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Human Abuse Liability of the Smoking Cessation Drug Varenicline in Smokers and Nonsmokers SL McColl1, AH Burstein2, KR Reeves2, CB Billing Jr3, M Stolar3 and EM Sellers1,4–6 Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist developed as an aid for smoking cessation. This study evaluated varenicline’s potential for abuse by smokers (n = 23) and nonsmokers (n = 22). The study used a randomized, double-blind, placebo-controlled, double-dummy crossover design with five treatment periods: 15 and 30 mg amphetamine, 1 and 3 mg varenicline, and placebo. Following each treatment, the participants were assessed on aspects relating to potential abuse of the drug (e.g., drug liking, drug high, and drug monetary value). The positive effects measured for 3 mg varenicline were similar to those for the placebo, and significantly lower than those for amphetamine in both smokers and nonsmokers. Unpleasant effects were reported for 3 mg varenicline in both participant groups. For 1 mg varenicline, the overall patterns were similar, with the exception that the nonsmokers group showed some small positive effects balanced by some negative effects when compared with the effects of placebo. These findings lead to the conclusion that varenicline is unlikely to be abused. Nicotine has potent reinforcing effects in animals,1–3 and the nicotine in cigarettes is highly addictive.4,5 In human abuse liability studies, both smoked and intravenous formulations indicate abuse liability.6–8 However, smoking cessation treatments such as nicotine replacement therapies (NRTs; e.g., transdermal patch, nasal spray, gum, lozenges, and inhaler) have slower nicotine absorption rates than cigarettes and have been shown to be associated with a much lower potential for abuse.9–11 Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist that has been shown to achieve higher continuous abstinence rates in smokers trying to quit, than the use of either placebo or sustained-release bupropion.12–17 It binds with high affinity to the α4β2 nicotinic acetylcholine receptor subtype and activates the mesocorticolimbic reward system in a manner similar to nicotine. Its partial agonist property is thought to help reduce craving and alleviate withdrawal symptoms by partially activating nicotinic acetylcholine receptors in the absence of nicotine, while its antagonist properties block the effects of nicotine received from smoking.18,19 The partial agonist property of varenicline would also be expected to reduce its potential for abuse as compared to nicotine, and this has been demonstrated in studies comparing other partial agonists with their full agonist counterparts.20–22 Partial agonists have a low potential for abuse because they do not attain maximal agonist response and result in
a weaker dose–response relationship. Additionally, the pharmacokinetic profile of varenicline (when delivered orally, the mean time taken to attain maximum observed plasma concentration (tmax) is >2 h23) would also suggest low potential for abuse. This is because, for drugs with similar pharmacologic properties, slowonset drugs with long-duration effects (long tmax and long t1/2) are associated with a lower potential for abuse than are rapid-onset drugs with short-duration effects (short tmax and short terminal elimination half-life (t1/2)).24–27 Consistent with this pharmacokinetic profile, the varenicline-induced increase in dopamine in rat Nucleus accumbens has a slower onset and is longer lasting when compared against the rapid increase and fast decline in dopamine release that characterize nicotine and other drugs of abuse. However, because varenicline does increase mesolimbic dopamine release and acts as a reinforcer in animals trained to self-administer nicotine,19 further testing was required to assess its human abuse potential. The purpose of this study, therefore, was to evaluate the potential for abuse of varenicline by humans. The effects of varenicline on human measures of abuse liability were compared with the effects of a placebo control or with amphetamine, a drug with an established pattern of abuse that was chosen as the positive control based on precedent abuse liability literature for psychomotor stimulants28 and smoking cessation aids including
1Clinical Pharmacology, DecisionLine Clinical Research Corporation, Toronto, Ontario, Canada; 2Neurosciences Development, Pfizer Global Research and
Development, Groton, Connecticut, USA; 3Neuroscience Statistics, Pfizer Global Research and Development, Groton, Connecticut, USA; 4Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. 5Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 6Department of Psychiatry,University of Toronto, Toronto, Ontario, Canada. Correspondence: EM Sellers (
[email protected]) Received 2 November 2007; accepted 19 December 2007; advance online publication 20 February 2008. doi:10.1038/sj.clpt.6100510 Clinical pharmacology & Therapeutics | VOLUME 83 NUMBER 4 | APRIL 2008
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articles sustained-release bupropion29,30 and NRTs,9,31 using paradigms similar to those in this study. Both smokers and nonsmokers were included in the study in order to control for the possible confounding effects of withdrawal from smoking and tolerance to nicotine. Results Validity of study
In the case of amphetamine, the effects were statistically significant for both 15 and 30 mg as compared to the effects with placebo (P < 0.01). Table 1 summarizes the mean values and 95% confidence intervals of the peak ratings for each treatment separately for smokers and nonsmokers. Table 2 provides results of the respective 4 degrees of freedom likelihood ratio tests for the multivariate comparisons of 15 or 30 mg amphetamine vs. placebo for smokers and nonsmokers. The specific variableby-treatment contrasts (Table 2) show that all four individual primary outcome measures were significantly elevated for both amphetamine doses relative to placebo. An examination of these contrasts, as well as the least-squares mean values in Table 1, strongly support the validity of the study, in that the effects of both dose levels of amphetamine differed from those of placebo, with the anticipated mean dose–response relationship being observed for each of the four primary outcome measures in smokers and nonsmokers. Table 1 Meana of peak ratings and 95% CIs for primary outcome measures VAS Drug Highb
VAS Drug ARCI/Cole Abuse Likingb Potentialb
Plac
17.2 (5.9, 28.5)
52.7 (45.7, 59.7)
16.1 (12.7, 19.6)
0.45 (−0.87, 1.77)
1 mg var
26.6 (15.0, 38.1)
54.5 (47.3, 61.6)
15.7 (12.3, 19.2)
1.13 (−0.20, 2.46)
3 mg var
21.9 (10.2, 33.6)
43.5 (36.4, 50.7)
15.0 (11.7, 18.4)
0.66 (−0.68, 1.99)
15 mg amp
55.2 (43.6, 66.7)
67.2 (60.2, 74.2)
19.8 (16.4, 23.2)
3.66 (2.33, 4.98)
30 mg amp
70.2 (59.0, 81.5)
79.4 (72.4, 86.3)
20.9 (17.6, 24.2)
4.46 (3.14, 5.78)
Plac
23.6 (11.8, 35.4)
49.6 (41.5, 57.7)
14.8 (11.1, 18.5)
0.56 (−0.96, 2.07)
1 mg var
41.4 (29.6, 53.3)
53.0 (44.9, 61.1)
17.7 (14.1, 21.4)
1.34 (−0.17, 2.86)
35.9 (24.3, 47.6)
43.7 (35.8, 51.7)
13.4 (9.6, 17.1)
0.36 (−1.16, 1.88)
15 mg amp
57.5 (45.6, 69.3)
64.6 (56.4, 72.7)
19.5 (15.7, 23.3)
3.07 (1.55, 4.59)
30 mg amp
69.1 (57.0, 81.3)
75.7 (67.4, 84.1)
21.0 (17.2, 24.7)
3.87 (2.33, 5.40)
ln(MCP)
Smokers
Nonsmokers
3 mg var
amp, amphetamine; ARCI, Addiction Research Center Inventory; CI, confidence interval; MCP, multiple choice/subjective price monetary procedure; plac, placebo; var, varenicline; VAS, visual analog scale. aLeast-squares mean. bAnalyses based on peak scores.
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Measures of positive drug effects Primary outcome measures. Figure 1 shows the mean values of
the peak ratings and 95% confidence intervals for visual analog scale (VAS) Drug Liking and mean ln(MCP) (Multiple Choice Subjective Price Monetary Value Procedure) scores following each treatment for smokers and nonsmokers. After the administration of 3 mg varenicline, the mean peak scores for VAS Drug Liking and the mean ln(MCP) score were similar to those of placebo and lower than those for 15 and 30 mg amphetamine, in both smokers and nonsmokers (Figure 1). Likewise, after administration of 1 mg varenicline, these parameters were similar to those of placebo and lower than those following administration of 15 and 30 mg amphetamine, in both smoking status groups (Figure 1). Unlike the case of amphetamine, for which the scores on both of these variables increase with increasing dose, the scores on both variables are lower for 3 mg varenicline than for 1 mg varenicline, in both smokers and nonsmokers, thereby indicating a negative dose response. Mean peak scores for VAS Drug High and Addiction Research Center Inventory (ARCI) Abuse Potential following 1 and 3 mg varenicline were similar to the patterns observed in Figure 1 for the VAS Drug Liking and ln(MCP) scores (see Table 1). Smokers rated 1 and 3 mg varenicline similar to the placebo, and lower than for 15 and 30 mg amphetamine. Nonsmokers rated varenicline 1 and 3 mg higher on the VAS Drug High scale than placebo at 1–2 h postdose. Varenicline also had a slight negative dose response on VAS Drug High and ARCI Abuse Potential scales in both smoking status groups, while amphetamine had a positive dose response on both scales. Multivariate treatment contrasts. The results of the respective 4 degrees of freedom likelihood ratio tests for the multivariate comparisons of the primary outcome measures for smokers and nonsmokers are given in Table 2. In the multivariate comparison, the smokers’ 3 mg varenicline scores significantly differed from their placebo scores (P = 0.03; Table 2). A similar statistical analysis for nonsmokers was also significant (P = 0.01; Table 2). Consequently, the four-dimensional experience of 3 mg varenicline differs from that of placebo, for both smokers and nonsmokers. Individual variable-by-treatment contrasts showed that smokers rated placebo significantly higher than 3 mg varenicline on the VAS Drug Liking scale (P = 0.04; Table 2), but that the other variables did not significantly differ with treatment in this group. For nonsmokers, none of the contrasts for the primary outcome measures for 3 mg varenicline were statistically significant when compared with placebo (Table 2). There was a statistically significant difference between 3 mg varenicline and 30 mg amphetamine (P < 0.01) in the 4 degrees of freedom multivariate test for both smokers and nonsmokers (Table 2). An examination of the specific variable-by-treatment contrasts show that each of the four individual primary outcome measures was significantly greater for 30 mg amphetamine than for 3 mg varenicline in both the participant groups (P < 0.01; Table 2). Post-hoc comparisons of 3 mg varenicline to 15 mg amphetamine indicated that 15 mg amphetamine also resulted in significantly higher results than 3 mg varenicline for each of the four individual primary outcome measures in smokers as VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
articles Table 2 Multivariate tests and variable-by-treatment contrasts for smokers and nonsmokers Multivariate testa (4 df)
VAS Drug Higha
VAS Drug Likinga
ARCI/Cole Abuse Potentiala
ln(MCP)
Smokers comparison (95% CIs) 1 mg var vs. plac
P = 0.38
1 mg var vs. 30 mg amp
P < 0.01
1 mg var vs. 15 mg amp 3 mg var vs. plac 3 mg var vs. 30 mg amp
P = 0.03 P < 0.01
3 mg var vs. 15 mg amp
9.4 (−4.8, 23.6; ns)
1.8 (−6.9, 10.5; ns)
−0.4 (−2.1, 1.2; ns)
0.68 (−0.29, 1.65; ns)
−5.23 (−6.9, −3.6)**
−3.33 (−4.29, −2.37)**
−12.8 (−21.5, −4.1)**
−4.1 (−5.8, −2.5)**
−2.53 (−3.49, −1.56)**
−43.7 (−57.7, −29.6)**
−24.9 (−33.5, −16.3) **
−28.6 (−42.9, −14.3)**
−9.1 (−17.9, −0.4)*
−1.1 (−2.7, 0.6; ns)
0.20 (−0.77, 1.18; ns)
−48.3 (−62.5, −34.1)**
−35.8 (−44.5, −27.1)**
−5.9 (−7.5, −4.2)**
−3.80 (−4.77, −2.84)**
−33.2 (−47.5, −19.0)**
−23.7 (−32.4, −14.9)**
−4.8 (−6.4, −3.1)**
−3.00 (−3.97, −2.03)**
26.7 (18.1, 35.3)**
4.8 (3.2, 6.4)**
4.01 (3.06, 4.96)**
4.7 (−9.6, 19.0; ns)
30 mg amp vs. plac
P < 0.01
53.1 (39.1, 67.0)**
15 mg amp vs. plac
P < 0.01
38.0 (23.9, 52.1)**
14.5 (5.9, 23.2)**
3.7 (2.1, 5.3)**
3.20 (2.24, 4.16)**
15.1 (1.2, 29.0)*
12.2 (3.7, 20.7)**
1.1 (−0.5, 2.7; ns)
0.80 (−0.14, 1.75; ns)
30 mg amp vs. 15 mg amp Nonsmokers comparison (95% CIs) 1 mg var vs. plac
P < 0.01
1 mg var vs. 30 mg amp
P < 0.01
1 mg var vs. 15 mg amp 3 mg var vs. plac 3 mg var vs. 30 mg amp
17.8 (3.3, 32.3)*
3.4 (−6.5, 13.3; ns)
2.9 (1.1, 4.8)**
0.79 (−0.34, 1.92; ns)
−27.7 (−42.4, −13.1)**
−22.8 (−32.7, −12.8)**
−3.3 (−5.1, −1.4)**
−2.52 (−3.67, −1.38)**
−16.1 (−30.5, −1.6)*
−11.6 (−21.5, −1.7)*
−1.8 (−3.6, 0.1; ns)
−1.73 (−2.86, −0.60)**
P = 0.01
12.3 (−2.0, 26.7; ns)
−5.8 (−15.6, 3.9; ns)
−1.4 (−3.2, 0.4; ns)
−0.19 (−1.32, 0.93; ns)
P < 0.01
−33.2 (−47.7, −18.7)**
−32.0 (−41.9, −22.1)**
−7.6 (−9.4, −5.8)**
−3.51 (−4.64, −2.37)**
−21.5 (−35.8, −7.2) **
−20.8 (−30.6, −11.1)**
3 mg var vs. 15 mg amp
−6.1 (−7.9, −4.3)**
−2.71 (−3.84, −1.59)**
26.2 (16.2, 36.1)**
6.2 (4.3, 8.0)**
3.31 (2.18, 4.45)**
30 mg amp vs. plac
P < 0.01
45.5 (31.0, 60.1)**
15 mg amp vs. plac
P < 0.01
33.8 (19.4, 48.3)**
15.0 (5.1, 24.8)**
4.7 (2.9, 6.5)**
2.52 (1.39, 3.64)**
11.7 (−3.0, 26.3; ns)
11.2 (1.2, 21.2)*
1.5 (−0.4, 3.3; ns)
0.80 (−0.35, 1.94; ns)
30 mg amp vs. 15 mg amp
amp, amphetamine; ARCI, Addiction Research Center Inventory; CI, confidence interval; DF, degrees of freedom; MCP, multiple choice/subjective price monetary procedure; ns, not significant; plac, placebo; var, varenicline; VAS, visual analog scale. aAnalyses based on peak scores. *P < 0.05. **P < 0.01.
well as in nonsmokers (Table 2). Comparisons of least-squares mean values after administering 1 and 3 mg varenicline (Table 1) show that 3 mg varenicline yielded lower estimated mean scores on all four primary outcome measures than 1 mg varenicline did in both subject groups. Smokers did not significantly differentiate 1 mg varenicline from placebo (P = 0.38; Table 2), but nonsmokers did (P < 0.01; Table 2). An examination of the specific variable-by-treatment contrasts in Table 2 shows no statistically significant differences between 1 mg varenicline and placebo on any of the four primary outcome measures. Table 2 shows that, for nonsmokers, the differences in VAS Drug Liking and ln(MCP) for 1 mg varenicline vs. placebo were not statistically significant, but that the differences in VAS Drug High (P < 0.05) and ARCI/Cole Abuse Potential (P < 0.01) were significant. In the multivariate analysis, there was a statistically significant difference between 1 mg varenicline and 30 mg amphetamine, for smokers (P < 0.01; Table 2) as well as nonsmokers (P < 0.01; Table 2). The specific variable-by-treatment contrasts in Table 2 show that each of the four individual primary outcome measures was significantly greater for 30 mg amphetamine than for 1 mg varenicline in smokers and nonsmokers alike. Post-hoc comparisons of 15 mg amphetamine and 1 mg varenicline indicated that 15 mg amphetamine was also significantly greater than 1 mg varenicline for each of the four individual outcome measures for smokers as well as nonsmokers, with the exception of ARCI/Cole Abuse Potential in the nonsmokers group (Table 2).
Timecourse. Figure 2 shows the mean timecourse scores for VAS Drug Liking for smokers and nonsmokers, respectively. The 3 mg varenicline VAS Drug Liking scores tended toward “dislike” through 8 h after the dose was administered in smokers (Figure 2). For nonsmokers, the 3 mg varenicline VAS Drug Liking Scores were also in the range of “Dislike” through 24 h postdose. The 1 mg varenicline VAS Drug Liking scores across timecourse for smokers and nonsmokers were consistently close to those of placebo over time (Figure 2). The mean timecourse scores for both doses of amphetamine were noticeably elevated relative to varenicline and placebo across most timepoints on all measures of positive subjective effects. Timecourse scores for the other measures of primary outcomes (ln(MCP), VAS Drug High and ARCI Abuse Potential) showed similar profiles with the pattern for 1 and 3 mg varenicline over time being more akin to that for placebo and less akin to the patterns of both doses of amphetamine.
Clinical pharmacology & Therapeutics | VOLUME 83 NUMBER 4 | APRIL 2008
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Outcomes of other measures of positive effects. In both smokers and nonsmokers, there was a negative dose response for varenicline on the VAS Energized and VAS Pleasant Physical State, and no dose response on the ARCI/Cole Stimulation-motor scale. In contrast, amphetamine showed a dose-dependent positive response on all three scales, as compared with placebo. Nonsmoking participants seemed to experience some positive subjective effects with 1 mg varenicline, which were higher than
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Table 3 summarizes adverse events. There were no deaths associated with this study. Most adverse events were classified as mild or moderate. There were two discontinuations on account of adverse events. No laboratory findings, vital signs,
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Figure 3 shows the mean peak ratings and 95% confidence intervals for VAS Bad Effects and VAS Nausea following each treatment for smokers and nonsmokers. After the administration of 3 mg varenicline, the mean peak scores for VAS Bad Effects and VAS Nausea were both higher than in all the other treatments, including placebo (Figure 3). After 1 mg varenicline, the smokers group had scores similar to placebo scores on both these scales (Figure 3); whereas nonsmokers scored higher than
Pl a
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placebo on these negative effect measurements. This indicates that nonsmokers may be more sensitive to these negative effects of varenicline than smokers (Figure 3). Figure 4 shows the mean timecourse data for VAS Nausea, after each of the treatments, for smokers and nonsmokers. Nausea ratings peaked at 1–2 h postdose for 1 and 3 mg varenicline in the nonsmoker group and for 3 mg varenicline in the smoker group. There was also a positive dose response (negative effects increasing with increased dose) on other measures of negative effects (VAS Fatigue; VAS Unpleasantness–dysphoria; VAS Unpleasantness–physical; and ARCI Lysergic Acid Diethylamide scales) for varenicline in both the smoker and nonsmoker groups.
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those for placebo, but less than those for 15 mg amphetamine. For example, they showed elevated scores on VAS Energized; ARCI/ Cole Stimulation–motor; ARCI/Cole Amphetamine; ARCI Stimulation–euphoria; and ARCI Stimulation–motor for some, if not all, points across the timecourse. The 1 mg varenicline scores for smokers were close to those of placebo for most of the positive subjective effects, but were slightly elevated in comparison to placebo on the VAS Energized across the timecourse.
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Figure 4 Time course plots of mean scores for VAS Nausea in smokers and nonsmokers. VAS, visual analog scale. VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
articles Table 3 Treatment-emergent adverse events Amphetamine MedDRA preferred term
Varenicline
3 mg Placebo 15 mg 30 mg 1 mg Sm/Ns Sm/Ns Sm/Ns Sm/Ns Sm/Ns
Headache
1/4
2/4
4/3
2/7
7/9
Nausea
0/0
0/0
1/0
0/2
9/16
Dry mouth
0/0
2/0
4/2
0/0
0/0
Vomiting
0/0
0/0
1/0
0/1
3/14
Dizziness
0/0
2/0
0/1
1/0
0/5
Number of AEs
4/9
26/15
30/26
6/25
24/60
Subjects with AEs
4/8
10/8
15/12
5/13
13/18
Discontinuations due to AEs
1/0
0/0
0/0
0/0
0/1
21/21
21/21
21/20
20/21
20/22
Subject exposed
AEs, adverse events; Ns, nonsmokers; Sm, smokers.
electrocardiogram results, or pulse oximetry readings associated with varenicline were identified as being of clinical concern. Discussion
This study evaluated the potential for abuse of varenicline by smokers and nonsmokers. The validity of the study was confirmed for smoker and nonsmoker cohorts: amphetamine produced the expected pharmacologic effects and dose–response profile of a drug of abuse. Participants’ ratings on primary abuse liability measures were positive and increased with each dose of amphetamine; ratings were significantly greater in response to both doses of amphetamine than in response to placebo. In contrast, varenicline’s pharmacologic effects and dose–response profile were unlike that of a drug of abuse. After administration of 1 and 3 mg varenicline, the mean peak responses of the participants were similar to those seen after administration of placebo and significantly less than for 15 and 30 mg amphetamine. The dose–response relationships for 1 and 3 mg varenicline were either flat or in the negative direction, indicating lower ratings of positive drug effects with higher dose. The timecourse analyses also demonstrated that varenicline was rated as similar to placebo and unlike that of amphetamine on measures of abuse liability in both smokers and nonsmokers. Varenicline was also associated with negative effects in smokers and nonsmokers. Negative effects were often rated as greater for varenicline in comparison with placebo and also in comparison with each of the doses of amphetamine. This was particularly evident in the 3 mg varenicline mean timecourse scores of ARCI/ Cole Unpleasantness–physical, VAS Fatigue, and VAS Nausea. There were few differences in the outcomes associated with varenicline in smokers compared with nonsmokers. The fact that the nonsmokers registered a significant difference between the scores for 1 mg varenicline and those for placebo in the multivariate analysis, whereas such a difference was absent in the smokers group, along with the findings of some higher scores across timecourse in the nonsmokers group in comparison to the smokers group, may indicate that nonsmokers were more sensitive to the effects of varenicline. However, any elevated positive effect outcomes for varenicline in nonsmokers tended Clinical pharmacology & Therapeutics | VOLUME 83 NUMBER 4 | APRIL 2008
to be offset by simultaneous negative effects. For example, the mean peak score for VAS Drug High at 1–2 h postdose in this group coincided with the mean peak score for VAS Nausea and was, therefore, not likely to be a positive experience. The findings in this study are not unlike those reported on the abuse liability of NRTs. These latter have formulations with slower absorption of nicotine, such as the transdermal patch, nasal spray, gum, inhaler, and lozenges which, in laboratory studies of smokers, present a much lower potential for abuse than nicotine from cigarettes.9–11 Low ratings of potential for abuse, such as Drug Liking, Good Effects, and Drug High, have been reported for NRTs,9–11 but the magnitude of the ratings for varenicline observed in the present study were even lower. Given that the predictive validity of these measures in NRTs has been established in the real world with low actual rates of abuse,10 it is also unlikely that varenicline would be abused in the real world. Consistent with this statement, there have been no postmarketing signals of potential for abuse after varenicline was approved for use in the United States (May 2006), the European Union (September 2006), and Canada (January 2007) (data on file, Pfizer). The pattern of results for both smokers and nonsmokers in this study is consistent with pharmacologic effects and a dose– response profile, unlike the pattern seen with drugs of abuse. The multivariate analyses of primary measures of abuse potential were consistent with the univariate analyses of the individual outcome measures and further evaluation of additional pharmacologic effects. The dose–response profiles on both the positive and negative scales for varenicline were notably different from those for amphetamine. The similarity of participant ratings of varenicline as compared to placebo, and varenicline’s unpleasant effects, limit the potential for its abuse. Methods Participants Participants were healthy men and women (smokers n = 23; nonsmokers n = 22). There were 16 men and 7 women in the smokers group and 20 men and 2 women in the nonsmokers group. The mean BMI (kg/m2) values were similar between groups, with a mean BMI of 23.8 (range 20.1–31.2) in the smokers and 24.0 (range 19.9–30.2) in the nonsmokers. In terms of race, there were 17 white and 4 black participants, 1 Asian participant, and 1 participant of “other race” in the smokers group. Nonsmokers consisted of 11 white, 2 black, 2 Asian participants, and 7 participants of “other races.” As regards consumption of alcohol, 12 participants in the smokers group and 11 participants in the nonsmokers group consumed 1–6 units of alcohol per week, while 7 smokers and 4 nonsmokers consumed between 7 and 12 units per week. The history of drug use among the study participants is given in Table 4. Participants in the smokers group smoked an average of at least 10 cigarettes per day with no period of continuous abstinence >3 months in the past year. Of the 23 smokers, 18 had smoked an average of 10–20 cigarettes per day over the previous year, and 5 had smoked an average of >20 cigarettes per day. On the Fagerström Test of Nicotine Dependence,32 each indicated that they smoked the first cigarette of the day within 30 min of waking. Current smoking status was also confirmed by urine cotinine measurements. Participants were excluded from the study if they were pregnant or nursing, or tested positive for the hepatitis B or the hepatitis C virus antigen. Those with evidence or history of any clinically significant medical or psychiatric disorder were also excluded, on the basis of medical history, physical examination, and 611
articles Table 4 Drug use history of study participants Smokers
Nonsmokers
Total (n = 23)
Total (n = 22)
Cannabis
22
21
Psilocybin
4
4
Reported use in previous year (n)a
D-amphetamine Other stimulants (cocaine, speed, methylphenidate, and ephedrine) Opiates (heroin and codeine) Hallucinogens (LSD, MDMA, GHB, and methamphetamine)
4
4
20
18
3
0
21
19
GHB, gamma hydroxy butyrate; LSD, lysergic acid diethylamide; MDMA, 3,4-methylenedioxy-N-methylamphetamine (ecstasy). aAs participants were polydrug users, some drugs may have been taken simultaneously. In addition to the drugs listed here, three subjects reported using other drugs on occasion (e.g., ketamine, Percocet) .
laboratory tests. Participants who had received treatment with any other investigational drug within 30 days preceding the first dose of study medication, or those with a history of alcohol consumption exceeding 7 drinks per week (women) or 14 drinks per week (men) within 6 months prior to screening, were also excluded. The use of prescription drugs (other than contraceptives) and nonprescription drugs (except ≤2 g acetaminophen), vitamins, and dietary supplements were not permitted within 7 days prior to receiving the first study dose. The study received approval from an ethics committee (Institutional Review Board Services, Aurora, Ontario, Canada). Each participant provided written informed consent prior to the commencement of the trial. Participants were paid for their participation.
Qualification procedure Ninety-one eligible participants underwent a single-blind amphetamine qualification procedure prior to entry into the study. This was to confirm that they could reliably distinguish a test dose of amphetamine from a placebo (see refs. 33–35 for discussion on prestudy enrichment procedures). The qualification period involved administration of four doses of “study” drug (three doses of placebo and one dose of 15 mg of d-amphetamine) at 90-min intervals. d-amphetamine was always the second dose administered in the series. Participants completed assessments for potential for abuse at baseline and 1 h after each dose. Participants were appropriately trained and given practice on all tests prior to baseline assessments. In order to qualify for inclusion, participants had to show a positive correlation of at least 0.7 between the response profile and the expected profile on the MCP and at least one of the VAS Drug Liking, Drug High or the ARCI/Cole Abuse Potential scale (see Methods section below). They also had to show a 25-unit increase in VAS Drug High between 15 mg amphetamine and placebo. Study design and experimental conditions The study was a randomized, double-blind, five-period, placebocontrolled, double-dummy, crossover design and was conducted in accordance with the Declaration of Helsinki and the Interna tional Conference on Harmonization of Good Clinical Practices Guidelines. Treatments were administered to each participant in 1 of 10 possible randomly assigned treatment sequences: 15 mg amphetamine; 30 mg amphetamine; 1 mg varenicline; 3 mg varenicline; placebo. Amphetamine was administered in multiples of 10 mg capsules; varenicline as 0.5 mg tablets. A total of four capsules and six tablets were administered in each session. 612
Drug supply and dose selection The amphetamine capsules, varenicline tablets, placebo tablets, and capsules were supplied by Pfizer Global Research and Development (Groton, CT). Amphetamine was sourced as United States Pharmacopeia commercial tablets from and encapsulated at Mallinckrodt-Tyco (Hobart, NY). The selection of the 1 mg varenicline dose was based on the projected therapeutic dose for smoking cessation (1 mg twice daily). The 3 mg dose of varenicline was selected to provide a supratherapeutic dose that might be tested by a potential abuser. Higher single doses >3 mg were not considered suitable for this trial because of the expected side effects of nausea and vomiting. Abuse liability measures All tests were computerized and administered using Scheduled Measurement System validated software. VAS. The VAS35–37 (comprising Drug Liking, Drug High, Good Effects,
Bad Effects, Nausea, Energized, Any Effects, Fatigue, Pleasant Mental State, Pleasant Physical State) were presented as 100-point horizontal lines, each labeled with a word or phrase (e.g., “I can feel a drug effect,” “I am feeling high,” etc.) with descriptive anchors at each end (e.g., “not at all” and “extremely”). Participants were asked to evaluate each statement based on how they felt “at that moment” and indicate their response by moving the cursor and clicking on the mouse along the line where appropriate. ARCI (Cole/ARCI version). A 57-item modified version of the origi-
nal Martin et al.38 ARCI39 included eight scales: Potential for Abuse, Stimulation–euphoria, Stimulation–motor, Amphetamine, Benzedrine Group, Unpleasantness–dysphoria, Unpleasantness–physical, Lysergic Acid Diethylamide. MCP. The MCP is a measure of perceived drug cash value. Participants
are asked to choose hypothetically between receiving another dose of the drug they just took or a specified amount of money. Depending on their answer, the monetary value increases or decreases in the next question according to a predetermined algorithm. At the end of the procedure, the “crossover” point is determined, which is the dollar amount at which the subject is indifferent to the choice of drug or money.
Experimental procedure The participants were admitted to the Clinical Research Unit on the evening prior to receiving the first dose. On the first day of each of the five treatment periods, the study medication was administered with 240 ml of ambient temperature water after breakfast, at ~08:00 hours. The participants stayed in the Clinical Research Unit for ~36 h during each treatment period. Treatment sessions were separated by at least 7 days. For each treatment, the participants completed the assessments of potential for abuse in the same order, at predose and at 1, 2, 3, 4, 6, 8, and 24 h postdose. The MCP was administered only at the time point of 8 h postdose. Serial measurements of blood pressure, heart rate, respiratory rate, pulse oximetry, and laboratory data relating to safety were obtained, using DINAMAP PRO 400 Monitors (GE Medical Systems, Tampa, FL). These safety evaluations were monitored prior to administering the dose and at ~0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h postdose. In addition, the participants were asked nonleading questions (e.g., “How do you feel?”) in each treatment period on day 0, and 1, 2, 4, 6, 8, and 24 h after dosing. Investigators recorded any observed or reported adverse events. Data analyses Four outcome measures considered predictive of abuse potential were considered primary: the maximum score over the 8 h postdose period for (i) Drug High scale of the VAS and (ii) Drug Liking scale of the VAS, (iii) the Abuse Potential scale of the ARCI/Cole, and (iv) the dollar value at crossover from the MCP at 8 h postdose. For the MCP, the logarithmic transform was analyzed because the choice algorithm forms a geometric rather than an arithmetic series. All analyses were performed separately for smokers and nonsmokers. VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
articles A sample size of 20 participants was estimated to provide at least 98% power to detect, with a paired t-test with two-sided type I error probability of 0.05, a standardized treatment difference (treatment difference divided by the within-subject standard deviation) of 1.0 for the analysis of any single primary outcome measure. The primary analyses were based on models for a multivariate outcome consisting of the four primary outcome measures. Treatment comparisons were (i) 30 mg amphetamine vs. placebo. A significant 30 mg amphetamine treatment difference from placebo was used for establishing the validity of the study. If the validity test succeeded, the following treatment comparisons were made: (ii) 15 mg amphetamine vs. placebo; (iii) 1 mg varenicline vs. placebo and 3 mg varenicline vs. placebo; (iv) 1 mg varenicline vs. 30 mg amphetamine and 3 mg varenicline vs. 30 mg amphetamine. The four primary outcome variables were analyzed using a mixed-effects model for a multivariate outcome consisting of the four outcome variables separately for both smokers and nonsmokers. The model contained baseline score as a covariate as appropriate (i.e., for VAS Drug High and ARCI/Cole Abuse Potential only); fixed effects for sequence, period, and treatment; and a random effect for participants (within sequence) for each of the four outcomes. The baseline score was the predose score from each study period. The mixed-effects model was implemented using the SAS MIXED procedure, with Restricted Maximum Likelihood estimation algorithm, a covariance structure consisting of the Kronecker product of an unstructured covariance matrix (to account for the covariance among outcome measures) with a compound symmetry covariance matrix (to account for the covariance of repeated measures within participants), and Satterthwaite degrees of freedom adjustment. Each of the treatment differences for comparisons (i)–(iv) above were tested with a 4 degrees of freedom likelihood ratio test: that is, simultaneous testing of four primary outcomes. Treatment differences in comparisons (i) and (ii) were each tested at the α = 0.05 significance level. Each difference in comparison (iii) was tested at α = 0.05, without any multiplicity correction. Differences in comparison (iv) were tested at α = 0.05, using a Hochberg multiplicity correction. If significance on a 4 degrees of freedom test was achieved, contrasts within the model for each of the primary outcome variables was examined to determine how each contributed and in which direction. Descriptive analyses were conducted for all time points and on the maximum scores (minimum scores for negative effect scales) for the remaining nonprimary outcome measures for smokers and nonsmokers separately for each treatment.
1. Shoaib, M., Schindler, C.W. & Goldberg, S.R. Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition. Psychopharmacology (Berl) 129, 35–43 (1997). 2. Mansvelder, H.D., Keath, J.R. & McGehee, D.S. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33, 905–919 (2002). 3. Corrigall, W.A. & Coen, K.M. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99, 473–478 (1989). 4. Benowitz, N.L. Pharmacology of nicotine: addiction and therapeutics. Annu. Rev. Pharmacol. Toxicol. 36, 597–613 (1996). 5. U.S. Department of Health and Human Services. Centers for Disease Control and Prevention. The Health Consequences of Smoking: Nicotine Addiction, A Report of the Surgeon General: Rockville, MD,1988 .
6. Henningfield, J.E. & Goldberg, S.R. Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacol. Biochem. Behav. 19, 989–992 (1983). 7. Henningfield, J.E., Miyasato, K. & Jasinski, D.R. Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine. J. Pharmacol. Exp. Ther. 234, 1–12 (1985). 8. Stitzer, M.L. & de Wit, H. Abuse liability of nicotine. In Nicotine Safety and Toxicity. (ed. Benowitz, N.L.) 119–131 (Oxford Univ. Press, New York, 1998). 9. Schuh, K.J., Schuh, L.M., Henningfield, J.E. & Stitzer, M.L. Nicotine nasal spray and vapor inhaler: abuse liability assessment. Psychopharmacology (Berl) 130, 352–361 (1997). 10. West, R., Hajek, P., Foulds, J., Nilsson, F., May, S. & Meadows, A. A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler. Psychopharmacology (Berl). 149, 198–202 (2000). 11. Houtsmuller, E.J., Henningfield, J.E. & Stitzer, M.L. Subjective effects of the nicotine lozenge: assessment of abuse liability. Psychopharmacology (Berl) 167, 20–27 (2003). 12. Tonstad, S. et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 296, 64–71 (2006). 13. Nides, M. et al. Smoking cessation with varenicline, a selective alpha-4 beta-2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch. Intern. Med. 166, 1561–1568 (2006). 14. Oncken, C. et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch. Intern. Med. 166, 1571–1577 (2006). 15. Williams, K.E., Reeves, K., Billing, C.B., Pennington, A.M. & Gong, J. A double-blind study evaluating the long-term safety of varenicline for smoking cessation. Curr. Med. Res. Opin. 23, 793 (2007). 16. Jorenby, D.E. et al. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296, 56–63 (2006). 17. Gonzales, D. et al. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296, 47–55 (2006). 18. Coe, J.W. et al. Varenicline: an α4β2 nicotinic receptor partial agonist for smoking cessation. J. Med. Chem. 48, 3474–3477 (2005). 19. Rollema, H. et al. Pharmacological profile of the α4β2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52, 985–994 (2007). 20. Jasinski, D.R., Pevnick, J.S. & Griffith, J.D. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch. Gen. Psychiatry 35, 501–516 (1978). 21. Jasinski, D.R. & Preston, K.L. Assessment of dezocine for morphine-like subjective effects and miosis. Clin. Pharmacol. Ther. 38, 544–548 (1985). 22. Busto, U., Kaplan, H.L., Zawertailo, L. & Sellers, E.M. Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans. Clin. Pharmacol. Ther. 55, 451–463 (1994). 23. Faessel, H.M., Smith, B.J., Gibbs, M.A., Gobey, J.S., Clark, D.J. & Burstein, A.H. Single-dose pharmacokinetics of varenicline, a selective nicotinic receptor partial agonist, in healthy smokers and nonsmokers. J. Clin. Pharmacol. 46, 991–998 (2006). 24. Balster, R.L. & Bigelow, G.E. Guidelines and methodological reviews concerning drug abuse liability assessment. Drug Alcohol Depend. 70, S13–S40 (2003). 25. Mumford, G.K., Evans, S.M., Fleishaker, J.C. & Griffiths, R.R. Alprazolam absorption kinetics affects abuse liability. Clin. Pharmacol. Ther. 57, 356–365 (1995). 26. O’Brien, C.P. Drug addiction and drug abuse. In The Pharmacological Basis of Therapeutics 10th edn., (eds. Hardman, J.G., Limbird, L.E. & Goodman-Gilman, A.) 621–642 (McGraw-Hill, New York, 2001). 27. Smith, B.J., Jones, H.E. & Griffiths, R.R. Physiological, subjective and reinforcing effects of oral and intravenous cocaine in humans. Psychopharmacology (Berl). 156, 435–444 (2001). 28. Schuh, L.M., Schuster, C.R., Hopper, J.A. & Mendel, C.M. Abuse liability assessment of sibutramine, a novel weight control agent. Psychopharmacology (Berl) 147, 339–346 (2000). 29. Griffith, J.D., Carranza, J., Griffith, C. & Miller, L.L. Bupropion: clinical assay for amphetamine-like abuse potential. J. Clin. Psychiatry 44, 206–208 (1983). 30. Miller, L. & Griffith, J. A comparison of bupropion, dextroamphetamine, and placebo in mixed-substance abusers. Psychopharmacology (Berl) 80, 199–205 (1983). 31. Houtsmuller, E.J., Fant, R.V., Eissenberg, T.E., Henningfield, J.E. & Stitzer, M.L. Flavor improvement does not increase abuse liability of nicotine chewing gum. Pharmacol. Biochem. Behav. 72, 559–568 (2002).
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Acknowledgments The clinical trial was performed at DecisionLine Clinical Research Corporation and funded by Pfizer, Inc. The authors gratefully acknowledge the contribution of Aniko Kalo in coordinating the study, Linda Ning and Julie Hancock for their research assistance, and Dr Kaplan for input regarding study design and statistical procedures. Editorial support was provided by Brenda Smith, PhD, of Envision Pharma and funded by Pfizer, Inc. Conflict Of Interest AB, KR, CB, and MS are all employees of Pfizer, Inc. SM and ES declared no conflict of interest. © 2008 American Society for Clinical Pharmacology and Therapeutics
articles 32. Fagerström, K.O. & Schneider, N.G. Measuring nicotine dependence: a review of the Fagerström Tolerance Questionnaire. J. Behav. Med. 12, 159–182 (1989). 33. Busto, U.E., Zawertailo, L.A., Kaplan, H.L. & Sellers, E.M. Identifying appropriate subjects for abuse liability studies using prestudy pharmacological testing. Can. J. Clin. Pharmacol. 6, 103–110 (1999). 34. McColl, S.L., Schoedel, K., Romach, M.K. & Sellers, E.M. Improving signal detection in human abuse liability studies: a case for using prestudy pharmacological testing. Abstract from the Annual Meeting of the College of Problem Drug Dependence 519, 131 (2006). 35. McColl, S. & Sellers, E.M. Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Depend. 83(Suppl. 1), S52–S62 (2006).
614
36. Griffiths, R.R., Bigelow, G.E. & Ator, N.A. Principles of initial experimental drug abuse liability assessment in humans. Drug Alcohol Depend. 70, S41–S54 (2003). 37. Preston, K.L. & Walsh, S.L. Evaluating abuse liability: methods and predictive value. In Drug Abuse Handbook (ed. Karch, S.B.) 276–306 (CRC Press, Boca Raton, LA, 1998). 38. Martin, W.R., Sloan, J.W., Sapira, J.D. & Jasinski, D.R. Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin. Pharmacol. Ther. 12, 245–258 (1971). 39. Cole, J.O., Orzack, M.H., Beake, B., Bird, M. & Bar-Tal, Y. Assessment of the abuse liability of buspirone in recreational sedative users. J. Clin. Psychiatry 43, 69–75 (1982).
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