Peripheral Neuropathy: Independent Evidence on Nerve Pain Drugs

Table of contents

• Evidence summary
• What peripheral neuropathy is
• Symptoms and red flags
• Causes and risk factors
• How it is diagnosed
• Treatments that work, with the evidence
• Medicines for nerve pain
• Supplements and lifestyle claims, graded
• Risks and side effects
• Foot care in diabetes
• Who to see
• Follow the money: who makes the drugs and who funded the evidence
• Related research
• Frequently asked questions
• Sources and funding notes

Evidence summary

Independent evidence and credibility scorecard

Independence tiers: 1 = regulator or government body; 2 = academic or Cochrane team with no declared commercial funding for the work; 3 = independent authors analysing mostly manufacturer-run trials, or minor declared industry ties; 4 = manufacturer-funded or manufacturer-authored. Credibility runs from A (highest) to D. Our sources cluster heavily in the UK (NICE, MHRA, NHS, NIHR, Oxford-based Cochrane authors) and the US (Department of Justice, ASCO, SWOG), with one German manufacturer trial and a Danish and French-led international panel, so the verdicts reflect largely UK and US lenses.

What peripheral neuropathy is

The peripheral nervous system is the network of nerves outside the brain and spinal cord. It includes sensory nerves (touch and pain), motor nerves (muscle control) and autonomic nerves (automatic functions such as blood pressure and bladder control). Peripheral neuropathy develops when these nerves, most often in the hands and feet, are damaged.

"Neuropathic pain" is a related but narrower term: pain caused by damage to, or disease of, the nerves themselves. NICE's guidance, for example, covers conditions such as neuralgia, shingles-related pain and diabetic neuropathy (NICE CG173 overview). Not everyone with peripheral neuropathy has pain. Some have mainly numbness or weakness, and for them pain drugs are not the answer. Ordinary painkillers often do not work for nerve pain, which is why different medicines are used (NHS).

Symptoms and red flags

The main symptoms listed by the NHS are numbness and tingling in the feet or hands; burning, stabbing or shooting pain; loss of balance and co-ordination; and muscle weakness, especially in the feet. They are usually constant but may come and go (NHS).

The NHS notes that the sooner neuropathy is diagnosed, the better the chance of limiting damage and preventing complications (NHS). We did not find a citable list of other emergency signs from the sources we opened, so we have not added one.

Causes and risk factors

There are many causes. The ones most searched for, and what the sources we opened say about each, are below.

Diabetes

In the UK, diabetes (type 1 and type 2) is the most common cause. Over time, high blood sugar can damage nerves, a pattern called diabetic polyneuropathy (NHS). The NHS says that for people with diabetes, better blood sugar control, stopping smoking and cutting down on alcohol may help. See our guides to type 2 diabetes and type 1 diabetes.

Vitamin B12 deficiency and medicines that lower it

The NHS lists pins and needles among the effects of vitamin B12 or folate deficiency, and warns that some problems, including those involving the nervous system, can sometimes be permanent if treatment is delayed (NHS). Pernicious anaemia, where the immune system stops B12 being absorbed, is the most common cause (NHS). Our guides to metformin (which covers its effect on B12) and atrophic and autoimmune gastritis cover two common routes to low B12.

Alcohol

The NHS lists drinking too much alcohol as a cause of peripheral neuropathy, and advises cutting down for people at risk (NHS). We did not find a number for how common alcohol-related neuropathy is in the sources we opened.

Chemotherapy

Some cancer drugs damage nerves, called chemotherapy-induced peripheral neuropathy (CIPN). The ASCO guideline update reviewed 28 prevention trials and 14 treatment trials and confirmed that no agent is recommended to prevent it. It advises clinicians to consider delaying, reducing, substituting or stopping chemotherapy when neuropathy becomes intolerable or limits function (ASCO 2020).

Other causes

The NHS also lists physical injury to nerves, viral infections such as shingles, and side effects of some medicines (NHS). Too much vitamin B6 can itself cause neuropathy (see below).

How it is diagnosed

According to the NHS, a GP will ask about symptoms and may arrange tests to find the cause, and may refer you to a neurologist. People at high risk, such as those with diabetes, may have regular nerve-function check-ups (NHS). In diabetes, NICE says to examine both feet with shoes and socks off, using a 10 g monofilament as part of a sensory examination, and to check for reduced blood supply, ulcers, callus, infection, deformity, gangrene and Charcot arthropathy (NICE NG19, 1.3.4). A blood test can check B12 or folate (NHS). The NHS diagnosis page and the detailed test lists in specialist guidance were not accessible to us, so we have not described nerve conduction studies or other specialist tests.

Treatments that work, with the evidence

Treatment depends on the symptoms and the cause, and not every cause can be treated (NHS). The table below separates what the sources support.

Medicines for nerve pain

The NICE CG173 ladder

NICE says to offer a choice of amitriptyline, duloxetine, gabapentin or pregabalin as the initial treatment for neuropathic pain, except trigeminal neuralgia. If the first is not effective or not tolerated, offer one of the remaining three, and consider switching again. It suggests considering tramadol only as short-term rescue treatment, and capsaicin cream for localised pain in people who wish to avoid or cannot tolerate oral drugs. For trigeminal neuralgia, the first choice is carbamazepine (NICE CG173). NICE lists drugs not to start in non-specialist settings unless a specialist advises, including cannabis sativa extract, capsaicin patch, lacosamide, lamotrigine, levetiracetam, morphine, oxcarbazepine, topiramate, long-term tramadol, venlafaxine and valproate (NICE CG173, 1.1.12). The guideline was published in November 2013 and last updated in September 2020, a change covering sciatica (NICE overview).

What each drug shows

• Amitriptyline (a tricyclic antidepressant used at doses below those for depression): decades of use but, in the Cochrane review, no high-quality supporting trials. Adverse events affected 55% on the drug versus 36% on placebo. The authors concluded it should still be used, but only a minority get satisfactory relief (Cochrane 2015). See our amitriptyline guide and the related nortriptyline guide.
• Duloxetine: 60 mg and 120 mg daily were effective in painful diabetic neuropathy over 12 weeks in manufacturer-run trials; lower doses were not. Most side effects were minor, but 16% stopped treatment because of them (Cochrane 2014). It is also the only agent ASCO supports for established painful chemotherapy neuropathy, with limited benefit (ASCO 2020). See our duloxetine guide.
• Gabapentin: doses studied were mostly 1,200 mg a day or more. Serious adverse events were no more common than placebo (3.2% vs 2.8%), but dizziness (19%), drowsiness (14%) and leg swelling (7%) were frequent (Cochrane 2017). We have no separate gabapentin guide; the pregabalin guide covers related ground.
• Pregabalin: trials used 150, 300 and 600 mg daily. Drowsiness and dizziness were more common than with placebo, for example dizziness in 29% vs 8.1% at 300 mg in postherpetic neuralgia (Cochrane 2019). See our pregabalin guide.

Head-to-head and combination evidence

In OPTION-DM, adults with painful diabetic neuropathy received three pathways for 16 weeks each, titrated toward maximum tolerated doses (amitriptyline 75 mg, duloxetine 120 mg and pregabalin 600 mg a day). Each started with 6 weeks of a single drug, with the second drug added if pain stayed above 3. Pain fell from 6.6 to 3.3 on average and the pathways did not differ significantly. Dizziness was more common with pregabalin, nausea with duloxetine and dry mouth with amitriptyline (trial record; PubMed). The doses above are those studied in the trial, not advice.

The 8% capsaicin patch

Capsaicin, the chemical that makes chilli hot, desensitises skin pain fibres after an initial burning sensation. The 8% patch is about 100 times stronger than conventional creams and must be applied under controlled conditions, often after local anaesthetic, with effects expected to last about 12 weeks (Cochrane 2017). Across eight trials with 2,488 people, about 10% more participants had a good response than with a low-strength control. Six trials used 0.04% capsaicin as an "active" placebo, which keeps blinding intact but may shrink the measured difference. For diabetic neuropathy there was one study of 369 people. The authors rated the evidence moderate to very low and said the effect is similar to other chronic pain therapies (Cochrane 2017). The IASP panel gave the patches a weak recommendation as second line, with a higher NNT than the first-line drugs (Finnerup 2015). In the EU, the patch was approved in 2009 with a label that excluded diabetic patients, and this was extended later (Pharmaceutical Technology). We did not find a NICE appraisal of the patch in the sources we opened.

Supplements and lifestyle claims, graded

Alpha-lipoic acid

NATHAN 1 randomised 460 people with mild to moderate diabetic neuropathy to 600 mg of alpha-lipoic acid or placebo daily for 4 years. The main composite endpoint did not differ (P = 0.105). Some secondary measures, such as the Neuropathy Impairment Score (P = 0.028), favoured the supplement. Serious adverse events were higher on alpha-lipoic acid (38.1% vs 28.0%), though tolerability overall did not differ (Ziegler et al. 2011). The tablets were the maker's own product (Thioctacid HR from MEDA Pharma), company staff were among the authors, and the company's statisticians produced the randomisation list (full text). We grade this Insufficient: a negative primary result from a manufacturer-run trial. Our cinnamon, chromium and ALA guide covers its blood-sugar claims.

B vitamins and benfotiamine

A 2026 meta-analysis pooled 13 trials (834 people) of B vitamins in any form, dose or route. Neuropathy examination scores improved but below the minimal important difference, and pain on standard scales did not change significantly, with large inconsistency between trials. The authors concluded that heterogeneity and risk of bias preclude firm recommendations (Mandra et al. 2026). B12 is different when someone is actually deficient: the NHS says deficiency can damage the nervous system and should be diagnosed and treated promptly (NHS). We grade B vitamins as a treatment for pain Weak, but treating a proven deficiency is standard care. We did not open a separate benfotiamine-specific trial to a standard we could cite, so we make no benfotiamine-specific claim.

Vitamin B6 can cause neuropathy

The NHS says taking 200 mg or more of vitamin B6 a day can cause loss of feeling in the arms and legs. It usually improves after stopping but can be permanent, and the effect of doses between 10 mg and 200 mg is unclear. Government advice is no more than 10 mg a day in supplements unless a doctor advises otherwise (NHS). Many "nerve health" products combine B vitamins, so check labels.

Acetyl-L-carnitine for chemotherapy neuropathy

In SWOG S0715, women starting taxane chemotherapy took 3,000 mg a day of acetyl-L-carnitine or placebo for 24 weeks. At 12 weeks there was no clear effect; by 24 weeks, scores were 1.8 points worse with the supplement (95% CI −3.2 to −0.4), and more women had grade 3 to 4 neurotoxicity (8 versus 1). The authors called it the first study to show a nutritional supplement increasing chemotherapy neuropathy (Hershman et al. 2013). ASCO says its use for prevention should be discouraged (ASCO 2020). Grade: Risk.

Lifestyle

The NHS says that for people with diabetes it may help to gain better blood sugar control, stop smoking and cut down on alcohol (NHS). We did not open trials on exercise for neuropathy, so we do not grade it. Our diabetes supplements guide covers wider supplement claims.

Risks and side effects

• Amitriptyline: more adverse events than placebo (55% vs 36%; number needed to harm 5.2) (Cochrane 2015); dry mouth was more common in OPTION-DM (trial record).
• Duloxetine: nausea in OPTION-DM; 16% stopped because of side effects in the Cochrane review (Cochrane 2014).
• Gabapentin: at least one adverse event in 63% vs 49% (number needed to harm 7.5) (Cochrane 2017).
• Pregabalin: somnolence and dizziness more common than placebo; for painful diabetic neuropathy at 600 mg, dizziness 22% vs 4.4% (Cochrane 2019).
• 8% capsaicin patch: local reactions were common; serious adverse events were similar to control (3.5% vs 3.2%) (Cochrane 2017).
• Supplements: high-dose B6 can cause neuropathy; acetyl-L-carnitine worsened chemotherapy neuropathy (see above).

We did not find, in the sources we opened, a full list of drug interactions or specific advice for pregnancy, breastfeeding, kidney disease or older adults beyond the MHRA warning. Ask a pharmacist before combining these medicines with sedatives, opioids or alcohol, and do not start or stop any of them without clinical advice. NICE says withdrawal should be tapered (NICE CG173, 1.1.7).

Foot care in diabetes

Numb feet are the main route from neuropathy to ulcers and amputation. NICE NG19 sets out the safety net (NICE NG19).

• Yearly checks. Adults with diabetes should have their risk of a foot problem assessed at diagnosis and at least annually, when any foot problem arises, and on admission to hospital (1.3.3).
• What is examined. Both feet, with shoes, socks and dressings removed: sensation with a 10 g monofilament, blood supply, ulcers, callus, infection, deformity, gangrene and Charcot arthropathy (1.3.4).
• Risk groups. Low risk means no risk factors except callus. Moderate risk means deformity, neuropathy or peripheral arterial disease. High risk includes previous ulceration or amputation, kidney replacement therapy, or neuropathy together with arterial disease, callus or deformity (1.3.6).
• Rapid referral. For an active diabetic foot problem, refer within 1 working day to the multidisciplinary foot care service or foot protection service (1.4.2).

We did not extract the review frequencies for moderate and high risk or the detail of footwear advice, so we leave those to the guideline.

Who to see

Start with a GP, who can look for causes and may arrange tests or refer to a neurologist (NHS). People with diabetes should be in regular contact with their diabetes team and foot protection service (NICE NG19). NICE suggests considering referral to a specialist pain service for trigeminal neuralgia when carbamazepine fails (NICE CG173, 1.1.14), and capsaicin patches are a specialist-led option. A pharmacist is a good first contact for drug interactions.

Follow the money: who makes the drugs and who funded the evidence

Who makes and sells the treatments

• Gabapentin (Neurontin): the US Department of Justice described Warner-Lambert as a subsidiary of Pfizer, which acquired it in June 2000 (DOJ). Neurontin was approved by the US FDA in December 1993 only as add-on treatment for epilepsy (same source). Gabapentin is now also sold as a generic; we did not find a citable market-size figure.
• Pregabalin: sold under the brand name Lyrica (MHRA). We did not verify the current brand owner from a source we opened, so we do not name one.
• Duloxetine: the Cochrane review notes it is licensed for major depression, urinary stress incontinence and diabetic neuropathic pain. It says almost every trial was performed or sponsored by the manufacturer. The manufacturer is not named in the abstract and we did not verify it (Cochrane 2014).
• 8% capsaicin patch (Qutenza): developed by NeurogesX and licensed to Astellas Pharma Europe in 2009. In December 2016 the German company Grünenthal agreed to take over exclusive European, Middle Eastern and African rights (Pharmaceutical Technology).
• Alpha-lipoic acid (Thioctacid HR): the NATHAN 1 tablets came from MEDA Pharma, a German company, which also employed several authors (NATHAN 1 full text). Over-the-counter alpha-lipoic acid supplements are sold by many other firms; we did not research them.

Who funded the evidence

• Public money, UK: OPTION-DM was paid for by the NIHR Health Technology Assessment programme (trial record), and the Cochrane pain reviews by an NIHR Cochrane Programme Grant (amitriptyline review).
• Public and charity money, US: the acetyl-L-carnitine trial was funded by the National Cancer Institute, the ASCO Conquer Cancer Foundation and the Avon Foundation, with no conflicts declared (SWOG S0715 full text).
• Manufacturer money: eight duloxetine trials in diabetic neuropathy were run by the maker, and the Cochrane authors said they would prefer investigator-led studies (Cochrane 2014). The gabapentin review records authors' links to Pfizer and Astellas, and Pfizer funded a neuropathic pain research project in which two authors were site investigators (gabapentin review full text). The capsaicin review declares consultancy for Astellas by one author and grant support from Grünenthal (for work on a different drug, tapentadol) to another, and notes that a 2019 audit found it did not meet Cochrane's current commercial sponsorship definition (capsaicin review full text).
• Guideline panel: the IASP meta-analysis was funded by NeuPSIG. Its role-of-funding statement says no author was paid by a drug company to write the article, yet many authors report advisory, speaker or study roles with drug makers (Finnerup full text).

Documented integrity events

• The 2004 gabapentin settlement (verified). On 13 May 2004 the US Department of Justice announced that Warner-Lambert had agreed to plead guilty and pay more than $430 million to resolve criminal charges and civil liabilities over illegal promotion of Neurontin for unapproved uses. These included pain disorders, bipolar disorder, migraine and others. The sum comprised a $240 million criminal fine, $83.6 million to federal Medicaid, $68.4 million to state Medicaid programmes and Washington, D.C., and $38 million to settle state consumer-protection claims. The department also described paid "consultants meetings" and misleading "independent" education events, and said a former medical liaison, Dr David Franklin, who filed the original suit, would receive about $24.64 million (DOJ). The criminal charges were misbranding and introducing an unapproved new drug. The release lists "pain disorders" generally and does not say that claims about neuropathic pain specifically were false; settlement terms are not a finding of efficacy either way.
• Selective outcome reporting. Using the company's own internal documents, researchers found 20 gabapentin trials for off-label use, of which 12 were published. In 8 of the 12, the primary outcome in the paper differed from the protocol. Trials with non-significant results on the protocol outcome were either not reported in full or reported with a changed primary outcome, and the primary outcome changed in 5 of 8 published trials with significant results favouring gabapentin (Vedula et al. 2009). Pfizer disputed the study's conclusions, according to press coverage we saw in search results, but we did not open its statement.
• Controlled-drug status. By April 2019 the MHRA had received reports of abuse and dependence with pregabalin and gabapentin and moved both into the controlled-drug regime (MHRA).

What this means: the 2004 case concerned marketing and the 2009 study concerned how trials were reported. Neither shows gabapentin does not work for nerve pain. The later independent Cochrane review still found moderate-quality evidence of benefit in postherpetic neuralgia and diabetic neuropathy. But the history is a reason to prefer publicly funded comparisons such as OPTION-DM over company-run trials, and to read published primary outcomes with care.

Related research

For wider, evidence-graded context, see these Pure City Research guides:

• Amitriptyline: independent evidence on pain, migraine, IBS, risks and withdrawal
• Duloxetine: independent evidence on depression, pain, side effects and withdrawal
• Pregabalin: independent evidence on pain, anxiety, side effects and withdrawal
• Nortriptyline: independent evidence on depression, nerve pain, smoking and risks
• Type 2 diabetes: diagnosis, treatment, remission and who funds it
• Type 1 diabetes: independent evidence on insulin, tech and cures
• Metformin: independent evidence on benefits, B12, kidneys and ageing
• Diabetes supplements: benefits, limits and safety
• Cinnamon, chromium and ALA for blood sugar
• Atrophic and autoimmune gastritis: biopsy, B12, iron and follow-up
• Hypoglycaemia: independent evidence on causes, glucagon and driving

Frequently asked questions

Sources and funding notes

What we could not verify: NICE blocked automated access to its pages through our standard fetch tool, so we read its guideline text by a direct page request; we could not open NICE's funding statement. We could not open the full text, funding or author declarations of the 2019 pregabalin and 2014 duloxetine Cochrane reviews, the NEJM paper's funding statement, the full ASCO guideline, the NIH Office of Dietary Supplements fact sheets, the NHS diagnosis page, the full BENDIP benfotiamine trial, or OPTION-DM's competing-interest statement. We found no NICE appraisal of the 8% capsaicin patch. We did not verify who currently owns the pregabalin and duloxetine brands and did not research over-the-counter supplement sellers or market sizes. The Pfizer response to the 2009 study comes from search-result summaries, not from a document we opened. NICE CG173 was not rewritten after OPTION-DM, so the guideline may lag newer evidence. The amount of pain relief reported in trials is an average and cannot predict an individual's response.

1. NICE CG173. Neuropathic pain in adults: pharmacological management, recommendations — UK guideline; public body.
2. NICE CG173 overview — publication and update dates.
3. NICE NG19. Diabetic foot problems: prevention and management — UK guideline; public body.
4. NHS. Peripheral neuropathy — UK public health service.
5. NHS. Vitamin B12 or folate deficiency anaemia — UK public health service.
6. NHS. Vitamin B — UK public health service; B6 safety.
7. MHRA. Pregabalin (Lyrica), gabapentin (Neurontin) and risk of abuse and dependence (April 2019) — UK medicines regulator; government.
8. US Department of Justice. Warner-Lambert to pay $430 million to resolve criminal and civil health care liability relating to off-label promotion (13 May 2004) — US government press release.
9. Vedula et al. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. NEJM 2009 — academic study of Pfizer and Parke-Davis documents; funding statement not seen.
10. Tesfaye et al. OPTION-DM. Lancet 2022 — publicly funded trial; NIHR.
11. OPTION-DM repository record — design, numbers and funding; NIHR HTA programme.
12. Finnerup et al. Pharmacotherapy for neuropathic pain in adults. Lancet Neurology 2015 — systematic review; funded by NeuPSIG.
13. Finnerup et al. 2015, full text — funding and conflict statements.
14. Moore et al. Amitriptyline for neuropathic pain in adults. Cochrane 2015 — NIHR Cochrane Programme Grant; Oxford Pain Relief Trust.
15. Amitriptyline Cochrane review, full text — sources of support and declarations.
16. Lunn et al. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane 2014 — review; funder not verified; included trials mostly maker-run.
17. Wiffen et al. Gabapentin for chronic neuropathic pain in adults. Cochrane 2017 — review; NIHR and others.
18. Gabapentin Cochrane review, full text — sources of support; authors' industry ties.
19. Derry et al. Pregabalin for neuropathic pain in adults. Cochrane 2019 — review; declarations not verified.
20. Derry et al. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane 2017 — review; NIHR; trials maker-run.
21. Capsaicin Cochrane review, full text — sources of support; declarations.
22. Pharmaceutical Technology. Grünenthal signs agreement with Astellas for Qutenza rights (December 2016) — trade press.
23. Ziegler et al. NATHAN 1. Diabetes Care 2011 — trial run by the maker, MEDA Pharma.
24. NATHAN 1 full text — authors' affiliations and conflicts.
25. Mandra et al. Vitamin B supplementation for diabetic peripheral neuropathy. J Clin Med 2026 — meta-analysis; funding not found; no conflicts declared.
26. Hershman et al. Acetyl-L-carnitine for prevention of taxane-induced neuropathy (SWOG S0715). J Clin Oncol 2013 — NCI, ASCO Conquer Cancer Foundation and Avon Foundation.
27. SWOG S0715 full text — funding and disclosures.
28. Loprinzi et al. Prevention and management of chemotherapy-induced peripheral neuropathy: ASCO guideline update. J Clin Oncol 2020 — professional society guideline; funding statement not seen.

Educational research reviewed 6 October 2026. This article is not medical advice; talk to a qualified clinician or pharmacist before starting, stopping or combining treatments.