First-Line Treatments for Neuropathy

What first line treatment means

First line treatments are the options experts recommend trying before others because the balance of benefit and risk is favorable for most people. For neuropathy, first line care focuses on two goals
1 improving the condition causing nerve injury and
2 easing nerve pain so you can function and stay safe.

You may need more than one approach over time. Many people try one option, adjust the dose, then switch to another or combine two options if pain relief is partial. A complete absence of pain is uncommon, so real world goals often aim for about a one third to one half reduction in pain with better sleep and daily function.

Treat the cause and protect your nerves

Addressing the root cause helps prevent further nerve damage

• If you live with diabetes, keeping blood glucose, blood pressure, and cholesterol near targets can limit progression and reduce complications. Daily foot checks and routine foot care lower the risk of sores and falls.
• If you have a vitamin deficiency such as low vitamin B12, correcting the deficiency can help.
• If alcohol use is high, cutting back protects nerves and improves sleep and balance.
• If an autoimmune, thyroid, kidney, or toxin related cause is suspected, your clinician may order tests or refer you to a specialist.
• Regular physical activity and balance training support strength, mood, and walking safety.
• Protective footwear and home fall safety steps such as good lighting and clear pathways reduce injuries when sensation is reduced.

First line medicines for painful peripheral neuropathy

Large guidelines and reviews consistently recommend starting with one of these groups. The choice depends on your other health conditions, current medicines, sleep and mood needs, and preferences.

Serotonin norepinephrine reuptake inhibitors

Common choices are duloxetine and sometimes venlafaxine or desvenlafaxine. These medicines can help nerve pain and may also support mood and sleep. They are often good options if you also have depression or anxiety. Typical effects include nausea or sleep changes early on which often improve after the first weeks. Your clinician may suggest taking with food and starting at a low dose.

Gabapentinoids

Gabapentin and pregabalin calm overactive nerve signaling. They are widely used for painful diabetic neuropathy and other neuropathic pains. Drowsiness and dizziness are the most common effects. A slow dose increase can improve comfort. Kidney function affects dosing, so your prescriber will adjust if needed.

Tricyclic antidepressants

Low nightly doses of amitriptyline or nortriptyline can reduce neuropathic pain and help sleep. They are often avoided if you have certain heart conditions, glaucoma, or trouble with urination. Dry mouth and constipation are common and can be managed with fluids, fiber, and oral moisturizers.

Sodium channel blockers

Some guidelines include medicines such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide as additional first line options. These may be considered when other medicines are not a good fit or if past response suggests benefit. Your clinician will review interactions and monitoring needs.

Topical therapies

For pain that is more localized, skin applied treatments can help with fewer whole body effects.

• High concentration capsaicin patch applied in a clinic setting can provide weeks of relief for some people with peripheral neuropathic pain. A short period of burning or redness at the application site is common.
• Lidocaine patches or gels can numb focal areas such as tender spots on the feet or after shingles. These are often used when pain is near the skin surface.

What is usually not first line

Opioids are generally not recommended first for neuropathic pain. Over time they provide limited additional benefit and carry higher risks like dependence, sedation, constipation, and falls. Some guidelines advise against their use for painful diabetic neuropathy, while others reserve tramadol or tapentadol for short courses when other options have not helped and risks are carefully managed.

How to choose your starting option

Think about your whole health picture and practical needs. These pointers can help you and your clinician pick a good starting point.

• If low mood, anxiety, or poor sleep are significant, an SNRI or a tricyclic can address more than one issue.
• If you have kidney disease, dose changes for gabapentinoids are needed.
• If you have heart rhythm disease or a history of heart attack, tricyclics may not be a good match.
• If your pain is mostly in a small area near the skin, a topical patch or gel can reduce whole body effects.
• If you retain fluid or have heart failure, gabapentinoids may be less desirable.
• If you need to keep daytime alertness, a nighttime tricyclic or an SNRI may fit better than a higher daytime dose of gabapentin.

Safe use and everyday tips

• Start with a low dose and increase slowly as directed. Many side effects fade after one to two weeks.
• Do not stop these medicines suddenly unless your clinician tells you to. Several require a gradual taper to prevent withdrawal symptoms or rebound pain.
• Limit alcohol since it can intensify drowsiness and dizziness.
• Review all of your medicines and supplements with your pharmacist to avoid interactions.
• Protect against falls. Stand up slowly, use handrails, add night lights, and wear sturdy shoes.
• Keep a simple pain and side effect diary with dose times to guide adjustments.
• Call your clinician right away for rash, severe dizziness or fainting, swelling of legs or face, shortness of breath, or mood changes such as agitation or thoughts of self harm.

When to combine or switch

If a single first line medicine provides partial relief, your clinician may add a second medicine from a different group. Common combinations pair a gabapentinoid with a tricyclic or an SNRI. If a medicine is not helping after a fair trial at a tolerated dose usually several weeks, switching to a different group is reasonable. If pain remains severe after trying several first line options, your team may discuss clinic based topical treatments, nerve stimulation procedures, psychological therapies to improve coping and sleep, or referral to a pain or neurology specialist.

How an advocate can help

Staying on track with neuropathy care often means coordinating refills and prior approvals, tracking side effects, and preparing for visits. A care advocate can help you list goals, organize questions for your clinician, and keep your plan moving. If you found this guide helpful, see our patient friendly guide to managing neuropathy medication side effects and our pages on appointments and care coordination listed in the references. For one on one support, connect with an Understood Care advocate at (646) 904-4027 or sign up at https://app.understoodcare.com/.

Frequently asked questions

• How long until I feel better
  Many people notice early changes within one to two weeks as doses increase. Full benefit often takes several weeks. Keep using your diary and share it at follow up so your clinician can adjust the plan.

• Can I use more than one medicine
  Yes. If one medicine gives partial relief, combining two from different groups can help. Your clinician will consider interactions and your health history.

• Are there non medicine options that truly help
  Yes. Consistent diabetes management, physical therapy, balance training, and protective footwear reduce complications and make pain easier to live with. For selected people, clinic applied capsaicin patches or nerve stimulation can be considered after medicines.

• When should I seek urgent care
  Seek urgent care for trouble breathing, swelling of the face or tongue, new chest pain, confusion with fever and muscle stiffness, or severe dizziness with falls.

References

• Mayo Clinic. Peripheral neuropathy diagnosis and treatment. https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/diagnosis-treatment/drc-20352067 Mayo Clinic‍
• National Institute of Neurological Disorders and Stroke. Peripheral neuropathy disorder information page. https://www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy NINDS‍
• NINDS. Peripheral neuropathy fact sheet PDF. https://www.ninds.nih.gov/sites/default/files/2025-05/peripheral-neuropathy.pdf NIND
• ‍National Institute of Diabetes and Digestive and Kidney Diseases. Diabetic neuropathy overview. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/nerve-damage-diabetic-neuropathies NIDDK‍
• American Academy of Neurology. Oral and topical treatment of painful diabetic neuropathy guideline Neurology 2022. https://www.neurology.org/doi/10.1212/WNL.0000000000013038 American Academy of Neurology‍
• American Academy of Neurology. Press release on updated guideline for painful diabetic neuropathy. https://www.aan.com/PressRoom/Home/PressRelease/4944 American Academy of Neurology‍
• Preston FG, et al. Painful diabetic peripheral neuropathy practical guidance and challenges. https://pmc.ncbi.nlm.nih.gov/articles/PMC10243347/ PMC‍
• Derry S, et al. Topical capsaicin high concentration for chronic neuropathic pain Cochrane review. https://pubmed.ncbi.nlm.nih.gov/23450576/ PubMed
• Cleveland Clinic. Peripheral neuropathy overview and treatment. https://my.clevelandclinic.org/health/diseases/14737-peripheral-neuropathy Cleveland Clinic

This article is for education and does not replace medical advice. Always talk with your clinician about your specific situation.