Clinical trial NCT06306157: Low Dose Naltrexone Therapy for Complex Regional Pain Syndrome
Official title: Low Dose Naltrexone (LDN) Therapy for Complex Regional Pain Syndrome (CRPS): a Feasibility Study
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Complex Regional Pain Syndrome
Chronic Pain
Causalgia
Complex Regional Pain Syndrome Type I
Complex Regional Pain Syndrome Type II
Keywords: Chronic pain
Pain management
Drug intervention
CRPS
Lead sponsor: Hospital for Special Surgery, New York
Sponsor class: OTHER
First posted: 2024-03-12
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a feasibility, randomized, placebo-controlled interventional drug study.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: Naltrexone, an FDA-approved medication since 1984, is classically prescribed in daily doses of at least 50 mg to mediate opiate and alcohol abuse as part of a comprehensive treatment program. By acting as an antagonist in the body, full-strength naltrexone competitively binds to opioid receptors and blocks the effects of opioid-classified drugs, thereby helping to reduce reliance and addiction. In much lower doses (1.5 - 4.5mg per day), naltrexone has been seen to reduce inflammation and nerve pain by instead blocking a different set of receptors involved in cytokine release and uptake. The exact mechanism of naltrexone's ability to decrease inflammation, swelling, and chronic nerve pain is unknown; however further research is being done to discover more. When healthcare providers prescribe naltrexone in these low doses, the medication is referred to as low-dose naltrexone-or LDN.

As of recently, healthcare providers have begun looking at the efficacy of low-dose naltrexone when treating pain caused primarily by the nervous system, referred to as neuropathic pain. Complex Regional Pain Syndrome (CRPS) is a debilitating chronic pain condition caused by dysfunction of or damage to the nervous system. CRPS can be caused by an injury, surgery, or have no obvious cause at all. CRPS typically affects a specific area of the body, such as the hands or feet, and symptoms may include extreme sensitivity, pins-and-needles sensation, color and/or temperature changes, swelling, and stinging. One treatment route commonly prescribed for CRPS is an anti-neuropathic medication regime of Gabapentin or Pregabalin-medications prescribed to specifically ease nerve-related pain. Targeted nerve blocks and epidural injections are other common treatments physiatrists and pain providers will perform for CRPS patients, often in conjunction with medication and physical therapy for a comprehensive pain management plan. However, for those who cannot take anti-neuropathic medications and are hesitant to pursue more invasive routes like nerve blocks or spinal cord stimulations, there is a lack of available treatment options which makes pain management uncertain and inconsistent. In an effort to diversify available treatments, there is a budding interest in the role that low-dose naltrexone may play in reducing chronic pain associated with CRPS.

There is currently only one other low-dose naltrexone study being conducted with Complex Regional Pain Syndrome patients as the primary study population. Dr. Sean Mackey is leading this study through the Stanford Division of Pain Medicine, and the study is still in the process of enrolling eligible patients. Published case studies demonstrate the promising nature of the drug in a multi-modal treatment course and suggest that more extensive research on the effectiveness of low-dose naltrexone would be beneficial. When physicians wish to incorporate LDN into the treatment course for a CRPS patient, they have additional barriers to cross because naltrexone is FDA-approved only for alcohol and opioid-use disorders. The lack of FDA-approval for naltrexone in CRPS treatment creates limited accessibility to the drug, the need for compounding pharmacy involvement, and a lack of education surrounding low-dose naltrexone in the CRPS and chronic pain community. Conducting controlled clinical trials and thereby learning more about the efficacy of low-dose naltrexone and possible side effects or adverse reactions would help establish LDN as another treatment possibility for frustrated patients dealing with this chronic pain syndrome.

Our feasibility study has two purposes: to evaluate the potential of LDN as CRPS pain management, and to evaluate whether such a long-term interventional drug study can be conducted at the Hospital for Special Surgery (HSS). Not only will the investigators be collecting pain scores over time to better understand whether LDN may help improve pain and symptom severity, but the investigators will also be collecting information regarding how many patients enroll, how many patients remain enrolled during the duration of the study, why patients may un-enroll, and how compliant patients are with taking the daily study medication. This study will be requesting that each enrolled patient take a medication every day for 6 months, consistently attend office visits when requested, and take record of how often they miss a dose. To date and to our knowledge, no similar study requiring such extensive participation and long-term medication consumption has been conducted at HSS-whether in the main hospital or through an outpatient clinic. In order to expand on the knowledge base HSS has developed regarding its chronic pain patient population, long-term research utilizing placebo and study medication is essential. Prior to conducting larger-scale interventional drug studies, it is imperative that the workflow is streamlined and established protocols are in place. Aside from looking into the LDN-CRPS relationship, the main purpose of this feasibility study is to develop an infrastructure to demonstrate that interventional drug studies of this magnitude are possible at HSS, establish novel protocols and standard operating procedures, and gauge the receptiveness of chronic pain patients to studies of this kind at HSS.

Over the course of two years, a total of 40 patients recently diagnosed with CRPS at the 75th St HSS outpatient location will be enrolled and randomized to receive either capsules with the active low-dose naltrexone medication, or placebo capsules which do not contain any active ingredient. The study medication will be supplied to study patients in addition to any standard CRPS therapies, including physical therapy, medication management, and interventional therapies. Enrolled patients will take the medication every day for a total of 6 months and will attend standard of care office visits after 1 month, after 3 months, and after 6 months. Before each visit, patients will be asked to record their daily average pain for one week leading up to the visit. In between office visits, a study team member will be calling the patients to record medication consumption compliance, pain scores, questionnaire responses, adverse reactions, and any side effects. Questionnaires will include PROMIS-10, S-LANSS, and an NRS screening. A study team member will also be calling patients as a reminder to record in their 7-day pain diary when necessary. A major component of the study protocol is the titration schedule-a schedule that defines how the drug dosage will increase over time-which Dr. Semih Gungor, the principal physician investigator, has already established at his clinic. While it is subject to change depending on the patient's CRPS symptom progression and medication-related side effects, the titration schedule built into the study protocol will be starting at 1.5mg during the 1st month, increasing to 3mg the 2nd month, and finally up to 4.5mg the 3rd month and beyond. The purpose of this titration schedule is to limit the side effects a patient may feel when starting on naltrexone and to gradually introduce them to the drug to facilitate a long-term treatment.

Through the enrollment of study patients and successful dispensation of daily medication over a 6-month time period, our study aims to collect preliminary data on pain scores, symptom severity, and side-effects in patients randomized to LDN vs. placebo, as well as determine the feasibility of conducting a long-term interventional drug study-with the goal of expanding future research opportunities at HSS and supplementing treatment courses for those struggling with this often debilitating chronic pain syndrome.

Eligibility criteria: Inclusion Criteria:

* Between 18 and 65 years old
* Meeting CRPS diagnostic criteria using the Budapest Clinical Diagnostic Criteria
* CRPS patients with severe pain (NRS\>3) that affects their daily life.
* CRPS patients with pain and other symptoms for more than 3 months.

Exclusion Criteria:

* Patients with suspected disc herniation, spinal stenosis, myelopathy, and suspected radiculopathy in detailed examinations and examinations (MRI, CT).
* Systemic or local infection
* Malignancy
* Current or planned pregnancy within the study period.
* Uncontrolled medical and psychiatric condition
* Patients with known liver issues, including but not limited to end-stage liver disease, severe cirrhosis or an acute hepatic state.
* Patients who are currently using opioid drugs
* Patients who are currently using alcohol or considering using alcohol during the study period.
* Allergy to naltrexone or naloxone

Primary outcomes:
measure: Number of study patients enrolled
timeFrame: Within 2 years of study start
measure: Number of study patients randomized
timeFrame: At initial time of enrollment
measure: Number of study patients who received the study medication
timeFrame: At initial time of enrollment and at 3 months.
Secondary outcomes:
measure: Incidence of side effects/adverse events
timeFrame: 1, 3, and 6 months
measure: Average NRS pain
timeFrame: Baseline, 1, 3, and 6 months.
measure: CRPS symptom severity
timeFrame: Baseline, 1, 3, and 6 months.
measure: PROMIS-10 score
timeFrame: Baseline, 1, 3, and 6 months
measure: S-LANSS score
timeFrame: Baseline, 1, 3, and 6 months
measure: Blinding assessment
timeFrame: 1, 3, and 6 months
Other outcomes:
measure: Enrollment rate
timeFrame: At study completion (approximately 2 years after study initiation)
measure: Study medication compliance
timeFrame: 1, 3, and 6 months
measure: Reasons for study medication non-compliance
timeFrame: 1, 3, and 6 months
measure: Drop-out rate
timeFrame: 1, 3, and 6 months
measure: Reasons for drop-out
timeFrame: 1, 3, and 6 months
Locations:
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
Study officials:
affiliation: Hospital for Special Surgery, New York
name: Semih Gungor, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital for Special Surgery, New York
name: Alexandra Sideris, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Med Sci (Basel). 2018 Sep 21;6(4):82. doi: 10.3390/medsci6040082.
citation: Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol. 2013 Jun;8(3):470-6. doi: 10.1007/s11481-013-9451-y. Epub 2013 Apr 2.