Management strategies for burning mouth syndrome: a comprehensive review

3.1 Clonazepam

Clonazepam continues to be a cornerstone treatment for BMS [14, 15]. As a benzodiazepine with anticonvulsant properties, clonazepam exerts its analgesic action by modulating gamma-aminobutyric acid (GABA) receptors as an agonist, specifically the GABA-A receptor complex, ubiquitously expressed throughout the central and peripheral nervous systems; thereby enhancing the efficacy of the pain-modulating pathways within both the peripheral and central nervous systems (CNS) [16]. Its role in decreasing neuronal excitability and modulating muscle tone is well-documented, and it is also implicated in the potentiation of descending pain modulation pathways [16]. This modulation is achieved by facilitating chloride channel opening, resulting in sustained hyperpolarization that mitigates neuronal hyperexcitability and forestalls depolarization and subsequent deafferentation neuronal firing [17] (Fig. 3).

Fig. 3.Mechanism of action of antiepileptic drugs. Pregabalin binds with high affinity to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. This subunit is an auxiliary component of these channels and modulates their function. By binding to the alpha-2-delta subunit, pregabalin reduces the influx of calcium ions (Ca²⁺) into neurons. This inhibition of calcium entry is particularly important in presynaptic excitatory neurons. The decreased calcium influx leads to a reduced release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P. These neurotransmitters are involved in the transmission of pain and other signals in the nervous system. By reducing the release of these excitatory neurotransmitters, pregabalin modulates synaptic transmission and neuronal excitability. Clonazepam binds to a specific site on the GABA-A receptor complex, which is distinct from the binding site of the endogenous neurotransmitter GABA (gamma-aminobutyric acid). This site is often referred to as the benzodiazepine binding site. Once bound, clonazepam acts as a positive allosteric modulator. This means it enhances the effect of GABA on the GABA-A receptor. The binding of clonazepam increases the receptor’s affinity for GABA, making it easier for GABA to activate the receptor, and when activated by GABA, it allows chloride ions (Cl⁻) to flow into the neuron. Clonazepam, by increasing GABA’s effect, enhances the opening of this chloride ion channel. The influx of chloride ions into the neuron results in hyperpolarization of the neuronal membrane. This makes it more difficult for the neuron to reach the threshold potential required for firing an action potential. As a result, neuronal excitability is reduced, leading to an overall inhibitory effect on neurotransmission. NMDAR: N-Methyl-D-Aspartate Receptor; AMPAR/KAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/Kainate Receptor; GAD: Glutamic Acid Decarboxylase.

Emergent data from an experimental animal study have identified the presence of GABA-A receptors within the tongue’s nerve fibers, positing a mechanistic basis for the localized analgesic effect of clonazepam in BMS [18].

Recent trials have substantiated the efficacy of clonazepam in ameliorating BMS symptoms, with variability in administration modalities, topical versus systemic, notwithstanding [19, 20]. However, the precise parameters for optimal administration and dosage remain to be fully elucidated. When administered systemically, this drug shows a rapid onset of action and high bioavailability—reaching 90% within one to four hours post-oral administration—and its extensive half-life ranging from 30 to 40 hours, contribute to its effectiveness in providing sustained pain relief [9].

Topical application of clonazepam within the oral cavity has been reported to offer more immediate analgesic benefits compared to systemic intake, with patients experiencing pain reduction within 10 minutes after dissolving a clonazepam tablet intraorally [21]. However, this method’s analgesic effect tends to subside within three to four hours. The topical route, favored for its simplicity and rapid yet transient efficacy, permits repeated dosing with a reduced risk of systemic side effects.

Gremeau-Richard et al. [9] conducted a double-blind, randomized study evaluating the efficacy of topical clonazepam in a cohort of 48 BMS patients. Under this protocol, subjects were administered a 1 mg clonazepam tablet or placebo buccally, retaining saliva at the site of pain for three minutes before expectoration. This regimen was repeated three times a day for 14 days, demonstrating a reduction in the intensity of pain measured with Numeric Rating Scale (NRS) scale [9].

In a longitudinal study extending over six months, the authors examined 66 BMS patients, comparing the analgesic effect of topical clonazepam with placebo [22]. The study reported a marked decrease in Visual Analogue Scale (VAS) scores among the clonazepam cohort, reinforcing the efficacy of topical administration. Complementary findings by De Castro et al. [23], involving 18 BMS patients treated with 10 mL of topical clonazepam (oral rinse solution 1 mg/10 mL) over a similar two-week period, further corroborated the symptomatic relief provided by the drug.

Moreover, investigations into the systemic administration of clonazepam have also indicated positive outcomes. Grushka et al. [24] found consistent pain relief with daily administration of 0.25 mg of systemic clonazepam, proposing an escalation in dosage for non-responders. Similarly, a double-blind, placebo-controlled study by Heckmann et al. [19] with a 0.5 mg daily dosage demonstrated a significant reduction in pain ratings.

Furthermore, Çinar et al. [25] conducted a comparative analysis of clonazepam, pregabalin, and alpha-lipoic acid (ALA) in three patient groups of 30 patients, each with results indicating a diminution in pain intensity in both clonazepam and pregabalin cohorts.

The dual administration approach was explored by Amos et al. [15], who documented a notable decline in pain intensity in patients administered with 0.5 mg of clonazepam orally thrice daily for six months. Similarly, Shin et al. [21] in a 6 weeks study, tested the efficacy of topical and systemic clonazepam on 41 BMS patients. Patients were instructed to take 0.75 mg clonazepam three times daily for the first 2 weeks (2.25 mg daily), with an increase of the dosage to 1.5 mg three times daily for the remaining 4 weeks (4.5 mg daily) if the patient didn’t report side effects or improve of the symptoms.

While these findings affirm the analgesic properties of clonazepam in BMS, the challenge of standardizing treatment due to the heterogeneity of administration routes and dosages remains. Additionally, a degree of uncertainty pervades the long-term efficacy of clonazepam, compounded by the potential for dependency associated with protracted systemic use. Clonazepam, used in the management of BMS-related symptoms, should be prescribed with caution due to the potential for dependency. Prescribing regulations vary across countries and often restrict its use to specific indications and specialist settings. Clinicians must therefore carefully consider both regulatory constraints and dependency risks. In some settings, topical formulations may offer a more practical alternative to systemic administration, serving as an adjunct for symptom control. The present evidence base, while supportive of clonazepam’s use in BMS symptom mitigation, necessitates further research to refine therapeutic protocols and ascertain optimal treatment outcomes for BMS patients.

3.2 Capsaicin

Capsaicin, a compound found in chili peppers, for its analgesic properties, has demonstrated efficacy in treating various peripheral neuropathies, in post-herpetic neuralgia, and in BMS [26].

Functioning as a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist localized on C fibers, capsaicin instigates neuronal activation accompanied by the release of pro-inflammatory agents, such as substance P, neurokinin A (NKA) and calcitonin-gene-related peptide (CGRP), leading to a phase of heightened sensitivity to pain [26]. Subsequent and continual administration results in a gradual desensitization of the TRPV1 receptor, rendering it less receptive to painful stimuli due to alterations in calcium ion influx, ultimately modifying receptor functions and neuronal architecture—thereby diminishing pain and burning sensations [27] (Fig. 4).

Fig. 4.Capsaicin and TRPV1 receptors. Capsaicin exerts its effects primarily through its interaction with TRPV1 receptors, which are localized in the plasma membrane of Aδ and C fiber primary afferents. The inactivation of voltage-gated Na⁺ channels and direct pharmacological desensitization of TRPV1 receptors in the plasma membrane may contribute to an immediate reduction in neuronal excitability and responsiveness. Prolonged or repeated exposure to capsaicin results in the desensitization of TRPV1 receptors. This desensitization reduces the sensitivity of sensory neurons to painful stimuli, leading to an analgesic (pain-relieving) effect. The exact mechanisms of desensitization also involve the depletion of neuropeptides like substance P, desensitization of the TRPV1 channels themselves, and modulation of downstream signaling pathways. TRPV1: transient receptor potential vanilloid subtype 1.

Notwithstanding its therapeutic potential in pain and inflammation management, its overactivation may induce cytotoxicity, which can damage cells and tissues [28].

Topical and systemic capsaicin applications for BMS have been examined.

Petruzzi et al. [29] investigated the effects of oral administration of capsaicin in patients with BMS. This pilot study involved administering 0.25% capsaicin capsules three times daily for 14 days and found significant decreases in VAS scores compared to placebo groups. Systemic capsaicin showed short-term efficacy for BMS but was associated with high gastric toxicity (32% vs. 0% in placebo), raising concerns about its long-term use. Further trials are needed to evaluate its safety and applicability [29].

Several studies have explored the topical administration of capsaicin in BMS patients using mouth rinse or oral gel.

Silvestre et al. [30] conducted a -blind, placebo-controlled study, which confirmed VAS score amelioration in subjects receiving a 0.02% capsaicin rinse for approximately 30 seconds, in 15 mL aliquots, thrice daily, when measured against a placebo. Similarly, in the study of Jørgensen, subjects were randomized to receive either 0.01% or 0.025% capsaicin oral gel applications on the tongue’s dorsal region, three times a day for a fortnight [31]. The study revealed a significant reduction in oral burning, with no notable efficacy disparity between the two gel concentrations. Moreover, Ricken et al. [32] corroborated these findings, with the 0.025% oral capsaicin gel formulation further evidencing its capacity to reduce VAS scores.

Additionally, Marino et al. [33] showed an improvement in symptoms using 250 mg of chilli powder emulsified in 50 mL of water with a dose concentration of 3.54 µg/mL of capsaicin in a group of BMS cohort. Azzi et al. [34] also contributed to the corpus of evidence, reporting a considerable decrease in oral discomfort among BMS patients subjected to a prolonged regimen of capsaicin mouth rinse applications.

Capsaicin may be a potential topical treatment for BMS, but prolonged or excessive use could cause mucosal damage, such as peeling or ulceration. Further research is needed to assess its efficacy and safety, determine the optimal concentration and application frequency, and investigate long-term outcomes to guide clinical practice.

3.3 Emerging and alternative topical therapies

Topical treatments studied within non-randomized controlled trial (RCT) contexts, including lidocaine, antihistamine agents, sucralfate, and lactoperoxidase oral solutions (Biotene®), have encountered disappointing efficacy [30, 35, 36]. Additionally, contemporary systematic analyses have revealed that neither benzydamine hydrochloride oral rinse (0.15%), topical urea (10%), nor chamomile extract (2%) do not significantly impact BMS symptomatology, with unsatisfactory outcomes [30, 35, 37].

The use of topical amitriptyline, which is commonly used to treat chronic neuropathic pain, was evaluated in a study by Lebel et al. [38] in which the authors compared the use of clonazepam drops with amitriptyline drops and observed a significant decrease in the VAS scores for both groups. The use of topical amitriptyline, which is commonly used to treat chronic neuropathic pain, was recently investigated in a retrospective real-world study by Lebel et al. [38]. In this study, 15 patients with BMS were treated with a topical solution (40 mg/mL), diluted by placing five drops (1 mg/drop) into 20 mL of water resulting in a 0.25 mg/mL solution administered twice daily. A significant reduction in pain intensity was observed with mild adverse events reported in 27% of cases, including somnolence, dry mouth, and dysgeusia. Although dry mouth was reported as a side effect in some patients, this may be advantageous in selected cases, particularly in those with sialorrhea. To reduce the incidence of dry mouth, strategies, such as further dilution of the solution, shortening mucosal contact time, or adjusting the frequency of application, may be considered.

Furthermore, in a more recent RCT by Hussein & El Marssafy (2025), patients used a mouthrinse prepared by dissolving a 10 mg or 25 mg amitriptyline tablet in 100 mL of distilled water. The rinse was applied for 2–3 minutes, three times daily for 8 weeks, resulting in dose-dependent pain reduction without any local or systemic adverse effects, further supporting the potential utility of topical amitriptyline in BMS [38, 39]. However, subjects treated with amitriptyline reported a worsening of pre-existing xerostomia, suggesting to avoid this formulation in BMS patients that report this additional symptoms.

Although these topical treatments have not demonstrated effectiveness when used independently, it is feasible to consider their use in conjunction with systemic medications, given that these treatments have not shown any side effects.

Recently, Gramacy and Villa assessed the effectiveness and safety of gabapentin (GB) topical solution (250 mg/mL) in a small retrospective study involving 19 BMS patients [40]. All patients were instructed to swish and spit 5 mL of the solution for 5 minutes, without swallowing, two to four times a day.

The hypothesis suggests that applying GB topically may block the alpha-2-delta1 (α2δ1) subunits, components of voltage-gated calcium channels (VGCCs) present in nociceptive neurons, and produce a local analgesic effect. GB could stabilize pain receptors in the mouth, potentially reducing pain [40]. Traditionally an antiepileptic, GB might also manage pain when used topically. However, further structured studies, including randomized and controlled trials with placebos, are needed to confirm these findings.

3.4 Antidepressants: efficacy and safety

Antidepressants (ADs), including tricyclics (TCAs), serotonin receptor antagonists and reuptake inhibitors (SARIs), selective serotonin reuptake inhibitors (SSRIs), and serotonin and noradrenaline reuptake inhibitors (SNRIs), have shown effectiveness in treating BMS. They offer pain relief and help with the accompanying psychological conditions. Studies indicate that improving mood disorders linked with BMS could indirectly lessen pain perception and bolster pain management strategies [41, 42]. While the exact mechanisms by which ADs alleviate pain are not completely understood, recent findings suggest their analgesic properties may function independently of their mood-enhancing effects [43, 44]. These drugs modulate pain transmission by elevating neurotransmitters like serotonin and noradrenaline levels in the synaptic cleft, which, in turn, may reduce the transmission of pain signals to the CNS by downregulating and desensitizing spinal dorsal horn receptors [45]. The initial delay in the effectiveness and subsequent tolerance to side effects might stem from the time required for receptor desensitization [46]. Moreover, higher neurotransmitter levels strengthen the descending inhibitory system, which is pivotal in managing nociceptive pathways that deliver pain signals [47] (Fig. 5).

Fig. 5.Descending pain modulation. There are several connections between the ascending and descending modulation systems. Descending modulation is mediated through projections from the amygdala to the periaqueductal gray (PAG), which also receives input from other brain areas including the hypothalamus. The PAG communicates with the rostral ventromedial medulla (RVM), which sends descending serotonergic projections to the Caudal Nucleus/Cervical Spinal Cord (NC/MS C1–C2), and with the locus coeruleus (LC), which sends inhibitory noradrenergic projections to the NC/MS C1–C2. Another descending modulation system involves neurons of the dorsal reticular nucleus (DRN). These circuits are sensitive to opioids because the PAG and the RVM are rich in µ receptors. The effect of serotonin (5HT) and noradrenaline (N) in the NC/MS C1–C2 can either inhibit or amplify pain, depending on the receptor subtype to which the neurotransmitters bind. Presynaptic activation of the 5-Hydroxytryptamine receptor 1B (5HT1B) receptor on the terminals of primary afferents has an anti-nociceptive effect because it reduces the release of glutamate in the NC/MS C1–C2, as does the activation of postsynaptic 5HT1A receptors on second-order neurons. In contrast, activation of the excitatory serotonin receptor 5HT7, identified in GABAergic interneurons of the NC/MS C1–C2, promotes the release of GABA, resulting in reduced excitability of secondary nociceptive neurons. Presynaptic activation of α2-adrenergic receptors inhibits the release of glutamate at the central nerve endings of primary nociceptive afferents and at the postsynaptic sites of second-order nociceptive neurons. SSRIs primarily act by blocking the reuptake of serotonin (5HT), increasing its availability in the synaptic cleft. In the diagram, they would modulate serotonergic neurons (blue pathways) at both the NC/MS C1–C2 and DRN, enhancing inhibitory control over pain pathways. SNRIs block the reuptake of both serotonin and norepinephrine, increasing their levels in the synapse. They would influence both serotonergic (blue pathways) and noradrenergic (red pathways) neurons, acting at NC/MS C1–C2 and LC to provide pain relief through enhanced inhibition and reduced excitation. TCAs inhibit the reuptake of serotonin and norepinephrine, similar to SNRIs, but also affect other neurotransmitters. Their action would be on both serotonergic and noradrenergic neurons, enhancing descending inhibitory pathways at NC/MS C1–C2 and LC, as well as potentially affecting other areas of pain modulation such as DRN. Vortioxetine has a multimodal mechanism: it inhibits serotonin reuptake, acts as an agonist on 5HT1A receptors, partial agonist on 5HT1B receptors, and antagonist on 5HT3, 5HT1D, and 5HT7 receptors. It would modulate serotonergic pathways (blue pathways) at various points, enhancing inhibitory signals and potentially reducing pain transmission through multiple receptor interactions. PAG: Mesencephalic periaqueductal gray; RVM: Rostral ventromedial medulla; NC/MS C1–C2: Caudal nucleus/Cervical spinal cord C1–C2; LC: Locus coeruleus; DRN: Dorsal reticular nucleus; µ-R: Opioid µ receptors; 5HT: Serotonin; N: Noradrenaline; α2: Noradrenergic receptor; TCAs: Tricyclic antidepressants; SSRI: Selective Serotonin Reuptake Inhibitors; SNRI: Serotonin and Noradrenaline Reuptake Inhibitors; GABA: gamma-aminobutyric acid.

Dysfunctions in these pathways can amplify chronic pain, underscoring the importance of serotonin and noradrenaline in the pain management process within BMS treatments [48].

Furthermore, ADs enhance synaptic neuroplasticity and mend disruptions in the hippocampus, amygdala, and cerebral prefrontal cortex connections by increasing Brain-Derived Neurotrophic Factor (BDNF) [49]. This aids in neuron restoration and contributes to chronic pain relief and the reduction of co-occurring anxiety and depression, particularly evident with long-term use [50].

Additionally, ADs provide pain relief by blocking sodium channels, thus preventing discharges in damaged nerves [51], and antagonizing N-methyl-D-aspartate (NMDA) receptors [52], implicated in the increased sensitivity characteristic of neuropathic pain [53].

Lastly, ADs may also offer anti-inflammatory benefits by decreasing pro-inflammatory cytokines such as Interleukin-6 (IL-6) [54], offering a potential therapeutic advantage in BMS treatment strategies where inflammation and elevated IL-6 levels are believed to play a critical role [55].

3.4.2 Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs)

SSRI and SNRI are being increasingly used in the treatment of BMS patients due to their effectiveness and milder adverse events compared with TCAs. When selecting an SSRI, factors such as side effect profiles and pharmacological properties, including drug half-life and interactions involving cytochrome P450 enzymes, are considered [63].

A review of multiple studies indicates that both paroxetine and sertraline have higher effectiveness rates compared to escitalopram and citalopram; fluoxetine has been evaluated in only one study.

In this context, Maina et al. [64] conducted an 8-week randomized trial with 70 BMS patients receiving either amisulpride (50 mg/day), paroxetine (20 mg/day), or sertraline (50 mg/day). All treatments were found to significantly alleviate BMS symptoms without severe adverse effects, that were similar across all groups.

Following this, a 12-week open-label, non-comparative prospective study by Yamazaki et al. [65] on 71 BMS patients reported a 70.4% remission rate of pain with paroxetine (10–30 mg/day), noting only minor and transient side effects. Another study by Ohga et al. [66] involving 43 BMS patients recommended initiating treatment with 10 mg/day of paroxetine, incrementally increasing it to 20 mg and 30 mg as needed, based on the patient’s response. This titration approach aimed to optimize therapeutic outcomes by minimizing adverse effects.

Finally, in a more extensive and long trial of 12 months, Adamo’s research included 150 BMS patients randomized to receive Vortioxetine (VO) (15 mg/day), paroxetine (20 mg/day), sertraline (50 mg/day), escitalopram (10 mg/day), or duloxetine (60 mg/day) [10]. The VO group exhibited the highest efficacy and shortest time to action with the fewest side effects. However, by the end of the study, all Ads were found to elicit a clinical response, with treatments being well-accepted and few dropouts. Among the SSRIs, sertraline was noted for better tolerability, a lower risk of drug interactions, and a minor impact on Corrected QT interval (QTc) prolongation—a significant consideration for patients with a history of myocardial infarction or other cardiac conditions—compared to paroxetine, which carried a higher risk of side effects, notably weight gain and sexual dysfunction [10].

Fluoxetine is approved for treating depression, but it also addresses anxiety disorders, bulimia nervosa, premature ejaculation, and recently, nociceptive pain [67]. Unlike other SSRIs, fluoxetine’s mechanism for alleviating pain may involve not only the serotoninergic system, but also the opioidergic system [68]. Although fluoxetine has a low affinity for opioid receptors, it appears to indirectly increase levels of opioid peptides, such as enkephalins and endorphins [69].

In a recent study on BMS, fluoxetine was evaluated in a placebo-controlled trial conducted by Zoric et al. [70]. The study involved 100 BMS patients, with half receiving fluoxetine and the other half a placebo. The treatment began with an initial dose of 20 mg/day for the first three months, which was subsequently maintained or increased to 40 mg/day for several additional months. Notably, 70% of patients treated with fluoxetine experienced significant reductions in Hamilton Depression and Anxiety (HAM-D and HAM-A), and VAS scores, demonstrating the drug’s effectiveness in treating mood disorders and alleviating pain. However, 20% of patients reported side effects, including transient nausea, occasional headaches, and dizziness.

Choosing SSRIs for treating BMS involves more than just their effectiveness in pain relief; it is crucial to consider their side effects and how they might impact patients. Each SSRI has unique characteristics that may make it more suitable for certain patients. For instance, paroxetine can cause significant withdrawal symptoms and has sedative effects, which might be either beneficial or detrimental. Fluoxetine, with its long half-life, minimizes withdrawal symptoms and is used for various conditions beyond depression, such as bulimia. Sertraline is often preferred for treating obsessive-compulsive disorder (OCD) due to its specific benefits in managing the condition.

A comprehensive evaluation of a patient’s mood and psychological conditions is crucial for selecting an SSRI that effectively treats BMS and supports overall mental health. Personalized treatment plans optimize both pain relief and psychological well-being in BMS patients.

Several studies have demonstrated the effectiveness of SNRIs, such as duloxetine, venlafaxine, and milnacipran, in treating various chronic pain conditions, including chronic low back pain, osteoarthritis, fibromyalgia, and peripheral diabetic neuropathy [43, 71].

Indeed, the increased level of noradrenaline caused by these drugs enhances the function of the periaqueductal grey, which is the origin of the descending pain inhibitory pathway, and the basal ganglia, which is the reward system involved in pain amelioration [72] (Fig. 6).

Fig. 6.Multifaceted mechanism of action of vortioxetine. Vortioxetine, administered at a dose of 10–20 mg, exerts a broad spectrum of effects through its interaction with various serotonin (5HT) receptors and the serotonin transporter (SERT). It acts as an agonist at 5HT1A receptors and a partial agonist at 5HT1B receptors, contributing to its antidepressant and pain control effects, respectively. Additionally, it inhibits serotonin reuptake by targeting SERT, leading to increased serotonin levels. Vortioxetine also functions as an antagonist at 5HT3, 5HT7, and 5HT1D receptors, which enhances its pro-cognitive effects and helps improve sleep. Furthermore, it promotes brain neuroplasticity by increasing brain-derived neurotrophic factor (BDNF) levels through interleukin-4 (IL-4) signaling.

In the study of Mignogna et al. [73] the authors found that 60 mg/day of duloxetine led to complete remission of symptoms in a 65-year-old woman with BMS. Similarly, Nagashima et al. [74] reported positive outcomes with duloxetine administered in a flexible dose ranging from 20 to 40 mg/day over a 12-week period. Another case report involved a 77-year-old female patient with BMS resistant to conventional treatments, who successfully managed her symptoms with duloxetine, thereby supporting its use in treatment-resistant BMS cases [75].

A study by Moon-Jong Kim and H. Kho found contrasting results. Four BMS patients treated with venlafaxine and nine with duloxetine (37.5–75 mg/day for venlafaxine, 30 mg/day for duloxetine) for four weeks showed limited relief after resistance to other treatments. While some patients improved, most did not experience significant symptom relief, and some discontinued due to intolerable side effects. This suggests that duloxetine’s efficacy may be limited in refractory BMS patients [76].

SNRIs affect both serotonin and norepinephrine and may cause side effects like increased blood pressure and heightened alertness, which can be either beneficial or detrimental. The choice between SSRIs and SNRIs for treating BMS depends on the patient’s specific symptoms and health conditions. SSRIs are preferred for patients sensitive to norepinephrine’s effects on heart rate and blood pressure, while SNRIs might be chosen for their energizing effects in patients with lethargic depression. The decision should be based on the individual’s health profile, disorder characteristics, and response to previous treatments, balancing efficacy and tolerability.

3.5 Antiepileptics (pregabalin and gabapentin)

Pregabalin (PGB) and gabapentin (GB) play a significant role in managing both acute and chronic pain by reducing pain intensity and opioid use, thereby improving quality of life through their modulation of pain pathways [102]. Both drugs work by binding to the alpha-2-delta subunit of voltage-gated calcium channels, thereby inhibiting calcium influx and reducing the release of neurotransmitters, including glutamate, noradrenaline, and substance P, involved in pain signaling [103] (Fig. 3).

PGB may also activate the descending noradrenergic system, which further alleviates neuropathic pain, and improves sleep quality and anxiety [104]. PGB is approved by the Food and Drug Administration (FDA) for neuropathic pain and for anxiety disorders [105].

Various studies have shown the effectiveness of PGB in treating BMS, especially when other treatments fail. Ito et al. [106] found PGB effective in five patients who did not respond to SNRI treatments. Heo et al. [107] reported that PGB provided pain relief for 70% of 19 BMS patients who were unresponsive to clonazepam. Choi et al. [80] also supported PGB’s benefits in a study of 33 BMS patients.

PGB is also considered for combined use with SSRIs or SNRIs in treating other chronic pain conditions and fibromyalgia when single-drug treatments are ineffective. Additionally, a study by Adamo with 203 patients showed that adding PGB (75 mg–150 mg/day) to VO (20 mg/day) increased its effectiveness. The study demonstrated that adding PGB to treatments with VO or SSRIs/SNRIs showed a positive response in the majority of patients, with the VO-PGB combination having a quicker onset and fewer side effects. This therapeutic strategy may be especially beneficial in cases where first-line BMS treatments have failed.

Research on the use of GB for treating BMS remains limited and yields mixed results. In a randomized, double-blind, controlled trial involving 120 BMS patients, Lopez-D’Alessandro et al. [108] found that administering alpha-lipoic acid (600 mg/day) and GB (300 mg/day) for two months provided greater pain relief compared to placebo or drug individually. This suggests that a combination of medications targeting different levels of the nociceptive system can be beneficial in managing this syndrome [108].

Despite these promising results, research on PGB’s use in BMS is still mixed. Some studies, like those by Heckmann et al. and White et al., found GB, a drug similar to PGB, did not significantly relieve BMS pain [109, 110]. Based on the currently available data, pregabalin may be preferred over gabapentin for BMS management, although further research is essential to confirm its effectiveness [111].

3.6 Antipsychotics

Antipsychotics, traditionally used for schizophrenia and depression, may also help manage chronic pain, including conditions like trigeminal neuralgia and diabetic neuropathy [112].

Specifically, second-generation antipsychotics, also known as atypical antipsychotics, impact various neurotransmitter systems in the brain. They block dopamine (D2) receptors and affect adrenergic, acetylcholine, catecholamine, histamine, and serotonin receptors. They also inhibit NMDA and AMPA receptors, which block glutamatergic transmission. In an animal model, this inhibition showed potential for pain modulation [52].

Given their broad effects on neurotransmitters, atypical antipsychotics have been considered for treating BMS, especially in patients who do not respond to ADs therapy.

The antipsychotics used in BMS include olanzapine, aripiprazole, quetiapine, levosulpiride, and amisulpride.

Ueda et al. [113] reported significant pain relief with olanzapine (2.5–5 mg/day) in two patients unresponsive to milnacipran and paroxetine.

A low dose of aripiprazole (1 mg/day) demonstrated efficacy in treating BMS in a 66-year-old woman resistant to other antidepressants [114]. Additionally, Takenoshita et al. [115] reported that two patients unresponsive to amitriptyline alone experienced substantial pain reduction when a low dose of aripiprazole was added to their regimen. These positive effects were maintained for over two years.

Poyurovsky et al. [116] reported the effectiveness of quetiapine fumarate (50 mg/day) in a 50-year-old woman suffering from both BMS and OCD. She had previously undergone treatment with escitalopram, clonazepam, and fluoxetine, none of which provided relief. However, after just one week of starting quetiapine, she experienced rapid improvement in both depressive and BMS symptoms. Notably, there was no recurrence in the following three years of observation.

An 8-week single-blind study compared amisulpride (50 mg/day) with SSRIs in treating BMS. All treatments improved BMS symptoms significantly, and amisulpride had a shorter response latency than SSRIs, making it potentially more suitable for initial therapy [64]. Another study found significant improvement in BMS symptoms over 24 weeks with amisulpride (50 mg/day). The treatment was well tolerated with no serious adverse effects.

Finally, a study using levosulpiride (100 mg/day for 8 weeks) found partial improvement in 28 out of 39 patients. However, no complete remission was reported, and the response was more notable in patients with shorter disease durations [117].

Despite these encouraging findings, antipsychotic safety profiles are a concern, particularly for elderly patients. Adverse effects like QT prolongation, metabolic syndrome, extrapyramidal symptoms, weight gain, and sedation can be significant challenges [58]. Physicians should titrate doses carefully and monitor patients to minimize these risks while maximizing therapeutic benefits.

A careful evaluation of risks and benefits is necessary before prescribing antipsychotics for BMS, as most of the available evidence derives from case reports rather than controlled trials. These medications may, however, offer therapeutic value in selected patients with comorbid psychiatric conditions, such as OCD. Combination therapy involving low-dose antipsychotics alongside SSRIs/SNRIs or antiepileptics has shown preliminary promise, but further studies are needed to define optimal regimens and dosing strategies. Ultimately, larger-scale clinical trials are essential to determine the role of antipsychotics in BMS management. Until such data are available, clinicians should proceed with caution, particularly when considering these treatments in routine practice.

4.1 Melatonin

Research indicates that melatonin has potential therapeutic benefits for managing chronic pain. Yang et al. [118] reported that melatonin reduces myocardial susceptibility to chronic pain-related stress by inhibiting necroptosis and minimizing oxidative stress in rodent models. Additionally, Kaur and Shyu highlighted melatonin’s neuroprotective properties, suggesting that chronotherapy could be a promising approach to chronic pain management, particularly for sleep-related discomfort [119]. Danilov and Kurganova found that melatonin helps normalize circadian rhythms, thereby improving sleep quality in patients with fibromyalgia, irritable bowel syndrome, and other conditions. Melatonin also provides analgesia via its receptors [120].

However, research on melatonin’s efficacy in treating BMS has yielded mixed results. A triple-blind, randomized clinical trial found that melatonin (12 mg/day) did not outperform placebo in alleviating BMS pain [121]. However, it improved anxiety scores and slightly increased sleep duration, while both placebo and melatonin had safe pharmacologic profiles. In contrast, a placebo-controlled trial by Nosratzehi et al. [122], using the same melatonin dosage, showed a reduction in burning sensations but no significant improvement in sleep quality.

In another prospective, double-blind study, a lower dose of melatonin (1 mg/day) effectively reduced burning sensations and improved the quality of life in BMS patients. Clonazepam showed similar results [123].

Given melatonin’s multifaceted properties in pain management, particularly its analgesic and neuroprotective effects, further exploration in clinical trials is warranted [124]. Despite mixed findings, its potential benefits in alleviating pain and improving mental health could offer a promising alternative or complementary approach for individuals with chronic pain conditions, including BMS.

4.2 Alpha lipoic acid (ALA)

ALA is sometimes used as a supplement in chronic pain management due to its potential anti-inflammatory and antioxidant properties [125]. Research suggests that ALA (600–800 mg daily) can improve nerve function by neutralizing free radicals and reducing oxidative stress, both of which can impact chronic pain conditions [126]. Diabetic peripheral neuropathy, fibromyalgia, certain musculoskeletal disorders, and BMS may benefit from ALA supplementation [127, 128]. However, studies on ALA’s efficacy in managing BMS have shown mixed results.

In a double-blind, placebo-controlled trial, 64% of patients receiving ALA showed improvement, with 69% maintaining the benefit one month post-treatment [129]. Additionally, López-D’alessandro and Escovich reported that combining ALA with gabapentin significantly reduced pain in BMS [108]. Furthermore, Femiano et al. [130] found a positive outcome when ALA was combined with psychotherapy.

Conversely, other studies found no significant difference between ALA and placebo in alleviating BMS symptoms. For instance, a randomized, double-blind study by Cavalcanti and da Silveira indicated that while some patients reported improvement with ALA, the results were not significantly different from placebo [131].

In summary, while ALA has shown potential benefits for some patients with BMS, results are not universally consistent, and further research is needed to establish clear guidelines for its use in this condition.

4.3 Palmitoylethanolamide (PEA)

PEA, a bioactive lipid related to endocannabinoids, is found throughout the body, including the brain. It is produced as a protective response to tissue damage and has anti-inflammatory, pain-relieving, and other therapeutic effects [132]. PEA works in pain management by activating a receptor called Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α), which reduces inflammation by lowering the levels of certain inflammatory molecules [133]. It also competes with similar compounds to inhibit an enzyme called Fatty Acid Amide Hydrolase (FAAH), increasing levels of protective bioactive lipids and reducing inflammation [134].

Additionally, PEA affects TRPV1 receptor channels, which are important for managing neuropathic pain and inflammation, thereby helping to reduce pain perception [135]. By inhibiting FAAH, PEA indirectly increases levels of anandamide, a naturally occurring cannabinoid, enhancing its pain-relieving effects through what’s known as the “entourage effect” [136].

Research, including studies on its ultra-micronized form, has shown that PEA can significantly reduce symptoms in conditions like BMS [133]. A double-blind, randomized, placebo-controlled trial involving 35 BMS patients found that those treated with ultramicronized-PEA 600 mg micro-granules/day (Normast®, 935939708, Epitech Group SpA, Padua, Italy) experienced a significant reduction in burning sensation compared to the placebo group [137]. Moreover, it has been demonstrated that PEA, especially when combined with medications like gabapentin, effectively reduces pain in BMS patients [138]. However, more research is needed to fully understand how PEA works and to confirm its effectiveness in treating BMS either alone or combined with other treatments.

5.1 Cognitive-behavioral therapy (CBT)

CBT is a non-invasive method used to manage chronic pain by addressing the psychological and emotional aspects that can intensify pain perception [139]. CBT operates on the idea that thoughts, behaviors, and emotions are interconnected, and modifying these can alleviate undue emotional responses to pain [140].

CBT assists patients in recognizing and challenging negative thought patterns, such as catastrophizing, and encourages replacing them with more positive and balanced thoughts, which can lessen distress and enhance pain tolerance [141]. It promotes patient motivation and independence, encouraging participation in enjoyable activities to break the cycle of pain and depression [141].

The therapy includes relaxation techniques, like deep breathing, progressive muscle relaxation, and guided imagery, to reduce stress and muscle tension, which can amplify pain [142].

Additionally, CBT provides coping strategies, such as problem-solving and seeking social support, which aid in managing the emotional impacts of pain [140]. Biofeedback is used to help patients monitor and respond to physical signs of stress, such as muscle tension and heart rate, allowing them to apply relaxation techniques effectively to decrease pain intensity [143].

CBT is considered an effective intervention for managing BMS symptoms especially when combined with medications or other treatments as demonstrated by studies and a systematic review [144] (Table 2).

Individual and group CBT intervention (1–2 sessions) treatment has been shown to reduce both pain and anxiety levels in patients [145, 146].

Although the treatment has considerable and lasting effects, which can last up to 12 months, a full course of CBT poses financial challenges due to the high treatment costs [147].

Streamlining the CBT protocol to focus exclusively on psychoeducation can significantly reduce costs [148]. This strategy involves offering patients comprehensive information about BMS, including its characteristics, underlying mechanisms, and available treatment options, such as medications [149]. Providing education helps alleviate patients’ concerns about the potential severity of the condition. Emphasizing the importance of maintaining a normal lifestyle despite fluctuating symptoms also leads to improved patient outcomes [150].

5.2 Low-level laser therapy (LLLT)

LLLT, also known as photo biomodulation therapy, is a non-invasive, chair-side treatment that uses near-infrared light to provide analgesic and anti-inflammatory effects [151]. It is a promising therapy for reducing pain in BMS and may positively influence quality of life and mental health. The wavelengths typically range from 600 to 1100 nm, offering an optimal window for tissue penetration [152, 153]. This range promotes peripheral nerve regeneration and reduces pro-inflammatory cytokines like IL-6 and Tumor Necrosis Factor-alpha (TNF-α) [154]. The analgesic and anti-inflammatory effects prevent the depolarization of peripheral C fibers by reducing action potential amplitude and slowing impulse conductivity velocity [155].

Several studies emphasize LLLT’s efficacy over placebo and alternative treatments such as clonazepam, particularly when lower treatment frequencies (1–2 times weekly) are employed over extended periods. In a recent systematic review and meta-analysis by Lu et al. [156], the authors analyzed 14 RCTs involving 550 patients. They found that LLLT significantly reduced burning pain when administered at frequencies of ≤2 times per week, with treatment durations longer than four weeks yielding better outcomes. While the effects on quality of life and negative emotions were positive but non-significant, LLLT was well tolerated without serious adverse effects and garnered high acceptance among BMS patients [156].

The positive biological effects and absence of severe adverse outcomes make LLLT a compelling option for managing BMS [157]. However, comparisons between studies are hindered by inconsistencies in irradiation parameters, such as power, fluence, exposure time, and continuous versus pulsed emission, and no standardized treatment protocol currently exists. Further research is needed to establish optimal parameters and determine overall efficacy [156].

5.3 Transcranial magnetic stimulation (TMS)

TMS techniques, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have shown promising results in managing BMS, especially when other treatments are ineffective [158, 159]. rTMS is a non-invasive brain stimulation technique that employs a coil to generate brief magnetic pulses, which penetrate the scalp and skull to induce electric currents in specific brain regions [160]. The treatment is typically administered daily over several weeks [159]. It is approved for treating MDD resistant to conventional treatments and is being explored for other neuropsychiatric conditions, such as anxiety disorders, OCD, and Post Traumatic Stress Disorder (PTSD) [161]. tDCS, on the other hand, is a non-invasive neuromodulation technique that applies weak direct electrical currents to the scalp via electrodes [162]. It aims to modulate cortical excitability by delivering anodal (excitatory) or cathodal (inhibitory) stimulation to specific brain regions [163]. Although not yet universally approved for clinical use, research indicates its potential for treating various neurological and psychiatric conditions, such as depression, chronic pain, and cognitive rehabilitation post-stroke [162].

A randomized controlled, single-blind study demonstrated that daily rTMS sessions over the left prefrontal cortex significantly reduced pain intensity in 20 BMS patients who received a total of 30,000 pulses at 10 Hz [159]. Approximately 75% of patients reported over 50% pain reduction following the treatment [158]. A pilot case study involving a 74-year-old female with BMS for two years showed that 10 tDCS sessions (using a combined protocol with anodal stimulation of the left dorsolateral prefrontal cortex) paired with exercise and cognitive training resulted in reduced pain perception and improved quality of life, with the benefits correlating with improved cognitive function, although pain relief was temporary [160].

TMS is generally well tolerated, although mild and transient adverse effects, such as headache, scalp discomfort, or fatigue, have been reported; rare but serious events like seizures are extremely uncommon and typically associated with predisposing conditions [160, 163]. TMS techniques offer viable alternatives especially in BMS patients resistant to conventional treatment for reducing pain intensity. Additional research efforts are needed to minimize bias, improve quality, and identify optimal brain stimulation parameters to enhance their efficacy.