One of the main causes of neuropathy, diabetes affects 382 million people globally [1], according to the International Diabetes Federation [2].  Over 90% of patients have distal symmetrical polyneuropathy (DSPN), the most prevalent clinical manifestation of diabetic neuropathy [3].  DSPN typically affects the distal foot and toes, but it gradually moves proximally to include the legs and feet in a stocking distribution.  Diabetic retinopathy and nephropathy may result from its progressive loss of nerve fibers, which affects both the autonomic and somatic divisions [3].  The primary clinical outcomes of DSPN, which are associated with increased morbidity and death, are severe neuropathy and foot ulceration [4]. Pain, which affects 10% to 26% of this population [6, 7], is often the only reason patients seek medical attention [5].

 One of the most prevalent side effects of diabetes mellitus (DM) is diabetic peripheral neuropathy (DPN).  After ruling out other potential causes, it involves peripheral neuropathy symptoms and signs in diabetic patients; it affects around 50% of diabetic people at some point in their lives [8, 9].  Depending on the type of diabetes, duration, and population under study, the prevalence of DPN varies in the literature (6–51%) [10]. A recent investigation indicated that the total prevalence was approximately 40.3% [11]. About 16% of diabetic individuals have painful diabetic neuropathy [12], and 10–30% of those with the disease also have neuropathic pain symptoms [10]. This usually impacts the patient's sleep and quality of life and is often unreported or mistreated.  Patients typically report deep-seated aches, burning sensations, or lancinating symptoms that primarily affect the lower extremities [13].

Numerous symptomatic medications, such as opioids, antidepressants, and anticonvulsants, are used to relieve pain.  Sometimes, though, these drugs don't work, or the patients can't handle the side effects or greater dosages.  This made it necessary to test an alternative that might have fewer adverse effects and a longer-lasting effect [14].  Promising outcomes were shown in earlier studies using botulinum toxin to treat diabetic neuropathy [13–15].  For many years, botulinum toxin (BoNT) has been used to treat dystonia and spasticity.  In addition to its muscle relaxant properties, it has been used to reduce pain in a variety of neuropathic pain conditions, including post-herpetic neuralgia, carpal tunnel syndrome (CTS), and trigeminal neuralgia [16]. It is believed to have an analgesic effect by inhibiting the release of neurotransmitters and inflammatory mediators from sensory nerves, including substance P, glutamate, glycine, serotonin, and CGRP, among many others [16].

RISK FACTOR MANAGEMENT

The effectiveness of an intense lifestyle intervention aimed at weight loss in reducing metabolic risk factors for DPN has been investigated.  The Michigan Neuropathy Screening Instrument (MNSI) questionnaire score significantly decreased in the Look Action for Health in Diabetes (AHEAD) trial in conjunction with weight loss; however, there was no significant difference in the MNSI physical examination score [17].  Bariatric surgery reduced diabetes-related foot disease (adjusted hazard ratio of 0.61), according to a database of primary care electronic records from the United Kingdom [18]. However, more information is still required, including standard ways to assess DPN.  Additionally, there is some evidence that exercise may enhance nerve function [19] and the density of intraepidermal nerve fibers [20]. To sum up, multifactorial risk management of DPN may help DPN, but large-scale treatments with DPN as the main outcome are still required to evaluate their effectiveness.

TREATMENT OF DNP

Since its mechanism is still unclear and its pain alleviation is still insufficient, DNP remains a therapeutic challenge.  Except for those that target glycemic control, pharmacological therapies are symptomatic, lack a focus on pathophysiological mechanisms, and are constrained by tolerance development and side effects [21].  In randomized controlled trials, a wide range of medications, either by themselves or in combination, have been demonstrated to considerably reduce neuropathic pain when compared to a placebo; yet, most patients still do not have appropriate pain relief [22]. In clinical trials, a treatment is generally deemed successful if patients have a 50% reduction in pain [23–25] along with some other positive benefits on quality of life, sleep, exhaustion, and depression [25]. Therefore, treating this illness essentially entails ruling out alternative causes of painful peripheral neuropathy, enhancing glycemic control as a preventative measure, and taking painkillers [26].

The main therapeutic pathway is pharmacologically based, even with multimodal and multidisciplinary treatments [27].  In the US, three distinct medications—pregabalin, duloxetine, and tapentadol—have received regulatory approval for the treatment of DNP [28].

Anticonvulsants

The Food and Drug Administration (FDA) approved pregabalin as the first anticonvulsant to treat neuropathic pain following spinal cord injury [31], DNP [29, 30], and postherpetic neuralgia.  Pregabalin is a GABA analogue that inhibits the release of excitatory neurotransmitters by selectively binding to pre-synaptic voltage-gated calcium channels in the brain and spinal cord that contain the α2δ subunit [32].  Furthermore, as a result of enhanced trafficking, α2δ1 subunits are in charge of boosting these channels' functional expression.  Therefore, it is also suggested that pregabalin's analgesic effect results from reduced α2δ1 subunit trafficking, which in turn leads to decreased production of functional calcium channels [33]. Pregabalin was found to be effective in treating DNP in a number of clinical trials [34, 35], with a number needed to treat (NNT) of 6.3 [25].

Not only does pregabalin have analgesic benefits, but it also has anxiolytic activity [32,35] and improves sleep and quality of life [32], all of which help patients' overall health.  Weight gain, headaches, peripheral edema, dizziness, and somnolence are some of the adverse effects.  Gabapentin has also been suggested by several guidelines as a treatment for DNP [36].  The only other anticonvulsant medication that has shown effectiveness in treating this disease, aside from pregabalin, is gabapentin [28], which has an NNT of 5.8 [37]. The mechanisms of action of pregabalin and gabapentin are similar, and the former is approved for neuropathic pain in the UK but not in the US [28].  According to certain clinical investigations, gabapentin and pregabalin are more effective at relieving pain than opioids or tricyclic antidepressants [38]. These medications' tolerance and lack of severe toxicity are other significant features [39].

Antidepressants

The first-line medications for managing DNP are antidepressants.  In the US, duloxetine, a serotonin and norepinephrine reuptake inhibitor, is authorized to treat this illness and has an efficacy rating of level A.  Furthermore, certain clinical studies have demonstrated duloxetine's efficacy in treating various chronic pain disorders, including fibromyalgia and chronic musculoskeletal pain [40, 41].

A meta-analysis of randomized, double-blind, placebo-controlled studies in DNP patients revealed that duloxetine was more effective than a placebo in reducing pain severity and improving patient perceptions of improvement or change. Its efficacy was comparable to that of gabapentin and pregabalin [42].  Furthermore, duloxetine was able to lower the pain score to levels comparable to those attained with pregabalin in a 2-week open-label randomized trial in diabetic patients who were not responding well to gabapentin [43, 44].  Additionally, duloxetine's analgesic efficacy in treating DNP is sustained for six months [45], highlighting the medication's significance as a therapy choice for this illness. In DNP patients, the NNT for duloxetine ranges from 1.3 to 5.1 [46, 47], and the most common adverse effects are nausea, somnolence, and dizziness [46].

As a selective inhibitor of serotonin and noradrenaline reuptake, venlafaxine primarily blocks the reuptake of serotonin at low dosages and noradrenaline at higher dosages [48].  Additionally, venlafaxine was demonstrated to be useful in lowering the severity of pain in diabetic neuropathy patients [49], with an NNT ranging from 2.2 to 5.1 and a number needed to harm (NNH) of 9.6 for minor side effects and 16.2 for serious side effects [50].

Another option for treating DNP is to use tricyclic antidepressants [51].  A direct meta-analysis research [52] found amitriptyline to be just as effective as gabapentin, while a randomized, double-blind, crossover experiment [53] found it to be just as effective as duloxetine.  Similarly, a double-blind crossover experiment that included diabetic patients found that nortriptyline was just as successful as gabapentin at reducing neuropathic pain [54].  According to DNP estimates, tricyclic antidepressants have an NNT of 1.3 [55] and a NNH ranging from 4.2 to 10.7 [51].  Dry mouth, postural hypotension, arrhythmias, cognitive impairment, constipation, and urine retention are the most prevalent adverse effects associated with the use of these medications, and they are more commonly seen following amitriptyline treatment than nortriptyline administration [55].

Opioids

For DNP, opioids are advised as a second or third line of treatment [51].  Tramadol has been shown in a multicenter, randomized, placebo-controlled research to be helpful in improving physical and social functional evaluations in patients with DNP, despite certain adverse effects, including headache, nausea, constipation, and somnolence [56].

 Additionally, morphine has been demonstrated to be useful in lowering the average daily pain scores associated with postherpetic neuralgia and diabetic neuropathy [57].  Furthermore, oxycodone medication significantly reduced pain intensity and improved quality of life for diabetic neuropathy patients, according to clinical study data, as compared to the placebo-exposed group [58, 59].  Additionally, oxycodone increased gabapentin's efficacy in producing DNP alleviation, but not pregabalin's [60, 61]. Preclinical results that have documented the efficacy of morphine [62, 63] and buprenorphine [64] in lowering mechanical or heat hypersensitivity in DNP animal models support the clinical evidence for the usefulness of opioids in the management of DNP.

Additionally, there is evidence that the anti-hyperalgesic impact of opioids is enhanced by their conjunction with some medications, including reboxetine, moclobemide, and amitriptyline, which are antidepressants [65].  Accordingly, in animal models of DNP, new compounds that incorporate other mechanisms to the opioid receptor agonism have been demonstrated to be effective in lowering nociceptive behavior. Examples of these include cebranopadol, an opioid receptor agonist and nociceptin/orphanin FQ peptide [66], and tapentadol, a muopioid receptor agonist and norepinephrine reuptake inhibitor [67]. Since 2012, the FDA has authorized the latter for the treatment of DNP.  With a manageable safety profile, tapentadol has demonstrated efficacy in treating a variety of chronic pain conditions, such as arthritic knee pain, low back pain, and DNP [68, 69].  Regarding DNP specifically, a randomized-withdrawal, placebo-controlled study found that around 50% of patients who took tapentadol saw a decrease in pain intensity of at least 30% [70].  Recent clinical trials in diabetic neuropathy patients with moderate to severe pain yielded similar results, with side effects included nausea (21.1%) and vomiting (12.7%)  [71].

Others agents

In order to improve pain relief in DNP situations, the medications included below are currently linked to pharmacological treatments that have already been detailed based on the needs and symptoms of the patients.  Nevertheless, more research and carefully monitored clinical trials are required to identify the safer, more effective, and more effective combinations to use in the treatment of DNP [28].

Capsaicin topical cream:

Compared to systemic medicines, topical treatments may have fewer and less clinically relevant side effects [72].  Additionally, the use of local treatments significantly lowers the likelihood of drug interactions, making them suitable choices for individuals with a variety of medical issues [28].  The capsaicin cream is authorized for the topical treatment of neuropathic pain [28] and has demonstrated efficacy in the treatment of neuropathic diseases [50].  Hot chilli peppers include capsaicin, which is a strong agonist of the transient receptor potential vanilloid 1. This receptor is a ligand-gated, nonselective cation channel that is mostly expressed on unmyelinated C nerve fibers [73]. These fibers lose substance P and other neurotransmitter content after being exposed to topical capsaicin repeatedly [73, 74].  Depletion and desensitization of C fibers lessen the transmission of painful impulses from peripheral nerves to the central nervous system [73].

Low-concentration (between 0.025% and 0.075%) capsaicin cream has been shown to be useful in DNP in certain clinical trials [74, 75].  Because desensitization of nociceptive sensory nerve endings may raise the risk of skin injury in DNP patients, higher dosages are not recommended [73, 74].  Many patients discontinue treatment as a result of side effects, which include itching, stinging, erythema, a brief burning sensation, and initial pain at the application site that goes away with repeated use [75, 73].

Lidocaine patch

Lidocaine patches are used in conjunction with other analgesic medications and function as peripheral analgesics with little systemic absorption [72].  Lidocaine inhibits sodium channels and reduces peripheral nociceptors' hyperexcitability, which is a factor in neuropathic pain [76].  The inhibition increases the discharge threshold of peripheral sensory neurons and decreases ectopic discharges [76].  Topical lidocaine's benefits on pain reduction appear to be equivalent to those of other medications, such capsaicin, gabapentin, amitriptyline [72], and pregabalin [72,74], according to the few DNP clinical trials that compared it with other pertinent therapies.  Itching, contact dermatitis, and local irritation [72] are examples of adverse effects [32].

Alpha lipoic acid:

Alpha lipoic acid (ALA) may be beneficial in the treatment of diabetic neuropathy (DNP) since it directly affects the neuropathy by lowering oxidative stress, which has been identified as a significant contributing element to the physiopathology of DNP [22].  Its anti-inflammatory and antioxidant properties may help to reduce diabetic neuropathy symptoms overall [35].  Pain was not the main outcome of certain clinical trials that assessed the impact of ALA in diabetic individuals.  But in terms of reducing pain, they have demonstrated a moderate benefit [32]. Patients receiving ALA reported a higher decrease in neuropathic pain than those receiving a placebo in a randomized double-blind study [22].  ALA has less adverse effects than a number of medications now used to treat DNP, with nausea and vomiting being the most frequent [32].

Isosorbide dinitrate spray:

Both veins and arteries can be affected by isosorbide dinitrate, a nitric oxide-dependent vasodilator [77].  Increased nitric oxide production may improve microvascular blood flow, which in turn may alleviate discomfort and burning sensations [78].  About 50% of patients in a clinical trial with diabetics indicated that the isosorbide dinitrate spray improved their overall neuropathic pain and burning sensation. These patients also reported improvements in their mood, mobility, and sleep quality [79].

GUIDELINES FOR MANAGING PAINFUL DIABETIC PERIPHERAL NEUROPATHY (DPN)

As advised by numerous professional practice recommendations and expert evaluations, managing painful DPN include managing the underlying diabetes disease and treating the related pain symptomatically. [80-82]

• In December 2021, the American Academy of Neurology (AAN) released the Oral and Topical Treatment of Painful Diabetic Neuropathy: Practice Guideline article.  Revise  Updated guidelines for treating painful DPN are included in the summary.  The results of 133 pertinent peer-reviewed randomized controlled trials (RCTs) were systematically and statistically analyzed to produce graded recommendations for the usage of various medication classes and individual medicines [83].
• o American Diabetes Association (ADA): The ADA has three publications that offer guidance on how to treat painful DPN.  Based on many technical studies and related supporting references, Diabetic Neuropathy: A Position Statement, which was released in 2017, offers graded recommendations on all facets of DPN care, including prevention, diagnosis, and treatment [84].  Standards of Medical Care in Diabetes 2022 and the Clinical Compendium on the Diagnosis and Treatment of Painful Diabetic Peripheral Neuropathy were released in 2022 [85-87]. In addition to summarizing the most recent recommendations on efficacious treatments, such as pharmaceutical agents, nutraceutical products, and non-pharmacological therapies, the clinical compendium concentrates on the screening, diagnosis, and treatment of painful DPN in routine clinical practice [85].  Chapter 12: Retinopathy, Neuropathy, and Foot Care [87] of the revised Standard of Medical Care in Diabetes ‒2022 also offer advice on how to treat uncomfortable DPN [86].
• The AACE stands for American Association of Clinical Endocrinology.  Based on a thorough search and evaluation of the most recent research, the AACE Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan‒2022 Update, which was published in 2022, offers graded recommendations for the treatment of diabetic patients, including the diagnosis and management of DPN.

FDA-APPROVED TREATMENTS FOR PAINFUL DPN

Based on their effectiveness and safety in RCTs in this patient population, the FDA presently approves five therapies to treat painful DPN.  These consist of one topical agent (capsaicin 8% topical system), three oral medications (duloxetine, pregabalin, and tapentadol extended release [ER]), and low- and high-frequency spinal cord stimulation (SCS) devices designed to treat chronic intractable painful DPN, which is characterized as persistent moderate to severe pain that has no known cure and necessitates daily medical care.

Spinal Cord Stimulation (SCS) for Intractable Painful DPN

In SCS therapy, wire leads are inserted into the spinal canal's epidural area, and an internal pulse generator device is implanted in the superficial tissue, typically the buttock or back [88,89].  For many years, SCS has been used to treat unmanageable limb and torso pain. It involves modest outpatient surgery.  Its indications were only recently expanded to include use in uncomfortable DPN.  Low-frequency (40–100 Hz) SCS is used by conventional tonic SCS devices to create paresthesia in anatomical areas that cause pain.  It is believed that high-frequency (10 kHz) SCS regulates chronic pain pathways by altering axonal activity in the superficial dorsal horn, resulting in little or no paresthesia [90].

Evidence for the Efficacy of SCS in Refractory Painful DPN

Three open-label multicenter RCTs of low-frequency or high-frequency SCS were used to support the FDA's approval of the Medtronic and Nevro SCS devices [91–93].  Patients had to have painful DPN that was unresponsive to standard pharmacological therapy for at least a year in order to be eligible for recruitment in these RCTs [91–93].  For six months, patients were randomly assigned to receive either best/conventional medical management (CMM) in addition to open-label SCS treatment or CMM alone.  For five to seven days, patients in the SCS plus CMM group received temporary trial stimulation; those who experienced a pain reduction of at least fifty percent qualified for device placement. A Medtronic investigation found that adjusted ≥50% response rates for low-frequency and high-frequency SCS were comparable (55% vs. 55%) [93, 94]. Results from a recent network meta-analysis of SCS RCTs for painful DPN [95] corroborate the findings.  Furthermore, SCS is a useful therapeutic adjuvant to the best medical therapy for lowering pain intensity and enhancing HR-QoL in patients with painful DPN, according to a systematic review and meta-analysis of individual patient and aggregate data [96].

Low-Frequency SCS

93% of the low-frequency SCS with CMM group experienced successful trial stimulation (i.e., ≥50% pain reduction) in the two clinical trials of low-frequency SCS for intractable painful DPN, which had a total sample size of 60 [91].  In addition to improvements in other pain and HR-QoL outcomes, this group's mean visual analog score (VAS) scores at 6 months decreased significantly (from 7.3 cm at baseline to 3.1 cm at 6 months; p < 0.001).  The CMM group, on the other hand, saw no gains in any of the outcomes.  Patients in the low-frequency SCS plus CMM group experienced ≥50% pain alleviation at a much higher rate than those in the CMM group (60% vs. 5%; p < 0.001).  Adverse occurrences did not necessitate the removal of any patients' devices.

High-Frequency SCS

Based on the findings of an open-label 6-month RCT with an optional crossover at 6 months, the high-frequency Nevro 10-kHz SCS device was approved to treat chronic retractable DPN [93].  Patients with refractory painful DPN were randomly assigned to either CMM alone (n = 103) or 10-kHz SCS plus CMM (n = 113).  Temporary trial stimulation was administered to 104 participants in the 10-kHz SCS plus CMM group.  Ninety of the 98 patients (94%), who had this procedure, chose to have the device implanted permanently.

Capsaicin 8% Topical System

The transient receptor potential vanilloid-1 (TRPV1) receptor is an ion channel-receptor complex that is expressed on nociceptive nerve fibers in the skin. Capsaicin is a highly selective agonist for this receptor.  For their separate ground-breaking discoveries of temperature receptors (TRPV1 receptors) and touch receptors (Piezo2 ion channels), Drs. David Julius and Ardem Patapoutian shared the 2021 Nobel prize in Physiology or Medicine [97].  The significance of the TRPV1 receptor in pain perception was recognized after its discovery.  TRPV1 receptors are up-regulated on neurons, have lower thresholds for activation, and heighten pain perception in chronic pain conditions.  Pain, burning, itching, stinging, and other physiological reactions are brought on by the activation of TRPV1 receptors.

OTHER GUIDELINE-SUPPORTED FIRST-LINE ORAL OPTIONS

In clinical practice, TCAs, gabapentinoids, SNRIs, and sodium channel blockers are recommended first-line oral alternatives for treating uncomfortable DPN because they are thought to modulate pain [98].

FUTURE RESEARCH IN PAINFUL DPN

The need to better understand the relationship between the severity of diabetes and its effects on painful DPN, as well as the cardiometabolic risk factors for painful DPN and their association with cardiovascular mortality, is at the core of research on painful DPN.  To elucidate the illness pathways that distinguish painful from non-painful DPN, genetic research is required.  Research into diagnostic tests employing novel biomarkers, though more work is needed in this area, and evaluation of more effective medicines for symptom management and eventually disease modification have matched the growing attention on the patient.

BOTULINUM NEUROTOXIN (BONT)

Derived from Clostridium botulinum, botulinum neurotoxin (BoNT) has been utilized globally to treat neurologic conditions like spasticity and dystonia in addition to cosmetic therapeutic uses [99, 100].  In the US, the Food and Drug Administration (FDA) has authorized it as a treatment for upper limb spasticity, hemifacial spasm, blepharospasm, strabismus, and focal dystonia [101].

Its primary mechanism is the suppression of acetylcholine (Ach) neurotransmitter release at presynaptic nerve terminals, which lowers muscle fiber activity [103]. BoNT contains seven antigenically distinct serotypes (A–G) [102].  By endocytosing into the presynaptic membranes of neuromuscular junctions and cleaving proteins necessary for Ach exocytosis, BoNT prevents Ach from being exocytosed from cholinergic nerve terminals [104].  The docking of Ach-containing vesicles to presynaptic membranes depends on these proteins.  Ach cannot be released into the synaptic cleft without this docking, which may paralyze the innervated tissue. By attaching a light chain, an active component of the toxin, each serotype of BoNT functions as a protease that selectively targets soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins [105].  To mediate the fusion of synaptic vesicles (SVs), the SNARE proteins must form a core with the plasma membrane.  The vesicle-associated membrane protein (VAMP)/synaptobrevin, target membrane proteins, syntaxin, and synaptosomal-associated protein of 25 kDa (SNAP-25) are examples of SNARE proteins.  SNAP-25 is cleaved at two distinct locations by BoNT/E and BoNT/A, the most well-known toxin.  While BoNT/C cleaves both syntaxin and SNAP-25, BoNT/B, /D, /F, and /G cleave VAMP/synaptobrevin at distinct locations [105].

In addition to preventing Ach release, BoNT, especially BoNT/A, has been proposed to suppress the expression of transient receptor potential vanilloid 1 (TRPV1) and the release of local nociceptive neuropeptides, including substance P, calcitonin gene related peptide (CGRP), and glutamate [106–109]. BoNT/A may prevent peripheral sensitization and neurogenic inflammation in this way.  In vivo studies that indicate BoNT may be a viable pain medication have been produced as a result of the various mechanisms of the various BoNTs being discovered. 

Furthermore, after examining its effectiveness in lowering the frequency and severity of chronic migraines, the FDA authorized Botox® for the treatment of chronic migraines in 2010 [110, 111]. The only preventive medication that has been licensed and has a peripheral use is BoNT/A [112].  This work showed that BoNT/A preferentially inhibits C- but not Aδ menigeal nociceptors, and it also impairs SNARE-mediated synaptic vesicle fusing to nerve terminals.  During extracranial administration, BoNT prevented mechanical transduction in the meningeal nociceptors' suture branches.  According to Burstein et al. [112], when BoNT/A is used prophylactically for migraines, it inhibits the fusion of high-threshold mechanosensitive ion channels into the nerve terminal membrane and decreases the expression of these channels on the neuronal surface.

BOTULINUM TOXIN FOR DIABETIC NEUROPATHIC PAIN

BoNT was utilized in two double-blind, randomized, placebo-controlled trials to manage diabetic neuropathy (DN) discomfort.  Yuan et al. found that when 4 U of BoNT-A per site (50 U) was applied to the dorsum of the foot in a trial of 20 DN patients, 44% of patients saw a noticeable three-month decrease in VAS and an improvement in sleep quality [113].  In a research akin to the one described above, Ghasemi et al. administered 8–10 U of BoNT per location to 40 DN patients.  That investigation found a decline in Douleur Neuropathique 4 (DN4) and neuropathic pain score (NPS) levels [114].  According to a meta-analysis of these two papers, DN significantly correlates BoNT with pain alleviation [115]. The above studies are described in Table 1.

Table 1: Botulinum toxin for diabetic neuropathy

In animal models of local pain, local accumulation of pain neurotransmitters such glutamate and calcitonin gene-related peptides can be prevented and pain can be alleviated by injecting botulinum toxin A or B into the skin of the painful location [116].  The presence of target proteins for botulinum toxins A and B in spinal cord sensory neurons following peripheral injection clearly implies an independent central mechanism in addition to the peripheral mechanism [117].  In 2010, the US and Europe licensed onabotulinumtoxin A (Botox) for the treatment of chronic migraine.  Numerous clinical studies conducted in recent years have strongly suggested that botulinum toxins are effective in treating a range of pain conditions [116]. Table 2 and 3 detailing regarding further related studies.

Table 2: Published study on BoNT treatment of painful diabetic neuropathy.

Table 3: Studies on botulinum toxin for Diabetes neuropathic pain

Additionally, a different study by Chen and Yuan et al. raised the prospect that BoNT/A injection could enhance tactile and mechanical pain perception in diabetic polyneuropathy patients [121].  Patients with diabetes participated in a randomized, double-blind, placebo-controlled clinical trial in 2014 [121].  The Douleur Neuropathique 4 (DN4) questionnaire and nerve conduction investigations were used to diagnose diabetic neuropathy in the participants in this class I study.  They had neuropathic pain in their feet and were younger than 70.  Forty patients were divided into two groups at random: the BoNT/A group and the placebo group.  Each patient in the intervention group received an injection of 100 units of BoNT/A, whereas the remaining 20 patients received injections of normal saline. The neuropathy pain scale (NPS) scores of the patients decreased for all items except cold feeling following the BoNT/A injections (p < 0.01).  Electric shocks, pins and needles, burning, and brushing were associated with lower DN4 scores (p < 0.05).  The class I and class II studies mentioned above [120] suggest that BoNT is probably a useful treatment for diabetic neuropathy.

More recent research has examined the analgesic effects of BTX-A in DPN in both human and animal populations [124]. The benefits of administering BTX-A for the aforementioned purpose include its effectiveness, long-lasting analgesic effects, good tolerance, and low side effects. [125] Nearly all of the research that has been done so far has confirmed the effectiveness of BTX-A administration in treating DPN, despite the fact that there are still few trials on the subject. Although the precise analgesic impact of BTX-A has not yet been established, it is thought to be useful due to the blocking of presynaptic nerve terminals that release acetylcholine. [126] According to Ranoux et al., BTX-A may have an analgesic effect because of its local peripheral action on nociceptive fibers [124].

The effects of BTX-A on the DN model in rats have been demonstrated by several experimental investigations.  In a rat model of DPN pain, Bach-Rojecky et al. in Croatia examined the antinociceptive properties of BTX-A.  Their findings showed that a unilateral BTX-A injection reduced bilateral discomfort for up to four weeks. [127] In France, Ranoux et al. investigated the analgesic effects of BTX-A administered intradermally once on DPN pain in 29 individuals with diabetes.  At baseline, four, twelve-, and twenty-four-weeks following injection, the results were reported.  They showed that between two- and fourteen-weeks following injection, BTX-A significantly reduced the severity of DPN pain. For the first time, they came to the conclusion that BTX-A had an analgesic impact on DPN pain regardless of how it affects muscle tone.  Thus, persistent discomfort associated with DPN is being explored as a new indication for intradermal BTX-A injection [124]. According to a different recent study conducted in France by Ranoux, patients with DPN can have long-lasting analgesic effects with a single intradermal BTX-A injection session.  The outcomes were consistent with a decrease in peripheral sensitivity [125].

Because of its good safety profile and long-lasting therapeutic effects following a single course of injection, botulinum toxin type A offers therapeutic utility in treating idiopathic trigeminal neuralgia or refractory neuropathic pain.  Patients with preserved heat sensitivity in the pain location and/or induced deep pain with pain paroxysms appear to have the best responder profiles to botulinum toxin A. Because DPN lowers quality of life and might negatively impact a diabetic patient's employment, it is imperative that DPN be treated appropriately.  DPN is treated with medications such topical capsaicin, sodium channel blockers, alpha-lipoic acid, TCAs, gabapentinoids, and SNRIs.  However, some people do not respond well to these medications, and their adverse effects might make them difficult to use. Early post-treatment reevaluation is crucial since pain alleviation and side effects typically manifest early.

Since these medications don't help patients with painless DPN, they shouldn't be used to treat it.  Combination therapy, 8% capsaicin patch, or SCS is the most effective therapeutic method for uncontrolled painful DPN that does not improve with monotherapy.  Since there are currently no medications that address the pathophysiology of DPN, new medications are required to treat DPN-related pain.

A common and incapacitating consequence of diabetes, painful DPN has a detrimental effect on patient function and HR-QoL and is linked to high rates of morbidity, death, and medical expenses.  Painful DPN can be treated using a range of pharmaceutical and non-pharmacological approaches, which can be integrated as part of a customized, all-encompassing pain management strategy.  Healthcare professionals are urged to become more knowledgeable about the options that are accessible and to integrate a thorough comprehension of the clinical data supporting their effectiveness.  Research on painful DPN has accelerated in response to the requirements of this rapidly expanding subset of the diabetic community.  Various noninvasive electrical stimulation devices and medications with unique modes of action are being evaluated in numerous research.

BoNT is increasingly being utilized to treat neuropathic pain.  In accordance with the American Academy of Neurology's recommendations, we evaluated the degree of evidence from clinical and experimental trials to look into the antinociceptive effects of BoNT.  Our evaluations indicate that recent research indicates that BoNT injection is a useful treatment for postherpetic neuralgia and is probably also good for treating post-traumatic neuralgia and trigeminal neuralgia. Diabetic neuropathy may benefit from the use of BoNT.  Its effectiveness in treating complex regional pain syndrome and occipital neuralgia has not been established.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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