Sequential Trial of Adding Buprenorphine, Cognitive Behavioral Treatment, and Transcranial Magnetic Stimulation to Improve Outcomes of Long-Term Opioid Therapy for Chronic Pain (ACTION)

ABSTRACT
A significant proportion of patients on Long Term Opioid Therapy (LTOT) have suboptimal pain relief and/or poor
functioning despite significant risks. Because LTOT tapering can cause disabling withdrawal symptoms, the
decision to taper or transition from LTOT can be daunting and create a clinical dilemma. Novel and effective
treatment approaches that improve pain and quality of life (QOL) for individuals on LTOT while reducing risk are
needed, but it is essential to ensure these initiatives are patient-centered. Offering treatment trials that can be
“added to” current LTOT management without having to prospectively commit to an opioid taper or experience
opioid withdrawal could significantly enhance the rates of safe, patient-centered, and effective LTOT risk
reduction while improving pain and QOL. The proposed study addresses this critical need by sequentially
evaluating trials of three evidence-based treatments for chronic pain that can be “added to” LTOT
without having to experience opioid withdrawal or commit to a taper. In this study, individuals on LTOT
will first trial a 7-day initiation of low-dose transdermal buprenorphine to determine safety and tolerability, and
then will enter a blinded randomized discontinuation trial to evaluate efficacy of transdermal buprenorphine on
pain severity among those on LTOT. Those who respond positively to the buprenorphine trial and want to
transition to buprenorphine (and off LTOT) will be transitioned and followed as a prospective cohort. Those who
do not respond to buprenorphine will undergo a second randomization evaluating the effectiveness of a Brief
Cognitive Behavioral Intervention (CBI) for Pain combined with a 3-day “accelerated” course of Brain Stimulation
(repetitive Transcranial Stimulation; rTMS) on pain severity. The proposed study aims to improve engagement
of individuals on LTOT to make informed treatment decisions about LTOT; provide much needed safety and
tolerability data on low-dose buprenorphine induction strategies; and evaluate the effectiveness of a novel
combined non-pharmacological treatment that can address pain, opioid risk, and depression among those who
do not respond to buprenorphine transition. Key innovations include the use of low-commitment, patient-centered
”trials” of treatment without mandating withdrawal and the evaluation of shorter “accelerated” protocols of brain
stimulation that can enhance CBI that make this novel intervention scalable, generalizable and sustainable. This
application is directly responsive to the FOA (RFA-DA-23-041), which underscores the importance of engaging
individuals with lived experience to inform multilevel interventions aimed at improving quality of life and reducing
harm for those on LTOT. It is also consistent with the research priorities of the HEAL initiative to optimize care
for individuals with chronic pain and those at risk for opioid-related harms. The findings from this study will provide
novel and critically needed empirical evidence to inform clinical practice and advance the science in this area.

Grant Number: 1R01DA058620-01
NIH Institute/Center: NIH
Principal Investigator: Kelly Barth