Adam bisaga and collegues

Title: Outpatient transition to extended-release injectable naltrexone for patients with opiod
use disorder: A phase 3 randomized trial

Introduction
 Due to increasing costs and limited availability for inpatient treatment, most patients
with opioid use disorder are being treated in the outpatient setting
 There’s a need to expand pharmacology to the outpatient setting with medications such as methadone
(opioid receptor agonist), buprenorphine (opioid receptor partial agonist), or extended-release naltrexone
(opioid receptor antagonist)
 Extended release naltrexone can only be started on patients who are not physically
dependent of opioids and it is recommended that patients abstain from opiods for 7-10
days before receiving extended release naltrexone. The issue is that many people
relapse in those 7-10 days that they are trying to remain clean.
 Previous studies have examined the use of various opioid agonist/antagonist-based
regimens to transition patients from agonists to the antagonist extended release
naltrexone.
o A study conducted by Mannelli and collegues introduced a brief Buprenorphine taper with
initiation of low doeses of naltrexone prior to a first XR naltrexone.
o Designed to reduce physiological dependence by providing treatment with a partial agonist while
also introducing a gradual opioid blockade through increasing doses of naltrexone.
o Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with
downward titration of low dose buprenorphine was safe, well tolerated, and completed by most
participants.

Objective:
 The purpose of the current study is to establish a standardized and well-tolerated
outpatient regimen for clinicians seeking to transition patients with OUD to an
antagonist therapy.

Study design:
 Phase 3, double-blind, randomized trial in patients seeking treatment for heroin or
prescription OUD
 Primary goal was to determine the efficacy, safety and tolerability of oral NTX in
conjunction with BUP prior to the first dose of XR-NTX.
 Secondary goal was to develop a regimen of ancillary meds that could be tested for
safety and efficacy to support outpatient management of opioid withdrawal.
o Conducted in 19 sites in the U.S. between august 2015 and Jan 2017
 Inclusion criteria
o 18-60 years old voluntarily seeking opioid withdrawal and transition to
antagonist treatment were eligible if they
 Had the diagnostic and statistical manual of mental disorders
 Reported consistently using opioids for at least 3 months
 Had a positive urine test result
 Demonstrated mild withdrawal symptoms
  Exclusion criteria
o Positive drug test for BUP or methadone
o Use of BUP or methadone within 7 days prior to randomization
o Use of XR-NTX within 90 days
o History of seizures, schizoaffective disorder/bipolar disorder, unstable major
depressive disorder,
o History of more than 3 unsuccessful inpatient or assisted outpatient opioid
detoxes
o History of accidental drug overdose in the past 3 years
 Primary endpoint:
o Proportion of patients who received and tolerated an XR-NTX injection as
demonstrated by mild opioid withdrawal symptoms 1 hr following XR-NTX
(clinical opiate withdrawal scale (COWS) score <12 or subjective opiate
withdrawal scale (SOWS) score <10
 Secondary endpoint:
o Means score for “desire of opioids” using the visual analog scale (VAS)
o Tolerability of the procedure as defined as the number of days with peak COWS
score <12
o Mean peak COWS score
o Area under the curve COWS score prior to XR-NTX injection
 Transition period of 7 days of low and ascending doses of oral NTX or placebo used in
conjunction with 3 days of tapered sublingual BUP or placebo and fixed dosed of
ancillary meds.
o 3 reginmens
 NTX + BUP
 NTX + placebo BUP
 Placebo NTX + Placebo BUP
o Lasted 7 days and conducted daily in an outpatient clinic followed by a naloxone
challenge and a first dose XR-NTX
o Patients went to clinic each day and they assessed their COWS, SOWS, and (Vas)
scores followed by administration of their regimen based on which group they
were in
o Tolerability was assessed at 30, 60, 90, 120 min following their first dose
 And depending on tolerability they would be given their second dose
 On day 8 patients with COWS score of <4 were given the 2 part naloxone challenge (0.4
mg followed by 0.8 mg)
o If negative (COWS <4) they received XR-NTX
o If positive they repeated day 8 procedures and returned for a repeat challenge
the next day
 If they failed again they were eliminated from the study

Statistics
 Logistic regression model and the Hochberg testing procedure were used to analyze the
primary endpoint
Results:
 Total 653 patients enrolled
 Excluded 275
 Randomized 374
o NTX/BUP (124); completed 27
o NTX/PBUP 126; completed 23
o PNTX/PBUP 124; completed 18
 Primary outcome
o Proportion who received and tolerated injection of XR-NTX on day 8/8a was
comparable in all 3 groups
 46%, 40.5%, 46%
 Secondary outcome
o All procedures were generally well tolerated
 Mean daily peak COWS decreased from day 1 to day 8
 P<0.001
 SOWS scores across all groups showed a similar pattern of decline
 P<0.01
 VAS craving scores generally decreases
o Patients in the NTX/BUP group were significantly more likely to reman abstinent
during the 7 day transition period than the other 2 groups (OR (odds ratio), 1.54;
CI (confidence interval) 1.31-1.8)
 Post hoc analyses
o Greater proportion of prescription opioid users (56%) vs heroin users (37%)
received and tolerated the first XR-NTX injection (OR (odds ratio) 2.17, RR
(relative risk) 1.51, p<0.001)
o Heroin users had an 81% higher risk of discontinuation than prescription
 Adverse events:
o Similar among groups
o Mostly symptoms of withdrawal

Conclusion
 The 7 day detoxification protocol with NTX alone or NTX + BUP provided similar rates of
inductions to XR-NTX as placebo. The use of ancillary medications showed that it is
useful for clinical practice for increasing the potential for patients to get on antagonist
therapies.

Questions:
 Why were the number of patients who enrolled so much different than the patients who
finished therapy?
o Most pts were lost in follow up
o And then some were lost due to withdrawal symtoms and lack of efficacy
 What was the main limitation that you found from the article?
  You mentioned the use of ancillary medications.. what were these and how were they
used?
o Clonidine 0.1 mg three times a day, trazadone 100 mg at bedtime and
clonazepam 0.5 mg three times a day were initiated on day 1 to manage
withdrawal symptoms and were administered daily during the transition period
and for up to 3 days after the first XR-NTX

Limitations:
 The frequency and duration of study visits exceeded those common in the outpatient
setting
 Excluded patients with psychiatric needs or have failed several detox attempts
 Doses of oral NTX used in this study are not FDA approved or commercially available
 65% were male and 73% were white
 Number of people
 How would this be funded in real life

Strengths
 Randomized double blind study
 Clear objectives
 Used appropriate scales COWS and SOWS to monitor patient progression
 Refrences the authors used
 States how it was funded

Evaluators conclusion
 This study showed that there was really no difference when comparing the placebo to
the treated group for use of XR-NTX
 The study was limited on the amount of participants and the variety of participants that
were included
 Clinically It was shown that there is some benefit in the treatment group when it comes
to abstinence from opioids in the transition period and a lower SOWS score in the week
after the XR-NTX induction.
 For future studies need to determine how this could be implemented into the
outpatient setting and how it would be funded