The study design is a randomized, double-blind, placebo-controlled, crossover trial. The
subjects and investigators will remain blinded for the duration of the study. Subjects
will be randomized under the direction of investigational pharmacy and will be randomized
in groups of 6 subjects with 3 being assigned to Group A and the other 3 being assigned
to Group B. The randomization information will remain under the purview of
Investigational Pharmacy until the conclusion of the study, who will be unblinded during
the study for management of appropriate medication dispersal following randomization. As
a crossover trial, all subjects will be exposed to both the investigational agent as well
as placebo for 8 and 4 weeks, respectively. There will be no washout period in order to
help maintain blinding.
The investigational agent in this study is naltrexone. Naltrexone is currently FDA
approved for treatment of alcohol and opioid dependence at doses of 50mg daily or higher.
Two placebo controlled trials involving 93 patients taking REVIA (naltrexone) 50mg daily
reported no serious adverse events during the course of the trials. In this study, the
drug will be used in an off-label capacity at lower doses to treat pain associated with
diabetic neuropathy. Placebo will be used for this study as a control. The maximum
duration of time a patient will receive placebo is 4 weeks. No prior and/or concomitant
medical therapies will be collected during the study. The following criteria outline
which concomitant medicines/therapies (including rescue therapies) are permitted/not
permitted during the study:
Opioid based medicines (including rescue therapies) are not permitted during the
study.
New pharmacologic therapies for pain not previously taken by the subject are not
permitted during the study period.
Any baseline (stable use at initiation of the study) non-opioid medication
(including rescued therapies) are permitted during the study.
Pre-study concomitant medications will be recorded via chart review prior to
enrollment.
The drug and placebo will be administered orally via identical capsules and filler
rendering them indistinguishable. Patients will take the investigational agent once daily
for eight weeks. The agent will be administered following the titration regimen
consisting of one week at 1.5mg daily, followed by one week of 3mg daily, then 4.5mg
daily for the remaining six weeks. The dose titration for naltrexone was developed in
clinical use and was the basis for our previous retrospective analysis (Retrospective
Analysis for Safety and Tolerability of Low Dose Naltrexone with a Novel Dosing Regimen)
that was accepted for a poster presentation at the American Society of Regional
Anesthesiology and Pain Medicine in 2018. This regimen was developed in order to reduce
the chance of a patient developing a particular side effect with their particular dose as
well as with the intent to identify what dose worked best for any particular patient.
Clinical trials have tested LDN at either 3mg/day or 4.5mg/day. No study, to our
knowledge, has looked at having a patient be able to identify a dose response and titrate
the medication to effect. This titration regimen allows patients to control their own
dose of medication without needing to call their provider's office to change their
regimen. Simply, the patient starts taking the smallest dose which is a 1.5mg capsule
each evening for one week. If the patient experiences disruption of sleep or vivid
dreams, they may switch from the evening to the morning. If no side effects develop, the
patient may escalate their dose to two capsules (3.0mg) per evening during the second
week of the trial and again switch to morning dosing if they develop any side effects.
Lastly, the patient may increase their dose to the maximum of 3 capsules (4.5mg) per
evening at the start of the third week of the trial and may transition to morning dosing
if they develop side effects of the drug. The flexibility inherent in this dosing regimen
is to optimize the potential effect of the medication and tolerance during this clinical
trial as it has been found to be flexible and well-tolerated in clinical use at our
institution where this regimen has been adapted by the majority of our providers.
Placebo will be administered once daily for four weeks for a total of 12 weeks including
the active drug. The order of placebo and drug will be determined by randomization of
subjects into one of two crossover timelines, one starting with the drug, the other
starting with the placebo and switching at 8 and 4 weeks, respectively. The drug/placebo
will be dispensed by investigational pharmacy and mailed in a packet directly to the
subjects every 4 weeks. The first packet will contain 4 pill bottles with 7 capsules
each, bottles will be clearly labeled week 1, week 2, week 3, week 4, to be taken in that
order. The second packet will contain bottles labeled weeks 5 through 8 and the third
packet with bottles labeled weeks 9 through 12.
Subject response to both LDN and placebo, as well as compliance, will be tracked via
assessment of weekly email surveys. The surveys will be conducted via REDCap through
Dartmouth's institutional license to ensure HIPAA compliance and optimum patient privacy.
The first survey will be administered in person on a laptop when the patient is enrolled.
Subsequently the patient will be sent a reminder email through REDCap to complete their
weekly survey. The weekly survey will consist of the following components:
Pain Disability Index Questionnaire (PDI)
Numeric Rating Scale (NRS)
Free text option for reported and adverse side effects
Pain Catastrophizing Scale (PCS) -- baseline survey only
Free text option for prompt asking the patient to describe their expectations or
goals for the new treatment -- baseline survey only If the subject fails to respond
to the survey they will be contacted the next day by phone to complete the survey.
If they are unable to be reached during the next 24 hour period the survey will be
considered missed for that week. In the event that a subject accrues at least three
consecutive misses or five total misses they be considered significantly
non-compliant and will be unenrolled from the study. There will be a
holiday/vacation exception, the subject may contact the nurse if anticipating
absence from the survey that week.The coordinator, investigator and pharmacy will be
informed as soon as possible and the subject will no longer receive medication or
email surveys. Subjects will have contact information for the study nurse to report
any adverse side effects and will be contacted at the end of the study by phone to
inquire about any adverse events.
There is no drug conversion plan needed for this study. The only contraindication for
this study if concomitant opioid therapy and those subjects will be excluded from the
study.
The most common side effect may be the development of vivid dreams, previous studies
suggest that some patients may have the onset of headaches or abdominal cramps associated
with their taking LDN as a medication. However, the incidence is similar to taking
placebo. To lessen the probability and magnitude of risks subjects will report any
adverse side effects in the weekly survey, which will be reviewed weekly by the
investigator. Subjects will have access to contact the study coordinator at any time with
concerns regarding adverse events. There are no parts of the study that involve the use
of procedures that are inconsistent with the standard of care at Dartmouth-Hitchcock
Medical Center.