperitoneal DEX administration decreases proinflammatory cytokines (TNF-α and IL-6) and protects brain function via α2-ARs in astrocytes or through vagal-anticholinergic pathways [52–56].

In brief, DEX inhibits inflammatory responses and reduces cytokine release, mitigating visceral pain through activation of cholinergic pathways, particularly involving the locus coeruleus and α₂-ARs.

IMMUNOMODULATORY EFFECTS OF DEX ON VISCERAL PAIN:

Surgical trauma triggers central responses via afferent nerves, stimulating the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis. This process releases stress hormones (eg, catecholamines, cortisol) and inflammatory mediators (eg, interleukins, TNF-α), mobilizing immune cells based on the duration and severity of surgical stress (Figure 1B). Catecholamines and cortisol are crucial for leukocyte redistribution [57]. Initially, rapidly responding catecholamines quickly mobilize white blood cells from the marginated pool into the central circulation, resulting in a transient increase in leukocyte counts. Subsequently, monocytes and T cells migrate to the surgical site or return to their original locations, regulated intricately by cortisol. Usually, catecholamines and cortisol determine the profile of cytokines. Initially, proinflammatory cytokines dominate at the incision site, but as the host response evolves, anti-inflammatory mediators typically prevail [57]. Sometimes, this serial response may increase the risk of infections, compromise incision healing, and even multiple organ dysfunction. The administration of DEX can partially regulate hormones and inflammatory status, thus balancing immune function, which can enhance recovery in patients after surgery.

Adrenergic receptors, especially α2-ARs, play a significant role in the sympathoadrenal pathway, regulating innate immune cell activity [58]. DEX activates α2-ARs on dendritic cells, neutrophils, monocytes, and macrophages, modulating their functions to inhibit inflammation and enhance immune homeostasis [59]. Recent studies have confirmed that perioperative use of DEX (1 μg/kg bolus, followed by 0.2–0.5 μg/kg/h infusion) effectively alleviated postoperative visceral pain, reducing analgesic requirements and enhancing recovery in patients undergoing laparoscopic cholecystectomy [60,61]. It is important to note that DEX alone is insufficient to completely reverse the endocrine stress response associated with surgery, and its administration is significantly associated with decreased blood pressure, thus necessitating careful risk–benefit evaluation in clinical practice.

At the mechanistic level, the visceral pain relief provided by DEX is closely linked to its immunomodulatory functions (Figure 1B). Studies have demonstrated that DEX suppresses the expression of CD40 and CD86 expression on the surface of macrophages and hence the decreased secretion of inflammatory cytokines [62]. In a murine liver ischemic-reperfusion model, DEX reduced proinflammatory responses and pain after surgery, dependent on activation of the peroxisome proliferator-activated receptor-γ/STAT3 pathway and macrophage polarization from M1 to M2 [63], promoting inflammation resolution and tissue repair. In addition, DEX modulates the F4/80+Ly6G+ macrophage subset, enhancing production of transforming growth factor-β1, a key biomarker in inflammation resolution, and markedly increasing its transcription activity and secretion within the inflamed area, ultimately facilitating the effective resolution of inflammation [55]. However, the causal relationship between visceral pain severity and inflammation or immune cell status remains unclear. Notably, its impact on tumors displays a dual nature: studies have revealed that DEX can promote angiogenesis and immunosuppression by inducing myeloid-derived suppressor cells, thereby accelerating the process of lung cancer metastasis [64] despite mounting evidence showing that DEX exerts positive effects on immune function and inflammatory regulation. This pro-metastatic effect exhibits a complex interplay with its immunomodulatory functions. DEX exerts significantly divergent biological effects across different cancer cell types, while its comprehensive impact on long-term survival rates of cancer patients remains unclear [65].

Overall, current data indicate that DEX effectively inhibits the glucocorticoid response, benefiting surgical outcomes and reducing visceral pain sensitivity and severity [66,67]. Future research should explore the effects of DEX on tumor-associated visceral pain and tumor metastasis, given the lack of corresponding randomized clinical studies and inconsistent results.

PROTECTIVE EFFECTS OF DEX ON INTESTINAL BARRIER INTEGRITY AND VISCERAL PAIN:

The intestinal barrier, consisting of digestive fluids, symbiotic bacteria, mucus layers, epithelial cells, junctional complexes, and immune cells, is essential for maintaining physiological functions and separating the internal and external environments of the body [68]. Surgical trauma can disrupt this barrier, leading to increased intestinal permeability, nerve activation, and heightened pain sensitivity [68–70]. Furthermore, this compromised barrier can trigger oxidative stress and bacterial translocation, contributing to gut-related pain and systemic inflammation [3,71]. Recent evidence suggests that DEX exerts protective effects on intestinal barrier integrity, thereby alleviating pain associated with its disruption (Figure 1C).

Results of animal studies have demonstrated that DEX significantly protects intestinal barrier function by enhancing microcirculation, stimulating intestinal motility, mitigating stress responses, and alleviating visceral pain. In 2012, based on the premise of surgical stress and pain impair intestinal microcirculation, in a study where rats were exposed to isoflurane inhaled anesthesia (1.2% vs 0.7%), DEX (bolus of 0.5 μg/kg with infusion of 0.5 μg/kg/h) counteracted the reduction in intestinal mucosal blood flow caused by surgical stress and pain, improving microcirculation. This effect is attributed to DEX’s ability to reduce microthrombus formation and attenuate sympathetic nervous system activation [72]. Sepsis is notorious for microcirculatory insults. In 2016, Yeh et al [73] conducted an animal experiment investigating DEX’s effects on gut microcirculation in endotoxemic rats. Their findings indicated that intravenous DEX at a rate of 0.5 μg/kg/h protects against gut epithelial disruption by enhancing micro-vessel opening and reducing tight junction damage. However, this study just concentrated on microcirculation and epithelial barrier, not alterations of pain sensitivity. An animal study published in 2017, using male C57BL/6 mice placed in a climate chamber at 40±1 °C to induce a heatstroke model, showed that DEX (25 μg/kg) injected intraperitoneally immediately after heatstroke could decrease levels of serum inflammatory cytokines by inhibiting the intestinal NF-κB activation [53]. This study also suggested that maintaining intestinal integrity is dependent on the Bax/Bcl-2 pathway [53]. To clarify whether DEX possesses anti-oxidative properties, DEX (25 μg/kg) was intraperitoneally administered 30 minutes before mesenteric ischemic injury, and the putative anti-apoptotic and anti-inflammatory biomarkers were assayed in the segments of the terminal ileum. The results revealed that DEX reduced the production of oxygen free radicals and preserved the integrity of intestinal barrier structure [74]. These findings indicated that the downregulation of caspase3 mRNA may be involved in this protective process. Additionally, cardiopulmonary bypass is a special entity of physiological perturbation and induces damage of intestinal mucosal barrier during surgery. Intravenous administration of DEX (5 μg/kg) 15 minutes prior to bypass suppressed inflammation and enhanced the expression of tight junction proteins [75], with downregulation of the TLR4/JAK2/STAT3 signaling pathway being crucial to this process. In liver transplantation models, DEX (10 μg/kg vs 50 μg/kg) reduced oxidative stress and intestinal injury via the Nrf2/HO-1 pathway [76]. These findings underscore DEX’s role in preserving intestinal mucosal barrier and that it might exert favorable effects on visceral pain (Figure 1C).

Clinical studies corroborate the protective effects of DEX on gut mucosal barrier and visceral pain. Among critically ill patients in the intensive care unit after gastrointestinal surgery, DEX administered at a rate of 0.7 μg/kg/h during sedation significantly shortened hospital stays and enhanced α7nAChR expression in peripheral blood mononuclear cells compared to midazolam (0.1 mg/kg/h) [77]. More importantly, DEX decreased the levels of D-lactate and diamine oxidase in the blood, with lowered levels often denoting better intestinal barrier integrity [77]. However, visceral pain was not studied because of difficulty in assessing pain severity under sedation. Studies in colorectal cancer surgery have yielded more contentious findings: although intraoperative DEX (bolus of 1.0 μg/kg followed by 0.5 μg/kg/h infusion) effectively controlled postoperative pain at rest, it unexpectedly failed to significantly reduce morphine consumption or improve key recovery indicators such as hospital length of stay [78]. These negative outcomes clearly suggest that the actual value of DEX in perioperative analgesia may be lower than anticipated, and its mechanisms of action and clinical benefits urgently require reassessment through more rigorous study designs. A retrospective study involving 539 patients after colorectal resection found that the addition of an extra dose of DEX (1.0 μg/kg) to the intravenous infusion (0.4 μg/kg/h) improved abdominal distension, accelerated flatus, and alleviated abdominal pain [79], attributed to DEX’s protective role in maintaining intestinal mucosal integrity. Similarly, in patients undergoing laparoscopic myomectomy and open hysterectomy, DEX expedited intestinal function recovery, attenuated visceral pain, and reduced perioperative opioid use [80]. Further, in parturients after delivery, DEX (300 μg) in conjunction with sufentanil (100 μg) for intravenous patient-controlled analgesia exhibited shorter time for first flatus, less rescue analgesia, less abdominal pain, improved patient satisfaction, and expedited bowel function recovery [81].

Additionally, esketamine combined with DEX for postoperative analgesia markedly reduced visceral pain severity [40]. Two large clinical trials further confirmed the beneficial effects of DEX as postoperative analgesia on intestinal barrier and bowel function [82,83]. However, multiple studies have yielded conflicting findings. A randomized crossover trial conducted in healthy volunteers confirmed that clinically administered doses of DEX significantly inhibit gastric emptying and gastrointestinal transit [84], suggesting a potential “double-edged sword” effect on postoperative gastrointestinal function recovery. Studies in animal models of severe infection/endotoxemia have found that in the context of sepsis, while DEX can exert positive effects by protecting the intestinal barrier, it can also inhibit intestinal motility [85]. Therefore, treatment should be individualized based on the patient’s specific pathophysiological condition [85].

In summary, DEX has significant therapeutic value in alleviating visceral pain and promoting postoperative recovery, attributable to its multifaceted benefits including improved intestinal microcirculation, preserved barrier integrity, enhanced motility, and reduced neural stimulation. Nonetheless, the existence of conflicting findings in the literature underscores the necessity of individualized clinical decision-making, based on the patient’s specific pathophysiological condition, to fully achieve its therapeutic potential.

DEX IMPROVES SLEEP QUALITY AND RELIEVES VISCERAL PAIN:

Many patients with chronic pain often have sleep disturbances such as having difficulty in falling asleep or staying awake and poor quality of sleep [86]. Chronic pain worsens sleep, and in turn, sleep disruptions or disturbances increase pain severity and sensitivity [87]. Pain and sleep are like twins, often interacting and affecting each other, and usually good pain control helps to improve sleep [88,89]. Numerous studies have demonstrated that perioperative administration of DEX significantly enhances sleep quality, alters sleep architecture, and modifies the proportions of sleep stages (Figure 1D).

Chronic colitis-induced visceral pain, mimicking human irritable bowel disease, was induced by trinitrobenzene sulfonic acid via intra-rectum, and visceral hypersensitivity, increased anxiety and impaired gut barrier were found 50 days after trinitrobenzene sulfonic acid administration in rats [90], which was attributed to higher inflammatory status. In this regard, DEX may be a novel therapeutic approach with its anti-inflammatory property [27,28]. A prospective randomized clinical study enrolled 99 patients undergoing gastrointestinal surgery, assigning them to receive either oxycodone (0.6 mg/kg) alone or in combination with DEX (2.4 or 4.8 μg/kg) for patient-controlled intravenous analgesia [91]. The findings indicated that, compared to oxycodone, the addition of DEX significantly increased the proportion of non-rapid eye movement (N2) sleep during the initial 2 nights after surgery and simultaneously decreased the proportion of light sleep (N1), thereby effectively enhancing sleep quality and providing good relief of visceral pain [91]. High-dose DEX did not further improve sleep quality compared to 2.4 μg/kg DEX [91]. Results of a meta-analysis involving 4324 patients further corroborated the positive effects of DEX on sleep quality and structure, revealing reductions in N1 sleep and increases in N2 sleep, with no significant changes in N3 sleep [27]. Concurrently, it improves analgesia and sleep quality by disrupting the vicious cycle between pain (especially visceral origin) and sleep disturbances [90,92,93].

Mini-doses of DEX with an average of 0.02 μg/kg/h supplementing patient-controlled intravenous analgesia also increased the percentage of N2 sleep (median difference, 10%; 95% CI, 1–20%; P=0.03) and also prolonged the total sleep time (median difference, 78 min; 95% CI, 21 to 143; P=0.01) without increasing sedation in 118 older patients after major non-cardiac surgery [94]. Unfortunately, visceral pain was not assessed in this study; hence, we cannot define the effects of mini-dose of DEX on visceral pain. DEX exerts its effects on sleep architecture through interaction with α2-ARs in the central nervous system, especially within the locus coeruleus. This action mimics physiological sleep processes, promoting non-rapid eye movement (N3) sleep while allowing patients to remain responsive to external stimuli, with minimal effects on respiratory drive [12,95].

Further, DEX eases preoperative anxiety, promoting good sleep after surgery and lowering pain scores, further promoting recovery [96]. Importantly, the intraoperative and postoperative administration of DEX was found to reduce the incidence of post-traumatic stress disorder from 24.0% to 14.1% within 1 month postoperatively in patients undergoing emergency trauma surgery [96]. Additionally, it significantly lowered postoperative anxiety scores and improved objective sleep quality among trauma patients [97]. Owing to its distinctive pharmacological properties, DEX is capable of both directly mitigating visceral pain and indirectly diminishing pain perception by enhancing sleep quality [27]. This dual mechanism of action makes DEX an important drug choice in postoperative and perioperative management. Future research should further explore the optimal dosing strategies and administration methods for DEX in various clinical contexts to maximize its efficacy in enhancing sleep quality and relieving visceral pain.

As shown in Figure 1, the complex mechanism by which DEX alleviates visceral pain is systematically summarized. This figure visually shows that DEX, through the synergistic action of multiple targets at the periphery, spinal cord, and central nervous system, provides analgesia, anti-inflammatory effects, immune regulation, protection of the intestinal barrier, and improvement of sleep, which together form the comprehensive network for its alleviation of visceral pain.

Various Administration Modes and Routes of DEX for Relieving Visceral Pain

INTRAVENOUS ADMINISTRATION:

Intravenous injection, one of the most common and effective routes for administering DEX, was effective in decreasing post-surgical pain and alleviating inflammatory responses when administered aa a bolus of 2 μg/kg/h following 0.2 μg/kg/h for maintenance [78]. DEX also eases pain at other timepoints, such as immediately after labor analgesia, as shown by studies in which parturients received DEX intravenously with 3 doses of 0.5 μg/kg, 0.75 μg/kg, and 1.0 μg/kg within 10 minutes [98]; before anesthesia induction with a single dose of 0.5 μg/kg or 0.6 μg/kg DEX [99,100]; as a bolus of 0.5 μg/kg combined with 0.4 μg/kg/h for infusion during surgery [101]; and with opioids [91,102–104] at the end of surgery. In line with these analgesic effects, intravenous administration of DEX at doses of 2.5, 5.0, 10.0, and 20.0 μg/kg has shown pronounced antinociceptive effects against colorectal distension-induced visceral pain in male Sprague–Dawley rats, with effects lasting up to 120 minutes at doses of 10.0 and 20.0 μg/kg [36].

These results provide robust evidence supporting the efficacy of DEX in the treatment of visceral pain. However, currently available clinical studies have a small sample size, short observation time, and a lack of long-term postoperative complications. A critical challenge remains in bridging the results from animal studies to clinical practice, while balancing the analgesic effects with safety considerations.

INTRATHECAL ADMINISTRATION:

In animal studies, a huge gap exists regarding the dosage required to produce antinociceptive effects on inflammatory or intestinal distension-related visceral pain when DEX is intrathecally administered. When DEX 150 μg/kg or 1500 μg/kg was subdurally injected 15 minutes before acetic acid (3%) was injected intraperitoneally in rats in an acute inflammatory visceral pain model, similar behaviors were observed under the same colorectal distension stimuli [56]. Notably, a dose of 7500 μg/kg also yielded comparable analgesic effects in the same pain model [38]. In chronic inflammatory visceral pain brought about by 2,4,6-trinitrobenzenesulfonic acid, subdurally-administered DEX 300 μg/kg suppressed visceral hypersensitivity through the miR-34a-mediated HDAC2 pathway [47]. When intrathecal dosages exceed 150 μg/kg, DEX alone exhibits analgesic effects in both acute and chronic visceral pain models (Table 1). Based on the above experimental results, there is an urgent need to conduct research on the optimal dose of DEX as an adjuvant to maximize the analgesic effect and minimize adverse effects.

In clinical trials (Table 2), DEX has been administered epidurally as an adjuvant agent for pain control, both during and after surgery. For example, in cesarean sections, 3 μg of DEX proved to be more effective than 5 μg when used with bupivacaine, as both doses inhibited the sharp rise in serum cortisol while providing effective postoperative analgesia [105]. A network meta-analysis of 15 randomized controlled trials indicated that the co-administration of DEX with ropivacaine intrathecally for obstetric analgesia effectively alleviated labor pain and reduced adverse effects such as nausea and vomiting [106]. Furthermore, when used as an adjuvant to local anesthetics in patient-controlled epidural analgesia, DEX can significantly improve analgesic efficacy while minimizing complications [107,108]. In thoracic surgery, administering 1.0 μg/kg of DEX epidurally along with a slow bolus of 0.375% ropivacaine (8 mL) resulted in lower thoracic cavity pain and a reduced need for rescue analgesia compared to ropivacaine alone within the first 24 hours after surgery. In this clinical trial concerning thoracoscopic surgery, although the anti-inflammatory effect of DEX was not as strong as that of low-dose dexamethasone, it had a more significant postoperative analgesic effect [109]. In addition, the results of this systematic analysis, including 18 studies with 1148 patients, demonstrated that the use of DEX as an adjuvant to ropivacaine, regardless of its application in epidural anesthesia or regional blockade, yielded superior visceral and parietal analgesic effects [110].

It is essential to extrapolate findings from animal studies to human applications, and further research is warranted to explore optimal dosing for spinal nerve injury or motor alterations, as well as the long-term outcomes of DEX in clinical practice.

INTRAPERITONEAL ADMINISTRATION:

Intraperitoneal injection is a common method of DEX administration in basic research (Table 1). For instance, administering 20 μg/kg of DEX in mice has anti-inflammatory effects [111], whereas doses exceeding 400 μg/kg can cause death [112], suggesting that the intraperitoneal dose of DEX should remain below this threshold. In a rat model of visceral pain induced by acetic acid, the sedative, analgesic, and anti-inflammatory effects of DEX were dose-dependent, with optimal anti-inflammatory effects observed at a dose of 10 μg/kg [113,114].

As shown in Table 2, in laparoscopic surgery, intraperitoneal instillation of 50 mL of 0.25% bupivacaine (125 mg) combined with 1 μg/kg of DEX effectively blocks visceral nociceptors exposed during the procedure, reducing postoperative visceral pain [115,116]. In 2024, an analysis of 11 studies involving 890 patients revealed that intraperitoneal administration of DEX with local anesthetics attenuated abdominal pain and prolonged the duration of action [117], which further strengthened the beneficial effect of intraperitoneal DEX. Moreover, intraperitoneal DEX, either before or after surgery, can markedly reduce the amount of analgesics required for patients undergoing laparoscopic oncological operations [118]. The combination of DEX with ropivacaine outperforms ketamine in prolonging analgesic duration and reducing opioid consumption within the first 24 hours after surgery [119,120]. Intraperitoneal injection of DEX with ropivacaine produced similar effects in gynecological patients [121]. Despite substantial clinical evidence supporting the effectiveness of intraperitoneal DEX in laparoscopic surgery, further research should not be limited to minor surgical procedures, and optimal dosing regimens for intraperitoneal DEX remain to be determined.

NERVE BLOCKADE:

DEX has been widely investigated as an adjuvant in nerve blocks, especially in coarse trunk nerves [122]. Concerning visceral pain, studies have concentrated on DEX as an adjuvant in the transversus abdominis plane blockade (Table 2). A study conducted by Urfali et al [123] demonstrated that a combination of DEX (1 μg/kg, 1 mL) with bupivacaine (0.5%, 10 mL) was better than bupivacaine alone for transversus abdominis plane blockade in patients undergoing cesarean section. Following the procedure, bilateral transversus abdominis plane blocks using an admixture of DEX (1 μg/kg) and ropivacaine (2.5 mg/kg; 0.75%) provided effective pain control, extended analgesia, and improved patient satisfaction [124]. Thoracotomy is accompanied by chest cavity pain, which is a typical type of visceral pain. Compared to ketamine 0.5 mg/kg and 0.4 ml/kg ropivacaine solution 0.25%, DEX 0.5 μg/kg combined with 0.4 ml/kg ropivacaine 0.25% diluted to 20 ml for anterior serratus plane block attained the same postoperative analgesia in patients undergoing thoracotomy, although pain scores were notably lower in the ketamine group [125]. Overall, these findings suggest that DEX is as effective as ketamine for pain management and is a useful adjunct for visceral pain. The clinical and preclinical evidence of DEX in alleviating visceral pain is presented in Table 1 (animal studies) and Table 2 (human studies).

Future Directions

Although multiple modes of administration have been investigated for DEX, obtaining seemingly promising results, several aspects should be further delineated for translation into clinical applications: (1) whether there are appropriate modes and doses for the administration of DEX under different routes; (2) additive effects and the safety margin of DEX for visceral pain; (3) consideration of the proportion of first-pass elimination when administering DEX intraperitoneally; (4) whether DEX affects the overall prognosis or even promotes metastasis when used as an adjuvant for long-time intravenous analgesia in patients with cancer after surgery [126,127]; and (5) DEX-mediated immunomodulation offers an interesting perioperative therapeutic option for patients with cancer [66]. These limited data underscore the need for large-scale, high-quality clinical studies to elucidate the impact of DEX on visceral pain in various types of surgery.

Conclusions

In summary, DEX, a highly selective alpha-2 adrenergic receptor (α2-ARs) agonist (α2: α1=1600: 1) with sedative, analgesic, anti-inflammation, sympatholytic properties, can be a useful adjuvant for visceral pain associated with surgery. DEX can be used via intravenous injections, intraspinal administration, intraperitoneal spraying, or other routes for alleviating pain. Recent animal studies and clinical research have confirmed that DEX plays a vital role in managing visceral pain through multiple mechanisms. However, it remains undetermined whether there is a single primary mechanism or if it is a combination of several effects. Hence, large-scale, high-quality clinical trials are needed to clarify its effects in combating both chronic and acute visceral pain in clinical practice.