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PHARMACOKINETICS AND PHARMACODYNAMICS |
From McNeil Pediatrics, Division of McNeil PPC, Fort Washington, Pennsylvania (Dr Parasrampuria, Ms Gu, Dr Ciccone, Dr Silber); DecisionLine Clinical Research Corporation, Toronto, Ontario, Canada (Dr Schoedel, Mr Schuller, Dr Sellers); and Departments of Pharmacology, Medicine, and Psychiatry, University of Toronto, Toronto, Ontario, Canada (Dr Sellers).
Address for correspondence: Dolly A. Parasrampuria, PhD, McNeil Pediatrics, Division of McNeil PPC, 420 Delaware Drive, Fort Washington, PA 19034; e-mail: DParasr{at}prdus.jnj.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Key Words: Methylphenidate • amphetamine • osmotic • extended release • pharmacodynamics • abuse • pharmacokinetics
Stimulant drugs such as methylphenidate are standard therapy for ADHD.2 Because of stimulant properties, methylphenidate is considered to have the potential for abuse and is classified as a schedule II drug. Although controlled human abuse liability studies have demonstrated abuse-related subjective effects in drug-inexperienced or stimulant-using subjects,3-10 actual abuse of oral methylphenidate appears to be relatively modest compared to other stimulant drugs such as cocaine and amphetamines,11-16 despite widespread medical use for the treatment of ADHD. The reported lifetime prevalence ("ever" used) for methylphenidate abuse was 1.8% compared to 4.0% for amphetamines (amphetamine, d-amphetamine, phentermine), 4.9% for methamphetamine, and 14.2% for cocaine.17 The most commonly reported abuse relates to intravenous or intranasal use of crushed immediate-release (IR) tablets.11,12,15
The formulation of a controlled substance can significantly affect its diversion and abuse potential. Formulations that deter tampering (ie, not readily crushed or not soluble in water) are less likely to be diverted for intravenous or intranasal administration. The pharmacokinetic properties associated with orally administered drugs of abuse include rapid absorption, rapid entry into the brain, high bioavailability, low protein binding, short half-life, small volume of distribution, and high free drug clearance.18,19 Controlled-release formulations that are tamper resistant and lessen the effects of the above-mentioned pharmacokinetic properties are likely to have a lower abuse potential than equivalent IR formulations.20 The unique osmotic-controlled extended-release (ER) methylphenidate formulation combines these properties. Its tough shell is difficult to compromise or crush to a fine powder for snorting, and its unique excipients make it difficult to extract pure drug in a form that could be abused via intravenous or intranasal routes. The intact formulation consists of an outer coat that releases a proportionally small amount of drug (22% of total dose) immediately to produce early therapeutic effects. The IR component is followed by controlled osmotic-driven release of drug for an extended period, resulting in a unique ascending profile over 5 to 9 hours that counters tachyphylaxis (tolerance) and produces therapeutic effects over 12 hours. This results in prolonged plasma (and, by corollary, brain) concentrations.
In this study, we examined whether the rate of drug delivery, in addition to the magnitude of drug delivery, was an important determinant of methylphenidate's abuse potential.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Subjects
There were 3 sequential phases in this study: a screening phase, a qualifying phase, and a treatment phase. Healthy subjects between the ages of 18 and 45 years, with a history of light recreational stimulant use (1-25 occasions of stimulant use in the previous year) and no more than 8 cannabis uses per month, were eligible for this study. Subjects were not substance dependent (DSM-IV criteria) and were required to test negative for urine drug screens at screening and admission (amphetamines, benzodiazepines, cannabinoids, cocaine, and opiates), except for tetrahydrocannabinol (THC) (long half-life metabolite), which was to be either stable or decreasing. After completely describing the study to the subjects, written informed consent was obtained. Subjects (N = 196) were screened for eligibility using the following additional criteria: body mass index (BMI) ranging from 20 to 30 kg/m2, physical examination, medical history, vital signs, clinical laboratory assessments, 12-lead electrocardiogram (ECG), and pregnancy test (at screening and admission) for women. Concomitant medications, except for birth control and acetaminophen up to 2 g/day, were not allowed during the study.
General Procedures
Subjects who met eligibility and screening criteria were enrolled in a 2-session, double-blind, crossover qualifying phase, in which they were required to demonstrate discrimination between single doses of 20 mg d-amphetamine (DEXEDRINE, GlaxoSmithKline, Research Triangle Park, North Carolina) and placebo, using visual analog scales (VAS), the Addiction Research Center Inventory with and without Cole rescoring (ARCI, Cole/ARCI), and the Subjective Drug Value Procedure (SDVP). Subjects were enrolled into the treatment phase of the study if they demonstrated a peak response to d-amphetamine between 1 and 3 hours postdose, an AUE (area under the effect curve) in response to d-amphetamine greater than that of placebo on at least 5 of 10 measures (Cole/ARCI Stimulation-Motor, Stimulation-Euphoria, and Abuse Liability scales; ARCI Amphetamine and Morphine Benzedrine Group [MBG] scales; VAS for Any Effects, Drug Liking, Good Effects, and High; and SDVP), and general behavior appropriate to complete study procedures.
The treatment phase was a randomized, double-blind, crossover study design in which each subject received a single oral dose of each of 5 treatments: placebo, 54 mg and 108 mg osmotic-controlled ER (OROS) methylphenidate (CONCERTA, McNeil Pediatrics, Fort Washington, Pennsylvania), and 50 mg and 90 mg IR methylphenidate (RITALIN, Novartis Pharmaceuticals Corp, East Hanover, New Jersey). Tablets were over-encapsulated to maintain blinding.
During the treatment phase, subjects remained housed at an inpatient facility for the duration of the study. After completion of admission procedures, subjects were randomized to 1 of 10 treatment sequences according to a Latin square design. Study drug administration in each period was separated by 48 hours.
Subjects checked into the clinic site on the day before first dose administration to complete assessments of continuing eligibility and a training session for the computerized pharmacodynamic assessments. Following an overnight fast of at least 8 hours, subjects received study drug with 240 mL of water at the same time in each period. Subjects continued to fast for an additional 2 hours after dosing. In each treatment period, serial blood samples were collected, and subjects completed pharmacodynamic assessments at specified times over a 24-hour period from dosing. In addition, vital signs, adverse events, and concomitant medications were monitored throughout the study. Although subjects could leave the site following completion of blood collections between treatment periods, all subjects chose to stay at the clinic for the duration of the treatment phase (11 days). Before discharge, subjects under-went a physical examination (including vital sign measurements), laboratory tests, ECG, and urine pregnancy test.
Treatment Day Testing Schedule
On each treatment day, blood samples (3 mL each) were collected at predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12, and 24 hours postdose for estimation of the rate and extent of methylphenidate exposure. Pharmacodynamic effects related to drug abuse (subjective measures) were assessed through the following: ARCI 49-item version comprising the MBG, Amphetamine (A), Benzedrine Group (BG), Pentobarbital and Chlorpromazine Group (PCAG), and LSD scales; ARCI with Cole rescoring (Cole/ARCI) composed of Stimulation-Motor, Stimulation-Euphoria, Abuse Liability, Sedation-Motor, Sedation-Mental, Unpleasantness-Physical, and Unpleasantness-Dysphoria scales24,25; VAS Drug Liking ("at the moment") rated on a scale of 0 to 100, Overall Drug Liking, Good Effects, High, Take Drug Again, Bad Effects, Any Effects, Alertness, Dizziness, Feeling Sick; and the SDVP (adapted procedure based on the money vs choice procedure).26,27 Among these, the primary dependent measures were positive effects (VAS Drug Liking and Overall Drug Liking, MBG scales), and the secondary dependent measures were stimulatory effects (ARCI A, Cole/ARCI Stimulation-Motor) and other positive effects (Cole/ARCI Stimulation-Euphoria, VAS Good Effects, High, Take Drug Again). Other measures were considered supportive.
Pharmacodynamic effects were assessed at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose, with the following exceptions: SDVP (at 3, 12, and 24 hours postdose), VAS Overall Drug Liking and Take Drug Again (at 12, 24 hours postdose), and selected ARCI and Cole/ARCI scales that were only assessed at predose and 1 and 3 hours postdose. Items referring to drug (ie, Drug Liking, Good/Bad/Any Effects) were not administered predose. The pharmacodynamic tests were administered through 21 CFR Part 11-validated proprietary computer software (Scheduled Measurement System, DecisionLine Clinical Research Corporation, Toronto, Canada). Blood pressure was measured at predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours postdose.
Bioanalysis
Blood was collected by individual venipuncture, stored immediately in ice, and centrifuged for 15 minutes (with refrigeration) at 2000 rpm, and the plasma was separated using disposable pipettes. Samples were stored at -20°C until analyzed. Plasma samples were analyzed for the active moiety, d-methylphenidate, using a validated liquid chromatography method with tandem mass spectrometric detection. A 200-µL plasma sample aliquot was fortified with 25 µL internal standard working solution, the sample was made basic, a liquid-liquid extraction was performed, and the fraction containing the methylphenidate components was collected and saved. The eluate was evaporated, and the remaining residue was reconstituted with 300 µL acetonitrile. A 35-µL volume of the final extract was injected and analyzed using high-performance liquid chromatography (HPLC) with tandem mass spectrometric detection using a 250 x 4.6-mm Astec Chirobiotic V2 HPLC column (5-m particle size) with a mobile phase of 0.02% ammonium formate and 0.04% formic acid in methanol, with a flow rate of 1.0 mL/min. MS (Waters Corporation Quattro Ultima, Electrospray Positive Detection Mode; Waters, Milford, Massachusetts) assignments were as follows: methylphenidate, 234.12/84.10; methylphenidate-D3, 237.12/84.10. Standard solutions for the analyte were prepared using d-methylphenidate (Sigma, St Louis, Missouri; lot no. 11K4609) and methylphenidate-D3 (Isotec [Racemic]). Linearity was evaluated by analyzing the calibration standards in duplicate over the nominal concentration range listed below using the appropriate linear-weighted (1/concentration), least squares regression algorithm to plot the peak height ratio of the appropriate analyte to its internal standard versus concentration. The method was linear for d-methylphenidate over the range 0.0500 to 50.0 ng/mL, and the lower limit of quantification was 0.05 ng/mL.
Statistical Methods
Plasma concentration-time data for d-methylphenidate were summarized descriptively, and the following parameters were estimated using noncompartmental methods (Kinetica, Version 4.3; InnaPhase Corporation, Philadelphia, Pennsylvania): maximum plasma concentration (Cmax), time to maximum concentration (tmax), area under the curve until the last point (AUC
), partial AUCs (0 to n = 1, 2, 3 hours postdose; AUC0-nh), and absorption rate ratio (Cmax/AUC).
All statistical tests for evaluation of significance were 2-sided at a level of .05. SAS Version 8.2 (SAS Institute, Inc, Cary, North Carolina) was used for analysis of covariance (ANCOVA; terms for subject, treatment, sequence, period, and baseline) and analysis of variance (ANOVA; terms for subject, treatment, sequence, and period) for scales not administered at baseline. The primary statistical comparisons were between IR methylphenidate and placebo, as well as between similar dose levels of IR versus osmotic-controlled ER methylphenidate (ie, 50 mg IR vs 54 mg osmotic-controlled ER; 90 mg IR vs 108 mg osmotic-controlled ER). Comparisons of 50 mg IR versus 108 mg osmotic-controlled ER were performed as exploratory analyses. Partial areas under the effect curves (0 to n = 1, 2, 3 hours postdose; AUE0-nh) or mean scores at each time point (for VAS Overall Drug Liking and Take Drug Again) were selected as the primary endpoints, whereas other endpoints were supportive and summarized graphically and/or by descriptive statistics. Pearson product-moment correlations (R2) were calculated for nominal time-matched plasma concentrations and VAS Drug Liking and ARCI MBG scores for each subject.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetic Results
Compared to similar dose levels of osmotic-controlled ER methylphenidate (MPH), absorption was more rapid for IR methylphenidate, with higher Cmax for 50 and 90 mg IR MPH versus equivalent osmotic-controlled ER MPH doses (54 and 108 mg; Table II), and earlier tmax for both doses of IR MPH versus both doses of osmotic-controlled ER MPH (Figure 1, Table II). Total plasma AUC values (AUC), reflective of total drug exposure, were similar between similar dose levels of the 2 formulations (50 mg IR MPH was similar to 54 mg osmotic-controlled ER MPH, and 90 mg IR MPH was similar to 108 mg osmotic-controlled ER MPH). However, early partial AUCs were greater for IR methylphenidate, reflecting earlier absorption of the majority of methylphenidate (AUC0-3 h, Table II) for IR 50 mg and 90 mg, whereas the majority of the drug from osmotic-controlled ER MPH doses of 54 and 108 mg was available at later times, consistent with a later peak plasma concentration.
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Pharmacodynamic Results
Significant overall treatment effects were observed for the ANCOVAs/ANOVAs (P < .05) for all variables/parameters for which statistically significant differences in the individual treatment contrasts were observed (ie, individual differences between treatments were only reported as statistically significant where significant overall treatment effects were observed on the ANCOVAs/ANOVAs).
Positive and Stimulant Effects
Comparisons to placebo. Both doses of IR methylphenidate (50 mg and 90 mg) were associated with significantly greater subjective effects than placebo on all primary and secondary dependent measures (partial AUEs for measures of positive and stimulant effects; P < .05). Osmotic-controlled ER methylphenidate 108 mg produced significantly greater subjective effects than placebo (P < .05) for most measures other than VAS Overall Drug Liking at 12 and 24 hours postdose (P = .07 and P = .18, respectively). Although the subjective response scores to osmotic-controlled ER methylphenidate 54 mg were numerically higher than placebo, many were not statistically significantly different (VAS Drug Liking AUE0-3 h, VAS Overall Drug Liking, and Take Drug Again, all P > .05).
IR versus osmotic-controlled ER methylphenidate. At the low doses of IR and osmotic-controlled ER methylphenidate (50 mg IR vs 54 mg osmotic-controlled ER), there were statistically significant differences between the 2 formulations on all primary (Table III) and secondary (Table IV) subjective measures other than Cole/ARCI Stimulation-Motor AUE0-1 h. At high doses (90 mg IR vs 108 mg osmotic-controlled ER), comparisons on all primary and secondary measures except VAS Drug Liking (AUE0-1 h and AUE0-2 h), Overall Drug Liking, and Take Drug Again were statistically significant (Tables III, IV).
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Trends across all treatments. The subjective responses were highly consistent across measures, with a rank order of magnitude (from highest to lowest): IR 90 mg > IR 50 mg > osmotic-controlled ER 108 mg > osmotic-controlled ER 54 mg > placebo for all primary and secondary measures. In addition, exploratory analyses showed that the low dose of IR methylphenidate (50 mg) produced greater subjective effects than the high dose of osmotic-controlled ER methylphenidate (108 mg); significant differences were seen in the ARCI MBG, Amphetamine, VAS High, and Cole/ARCI Stimulation-Euphoria and Stimulation-Motor scales (all P < .05). The supportive endpoints (Emax and AUE0-24 h) of primary and secondary measures showed results that were similar to the primary endpoints (partial AUEs). The time course profiles of positive and stimulant effects are demonstrated in Figure 2A (VAS Drug Liking) and 2B (ARCI Amphetamine).
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Negative and General Effects
The rank order for negative effects (VAS Bad Effects, Feeling Sick, ARCI LSD, Cole/ARCI Unpleasantness-Physical/Dysphoria) was similar to that observed for positive effects (from highest to lowest): IR methylphenidate 90 mg > IR methylphenidate 50 mg > osmotic-controlled ER methylphenidate 108 mg > osmotic-controlled ER methylphenidate 54 mg > placebo (Table VI). The magnitude of negative effects scores was relatively low and peaked at later time points (4-6 hours or later) compared to positive effects scores. VAS Any Drug Effect scores were consistent with the positive effects, whereas VAS Dizziness and sedative effects (ARCI PCAG, Cole/ARCI Sedation-Motor and Sedation-Mental) were weak and, in most cases, not markedly different from placebo (except Cole/ARCI Sedation-Motor scale; scores for IR methylphenidate and osmotic-controlled ER methylphenidate 108 mg were higher than placebo) (Table VI).
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The changes expected in blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]; objective measure of pharmacologic effect) were consistent with methylphenidate concentrations for each treatment arm. For IR methylphenidate, there was an initial increase in blood pressure in the first 3 hours postdose (peak change from baseline for SBP/DBP of 13.5 ± 12.82/6.7 ± 8.19 mm Hg for 50 mg and 19.4 ± 13.37/9.1 ± 9.91 mm Hg for 90 mg), followed by a relatively rapid decline. For osmotic-controlled ER methylphenidate, blood pressure values tended to rise more slowly (eg, over 4-6 hours postdose) and decline more gradually with a mean peak change from baseline for SBP/DBP of 9.71 ± 0.07/4.9 ± 7.48 for 54 mg and 10.8 ± 12.15/7.3 ± 8.03 for 108 mg.
Pharmacokinetic-Pharmacodynamic Relationships
In general, pharmacokinetic-pharmacodynamic correlations were low to modest. No correlations were apparent between plasma methylphenidate concentrations and positive subjective effects scores (VAS Drug Liking and ARCI MBG scores) for osmotic-controlled ER methylphenidate. For IR methylphenidate, there was a modest trend of increasing positive effects scores with increasing methylphenidate concentrations. Correlations for both doses of IR methylphenidate were higher than both doses of osmotic-controlled ER methylphenidate. The coefficients of correlation (R2) between plasma methylphenidate concentrations and VAS Drug Liking scores were as follows (all values expressed as mean ± SD): -0.05 ± 0.31 for osmotic-controlled ER 54 mg, 0.02 ± 0.33 for osmotic-controlled ER 108 mg, 0.48 ± 0.47 for IR 50 mg, and 0.54 ± 0.40 for IR 90 mg. Results were similar for the ARCI MBG: 0.04 ± 0.31 for osmotic-controlled ER 54 mg, 0.13 ± 0.32 for osmotic-controlled ER 108 mg, 0.58 ± 0.41 for IR 50 mg, and 0.68 ± 0.27 for IR 90 mg.
Safety Evaluations
There were no serious adverse events in this study. Approximately half of subjects in the 54-mg osmotic-controlled ER MPH group and the 50-mg IR MPH group experienced at least 1 adverse event. Approximately one third of subjects in the 108-mg osmotic-controlled ER MPH group experienced at least 1 adverse event, and in the 90-mg IR MPH group, approximately two thirds of subjects experienced at least 1 adverse event. In the placebo group, approximately 1 in 5 subjects reported at least 1 adverse event. No adverse event was rated with an intensity of severe; most adverse events (89.3%) were rated with an intensity of mild, and the remaining adverse events (10.7%) were rated as moderate. The recorded adverse events were consistent with those previously described in the respective product monographs.
There were no clinically significant out-of-range clinical laboratory findings. There were occasional nonsignificant clinical laboratory findings that were out of range, although these do not appear to be related to any of the 5 treatment groups. These out-of-range findings were approximately evenly distributed among the treatment groups. Safety laboratory assessments were made at screening and at final discharge; all nonsignificant findings were recorded at final discharge.
All values for vital signs outside of treatment days fell within normal ranges. All values for vital signs on treatment days are consistent with the pharmacologic profiles of osmotic-controlled ER MPH and IR MPH. There were no abnormal and clinically significant ECG findings for any treatment group at either baseline or final discharge. Overall, more subjects had normal clinical ECG assessments at final discharge than at baseline (86.8% vs 77.4%, respectively).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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A consistent rank order was observed for all primary and secondary subjective measures of abuse and is described as follows: IR 90 mg > IR 50 mg > osmotic-controlled ER 108 mg > osmotic-controlled ER 54 mg > placebo.
Both doses of IR methylphenidate produced statistically significantly higher subjective effects (eg, positive, stimulant effects) compared to placebo with a dose response indicating increased effects with increasing dose, observed for most measures. The distinct responses of both doses of IR methylphenidate versus placebo support the sensitivity and validity of the study design. The 108-mg dose of osmotic-controlled ER methylphenidate was also associated with statistically significantly higher subjective effects than placebo. The most commonly used therapeutic dose (54 mg) of osmotic-controlled ER methylphenidate produced modest effects, and many were not statistically significantly different from placebo, likely due to the small fraction of IR methylphenidate (22% of total dose) and the unique slow ascending plasma concentration profile.
These findings are in agreement with previous studies, where sustained-release formulations produced lower subjective ratings compared to IR methylphenidate in stimulant-using and stimulantnaive subjects20,28,29 and consistent with the observation that drugs with rapid onset and offset of action are more likely to be abused than drugs with a slower onset and sustained action.30,31 It has been hypothesized that rapid delivery is more likely to be associated with abuse because subjective (euphoric) effects are more immediate, intense, and reinforcing (ie, closer temporal pairing of drug with reward). The capacity of methylphenidate to increase extracellular dopamine is associated with its positive subjective effects, which is likely to be one of the main mechanisms underlying its potential for abuse. However, methylphenidate-induced increases in dopamine that are associated with therapeutic effects (slow, tonic cell firing) differ from those accounting for positive subjective effects (fast, phasic cell firing). Therefore, the rate at which methylphenidate enters the brain will determine whether it induces fast versus slow increases in dopamine.32 Even if a methylphenidate formulation results in high dopamine transporter occupancy, if it does so slowly rather than rapidly, as evidenced by this and a previous study, it will elicit less intense subjective effects.29
In addition, sustained plasma levels of methylphenidate may prevent potential abusers from experiencing repeated "highs" (euphoria) following repeat administration.15,33 This may be true due to the high Cmax, relatively high transporter occupancy, and later tmax of osmotic-controlled ER methylphenidate, at which time very little feeling, liking, or disliking was observed. There was an apparent lack of linear correlation between pharmacokinetic and pharmacodynamic parameters for osmotic-controlled ER MPH; thus, increasing subjective effects were not observed when plasma concentrations and, by corollary, brain concentrations would be highest. As hypothesized in the literature,33 sustained drug concentrations would result in continued dopamine transporter occupancy, thereby preventing the subjective effects from recurring at a time when peak plasma concentrations are achieved. Alternatively, this may be an effect of acute tolerance (tachyphylaxis), which has been previously observed for other stimulants.34-38
Limitations
Human abuse liability studies are thought to be reasonably predictive of actual rates of abuse,22 but dissociations have been observed between subjective effects in abuse liability studies and drug self-administration studies,39,40 as well as both types of studies and actual rates of abuse.12 In the case of methylphenidate, this dissociation may be partly explained by the perception of methylphenidate effects by some subjects as negative, thus reducing the overall likelihood of abuse. For example, in the current study, the global (VAS Overall Drug Liking and Take Drug Again) ratings showed less distinction between treatment groups (including placebo). This may be due to subjects' familiarity with other stimulant drugs with more value to them (eg, more than 70% had used cocaine and/or methylenedioxy-methamphetamine [MDMA]), but it may also have been due to negative effects. Although the results suggest that osmotic-controlled ER methylphenidate may have less abuse liability than IR methylphenidate, the comparative rates of abuse in the general population can only be confirmed through a prospective epidemiological study.
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CONCLUSIONS |
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ACKNOWLEDGEMENTS |
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Financial disclosure: McNeil Consumer & Specialty Pharmaceuticals provided financing for this study, and the authors are employees of McNeil Pediatrics or DecisionLine Clinical Research Corporation.
This study was presented as a poster (200-word abstract) at the 53rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry, San Diego, California, October 27, 2006. Location of work: DecisionLine Clinical Research Corporation, Toronto, Ontario, Canada.
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REFERENCES |
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