NIH Public Access
`Author Manuscript
`Addiction. Author manuscript; available in PMC 2013 September 18.
`Published in final edited form as:
`Addiction. 2011 August ; 106(8): 1460–1473. doi:10.1111/j.1360-0443.2011.03424.x.
`
`The pharmacodynamic and pharmacokinetic profile of intranasal
`crushed buprenorphine and buprenorphine/naloxone tablets in
`opioid abusers
`
`L.S. Middleton1,3, P.A. Nuzzo1,3, M.R. Lofwall1,2,3, D.E. Moody4, and S.L. Walsh1,2,3
`1Department of Behavioral Science, University of Kentucky, Lexington, KY, USA
`2Department of Psychiatry, University of Kentucky, Lexington, KY, USA
`3Center on Drug and Alcohol Research, University of Kentucky, Lexington, KY, USA
`4University of Utah, Center for Human Toxicology, Salt Lake City, UT, USA
`
`Abstract
`Aims—Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence
`pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The
`study objectives were to characterize and compare their intranasal pharmacodynamic and
`pharmacokinetic profiles.
`Design—A randomized, double-blind, placebo-controlled, crossover study.
`Setting—An in-patient research unit at the University of Kentucky.
`Participants—Healthy adults (n=10) abusing, but not physically dependent on, intranasal
`opioids.
`Measurements—Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed
`buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous
`dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples,
`physiological, subject- and observer-rated measures were collected before and for up to 72 hours
`after drug administration.
`Findings—Both formulations produced time- and dose-dependent increases on subjective and
`physiological mu-opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective
`ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically
`significant. No significant formulation differences in peak plasma buprenorphine concentration or
`time-course were observed. Buprenorphine bioavailability was 38–44% and Tmax was 35–40
`minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and
`8/2 mg, respectively.
`Conclusions—It is difficult to determine if observed differences in abuse potential between
`intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested.
`Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual
`administration suggests a motivation for intranasal misuse in non-dependent opioid abusers.
`However, significant naloxone absorption from intranasal buprenorphine/naloxone administration
`
`Declaration of Interest: Dr. Michelle Lofwall has received speaker honoraria and is the recipient of an investigator-initiated
`educational research contract from Reckitt Benckiser Pharmaceuticals, a manufacturer of buprenorphine and buprenorphine/naloxone.
`Dr. David Moody has received research funding (including contractual support for the pharmacokinetic analyses performed for this
`study) and consultation fees from Reckitt Benckiser Pharmaceuticals. Dr. Sharon Walsh has received travel reimbursement and
`honoraria from Reckitt Benckiser Pharmaceuticals as a speaker and consultant.
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`may deter the likelihood of intranasal misuse of buprenorphine/naloxone, but not buprenorphine,
`in opioid-dependent individuals.
`
`INTRODUCTION
`Buprenorphine, a partial mu opioid agonist, is an effective treatment for opioid dependence
`[1, 2] when administered alone or combined with naloxone. Buprenorphine was first
`introduced for opioid dependence treatment in 1996 in France [3] and is registered for use in
`countries across Europe, North America, Asia and in Australia. Food and Drug
`Administration (FDA) approval of buprenorphine has greatly increased treatment access in
`the United States where prescriptions for buprenorphine (primarily buprenorphine/naloxone)
`increased from approximately 267 000 in 2004 to more than 3.3 million in 2008 [4]. Not
`surprisingly, as availability increased, so have reports of diversion and misuse [5].
`
`Buprenorphine produces a dose-response that is characterized by a ceiling on the magnitude
`of its pharmacodynamic effects (e.g. respiratory depression; [6–9]) providing a more
`favorable safety profile than full agonists. However, human laboratory studies demonstrate
`that buprenorphine has abuse liability, as it can produce euphorigenic effects comparable to
`full opioid agonists and is self-administered by nondependent opioid users [10, 11]. Because
`of its lower intrinsic activity and high affinity, buprenorphine may precipitate opioid
`withdrawal in opioid-dependent individuals, thereby reducing its abuse liability [12–14].
`This is supported by epidemiological data indicating that buprenorphine is infrequently
`(<3%) reported as the drug of choice among prescription opioid-dependent people seeking
`treatment [15]. The buprenorphine/naloxone combination product was developed to
`decrease further the abuse potential of buprenorphine and limit its parenteral (i.e.,
`intravenous) diversion. Naloxone is virtually inactive sublingually [16] but, when injected,
`can precipitate withdrawal [17, 18]. In subjects without physical dependence, there are not
`clear differences in abuse liability between these formulations [10, 19, 20].
`
`Diversion and misuse of both formulations have been reported. Specifically, buprenorphine
`and buprenorphine/naloxone tablets are being crushed and then taken by injection [21–23]
`or intranasally [24–26] in the United States and abroad. While studies have characterized the
`effects of buprenorphine sublingually and by injection [27–32], no studies, to date, have
`examined the profile of intranasal (i.e. snorting, inhalation) buprenorphine. The purpose of
`this study was to examine the intranasal pharmacodynamic and pharmacokinetic profile of
`crushed buprenorphine and buprenorphine/naloxone in intranasal opioid abusers without
`opioid physical dependence. The hypotheses were that intranasal buprenorphine/naloxone
`would have modestly decreased abuse potential compared to buprenorphine alone and that,
`like other opioids, both buprenorphine and naloxone would exhibit significant intranasal
`absorption.
`
`Twelve recreational prescription opioid users were recruited by advertisements and admitted
`as in-patients. All were in good health according to medical history, physical examination,
`electrocardiogram and laboratory tests. Exclusion criteria included those with: seizure
`disorders, history of asthma or respiratory disorders, head injury, hypertension,
`cardiovascular disease, abnormal electrocardiogram or required daily prescribed medication.
`All subjects reported illicit opioid use (confirmed by urinalysis during multi-day intake) and
`intranasal as their preferred administration route. An opioid-negative urine sample was also
`required during screening in the absence of withdrawal symptoms to exclude opioid physical
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`METHODS
`Subjects
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`Drugs
`
`dependence. Individuals seeking treatment for substance abuse or successfully sustaining
`abstinence were excluded.
`
`Two subjects were discharged before study completion for personal reasons or failure to
`comply with study procedures. Of the ten who completed (seven male, three female), all
`were Caucasian, with a mean [± standard error of the mean (SEM)] age of 31.2 ± 2.27 years.
`Subjects reported using illicit opioids 10 ± 2.3 days of the preceding 30 days. Average
`reported age of first use of illicit opioids was 16 ± 0.9 years with a lifetime history use of
`opioids of 7.7±1.7 years. Subjects also reported current use of cigarettes (n=9), alcohol
`(n=10), cocaine (n=6), sedatives/hypnotics/tranquilizers (n=6), marijuana (n=8) and
`amphetamines (n=1). The University of Kentucky (UK) Institutional Review Board
`approved this study; all subjects gave written informed consent and were paid for
`participation. This study was conducted in accordance with the Helsinki guidelines for
`ethical human research. A Certificate of Confidentiality was obtained from the National
`Institutes of Health.
`
`This study was performed under an investigator-initiated Investigational New Drug
`Application (#69214) with the FDA. All study medications were stored and prepared in the
`UK Investigational Pharmacy. Subutex® (2 and 8 mg tablets and matched placebos; all
`white in color) was obtained through the National Institute on Drug Abuse. Suboxone®
`(2/0.5 and 8/2 mg tablets and matched placebos; all white in color) was imported from Hull,
`England (Reckitt Benckiser Pharmaceuticals) because in the United States Suboxone® is
`orange, which would have broken the subject blind. These doses were selected for testing
`because they are the currently marketed dose strengths and are available for clinical use and
`misuse. Individual ampoules containing buprenorphine/naloxone solution (4 mg
`buprenorphine/1 mg naloxone/1 ml) were obtained through the NIDA drug supply (Murty
`Pharmaceuticals, Lexington, KY, USA) and diluted 1:5 for a final dose of 0.8 mg
`buprenorphine/0.2 mg naloxone/1 ml for intravenous administration. Intravenous doses of
`both drugs were included primarily to assess bioavailability. The intravenous naloxone dose
`was selected because 0.2 mg naloxone is sufficient to precipitate withdrawal in opioid
`dependent individuals; thus, the expected plasma concentrations would be clinically
`informative and relevant. The intravenous buprenorphine dose was selected to maintain the
`4:1 ratio of buprenorphine and naloxone used in the marketed medication.
`
`Study Design
`This 3.5 week in-patient study employed a randomized, double-blind, within-subject,
`placebo-controlled design. It was conducted at the Clinical Research Development and
`Operations Center (CR DOC), a research unit in the UK hospital. Subjects participated in six
`6.5-hour experimental sessions scheduled minimally 72 hours apart.
`
`Experimental Sessions
`Following admission, subjects were familiarized with and trained on all procedures. Subjects
`were maintained on a caffeine-free diet, allowed a light breakfast 2 hours before session, and
`could smoke up to 30 minutes before session. Females were tested weekly for pregnancy
`with no positive results. On session days, subjects received powder from crushed placebo,
`buprenorphine (2 or 8 mg) or buprenorphine/naloxone (2/0.5 or 8/2 mg) tablets of equivalent
`volume (100 mg). The placebo dose contained powder from the matched placebo tablets of
`both buprenorphine (50%) and buprenorphine/naloxone (50%). Subjects transferred the
`powder to a mirror, split the powder into two lines, and snorted one line through each nostril
`using a straw. Subjects completed computerized questionnaires using a keyboard and/or
`mouse. A trained research assistant used a keyboard to initiate tasks and to enter observer-
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`rated measures. Baseline data were collected for 30 minutes prior and 6 hours after drug
`administration (at 0900). Table 1 details the timing of all pharmacodynamic measures.
`
`Subject and Observer-Rated Measures
`Subject-rated measures included: six visual analog scales (VAS) rated from 0 (‘not at all’) –
`100 (‘extremely’; [33]); the Addiction Research Center Inventory (ARCI) short form [34];
`street value questionnaire; a 25-item adjective checklist that encompassed both an Agonist
`scale and mixed Agonist-Antagonist scale [16, 35]; and an observer-rated opioid adjective
`rating scale.
`
`Subjects also completed two locally developed questionnaires to characterize the sensations
`related to nasal inhalation of the test drugs using a 5-point Likert scale: (i) ‘When I snorted
`this drug it tasted or smelled…’ sweet, salty, sour, bitter, like metal, like medicine, like
`chalk, like fruit, bad, good; and (ii) ‘When I snorted this drug, my nose or throat felt…’
`burning, tingling, itching, pain, congestion, numbness, stinging, thirsty, dry mouth. This
`second questionnaire also included a ‘yes’ or ‘no’ question ‘Was it difficult to snort the
`amount of powder provided?’
`
`Performance and Ocular Tasks
`The digit symbol substitution task (DSST) was used to measure information processing [36].
`The Maddox-Wing test (Model CE0120, Clement Clarke Ltd., London, UK) was used to
`assess ocular exophoria or under convergence [33].
`
`Physiological Measures
`Oxygen saturation, heart rate and blood pressure were collected every min using a Dinamap
`Non-Invasive Patient Monitor (GE Medical Systems, Tampa, FL) for 30 minutes before and
`for 6 hours after drug administration. Respiratory rate was determined by counting the
`number of breaths within 30 seconds and multiplying by 2. Pupil diameter was determined
`using a pupillometer (NeurOptics, San Clemente, CA) in constant lighting conditions.
`
`Blood Sample Collection and Pharmacokinetic Analysis
`Intravenous catheter(s) were placed into the antecubital vein(s) prior to the start of session,
`one for intranasal sessions and two (in separate arms) for the intravenous session (the second
`for drug administration). Catheters remained in place for up to 72 hours and were flushed
`regularly to maintain patency. Blood samples (7 ml/sample) were collected into two 4-ml
`green heparinized vacutainers for determination of buprenorphine, norbuprenorphine,
`buprenorphine-3-glucuronide, norbuprenorphine-3-glucuronide and naloxone levels.
`Samples were collected at baseline and 5, 10, 15, 20, 30, 45 minutes, 1, 2, 4, 8, 12, 24, 48
`and 72 hours post-drug administration and one sample at 2 minutes during the intravenous
`session. Vacutainers were inverted 8–10 times and centrifuged (3000 g × 15 minutes)
`immediately to prevent hemolysis. Plasma was transferred to a vial, stored at −80°C,
`shipped to the University of Utah Center for Human Toxicology and assayed for
`buprenorphine (and metabolites) and naloxone (the latter only for those sessions testing
`buprenorphine/naloxone). Analysis was performed as previously described [37]. This
`technique reliably quantifies buprenorphine (and metabolites) and naloxone levels with a
`lower limit of quantitation (LLOQ) of 0.1 ng/ml and 0.025 ng/ml, respectively.
`
`Statistical Analysis
`All measures were analyzed as raw time-course data with two-factor within-subject analysis
`of variance [ANOVA; dose (five levels) × time (intervals in Table 1)] followed by Tukey
`post-hoc analyses. Physiological measures collected every minute were first averaged across
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`time to yield intervals (5–30 minutes) corresponding to collection of subjective reports. Peak
`scores (minimum or maximum depending upon the a priori predicted direction of effect)
`were derived from time-course data and analyzed using one-factor ANOVA for dose.
`Planned comparisons with Bonferroni corrections were used for active dose comparisons to
`placebo and between formulations.
`
`Buprenorphine concentrations were analyzed using 3-factor ANOVA [dose (two levels) by
`formulation (two levels) by time]. Naloxone concentrations were analyzed for 8 hours after
`buprenorphine/naloxone with two-factor ANOVA [dose (two levels) × time]. Plasma area-
`under-the-curve (AUC) was calculated by the trapezoidal rule (0–72 hours). Mean
`maximum concentrations (Cmax) and time-to-maximum concentrations (Tmax) were
`calculated for buprenorphine, its metabolites, and naloxone. Observed absolute
`bioavailability (Fobs) of intranasal buprenorphine and naloxone was determined as follows:
`Fobs = (AUC intranasal/AUC intravenous) × (dose intravenous/dose intranasal). Values
`below the LLOQ were scored as zero for mean concentrations and AUC calculations. The
`elimination rate constant (λz) was estimated by linear regression from a natural log linear
`plot of data from 12, 24 and 48 hours for 8 and 8/2 mg buprenorphine and data from 45
`minutes, 1, 2 and 4 hours naloxone (the terminal post-distribution phases). Buprenorphine
`concentrations below the LLOQ at these times or with a slope approaching 0 for these time
`points were excluded from the λz calculation. For low doses of buprenorphine and all
`buprenorphine metabolites, λz was not calculated due to insufficient concentrations at these
`times. The terminal half-life (t1/2) was calculated as 0.693/λz. One-factor ANOVA along
`with Tukey tests were used to determine differences among the buprenorphine parent and
`metabolite conditions on pharmacokinetic parameters. Paired t-tests were used to compare
`pharmacokinetic parameters for naloxone. All ANOVA models were run with SAS 9.1 Proc
`Mixed software for Windows and were considered significant when P < 0.05.
`
`RESULTS
`Physiological Measures
`Figure 1 illustrates the time-course for pupil diameter over the first 72 hours after intranasal
`dosing. There were significant effects of dose and time (see figure legend for statistical
`outcomes). Significant miosis was observed within 30 minutes of dosing after 8 and 8/2 mg,
`but not until 45 minutes for the lower doses (2 and 2/0.5 mg; Tukey test P < 0.05). Data
`from the first hour reveal a slightly earlier onset for buprenorphine alone compared to the
`same doses of the combination; however, these were not significant. Tukey post-hoc
`analyses revealed that miosis lasted for up to 6 hours for the low doses (2 and 2/0.5 mg), but
`was still evident 24 hours after administration of 8 and 8/2 mg. Similarly, peak analysis of
`minimum diameter scores revealed a main effect of dose (Table 2) with all active doses
`significantly different from placebo (P < 0.0001; planned comparisons).
`
`Figure 2 illustrates the time-course for oxygen saturation over the first 6 hours after
`intranasal dosing. There were significant effects of dose and time (see figure legend for
`statistics). While all active doses decreased oxygen saturation compared to placebo, Tukey
`post-hoc analyses revealed significant differences for only the 8 mg dose that occurred after
`peak effect was reached (1.5 – 4 hours). Peak analyses revealed significant dose effects and
`planned comparisons revealed a reduction in oxygen saturation for all active doses
`compared to placebo (P < 0.05; Table 2). Similarly, there was a significant effect of dose on
`respiratory rate for both time-course and peak analysis (see Table 2) with the 8, 2/0.5 and
`8/2 mg doses significantly decreased compared to placebo (P < 0.05; planned comparisons).
`Time-course analyses revealed no significant dose effects for heart rate, systolic or diastolic
`blood pressure. However, planned comparisons revealed that the peak increase in systolic
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`and diastolic blood pressure following 2 mg buprenorphine was significantly greater than
`placebo (P < 0.05).
`
`Subject-Rated Measures
`Time-course data for the first 6 hours after intranasal dosing for the visual analog rating
`‘How much do you LIKE the drug?’ are illustrated in Fig. 3 (top panel). Analyses of the
`time course data for ratings of ‘like’, ‘high’, ‘drug effect’ and ‘good’ (data not shown)
`revealed significant dose dependent effects (P < 0.001). Compared to placebo, a significant
`increase in ratings of “liking” was observed by 20 minutes after the 8 mg dose and 45
`minutes after the 8/2 mg dose (Tukey test P < 0.05), while 2 and 2/0.5 mg doses were not
`significantly different from placebo. For both 8 and 8/2 mg, this effect persisted for 2.5
`hours post-dosing. Peak analysis of VAS measures revealed significant dose effects for
`‘high’, ‘drug effect’, ‘like’, ‘good’ and ‘bad’ (P < 0.01; results from planned comparison
`described in Table 2).
`
`Figure 3 (bottom panel) illustrates the time-course for street value estimates for the
`intranasal test conditions. There was a significant dose dependent increase on ratings of
`street value for both the time course and peak analyses (see Table 2). The 8 mg dose was
`rated, on average, as having the highest value during the period of drug onset. Peak analyses
`revealed that all active doses differed from placebo (Table 2; P < 0.05; planned
`comparisons).
`
`Time-course analyses revealed significant dose effects for a number of prototypic opioid
`agonist symptoms, including tingling, itchy, pleasant, talkative, dry mouth, good mood,
`energetic and sweating, and on the composite Agonist scale (P < 0.05). No significant
`effects were found for the mixed agonist-antagonist scale. Similarly, peak score analyses
`revealed endorsement of typical mu agonist effects as a function of dose, including tingling,
`itchy, nodding, relaxed, coasting, talkative, dry mouth, good mood, energetic and floating
`and are reflected in the composite Agonist scale (P < 0.05); planned comparisons are shown
`in Table 2. Both the ARCI Benzedrine and morphine-benzedrine group (MBG) scales
`increased significantly as a function of dose (P < 0.05) on the time course analysis. Peak
`score analyses revealed significant increases for the pentobarbital-chlorpromazine-alcohol-
`general (PCAG), amphetamine, MBG and lysergic acid diethylamide (LSD) scales
`compared to placebo (P < 0.05; see Table 2).
`
`Analysis of the results from the questionnaire on sensations in the nose and throat after drug
`administration revealed no significant main effect of dose. However, planned comparisons
`revealed that 8 mg buprenorphine increased ratings of ‘itching’ and ‘numbness’ compared to
`placebo, and 2/0.5 mg buprenorphine/naloxone produced more ‘stinging’ than placebo.
`Results from the questionnaire querying subjects about the taste of the drug revealed
`significant main effects of dose for ‘sweet’, ‘bitter’, ‘like medicine’, ‘like chalk’ and ‘like
`fruit’ (P < 0.05; Table 2). Buprenorphine 8 mg produced more ‘numbness’ than 8 mg
`buprenorphine/naloxone, 2/0.5 mg buprenorphine/naloxone produced more ‘stinging’ than 2
`mg buprenorphine. Both doses of buprenorphine/naloxone tasted more ‘like fruit’ and
`‘sweet’ than the corresponding buprenorphine doses, and both doses of buprenorphine alone
`tasted more ‘like chalk’ and ‘like medicine’ than the corresponding buprenorphine/naloxone
`doses. The high dose of buprenorphine alone was also more ‘bitter’ than the high dose of
`buprenorphine/naloxone. Four subjects reported that it was difficult to snort the amount of
`powder during at least one experimental session (on 13 of 50 sessions).
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`Observer-Rated Measures
`Time-course analyses of the observer-rated scales revealed dose-related increases on itchy,
`talkative and energetic (P < 0.05). Peak analysis revealed significant increases of observer
`ratings of itchy, nodding, coasting, talkative and energetic (P < 0.05; Table 2) also reflected
`by the composite Agonist Scale (P < 0.01; see Table 2).
`
`Ocular and Performance Measures
`There was a significant effect of dose on Maddox Wing scores for both the time-course and
`peak analysis (see Table 2). Maddox Wing scores for all active doses were significantly
`higher than placebo (P < 0.01; planned comparisons).
`
`Analysis of the DSST time-course data revealed a main effect of dose for number of trials
`attempted and number of correct trials (P < 0.05). Peak DSST scores decreased as a function
`of dose for the number of trials attempted and the number of trials correct (P < 0.05; Table
`2).
`
`Pharmacokinetic Outcomes
`Figure 4 illustrates the 72-hour time-course for buprenorphine (top left), norbuprenorphine
`(top right), buprenorphine-3-glucuronide (bottom left) and norbuprenorphine-3-glucuronide
`(bottom right) as a function of dose; key outcome measures are shown in Table 3. Analysis
`of the plasma buprenorphine and the metabolites time course, AUC and Cmax revealed
`significant dose effects (P < 0.0001) with 8 and 8/2 mg greater than 2 and 2/0.5 mg,
`respectively. No differences for Tmax, t1/2 or bioavailability were observed for
`buprenorphine among the four active conditions. Buprenorphine concentrations returned to
`baseline levels (<LLOQ) prior to the start of the subsequent session (with the exception of
`three sessions in which buprenorphine concentration was slightly above the LLOQ).
`
`Naloxone plasma concentrations after intranasal buprenorphine/naloxone (Fig. 5; Table 3)
`increased dose-dependently (P < 0.0001). Plasma naloxone concentration returned to
`baseline levels (<LLOQ) within 8 hours following drug administration (with the exception
`of one session in which naloxone concentration was 0.025 ng/ml, the LLOQ for naloxone).
`Significant differences between 2/0.5 and 8/2 mg buprenorphine/naloxone were observed for
`naloxone bioavailability, t1/2, AUC and Cmax (P < 0.05) but not Tmax.
`
`Safety
`
`No serious adverse events occurred. Side effects reported/observed after active drug
`administration included vomiting during (n=4) and after (n=5) a test session, constipation
`(n=5), and headache during (n=4; three during an active drug session and one after placebo)
`and after (n=7; five after an active drug session and two after placebo) a test session. One
`subject reported blurry vision during session after an active dose.
`
`DISCUSSION
`This study examined the intranasal pharmacodynamic and pharmacokinetic profile of
`crushed buprenorphine and buprenorphine/naloxone tablets among sporadic opioid users.
`This study employed crushed buprenorphine and buprenorphine/naloxone tablets, which is
`important because these are the tablets used to treat opioid dependence and for which there
`are reports of intranasal misuse. Both formulations were safely tolerated (with minimal
`effects on oxygen saturation and respiratory rate) and produced dose-dependent prototypic
`subjective and physiological mu opioid effects. Overall, there were few statistical
`differences between buprenorphine alone and buprenorphine/naloxone; however, subjects
`reported the highest ratings of positive mood effects (‘like’, ‘high’, ‘drug effect’, ‘good
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`effects’) and street values for 8 mg of buprenorphine. Physiological and subjective time
`course data reveal a modestly slower onset of action for 8/2 mg buprenorphine/naloxone
`compared to 8 mg buprenorphine alone, and subjects were able to differentiate between
`formulations based on medication taste when snorted. Buprenorphine was well absorbed
`intranasally with no differences between formulations in time course, Cmax of the parent
`drug or metabolites. Naloxone was readily absorbed after intranasal buprenorphine/naloxone
`administration with an estimated bioavailability between 24 and 30%.
`
`Consistent with earlier studies of sublingual buprenorphine, with and without naloxone [8,
`11, 19, 20, 38, 39], intranasal administration increased subjective ratings significantly on
`abuse liability measures in non-dependent opioid abusers. Moreover, the peak ratings for
`visual analog indices of ‘high’ and ‘liking’ and pupillary miosis observed here after
`intranasal doses of 8 mg were comparable in magnitude to peak responses after sublingual
`administration of that same dose [8, 19]. The onset of pharmacodynamic effects was
`modestly, but not significantly, slower for buprenorphine/naloxone compared to
`buprenorphine alone, a pattern previously reported after intramuscular administration of the
`single and combination products [20]. Importantly, intranasal administration of
`buprenorphine did differ significantly from sublingual dosing with regard to the speed of
`drug onset and the time-required-to-reach the maximum effect, both factors known to
`influence abuse liability. In the present study, the onset of drug action was evident within 15
`minutes of drug administration and peak pharmacodynamic responses were achieved on
`average between 60 and 75 minutes after dosing. In contrast, studies of sublingual
`buprenorphine have reported a slower onset of action (30–45 minutes) and peak
`pharmacodynamic responses occurring between 2 and 3 hours after dosing [8, 19].
`Buprenorphine concentrations following intranasal administration of the high doses of
`buprenorphine and buprenorphine/naloxone in the current study were approximately 2–3
`fold higher than studies of sublingual dosing [30, 31, 40, 41] and peak plasma
`concentrations were reached at least 30 minutes earlier compared to the Tmax for sublingual
`administration. Thus, it is possible that opioid abusers are misusing buprenorphine by the
`intranasal route to attain higher concentrations more rapidly than if buprenorphine is taken
`as prescribed.
`
`When administered as a sublingual tablet, bioavailability of buprenorphine can be as low as
`15% [30], while a study of an intranasal buprenorphine solution reported bioavailability at
`48% [42]. In the current study, the bioavailability of intranasal buprenorphine from crushed
`tablets ranged between 38 and 44%. Naloxone did not alter the pharmacokinetic action of
`buprenorphine or its metabolites. When taken sublingually, naloxone has poor absorption
`and bioavailability (16). To our knowledge, only one study by Dowling and colleagues has
`examined naloxone absorption following intranasal administration in humans and
`determined that naloxone was detectable in only 1/3 of the subjects receiving 2 mg naloxone
`(in solution) and was not detectable following 0.8 mg [43]. The same study also determined
`that intranasal naloxone had poor intranasal bioavailability (i.e. 4%). The current study
`determined that naloxone bioavailability was 24% and 30% for doses containing 0.5 and 2
`mg naloxone, respectively. Dowling et al. [43] administered 0.5 ml of naloxone through a
`cannula and flushed with 5 ml of saline. For that study, the solution volume exceeded the
`nasal mucosa limit for absorption (i.e., 0.3–0.4 ml; [44]); thus, excess solution may have
`been swallowed decreasing the naloxone available for intranasal absorption. Also, nasal
`inhalation of powder versus solution may result in differential absorption characteristics.
`Previous studies in rats and rabbits have shown increased absorption of insulin following
`administration of powder drug formulation compared to liquid formulation [45, 46].
`
`Based on the current results, it is not evident that the observed differences with regard to
`abuse potential between the two formulations are clinically relevant at the doses tested here.
`
`Addiction. Author manuscript; available in PMC 2013 September 18.
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`It is important to note that the doses tested here are in the low range of therapeutic use, and
`persons misusing drugs often misuse higher doses. It is possible that intranasal
`administration of higher doses (e.g., 16 or 24 mg) may show differences between
`formulations, as naloxone is clearly bioavailable. Administration of low doses of naloxone
`(0.1–0.5 mg, intravenously or intramuscularly) will precipitate withdrawal in patients who
`are dependent on most opioids [16–18, 47–58]. In the current study, bioavailability and
`Cmax of intranasal naloxone were approximately three- and five-times greater, respectively,
`compared to sublingual naloxone studies [16, 27, 40]. Given the plasma concentrations and
`bioavailability of naloxone observed in this study, it is likely (but has not yet been reported)
`that intranasal use of buprenorphine/naloxone may lead to precipitated withdrawal in opioid
`dependent individuals.
`
`Epidemiological and post-marketing surveillance studies have shown that buprenorphine is
`misused by the intranasal route [24–26, 59]. The greater bioavailability (i.e., higher plasma
`