Full length articleIntranasal buprenorphine alone and in combination with naloxone: Abuse liability and reinforcing efficacy in physically dependent opioid abusers
Introduction
Buprenorphine (BUP), a partial mu opioid agonist, has been successfully used for the treatment of opioid dependence since the 1990’s (see recent reviews Fullerton et al., 2014, Mattick et al., 2014). Following the passage of the U.S. Drug Addiction Treatment Act of 2000 and FDA approval of Suboxone® and Subutex® in 2002, BUP implementation in the U.S. became widespread. While the majority of BUP sold in the U.S. is buprenorphine/naloxone (BUP/NX), many countries outside the U.S. primarily use BUP alone (e.g., France). In part, this was because BUP was introduced in these countries before BUP/NX was available; however, now that BUP/NX is available, reasons for continued preference for BUP alone may not be empirically justified given growing concerns about diversion, misuse, and adult and pediatric overdose (Hayes et al., 2008, Kintz, 2002, Lai and Teo, 2006, Lavonas et al., 2013, Lovegrove et al., 2014, Reynaud et al., 1998, Simonsen et al., 2011, Tracqui et al., 1998). The preferential use of BUP/NX in the U.S. occurred because the FDA approved both formulations simultaneously and the manufacturer, Reckitt-Benckiser Pharmaceuticals, priced BUP/NX lower than BUP to discourage widespread prescribing of BUP. Also, physician trainings and published treatment guidelines (e.g., CSAT, 2004) preferentially recommended BUP/NX (except for induction and supervised dosing and treatment of pregnant women).
The rationale for the combination BUP/NX development was based upon the assumption that adding naloxone would reduce potential misuse and diversion compared to BUP alone, as has been observed with pentacozine/naloxone and tilidine/naloxone (Johnson and McCagh, 2000). Naloxone has poor sublingual bioavailability (Preston et al., 1990) and is functionally inactive when sublingual BUP/NX is taken as directed. However, if misused parenterally, naloxone becomes 100% bioavailable and can precipitate opioid withdrawal in opioid-dependent individuals (e.g., Fudala et al., 1998, Stoller et al., 2001). However, studies and clinical experience have demonstrated that whether BUP and BUP/NX administration is or is not associated with abuse liability and does or does not precipitate opioid withdrawal in opioid-dependent individuals is complicated and determined by numerous factors, including opioid maintenance drug, maintenance dose, time since last dose, BUP or BUP/NX dose, and route of BUP or BUP/NX administration (Clark et al., 2002, Harris et al., 2000, Larance et al., 2014, Mendelson et al., 1996, Preston et al., 1988, Rosado et al., 2007, Schuh et al., 1996, Stoller et al., 2001, Walsh et al., 1995).
Reports indicate that BUP tablets with and without naloxone are being crushed (and sublingual films dissolved) and subsequently injected or insufflated intranasally (Alho et al., 2007, Bruce et al., 2009, Horyniak et al., 2011, Jenkinson et al., 2005, Lofwall and Walsh, 2014, Nordmann et al., 2012, Young et al., 2010). For instance, two studies report that up to 30% of patients enrolled in BUP therapy were snorting their medication (Barrau et al., 2001, Roux et al., 2008). Case reports describe adverse consequences from intranasal BUP, including acute hepatitis and renal failure (Eiden et al., 2013) and fatal overdose (Ferrant et al., 2011, Megarbane et al., 2011). Few controlled human studies have characterized the response to intranasal BUP, BUP/NX or naloxone. We previously examined the pharmacodynamic and pharmacokinetic profiles of intranasal BUP and BUP/NX in opioid abusers who were not physically dependent on opioids (Middleton et al., 2011). That study demonstrated significant intranasal absorption of buprenorphine (∼38–44%) and naloxone (∼24–30%) from BUP/NX yielding naloxone plasma concentrations comparable to those produced by doses that precipitate withdrawal in opioid-dependent individuals; however, this did not translate into meaningful pharmacodynamic differences between BUP and BUP/NX in non-dependent abusers. Jones and colleagues recently reported that intranasal BUP and BUP/NX do have reinforcing efficacy in BUP-maintained individuals (mimicking those receiving treatment with BUP), and this declines as a function of maintenance dose (Jones et al., 2015). Further, they reported that BUP/NX produced decreased positive subjective effects compared to BUP and was associated with increased ratings of aversive effects in BUP-maintained individuals. However, as BUP is known to have very high affinity for the mu receptor and a long duration of action, the effects of intranasal BUP/NX in individuals dependent on BUP may differ substantially from its effects in those dependent on short-acting opioids with lower affinity (e.g., see Schuh et al., 1996, Walsh et al., 1995). Thus, the present study sought to examine the effects of intranasal BUP compared to BUP/NX among opioid-dependent individuals maintained on a short-acting full mu opioid agonist, mimicking the typical out-of-treatment scenario for those dependent on heroin or short-acting prescription opioids who may misuse buprenorphine products.
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Participants
Eleven adult volunteers completed this study. All were physically dependent on short-acting opioids, recruited through advertisements, and determined to be in good health by history, physical examination, electrocardiogram and laboratory tests. Inclusion criteria included ages 18–50 years, within 25% of ideal body weight or BMI <30, prior intranasal opioid use, ≥21 of last 30 days short-acting illicit opioid use. Exclusion criteria included: seizure or respiratory disorders, head injury,
Participant characteristics
Sixty-two individuals were screened in-person, twenty were admitted as inpatients, and eleven completed the protocol. Early discharge reasons were: couldn’t tolerate spontaneous withdrawal during first week (n = 1), no naloxone response (n = 1), personal reasons (n = 2), provided poor/inconsistent data (n = 3), and contraband activities (n = 2). Completers were 7/4 males/females, mean age = 28.4 years; all Caucasian, 11.7 mean years of education, 5/2/4 were single/married/divorced. Based upon TLFB, the
Discussion
This inpatient study examined a range of intranasal BUP and BUP/NX doses in opioid-dependent individuals maintained on the short-acting opioid, oxycodone, to assess opioid agonist and antagonist effects, reinforcing efficacy and safety. It was hypothesized that higher doses (e.g., 16/4) of BUP/NX would potentially precipitate robust and frank withdrawal (Stoller et al., 2001, Walsh et al., 1995) and, thus, a priori safety criteria were set to preclude dose escalation to ensure the safety and
Funding
This study was supported by a grant from the National Institute on Drug Abuse, R01 DA016718-04 (SLW) and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, UL1TR000117. Reckitt Benckiser and the National Institute on Drug Abuse provided the drug supply at no cost. None of these agencies had any role in the study design; in the collection, analysis and interpretation of the data; in writing of the report; and in
Contributors
SLW, SB and MRL conceived and designed the study. SLW, SB, VAC and PN provided oversight for the conduct of the study and enrollment of volunteers. MRL provided medical evaluations and medical oversight. VAC and PN managed data collection and conducted data analyses. All authors participated in the preparation and review of the final manuscript.
Conflicts of interest
Conflicts of interest for SB, VV and PN: none. SLW and MRL have received honoraria and travel reimbursement for developing and delivering educational talks through an arms-length unrestricted educational grant from Reckitt Benckiser Pharmaceuticals to PCM Scientific, UK; SLW has also received honoraria from the same grant for organizing and serving as a conference chairperson. SLW and MRL are also serving as consultants to Braeburn Pharmaceuticals and Camurus in the development of novel
Acknowledgements
The authors would like to thank the nursing staff at the Center for Clinical and Translational Research, the research staff at the Center on Drug and Alcohol Research, the pharmacy staff at the Investigational Drug Services Pharmacy at the University of Kentucky for support of this project, and Lisa Middleton, Ph.D. for work on an early draft of the protocol. The authors also thank Reckitt Benckiser Pharmaceuticals, especially Dr. Neil Hyde and Dr. Chris Chapleo, for assistance in obtaining the
References (53)
- et al.
Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users
Drug Alcohol Depend.
(2007) - et al.
Abuse liability and reinforcing efficacy of oral tramadol in humans
Drug Alcohol Depend.
(2013) - et al.
Factors influencing the selection of hydrocodone and oxycodone as primary opioids in substance abusers seeking treatment in the United States
Pain
(2013) - et al.
Fatal poisoning due to snorting buprenorphine and alcohol consumption
Forensic Sci. Int.
(2011) - et al.
Effects of buprenorphine and naloxone in morphine-stablized opioids addicts
Drug Alcohol Depend.
(1998) - et al.
Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine
Drug Alcohol Depend.
(2000) - et al.
The prevalence and correlates of buprenorphine inhalation amongst opioid substitution treatment (OST) clients in Australia
Int. J. Drug Policy
(2011) A new series of 13 buprenorphine-related deaths
Clin. Biochem.
(2002)- et al.
The diversion and injection of a buprenorphine-naloxone soluble film formulation
Drug Alcohol Depend.
(2014) - et al.
The fifth edition of the addiction severity index
J. Subst. Abuse Treat.
(1992)