2. ESSENTIALS OF ASSESSMENT
See part 1.
3. 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 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.
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 Adverse effects include nausea, somnolence, hyperhidrosis, and anorexia. 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.
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
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, the few studies available demonstrate conflicting evidence.5
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.
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
Sodium valproate increases GABA in the brain and prolongs depolarization of voltage-sensitive sodium channels. Although well tolerated, its use is limited by side effects, potential hepatotoxicity and hematologic effects, and drug-drug interactions.7 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 lacosamine were promising, recent results are conflicting.1 A large-scale study of topiramate demonstrated no benefit.1 Studies of lamotrigine demonstrate mixed results5,7 and serious adverse events limit its utility. Case reports of levetiracetam appear promising; quality trials are needed.8
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 noradrenaline reuptake inhibition with promising but mixed results in trials; studies of the extended release formulation may have potential bias owing to study design9.
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. 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 A single study demonstrated moderate efficacy of isosorbide dinitrate spray.1
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.7
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
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
High costs and risks of spinal cord stimulation (SCS) limit its availability.5 Despite reports of both efficacy and safety for treating chronic refractory pain, randomized controlled long-term studies of SCS in patients with peripheral neuropathy are lacking.
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), but rigorous studies using sham-acupuncture are needed12. A Cochrane review is underway.13
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 The AAN regards surgery for DPNP as unproven.1
SUMMARY OF RECOMMENDED PHARMACOTHERAPY FOR NEUROPATHIC PAIN IN ADULTS9:
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)
- combination therapy
- capsaicin cream
- clonidine topical
- NMDA antagonists
- SSRI antidepressants
Weak recommendations against use:
Strong recommendations against use:
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.15, 16
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.
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. 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.
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
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.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge 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 neuropathy20.
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 is a well-tolerated supplement with an excellent safety profile typically prescribed in doses up to 600 mg/day, yet further efficacy studies are warranted21.
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 warranted22.
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 cure21.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
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 algorithms23.
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 therapies24.
- Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy-Report of the AAN, AANEM, and the AAPMR. PM&R. 2011;3(4):345-352.
- Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Systemic Reviews. 2007;4:1-19.
- American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012; 60: 616–31.
- Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther 2004; 75: 234–41.
- Argoff CE, Backonja MM, Belgrade MJ, et. al. Consensus guidelines for treatment of diabetic peripheral neuropathic pain: Treatment planning and options. Mayo Clin Proc. 2006;81(4,suppl):S12-S25.
- Lindsay TJ, Rodgers BC, Savath V, et al. Treating diabetic peripheral neuropathic pain. Am Fam Physician. 2010;82(2):151-158.
- Wolfe G, Trivedi J. Painful peripheral neuropathy and its nonsurgical treatment. Muscle & Nerve. 2004;30(1):3-19.
- Rowbotham MC. Mechanisms and pharmacologic management of neuropathic pain. In: Dyck PJ, Thomas PK. Peripheral Neuropathy. 4th ed. Philadelphia, PA: Elsevier; 2005:2637-2652.
- Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73.
- Anjayani S, Wirohadidjojo YW, Adam AM. Sensory improvement of leprosy peripheral neuropathy in patients treated with perineural injection of platelet-rich plasma. International Journal of Dermatology 2014, 53, 109–113.
- McNamara VF, Vinik AI, Barrentine L, et al. Effectiveness of Metanx Prescription Medical Food on Small Nerve Fibers and Monofilament Sensation in Patients with Diabetic Peripheral Polyneuropathy. Journal of Diabetes Mellitus, 2016, 6, 166-174.
- Dimitrova A, Murchison C, Oken B. The Journal of Alternative and Complementary Medicine. March 2017, 23(3): 164-179.
- Ju ZY, Wang K, Cui HS, Yao Y, Liu SM, Zhou J, Chen TY, Xia J. Acupuncture for neuropathic pain in adults (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 1.
- Chaudhry V, Stevens JC, Kincaid J, et al. Practice Advisory: Utility of surgical decompression for treatment of diabetic neuropathy: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2006;66:1805-1808.
- Dombovy ML. Rehabilitation Management of Neuropathies. In: Dyck PJ, Thomas PK. Peripheral Neuropathy. 4th ed. Philadelphia, PA: Elsevier; 2005:2621-2636.
- Yoo, M, D’Silva LJ, Martin K. Pilot Study of Exercise Therapy on Painful Diabetic Peripheral Neuropathy. Pain Medicine 2015; 16: 1482–1489
- Galer BS, Jensen MP. The development and preliminary validation of a pain measure specific to neuropathic pain: The Neuropathic Pain Scale. Neurology. 1997;48:332-338.
- Cella D, Lai JS, Nowinski CJ. Neuro-QOL: Brief measures of health-related quality of life for clinical research in neurology. Neurology. 2012;78(23):1860-1867.
- Quality Tool: Enhancing the Management of Neuropathic Pain in the Long-Term Care Setting. Agency for Healthcare Quality and Research website. http://www.innovations.ahrq.gov/content.aspx?id=3805 January 2013. Accessed April 7, 2013.
- Calcutt NA, Smith DR, Frizzi K, et al. Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy.Clin Invest. 2017;127(2):608–622.
- Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Therapeutic Advances in Chronic Disease. 2015;6(1):15-28.
- Li S, Li Q, Li Y, et al. Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta- Analysis of Randomized Controlled Trials. PLoS ONE 10(3): e0119479.
- Cohen K, Shinkazh N, Frank J, Israel I, Fellner C. Pharmacological Treatment of Diabetic Peripheral Neuropathy. Pharmacy and Therapeutics. 2015;40(6):372-388.
- Ahmet H, Simpson DM, Freeman R. Challenges in developing novel therapies for peripheral neuropathies: a summary of The Foundation for Peripheral Neuropathy Scientific Symposium 2012. Journal of the Peripheral Nervous System 18:1–6 (2013).
Original Version of the Topic
Michele Arnold, MD. Peripheral Polyneuropathy: Treatment. 07/17/2013.
Michele Arnold, MD
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