Terapia con naltrexone a basse dosi per la sindrome dolorosa regionale complessa (LDN-CRPS)

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.

The external appearance of the capsules prepared by the pharmacy will be identical to the LDN capsules. The inactive capsule ingredients will be microcrystalline cellulose (MCC) and Magnesium stearate

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.

While naltrexone is FDA-approved for treatment of alcohol or opioid addition, this study will be looking at how naltrexone, when dosed very low, may reduce the painful symptoms associated with CRPS. Naltrexone is not FDA-approved for pain management treatment of CRPS at this time, and therefore the study intervention is using the drug in an off-label manner.

• LDN

Enrollment of 40 patients within two years is the target (i.e. enrollment of 1-2 patients a month). If 1-2 patients a month is not being met within first 6 months, an invitation to other chronic pain co-investigators with high volume CRPS will be considered. Because this is a feasibility study, determining whether 40 patients can be enrolled with the current inclusion and exclusion criteria within a specified time frame is an essential step in ensuring such a long-term outpatient study can be conducted.

Measured as completed or not. Quadruple blinded randomization of each study patient to one of the two treatment arms after enrollment and before medication dispensation will be deemed successful. Because this is a feasibility study, determining whether 40 patients can be blindly randomized to a group according to the protocol is an essential step in ensuring such a long-term drug study can be conducted.

Dispensation of medication to all enrolled study patients at point of enrollment and at 3 months will be considered successful. If deemed necessary, dispensation can occur at time points other than the two previously defined and will still be considered successful if patient receives medication on time. Because this is a feasibility study implementing a long-term interventional drug treatment, it is essential that the investigators are measuring whether medication dispensation is occurring on time and according to the protocol.

Side effects or adverse events, including sleep disturbances, mild headaches, mild agitation, and nausea. Study patients are encouraged to contact the study team outside of study visits to report side effects/adverse events as they arise throughout course of the study, but the outcome is formally assessed at the below time points.

Pain measured using numerical rating scale (NRS) from 0-10, with 0 being no pain at all to 10 being the worst pain imaginable. NRS at baseline will be self-reported average at time of visit; NRS at 1, 3, and 6 months will be 7-day average leading up to those timepoints, collected via a patient diary.

CRPS symptom severity score (CSS) based on the Budapest Criteria which measures the severity of CRPS over time on a scale from 0-16 via the presence or absence of 8 specific symptoms and 8 specific signs. CSS will be measured at the respective in-person office visit.

The PROMIS-10 (Patient-Reported Outcomes Measurement Information System) score has two components, a physical score and a mental score, and is captured via a self-administered questionnaire with the purpose of assessing the patient's health-related quality of life. PROMIS-10 assessments are scored using T-score metrics and are calculated based on patient responses to the 10-item questionnaire. For the physical PROMIS-10 score, the lowest possible is 16.2 and the highest possible is 67.7. For the mental score, the lowest is 21.2 and the highest is 67.6. The higher a patient scores in each category, the greater their respective health is. A physical and mental T-score above 58 and 56, respectively, is rated "Excellent", whereas a physical and mental T-score below 35 and 29 is rated "Poor".

S-LANSS (Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs) score which aims to characterize the extent to which pain is neuropathic in origin on a scale from 0-24. The score is captured via a 7-item self-administered questionnaire.

Patients are asked which treatment they think they received. The correctness of their guesses is then measured using the bang-blinding index to see if patients were able to accurately guess which treatment they received. It is measured on a scale of -1 to 1. Scores closer to 0 indicate better blinding, or patients not being able to guess their treatment.

Monitored over the course of the study and measured by number of eligible patients who enroll/total number of eligible patients.

Patient-reported and patient-prompted qualitative measure of the extent to which a patient complied with the study medication regimen, including taking the daily medication at the appropriate dose. Recorded at office visits and via daily patient diary. At the below time points, medication compliance during the previous time period is being recorded. (i.e During the 3-month office visit, the patient will be asked "Have you missed taking your daily medication on any day since the 1-month visit").

Reasons for missing a dose, including side effect(s), forgetting, unsuccessful medication dispensation, or being away from medication (i.e. vacation). Recorded at office visits and via patient diary. At the below time points, reasons for medication non-compliance during the previous time period is being recorded. (i.e During the 3-month office visit if the patient reports missing the medication at least once, they will be asked for the corresponding reason).

Whether a patient prematurely withdrew due to any reason from the study before reaching the final 6-month office visit, measured as "Yes, patient dropped out of the study," or "No, patient did not drop out". The investigators will consider the study as having a low-drop rate at its conclusion if 80% of patients are retained through the 6-month follow-up. If the patient contacts the study team to drop out in between the time points listed below, the data will be recorded on the form corresponding to the next office visit. (i.e. if the patient contacts the study team on day 70 and requests to drop out, the team will record the subsequent information in the 3-month office visit form, recording the exact day the patient dropped out. Otherwise, the data will be collected at the time points listed below).

Reasons for a patient dropping out of the study early, including whether it was a self-withdrawal or study team-withdrawal. Reasons include compliance issue, undesirable side effect, lost to follow up, medication dispensation logistic issue, or major contraindication to the study protocol.