LDN for Complex Regional Pain Syndrome

(LDN-CRPS Trial)

Overseen By Sean Mackey, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Stanford University

Must not be taking: Opioid analgesics

Disqualifiers: Allergy to naltrexone, Pregnancy, others

Compensation: Varies

Number of Visits: Unknown

Duration: Several weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators are testing treatment with low-dose naltrexone (LDN) for symptom relief of complex regional pain syndrome (CRPS). Study participants will be randomly assigned to receive either LDN or placebo for a period of several weeks. During this period participants will be asked to attend either in-person or virtual study visits and complete questionnaires.

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 must not be using prescription opioids or illegal opioids.

What evidence supports the effectiveness of the drug LDN (Low Dose Naltrexone) for treating Complex Regional Pain Syndrome?

Research on similar drugs suggests that opioid receptor agonists, like those in LDN, can help manage pain by reducing sensitivity to pain and inflammation. Studies on other opioid receptor drugs show they can be effective in treating chronic pain conditions with fewer side effects, which may indicate potential benefits for LDN in Complex Regional Pain Syndrome. ^{1 2 3 4 5}

Is low-dose naltrexone (LDN) safe for use in humans?

Current studies suggest that low-dose naltrexone (LDN) is generally safe for use in humans, with no severe adverse events reported in the majority of studies reviewed. However, more well-designed trials with larger sample sizes are needed to confirm its safety. ^{6 7 8 9 10}

How does the drug LDN work for Complex Regional Pain Syndrome?

LDN (low-dose naltrexone) is unique for treating Complex Regional Pain Syndrome because it works by reducing inflammation in the nervous system through a specific pathway (Toll-like Receptor 4) and calming overactive immune cells (microglia), which is different from other treatments that often focus on pain relief or physical therapy. ^{11 12 13 14 15}

Research Team

Sean Mackey, MD, PhD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for individuals with Complex Regional Pain Syndrome (CRPS) in an arm or leg, who have been on a stable treatment plan for at least 3 months and have had CRPS for over a year. They must meet specific criteria called the Budapest criteria to participate. People allergic to naltrexone or naloxone, using opioid painkillers or illegal opioids, or who are pregnant or planning pregnancy cannot join.

Inclusion Criteria

I have CRPS in my arms and/or legs.

I have been on the same treatment for at least 3 months.

You have been diagnosed with Complex Regional Pain Syndrome (CRPS) according to specific criteria.

Exclusion Criteria

I use prescription painkillers or have used illegal opioids.

Current of planned pregnancy

You are allergic to naltrexone or naloxone.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either low-dose naltrexone or placebo for symptom relief of complex regional pain syndrome

Several weeks

In-person or virtual study visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• LDN
• Placebo

Trial Overview The study is examining if low-dose naltrexone (LDN) can help relieve symptoms of CRPS compared to a placebo. Participants will be randomly chosen to receive either LDN or a placebo and will attend study visits and fill out questionnaires over several weeks.

Participant Groups

Group I: LDN Experimental Treatment 1 Intervention

Naltrexone HCL, 4.5 mg, Once a day.

Group II: Placebo Placebo Group 1 Intervention

Sugar pill

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

Approved in United States as Naltrexone for:

• Alcohol dependence
• Opioid dependence

Approved in European Union as Naltrexone for:

• Alcohol dependence
• Opioid dependence

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Findings from Research

D1-like receptors (D1LRs) in the spinal cord play a crucial role in modulating pain by regulating the activation of μ-opioid receptors (MOR), which helps to suppress synaptic plasticity related to pain signaling.

Sustained activation of D1LRs can impair the pain-relieving effects of MOR, leading to increased sensitivity to pain after nerve injury, indicating that while D1LRs initially help in pain management, their prolonged activation can worsen pain conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dopamine D1-like Receptors Regulate Constitutive, μ-Opioid Receptor-Mediated Repression of Use-Dependent Synaptic Plasticity in Dorsal Horn Neurons: More Harm than Good? Aira, Z., Barrenetxea, T., Buesa, I., et al.[2020]

In a study involving 15 volunteers, naloxone did not significantly alter pain ratings or areas of hyperalgesia at low doses, indicating limited efficacy in this context.

However, naloxone at a higher dose (10 ng/mL) reversed the pain relief effects achieved during sessions of high-current-density electrical stimulation, suggesting that while naloxone-sensitive systems are activated, there are also naloxone-insensitive mechanisms at play in pain modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. Koppert, W., Filitz, J., Tröster, A., et al.[2013]

The delta opioid receptor (deltaOR) agonist, deltorphin II, effectively reduced cold hyperalgesia and mechanical allodynia in rats with neuropathic pain, indicating its potential as a treatment option for this type of chronic pain.

The pain-relieving effects of deltorphin II were specifically linked to deltaOR activation, as they were blocked by a delta-selective antagonist, suggesting that targeting deltaORs could be a promising strategy for managing neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Holdridge, SV., Cahill, CM.[2007]

The dual MOR-DOR agonist SRI-22141 was found to be more potent than morphine in treating neuropathic pain in mice, showing enhanced efficacy and significantly reduced tolerance compared to traditional opioids.

SRI-22141 demonstrated minimal dependence and an anti-inflammatory effect by reducing specific inflammatory markers in the spinal cord, indicating its potential as a safer alternative for chronic pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models. Lei, W., Vekariya, RH., Ananthan, S., et al.[2021]

Buprenorphine (BUP) at analgesic doses (0.2mg/70 kg IV and 2mg sublingual) effectively modulates brain responses to pain, showing a dose-dependent effect on central nervous system pain circuitry in healthy subjects.

The study highlights that BUP administration leads to changes in brain connectivity related to pain perception, suggesting that fMRI can be a valuable tool for optimizing dosing in the development of new pain medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine. Upadhyay, J., Anderson, J., Baumgartner, R., et al.[2013]

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]

This randomized controlled trial will assess the efficacy of low-dose naltrexone (LDN) in reducing pain intensity in 100 women with fibromyalgia over 12 weeks, providing high-level evidence on its effectiveness compared to placebo.

In addition to pain reduction, the study will evaluate LDN's impact on various fibromyalgia-related symptoms, such as fatigue and sleep disturbance, and explore its mechanism of action through exploratory outcomes like pain sensitivity and muscle performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial. Bruun, KD., Amris, K., Vaegter, HB., et al.[2021]

Low-dose naltrexone (LDN) appears to be effective in managing symptoms of fibromyalgia, based on a systematic review of 9 studies, including one randomized controlled trial and several case reports and pilot trials.

Safety assessments from 78% of the studies indicated no severe adverse events associated with LDN, suggesting it may be a safe treatment option, although the overall evidence is limited and more rigorous trials are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Safety and Efficacy of Low-Dose Naltrexone in Patients with Fibromyalgia: A Systematic Review. Yang, J., Shin, KM., Do, A., et al.[2023]

Low dose naltrexone (LDN) may help reduce pain and improve quality of life in patients with fibromyalgia, based on a systematic review of three small studies, but the overall evidence is considered weak due to high risk of bias and small sample sizes.

Some evidence suggests that inflammatory markers, such as erythrocyte sedimentation rate (ESR) and cytokines, may play a role in how LDN works, but more research is needed, especially with larger and more diverse populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia. Partridge, S., Quadt, L., Bolton, M., 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]

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]

A case study of a patient suffering from 2 years of phantom limb pain (PLP) showed significant improvement with sublingual buprenorphine/naloxone, highlighting its effectiveness in treating this challenging condition.

Buprenorphine/naloxone works through multiple mechanisms, including acting as a long-acting mu-opioid agonist and antagonizing other opioid receptors, suggesting it could be a promising early treatment option for PLP compared to traditional opioid therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haunting of the phantom limb pain abolished by buprenorphine/naloxone. Srejic, U., Banimahd, F.[2023]

Complex regional pain syndrome (CRPS) affects about 7% of patients after limb injuries and can transition from an inflammatory 'warm' phase to a 'cold' phase dominated by autonomic features, complicating treatment.

Management of chronic CRPS is challenging due to a lack of high-quality evidence for many treatments; however, multidisciplinary approaches including physical therapy, bisphosphonates, and spinal cord stimulation may improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complex regional pain syndrome. Bruehl, S.[2022]

A randomized double-blind placebo-controlled trial involving subjects with complex regional pain syndrome (CRPS) demonstrated that intravenous ketamine significantly reduced pain levels over a 3-month follow-up period, indicating its efficacy as a treatment option.

In contrast, the placebo group showed no significant changes in pain parameters, highlighting the effectiveness of ketamine compared to a non-active treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Schwartzman, RJ., Alexander, GM., Grothusen, JR., et al.[2022]

A randomized controlled trial with 45 participants suffering from Complex Regional Pain Syndrome (CRPS) showed that using virtual reality to alter the visual appearance of the affected hand led to significant reductions in both body perception disturbance and pain intensity after a single exposure.

Follow-up results indicated that the pain reduction was sustained for at least two weeks after repeated interventions, suggesting that this visual illusion technique could be a promising drug-free treatment option for individuals with refractory CRPS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Visual illusions modulate body perception disturbance and pain in Complex Regional Pain Syndrome: A randomized trial. Lewis, JS., Newport, R., Taylor, G., et al.[2021]

References

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

Dopamine D1-like Receptors Regulate Constitutive, μ-Opioid Receptor-Mediated Repression of Use-Dependent Synaptic Plasticity in Dorsal Horn Neurons: More Harm than Good? [2020]

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

Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. [2013]

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

Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. [2007]

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

A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models. [2021]

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

Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine. [2013]

6. England pubmed.ncbi.nlm.nih.gov

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

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

Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial. [2021]

8. New Zealand pubmed.ncbi.nlm.nih.gov

The Safety and Efficacy of Low-Dose Naltrexone in Patients with Fibromyalgia: A Systematic Review. [2023]

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

A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia. [2023]

10. 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]

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

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

12. England pubmed.ncbi.nlm.nih.gov

Haunting of the phantom limb pain abolished by buprenorphine/naloxone. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Complex regional pain syndrome. [2022]

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

Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. [2022]

15. England pubmed.ncbi.nlm.nih.gov

Visual illusions modulate body perception disturbance and pain in Complex Regional Pain Syndrome: A randomized trial. [2021]