What evidence-based treatments are recommended for peripheral neuropathy?
Executive summary
Evidence-based care for peripheral neuropathy focuses on treating the underlying cause where possible and using a stepped approach to symptom control: first-line oral pharmacotherapies (antidepressants and gabapentinoids), topical agents for focal pain, and device-based neuromodulation or specialized injections for refractory cases, with lifestyle and multidisciplinary measures running in parallel [1] [2] [3]. Newer or experimental modalities—spinal cord stimulation, regenerative injections, and novel small molecules—show promise but have variable evidence and access issues, so they remain adjuncts or options for selected patients [4] [5] [6].
1. First-line oral medications: antidepressants and gabapentinoids
Clinical guidelines and narrative reviews identify serotonin–norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine, tricyclic antidepressants like amitriptyline, and gabapentinoids (gabapentin, pregabalin) as primary pharmacologic treatments for neuropathic pain, supported by multiple trials and guideline recommendations [1] [2]. These agents aim to reduce pain severity via central and peripheral mechanisms, but real-world effectiveness is modest—fewer than half of patients achieve satisfactory relief—and tolerance, side effects, and comorbidity profiles guide selection [1].
2. Topical therapies for focal peripheral neuropathic pain
For localized neuropathic pain, high-concentration capsaicin 8% patches and lidocaine 5% plasters are recommended as second-line or sometimes first-line options in vulnerable patients because they have favorable safety and tolerability despite modest effect sizes; capsaicin 8% has the strongest certainty of evidence among topicals and may even show structural nerve fiber regeneration in some studies of diabetic neuropathy [3] [7]. Lower‑concentration capsaicin creams and topical lidocaine have weaker evidence but remain useful for focal symptoms and to minimize systemic drug exposure [3] [1].
3. Third-line pharmacologic and injection options
When first- and second-line therapies fail, clinicians may consider tramadol, certain NMDA‑antagonists, cannabinoids in limited settings, and botulinum toxin A injections—botulinum A has moderate-certainty evidence from small trials and a good safety profile for refractory focal neuropathic pain [1] [3]. Opioids are generally reserved as third-line due to risks and limited long-term benefit, and combination therapy or psychotherapy may be used as adjuncts where appropriate [1] [2].
4. Neuromodulation and procedural interventions
Procedural neuromodulation—spinal cord stimulation (SCS), peripheral nerve stimulation, and transcutaneous electrical nerve stimulation (TENS)—is supported for selected refractory cases; randomized and controlled studies of SCS (including high-frequency/10-kHz systems) have shown clinically meaningful pain reductions in painful diabetic peripheral neuropathy and have led to adoption and regulatory clearances in some settings [4] [6] [8]. Evidence quality varies by modality: SCS has the strongest trial data among devices, whereas evidence for scrambler therapy and some other non-invasive neuromodulation techniques is mixed and requires more robust trials [9] [10].
5. Regenerative and experimental therapies: promising but not yet standard
Regenerative approaches—platelet-rich plasma (PRP), mesenchymal stem cells, gene strategies, and new small molecules targeting chemokine receptors—are being investigated and have encouraging preclinical or small clinical signals, but current clinical evidence remains limited and heterogeneous, so these remain investigational or available in selected trials/centers rather than routine care [5] [6]. Likewise, emerging pharmacologic agents and neuromodulatory devices are entering trials and early approvals, but long-term effectiveness, comparative benefit, and access are still being established [11] [6].
6. Non-pharmacologic, lifestyle, and multidisciplinary care
Controlling causative factors (for example diabetes management in diabetic peripheral neuropathy) and integrating exercise, sensorimotor training, psychological support, and multidisciplinary pain programs are recommended adjuncts because they address function and quality of life even when analgesia is partial; some preventive neuromuscular training trials have reduced chemotherapy‑induced neuropathy incidence, illustrating the role of proactive non-pharmacologic strategies [7] [12] [10]. Nutraceuticals and supplements are advised only when a deficiency is documented, as evidence for most is insufficient to recommend routine use [7].
7. How to interpret the evidence and choose treatment
Treatment must be individualized: guideline-recommended first-line drugs remain the backbone of therapy but often provide partial relief, topicals are preferred for focal pain and vulnerable patients, neuromodulation is effective for refractory cases but requires specialist assessment and resource consideration, and regenerative or novel therapies are promising but not yet definitive—thus shared decision-making and referral to specialty centers or trials are appropriate when standard options fail [1] [3] [4].