Low-Dose Naltrexone for Diabetic Neuropathy

Recruiting in Palo Alto (17 mi)

Overseen by Bruce M Vrooman, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Dartmouth-Hitchcock Medical Center

Must not be taking: Opioids

Disqualifiers: Substance use disorder, others

No Placebo Group

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing Low-Dose Naltrexone (LDN) to see if it can help people with diabetes who have painful neuropathy in their legs and feet. LDN aims to reduce pain by enhancing the body's natural pain relief and decreasing inflammation. The study hopes to find a safer, non-opioid alternative for managing this difficult-to-treat pain.

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.

What evidence supports the effectiveness of the drug low-dose naltrexone for diabetic neuropathy?

Low-dose naltrexone has shown potential benefits in managing pain and inflammation in conditions like multiple sclerosis, fibromyalgia, and Crohn's disease, suggesting it might help with diabetic neuropathy. However, more studies are needed to confirm its effectiveness specifically for diabetic neuropathy. ^{1 2 3 4 5}

Is low-dose naltrexone safe for humans?

Low-dose naltrexone has been shown to have a good safety profile in treating chronic pain conditions, including diabetic neuropathy, with doses as low as 5.4 mg being well-tolerated by patients. ^{6 7 8 9 10}

How is the drug low-dose naltrexone different from other treatments for diabetic neuropathy?

Low-dose naltrexone is unique because it is as effective as amitriptyline for treating painful diabetic neuropathy but has a better safety profile, meaning it may cause fewer side effects. It is used in low doses (1-5 mg) and has shown effectiveness in reducing pain in various chronic conditions. ^{7 9 10 11 12}

Research Team

Bruce M Vrooman, MD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Naltrexone (Opioid Antagonist)
• Placebo (Other)

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.

Participant Groups

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 Canada for the following indications:

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+

Jonathan T. Huntington

Dartmouth-Hitchcock Medical Center

Chief Medical Officer since 2024

MD, PhD, MPH

Joanne M. Conroy

Dartmouth-Hitchcock Medical Center

Chief Executive Officer since 2017

MD from Medical University of South Carolina

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Adherence monitoring in naltrexone pharmacotherapy trials: a systematic review. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. England pubmed.ncbi.nlm.nih.gov

Long-acting injectable naltrexone for the treatment of alcohol dependence. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. United States 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. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Tapentadol-ER for the treatment of diabetic peripheral neuropathy. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Clinical value of tapentadol extended-release in painful diabetic peripheral neuropathy. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Painful Diabetic Neuropathy: The Need for New Approaches. [2022]

9. Australia 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. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Is low-dose naltrexone effective in chronic pain management? [2023]

11. United States 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. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Concentration-response relationship in imipramine treatment of diabetic neuropathy symptoms. [2019]