Low Dose Naltrexone for Pain in HIV/AIDS

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Anne M McKenzie-Brown, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Emory University

Must not be taking: Opioids

Disqualifiers: Pregnancy, Bipolar, Liver disease, others

No Placebo Group

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The increased life expectancy of Patients Living With HIV/AIDS (PLWHA) has increased the need for therapies for chronic conditions, such as chronic pain. Pain in the HIV population is often refractory and ends up being treated with chronic opioids, which are associated with adverse effects, including hyperalgesia, constipation, and risk of overdose. Naltrexone is an opioid antagonist used in the treatment of alcohol and opioid use disorders. Low Dose Naltrexone (LDN), naltrexone at a much lower dose, is thought to be an immune modulator and has been associated with an increased CD4 count in PLWHA. Repurposing this medication is relatively inexpensive and has the potential to expand access to treatment for a painful condition experienced in PLWHA. While there are many case reports on the efficacy of LDN in symptom reduction, there are only a small number of clinical trials that specifically examine pain and symptom relief. This study will include patients who are not completely virologically controlled and will monitor the CD4 counts drawn as a part of routine care. If the CD4 count improves with LDN and with reduced symptoms, this could be a significant improvement in HIV therapy for symptom control. There have been studies showing cytokine reduction in fibromyalgia patients but they did not investigate the correlation with cytokines and pain relief. This study involves repurposing a drug used for substance use disorder to a medication with the potential to treat pain and improve symptoms for PLWHA.

Will I have to stop taking my current medications?

The trial requires that you stop using any opioids at least 10 days before starting the study. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Low Dose Naltrexone for pain in HIV/AIDS?

Research shows that Low Dose Naltrexone (LDN) has been used to reduce chronic pain in conditions like arthritis, suggesting it might help with pain in HIV/AIDS as well. Additionally, naltrexone is known to act on opioid receptors, which are important for pain regulation. ^{1 2 3 4 5}

Is low dose naltrexone safe for humans?

Naltrexone, including its low-dose form, is generally considered safe for humans, but it can have potential liver-related side effects, especially in those with existing liver conditions. Studies have evaluated its safety in people with chronic hepatitis C and HIV, and it is used for various conditions, indicating a recognized safety profile. ^{1 2 3 6 7}

How is low-dose naltrexone different from other drugs for pain in HIV/AIDS?

Low-dose naltrexone is unique because it is a non-opioid drug that can help manage chronic pain with minimal side effects and no drug interactions, unlike traditional pain medications that often have significant adverse effects. It works by blocking opioid receptors and may reduce pain through a mechanism involving TLR-4 antagonism, making it a novel option for those with chronic pain in HIV/AIDS. ^{1 3 4 8 9}

Research Team

Anne M McKenzie-Brown, MD

Principal Investigator

Emory University

Eligibility Criteria

This trial is for adults aged 18-65 with HIV and chronic neuropathic pain, who have a viral load under 1000 copies/ml. Participants must be fluent in English and willing to follow study rules. Excluded are those using opioids or at risk of needing them, with allergies to naltrexone, severe liver or kidney disease, certain psychiatric conditions, active substance abuse disorders, pregnant/nursing women, or not using effective contraception.

Inclusion Criteria

I have been experiencing pain greater than 4 out of 10 for more than 3 months.

Fluent English-speaking

Diagnosis of neuropathic pain using the neuropathic pain screening tool, painDETECT17

Exclusion Criteria

Prisoners

I am not breastfeeding and use effective birth control.

Allergy to naltrexone

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive low-dose naltrexone (LDN) for 12 weeks to treat neuropathic pain

12 weeks

Weekly assessments (virtual or in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Low Dose Naltrexone (Opioid Antagonist)

Trial Overview The trial tests Low Dose Naltrexone (LDN) as a treatment for chronic pain in patients living with HIV/AIDS. LDN is an immune modulator that may reduce pain by affecting the immune system without the adverse effects associated with opioids.

Participant Groups

Group I: Low Dose Naloxone (LDN) Experimental Treatment 1 Intervention

Once a potential subject has been identified they may be contacted with information about the study in advance of their appointment in order to allow time for them to consider the study. A qualifying pain score will be confirmed with the subject prior to initiating consent. This may occur up to 30 days before the baseline, treatment visit, but inclusion/exclusion criteria will be re-confirmed prior to initiating study treatment. Patients may also be approached during a clinic visit. Subjects will be started with 3mg LDN orally administered daily for one week with a planned increase to 4 mg/day beginning week two, if tolerated. They will be provided a 4 week supply of study medication. LDN will be given as a daytime dose.

Group II: Control Active Control 1 Intervention

Once a potential subject has been identified they may be contacted with information about the study in advance of their appointment in order to allow time for them to consider the study. A qualifying pain score will be confirmed with the subject prior to initiating consent. This may occur up to 30 days before the baseline, treatment visit, but inclusion/exclusion criteria will be re-confirmed prior to initiating study treatment. Patients may also be approached during a clinic visit. Should a patient decline participation in the treatment plan, they will be invited to participate in a control group. They will be invited to complete the PROMIS questionnaire every 4 weeks, and the NPRS pain assessment every week from Baseline through week 12. These participants will receive follow up phone calls to confirm completion of these assessments weekly and will not have any in-person visits.

Low Dose Naltrexone is already approved in Canada for the following indications:

Approved in Canada as Naltrexone Hydrochloride for:

• Alcohol dependence
• Opioid dependence

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Dr. R. Donald Harvey

Emory University

Chief Medical Officer

MD from Emory University School of Medicine

Dr. George Painter

Emory University

Chief Executive Officer since 2013

PhD in Synthetic Organic Chemistry from Emory University

Findings from Research

In a pilot study involving 23 patients with osteoarthritis and inflammatory arthritis, low-dose naltrexone (LDN) did not show a significant difference in reducing pain interference compared to a placebo, suggesting it may not be effective for nociceptive pain associated with arthritis.

The study also found no significant changes in pain severity, fatigue, depression, or quality of life, indicating that LDN may not provide the expected benefits for patients with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot Study of Low-dose Naltrexone for the Treatment of Chronic Pain Due to Arthritis: A Randomized, Double-blind, Placebo-controlled, Crossover Clinical Trial. Beaudette-Zlatanova, B., Lew, RA., Otis, JD., et al.[2023]

Following a 2013 TV documentary, the use of low dose naltrexone (LDN) in Norway surged, with 15,297 patients (0.3% of the population) receiving prescriptions, indicating a significant increase in off-label use despite limited evidence.

The median daily dose of LDN was 3.7 mg, and a notable 20% of doctors, including 71% of general practitioners, prescribed LDN at least once, reflecting a high willingness to adopt this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A sudden and unprecedented increase in low dose naltrexone (LDN) prescribing in Norway. Patient and prescriber characteristics, and dispense patterns. A drug utilization cohort study. Raknes, G., Småbrekke, L.[2022]

In a 48-week study involving 200 participants with opioid addiction and HIV, the naltrexone implant group showed a significant improvement in maintaining viral loads below 400 copies per mL at 48 weeks compared to the oral naltrexone group, suggesting that long-acting naltrexone may enhance HIV treatment outcomes.

Despite some serious adverse events, including deaths in both groups, the study indicates that longer opioid blockade from the implant may help protect against missed antiretroviral therapy doses and impulsive behaviors that could lead to relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Slow-release naltrexone implant versus oral naltrexone for improving treatment outcomes in people with HIV who are addicted to opioids: a double-blind, placebo-controlled, randomised trial. Krupitsky, E., Blokhina, E., Zvartau, E., et al.[2020]

In a study of 2334 individuals living with HIV, chronic pain was found to significantly increase the risk of suboptimal retention in care and virologic failure, particularly in those not receiving long-term opioid therapy (LTOT).

Interestingly, among those with chronic pain, LTOT was associated with lower rates of virologic failure, suggesting that LTOT may have a protective effect on HIV outcomes that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brief Report: The Association of Chronic Pain and Long-Term Opioid Therapy With HIV Treatment Outcomes. Merlin, JS., Long, D., Becker, WC., et al.[2022]

In a study of 194 women living with HIV, those who used alcohol to manage pain reduced their drinking more slowly than those who did not, indicating that pain management strategies may influence alcohol consumption patterns.

Naltrexone treatment was effective in reducing alcohol consumption overall, but the most significant reductions were observed in women not using alcohol for pain relief, suggesting that addressing pain in treatment guidelines could improve outcomes for those with hazardous drinking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does treating pain with alcohol affect drinking reduction among women with HIV enrolled in a clinical trial of naltrexone? Parisi, CE., Gracy, HR., Bush, NJ., et al.[2023]

A study involving 250 opioid-dependent patients, many of whom had chronic hepatitis C virus (HCV) and HIV, found that intramuscular extended-release naltrexone (XR-NTX) did not significantly increase liver enzyme levels compared to a placebo, indicating its safety in this population.

Even though some patients experienced elevated liver enzymes, these levels improved over time, and no specific symptoms were linked to these elevations, suggesting that XR-NTX can be safely administered to patients with mild to moderate chronic HCV and/or HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. Mitchell, MC., Memisoglu, A., Silverman, BL.[2019]

In a 1-year open-label extension study involving 114 patients, injectable extended-release naltrexone (XR-NTX) demonstrated long-term efficacy, with 50.9% of participants remaining abstinent from opioids throughout the study.

The treatment was generally safe, with only 21.1% of patients reporting adverse events and no severe adverse events noted, although 16.7% experienced elevated liver function tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy]. Krupitsky, EM., Nunes, EV., Ling, W., et al.[2016]

In a study of 36 patients using low-dose naltrexone (LDN) for at least 2 months, significant pain reduction was observed, with a 37.8% decrease in pain scores compared to only 4.3% in the control group, indicating LDN's efficacy as an analgesic.

LDN appears particularly beneficial for patients with neuropathic pain, and the study suggests that its pain-relieving effects may be mediated through TLR-4 antagonism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose naltrexone, an opioid-receptor antagonist, is a broad-spectrum analgesic: a retrospective cohort study. Martin, SJ., McAnally, HB., Okediji, P., et al.[2022]

References

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

Pilot Study of Low-dose Naltrexone for the Treatment of Chronic Pain Due to Arthritis: A Randomized, Double-blind, Placebo-controlled, Crossover Clinical Trial. [2023]

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

A sudden and unprecedented increase in low dose naltrexone (LDN) prescribing in Norway. Patient and prescriber characteristics, and dispense patterns. A drug utilization cohort study. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Slow-release naltrexone implant versus oral naltrexone for improving treatment outcomes in people with HIV who are addicted to opioids: a double-blind, placebo-controlled, randomised trial. [2020]

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

Brief Report: The Association of Chronic Pain and Long-Term Opioid Therapy With HIV Treatment Outcomes. [2022]

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

Does treating pain with alcohol affect drinking reduction among women with HIV enrolled in a clinical trial of naltrexone? [2023]

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

Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. [2019]

7. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy]. [2016]

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

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

9. England pubmed.ncbi.nlm.nih.gov

Low-dose naltrexone, an opioid-receptor antagonist, is a broad-spectrum analgesic: a retrospective cohort study. [2022]