A Randomized, Placebo-Controlled Trial of Sustained-Release Dextroamphetamine for Treatment of Methamphetamine Addiction
ARTICLES nature publishing group
A Randomized, Placebo-Controlled Trial of Sustained-Release Dextroamphetamine for Treatment of Methamphetamine Addiction
GP Galloway1, R Buscemi1, JR Coyle1, K Flower1, JD Siegrist1, LA Fiske1, MJ Baggott1, L Li1, D Polcin2, CYA Chen1 and J Mendelson1
Sixty treatment-seeking individuals with methamphetamine (MA) dependence entered a randomized, placebo-controlled, double-blind clinical trial of oral dextroamphetamine (d-AMP) as a replacement therapy for MA dependence. The subjects took 60 mg sustained-release d-AMP for 8 weeks, during which time they received eight 50-min sessions of individual psychotherapy. Adverse events and urine toxicology for MA were assessed two times a week. There were no serious adverse events. Urine samples containing <1,000 ng/ml of MA were classified as negative for MA. The MA-negative scores in the d-AMP group (3.1 p SD 4.6) were no higher than those in the placebo group (3.3 p SD 5.3; P > 0.05). However, withdrawal and craving scores were significantly lower in the d-AMP group (P < 0.05 for both). Although subjects taking d-AMP did not reduce their use of MA, the significant reductions observed in withdrawal and craving scores in this group support the need for further exploration of d-AMP as a pharmacologic intervention for MA dependence, possibly at higher doses.
Methamphetamine (MA) dependence is endemic worldwide Behavioral interventions have limited effectiveness, and and produces serious public health consequences.1–4 !e annual patients treated for MA dependence have a high rate of relapse.9 economic impact of MA in the United States in terms of lost Although several medications have been tested, none has been productivity, environmental damage, law enforcement costs, and proven to signi#cantly reduce MA use in MA-dependent patients health-care expenses, is estimated to be more than $20 billion.5 seeking treatment.10–12 A promising approach that has not been Persons addicted to MA have one of two distinct patterns of thoroughly assessed is substitution therapy. Substitution thera- use. Some pursue a chronic, periodic pattern of self-adminis- pies are well established in other addictions: methadone and tration throughout the day;6 others follow a “binge and crash” buprenorphine reduce the use of heroin,13 and nicotine replace- pattern, paying little heed to the need for food and sleep until ment therapy doubles smoking cessation rates.14 they run out of the drug or are too exhausted to continue its !e exact mechanism of e$cacy for substitution therapies is use. Both patterns result in substantial accumulation of MA in not yet understood, although several possibilities have been sug- the brain because of the comparatively short intervals between gested. Such medications attenuate withdrawal symptoms,15–17 doses relative to the long half-life of the drug. A withdrawal syn- potentially promoting engagement and retention in behavioral drome, o"en referred to as the “crash,” has been demonstrated; and psychosocial treatment; however, research #ndings to date this consists of strong craving, electroencephalography abnor- have been mixed.18,19 !ese substitute medications are cross- malities, depression, alterations in sleep patterns, hypersomno- tolerant with the respective abused substances that they replace lence, and hyperphagia.7,8 !e clinical features of chronic MA and similarly discriminated, but they typically have slower use are associated with neurotransmitter depletion. !ese signs onsets of action and longer half-lives and are less reinforcing. and symptoms include depression, fatigue, poor concentration, !e relatively stable pharmacokinetic pro#les of the replacement loss of self-esteem, decreased libido, mild Parkinsonian features medications provide more constant drug levels as compared with (myoclonus, tremor, bradykinesis), and insomnia. the erratic concentrations characteristic of illicit drugs, possibly
1Addiction and Pharmacology Research Laboratory, California Pacific Medical Center, San Francisco, California, USA; 2Alcohol Research Group, Public Health Institute, Emeryville, California, USA. Correspondence: GP Galloway ([email protected]) Received 16 August 2010; accepted 14 October 2010; advance online publication 22 December 2010. doi:10.1038/clpt.2010.307
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Assessed for eligibility (n = 230)
Enrollment
Excluded (n = 170) g Did not meet inclusion criteria (n = 148) g Declined to participate (n = 20) g Eligible but did not attend randomization (n = 2)
Randomized (n = 60)
Allocation
Allocated to intervention (active) (n = 30) Allocated to intervention (placebo) (n = 30) g Received allocated intervention (n = 30) g Received allocated intervention (n = 30) g Did not receive allocated intervention (n = 0) g Did not receive allocated intervention (n = 0)
Follow-up
Lost to follow-up (n = 3, did not attend visits or Lost to follow-up (n = 1, did not attend visits or return telephone calls) return telephone calls)
Discontinued intervention (n = 1, discontinued Discontinued intervention (n = 4: treatment at week 6 due to adverse reaction to 1 moved from area; 1 had transportation medication; continued attending and issues; 2 withdrew due to time commitment) completed study)
Analysis Analyzed (n = 30) Analyzed (n = 30) g Excluded from analysis (n = 0) g Excluded from analysis (n = 0)
Figure 1 Subject flow diagram. attenuating the subjective experiences of both intoxication and drug use,19 including IV administration of the drug,26 thereby withdrawal. suggesting that d-AMP is an e%ective intervention in those with No substitution therapy has been established for MA more severe dependence, who tend to use the IV route. dependence.20 Dextroamphetamine (d-AMP) is one of several agonist-like replacement therapies that have shown promise in RESULTS preclinical studies as well as in laboratory studies in humans.21 Clinical characteristics Oral d-AMP has been prescribed for thousands of MA users in Of 230 subjects screened, 60 were randomized to either a pla- England and Wales22 and has been associated with decreases cebo group (n = 30) or a d-AMP group (n = 30; see Figure 1 in intravenous (IV) MA use and criminal activity19 and with for study enrollment &ow). !e placebo and d-AMP groups increased treatment engagement.23–25 Prior to the commence- did not di%er signi#cantly with respect to race, average age, ment of this study, there had been no placebo-controlled or days of use of MA in the 30 days preceding screening. !e randomized trial of d-AMP for treatment of MA dependence. majority of the subjects were Caucasian and male, with similar !e goal of our study was to determine the safety and e$- average ages (see Table 1 for participant demographics). At cacy of 60 mg sustained-release (SR) d-AMP in treating MA enrollment, subjects in the placebo group reported using MA dependence. We selected the dosage of 60 mg per day on the a mean of 15.3 p 8.5 days out of the prior 30, and d-AMP group basis of the available research to date. In a retrospective study subjects reported 18.9 p 9.7 days of use. !e quantity of MA of MA-dependent adults in treatment, an average of 43 mg of used per day in the 30 days prior to enrollment by subjects in oral d-AMP was found to be as e%ective in reducing IV use of the placebo group was 319 p 353 mg; those in the d-AMP group MA as methadone had proved to be in reducing IV heroin use.26 used 307 p 283 mg. MA-experienced subjects who received a daily dose of 40 mg immediate-release d-AMP experienced improved treatment Safety of d-AMP retention, reduced MA use, and less use of injection as a route No serious adverse events occurred during the trial. No adverse of MA administration.23 Previous studies also found that the events were more likely to be reported by subjects in the d-AMP use of d-AMP decreased problematic behaviors associated with group than by subjects in the placebo group (Figure 2). Dosing
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MA use condition also did not signi#cantly a%ect heart rate (F1,57 = 0.008, P = 0.929) or blood pressure (systolic: F1,57 = 0.709, P = 0.403; No di%erences were found between the placebo and d-AMP diastolic: F1,57 = 1.1488, P = 0.288). !e number of subjects with groups with respect to measures of MA use. !e number of clinically signi#cant abnormalities in electrocardiography results self-reported MA-abstinent days did not di%er signi#cantly by was similar in the two groups: one in the d-AMP group and two group. Of a possible 56 days of abstinence, the placebo group in the placebo group. reported 27.5 p 16.8 days of abstinence, whereas the d-AMP group reported 27.2 p 17.3 days (Mann–Whitney U-test: Table 1 Clinical characteristics of the subjects W = 464, P = 0.842). Similarly, the number of MA-negative Placebo Active P value urine test results did not di%er signi#cantly by group (Mann– Whitney U-test: W = 441, P = 0.894). Of a possible 16 urine test n 30 30 results, the placebo group had 3.2 p 5.0 MA-negative results, Age (years), mean (SD) 37.5 (7.2) 37.0 (7.2) 0.75 and the d-AMP group had 2.9 p 4.3 MA-negative results (see Male, n (%) 19 (63%) 15 (50%) 0.43 Figure 3). Of 16 possible instances of no new use, the placebo Caucasian, n (%) 21 (70%) 20 (67%) 1 group had 2.9 p 4.9 instances, whereas the d-AMP group had Smoking as primary route 20 (67%) 24 (80%) 0.38 2.6 p 4.2. of administration, n (%) AWQ withdrawal score 14.9 (6.9) 14.6 (8.0) 0.72 Withdrawal and craving (0–40), mean (SD) d-AMP reduced MA withdrawal symptoms as measured ADHD diagnosis, n (%) 4 (13%) 5 (17%) 1 by the Amphetamine Withdrawal Questionnaire (AWQ; ADHD, attention deficit hyperactivity disorder; AWQ, Amphetamine Withdrawal Figure 4). In a linear model in which the group and time Questionnaire. predicted AWQ score, there was a main effect of group
I have been happier I have been more anxious I have been sleeping better I have had a runny nose My mouth is dry I have been sleeping more I have felt high I am feeling more alert My heart beats fast sometimes I have been eating more I have been more unhappy My muscles or bones have been aching I have been drowsy I have had trouble concentrating I have been sleeping less I have been feeling sick to my stomach ent I am angry more than I was before Condition I breathe faster sometimes Placebo erse ev I have less energy I have more energy d−AMP Adv My medication dose is too low My weight is changing I have felt dizzy My hands have been shaking I have been eating less I have been urinating more frequently I have had trouble with my eyes I have had chills I have been less anxious I have felt paranoid I have had diarrhea My medication dose is too high I have had a fever I have been constipated My heart has been beating slower
510152025 Number of subjects who reported adverse event (N = 30)
Figure 2 Adverse events by group. d-AMP, dextroamphetamine.
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0.5
0.4
0.3 Condition Placebo 0.2 d−AMP Proportion of samples 0.1
02468
Week
Figure 3 Proportions of methamphetamine-negative urine samples by time and group. d-AMP, dextroamphetamine.
17
16
15
14 Condition al score w Placebo 13 d−AMP Withdra 12
11
02468
Week
Figure 4 Amphetamine Withdrawal Questionnaire scores by time and group. d-AMP, dextroamphetamine.
55
50
45 Condition 40 Placebo ving score a
Cr 35 d−AMP
30
25
02468 Week
Figure 5 Methamphetamine craving visual analog scale scores by time and group. d-AMP, dextroamphetamine.
Medication adherence and attendance (F1,431 = 5.741, P = 0.018). This model indicated signifi- cantly attenuated withdrawal symptoms in the d-AMP group at psychosocial treatment sessions (t = −2.421, P = 0.016). d-AMP also reduced subjects’ crav- !ere was no signi#cant e%ect of group on medication adherence ing as measured by visual analog scale (Figure 5). In a linear or attendance at psychosocial treatment sessions. !e percent- model in which group and time predicted MA craving, there age of dispensed medication taken did not signi#cantly di%er were main e%ects of group (F1,408 = 5.116, P = 0.024) as well between the groups. Placebo subjects took 73.6% p 15.2% and as of time (F8,408 = 3.110, P = 0.002). No signi#cant interac- d-AMP subjects took 74.2% p 12.2% of the dispensed medica- tion was found between group and time. !is model indi- tion (Mann–Whitney U-test: W = 457, P = 0.923). !e number cated signi#cantly lower craving scores in the d-AMP group of psychosocial treatment sessions attended was also not a%ected (t = −2.302, P = 0.022). by group. Of a possible nine sessions, placebo group subjects
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attended 5.1 p 3.0, and d-AMP group subjects attended 5.6 p 3.0 the d-AMP dose, considered alongside self-reports of high doses sessions (Mann–Whitney U-test: W = 408, P = 0.535). At the of MA used, suggests that this population may have signi#cant #rst visit a"er day 1, all the subjects were asked which group they tolerance to amphetamines. !e absence of any signi#cant dif- thought they were randomized to; 67% of the subjects in each ference between the two groups with respect to adherence to the group believed that they had been randomized to d-AMP. regimen implies that the oral d-AMP dispensed to the treatment group had not been diverted elsewhere; this also suggests toler- DISCUSSION ance to d-AMP. Our data are consistent with #ndings to date !e goal of our study was to determine the safety and e$cacy of suggesting that, if d-AMP is to be e%ective for the treatment of 60 mg SR d-AMP as substitution therapy for MA dependence. MA dependence in highly amphetamine-tolerant individuals, it A variety of preclinical and clinical data indicate that this may would have to be administered at higher doses.37,38 be a useful approach for the treatment of MA dependence and could also serve to guide dose selection. Although we found METHODS that the overall e%ect of d-AMP on MA use was not signi#cant, Study design. This was a placebo-controlled, double-blind, randomized the results show that 30 mg d-AMP taken twice daily is safe for clinical trial. Subjects received either 60 mg d-AMP SR or placebo daily for 8 weeks. This was given as a single dose on the first day and MA users. !e main #nding of the study is that d-AMP reduces as two equally divided doses on subsequent days. Urn randomization withdrawal symptoms and craving for MA. Although reductions was used to assign subjects to study groups so as to balance the groups in withdrawal and craving scores do not by themselves con#rm with respect to baseline variables.39 Factors controlled for were current the e$cacy of d-AMP as a substitution therapy, the #ndings in attention deficit hyperactivity disorder, AWQ (score <18 vs. r19), and these domains do support the need for further exploration of days of MA use in the 30 days prior to randomization (<12 days vs. r13 days). For the latter two variables, median splits were determined on d-AMP as a treatment for MA dependence. Both withdrawal the basis of our previous work with MA. The trial was conducted at a symptoms and craving are postulated to increase relapse rates single site, the Addiction & Pharmacology Research Laboratory in San among MA users.27–30 !erefore, these #ndings suggest that one Francisco, CA. The protocol was approved by the institutional review avenue for further consideration of d-AMP’s e$cacy is among board of California Pacific Medical Center Research Institute and was more dependent, long-term MA users, who have been shown to registered at clinicaltrials.gov (identifier: NCT00630682). experience more severe withdrawal symptoms.31 Subjects. !e study criteria required that subjects be between the ages We limited our dose to the maximum dose of SR d-AMP of 18 and 50 years, meet Diagnostic and Statistical Manual of Mental approved for use in the United States. A recent randomized Disorders IV–Text Revision criteria for MA dependence, be seeking placebo-controlled trial of d-AMP for MA dependence in treatment for MA dependence, and provide at least one MA-positive Australia32 used a design in which subjects could be titrated to urine sample during screening. Exclusion criteria included serious a maximum dose of 110 mg/day. Signi#cant improvements in medical illness, pregnancy, use of any investigational medication in the previous 30 days, a court mandate to participate in drug abuse treatment retention and reduction in MA dependence sever- treatment, and attendance in a drug or alcohol dependence treatment ity scores were reported. As compared with placebo, d-AMP program within the 30 days prior to screening. Subjects were also signi#cantly attenuated withdrawal symptoms, and a trend was excluded for the following diagnoses as determined by the Diagnostic noted for decrease in MA use. Severity of MA dependence was Interview Schedule: current alcohol, opiate, or sedative-hypnotic signi#cantly reduced in the d-AMP group. dependence disorder requiring medical detoxi#cation; presence of severe post-traumatic stress disorder, mania, or hypomania within the !e primary limitation of this study was the moderate size past 90 days; and lifetime history of schizophrenia, schizophreniform, of the sample. Although it may be argued that an e%ect that is or schizoa%ective disorder. detected in a study with only 30 subjects per group is not clini- cally signi#cant, even a small e%ect could be useful in guiding Study medication. d-AMP is a US Food and Drug Administration– medication development e%orts in a condition such as this, for approved stimulant indicated for the treatment of attention de#cit hyper- activity disorder and narcolepsy. It is not detected as MA in urine or other which there is no e%ective pharmacotherapy. In addition, given specimens and is available commercially in sustained-release form. Peak the time and expense required to conduct addiction treatment blood levels are reached 8–10 h a"er the dose is taken.40 trials, developing more sensitive outcome measures of drug use We used d-AMP SR capsules manufactured by Barr Laboratories, should be a priority.33 Pomona, NY. !e Drug Prod Services Laboratory at University of Cali- !ere are several indicators of tolerance to d-AMP in our study fornia, San Francisco, prepared both the active and the placebo capsules. d-AMP capsules for the study were made by repackaging 15-mg SR cap- sample. In a previous study, in which low doses of immediate- sules purchased from Barr Laboratories into 30-mg capsules. !e latter release d-AMP (0.035–16 mg) were given to amphetamine-naive were identical in appearance to the placebo capsules, which were #lled subjects, the drug produced stimulant-like e%ects, including with lactose. subjective ratings of “stimulated” and “like drug,” and increased diastolic and systolic blood pressure.34,35 In our study, d-AMP Psychosocial treatment. Subjects received 50-min, manual-based, individ- administration had no signi#cant e%ect on heart rate or blood ual motivational enhancement therapy sessions once a week for 9 weeks. !is intensive therapy41 is a modi#cation of Miller’s three-session treat- pressure. Our subjects reported using >300 mg/day of MA, ment for alcohol-dependent subjects.42 substantially more than the average daily amount of r50 mg 36 reported in another study of MA-dependent adults. Although MA urinalysis. Urine samples were collected two times a week and assayed we could not measure the purity of the MA used by our subjects, for MA qualitatively on site with immunoassay devices (Redwood the absence of any e%ect on heart rate and blood pressure a"er Biotech, Santa Rosa, CA); the cuto% value was 1,000 ng/ml. Urine samples
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that tested positive were then sent to Quest Diagnostics (Nichols Institute, CONFLICT OF INTEREST San Juan Capistrano, CA) for quanti#cation of MA levels using gas chro- The authors declared no conflict of interest. matography/mass spectrometry. !e subjects were asked at each visit to © 2011 American Society for Clinical Pharmacology and Therapeutics report the days of MA use since the previous study visit. Although the presence of MA in urine indicates use at some time, 1. Substance Abuse and Mental Health Services Administration. National Survey it may be due to carryover from the preceding sample. Using known on Drug Use and Health, 2006
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