Low Dose Naltrexone for Complex Regional Pain Syndrome

(LDN-CRPS Trial)

Overseen By Alexandra Sideris, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Hospital for Special Surgery, New York

Must not be taking: Opioids, Alcohol

Disqualifiers: Disc herniation, Infection, Malignancy, Pregnancy, others

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

Compensation: Varies

Number of Visits: 3

Duration: 6 months

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Complex Regional Pain Syndrome (CRPS) is a rare and often debilitating chronic pain condition whereby individuals may experience extreme sensitivity, discoloration, and swelling of the affected area -- along with numerous other painful symptoms. There are currently a limited number of treatment options available to those suffering with the condition, with various treatments including nerve blocks, neuropathic medications, and desensitization physical therapy modules. There is budding interesting in the role naltrexone, an opiate antagonist, may play in the pain management of CRPS when prescribed in very low doses. This study aims to collect preliminary data on pain scores, symptom severity, and side-effects in patients with Complex Regional Pain Syndrome randomized to receive low dose naltrexone or placebo capsules. Enrollment of 40 patients total will occur over two years from study start to study end. Each patient will be randomized to receive placebo capsules or active low dose naltrexone capsules, with both the patient and treating clinician blind to the randomization. Each patient will be actively enrolled in the study for six months and will take the medication daily at the instructed dose for the respective duration of time. Following the initial visit and study enrollment, the investigators are asking each patient to return for three (3) in-person follow-up office visits. These office visits will occur 1 month after the patient starts the medication, 3 months afterwards, and 6 months afterwards. The final 6-month office visit will mark the conclusion of the patient's active participation in the study.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using opioid drugs or alcohol.

What data supports the effectiveness of the drug low dose naltrexone for treating Complex Regional Pain Syndrome?

Research shows that low dose naltrexone helped two patients with Complex Regional Pain Syndrome by reducing symptoms like muscle spasms and abnormal muscle contractions, especially when other treatments didn't work. This suggests it might be effective for some people with this condition. ^{1 2 3 4 5}

Is low dose naltrexone safe for humans?

The research on low dose naltrexone (LDN) for Complex Regional Pain Syndrome (CRPS) does not provide specific safety data, but LDN has been used in other conditions with a generally good safety profile. It is known to work by affecting certain pathways in the brain and immune system, and is typically well-tolerated in low doses. ^{1 5 6 7 8}

How does the drug low-dose naltrexone differ from other treatments for complex regional pain syndrome?

Low-dose naltrexone is unique because it is a nonopioid alternative that works by reducing inflammation and enhancing the body's natural pain relief mechanisms, unlike traditional pain medications that often have significant side effects. It is used in much lower doses than when prescribed for addiction, making it a novel option for managing chronic pain with minimal adverse effects. ^{2 9 10 11 12}

Research Team

Semih Gungor, M.D.

Principal Investigator

Hospital for Special Surgery, New York

Alexandra Sideris, PhD

Principal Investigator

Hospital for Special Surgery, New York

Eligibility Criteria

This trial is for individuals with Complex Regional Pain Syndrome (CRPS), a rare chronic pain condition. Participants should be willing to take medication daily and attend three in-person follow-up visits over six months. Specific inclusion and exclusion criteria details are not provided.

Inclusion Criteria

I have CRPS with severe pain that disrupts my daily activities.

Meeting CRPS diagnostic criteria using the Budapest Clinical Diagnostic Criteria

I have had CRPS pain and symptoms for over 3 months.

Exclusion Criteria

Uncontrolled medical and psychiatric condition

I currently have an infection.

Current or planned pregnancy within the study period

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive low dose naltrexone or placebo capsules daily for 6 months, with titration of dosage over the first 3 months

6 months

3 visits (in-person) at 1, 3, and 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Low dose naltrexone

Trial Overview The study is testing the effectiveness of low dose naltrexone, an opiate blocker, compared to placebo sugar capsules in managing CRPS pain. Patients will be randomly assigned to either treatment without knowing which one they receive.

Participant Groups

Group I: Low dose naltrexone Experimental Treatment 1 Intervention

Half of all enrolled patients will be randomized to receive capsules with the active low dose naltrexone (LDN) ingredient. LDN will be titrated over time to minimize potential side effects, with the initial dose starting at 1.5mg and eventually increasing up to 4.5mg. Neither the patient nor treating physician will be aware of the group in which the patient was randomized into until after study conclusion. All patients will be requested to take the respective daily dose and follow the titration schedule as instructed. All patients enrolled in the study, regardless of their randomization, will have standard of care treatment for CRPS according to their symptoms and the clinical judgment of the treating clinician.

Group II: Placebo sugar capsules Placebo Group 1 Intervention

Half of all enrolled patients will be randomized to receive placebo sugar capsules. Neither the patient nor treating physician will be aware of the group in which the patient was randomized into until after study conclusion. All patients will be requested to take the respective daily dose and follow the titration schedule as instructed. All patients enrolled in the study, regardless of their randomization, will have standard of care treatment for CRPS according to their symptoms and the clinical judgment of the treating clinician.

Who Is Running the Clinical Trial?

Hospital for Special Surgery, New York

Lead Sponsor

Trials

257

Recruited

61,800+

Findings from Research

Two patients with Complex Regional Pain Syndrome (CRPS) experienced significant symptom relief, including dystonic spasms and fixed dystonia, after being treated with low-dose naltrexone (LDN) alongside other therapies.

LDN works by antagonizing the Toll-like Receptor 4 pathway and reducing activated microglia, suggesting it may be an effective option for patients who do not respond to conventional CRPS treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). Chopra, P., Cooper, MS.[2021]

Transdermal buprenorphine was effective in reducing pain intensity by approximately 50% in two patients with refractory complex regional pain syndrome (CRPS).

The treatment was generally safe, with manageable side effects such as application site rash, which was treated with a topical steroid spray.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Transdermal Buprenorphine in Complex Regional Pain Syndrome: A Report of Two Cases. Onofrio, S., Vartan, CM., Nazario, M., et al.[2018]

In a study of 50 patients with complex regional pain syndrome type I (CRPS-I), prednisolone 20 mg was found to be as effective as 40 mg in reducing pain, with all patients achieving over 50% reduction in pain scores after one month.

The lower dose of prednisolone (20 mg) was safer for diabetic patients, requiring fewer adjustments to their antidiabetic medications compared to the higher dose (40 mg).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prednisolone 20 mg vs 40 mg in complex regional pain syndrome type I: A randomized controlled trial. Kalita, J., Pandey, PC., Shukla, R., et al.[2023]

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, ranging from 1 mg to 4.5 mg, is a promising nonopioid alternative for managing chronic pain, autoimmune disorders, and dermatologic conditions, despite being used off-label.

It offers a safer profile compared to traditional pain medications, as it has minimal adverse effects, no significant drug-drug interactions, and is more cost-effective, reducing risks associated with other pain management options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Low-Dose Naltrexone for Chronic Pain. Bostick, KM., McCarter, AG., Nykamp, D.[2019]

References

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

Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). [2021]

2. England pubmed.ncbi.nlm.nih.gov

The Use of Transdermal Buprenorphine in Complex Regional Pain Syndrome: A Report of Two Cases. [2018]

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

What is a meaningful pain reduction in patients with complex regional pain syndrome type 1? [2019]

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

NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Intravenous Ketamine Infusion for Complex Regional Pain Syndrome: Survey, Consensus, and a Reference Protocol. [2020]

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

Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. [2022]

7. Hungary pubmed.ncbi.nlm.nih.gov

[Treatment of complex regional pain syndrome with amitriptyline]. [2019]

8. Scotland pubmed.ncbi.nlm.nih.gov

Prednisolone 20 mg vs 40 mg in complex regional pain syndrome type I: A randomized controlled trial. [2023]

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

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

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

The Use of Low-Dose Naltrexone for Chronic Pain. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects. [2013]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. [2020]