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/.

FAQ: First Line Treatments for Neuropathy

• What does “first line treatment” mean for neuropathy?
  ‍First line treatments are the options experts recommend trying before others because they usually offer the best balance of benefit and risk for most people. In neuropathy, first line care has two main goals: improve the condition that is damaging the nerves and ease nerve pain so you can sleep, move, and stay safe. Many people need to try more than one option or a combination over time. The realistic goal is usually to reduce pain by about one third to one half and improve daily function, not to remove pain completely.
• ‍Why is treating the cause as important as treating the pain?
  If the underlying problem keeps damaging nerves, pain and weakness are more likely to worsen. Improving blood sugar, blood pressure, and cholesterol in diabetes, correcting vitamin B12 deficiency, cutting back alcohol, and managing autoimmune, thyroid, kidney, or toxin related causes can slow or limit further nerve injury. Regular activity, balance training, protective footwear, and home fall prevention also protect the nerves you still have and reduce injuries.

• What are the main first line medicines for painful peripheral neuropathy?
  Large guidelines recommend starting with one of a few main groups:
  Serotonin norepinephrine reuptake inhibitors (often duloxetine, sometimes venlafaxine or desvenlafaxine)
  Gabapentinoids (gabapentin or pregabalin)
  Tricyclic antidepressants at low doses (such as amitriptyline or nortriptyline)
  Sodium channel blockers in selected situations (such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide)
  Topical therapies for localized pain (high concentration capsaicin patch in clinic or lidocaine patches or gel)
• How do SNRIs like duloxetine help with nerve pain?
  SNRIs such as duloxetine and sometimes venlafaxine affect chemical messengers in the brain and spinal cord that are involved in pain signaling. They can reduce neuropathic pain and may also improve mood and sleep. They are often a good choice if you also have depression or anxiety. Early side effects can include nausea or sleep changes, which often ease after the first couple of weeks, especially if you start at a low dose and take them with food.
• What should I know about gabapentin and pregabalin?
  Gabapentin and pregabalin calm overactive nerve firing and are widely used for painful diabetic neuropathy and other neuropathic pains. Common side effects are drowsiness and dizziness. Increasing the dose slowly can improve comfort. Because they are cleared by the kidneys, your dose may need to be adjusted if you have reduced kidney function.
• How do tricyclic antidepressants fit in?
  Low nightly doses of tricyclic antidepressants such as amitriptyline or nortriptyline can reduce nerve pain and help with sleep. They are usually avoided in people with certain heart rhythm problems, some types of glaucoma, or serious trouble with urination. Dry mouth and constipation are common and can often be managed with fluids, fiber, and oral moisturizers.
• What are sodium channel blockers and when are they used?
  Medicines such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide affect sodium channels in nerves and can reduce some types of neuropathic pain. They are not always first choice, but may be considered when other options are not a good fit or if you responded well to them in the past. They require careful review of interactions and monitoring.
• When are topical treatments like capsaicin or lidocaine helpful?
  Topical treatments are most useful when pain is limited to a smaller, more surface area such as part of the foot or an area affected by shingles. A high concentration capsaicin patch applied in a clinic can provide weeks of relief for some people with peripheral neuropathic pain, though there is usually a short period of burning or redness at the site. Lidocaine patches or gels can temporarily numb focal painful spots and tend to have fewer whole body side effects.
• Why are opioids usually not first line for neuropathic pain?
  For chronic neuropathic pain, opioids such as oxycodone or hydrocodone often provide limited extra benefit over time and carry higher risks, including dependence, sedation, constipation, and falls. Many guidelines advise against using them for painful diabetic neuropathy, or reserve medicines like tramadol or tapentadol for short courses only when other options have not helped and risks are very carefully managed.
• How do I choose a good starting treatment with my clinician?
  Choosing a starting option depends on your overall health, other medicines, and daily needs.
  If low mood, anxiety, or poor sleep are major concerns, an SNRI or a tricyclic may be a better fit because they can help more than one problem.
  If you have kidney disease, gabapentinoid doses must be adjusted.
  If you have heart rhythm issues or a past heart attack, tricyclics may not be appropriate.
  If your pain is mostly in a small area near the skin, a topical treatment may be a good first step.
  If you have fluid retention or heart failure, gabapentinoids may be less desirable.
  If daytime alertness is very important, a nighttime tricyclic or an SNRI may fit better than a higher daytime gabapentin dose.
• What safety tips should I keep in mind while using these medicines?
  Start with a low dose and increase slowly as directed. Many side effects improve after one to two weeks.
  Do not stop these medicines suddenly unless your clinician tells you to. Several need to be tapered to avoid withdrawal symptoms or rebound pain.
  Limit alcohol because it can worsen drowsiness and dizziness.
  Ask your pharmacist to review all your prescriptions and supplements for interactions.
  Protect against falls by standing up slowly, using handrails, adding night lights, and wearing sturdy shoes.
  Keep a simple diary that notes your pain level, medicine doses, and side effects, and bring it to visits.
  Call your clinician right away if you notice a rash, severe dizziness or fainting, swelling in the legs or face, shortness of breath, or mood changes such as agitation or thoughts of self harm.
• When should medicines be combined or switched?
  If a single first line medicine gives partial relief, your clinician may add a second medicine from a different group, for example pairing 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 several first line trials, your team may discuss clinic based topical treatments, nerve stimulation procedures, pain coping therapies, or referral to a pain or neurology specialist.
• How can an advocate help with first line neuropathy treatment?
  Neuropathy care often involves many details, such as refills, prior authorizations, dose changes, and monitoring side effects. A care advocate can help you list your goals, organize questions for your clinician, prepare for visits, coordinate appointments, and keep track of what you have tried. They can also help connect you with education on managing medication side effects and with care coordination services if needed.
• When should I seek urgent care while on these treatments?
  Seek urgent care or emergency care if you have trouble breathing, swelling of the face or tongue, new chest pain, confusion with fever and muscle stiffness, or severe dizziness that leads to falls. These symptoms can signal serious reactions or other urgent problems that need fast evaluation.

References

Clinical and guideline sources

• 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

Related Understood Care resources

• Managing neuropathy medication side effects. understoodcare.com/articles/managing-neuropathy-medication-side-effects-wu2h8 understoodcare.com‍
• Care coordination support. https://understoodcare.com/care-types/care-coordination understoodcare.com‍
• Help with medical appointments. https://understoodcare.com/care-types/appointments understoodcare.com
  Meet our advocates. https://understoodcare.com/advocates understoodcare.com‍

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