Clinical trial NCT04126083
Conditions: Opioid Withdrawal
Keywords: Opioid tapering Spine surgery
Sponsor: Mayo Clinic
Start date: 2019-09-01; Completion date: 2021-04-15
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective is to investigate the effects of lofexidine in adults undergoing opioid tapering prior to elective lumbar spine surgery.

Detailed description:
In this clinical trial, an open label design will be used to facilitate opioid tapering during a 12-day period prior to elective spine surgery. The primary outcome measure of this study is the number of patients who achieve a 50% reduction in daily opioid dose at day 12.

Arms: arm 1: Patients will receive lofexidine 0.54 mg 4 times daily and the baseline opioid dose will be reduced by 10% daily.
Interventions: intervention 1: Lofexidine Oral Tablet
Intervention descriptions: intervention 1: lofexidine 0.54 mg 4 times daily

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Lofexidine for Rapid Opioid 
Tapering in Adults 
 
 
 NCT04126083   
 
 
12/30/2019 


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Lofexidine for Rapid Opioid Tapering in Adults 
 
A.  BACKGROUND 
Lofexidine has recently been approved by the U.S. Food and Drug Administration (FDA) for 
mitigation of opioid withdrawal symptoms in order to facilitate abrupt or tapered opioid 
discontinuation in adults.  One potential use of the compound is in situations where rapid 
detoxification (partial or complete) is desired, such as impending surgery. Lofexidine (racemic 
mixture of R-/+ and S-/-enantiomers, dexlofexidine and levlofexidine, respectively) is a full 
alpha-2 receptor agonist.(1-5) However, lofexidine is pharmacologically distinct from other 
alpha-2 agonists, such as clonidine whose use has previously been described for the treatment 
of opioid withdrawal syndrome (OWS). (6-8)  
Concerns about OWS are major deterrent for patients on opioid therapy, often hampering 
success and compliance with opioid tapering regimens.(9-11) Fortunately, amelioration of 
such negatively experienced signs and symptoms may be accompanied by improved patient 
outcomes. Lofexidine was originally approved as a pharmacologic agent for opioid 
detoxification in the United Kingdom and other countries, including much of the European 
Union, starting in the 1980s. Studies have demonstrated efficacy in the amelioration of OWS 
with fewer adverse effects and a better safety profile than clonidine.(12, 13) Specifically, 
lofexidine has a lower incidence of hypotension than clonidine, making it more suitable for 
the management of OWS in outpatient settings.(12) Additionally, unique from clonidine, 
lofexidine also binds to 5-HT1A (i.e. serotonin) receptors. As serotonin levels decrease during 
periods of withdrawal from opioids,(14) compounds with 5-HT1A agonism could potentially be 
beneficial in combatting OWS.  As an example, a compound with 5-HT1A agonist properties 
was recently shown to decrease withdrawal symptoms in opioid-dependent mice. (15, 16)  
Hence, activity mediated through 5-HT1A receptors may help explain additional benefit of 
lofexidine for OWS treatment beyond that of simple alpha-2 agonism.   
In a recently published multicenter phase III randomized controlled trial of more than 600 
patients dependent on opioid therapy, lofexidine at doses of 2.16 and 2.88 mg/day significantly 
reduced OWS versus placebo.(17) Additionally, lofexidine increased the rate of completing the 
7-day period of ‘abrupt discontinuation’ by 14% and 12% for the 2.16 and 2.88 mg/day dosing 
groups, respectively. Hence, lofexidine has the potential to serve as a withdrawal treatment 
option when non-opioid agents are preferred or required or when opioid agonist-assisted 
withdrawal is unavailable.  Additionally, lofexidine may potentially be used to manage 
withdrawal symptoms that occur during induction or maintenance treatment with mixed opioid 
agonists and antagonists.  
With increased attention on a widespread national problem of opioid misuse and abuse, recently 
declared a national Public Health Emergency by the U.S. Department of Health and Human 
Services, medical practices in the U.S. are trying to shift towards more conservative approaches 
to pain management with less reliance on opioids as first-line therapy.  Consistent with this, 
recent guidelines released by the Centers for Disease Control and Prevention (CDS) endorse 
avoidance of opioid therapy to the greatest extent possible for chronic pain states.(18) However, 
chronic opioid use remains a significant national problem. Data from acute pain and 
postoperative states suggests that patients taking opioids preoperatively, especially at high 
doses, have poorer outcomes than those not taking opioids.(19-29) This includes heightened 
risk for immediate postoperative outcomes such as infection, ileus, and respiratory depression 
and longer-term complications such as poor wound healing and decreased success rates 
following spinal fusion.(30) Moreover, patients on opioids preoperative typically require higher 
doses and durations of opioid therapy postoperatively and generally consume more health care 


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resources than their opioid-naïve counterparts.(19, 21, 31-35)  Given these findings, a drug that 
facilitates reliable, safe, and rapid detoxification or partial detoxification may be particularly 
beneficial for patients on chronic opioid therapy preparing to undergo a planned surgical 
procedure. Patients presenting for elective spine surgery are at particularly high risk for chronic 
preoperative opioid use,(34) and hence, this group may particularly benefit from targeted 
approaches to wean opioids preoperatively.   
Specific aims 
Specific Aim 1: The primary objective is to investigate the effects of lofexidine in adults (N=25) 
undergoing opioid tapering.  In this phase 4 clinical trial, an open label, variable dose design will 
be used to facilitate opioid tapering during a 15-day period.  The primary outcome measure 
of this study is the number of patients who discontinue opioid use at day 15. 
Specific Aim 2:  Secondary aims include investigating the effects of lofexidine on the severity of 
OWS, pain intensity, negative affect, and opioid craving following completion of the 15-day 
study period.  Secondary outcome measures will include the Clinical Opiate Withdrawal Scale, 
the Short Opiate Withdrawal Scale-Gossop, the numerical pain rating scale, Center for 
Epidemiologic Studies-Depression scale, the Pain Catastrophizing scale, and a composite scale 
of opioid craving.  
 Specific Aim 3:  This exploratory aim will investigate the change in heat pain perception 
attributed to changes in opioid induced hyperalgesia.  Prior to the opioid taper and on day 15, 
quantitative sensory testing will be conducted using the Computer Aided Sensory Evaluator IV 
(WR Electronics, Stillwater, MN).  
B.  PROCEDURES AND METHODS  
B.1.  Study Site 
The study will be conducted at the medical (e.g., pain clinic, pain rehabilitation center) and 
surgical (e.g.,  orthopedic and spine surgery clinics) clinics at Mayo Clinic Rochester, MN. All 
patients will be recruited from the medical and surgical clinics at Mayo, and all assessments and 
follow-up will be conducted in the pain clinic and pain rehabilitation center. 
B.2.  Study Design  
B.2.1. Study methodology 
A prospective, open label, single center, variable dose design will be used to investigate the 
effects of lofexidine in adults undergoing a 15-day taper. The primary outcome will be the 
number of subjects who discontinue opioid use at day 15.   
B.2.2.  Opioid tapering 
Following informed consent, the baseline opioid dose will be reduced 5% to 50% based on the 
physician investigators clinical discretion and patient acceptability of the dose reduction.  The 
physician investigators will reassess each patient for further opioid dose reductions (5% to 50% 
allowed) in the pain clinic or pain rehabilitation center on study days 3, 6, and 9.  On all other 
study days, patients will be contacted by telephone by study personnel to assess for OWS and 
adverse effects related to lofexidine use.   
Prior to initiating the opioid taper, the physician investigators will contact the physician or 
provider responsible for prescribing long-term opioid therapy.  During the 15-day study period, 
the physician investigators will assume full prescribing authority, and patients and their 
established prescribers will be asked to halt the provision of all opioid prescriptions during the 
study period.  Upon completion of the study, the physician investigators will contact the 


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established long-term prescriber to ensure continuity of care with the provision of ongoing 
prescriptions. 
B.2.3.  Variable lofexidine dosing     
Upon initiation of the opioid taper, patients will receive oral lofexidine 0.54 mg 4 times daily (3 
tablets of 0.18 mg 4 times daily) for a total daily dose of 2.16 mg.  The variable dose design 
will allow the lofexidine dose to be increased up to 0.72 mg 4 times daily (4 tablets of 0.18 
mg 4 times daily) by the physician investigators if OWS are elevated.  The lofexidine dose 
may also be reduced by the physician investigators to 0.18 mg 4 times daily (1 tablet of 0.18 
mg 4 times daily) to relieve adverse effects attributed to lofexidine.   
On study days 10 through 15, equal quantities of the baseline lofexidine dose will be 
reduced, and lofexidine will be discontinued on day 15.  All patients will be contacted within 
24 hours of study completion to assess for any residual or late emerging adverse effects.  
B.2.4.  Heat pain perception   
Prior to opioid tapering and on day 15, quantitative sensory testing will be conducted using the 
automated Computer Aided Sensory Evaluator IV (CASE IV; WR Medical Electronics, Stillwater, 
MN) system based on the method of levels.  The CASE IV system delivers a series of short 
duration heat stimuli of variable magnitude interspersed with null stimuli in random order 
through a thermode with surface area of 10 cm2.  The validated HP test algorithm takes less 
than 5 minutes to complete.  This protocol includes the standardized test procedures, stimulus 
waveform, null stimulus, and non-repeating stepping algorithm between the different levels of 
heat stimuli.  The subject is masked to each level of stimulus delivered, including the null 
stimulus.  Immediately after the stimulus is given, the subject then rates the stimulus intensity on 
an 11-point rating scale (0 denotes no pain, 10 denotes the most intense possible pain).  The 
test is completed when either the maximum stimulus has been delivered, or when the subject 
grades the stimulus intensity ≥ 5.  
In total, there are 25 different magnitudes of heat stimuli, expressed in units termed “just 
noticeable difference” (JND).  The heat stimuli magnitude of each level is comprised of 2 
elements: (1) temperature, and (2) duration of exposure.  The baseline temperature is 34◦C and 
the thermal rise rate is 4◦C/second.  There is an exponential increase in the temperature and the 
thermode reaches 48◦C at level 21 for a duration of 1 second.  For levels 22, 23, and 24, the 
temperature remains at 48◦C for a duration of 1.5, 5, and 10 seconds, respectively. The 
maximum heat stimulus is level 25, which is comprised of a temperature of 49◦C for a duration 
of 10 seconds.  Higher temperatures are not used in order to avoid thermal tissue injury. 
The CASE IV software program (WR TestWorks, version 2.0) adjusts the raw sensory data, 
recorded in units of JND, to account for age, sex, height, weight, body surface area, body mass 
index, and body region of testing.(36-38)  Then, a quadratic regression equation is fitted to the 
pain ratings, and the CASE IV software calculates HP 0.5, HP 5, and HP 5-0.5.  The midpoint 
between a nonpainful stimulus and the least stimulus magnitude necessary to elicit a threshold 
sensation of pain is termed HP 0.5.  The stimulus magnitude necessary to elicit a pain rating of 
5, indicating intermediately intense pain, is labeled HP 5.  HP 5-0.5 is named the pain-stimulus 
response slope and signifies the difference between HP 5 and HP 0.5.   
The testing conditions will be consistent between patients. The anatomical site selected for 
testing (due to ease of accessibility) will be the dorsal surface of the non-dominant hand.  If the 
non-dominant hand is an anatomical site of pain, then the dominant hand will be used.    
B.2.5.  Postoperative opioid use 


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For surgical patients, immediate preoperative opioid dose and pain scores will be assessed 
upon admission to the preoperative area.  Opioid dose and pain scores will be reassessed 
upon hospital dismissal and at day 30  (+/- 5 days) following lumbar spine.  The preoperative 
and hospital dismissal assessments will be performed by members of the study team, and 
the day 30 assessments will performed via telephone.  
B.3.  Study Participants 
B.3.1. Inclusion criteria 
1. 
Age 18 to 70 years. 
2. 
Chronic pain for ≥ 3 months duration.  
3. 
Daily morphine equivalent dose between ≥ 20 mg. 
B.3.2. Exclusion criteria 
1. 
Cancer-related pain. 
2. 
Medical or surgical conditions that could be adversely impacted by opioid tapering or use 
of lofexidine including, but not exclusively limited to, cardiac disease, inflammatory bowel 
disease, renal or hepatic impairment, vascular disease, and history of anaphylaxis.  
Patients may be excluded for other comorbid medical or surgical conditions based on 
the physician investigator’s discretion. 
3.   
History of schizophrenia or other chronic psychiatric disorder that could be adversely 
impacted by opioid tapering or use of lofexidine. Patients may be excluded for other 
comorbid mental health conditions based on the physician investigator’s discretion. 
4. 
Neurological condition that impair functioning in an ambulatory setting or could be 
adversely impacted by opioid tapering or use of lofexidine including, but not exclusively 
limited to, Parkinson’s disease, amyotrophic lateral sclerosis, or a dementing illness.  
Patients may be excluded for other neurological conditions based on the physician 
investigator’s discretion. 
    
5. 
Active substance abuse disorder. 
6. 
Inability to function in an ambulatory care setting due to severe deconditioning requiring 
use of supportive gait aids including a cane or walker.  Patients may be excluded for 
other functional problems based on the physician investigator’s discretion.   
7. 
History of adverse effects attributed to opioid tapering or lofexidine use. 
8. 
Use of medications from drug classes known to have adverse interactions with lofexidine 
including, but not exclusively limited to, beta-blockers, calcium channel blockers, alpha 1 
and 2 receptor antagonists, tricyclic antidepressants, benzodiazepines, and selective 
serotonin reuptake inhibitors.  Patients may be excluded for use of other medications 
based on the physician investigator’s and research pharmacy’s discretion.  
B.4.  Sample Size 
The primary aim of this study is to assess the effects of lofexidine on opioid tapering in adults. The 
purpose of this open label study is to decide whether additional studies using an experimental design 
are warranted, and to provide preliminary data for designing a larger efficacy trial.  The primary 
outcome will be the number of subjects who discontinue opioids at day 15.  We anticipate opioid 
discontinuation will be observed in 50% to 70% of patients.  Thus, a sample-size of N=25 will be 
sufficient to assess whether additional studies of lofexidine in this patient population are 
warranted. 
B.5.  Data Collection and Assessments 
B.5.1.  Demographics and clinical characteristics 


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Baseline demographic and clinical characteristics will be collected including age, sex, race and 
ethnicity, marital status, work status, educational status, pain diagnosis, pain duration, smoking 
status, use of non-opioid medications, previous spine surgery history or other non-spine 
surgery, and indication for current surgery. 
B.5.2.  Determination of morphine equivalent dose 
The daily opioid dose of each patient will be determined by self-report and review of pharmacy 
and medical records. Using a software program available at our institution, the daily opioid dose 
will be converted to an oral morphine equivalent dose expressed in milligrams (mg) per day. 
B.5.3.  Opioid tapering 
The primary outcome measure of this study is the number of patients who discontinue opioids at 
day 15.  
B.5.4.  Pain intensity 
Pain intensity will be assessed using the 11-point numerical pain rating scale (NRS). The 
validity of the NRS has been well established. 
B.5.5.  Negative affect 
Depressive symptoms and pain catastrophizing are key components of negative affect.  The 
Center for Epidemiologic Studies-Depression scale provides a validated measure of depressive 
symptoms in patients with chronic pain.  The Pain Catastrophizing Scale provides a measure of 
negative cognitions and emotions associated with actual or anticipated pain experiences.  
B.5.6.  Opioid craving 
Opioid craving will be assessed using responses (0 to 100 VAS) to 3 questions: (1) How much 
do you crave opioids? (2) How often do you think about the next dose? (3) How strong is your 
urge to take more medication than prescribed? This approach has been used to assess craving 
in patients with chronic pain. 
B.5.7.  Heat pain perception 
Heat pain perception will be quantified using the Computer Aided Sensory Evaluator IV (WR 
Electronics, Stillwater, MN). This QST device has been validated, and we have used it to 
quantify opioid-induced hyperalgesia and to study other pain-related states associated with 
altered heat pain perception. 
B.5.8.  Signs and symptoms of opioid withdrawal 
The severity of opioid withdrawal symptoms will be assessed using two measures. First, the 
Clinical Opiate Withdrawal Scale (COWS) is an observer-rated instrumaent. Total score range 
from 0 to 47. Scores ranging from 5-12 denote mild withdrawal symptoms, scores from 13-24 
signify moderate withdrawal, scores from 25-36 indicate moderately severe symptoms, and 
scores greater than 36 indicate severe withdrawal symptoms. Second, the Short Opiate 
Withdrawal Scale-Gossop (SOWS-Gossop) is a subjective score provided by the subject. It 
includes 10 items assessed by the patient as none/not present (0 points), mild (1 point), 
moderate (2 points), or severe (3 points). 
B.5.9.  Lofexidine adverse effects 
According to previous reports, common adverse effects associated with lofexidine include 
orthostatic hypotension, hypotension, bradycardia, insomnia, somnolence, sedation, dry mouth, 
syncope, and tinnitus. Management of adverse effects is described in the Human Subjects 
section. 


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B.5.10.  Urine toxicology screening 
The opioid status of all patients will be biochemically verified with a confirmed urine toxicology 
screen prior to the opioid taper and at day 15.  
B.5.11.  Timeline of patient assessments 
Screening visit (at least  (7) days before baseline assessment) 
 
Screen for inclusion and exclusion criteria. 
 
Obtain informed consent. 
 
Obtain urine toxicology screen and ECG. 
 
Day 1 (baseline) 
 
Informed consent reviewed and documented. 
 
Physical examination performed, vital signs documented. 
 
Determine opioid dose reduction. 
 
Start lofexidine. 
 
Obtain baseline assessments. 
 
 Day 3+3 days (pain clinic follow-up with physician investigator) 
 
Physical examination performed, vital signs documented.  
 
Determine opioid dose reduction. 
 
Assess for opioid withdrawal and lofexidine adverse effects. 
 
Lofexidine dose adjustment if indicated. 
 
Day 6 +3 days(pain clinic follow-up with physician investigator) 
            Physical examination performed, vital signs documented.  
 
Determine opioid dose reduction. 
 
Assess for opioid withdrawal and lofexidine adverse effects. 
 
Lofexidine dose adjustment if indicated. 
 
Day 9 + 3 days (pain clinic follow-up with physician investigator) 
Physical examination performed, vital signs documented.  
 
Determine opioid dose reduction. 
 
Assess for opioid withdrawal and lofexidine adverse effects. 
 
Lofexidine dose reduction initiated. 
 
Day 12 to 15 (pain clinic follow-up with physician investigator) 
Physical examination performed, vital signs documented.   
 
Assess for opioid withdrawal and lofexidine adverse effects. 
 
Determine opioid new baseline dose. 
 
Lofexidine discontinued. 
 
Obtain day 15 assessments. 
 
Days 1-15 (telephone assessment) 
Daily telephone call to assess for opioid withdrawal, pain, and lofexidine adverse 
effects.  
 
B.6.  Data Handling 


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The working database will be maintained on a secure institutional server.  All computer files and 
systems will be password protected and accessible by authorized study personnel only.  Data 
entry will be performed by the research coordinator. 
B.7.  Data Analysis 
Demographics (e.g., age, sex, marital status, educational status, employment status), and 
clinical characteristics (e.g., pain duration, depression, pain intensity) will be summarized.  
Mean and standard deviation will be calculated for continuous variables, and count and 
proportion will be calculated for categorical variables.  The primary outcome measure will be the 
number of patients who discontinue opioid use at day 15.  In the analysis of secondary aims, 
nonparametric paired tests will be used to assess for differences in pre- and post-taper scores 
of opioid withdrawal, pain intensity, negative affect, and heat pain perception.   The frequency of 
all lofexidine adverse effects will be documented.  Perioperative opioid use and pain scores will 
be summarized.  
B.8.  Strengths and Limitations 
At the conclusion of this project, we will have investigated the effects of lofexidine in adults 
undergoing opioid tapering.  These data will be critical to the design of a future efficacy trial of 
lofexidine in this patient population. 
All study participants will be recruited from the medical and surgical clinics at a tertiary referral 
medical center.  As a result, the study findings may not be applicable to all adults undergoing 
elective lumbar spine surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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