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See Peripheral Polyneuropathy Part 1: Evaluation and Differential Diagnosis

Essentials of Assessment

See Peripheral Polyneuropathy Part 1: Evaluation and Differential Diagnosis

Rehabilitation Management and Treatments

Available or current treatment guidelines

Pharmacologic treatment of peripheral neuropathy hinges upon treating the underlying etiology, when known. Treatment of reversible causes during the acute stage may aid axonal regeneration and remyelination. Immunotherapy for immune-mediated polyneuropathy is beyond the scope of this review and will not be covered.

In subacute and chronic cases, palliative care becomes the primary goal of treatment, focusing on symptomatic control.

Medications with labeled indications for neuropathic pain in the Unites States are limited to:

  • carbamazepine (trigeminal neuralgia)
  • lidocaine 5% patch, capsaicin 8% patch (postherpetic neuralgia)
  • pregabalin (diabetic peripheral neuropathic pain (DPNP), postherpetic neuralgia, neuropathic pain due to spinal cord injury)
  • duloxetine (DPNP)
  • gabapentin (postherpetic neuralgia) – including extended formulation and combination gabapentin enacarbil
  • tapentadol extended-release (ER) – neuropathic pain associated with diabetic peripheral neuropathy


Longevity of use has afforded tricyclic antidepressants (TCAs) an abundance of studies showing treatment efficacy in a wide variety of neuropathic pain disorders. TCAs modulate voltage-gated sodium channels, inhibiting the reuptake of norepinephrine and serotonin. A 2011 practice guideline affirms the efficacy of amitriptyline, but less robust evidence exists for the use of desipramine, imipramine, fluoxetine, or nortriptyline + fluphenazine.1,2 Where prior studies were unable to support use of nortriptyline, a recent prospective clinical trial demonstrated some effectiveness of nortriptyline in cryptogenic sensory polyneuropathy specifically.28 Tertiary amine TCAs (amitriptyline, imipramine, and clomipramine) are not recommended at doses greater than 75 mg/day in adults 65 years and older, due to major anticholinergic and sedative side-effects and potential fall risk.3  An increased risk of sudden cardiac death has been reported with TCAs at doses >100 mg daily.4 TCAs are contraindicated in patients with cardiac arrhythmia, congestive heart failure, recent myocardial infarction, glaucoma, urinary retention, bladder outlet obstruction or benign prostatic hypertrophy, and prolonged QTc interval. Therefore, these drugs require close monitoring and are only recommended as a last resort due to high risk of side effects.25, 26

Recent studies of serotonin-norepinephrine reuptake inhibitors (SNRIs) in painful neuropathy and DPNP have shown efficacy, as well as better tolerance than TCAs.5 Duloxetine has been well studied with regard to DPNP and has the benefit of once-daily dosing.1,6 It is considered a first line agent for DPNP by the FDA. Adverse effects include nausea, somnolence, hyperhidrosis, and anorexia, with vomiting and nausea being the most common reason for discontinuation.26,27 There is some association with mild elevations of fasting plasma glucose, yet no significant changes in HbA1c.25 It is contraindicated in narrow-angle glaucoma and concurrent-dosing with monoamine oxidase inhibitors and should be used cautiously in the setting of chronic liver disease or excessive alcohol consumption. Duloxetine also carries a black box warning for suicidal thinking and behavior in children and young adults.27

Both venlafaxine and venlafaxine ER demonstrate efficacy comparable to imipramine for treatment of painful neuropathy, and they share a similar side effect profile, including nausea, somnolence, dyspepsia, insomnia, and sweating.1,2,6 Less data overall is available for venlafaxine than duloxetine—it is considered for treatment for DPNP by the ADA but has not received FDA approval. Venlafaxine thus should only be considered if duloxetine fails or side effects are not tolerable.25,27

Although selective serotonin reuptake inhibitors (SSRIs) have far fewer reported adverse effects, TCAs have consistently demonstrated greater efficacy.6 Treatment with SSRIs could be considered in patients who respond but are intolerant of TCAs. One study of buproprion demonstrated benefit in neuropathic pain and was better tolerated than TCAs.7


Among traditional anticonvulsants, carbamazepine has been studied most extensively for treatment of trigeminal neuralgia, with reported success in DPNP, and anecdotal evidence of benefit in glossopharyngeal neuralgia.5,7 Carbamazepine stabilizes the neurilemma by inhibiting voltage-gated sodium channels. Drawbacks include drug-drug interactions, ataxia, sedation, risk of aplastic anemia, and the need for regular monitoring of hematologic and hepatic function. Although oxcarbazepine boasts a safety advantage over carbamazepine, there is conflicting evidence, and some clinical experience suggests there is variability of individual responses to either medication. Oxcarbazepine may have lower potential for drug interactions overall but does carry a higher risk of central nervous system depression and hyponatremia.29,30 Ultimately, carbamazepine has demonstrated to be less effective than pregabalin and therefore not recommended for DPNP in international guidelines.32

Gabapentin and pregabalin bind to the α2-δ subunit of voltage-activated calcium channels. This group boasts the highest demonstrated efficacy among all anticonvulsants, require no laboratory monitoring, and have few serious adverse effects and few drug-drug interactions.5,7 Side effects are similar for both agents, including dizziness, somnolence, peripheral edema, and weight gain. One study suggests a synergistic effect of dual therapy with gabapentin and morphine. Total daily dose should be reduced in patients with renal dysfunction. Limitations of gabapentin include its lengthy titration, as well as multiple daily doses. Newer formulations of once-daily extended-release gabapentin are available as well as in combination with enacarbil. While gabapentin is not approved, it is recommended for diabetic neuropathy by both the American Academy of Neurology (AAN) and the ADA. It is considered a second line alternative as there is lower quality clinical data available than pregabalin.26 These gabapentinoids are also indicated in the treatment of central neuropathic pain, the neuropathic component of cancer pain, and post-herpatic neuralgia.31

Many large-scale studies of pregabalin render it the only agent with Level A evidence of efficacy in the 2011 published practice guideline by the American Academy of Neuromuscular and Electrodiagnostic Medicine (AANEM)/American Academy of Neurology (AAN)/American Academy of Physical Medicine and Rehabilitation (AAPMR).1 There is also some consideration that pregabalin is beneficial due to its effect on concomitant anxiety, depression, and sleep disturbance.32

Mirogabalin is a novel gabapentinoid recently approved for peripheral neuropathic pain in Japan in 2019. With similar mechanism of action to pregabalin but with longer duration of action, several studies suggest mirogabalin is an alternative in patients’ refractory to pregabalin. It is also thought that mirogabalin produces less CNS specific adverse reactions and reaches maximum plasma concentration faster than both pregabalin and gabapentin. However, more studies with comparison trials and longer durations of observation are required.33,34

Sodium valproate increases GABA in the brain and prolongs depolarization of voltage-sensitive sodium channels. Although well tolerated, it is considered less effective than pregabalin, and its use is limited by side effects, potential hepatotoxicity and hematologic effects, and drug-drug interactions.7,31 Liver enzymes should be monitored.

Phenytoin stabilizes the neurilemma by blocking sodium channels. However, it is used infrequently due to complex kinetics, drug-drug interactions, and neurotoxicity related to secondary folate deficiency.7 Although initial studies of lacosamide were promising, recent results are conflicting, and studies with higher subjects and control groups are needed.1, 35 Whereas previous studies were inconclusive on the efficacy of topiramate, recent trials comparing it to gabapentin showed evidence that topiramate is a good alternative—larger sample sizes are still needed.1,36 Studies of lamotrigine demonstrate mixed results5,7 and serious adverse events limit its utility. Levetiracetam studies continue to report conflicting results with possible promise, so more evidence is necessary.37,38

All anticonvulsants, when discontinued, should be tapered carefully to minimize seizure risk.


When prescribing opioids for peripheral neuropathic pain, risks of adverse effects, tolerance, dependence, abuse, and diversion must be weighed against the potential benefits. Long-acting oxycodone has demonstrated significant reduction in DPNP, at the expense of constipation, somnolence, nausea, dizziness, pruritis, vomiting, and dry mouth and increased risk of hip fracture in elderly.7 Tramadol, a weak SNRI with low affinity for µ-receptors, shows benefit in both polyneuropathy as well as DPNP.7 Reported side effects include nausea, constipation, headache, and somnolence, and it carries both a moderate seizure risk and risk of serotonin syndrome, particularly when dosed with antidepressants.6

Tapentadol is a μ opioid agonist with norepinephrine reuptake inhibition showing promise in for multiple causes of pain. While there is only preliminary evidence to support use in peripheral artery disease and Parkinson’s disease related pain, it is the first central-acting analgesic with FDA recognition for efficacy in DPNP. Likely due to the action on norepinephrine reuptake, tapentadol’s side effects are less typical of opioids and therefore better tolerated. There are still opportunities for further quality conclusive studies in other neuropathic pain syndromes.25,39

Synthetic opioids exist that have demonstrated efficacy has well, however both require additional evidence. Levorphanol has been comparable to gabapentin and TCAs in high strength formulations, and methadone can be effective in cases of failed conventional opioids.25

Topical agents

Topical agents make ideal adjuncts in the treatment of neuropathic pain, due to limited systemic effects. Prolonged topical application of capsaicin reversibly depletes substance P from sensory neurons.6,7 Capsaicin is available in both over the counter and prescription creams, as well as a prescription transdermal delivery system. The 8% topical patch was approved by the FDA in 2020 for treatment of DPNP.26 Many patients report burning and stinging5 at the site of application and following inadvertent contact with mucous membranes. Transdermal lidocaine blocks neuronal sodium channels and has demonstrated efficacy, limited by rash and pruritis.1,5,6

While topical nitrates are not recommended in any guidelines, a single study demonstrated moderate efficacy of isosorbide dinitrate spray,1 and they are frequently used off label for this purpose.32

Topical phenytoin is being studied in 5% and 10% concentrations and has initially demonstrated the ability to reduce neuropathic pain in non-responders to other topical agents.40 Topical ketamine and clonidine have also been trialed, however there is limited and inconsistent evidence of the benefits of either medication. In the case of all three of these topical analgesics, high quality RTCs are required.25

Combination therapy

Use of the medications in combination shows potential for great benefit. Due to unreliable efficacy and limitations brought on by undesirable side effects, which can be alleviated by use of therapies on concert. Duloxetine combined with either opioids and gabapentinoids have showed benefit, and was found to be more effective than gabapentin alone. While the addition of THC/CBD to medication regimens was no more effective than monotherapy, combining THC alone with gabapentin did show improvement over monotherapy. The grouping of pregabalin and TCAs is an alternative to high dose monotherapy and would help avoid the adverse effects of either medication at increased doses. There are many possibilities of using established medications together, and this is an area that requires further studies and improved evidence.41


A single placebo-controlled trial of perineural platelet rich plasma injections demonstrated improved VAS pain scores and 2-point discrimination in patients with Hansen’s disease.10

There is limited evidence that dextromethorphan, with or without added benztropine, demonstrates reduction in DPNP, and currently has only “Level B” indication for treatment of DPNP.7,31

IV lidocaine has shown efficacy in acute management, providing a safe alternative to opioid medications. IV fosphenytoin has been trialed as a substitute for lidocaine. Guidelines on clinical use can be determined with further research.25,31

A supplement combination of L-methylfolate, pyridoxal 5′-phosphate, and methylcobalamin has been introduced, indicated for treatment of DPNP. Preliminary studies demonstrate significant improvements in epidermal nerve fiber density, sensory nerve conduction velocities, and monofilament sensation in patients with DPNP.11

Flavonoids demonstrate some efficacy in attenuating multiple causes of neuropathic pain and there is need for future studies to address the role of flavonoids in these patients.41

An Ayurvedic herb, centella asiatica (CA) triterpenes, is thought to have rejuvenating properties, especially in the nervous system, with improvements of microcirculation and edema. A preparation of CA triterpenes, named CAST, was well tolerated in a trial of diabetic neuropathy, offering a possible mechanism of reducing or reversing nerve damage.55

Placebo-controlled trials are warranted to determine efficacy as stand-alone or adjunctive therapy.


One study of 3-4 weeks’ percutaneous electrical stimulation demonstrated benefit over sham treatment. Two small studies show benefits with frequency-modulated electromagnetic neural stimulation 30 minutes per day in a crossover trial.1,5 Results with transcutaneous electrical nerve stimulation (TENS) units are inconclusive in DPNP and are less convincing for other neuropathic pain syndromes. While AAN considers it likely effective for DPNP, larger studies are still required.43 Regardless, it is still a favorable modality as it is non-invasive and has minimal contraindications.44

High costs and risks of spinal cord stimulation (SCS) limit its availability,5 however it is becoming more commonly used. Low frequency SCS has been used for chronic pain for many years and high-quality evidence exists, with the most common pain etiology being DPNP. Tolerance is a main limitation due to associated paresthesia. Multiple new studies have explored high frequency SCS further, which has the benefit of avoiding paresthesia. HF SCS also offers better overall pain relief with higher success and is also hypothesized to provide neuromodulation. These results have been demonstrated in long term studies, with current trials monitoring response beyond two years.45,46 Added proposed benefits of HF SCS include foot ulcer and infection reduction, enhanced proprioception, and improved sleep quality.47 Burst SCS produces clusters of high frequency pulses, mimicking naturally occurring firing mechanisms, but there is limited evidence for this modality.26

DRG stimulation is emerging with studies of pain in specific dermatomal patterns. In patients with complex regional pain syndrome (CRPS), DRG stimulation was noted to have improved efficacy in pain relief compared to tonic SCS.25

Intrathecal pain therapy has been approved by the FDA in cases of chronic neuropathic pain, with medication options including either ziconitide or morphine. Ziconitide, a synthetic omega-conotoxin peptide, is a non-opioid analgesic supported by well-designed trials and has less adverse effects. It also does not develop tolerance and has no risk of withdrawal. However, as the medication is targeted to the spine, there is less chance of adverse effects with morphine as well.26

Photobiomodulation, low-level laser therapy, uses red and infra-red light to improve tissue healing and provide pain relief. There are some studies that show relief with DPNP, but the duration and long-term benefit are uncertain.25

Acupuncture may relieve pain and/or reduce the need for pain medications in some patients with DPNP5 and has demonstrated benefit in some peripheral neuropathies (diabetic neuropathy, Bell’s palsy, carpal tunnel syndrome and possibly HIV-associated neuropathies). A Cochrane review concluded there were no clear benefits or harms of acupuncture on chronic neuropathic pain, and existing evidence had limited generalizability.48 Further reviews agree that enhanced clinical trials are necessary, but as it is overall well tolerated, acupuncture can be considered treatment for neuropathic pain.49


Studies of surgical decompression for the treatment of DPNP are fraught with poor quality and design. There are no randomized controlled trials to either support or refute the practice. Outcomes were based not on standard neurologic exams or electrodiagnostic data, but on subjective reports from patients and observations of the operating surgeon.14 It has been believed to be beneficial with DPNP and focal nerve entrapment, yet there is conflicting data and the AAN regards surgery for DPNP as unproven.1,31

Summary of recommended pharmacotherapy for neuropathic pain in adults9,25:

Strong Recommendations for Use (First line):

  • gabapentin 1200-3600 mg, in three divided doses
  • gabapentin extended release (ER) or enacarbil, 1200-3600 mg, in two divided doses
  • pregabalin, 300-600 mg, in two divided doses
  • Serotonin-noradrenaline reuptake inhibitors duloxetine or venlafaxine:
    • duloxetine 60-120 mg once daily (most studied, preferred)
    • venlafaxine ER 150-225 mg once daily
  • Tricyclic antidepressants, 25-150 mg once daily or in two divided doses

Weak Recommendations for Use (Second line):

  • Capsaicin 8% patch, 1-4 patches applied to the painful area for 30-60 minutes every three months
  • Lidocaine patch, 1-3 patches to the region of pain once daily for up to 12 hours
  • Tramadol, 200-400 mg in two (ER) or three divided doses

Weak Recommendations for Use (Third line):

  • Botulinum toxin A subcutaneous, 50-200U to the painful area every three months
  • Strong opioids, titrated to effect; sustained release oxycodone and morphine have been the most studied (maximum doses of 120 mg/day and 240 mg/day, respectively)
  • tapentadol

Inconclusive Recommendations:

  • combination therapy
  • capsaicin cream
  • carbamazepine
  • clonidine topical
  • lacosamide
  • lamotrigine
  • levetiracetam
  • NMDA antagonists
  • Oxcarbazepine
  • phenytoin (topical)
  • SSRI antidepressants
  • topiramate
  • zonisamide

Weak recommendations against use:

  • cannabinoids
  • valproate

Strong recommendations against use:

  • mexiletine

At different disease stages

In chronic cases, appropriate steps should be taken to prevent complications. Loss of protective sensation prompts the need for routine foot care and skin checks. Proprioceptive loss and imbalance can be ameliorated with gait aides and fall prevention strategies. When ankle dorsiflexion weakness is identified, ankle foot orthoses can significantly improve gait function and prevent falls and ankle injuries. Static orthoses may play a role in contracture prevention. Therapeutic exercise can maintain and improve strength, endurance, coordination, balance, agility, flexibility, and range of motion, and may reduce perceived pain interference, but imparts no direct benefit on neurologic recovery. Physical therapy is also important to avoid or reverse disuse atrophy, contractures, deformities, trophism changes, and to prevent ankylosis and general deconditioning.15,16,44

Coordination of care

Treatment of underlying etiologies is paramount and often requires collaboration among treating practitioners. Underlying endocrine conditions should be addressed and medical treatments titrated to achieve optimal control. In diabetics, glycemic control is pivotal, with goal HbA1c <6.5%, fasting blood glucose <108 and postprandial blood glucose <140. Thyroid replacement therapy should be optimized, though ideal target thyroid levels remain disputed. Physiatrists are well suited to apply multidisciplinary approaches with health care professionals from different fields to best manage patients’ needs.44

Patient & family education

Patients with hereditary neuropathy should specifically be counseled regarding risk to future family members and avoiding common exacerbating factors and certain medications.

Providers should educate patients and families regarding skin and foot care, burn prevention, impact from possible autonomic dysfunction, as well as the prognosis and course of their condition. Patients should be reassured that physical activity will not cause neurologic decline or progression of disease but may exacerbate symptoms. In fact, there are ongoing trials to study whether weight loss, medically or surgically, improves outcomes with neuropathy.50 Fall prevention skills should be outlined, including a higher fall risk in low light conditions (due to lack of visual inputs for balance) and on uneven and unfamiliar surfaces.

Emerging/unique interventions

Goals of treatment hinge upon symptomatic control, weighing risks and benefits. Patient goals may include restoration, optimization, and preservation of function and quality of life (QOL). Tools such as the Neuropathic Pain Scale17 and Neuro-QOL18 are used to quantify pain and QOL measures. Improvements in various aspects of QOL (social functioning, mental health, bodily pain, vitality, sleep, disability, physical functioning, vocational and recreational activities) have been demonstrated with pregabalin, oxycodone, tramadol, capsaicin, buproprion, and with venlafaxine added to gabapentin.5,1,7

Current research being conducted to target specific mechanisms including the following: polyol pathway, hexamine pathway, PKC, oxidative stress, PARP, MAPK, AGE, NF-KB, Hh, COX, IL, TNF-alpha, NGF, autophagy, and GSK3. These mechanisms are thought to have contribution to pain pathways and can be modulated by activation or suppression.32

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Underlying cause(s) of peripheral neuropathy and potential exacerbating factors should be identified and mitigated. Providers should adhere to recommended treatment guidelines, and clearly communicate treatment goals. Treatment risks should be minimized with appropriate titration and dose adjustment, reassessment of ongoing need, routine follow-up, and laboratory monitoring when indicated.

Fall risk should be assessed in all patients with peripheral neuropathy, and appropriate preventive measures implemented.

A performance improvement project designed by the Agency for Healthcare Research and Quality (AHRQ) has published a toolkit for enhancing the management of neuropathic pain specifically in the long-term care setting,19 available at http://achlpicme.org/ltc/CMEInfo.aspx.

Cutting Edge/ Emerging and Unique Concepts and Practice

Antimuscarinic drugs (M1R antagonists) demonstrated promise in the prevention and reversal of peripheral neuropathy in rodent models of diabetes and were neuroprotective in rat models of chemotherapy and HIV-induced peripheral neuropathy.20

Regardless of etiology, mitochondrial dysfunction has been found to contribute to the underlying neuronal dysfunction associated with peripheral neuropathies. Pharmacotherapies aimed at modulation of mitochondria may become a new therapeutic target.  Among them, alpha-lipoic acid (ALA) is a well-tolerated supplement with an excellent safety profile typically prescribed in doses up to 600 mg/day. It is available as a supplement without prescription in the United States. ALA is thought to work by reducing excitability of DRG neurons via NF-κB inhibition, which may improve local blood flow and increase nerve conduction speed.21,25,42,56. ALA is also being studied in combination with electro-acupuncture with promising results, though further evidence is still needed.57

According to a recent meta-analysis, acetyl-L-carnitine may have a moderate effect in reducing neuropathy pain with a favorable safety profile, but larger trials with longer follow-up are warranted. Data on symptoms and impairment is of low certainty, and adverse effect evidence is too uncertain for safety conclusions.22,51

Vitamin D supplementation has been shown to decrease pain severity and improve mood in small trials, highlighting the importance of full laboratory studies and benefits of supplements.54,55

NYX-2925 is a novel N-methyl-D-aspartate receptor modulator currently in development for chronic pain conditions. With the ability to cross the blood brain barrier, NYX-2925 acts at the central nervous system level in neuropathic pain. Initial human trials have shown promise with minimal safety and tolerance concerns and further evaluation is warranted.52

Benfotiamine is a synthetic form of thiamine that is proposed to help prevent microvascular complications in diabetes. However, evidence is currently poor due to limited studies. There is utility in further research as it is economical and readily available, with implications towards other diabetes complications.51

Several other experimental drugs that are emerging include: vixotirgine, a voltage-gated sodium-channel agonist; olodanrigan, an angiotensin 2 receptor antagonist; enkephalinase inhibitors; a combination pill of trazodone and pregabalin.54

Ongoing work in genetics may identify patients at risk, leading to presymptomatic diagnosis and early treatment interventions, as well as gene replacement therapy for inheritable forms. Studies of neurotrophic factors may unveil new treatment paradigms in search of disease reversal and cure.21

Gaps in the Evidence-Based Knowledge

Even the most efficacious medications provide moderate relief in 50-60% of patients, and there is only a 20% probability of complete pain relief with a single prescription. This leads practitioners to pursue combination therapy, however, there are no proven polypharmacy algorithms.23

Although the above meta-analysis specified a weak recommendation against the pharmacologic use of cannabinoids for peripheral neuropathic pain, more prospective clinical studies with different cannabis subtypes need to be performed before making a final recommendation for or against their use.

Animal models have limited relevance owing to lack of human outcomes measures and low rigor. Even human clinical trials are often fraught with false negatives, for which innovative trial designs and identification of surrogate outcomes markers may be promising.24

Better understanding of the mechanisms of axonal degeneration in multiple disease models is necessary for the development of potential regenerative therapies.24

Currently, there are no approved disease-modifying agents available for treatment of neuropathic pain. Larger trials are needed prior to recommending any disease-modifying agent that currently demonstrate any efficacy.53


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Original Version of the Topic

Michele Arnold, MD. Peripheral Polyneuropathy: Treatment. 7/17/2013

Previous Revision(s) of the Topic

Michele Arnold, MD. Peripheral Polyneuropathy: Treatment. 7/31/2017

Author Disclosure

Dennis Keane, MD
Nothing to Disclose

Taylor Stinnett, DO
Nothing to Disclose