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a r t i c l e
i n f o
Article history:
Received 20 November 2012
Received in revised form 12 April 2013
Accepted 1 May 2013
Keywords:
Buprenorphine
Chronic pain
Opioid dependence
Oxycodone
Reinforcing effect
a b s t r a c t
Few studies have examined abuse of prescription opioids among individuals with chronic pain under
buprenorphine/naloxone (Bup/Nx) maintenance. The current 7-week inpatient study assessed oral oxycodone self-administration by patients with chronic pain who had a history of opioid abuse. Participants
(n = 25) were transitioned from their preadmission prescribed opioid to Bup/Nx. All of the participants
were tested under each of the sublingual Bup/Nx maintenance doses (2/0.5, 8/2 or 16/4 mg) in random
order. During each maintenance period, participants could self-administer oxycodone orally (0, 10, 20,
40 or 60 mg prescription opioids) or receive money during laboratory sessions. Drug choice (percentage)
was the primary dependent variable. Subjective ratings of clinical pain and withdrawal symptoms also
were measured. Mann-Whitney tests compared percentage of drug choice for each active oxycodone dose
to placebo. Logistic regression analyses identied correlates of oxycodone preference, dened as 60% or
greater choice of oxycodone compared to money. Pain was signicantly reduced while participants were
maintained on Bup/Nx compared to preadmission ratings. No differences in percentage drug choice were
observed between the active oxycodone doses and placebo under each Bup/Nx maintenance dose. However, factors associated with oxycodone preference were lower Bup/Nx maintenance dose, more withdrawal symptoms and more pain. These data suggest that Bup/Nx was effective in reducing pain and
supplemental oxycodone use. Importantly, adequate management of pain and withdrawal symptoms
by Bup/Nx may reduce oxycodone preference in this population.
Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
1. Introduction
In the United States, the problem of nonmedical use of prescription opioids has emerged as a major public health issue [1]. Other
countries, such as Australia, New Zealand [12] and Canada [33],
also are concerned about the phenomenon of prescription opioids
abuse. In the United States, oxycodone and hydrocodone are
among the most commonly prescribed or regularly used opioids,
as well as the most commonly diverted prescription opioids analgesics [5,25]. These data indicate that prescription opioids abuse
has steadily increased among heroin and recreational polydrug
users since 2000 [5]. An additional concern related to the increased
Corresponding author at: INSERM U912 (SESSTIM), Marseille, France. Tel.: +33 4
96102876.
E-mail address: perrine.roux@inserm.fr (P. Roux).
0304-3959/$36.00 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
http://dx.doi.org/10.1016/j.pain.2013.05.004
1443
naloxone combination (Bup/Nx). During the rst week after admission, participants were withdrawn from their previous opioid analgesic regimen and stabilized on 1 of 3 doses of Bup/Nx (2/0.5, 8/2
or 16/4 mg/d). The total daily Bup/Nx dose was administered q.i.d.
in equally divided doses throughout the day (Fig. 1). Participants
were treated for emergent withdrawal symptoms with various
supplemental medications until withdrawal symptoms dissipated
based on self-report and observer ratings. Patients were maintained on each Bup/Nx dose for approximately 2 weeks: 1 week
of stabilization followed by 1 week of laboratory testing. Each participant received all 3 Bup/Nx doses in random order under double-blind conditions.
2.4. Reinforcing effects
During each maintenance period, participants could self-administer oral oxycodone (0, 10, 20, 40 or 60 mg) during separate laboratory sessions. Each laboratory day consisted of 2 types of
sessions, a sample session during which participants were provided with one of the possible doses of drug (oxycodone) and
US$20, and a self-administration (choice) session that occurred a
few hours later on the same day. During the sample session, the
subjective, physiological and analgesic effects of oxycodone were
measured. During the choice session, participants could selfadminister the dose of oxycodone that was provided during the
sample session or receive money. Participants then completed a
self-administration task to receive portions of the dose of drug or
money they sampled (0100% in increments of 10%). For each
10% increment of drug or money, participants were required to
complete an increasing number of nger presses on a computer
mouse (50, 100, 200, 400, 800, 1200, 1600, 2000, 2400, 2800).
Immediately after the self-administration task, money and/or the
total amount of drug earned during the task was administered.
The sample session began at approximately 11 AM, and the choice
session began at approximately 3 PM (Fig. 1).
2.5. Subjective effects
All of the questionnaires used in this study have been described
previously [17]. For the present analysis, opioid withdrawal symptoms and clinical pain were measured after administration of the
rst daily Bup/Nx maintenance dose. Subjective symptoms of opioid withdrawal were assessed with the Subjective Opioid Withdrawal Scale (SOWS; range 064 [9]). Clinical pain assessment
was made with the 15-item Short-Form McGill Pain Questionnaire
[26] based on their general pain condition while maintained on
Bup/Nx. Clinical pain was also assessed with the McGill Pain Questionnaire (MPQ) at the rst screening visit before initiation of Bup/
Nx maintenance.
Fig. 1. Time points of a laboratory session day during the second week of
maintenance. Oxy, oxycodone; Bup, buprenorphine; Nx, naloxone.
1444
3. Results
During the enrollment phase of the study, 191 individuals were
assessed for eligibility and 140 were excluded because they did not
meet the inclusion criteria [(n = 78; medical exclusion (n = 21),
psychiatric exclusion (n = 10), not opioid abusing/dependent
(n = 29), other substance dependence (n = 13), or other (n = 5)] or
lost to follow-up (n = 62). Of the 51 who were randomized to the
trial, 8 discontinued before the inpatient phase [medical drop
(n = 2), not interested in treatment (n = 5) and lost to follow-up
1445
Table 1
Factors associated with oxycodone self-administration in a sample of opioid-dependent pain participants under buprenorphine maintenance during laboratory drug choice
sessions.a
Characteristic
Age, y
Gender
Female
Male
Years of educationb
Ethnicity
African American
White
Hispanic
Percentage of participants employed
Prescription opioids pills/d c,d
Morphine equivalents, mg/d c
Duration of prescription opioids use, y
Benzodiazepine-positive urine
Methadone-positive urine e
Cannabis-positive urine c,e
Cocaine-positive urine c
Self-reported heroin use c,e
Self-reported cocaine use c
Self-reported alcohol use c,f
Buprenorphine/naloxone dose
2/0.5 mg (ref)
8/2 mg
16/4 mg
Oxycodone dose (prescription opioids)
0 mg (ref)
10 mg
20 mg
40 mg
60 mg
MPQ score g,h
SOWS score g,h
Value
No. of participants
48 (4354)
135 (36)
240 (64)
13 (1214)
9
16
135 (36)
120 (32)
120 (32)
75 (20)
7 (410)
60 (38144)
5 (28)
60 (16)
30 (8)
30 (10)
69 (14)
15 (4)
45 (12)
0 (04)
9
8
8
5
4
2
2
9
1
3
Bivariate analysis
OR (95% CI)
P value
1.02 (0.911.15)
.71
.54
1
1.84 (0.2613.08)
0.81 (0.551.19)
.29
1
4.76
0.36
0.28
1.09
1.23
1.03
4.76
0.74
1.57
0.83
.08
.49
.42
.04
.08
.76
.13
.77
.14
.84
.08
.65
.31
(0.8327.2)
(0.026.72)
(0.016.46)
(1.001.19)
(0.971.55)
(0.861.23)
(0.6335.9)
(0.0414.78)
(0.2211.14)
(0.571.20)
125 (33)
125 (33)
125 (33)
25
25
25
1
0.79 (0.471.30)
0.38 (0.190.77)
.35
.007
75 (20)
75 (20)
75 (20)
75 (20)
75 (20)
21 (1531)
4 (19)
25
25
25
25
25
1
1.32
1.36
1.00
1.54
1.30
1.89
.46
.42
1.00
.26
.003
.003
(0.632.81)
(0.642.89)
(0.462.19)
(0.733.23)
(1.091.55)
(1.242.86)
SA, self-administration of more than 60% of the total dose of oxycodone (drug break point >1200); OR, odds ratio; CI, condence interval; MPQ, McGill Pain Questionnaire;
SOWS, Subjective Opioid Withdrawal Scale.
a
Logistic regression model based on generalized estimating equations: bivariate analysis (n = 25 participants, 375 observations). Data are expressed as no. of sessions (%) or
median (interquartile range).
b
For each grade year increase.
c
At the consent visit before entering the study (baseline visit).
d
For 100 point-increase.
e
Not included in the nal model; number of subjects <10%.
f
Number of drinks per month.
g
One hour after the rst daily dose of buprenorphine/naloxone.
h
For each 10-unit increase.
In addition, higher total SOWS scores were associated with oxycodone preference.
The results presented in Table 2 show 2 different models after
multiple adjustments, one including a withdrawal symptoms variable and the other a pain variable. Both models in Table 2 demonstrate that 2 variables remained associated with oxycodone
preference, Bup/Nx dose and withdrawal/pain variable. When
participants were maintained on the highest dose of Bup/Nx
(16/4 mg), they had a 2-fold lower risk of preferring oxycodone.
Furthermore, those who reported more withdrawal symptoms
(OR 1.96, 95% CI 1.293.00, P = .002) and those who had higher
pain scores (OR 1.59, 95% CI 1.152.20, P = .005) were more likely
to self-administer oxycodone. Interestingly, the number of morphine equivalents used per day at baseline did not remain signicantly associated with the outcome. No signicant interaction was
found between MPQ pain score and SOWS score regarding oxycodone preference (P = .44). However, we found a signicant association between MPQ pain score and SOWS score (OR 0.85, 95% CI
0.631.07, P < .001).
4. Discussion
Overall, the data indicate that Bup/Nx-maintained opioiddependent patients with pain do not robustly self-administer
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Mann-Whitney tests:
- placebo versus 10mg Oxy : Bup/Nx 2/0.5 mg p=0.54 ; Bup/Nx 8/2 mg p=0.71;
Bup/Nx 16/4 mg p=0.29)
- placebo versus 20mg Oxy : Bup/Nx 2/0.5 mg p=0.29 ; Bup/Nx 8/2 mg p=0.74;
Bup/Nx 16/4 mg p=0.14)
- placebo versus 40mg Oxy : Bup/Nx 2/0.5 mg p=0.59 ; Bup/Nx 8/2 mg p=0.97;
Bup/Nx 16/4 mg p=0.47)
- placebo versus 60mg Oxy : Bup/Nx 2/0.5 mg p=0.18 ; Bup/Nx 8/2 mg p=0.36;
Bup/Nx 16/4 mg p=0.37)
Fig. 2. Percentage of the sampled oxycodone dose chosen under each Bup/Nx maintenance dose. Mann-Whitney tests: placebo vs 10 mg Oxy: Bup/Nx 2/0.5 mg, P = .54; Bup/
Nx 8/2 mg, P = .71; Bup/Nx 16/4 mg, P = .29; placebo vs 20 mg Oxy: Bup/Nx 2/0.5 mg, P = .29; Bup/Nx 8/2 mg, P = .74; Bup/Nx 16/4 mg, P = .14; placebo vs 40 mg Oxy: Bup/Nx
2/0.5 mg, P = .59; Bup/Nx 8/2 mg, P = .97; Bup/Nx 16/4 mg, P = .47; placebo vs 60 mg Oxy: Bup/Nx 2/0.5 mg, P = .18; Bup/Nx 8/2 mg, P = .36; Bup/Nx 16/4 mg, P = .37. Oxy,
oxycodone; Bup, buprenorphine; Nx, naloxone.
Table 2
Factors associated with oxycodone self-administration.a
Model
Multivariate analysis
Buprenorphine/naloxone dose
2/0.5 mg (ref)
8/2 mg
16/4 mg
SOWS score b,c
Buprenorphine/naloxone dose
2/0.5 mg (ref)
8/2 mg
16/4 mg
MPQ score b,c
aOR (95%CI)
P value
1
0.84 (0.501.42)
0.41 (0.200.82)
1.96 (1.293.00)
.002
1
0.75 (0.421.33)
0.42 (0.200.90)
1.59 (1.152.20)
.47
.03
.005
aOR, adjusted odds ratio; CI, condence interval; SOWS, Subjective Opioid Withdrawal Scale; MPQ, McGill Pain Questionnaire.
a
Multivariate logistic regression model based on generalized estimating equations. Multivariate analysis of 25 subjects, 369 observations; only sessions with complete
data for all variables were included in the nal model.
b
One hour after the rst daily dose of buprenorphine/naloxone.
c
For each 10-unit increase.
in-depth analysis of the correlates of preference for oxycodone under Bup/Nx maintenance seemed to be important to identify some
potential factors associated with the abuse liability of oxycodone
in this population. After adjusting the model aimed at identifying
factors associated with oxycodone preference, no variable related
to participant baseline characteristics remained associated with
oxycodone preference. It is interesting to note that participants
who reported using a higher number of morphine equivalents before entering the study were not more likely to self-administer
oxycodone. This result suggests that Bup/Nx is effective in reducing
the abuse liability of oxycodone regardless of level of prescription
opioids use. However, caution is required because our participants
were selected according to specic inclusion criteria that could
have selected less heavy prescription opioids users.
It is known that specic subpopulations might be at risk of
abusing prescription opioids such as oxycodone [29]. Our bivariate
analysis demonstrated that benzodiazepine users, cannabis users
and those who endorsed using heroin at baseline were more likely
to self-administer oxycodone. These ndings highlight the importance of identifying patients at higher risk of opioid misuse or
addiction as recommended by the Canadian guideline for safe
and effective use of opioids for chronic pain [19], as well as circumstances under which opioid misuse is more likely. Interestingly, the
variables that remained associated with the oxycodone selfadministration were pain score, withdrawal symptoms, and Bup/
Nx dose. The results suggested that pain assessment remains a
key component to adapt the pharmacological treatment. In this
study, higher pain scores and higher withdrawal symptoms scores
were associated with more oxycodone self-administration. It has
been previously demonstrated that nonmedical use of prescription
opioids was associated with bodily pain in a population of injecting
drug users [21]. Moreover, withdrawal symptoms have been found
to be a predictor of nonmedical use of opioids during opioid maintenance treatment [32]. Our results highlight the difculty in differentiating pain from withdrawal and from a chronic pain
condition. For this reason, several studies have noted the importance of including opioid withdrawal assessments in the management of pain, especially in an opioid-dependent population
[35,37].
In addition, our ndings demonstrated that buprenorphine
maintenance dose could play a role in oxycodone preference. It is
known that suboptimal doses of buprenorphine may have negative
consequences on treatment efcacy [24]. Because dose adjustment
depends on multiple pharmacokinetic and pharmacodynamic
parameters, characterized by interindividual differences, it is crucial to measure patient perceptions regarding the effectiveness of
buprenorphine in alleviating withdrawal symptoms and pain.
One strategy for treating chronic pain is to administer opioid doses
in an escalating manner. Naliboff and colleagues used this method
and demonstrated some improvements in self-reported acute relief
from pain without an increase in supplemental opioid use compared to a stable dose strategy [27]. Previous studies have found
that the analgesic effects of buprenorphine could be improved by
increasing the dose or by prescribing daily divided doses [22]
and that doses of 32 mg or higher could be safe and effective
[15]. Indeed, the therapeutic choice of using a partial l-agonist
medication is known to reduce the risk of overdoses compared to
other full agonist analgesics [3]. A previous study found that buprenorphine causes limited respiratory depression with a ceiling effect at higher dose [6].
Although use of a within-subjects, repeated-measures design in
participants housed on an inpatient research unit is strong experimentally, some limitations also must be acknowledged. First, the
participants we enrolled had to fulll several inclusion and exclusion criteria, which may have reduced the external validity of the
results. Indeed, our sample excluded the most severely opioid
dependent individuals and those with certain types of pain (eg,
those with neuropathic pain, multiple failed back surgeries, as well
as those with a previous lack of analgesic response to buprenorphine). Thus, further studies are needed in opioid dependent individuals with other types of pain and a more complex addictive
prole. Moreover, the highest dose we tested (16 mg) may be considered as inadequate for some patients and may need to be increased to manage both pain and opioid dependence. Also,
because oxycodone is commonly abused by the intranasal or intravenous routes, future studies should test higher doses of Bup/Nx in
combination with opioid agonists administered by nonoral routes.
Finally, the context of laboratory sessions is different from the ecological context of the participants lives. Therefore, a clinical trial
conducted on an outpatient basis and/or an epidemiological study
would be appropriate to conrm the present results [36].
Nevertheless, our data suggest that buprenorphine could be an
effective medication for those patients who need to be treated for
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[31] Ripa SR, McCarberg BH, Munera C, Wen W, Landau CJ. A randomized, 14-day,
double-blind study evaluating conversion from hydrocodone/acetaminophen
(Vicodin) to buprenorphine transdermal system 10 mug/h or 20 mug/h in
patients
with
osteoarthritis
pain.
Expert
Opin
Pharmacother
2012;13:122941.
[32] Roux P, Carrieri PM, Cohen J, Ravaux I, Spire B, Gossop M, Comer SD. Nonmedical use of opioids among HIV-infected opioid dependent individuals on
opioid maintenance treatment: the need for a more comprehensive approach.
Harm Reduct J 2011;8:31.
[33] Silversides A. Use of strong opioids in Canada rose sharply between 2005 and
2010. BMJ 2011;343:d5441.
[34] Steiner DJ, Sitar S, Wen W, Sawyerr G, Munera C, Ripa SR, Landau C. Efcacy
and safety of the seven-day buprenorphine transdermal system in opioidnaive patients with moderate to severe chronic low back pain: an enriched,
randomized, double-blind, placebo-controlled study. J Pain Symptom Manage
2011;42:90317.
[35] Townsend CO, Kerkvliet JL, Bruce BK, Rome JD, Hooten WM, Luedtke CA,
Hodgson JE. A longitudinal study of the efcacy of a comprehensive pain
rehabilitation program with opioid withdrawal: comparison of treatment
outcomes based on opioid use status at admission. PAIN 2008;140:17789.
[36] Turk DC, OConnor AB, Dworkin RH, Chaudhry A, Katz NP, Adams EH,
Brownstein JS, Comer SD, Dart R, Dasgupta N, Denisco RA, Klein M,
Leiderman DB, Lubran R, Rappaport BA, Zacny JP, Ahdieh H, Burke LB, Cowan
P, Jacobs P, Malamut R, Markman J, Michna E, Palmer P, Peirce-Sandner S,
Potter JS, Raja SN, Rauschkolb C, Roland CL, Webster LR, Weiss RD, Wolf K.
Research design considerations for clinical studies of abuse-deterrent opioid
analgesics: IMMPACT recommendations. PAIN 2012;153:19972008.
[37] Vowles KE, Ashworth J. Is opioid withdrawal necessary within comprehensive
pain rehabilitation programs? PAIN 2011;152:194850.
[38] Wesson DR, Smith DE. Buprenorphine in the treatment of opiate dependence. J
Psychoactive Drugs 2010;42:16175.
[39] Wolfert MZ, Gilson AM, Dahl JL, Cleary JF. Opioid analgesics for pain control:
Wisconsin physicians knowledge, beliefs, attitudes, and prescribing practices.
Pain Med 2010;11:42534.
[40] Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous
outcomes. Biometrics 1986;42:12130.