Low-Dose Naltrexone for Diabetic Neuropathy

Overseen By Bruce Vrooman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dartmouth-Hitchcock Medical Center

Must not be taking: Opioids

Disqualifiers: Substance use disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called Low-Dose Naltrexone (LDN) to determine if it can relieve pain from diabetic neuropathy, a condition affecting the nerves in the legs and feet of people with diabetes. LDN boosts the body's natural pain relief and reduces inflammation. The trial compares the effects of LDN to a placebo (a non-active pill) to assess its effectiveness. Individuals with painful diabetic neuropathy for more than six months who haven't found relief with standard treatments might be suitable for this study. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group, offering a chance to benefit from a potentially effective new therapy.

Will I have to stop taking my current medications?

The trial requires that you have been stable on all your current non-opioid pain medications for at least 1 month, so you won't need to stop those. However, you cannot be on opioid therapy or have been on it within the past month.

Is there any evidence suggesting that Low-Dose Naltrexone is likely to be safe for humans?

Research has shown that Low-Dose Naltrexone (LDN) is generally safe and has few side effects. In studies, LDN has treated other painful conditions with good safety results. Patients have reported only minor side effects, making it a well-tolerated option. Although LDN's use for diabetic nerve pain remains underexplored, its safety in similar conditions is encouraging. This suggests that LDN could manage pain safely without the risks associated with opioids. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for diabetic neuropathy?

Unlike the standard treatments for diabetic neuropathy, which often involve pain relief through medications like gabapentin or duloxetine, low-dose naltrexone stands out due to its unique mechanism of action. Naltrexone works by modulating the body's immune response and reducing inflammation, offering a different approach to managing symptoms. Researchers are particularly excited about its potential to effectively alleviate nerve pain with fewer side effects, given its lower dosage compared to traditional treatments. This novel approach could provide substantial relief to patients who do not respond well to current standard therapies.

What evidence suggests that Low-Dose Naltrexone might be an effective treatment for diabetic neuropathy?

Research has shown that low-dose naltrexone (LDN) might help relieve pain from diabetic nerve damage. In this trial, participants will receive LDN in one of the study arms. One study found that LDN worked as well as amitriptyline, a common pain medicine, in easing pain for people with this condition. LDN enhances the body's natural pain relief and reduces inflammation by affecting certain cells involved in long-term pain. It is considered safe and has few side effects. While more studies are needed specifically for diabetic nerve pain, LDN has shown promise in other pain conditions, suggesting it could be a useful alternative to opioids. ^{1 2 3 4 6}

Who Is on the Research Team?

Bruce M Vrooman, MD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Are You a Good Fit for This Trial?

Adults over 18 with painful diabetic neuropathy for more than 6 months, who've tried and failed at least one standard treatment like Gabapentin or duloxetine. Participants must be stable on current non-opioid pain meds for a month, speak English, and can't have other causes of lower leg pain or any substance use disorders.

Inclusion Criteria

English as primary language

Subjects capable of giving informed consent

I have been diagnosed with painful diabetic neuropathy for over 6 months.

Exclusion Criteria

You are allergic to naltrexone or naloxone.

You currently have a problem with drugs or alcohol, as diagnosed by a specific manual used by doctors.

I have nerve pain in my legs not caused by diabetic nerve damage.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Low-Dose Naltrexone or placebo in a crossover design, with 8 weeks of active drug and 4 weeks of placebo

12 weeks

Weekly email surveys, initial in-person enrollment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Naltrexone
• Placebo

Trial Overview

The trial is testing Low-Dose Naltrexone (LDN) against a placebo to see if it helps with the pain from diabetic neuropathy without using opioids. LDN works by boosting natural pain relief in the body and reducing inflammation.

How Is the Trial Designed?

Group I: Group B, Placebo, Then Low-Dose Naltrexone Experimental Treatment 2 Interventions

Group B will receive 4 weeks of placebo (placebo capsule will be matched with LDN capsule, microcrystalline cellulose filler, 1 capsule daily). Then followed by active drug (Naltrexone 1 capsule by mouth daily, 1.5mg x1 week, 3mg x1 week, and 4.5 mg x6 weeks) for the last 8 weeks. Capsules of different dosages will be indistinguishable.

Group II: Group A, Low-Dose Naltrexone, Then Placebo Experimental Treatment 2 Interventions

Group A will receive active drug (Naltrexone 1 capsule by mouth daily, 1.5mg x1 week, 3mg x1 week, and 4.5 mg x6 weeks) for the first 8 weeks. Capsules of different dosages will be indistinguishable. Then followed by 4 weeks of placebo (placebo capsule will be matched with LDN capsule, microcrystalline cellulose filler, 1 capsule daily).

Naltrexone is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Vivitrol for:

• Alcohol dependence
• Opioid use disorder

Approved in European Union as Naltrexone for:

• Opioid dependence
• Alcohol dependence

Approved in Canada as Vivitrol for:

• Opioid use disorder
• Alcohol dependence

Who Is Running the Clinical Trial?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

Published Research Related to This Trial

In a study involving 67 participants with painful diabetic neuropathy, low-dose naltrexone (2 mg) showed similar efficacy to amitriptyline (10 mg) in reducing pain over 6 weeks, indicating it could be a viable alternative treatment.

Naltrexone had a significantly better safety profile, with only 8 adverse events reported compared to 52 for amitriptyline, suggesting it may be a safer option for patients suffering from this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial. Srinivasan, A., Dutta, P., Bansal, D., et al.[2022]

Low-dose naltrexone is as effective as amitriptyline for treating painful diabetic neuropathy, while also having a better safety profile, based on a single randomized controlled trial.

In patients with fibromyalgia, doses as low as 5.4 mg of low-dose naltrexone reduced pain in 95% of cases, indicating its strong efficacy in managing pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is low-dose naltrexone effective in chronic pain management? Radi, R., Huang, H., Rivera, J., et al.[2023]

Pregabalin is established as an effective treatment for painful diabetic neuropathy (PDN) and should be offered to patients, based on a systematic review of literature from 1960 to 2008 involving various treatment options.

Other treatments like venlafaxine, duloxetine, and gabapentin are probably effective for PDN, but many effective options have side effects that may limit their usefulness, highlighting the need for more studies on their impact on physical function and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-based guideline: treatment of painful diabetic neuropathy--report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation. Bril, V., England, JD., Franklin, GM., et al.[2018]

In a study of 15 diabetic patients with neuropathy, imipramine treatment provided significant symptom relief for 14 patients, indicating its efficacy in managing neuropathy symptoms.

The study found that while many patients experienced relief at lower plasma levels of imipramine, concentrations above 400-500 nmol/L were necessary for optimal effect, highlighting the importance of careful dose titration and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concentration-response relationship in imipramine treatment of diabetic neuropathy symptoms. Sindrup, SH., Gram, LF., Skjold, T., et al.[2019]

Tapentadol extended-release is specifically FDA-approved for treating painful diabetic peripheral neuropathy and works through a dual mechanism as both a mu-opioid receptor agonist and a norepinephrine reuptake inhibitor.

This review aims to evaluate the efficacy and safety of tapentadol in adults with this condition, highlighting its potential as a first-line treatment option alongside traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical value of tapentadol extended-release in painful diabetic peripheral neuropathy. Desai, B., Freeman, E., Huang, E., et al.[2018]

Tapentadol-ER has recently been approved by the FDA as a new treatment option for painful diabetic peripheral neuropathy (DPN), expanding the available therapies beyond pregabalin and duloxetine.

This medication works through a unique dual mechanism, acting as both a weak mu-opioid receptor agonist and a norepinephrine reuptake inhibitor, which may enhance its effectiveness and tolerability for patients suffering from DPN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tapentadol-ER for the treatment of diabetic peripheral neuropathy. Games, G., Hutchison, A.[2018]

Painful diabetic neuropathy is a common and costly issue for people with diabetes, often linked to poor glycemic control, but current treatments are inadequate and lack a mechanistically-based approach.

New neuromodulation devices have been recently approved by the FDA as potential next-line therapies for painful diabetic neuropathy, offering hope for patients who do not respond to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Painful Diabetic Neuropathy: The Need for New Approaches. Yeung, AM., Huang, J., Nguyen, KT., et al.[2022]

A systematic review of 49 trials found that only 14% of studies on naltrexone for alcohol dependence had high adherence assurance, which may explain the variability in treatment efficacy observed.

The study revealed a significant correlation between adherence levels and treatment outcomes, suggesting that improving adherence monitoring could enhance the effectiveness of naltrexone in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence monitoring in naltrexone pharmacotherapy trials: a systematic review. Swift, R., Oslin, DW., Alexander, M., et al.[2022]

Injectable extended-release naltrexone, developed using biodegradable polymer microspheres, maintains stable plasma levels for about one month after a single injection, which could improve patient compliance compared to oral formulations.

Pharmacokinetic studies in rats and monkeys showed that this formulation effectively antagonizes morphine analgesia without affecting the brain's mu-opioid receptor density, indicating its potential safety and efficacy in treating alcohol and opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The preclinical development of Medisorb Naltrexone, a once a month long acting injection, for the treatment of alcohol dependence. Dean, RL.[2019]

The FDA-approved extended-release injectable formulation of naltrexone (Vivitrol) offers a promising alternative to daily oral medication for alcohol dependence, potentially improving adherence and treatment outcomes.

When combined with psychosocial support, long-acting naltrexone has shown significant improvements in drinking outcomes, particularly for patients who are abstinent at the start of treatment, suggesting its efficacy in managing alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting injectable naltrexone for the treatment of alcohol dependence. Mannelli, P., Peindl, K., Masand, PS., et al.[2013]

Low-dose naltrexone, at doses one-tenth of those used for treating alcohol and opioid dependency, has shown potential in alleviating pain, as demonstrated in a case study.

Although there are no randomized clinical trials yet, the case study indicates that low-dose naltrexone can significantly improve pain symptoms that have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Dose Naltrexone: A New Therapy Option for Complex Regional Pain Syndrome Type I Patients. Sturn, KM., Collin, M.[2017]

Low-dose naltrexone is considered safe and well-tolerated for treating chronic inflammatory conditions like multiple sclerosis, fibromyalgia, and Crohn's disease, based on current evidence.

While low-dose naltrexone shows subjective benefits in improving quality of life and reducing self-reported pain compared to placebo, more rigorous randomized controlled trials are needed to establish its efficacy through objective measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders. Patten, DK., Schultz, BG., Berlau, DJ.[2019]

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