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.