One of the proposed mechanisms by which intradermal glucopuncture exerts its analgesic effects involves the modulation of TRPV1 receptors (Fig. 3) [20]. TRPV1 is a nonselective cation channel predominantly expressed in nociceptive neurons, and it plays a key role in the transduction and modulation of thermal and chemical pain stimuli [21]. It is activated by various endogenous and exogenous agents, including capsaicin, protons, and heat, and contributes to peripheral sensitization under inflammatory and neuropathic pain conditions [20]. It opens calcium and sodium channels, triggers action potentials, and releases neuropeptides such as substance P and CGRP. These neuropeptides drive neurogenic inflammation: substance P directly causes pain and hyperalgesia, whereas CGRP causes vasodilation, edema, and tissue destruction during chronic inflammation [19]. Although the precise molecular interactions have not been fully delineated, dextrose is thought to indirectly inhibit TRPV1 signaling, thereby limiting neuropeptide release [5]. Glucose halts neurogenic inflammation by turning off the peripheral pain switch. In practical terms, this implies a reduced release of P/CGRP and thus a consequent dampening of peripheral sensitization and inflammatory cascades [5,19]. This mechanism is particularly relevant in neuropathic pain states, where ectopic firing of damaged nerves and neurogenic inflammation maintain pain. Indeed, perineural dextrose has been described as a ‘capsaicin antagonist’ in effect, producing a long-lasting desensitization of TRPV1-bearing fibers without the tissue damage caused by capsaicin itself.

Although glucose and its analogs, such as mannitol, do not have known direct binding sites on the TRPV1 receptor, experimental evidence suggests that glucose may exert an indirect inhibitory effect on TRPV1-mediated nociceptive signaling [22]. For instance, in a placebo-controlled clinical study, the topical application of mannitol cream, a glucose analog, led to a statistically significant reduction in capsaicin-induced lip pain, which is specifically mediated by TRPV1 activation [23]. This observed antinociceptive effect implies that glucose may share similar modulatory properties through non-receptor-mediated pathways, such as through alterations in local osmotic gradients, membrane stabilization, and interference with inflammatory mediators that sensitize TRPV1 [22]. Furthermore, intradermal glucopuncture may mitigate the neurogenic inflammation associated with TRPV1 activation by reducing the release of pro-nociceptive neuropeptides such as substance P and CGRP [22]. This reduction in neuropeptide activity can stabilize peripheral nociceptors and decrease the spontaneous firing of C-fibers, thereby contributing to the overall analgesic effect [24]. Collectively, these findings suggest that the analgesic efficacy of intradermal glucopuncture may, at least in part, be attributed to the indirect modulation of TRPV1 activity, leading to decreased peripheral sensitization and an enhanced nociceptive threshold.

Intradermal glucopuncture is believed to modulate neurogenic inflammation by targeting the dense network of nociceptive C-fiber terminals located within the dermis [25]. Intradermal glucopuncture may modulate neurogenic inflammation and neuronal excitability through multiple pathways, including direct effects on C-fiber terminals, the suppression of cytokine-mediated inflammation, and the stabilization of neuronal metabolism and ion channel activity [22,24,26]. Recent in vitro studies have demonstrated that high concentrations of glucose attenuate neuroinflammatory responses in neuronal cells. Specifically, exposure of SH-SY5Y neuroblastoma cells to tumor necrosis factor (TNF)-α was shown to reduce cell viability and increase the expression of proinflammatory mediators including interleukin (IL)-6, IL-1β, nuclear factor kappa B (NF-κB), and COX-2. Subsequent treatment with 25 mM glucose significantly reversed these effects by reducing cytokine expression and restoring cellular metabolic activity. These findings suggest that elevated extracellular glucose levels suppress cytokine-induced neuroinflammation and protect neuronal function under inflammatory conditions [22]. Consistent with these findings, intradermal glucopuncture has also been shown to reduce levels of TNF-α and IL-1β, which are key activators of the NF-κB signaling pathway responsible for sustaining chronic inflammation and nociceptor sensitization. By inhibiting both the expression of proinflammatory cytokines and NF-κB activation, glucose may help restore immune homeostasis and interrupt the cycle of neurogenic inflammation and metabolic dysfunction in inflamed peripheral tissues [22,27].

Although the peripheral nervous system is less glucose-dependent than the brain, experimental studies have demonstrated that it remains metabolically vulnerable under hypoglycemic conditions. In rodent models of insulin-induced hypoglycemia, recurrent glucose deprivation resulted in axonal atrophy, segmental demyelination, and Wallerian degeneration within sciatic and tibial nerves. These structural changes were associated with progressive sensorimotor neuropathy. Jensen et al. [24] further described insufficient protective responses, including altered Schwann cell metabolism and changes in myelin maintenance pathways, which failed to prevent neuropathic injury under repeated hypoglycemia. These findings emphasize that insufficient glucose supply can directly damage the peripheral nervous system, despite its lower baseline energy requirements compared to the central nervous system.

In addition to its role as a metabolic substrate, glucose also directly modulates neuronal excitability. Recent electrophysiological studies have shown that extracellular glucose directly reduces the firing activity of hypothalamic orexin/hypocretin neurons, which are critical for the regulation of arousal and energy balance. This inhibitory effect is mediated through the activation of tandem-pore potassium channels. When these channels open, potassium efflux increases, the neuronal membrane becomes hyperpolarized, and action potential generation is suppressed. Burdakov et al. [26] further demonstrated that this glucose-sensitive current displayed the characteristic features of tandem-pore potassium channels, including inhibition by extracellular acidification and potentiation by halothane. These findings indicate that glucose can act as a neuromodulator by stabilizing neuronal excitability through ion-channel regulation, and may contribute to the observed analgesic effects of intradermal glucopuncture in peripheral sensory afferents [26]. Glucose has been reported to inhibit the local release of pro-nociceptive neuropeptides such as substance P and CGRP, both of which are critical mediators of neurogenic inflammation, vasodilation, and peripheral sensitization [22,28,29]. This inhibitory effect may occur through the modulation of presynaptic calcium influx and disruption of neuropeptide exocytosis from small-diameter sensory afferents [24]. The relatively prompt pain relief may reflect a direct neural effect, most likely through membrane hyperpolarization, stabilization of sensory neuron excitability, and inhibition of neuropeptide release.

In myofascial pain syndrome, trigger points are thought to represent sites of local metabolic crisis characterized by ischemia, ATP depletion, and accumulation of anaerobic metabolites such as lactate. While this condition cannot be resolved by glucose supplementation alone, intramuscular injection of dextrose may provide partial metabolic support and help stabilize local energy balance. Such supplementation, together with improved oxygen delivery and clearance of metabolites, could contribute to interrupting the vicious cycle of contracture and pain [3].

Collectively, these findings suggest that intradermal glucopuncture injections exert multifaceted neurochemical, metabolic, and immunomodulatory effects, suppress pro-nociceptive signaling, stabilize neuronal excitability, and restore immune homeostasis in inflamed peripheral tissues. These combined actions may contribute meaningfully to the alleviation of localized inflammatory pain and reversal of peripheral sensitization, supporting its therapeutic potential in neuropathic and neurogenic pain states.

The use of intradermal glucopuncture as a therapeutic modality for PHN has been gaining attention in recent years. Although the mechanistic basis remains under investigation, early clinical reports have suggested potential analgesic effects with minimal adverse events. However, to date, the clinical evidence is limited and primarily consists of case reports and small observational studies; no large-scale RCTs have been published. One clinical report describes the use of intradermal glucopuncture in an 88-year-old patient with persistent refractory PHN despite antiviral therapy, analgesics, and transdermal lidocaine patches. The patient underwent weekly intradermal glucopuncture for 4 weeks, which was administered intracutaneously, rather than subcutaneously, along the T11-12 dermatomes. Approximately 20 intradermal injections were administered per session with a 30-gauge, ½-inch needle-syringe containing 5 mL of D5W. The patient demonstrated substantial pain reduction; analgesics were withdrawn, and symptom relief was sustained for 4 months following treatment. The authors proposed that glucose may modulate neural inflammation and promote pro-inflammatory cytokine productions [17].

Another relevant case report described the use of perineural D5W injections into the affected dermatomes (V1–V3, C3) in a patient with craniofacial PHN. The injections were administered under anatomical guidance. In addition, transcutaneous electrical nerve stimulation and low-level laser therapy were administered once weekly to the left facial region in combination with perineural D5W injections. The patient showed physical, psychological, and functional improvement. After three sessions of perineural D5W injections, the severe pain subsided, the burning sensation diminished, and motor function in the left masseter and temporalis muscles improved. Pain intensity, as measured by the Visual Analog Scale (VAS), decreased from 9–10 to 6 after a repeated treatment session at 3 weeks. These findings highlight the potential of this minimally invasive approach for rapid symptom relief [39].

A case series reported the clinical effectiveness of ultrasound-guided subcutaneous glucopuncture in three patients with persistent PHN unresponsive to conventional pharmacological treatments. Each patient presented with chronic pain lasting more than 1 year that was localized in distinct dermatomes affected by a prior herpes zoster infection. The patients had previously been treated with antiviral agents, oral analgesics, and, in some cases, gabapentin, but continued to experience significant neuropathic symptoms. The treatment involved ultrasound-guided subcutaneous glucopuncture directly into the symptomatic area, performed in one to three sessions depending on the clinical response. The injected volume ranged from 5–8 mL to 18 ml per session, depending on the size of the affected dermatome. All three patients showed marked reductions in pain intensity as measured by the VAS. The initial pain intensity scores ranged from 5 to 6; after the final injection, the scores decreased to 0 or 1. In one patient, gabapentin was successfully discontinued after the first injection, and the pain remained well controlled throughout the follow-up period. No adverse events or procedure-related complications occurred. These findings suggest that subcutaneous glucopuncture is a safe, minimally invasive, and effective treatment option for patients with treatment-refractory PHN [18].

CRPS is a particularly severe form of chronic neuropathic pain with both peripheral and central sensitization components. However, the role of perineural dextrose in CRPS remains unclear. The rationale is plausible; however, clinical evidence remains preliminary. CRPS involves intense neurogenic inflammation, and case reports have documented dramatic pain relief in CRPS using weekly perineural D5W injections [19,40]. For example, Thor et al. [41] used D5W injections around affected nerves as a ‘sweet solution’ for CRPS pain with positive outcomes in a small series.

However, in practice, responses have been variable. A recent retrospective study in Korea found that CRPS patients did not experience significant pain reduction after four sessions of dextrose perineural injection, even though patients with PHN, trigeminal neuralgia, and localized neuropathies in the same study improved markedly [19]. The authors hypothesized that the complex pathophysiology of CRPS, particularly central sensitization and spinal cord changes, may render peripheral treatment alone insufficient. In CRPS, pain persists because of dorsal horn hyperexcitability and cortical reorganization, in addition to peripheral nerve dysfunction. Therefore, although dextrose injections can quell peripheral neurogenic inflammation in CRPS, they may need to be combined with other therapies that target central mechanisms. Further controlled studies are needed in the CRPS population. Considering its limited side effect profile, dextrose may be considered an adjunctive option for peripheral limb pain in CRPS, with the recognition that therapeutic benefits are likely to be modest unless central sensitization is simultaneously managed.

Peripheral neuropathies, encompassing entrapment neuropathies such as carpal tunnel syndrome and ulnar neuropathy, are common causes of neuropathic pain and have a substantial impact on quality of life. Minimally invasive perineural injection therapies have been increasingly investigated as alternatives to pharmacological management, with D5W emerging as a promising agent [5].

In a retrospective study involving patients with peripheral neuropathy, the D5W group received either perineural D5W injections or subcutaneous glucopuncture at the site of pain, while the control group received 0.5% lidocaine injections. The treatment was administered once a week for a total of four sessions. The D5W group showed a marked reduction in numeric rating scale scores from baseline to the final follow-up, with progressive improvement after each session, whereas the lidocaine group demonstrated no significant change. Patient satisfaction increased substantially in the D5W group compared to the control group [19].

Multiple RCTs and meta-analyses have confirmed the efficacy of perineural D5W injections. A recent systematic review and meta-analysis in carpal tunnel syndrome that included 13 trials (n = 754) reported that D5W significantly reduced pain versus normal saline in the short term (≤ 4 weeks) and was superior to corticosteroids in the mid-term (4–24 weeks), with additional gains in functional status scores and no significant adverse events [42]. Similarly, a dedicated meta-analysis including four RCT and one non-RCT (n = 212) comparing perineural D5W injections and corticosteroid injections in mild to moderate carpal tunnel syndrome found that D5W provided greater long-term pain reduction and functional improvement, whereas corticosteroids yielded more rapid short-term relief but with diminished efficacy beyond 3 months. Patients treated with D5W showed greater improvements in hand function and fewer side effects while achieving similar gains in nerve conduction and symptom severity scores [43].

Ulnar elbow neuropathy (cubital tunnel syndrome) is another such condition. An RCT in 2020 compared a single ultrasound-guided perineural D5W injection vs. a corticosteroid around the ulnar nerve and reported that both treatments led to significant improvements in symptoms and nerve conduction over 6 months with no complications. However, the dextrose group showed a slightly greater reduction in symptom severity scores and equally good functional recovery [44]. It has also been used to treat other chronic neuropathic pain conditions. Injections of D5W along the superficial sensory nerves have yielded promising results in a number of cases. For instance, a case series documented that ultrasound-guided perineural D5W injections around the lateral femoral cutaneous nerve (entrapped in meralgia paresthetica) produced marked relief of numbness and burning pain, with improvement persisting at the 6-month follow-up after a series of injections [45]. Similarly, radial nerve palsy due to spiral groove entrapment and posterior interosseous nerve syndrome (supinator syndrome) has responded to targeted perineural D5W in small studies [46,47]. Collectively, these studies indicate that for entrapment neuropathies, perineural D5W injections can achieve durable pain relief and neurologic improvement on par with or exceeding that of standard steroid injections, without the risk of steroid-induced nerve damage. Mechanistically, D5W may confer benefits in these cases through mechanical hydrodissection, alleviation of nerve compression, and biochemical modulation of neurogenic inflammation, with the potential to promote remyelination and axonal regeneration. Compared with corticosteroids, D5W avoids risks such as tendon rupture, dermal atrophy, and depigmentation, making it a viable option for patients requiring repeated injections [2].

Hypertonic dextrose injections as prolotherapy have been the predominant approach in the management of chronic tendinopathies and ligament injuries, with the aim of inducing controlled inflammation and stimulating tissue repair in chronically degenerated connective structures. Most clinical studies on prolotherapy focus on 10% to 25% dextrose. However, there have also been reports of D5W injections being applied under certain tendinopathic conditions, often via perineural or subcutaneous injections, suggesting a potential role for low-concentration dextrose beyond neurogenic pain syndromes.

In a RCT, the efficacy of subcutaneous glucopuncture was compared with subacromial-subdeltoid bursa corticosteroid injections in patients with chronic rotator cuff tendinopathy. A total of 57 participants were randomized into two groups: one received a single injection of triamcinolone with 1% lidocaine, and the other received subcutaneous glucopuncture mixed with 2% lidocaine, administered three times per week. After 1 month, both groups demonstrated significant pain reduction from baseline (P < 0.001). Although the overall pain reduction between the groups was not statistically significant (P = 0.052), the proportion of patients achieving clinically meaningful improvement (≥ 2.8-point reduction on the VAS) was significantly greater in the D5W group (P = 0.046). No major adverse events were observed. These findings suggest that subcutaneous glucopuncture is at least as effective as corticosteroid injection for short-term pain relief, and may serve as a safer alternative for managing chronic tendinopathy [48]. A double-blind RCT in chronic tennis elbow compared 5% dextrose vs. 15% dextrose vs. saline injections into the common extensor tendon entheses (three sessions for each) and found that both low-dose and high-dose dextrose were superior to saline in reducing pain and improving hand grip strength at 12 weeks. The 5% performed as well as 15% in that study, indicating that low-concentration dextrose can provide clinical improvement in pain comparable to higher concentrations [49].

In knee osteoarthritis (OA), intra-articular steroid injections provide only short-term relief (often 4–6 weeks) and may hasten cartilage degeneration with repeated use. Dextrose prolotherapy offers an alternative regenerative treatment. In an RCT involving 50 patients with knee OA, a single combined dextrose treatment (injection of 16% dextrose intra-articularly plus 12% dextrose intradermally around the joint) was directly compared with a single 40 mg triamcinolone injection. Specifically, the protocol consisted of a single intra-articular injection comprising 8 mL of 20% dextrose mixed with 2 mL of 1% lidocaine, combined with periarticular intradermal injections of 12% dextrose at four sites: two above the patella on the medial and lateral aspects, one at the medial joint line, and one lateral to the knee, anterior to the fibular head. Both interventions yielded significant improvements in pain (VAS) and function at 1 month. However, after 3 months, the improvements in the steroid group waned, whereas the dextrose group continued to improve, exhibiting significantly better pain relief and functional scores without the adverse joint effects commonly associated with steroids [50].

Other RCTs support the efficacy of subcutaneous glucopuncture in OA, while highlighting the potential differences between injection approaches. Farpour and Fereydooni [51] found that both intra-articular and periarticular techniques were effective for pain and function, with periarticular injections demonstrating comparable results over 8 weeks. The protocol involved two treatment sessions (on days 0 and 2). In the periarticular group, up to three tender points around the knee were identified, and a total of 6 mL of 25% dextrose (2 mL per site) was injected subcutaneously using a fan-shaped redirection technique with a 25G needle. In the intra-articular group, 6 mL of 25% dextrose was injected via the inferolateral approach under sterile conditions. The authors concluded that both intra-articular and subcutaneous glucopuncture are inexpensive and effective options for the management of knee OA [51]. Similarly, Rezasoltani et al. [52] reported significant improvements with periarticular injections and proposed this method as a less invasive and potentially safer alternative to intra-articular delivery. In their RCT involving 104 patients with chronic knee OA, the periarticular group received 20% dextrose with lidocaine injected subcutaneously at four periarticular sites, whereas the intra-articular group received 10% dextrose with lidocaine. Both groups showed significant improvements in pain and function, but the periarticular group demonstrated greater pain reduction at 2–5 months while avoiding the potential risks associated with intra-articular injection [52].

Lam et al. [53] reported a case series of three patients with chronic fascial pain who were successfully treated with glucopuncture. A 45-year-old man who had been experiencing groin pain for 9 months with no muscular trigger points received four weekly sessions of ultrasound-guided superficial and deep fascial injections below the inguinal ligament, leading to complete pain resolution. A 36-year-old woman with 2 years of neck and arm pain and normal neuromuscular function resistant to conservative measures underwent six sessions of multifocal injections into the superficial fascia of the neck, scapular region, and triceps, achieving gradual but complete symptom relief. Finally, a 67-year-old woman having low back and buttock pain for 6 months improved substantially after four weekly sessions of multiple injections into the thoracolumbar fascia and gluteal fascia. In all three cases, localized injections of small aliquots, 0.5–1 mL per site and 5–10 mL per session, yielded significant pain reduction without major adverse events [53].

The fascial system comprises two primary layers: the superficial fascia, a membranous layer situated directly beneath the dermis within the subcutaneous tissue that lies between the superficial and deep adipose compartments, and deep fascia, a dense, fibrous connective tissue that envelopes muscles, tendons, nerves, and blood vessels, forming a continuous, tension-transmitting network throughout the body [54]. Both superficial and deep fasciae are richly innervated by mixed sensory receptors, including nociceptors, mechanoreceptors, and proprioceptors, making them capable of perceiving and modulating painful and mechanical stimuli [55]. Glucopuncture targets these fascial layers, typically just millimeters beneath the skin, by delivering D5W via tangential needle placement to modulate nociceptive input, reduce fascial stiffness, and support biomechanical homeostasis without triggering inflammation or tissue injury [53]. Recent evidence highlights the fascia as an active participant in the pathophysiology of CRPS rather than a passive connective framework. In CRPS, pathological changes such as fibrosis, altered microcirculation, and sympathetic–immune–vascular crosstalk within fascial tissues may amplify pain and autonomic dysfunction, thereby perpetuating the chronic pain state. This perspective reframes the fascia as a dynamic and modifiable pain generator, suggesting that targeted interventions directed at the fascial tissues could represent a novel paradigm in the management of CRPS, complementing or extending beyond conventional nerve-focused approaches [56].