Painful Diabetic Neuropathy: A Gift of God but Curse for Some!

INTRODUCTION Diabetic peripheral neuropathy affects approximately 50% of individuals with diabetes, often presenting with a range of distressing symptoms.[1] Positive symptoms include burning sensations, electric shock-like pain, stabbing or shooting pain, as well as deep, excruciating aches in the legs and feet. Negative symptoms may also occur, such as numbness, a sensation of walking on cotton, or an abnormal perception of the floor. Pain is a protective sensation, a “gift of God” that prevents tissue damage from recurrent trauma.[2] Unfortunately, it may be lost in few people with diabetes that contributes to foot ulcer and eventual lower extremity amputations.[3] On the other hand, patients with diabetes may have excruciating pain as a predominant symptom of peripheral neuropathy. Painful diabetic neuropathy (PDN) or diabetic peripheral neuropathic pain (DPNP) is characterized by positive symptoms, impacts around 10%–26% of people with diabetes and is frequently associated with heightened sensitivity to pain (hyperalgesia) and pain from nonpainful stimuli (allodynia).[4] DPNP condition significantly diminishes the quality of life, disrupting daily activities, social interactions, and sleep. Various treatment modalities have been explored, yielding mixed results. The assessment of treatment outcomes in such patients often relies on subjective measures, which are evaluated using standardized tools such as the numerical rating scale (NRS), McGill Pain Questionnaire, Pittsburgh Sleep Quality Index, Visual Analog Scale, and the RAND 36-Item Short-Form Survey (SF-36). HOW TO TREAT DIABETIC PERIPHERAL NEUROPATHIC PAIN? What should be considered a successful treatment for DPNP? A 50% reduction in the subjective pain assessed by above-mentioned tools suggests a significant treatment response, especially if it accompanies improvement in quality of life, quality of sleep.[5] The treatment approaches that have been explored to manage PDN focus on modulating neurotransmitter activity and various ion channels. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, enhances serotonin and norepinephrine levels at the synaptic cleft to modulate nociceptive signals and reduce pain transmission from peripheral nerves. Previous randomized controlled trials (RCTs) with duloxetine have shown a 50% reduction in the 24-h average pain score on an 11-point Likert scale after 12 weeks.[6,7] Amitriptyline, another antidepressant, also provides relief in DPNP by reducing the reuptake of serotonin and norepinephrine. Studies indicate significant pain improvement as early as the 2nd week of treatment. A head-to-head trial between amitriptyline and gabapentin over 12 weeks showed better pain reduction and tolerability with gabapentin.[8] Similarly, when compared to pregabalin, no significant difference in pain reduction was observed, as assessed by the Visual Analog Scale. In a comparison of amitriptyline with duloxetine, both drugs achieved similar pain reductions, but amitriptyline was more frequently associated with dry mouth.[9] Pregabalin is a Food and Drug Administration-approved medication for treating DPNP. Pregabalin acts on the α2 δ subunit of voltage-gated calcium channels in the central and peripheral nervous systems, reducing calcium influx into presynaptic nerve terminals and decreasing the release of excitatory neurotransmitters such as glutamate and substance P. Pregabalin also exerts central effects by modulating the pain pathway, resulting in a central desensitization effect. A randomized, double-blind, placebo-controlled study demonstrated its efficacy in doses of 300 mg/day, resulting in 46% of patients achieving >30% pain reduction and 50% reduction in pain scores.[10] Increasing the dose to 600 mg/day improved its efficacy, with greater pain reduction in 54% of patients.[10] The reduction in pain is associated with significant improvements in quality of life and functionality. Gabapentin, a widely used drug structurally related to ɤ-aminobutyric acid (GABA), modulates pain by altering GABA synthesis, interacting with the L-amino acid transporter, and inhibiting voltage-activated sodium channels. Clinical trials have shown significantly reduced daily pain scores and improved quality of life (e.g. SF-36 questionnaire) compared to placebo.[11] Extended-release formulations have also demonstrated notable pain reductions with once daily dosing regimens. Opioid analgesics have been employed in the management of PDN, although their effectiveness remains controversial. Oxycodone has shown variable results, and a recent Cochrane review concluded that there is insufficient evidence to support its superior efficacy in treating painful neuropathy.[12] In contrast, tapentadol, a dual-acting µ-opioid receptor agonist and norepinephrine reuptake inhibitor, has demonstrated more promising outcomes. A 12-week trial with tapentadol reported a significant reduction in pain intensity (mean change: −2.3 vs. −1.3 on a 10-point scale) and notable improvements in sleep quality and functional ability.[12] In addition, over 50% of patients experienced a >30% reduction in pain intensity, highlighting the potential of tapentadol in managing effective management of DPNP.[13] COMBINING PHARMACOTHERAPY FOR PAINFUL DIABETIC NEUROPATHY Often, patients do not have a significant response to a single drug, where a combination of drugs acting on two different pathways for pain relief seems a plausible treatment option. Two randomized trials evaluating combination therapy need mention, i.e. OPTION-DM and COMBO-DN trials that explored the effectiveness of combination therapy versus monotherapy in managing DPNP. The OPTION-DM trial was a multicenter, double-blind, randomized crossover study that assessed three treatment pathways, namely amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P). Each pathway involved 6 weeks of monotherapy, followed by 10 weeks of combination therapy for patients with suboptimal pain relief (NRS >3). Monotherapy resulted in an average pain reduction of 2.5–2.9 points on the NRS, with around 37% of patients achieving mild pain (NRS <3). For patients transitioning to combination therapy, there was an additional reduction of ~1 point, with 47%–50% achieving mild pain (NRS <3) and more achieving significant pain reduction (≥50%). Combination therapy showed better responder rates (≥30% or ≥50% reduction in pain) than monotherapy for nonresponders. However, adverse effects were more frequent with combination therapy due to higher drug exposure, including dizziness (pregabalin), nausea (duloxetine), and dry mouth (amitriptyline), though it was generally well tolerated.[14] The COMBO-DN trial, a multinational, double-blind, randomized parallel-group study, evaluated monotherapy with duloxetine (60 mg/day) or pregabalin (300 mg/day) and transitioned nonresponders to either combination therapy (60 mg/day duloxetine + 300 mg/day pregabalin) or high-dose monotherapy (120 mg duloxetine or 600 mg pregabalin). Both high-dose monotherapy and combination therapy provided similar pain control in patients not responding to the standard doses of monotherapy as measured by changes in the Brief Pain Inventory-Modified Short Form 24-h average pain scores.[15] Standard-dose combination therapy was not found to be superior to high-dose monotherapy for pain control. Hence, if the patient tolerates a monotherapy than increasing dosage of the same medication to tolerable limits is a better option than the dual combination therapy as combination therapy is also which difficult to titrate, in case of adverse events. Topical preparations have also been utilized for treating painful neuropathy, including capsaicin creams (0.025%–0.075%), capsaicin 8% patches, lidocaine patches, pregabalin, clonidine, amitriptyline, and ketamine cream. Capsaicin is best studied of all which act by binding to the transient receptor potential vanilloid 1 receptor. Capsaicin causes initial burning, but prolonged activation of the receptor depletes associated neurotransmitters and dampens the ability of neurons to transmit pain signals. Two RCTs, namely STEP[16] and PACE trials,[17] confirmed the efficacy of capsaicin 8% for pain relief in addition to improving the quality of life. A recent meta-analysis found comparable efficacy of topical capsaicin to oral agents such as pregabalin and duloxetine.[18] Localized pain relief has also been shown with lidocaine patches applied near to the site of the pain.[19] Limited studies with other topical agents have suggested the usefulness of topical agents for pain relief in diabetic neuropathy with limited systemic side effects. Among nonpharmacological approaches, transcutaneous electrical nerve stimulation and spinal cord stimulation have shown significant pain reduction compared to sham therapy in patient’s refractory to medical therapy. However, long-term adherence is limited due to variable efficacy and patient preferences. Another promising modality is monochromatic infrared energy (MIRE), which works by reversing the loss of small nerve fibers in the epidermis. MIRE therapy increases intraepidermal nerve fiber density, improving nerve function and reducing pain perception as demonstrated in a 12-week trial with a 56.7% decrease in pain scores (Visual Analog Scale) and significant improvements in the Norfolk Quality of Life-Diabetic Neuropathy scores, alongside increased intraepidermal nerve fiber density.[20] Many novel agents targeting various pathways of pain have been studied in animal models with limited efficacy.[21] CONCLUSION PDN significantly impacts the quality of life for patients, presenting with distressing symptoms such as burning, shooting pain, and allodynia. Despite its prevalence, achieving optimal management remains challenging due to variable responses to treatment and subjective assessment methods. Pharmacological interventions such as duloxetine, pregabalin, amitriptyline, and gabapentin have demonstrated efficacy in reducing pain, but initial choice of therapy requires an individualized approach. Combination pharmacological therapy has shown enhanced pain relief for patients with inadequate response to monotherapy, although with an increased risk of adverse events. Topical agents (capsaicin and lidocaine patches) and nonpharmacological approaches may be utilized in the treatment for refractory cases. The integration of personalized medicine incorporating patient preferences with careful monitoring for side effects is crucial to improving outcomes and quality of life in individuals with PDN. Further research into novel therapies and combination strategies is essential to optimize treatment pathways.

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