- Email: [email protected]
Efficacy of dose and contingency management procedures in LAAM-maintained cocaine-dependent patients
Drug and Alcohol Dependence 79 (2005) 157–165
Efficacy of dose and contingency management procedures in LAAM-maintained cocaine-dependent patients Alison Oliveto ∗ , James Poling, Kevin A. Sevarino 1 , Kishorchandra R. Gonsai, Elinore F. McCance-Katz 2 , Susan M. Stine 3 , Thomas R. Kosten Department of Psychiatry, Yale School of Medicine and the VA CT Healthcare System, West Haven, CT, USA Received 12 August 2004; received in revised form 3 January 2005; accepted 24 January 2005
Abstract Opioid- and cocaine-dependent participants (N = 140) were randomly assigned to one of the following in a 12-week clinical trial: LAAM (30, 30, 39 mg/MWF) with contingency management (CM) procedures (LC); LAAM (30, 30, 39 mg/MWF) without CM (LY); LAAM (100, 100, 130 mg/MWF) with CM (HC); LAAM (100, 100, 130 mg/MWF) without CM (HY). Urine samples were collected thrice-weekly. In CM, each urine negative for both opioids and cocaine resulted in a voucher worth a certain monetary value that increased for consecutively drug-free urines. Subjects not assigned to CM received vouchers according to a yoked schedule. Vouchers were exchanged for mutually agreed upon goods and services. Groups generally did not differ on retention and baseline characteristics. Overall opioid use was least in the HC and HY groups; opioid use decreased most rapidly over time in the HC group relative to the HY, LC and LY groups. Overall cocaine use was least in the HC group relative to the HY, LC, and LY groups; cocaine use decreased over time most rapidly in the HC and LY groups. Abstinence from both was greatest in the HC group. Opioid withdrawal symptoms decreased most rapidly in the high-dose groups relative to the low-dose groups. These results suggest that an efficacious maintenance dose is necessary for contingencies to be effective in facilitating both opioid and cocaine abstinence. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Opioid agonist maintenance; Cocaine dependence; Opioid dependence; Contingency management procedures; Clinical trial; Humans
1. Introduction Cocaine use in the context of methadone maintenance has been associated with a number of problems, including higher incidence of HIV risk behaviors such as intravenous drug use and unprotected sex (Bux et al., 1995; Meandzija et al., ∗ Corresponding author. Present address: University of Arkansas for Medical Sciences, 4301 West Markham, Slot 554, Little Rock, AR 72205, USA. Tel.: +1 501 686 8969; fax: +1 501 686 8154. E-mail address: [email protected] (A. Oliveto). 1 Current address: Department of Psychiatry MC 1410, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-1410, USA. 2 Current Address: Virginia Commonwealth University, Box 980109, Richmond, VA 23298, USA. 3 Current Address: Addiction Research Institute, Substance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2761 E. Jefferson Ave., Detroit, Michigan 48207, USA.
0376-8716/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2005.01.007
1994), illicit opioid use (Hartell et al., 1995), criminal activity (Grella et al., 1995; Hunt et al., 1986), psychopathology (Compton et al., 1995; Grella et al., 1995) and poorer outcome (Kosten et al., 1988). Comorbid cocaine dependence is a major issue among methadone maintenance programs, where rates of cocaine use have been reported to be as high as 70% (Black et al., 1987). Methadone maintenance also does not appear to decrease the use of cocaine and, indeed, cocaine use may increase in some methadone-maintained patients (Kosten et al., 1987). These issues suggest that more effective maintenance strategies need to be developed in order to improve upon the feasibility and efficacy of treatment for combined opioid and cocaine dependence. One strategy for improving opioid dependence has been the development of a longer-acting opioid agonist maintenance medication, levo-alpha-acetylmethadol (LAAM). Numerous clinical trials since then have demonstrated that thrice-weekly LAAM maintenance is comparable to, if not
158
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
superior than, daily methadone maintenance by various outcome criteria, including reduction of opiate positive urines or morphine concentration in hair (e.g., Johnson et al., 2000; Ling et al., 1978; see Clark et al., 2004; Senay et al., 1977; White et al., 2002) and suppression of withdrawal symptoms (Jaffe et al., 1970, 1972; Sorenson et al., 1982). In addition, although in some trials there was a small increase in the dropout rate for LAAM as opposed to methadone maintenance (e.g., Farre et al., 2002; Johnson et al., 2000; see Clark et al., 2004), this appeared in some instances to be a result of differentially greater dropout during the induction phase (Jaffe et al., 1970, 1972; Senay et al., 1977). However, to our knowledge, several issues have not been addressed with regard to LAAM maintenance. First, few studies have examined the relationship between the maintenance dose of LAAM and treatment outcome (Eissenberg et al., 1997; Oliveto et al., 1998). Second, the impact of LAAM on cocaine use in a cocaine-abusing opioid-dependent population has not been systematically examined. Among individuals admitted to methadone maintenance programs, intravenous cocaine abuse is endemic and undermines both treatment effectiveness and the prevention of the HIV virus. Given that LAAM produces effects similar to methadone and is administered in the same milieu, it is conceivable that rates of cocaine use will be similar in cocaine abusers maintained on LAAM. Alternatively, the facilitation of cocaine use with LAAM may be less than that with methadone, in that LAAM is administered on a thriceweekly rather than daily basis. Clients will, therefore, attend the clinic less often, thereby reducing their exposure to cocaine in the clinic environment. Thus, the impact of LAAM maintenance on cocaine use is important to clarify. Third, behavioral interventions, notably contingency management procedures, have demonstrated some efficacy in facilitating illicit drug abstinence in methadone-maintained individuals (e.g., Griffith et al., 2000; Jones et al., 2001; Rawson et al., 2002; Rowan-Szal et al., 1994; Silverman et al., 1996, 1998), but have not been examined in LAAM-maintained individuals. Thus, this trial examined the efficacy of a high and low maintenance dose of LAAM with and without the application of contingency management procedures aimed at facilitating opioid and cocaine abstinence in opioid-dependent cocaine abusers. Our hypotheses were the following: (1) LAAM dose would have greater influence on the degree of opioid than cocaine use; (2) the contingency management procedures would affect the degree of cocaine use more than LAAM dose; (3) abstinence from both opiates and cocaine would be greatest in the high-dose LAAM group that received the contingency management procedure.
2. Methods 2.1. Subjects One hundred forty male and female cocaine-abusing, opioid-dependent individuals (ages 21–55, including 45 fe-
males, 39 African-Americans, 10 Hispanics, and 91 Caucasians) seeking opioid maintenance treatment were recruited from the greater New Haven area after giving informed consent to participate in this randomized clinical trial approved by the Yale Human Investigations Committee and the VA CT Human Studies Subcommittee. All participants met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for opioid and cocaine dependence, as determined from the Structured Clinical Interview for DSM-IV (SCID), and had urine toxicologies positive for both drugs. Exclusions included medical reasons contraindicating LAAM maintenance (e.g., pregnancy, respiratory condition such as asthma, abnormal liver enzyme levels, or use of medications that might interact with LAAM), a current diagnosis of other drug or alcohol physical dependence (other than tobacco), a history of major psychiatric disorder (psychosis, schizophrenia, bipolar), current suicidality, and an inability to read and understand the consent form. Women of childbearing age were included provided they had a negative urine pregnancy test, agreed to use adequate contraception to prevent pregnancy during the study, and agreed to monthly pregnancy tests. 2.2. Research design and procedures In this 12-week randomized, double blind, outpatient clinical trial, 140 patients were randomized by sex to one of the following treatment groups: low-dose LAAM (30, 30, 39 mg/MWF) with contingency management procedures (LC); low-dose LAAM (30, 30, 39 mg/MWF) without contingency management procedures (LY); high-dose LAAM (100, 100, 130 mg/MWF) with contingency management procedures (HC); high-dose LAAM (100, 100, 130 mg/MWF) without contingency management procedures (HY). During LAAM induction, patients received an initial dose of 20 mg of LAAM on Monday of week 1. This dose was increased by 10 mg at next dosing such that patients received 30 mg on Wednesday of week 1. The patients in the low-dose group then received their maintenance doses of LAAM (30 mg on Mondays and Wednesdays; 39 mg on Fridays), while subjects in the high-dose group continued to be inducted onto LAAM in 10 mg dose increments until they received their maintenance dose of 100 mg by Friday of week 4. All patients were then maintained on their respective maintenance dose of LAAM through week 12. If a subject missed one dose, he/she was administered their usual dose if they came to the clinic on the day of the next scheduled dose as it is well tolerated in most instances (LAAM labeling instructions, Biodevelopment Corporation). If a subject missed Monday–Wednesday consecutive doses or a Friday dose, he/she was discharged from the study. The reason for discharging a participant for missing the Friday dose was that adjusting the dose after five consecutive days without LAAM would have involved dose adjustments and therefore not kept the integrity of the fixeddose design.
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
The contingency management procedures used in this study were adapted from those developed by Higgins et al. (1991, 1993), which have been demonstrated to facilitate initial cocaine abstinence in nonopioid-dependent cocaine abusers. Supervised urines were collected thriceweekly (MWF) prior to being medicated in order to implement the contingency management procedures, which began during week 1 along with weekly group and weekly individual therapy sessions. For the contingency group, urines free from both opioids and cocaine resulted in a voucher worth a monetary value, such that the first urine was worth $3. Each consecutive, drug-free urine sample thereafter increased in monetary value by $1. If a urine sample was missed or contained cocaine or opioids, the value of the next drugfree urine reset back to $3. Patients in the contingency group who remained abstinent during the entire 12-week trial were able to earn goods and services worth a maximum of $738. For the yoked group, each patient was yoked to a person in the contingency group, such that the yoked person earned vouchers based on the contingency person’s performance, not their own. Each person in the yoked group was told that they would receive vouchers on a random basis. Feedback concerning urine results was given to patients in both groups at their weekly individual sessions, at which time vouchers were given as appropriate. Vouchers could be exchanged for mutually agreed upon goods and services at any time during the study. Typically, patients accumulated vouchers for larger goods or services than a day or week’s earnings would allow. The larger reinforcers were often obtained within one day of the request, but some items took up to 7 days to purchase. In addition to reviewing urine results and vouchers, each weekly individual session focused on identifying antecedents and consequences of drug-taking behavior during that week, discussing strategies to initiate or maintain abstinence, and discussing case management issues. Weekly group sessions were manual guided, based on an expanded version of the Group Drug Counseling Manual (Mercer et al., 1992). Patients were discharged from the study if they missed more than three consecutive therapy sessions. Assessments of treatment outcome included retention in treatment, illicit opioid and cocaine use, as measured by urine toxicologies and self-reported use, opiate withdrawal symptoms and depressive symptom severity. 2.3. Laboratory tests Urine samples were analyzed for the presence of opioids and cocaine metabolites upon submission of a urine sample on a thrice-weekly basis. This frequency of urine testing was employed in order to detect most opioid and cocaine use. Breath analysis for alcohol was performed on a random basis or when recent alcohol use had been suspected. If the breath alcohol level was >0.00 and <0.05, one-half the LAAM dose was administered. Breath alcohol levels ≥0.05 resulted in the LAAM being withheld on that day. Urines were also screened for barbiturates and benzodiazepines on a weekly basis. A
159
urine sample was rated positive if the quantity of opioids was greater than 200 ng/ml for opioids and quantity of other drugs or their metabolites was 300 ng/ml. Urine toxicology results were available the next day from the VA Clinical Laboratory. Blood chemistries (SMA 20, CBC) and electrocardiogram (ECG) as well as a general physical examination were performed during screening. 2.4. Psychosocial assessments Self-reported opioid and cocaine use, as well as opiate withdrawal symptoms, were assessed at baseline and weekly using instruments we have developed in previous studies (Kosten et al., 2003; Oliveto et al., 1999). Since medication hours were between 7 and 10 a.m., the time of day for these ratings was relatively standardized. Ratings were completed before LAAM dosing. At intake, the SCID interview was completed for DSMIV psychiatric diagnoses, including depression and substance use disorders (First et al., 1995). Substance-related problems and psychosocial functioning were assessed at intake using the addiction severity index (ASI), a 140-item structured clinical interview using both subjective and objective information to make severity ratings on 10-point scales in seven areas: alcohol and drug use, medical status, legal status, psychiatric symptoms, occupational functioning, and family/social functioning (McLellan et al., 1992). Depressive symptoms were measured at baseline and monthly using the Center for Epidemiological Studies Depression Inventory (CES-D) and at baseline only using the Hamilton Depression Scale. The CES-D inventory is a 20item self-report with item scores ranging from 0 to 3 and total scores ranging from 0 to 60. Means for the general population range from 8 to 9 and for depressed patients are 24 (Radloff, 1977). The Hamilton observer-rated scale covers 21 symptoms with a total score ranging from 0 to 62 and a cutoff of 15 for moderate depression. 2.5. Training of raters The raters had previous experience in clinical rating and interviewing and at least a Bachelors level education or its equivalent in experience. Under supervision, each rater received 1 month of training on the ASI, SCID and DSM-IV. Training included observation of interviews and ratings, corating, and interviewing with the supervisor present. In order to conduct interviews for this study, it was required that the rater complete three consecutive conjoint interviews on which DSM IV diagnoses are in complete agreement with those of more experienced raters. After training, reliability was periodically spot-checked. 2.6. Data analyses The intent to treat sample of 140 participants was used for the statistical analyses. The four treatment groups were com-
160
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
pared for baseline differences using Chi-square for categorical characteristics and analysis of variance (ANOVA) for continuous variables such as age, CES-D score and withdrawal symptoms. The amount of voucher reinforcement and overall urine results across groups were compared using Mann Whitney U tests, because the distributions were skewed. The primary outcome in the intent to treat sample was urine toxicology screening result. We compared the mean proportion of the three weekly urine samples that were opiatepositive, cocaine-positive, and negative from both each week ranging between 0 and 1 in a manner similar to that described previously (Kosten et al., 2003; Oliveto et al., 1999). In order to make analyses amenable to ordinal analysis, urinalysis data were first calculated as weekly mean proportion of urines positive for the target drug. Then zero reflected “no use,” proportions between 0 and 1 were recoded 1 for “some use,” and a proportion of 1 was recoded 2, reflecting “all use,” These data were entered into a 2 × 2 × 12 hierarchical linear modeling analyses with LA AM dose, contingency condition, and time as factors for these comparisons and present the odds ratio of drug-free urines to total urines as a measure of difference at week 12 (Bryk and Raudenbush, 1987; Gibbons et al., 1993). We used the MIXOR program of Hedeker (University of Chicago) for HLM analyses and SPSS for other statistics. These analyses yielded z tests that assessed the overall magnitude as well as that of the linear increase or decrease in data values over the course of the study as a function of LAAM dose and contingency management condition. In reporting significance levels, the HLM models included all interaction terms as well as the main factors. When the interaction among LAAM dose, contingency condition, and time was
significant, we also conducted statistical contrasts between each of the four groups and the other three groups. Because the ordinal data had a limited number of outcomes that was not normally distributed, we determined whether there were overall differences (i.e., not over time) among groups using the Kruskal–Wallace nonparametric test. Weekly self-reported opioid use, cocaine use, and CESD scores were analyzed using HLM similarly to the urine toxicology results. Opioid withdrawal ratings during the first half of the study were also analyzed using HLM. For all analyses, statistical significance was inferred by a p value less than 0.05.
3. Results 3.1. Baseline characteristics, treatment retention and reinforcement values The 140 subjects who were initially randomized and started on LAAM maintenance are compared in Table 1 on baseline and demographic comparisons among the four treatment conditions. These subjects showed no significant differences on demographics, drug and alcohol use, or depressive symptoms, except for net income in the month prior to study entry. The LY group had significantly greater income than the HC (z = −2.4, p = 0.02) and HY (z = 2.6, p = 0.009), but not LC (z = −1.0, p = 0.30) groups (Kruskal–Wallis χ = 11.1, p = 0.01). The LC group had significantly greater income than the HC (z = −2.0, p = 0.04) and HY (z = −2.1, p = 0.04) groups.
Table 1 Means (S.D.) on baseline measures for the four treatment groups Measure
Treatment groupsa HC
HY
LC
LY
N Age (years) Sex (no. of male/female) Race (no. of C/AA/H)b Education (nhs/hs/col+)c Net income ($/month)d Lifetime heroin use (years) Lifetime cocaine use (years) Heroin use (no. of days/month)e Cocaine use (no. of days/month)e Alcohol use (no. of days/month)e Rte for primary drug (no. of IV/IN/S)f CES-D Prior methadone treatment (%) Prior LAAM treatment (%) Current major depression (%)
35 36.8 (4.8) 23/12 25/8/2 7/27/1 373 (710) 8.6 (7.0) 9.6 (7.9) 29.2 (2.1) 12.5 (10.1) 2.3 (4.3) 18/16/1 16.9 (13.1) 45.7 8.6 8.6
35 37.7 (7.6) 20/15 25/8/2 11/22/2 319 (517) 11.5 (7.9) 11.4 (8.2) 28.6 (4.1) 15.9 (10.0) 1.5 (2.9) 20/14/1 21.8 (13.7) 68.6 5.7 20.0
35 36.6 (6.0) 27/8 19/13/3 9/26/0 579 (653) 10.1 (6.6) 9.6 (7.2) 27.6 (7.1) 13.4 (9.6) 3.3 (6.0) 19/4/2 20.1 (14.5) 57.1 8.6 22.9
35 34.9 (6.2) 25/10 22/10/3 6/29/0 947 (1065) 9.1 (7.2) 9.2 (7.8) 28.5 (5.0) 15.3 (9.1) 3.7 (7.8) 19/16/0 20.1 (12.9) 65.7 2.9 28.6
a
Treatment groups: HC, high-dose LAAM plus contingency; HY, high-dose LAAM plus yoked control; LC, low dose LAAM plus contingency; LY, low dose LAAM plus yoked control. b Race: C, Caucasian; AA, African–American; H, Hispanic. c Education: nhs, non-high school graduate; hs, high school graduate; col+, college graduate or more. d Net income ($/month) – dollars earned in the month prior to study entry. e No. of days/month – number of days used substance in the month prior to study entry. f Route for primary drug: IV, intravenous; IN, intranasal or inhaled; S, smoked. Bold values – significant difference among groups (p < 0.05).
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
161
Fig. 1. Weekly number of patients retained in each of the four treatment groups across the 12-week trial: high-dose LAAM with contingencies (HC, filled circles), high-dose LAAM without contingencies (HY, open circles), low-dose LAAM with contingencies (LC, filled squares), and low-dose LAAM without contingencies (LY, open squares).
The average length of retention was 9.1 ± 3.9 (mean ± S.D.) weeks with 74 completing the trial (53%), which did not differ among the four treatment groups, as shown in Fig. 1 (log rank = 2.7, p < 0.44). Reasons for premature termination from the study included leaving at the patient’s request (N = 6), non-compliance with the study protocol (N = 15), medical issues unrelated to study participation (N = 3), being jailed (N = l), lacking tolerance to the LAAM induction (N = 2), and missing medication on a consecutive Monday–Wednesday or on a Friday (N = 39). Although groups did not differ by LAAM dose on dropping out due to missed medication (log rank = 7.32, p = 0.06), two-thirds of those who missed medication were receiving low-dose LAAM. The mean weekly proportion of counseling sessions attended was 55% for weekly groups and 75% for weekly individual sessions, with no difference across the four treatment groups. The HC group earned a higher mean voucher amount ($138.34) than the LC ($49.86; z = −2.5, p = 0.01) and the LY ($62.11; z = −2.7, p = 0.007) groups. The HC group voucher amount did not differ from that of the HY group ($87.26; z = −1.5, p = 0.14), which also did not differ from the LC (z = −1.2, p = 0.25) and LY (z = −1.4, p = 0.16) groups. 3.2. Illicit opioid and cocaine use during the trial Opioid and cocaine use, as measured by urine toxicology tests, are shown in Fig. 2. There were no baseline differences across groups in opioid and/or cocaine negative urines. In terms of opioid use, the HC (52.0%) and HY (51.0%) groups overall had significantly greater urines negative for opioids relative to the LC (29.8%; z = −6.1, p < 0.001 and z = −6.1, p < 0.001, respectively) and LY (40.6%; z = −6.8, p < 0.001 and z = −6.9, p < 0.001, respectively) groups. Opi-
Fig. 2. Weekly proportion of urines free of opioids (top panel), cocaine (middle panel) and both opioids and cocaine (bottom panel) for the four treatment groups: high-dose LAAM with contingencies (HC, filled circles), high-dose LAAM without contingencies (HY, open circles), low-dose LAAM with contingencies (LC, filled squares), and low-dose LAAM without contingencies (LY, open squares) in 140 opioid- and cocaine-dependent patients maintained on LAAM for 12 weeks.
oid negative urines increased most rapidly over time in the HC group relative to the HY (z = 4.6, p = −0.00001), LC (z = 8.3, p < 0.00001) and LY (z = 5.5, p < 0.00001) groups (Fig. 2, top panel). Overall, the HC group had significantly greater urines negative for cocaine (51.0%) relative to the HY (33.7%;
162
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
z = −5.0, p < 0.001), LC (39.6%; z = −3.3, p = 0.001), and LY (37.5%; z = −3.7, p < 0.001) groups. Cocaine negative urines increased most rapidly over time in the HC and LY groups relative to the HY (z = 4.1, p = 0.00004 and z = 4.2, p = 0.00003, respectively) and LC (z = 2.3, p = 0.02 and z = 2.4, p = 0.02, respectively) groups (see Fig. 2, middle panel). Abstinence from both opiates and cocaine, as measured by urine toxicology tests, are shown in Fig. 2 (bottom panel). The HC (26.4%) group had significantly more urines negative for both opioids and cocaine than the HY (12.7%; z = −6.0, p < 0.0001), LC (13.1%; z = −4.2, p < 0.0001), and LY (15.1%; z = −4.1, p < 0.0001) groups. The rate at which urines negative for both opioids and cocaine increased most rapidly over time in the HC group relative to the HY (z = 2.6, z = 0.009) and LC (z = 3.8, p = 0.0001), but not LY (z = 1.0, p = 0.32) groups. The HC ($87.00) and HY ($87.00) groups reported significantly lessheroin use overall relative to LC ($104.00; z = −4.6, p < 0.001 and z = −4.1, p < 0.001, respectively) and LY ($148.00; z = −6.4, p < 0.001 and z = −6.0, p < 0.001, respectively) groups. The rate at which reported heroin use changed over time did not differ across groups (data not shown). The HC group reported significantly less cocaine use ($35.00) relative to the HY ($62.00; z = −4.9, p < 0.001) and LY ($67.00; z = −3.13, p = 0.002), but not LC ($36.00; z = −1.4, p = 0.15) groups. The LC group reported significantly less cocaine use relative to the HY (z = −3.8, p < 0.001) and LY (z = −2.0, p < 0.05) groups. The rate at which reported cocaine use changed overtime did not differ across groups (data not shown). 3.3. Withdrawal and depression symptoms At baseline, withdrawal symptoms did not differ across groups (HC 12.8; HY 15.1; LC 10.5; LY 13.3; z = 0.5, p = 0.68). During the first 6 weeks of the study, opioid withdrawal symptoms decreased most rapidly over time in the HC and HY groups relative to the LC (z = 2.4, p = 0.02 and z = 2.5, p = 0.01) and LY (z = −2.6, p = 0.01 and z = −2.7, p = 0.006, respectively) groups (Fig. 3). At baseline, severity of depressive symptoms did not differ across groups (F = 1.4, p = 0.25, see Table 1). Depressive symptom severity rating significantly decreased over time during the 12-week study (z = −5.1, p < 0.0001), but did not differ across groups (data not shown).
4. Discussion Consistent with our first hypothesis, the efficacy of LAAM in reducing opioid use was dose-related, with greater reductions in opioid-positive urines, self-reported opioid use and opioid withdrawal symptoms at the high than low dose. This is in agreement with the results of previous studies examining the efficacy of different LAAM (e.g., Eissenberg et
Fig. 3. Weekly mean opiate withdrawal scores over the first 6 weeks of the study for the four treatment groups: high-dose LAAM with contingencies (HC, filled circles), high-dose LAAM without contingencies (HY, open circles), low-dose LAAM with contingencies (LC, filled squares), and lowdose LAAM without contingencies (LY, open squares) in 140 opioid- and cocaine-dependent patients maintained on LAAM for 12 weeks.
al., 1997; Oliveto et al., 1998) as well as methadone (e.g., Johnson et al., 2000; Kosten et al., 1993; Ling et al., 1996) and buprenorphine (Johnson et al., 1995; Kosten et al., 1993; Schottenfeld et al., 1997) maintenance dose regimens. Opioid use was relatively unaffected by contingency management condition, except in the high-dose group where the addition of the contingency management procedure appeared to facilitate a more rapid reduction in opioid-positive urines over time. These findings suggest that, for opioid use, effective opioid agonist maintenance doses have greater efficacy in facilitating abstinence than contingency management procedures; however, at effective maintenance doses, contingency management procedures may facilitate a faster reduction in opioid use. Although we hypothesized that contingency management procedures would have a greater effect on cocaine use than LAAM dose, cocaine use, as measured by urine toxicologies, was reduced most only in the contingency management group that received high-dose LAAM. The reason for this finding is unclear. To our knowledge, this is the first study to examine the efficacy of contingency management procedures in a dually cocaine- and opioid-dependent population maintained at different doses of an opioid maintenance agent and so comparisons with other studies based on maintenance dose cannot be made. Nevertheless, the observation that contingency management procedures were not effective in reducing cocaine use at the low dose of LAAM may be related to the fact that the contingency management procedures targeted both opioid and cocaine use. For instance, a similar finding was observed in buprenorphine-maintained cocaine abusers receiving desipramine or placebo with or without contingency management procedures targeting both cocaine and opiates, such that the desipramine plus contingency man-
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
agement group showed the greatest efficacy in reducing cocaine use (Kosten et al., 2003). A 1–3 days delay in receiving feedback regarding urine results may also have decreased the impact of the contingencies relative to the opioid maintenance dose. In addition, the total magnitude of the vouchers, though similar to the Kosten et al. (2003) study, was less than that in other studies (e.g., Silverman et al., 1996). Be that as it may, the findings of the present study suggest that an efficacious opioid agonist maintenance dose is necessary in order for these contingency management procedures to be effective in a dually opioid- and cocaine-dependent population. Consistent with our third hypothesis, abstinence from both cocaine and opioids was greatest in the group receiving both the high LAAM dose and contingency management procedures. This is similar to the findings of Kosten et al., (2003) showing that the buprenorphine-maintained group receiving both desipramine and contingency management procedures had the greatest degree of abstinence from cocaine and opioids. However, the degree of abstinence from illicit opioids (51% negative urines), cocaine (49% negative urines) as well as from both (26% negative urines) was still quite low in the HC group. The reason for this is unclear, but may be due to several factors. For instance, the methodology of the present study had at least a 1-day delay in patients receiving feedback regarding their urine result, which may have reduced the impact of the reinforcement strategy. In addition, the lack of impressive abstinence rates may be due to the fact that the contingencies targeted both opioid and cocaine use, as opposed to just cocaine use. The results of the present study were similar to (Kosten et al., 2003) or better than (Downey et al., 2000) those in buprenorphinemaintained cocaine- and opioid-dependent patients receiving similar contingencies aimed at combined opioid and cocaine use, but much worse than those in cocaine-abusing methadone patients (e.g., Silverman et al., 1996, 1998, 1999), and primary cocaine-dependent patients (e.g., Higgins et al., 1991, 1993, 1994) receiving contingencies aimed only at cocaine use. These findings suggest that contingencies might be more effective when targeting one drug at a time. Indeed, a study employing contingencies aimed at multiple drugs in methadone-maintained poly-drug abusers showed outcomes similar to those in the present study (Piotrowsky et al., 1999). Although Correia et al. (2003) showed no differences in rates of cocaine abstinence in methadone-maintained cocaine abusers when contingencies targeted either cocaine alone or both cocaine and opiates, the brief intervention period (4 days) and large voucher value for abstinence ($200) make comparisons of this study with the present trial difficult. Nevertheless, Petry and Martin (2002) demonstrated that a low-cost alternative in which patients receive opportunities to earn small prizes contingent on urines negative for cocaine, opioids, or both cocaine and opioids might be very effective in achieving and sustaining abstinence from both cocaine and opioids in this population. Only 53% of participants remained in treatment for the entire 12 weeks. Although the level of retention observed
163
in the present study is similar to that observed in studies involving buprenorphine maintenance (e.g., Kosten et al., 2003; Johnson et al., 1992; Ling et al., 1996), LAAM maintenance has been associated with significantly less retention than methadone maintenance (e.g., Farre et al., 2002; Clark et al., 2004). Nevertheless, the rigidity of the dosing regimen in the present study may have accounted for the greater dropout observed, with 28% of participants being administratively discharged for missing either consecutive Monday and Wednesday doses or a Friday dose. This finding may suggest that a more flexible schedule would enhance retention. LAAM has been demonstrated to prolong the QT interval (Ingersoll et al., 2004; Kang et al., 2003), which is believed to contribute to a potentially life-threatening ventricular arrhythmia including torsades de pointes (Ben-David and Zipes, 1993). Due to reports of ventricular arrhythmias associated with LAAM maintenance (Deamer et al., 2001), a “black box” labeling for LAAM warning of QT prolongation and severe arrhythmia has been issued by the United States Food and Drug Administration (Schwetz, 1990). In the present study, the only study-related adverse events were a lack of tolerance to LAAM dosing (i.e., nausea and vomiting). Whether LAAM will reemerge as a primary pharmacotherapy for opioid dependence is unclear. Several reports have indicated that methadone (e.g., Gil et al., 2003; Krantz et al., 2003; Martell et al., 2003; Walker et al., 2003) also produces prolongation of the QT interval, particularly at high doses, suggesting that this may a side effect of opioid agonists in general. Overall these findings suggest that more research is necessary to determine the relative safety profiles of these agents and measures to limit harm while providing as many choices for opioid agonist maintenance treatment as possible. To our knowledge this was the first study to examine the interaction between opioid agonist maintenance and contingency management procedures aimed at facilitating illicit drug abstinence. Results demonstrate that an effective opioid agonist dose not only is more important than contingency management procedures in facilitating opioid abstinence, but also may be necessary for contingencies on cocaine use to be effective. As such, these finding suggest that employing an optimal opioid agonist maintenance dose strategy is a vital first step in treating dual opioid and cocaine dependence. More work is necessary to clarify how contingency management strategies aimed at facilitating different behavioral changes (e.g., cocaine abstinence vs. both opiate and cocaine abstinence) may interact with opioid agonist maintenance dose in treating this dually dependent population.
Acknowledgements This work was supported by the National Institute on Drug Abuse grants R01-DA09876 and K05-DA0454 (TRK). A preliminary report of this work was presented at the Annual Meeting of the College on Problems of Drug Dependence, Scottsdale, AZ, June 2001.
164
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
References Ben-David, J., Zipes, D.P., 1993. Torsades de pointes and proarrhythmia. Lancet 341, 1578–1582. Black, J.L., Dolan, M.P., Penk, W.E., Robinowitz, R., DeFord, H.A., 1987. The effect of increased cocaine use on drug treatment. Addict. Behav. 12, 289–292. Bryk, A.S., Raudenbush, S.W., 1987. Application of hierarchical linear models to assessing change. Psychol. Bull. 101, 147–158. Bux, D.A., Lamb, R.J., Iguchi, M.Y., 1995. Cocaine use and HIV risk behavior in methadone maintenance patients. Drug Alcohol Depend. 37, 29–35. Clark, N., Lintzeris, N., Gijsbers, A., Whelan, G., Dunlop, A., Ritter, A., Ling, W., 2004. LAAM maintenance vs. methadone maintenance for heroin dependence (Cochrane review). In: The Cochrane Library, Issue 1. Wiley, Chichester, UK. Compton, W.M., Lamb, R.J., Fletcher, B.W., 1995. Results of the NIDA treatment demonstration grants’ cocaine workgroup: Characteristics of cocaine users and HIV risk behaviors. Drug Alcohol Depend. 37, 1–6. Correia, C.J., Dallery, J., Katz, E.C., Silverman, K., Bigelow, G., Stitzer, M.L., 2003. Single-versus dual-drug target: effects in a brief abstinence incentive procedure. Exp. Clin. Psychopharmacol. 11, 302–308. Deamer, R.L., Wilson, D.R., Clark, D.S., Pritchard, J.G., 2001. Torsades de pointes associated with high dose levomethadyl acetate (ORLAAM). J. Addict. Dis. 20, 7–14. Downey, K.K., Helmus, T.C., Schuster, C.R., 2000. Treatment of heroindependent poly-drug abusers with contingency management and buprenorphine maintenance. Exp. Clin. Psychopharmacol. 8, 176– 184. Eissenberg, T., Bigelow, G.E., Strain, E.C., Walsh, S.L., Brooner, R.K., Stitzer, M.L., Johnson, R.E., 1997. Dose-related efficacy of levomethadyl acetate for treatment of opioid dependence. A randomized clinical trial. JAMA 277, 1945–1951. Farre, M., Mas, A., Torrens, A., Moreno, V., Cami, J., 2002. Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis. Drug Alcohol Depend. 65, 283–290. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1995. Structured Clinical Interview for DSM-IV, Patient ed. American Psychiatric Press, Washington, DC. Gibbons, R.D., Hedeker, D., Elkin, I., Waternaux, C., Kraemer, H.C., Greenhouse, J.B., Shea, M.T., Imber, S.D., Sotsky, S.M., Watkins, J.T., 1993. Some conceptual and statistical issues in analyses of longitudinal psychiatric data. Arch. Gen. Psychiat. 50, 739–750. Gil, M., Sala, M., Anguerra, I., Chapinal, O., Cervantes, M., Guma, J.R., Segura, F., 2003. QT prolongation and Torsades de Pointes in patients infected with Human Immunodeficiency virus and treated with methadone. Am. J. Cardiol. 92, 995–997. Grella, C.E., Anglin, M.D., Wugalter, S.E., 1995. Cocaine and crack use and HIV risk behaviors among high-risk methadone maintenance clients. Drug Alcohol Depend. 37, 15–21. Griffith, J.D., Rown-Szal, G.A., Roark, R.R., Simpson, D.D., 2000. Contingency management in outpatient methadone treatment: a metaanalysis. Drug Alcohol Depend. 58, 55–66. Hartell, D.M., Schoenbaum, E.E., Selwin, P.A., Kline, J., Davenny, K., Klein, R.S., Friedland, G.H., 1995. Heroin use during methadone maintenance treatment: The importance of methadone dose and cocaine use. Am. J. Public Health 85, 83–88. Higgins, S.T., Budney, A.J., Bickel, W.K., Foerg, F., Donham, R., Badger, G., 1994. Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch. Gen. Psychiat. 51, 568– 576. Higgins, S.T., Budney, A.J., Bickel, W.K., Hughes, J.R., Foerg, F., Badger, G., 1993. Achieving cocaine abstinence with a behavioral approach. Am. J. Psychiat. 150, 763–769. Higgins, S.T., Delaney, D.D., Budney, A.J., Bickel, W.K., Hughes, J.R., Foerg, F., Fenwick, J.W., 1991. A behavioral approach to achieving initial cocaine abstinence. Am. J. Psychiat. 148, 1218–1224.
Hunt, D., Spunt, B., Lipton, D., Goldsmith, D., Strug, D., 1986. The costly bonus: cocaine-related crime among methadone-maintenance treatment clients. Adv. Alcohol Substance Abuse 6, 107–122. Ingersoll, G., Mooney, M., McQueen, K., Grabowski, J., 2004. An examination of adverse events in a sample of LAAM-maintained patients. In: Presented at the 2004 Annual Meeting of the College on Problems of Drug Dependence, San Juan, P.R. Jaffe, J.H., Schuster, C.R., Smith, B.B., Blachley, P.H., 1970. Comparison of acetylmethadol and methadone in the treatment of long-term heroin users – a pilot study. JAMA 211, 1834–1836. Jaffe, J.H., Senay, E.C., Schuster, C.R., Renault, P.F., Smith, B., DiMenza, S., 1972. Methadyl acetate vs. methadone. A double blind study in heroin users. JAMA 222 (4), 437–442. Johnson, R.E., Chutuape, M.A., Strain, E.C., Walsh, S.L., Stitzer, M.L., Bigelow, G.E., 2000. A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence. N Engl. J. Med. 343, 1290–1297. Johnson, R.E., Eissenberg, T., Stitzer, M.L., Strain, E.C., Liebson, I.A., Bigelow, G.E., 1995. A placebo-controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Depend. 40, 17–25. Johnson, R.E., Jaffe, J.H., Fudala, P.J., 1992. A controlled trial of buprenorphine treatment for opioid dependence. JAMA 267, 2750–2755. Jones, H.E., Haug, N., Silverman, K., Stitzer, M., Svikis, D., 2001. The effectiveness of incentives in enhancing treatment attendance and drug abstinence in methadone-maintained pregnant women. Drug Alcohol Depend. 61, 297–306. Kang, J., Chen, X.-L., Wang, H., Rampe, D., 2003. Interactions of the narcotic 1-a-acetalmethadol with human cardiac K+ channels. Eur. J. Pharmacol. 458, 25–29. Kosten, T.R., Oliveto, A., Feingold, A., Poling, J., Sevarino, K., McCanceKatz, E., Stine, S., Gonzalez, G., Gonsai, K., 2003. Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients. Drug Alcohol Depend. 70, 315–325. Kosten, T.R., Rounsaville, B.J., Kleber, H.D., 1987. A 2.5 year follow-up of cocaine use among treated opioid addicts. Arch. Gen. Psychiat. 44, 281–284. Kosten, T.R., Rounsaville, B.J., Kleber, H.D., 1988. Antecedents and consequences of cocaine abuse among opioid addicts – a 2.5 year followup. J. Nerv. Mental Dis. 176, 176–181. Kosten, T.R., Schottenfeld, R., Ziedonis, D., Falcioni, J., 1993. Buprenorphine versus methadone maintenance for opioid dependence. J. Nerv. Mental Dis. 181, 358–364. Krantz, M.J., Kutinsky, I.B., Robertson, A.D., Mehler, P.S., 2003. Doserelated effects of methadone on QT prolongation in a series of patients with torsade de pointes. Psychopharmacology 23, 802–805. Ling, W., Klett, J., Gillis, R.D., 1978. A cooperative clinical study of methadyl acetate I. Three-times-a-week regimen. Arch. Gen. Psychiat. 35, 345–353. Ling, W., Wesson, D.R., Charuvastra, C., Klett, C.J., 1996. A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch. Gen. Psychiat. 53, 401–407. Martell, B.A., Arnsten, J.H., Beevash, R., Gourevitch, M.N., 2003. Te impact of methadone induction on cardiac conduction in opiate users. Ann. Int. Med. 139, 154–155. McLellan, A.T., Alterman, A.I., Cacciola, J., Metzger, D., O’Brien, C.P., 1992. A new measure of substance abuse treatment. Initial studies of the treatment services review. J. Nerv. Mental Dis. 180, 101–110. Meandzija, B., O’Connor, P., Fitzgerald, B., Rounsaville, B.J., Kosten, T.R., 1994. HIV infection and cocaine use in methadone-maintained and untreated drug users. Drug Alcohol Depend. 36, 109–113. Mercer, D., Carpenter, G., Daley, D., Patterson, C., Volpicelli, J., 1992. Group Drug Counseling Manual. University of Pennsylvania/Philadelphia VAMC Center for Studies on Addiction, Philadelphia, PA.
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165 Oliveto, A.H., Farren, C., Kosten, T.R., 1998. Effects of LAAM dose on opiate use in opioid-dependent patients: A pilot study. Am. J. Addict. 7, 272–282. Oliveto, A., Feingold, A., Schottenfeld, R., Jatlow, P., Kosten, T.R., 1999. Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs. methadone. Arch. Gen. Psychiat. 56, 812– 820. Petry, N.M., Martin, B., 2002. Low-cost contingency management for treating cocaine- and opioid-abusing methadone patients. J. Consult. Clin. Psychol. 70, 398–405. Piotrowsky, N.A., Tusel, D.J., Sees, K.L., Reilly, P.M., Banys, P., Meek, P., Hall, S.M., 1999. Contingency contracting with monetary reinforcers for abstinence from multiple drugs in a methadone program. Exp. Clin. Psychopharmacol. 7, 399–411. Radloff, L.S., 1977. A CES-D Scale: A self-report depression scale for research in the general population. Appl. Psychol. Meas. I, 385– 401. Rawson, R.A., Huber, A., McCann, M., Shoptaw, S., Farabee, D., Reiber, C., Ling, W., 2002. A comparison of contingency management and cognitive-behavioral approaches during methadone maintenance treatment for cocaine dependence. Arch. Gen. Psychiat. 59 (9), 817–824. Rowan-Szal, G., Joe, G.W., Chatham, L.R., Simpson, D.D., 1994. A simple reinforcement system for methadone clients in a community-based treatment program. J. Substance Abuse Treat. 11 (3), 217–223. Schottenfeld, R.S., Pakes, J.R., Oliveto, A.H., Ziedonis, D., Kosten, T.R., 1997. Buprenorphine vs. methadone maintenance treatment for con-
165
current opioid dependence and cocaine abuse. Arch. Gen. Psychiat. 54, 713–720. Schwetz, B.A., 1990. Labeling changes for ORLAAM. JAMA 285, 2705. Senay, E.C., Dorus, W., Renault, P.F., 1977. Methadyl acetate and methadone: an open comparison. JAMA 237, 138–142. Silverman, K., Chutuape, M.A., Bigelow, G.E., Stitzer, M.L., 1999. Voucher-based reinforcement of cocaine abstinence in treatmentresistant methadone patients: effects of reinforcement magnitude. Psychopharmacology 146, 128–138. Silverman, K., Higgins, S.T., Brooner, R.K., Montoya, I.D., Cone, E.J., Schuster, C.R., Preston, K.L., 1996. Sustained cocaine abstinence in methadone-maintained patients through voucher-based reinforcement therapy. Arch. Gen. Psychiat. 53, 409–415. Silverman, K., Wong, C.J., Umbricht- Schneiter, A., Montoa, I.D., Schuster, C.R., Preston, K.L., 1998. Broad beneficial effects of cocaine abstinence reinforcement among methadone patients. J. Consult. Clin. Psychol. 66 (5), 811–824. Sorenson, J.L., Hargreaves, W.A., Weinberg, J.A., 1982. Withdrawal from heroin in three or six weeks – comparison of methadyl acetate and methadone. Arch. Gen. Psychiat. 39, 167–171. Walker, P.W., Klein, D., Kasza, L., 2003. High dose methadone and ventricular arrhythmias: a report of three cases. Pain 103, 321–324. White, J.M., Danz, C., Kneebone, J., La Vincente, S.F., Newcombe, D.A.L., Ali, R.L., 2002. Relationship between LAAM-methadone preference and treatment outcomes. Drug Alcohol Depend. 66, 295–301.
Efficacy of dose and contingency management procedures in LAAM-maintained cocaine-dependent patients Alison Oliveto ∗ , James Poling, Kevin A. Sevarino 1 , Kishorchandra R. Gonsai, Elinore F. McCance-Katz 2 , Susan M. Stine 3 , Thomas R. Kosten Department of Psychiatry, Yale School of Medicine and the VA CT Healthcare System, West Haven, CT, USA Received 12 August 2004; received in revised form 3 January 2005; accepted 24 January 2005
Abstract Opioid- and cocaine-dependent participants (N = 140) were randomly assigned to one of the following in a 12-week clinical trial: LAAM (30, 30, 39 mg/MWF) with contingency management (CM) procedures (LC); LAAM (30, 30, 39 mg/MWF) without CM (LY); LAAM (100, 100, 130 mg/MWF) with CM (HC); LAAM (100, 100, 130 mg/MWF) without CM (HY). Urine samples were collected thrice-weekly. In CM, each urine negative for both opioids and cocaine resulted in a voucher worth a certain monetary value that increased for consecutively drug-free urines. Subjects not assigned to CM received vouchers according to a yoked schedule. Vouchers were exchanged for mutually agreed upon goods and services. Groups generally did not differ on retention and baseline characteristics. Overall opioid use was least in the HC and HY groups; opioid use decreased most rapidly over time in the HC group relative to the HY, LC and LY groups. Overall cocaine use was least in the HC group relative to the HY, LC, and LY groups; cocaine use decreased over time most rapidly in the HC and LY groups. Abstinence from both was greatest in the HC group. Opioid withdrawal symptoms decreased most rapidly in the high-dose groups relative to the low-dose groups. These results suggest that an efficacious maintenance dose is necessary for contingencies to be effective in facilitating both opioid and cocaine abstinence. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Opioid agonist maintenance; Cocaine dependence; Opioid dependence; Contingency management procedures; Clinical trial; Humans
1. Introduction Cocaine use in the context of methadone maintenance has been associated with a number of problems, including higher incidence of HIV risk behaviors such as intravenous drug use and unprotected sex (Bux et al., 1995; Meandzija et al., ∗ Corresponding author. Present address: University of Arkansas for Medical Sciences, 4301 West Markham, Slot 554, Little Rock, AR 72205, USA. Tel.: +1 501 686 8969; fax: +1 501 686 8154. E-mail address: [email protected] (A. Oliveto). 1 Current address: Department of Psychiatry MC 1410, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-1410, USA. 2 Current Address: Virginia Commonwealth University, Box 980109, Richmond, VA 23298, USA. 3 Current Address: Addiction Research Institute, Substance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2761 E. Jefferson Ave., Detroit, Michigan 48207, USA.
0376-8716/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2005.01.007
1994), illicit opioid use (Hartell et al., 1995), criminal activity (Grella et al., 1995; Hunt et al., 1986), psychopathology (Compton et al., 1995; Grella et al., 1995) and poorer outcome (Kosten et al., 1988). Comorbid cocaine dependence is a major issue among methadone maintenance programs, where rates of cocaine use have been reported to be as high as 70% (Black et al., 1987). Methadone maintenance also does not appear to decrease the use of cocaine and, indeed, cocaine use may increase in some methadone-maintained patients (Kosten et al., 1987). These issues suggest that more effective maintenance strategies need to be developed in order to improve upon the feasibility and efficacy of treatment for combined opioid and cocaine dependence. One strategy for improving opioid dependence has been the development of a longer-acting opioid agonist maintenance medication, levo-alpha-acetylmethadol (LAAM). Numerous clinical trials since then have demonstrated that thrice-weekly LAAM maintenance is comparable to, if not
158
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
superior than, daily methadone maintenance by various outcome criteria, including reduction of opiate positive urines or morphine concentration in hair (e.g., Johnson et al., 2000; Ling et al., 1978; see Clark et al., 2004; Senay et al., 1977; White et al., 2002) and suppression of withdrawal symptoms (Jaffe et al., 1970, 1972; Sorenson et al., 1982). In addition, although in some trials there was a small increase in the dropout rate for LAAM as opposed to methadone maintenance (e.g., Farre et al., 2002; Johnson et al., 2000; see Clark et al., 2004), this appeared in some instances to be a result of differentially greater dropout during the induction phase (Jaffe et al., 1970, 1972; Senay et al., 1977). However, to our knowledge, several issues have not been addressed with regard to LAAM maintenance. First, few studies have examined the relationship between the maintenance dose of LAAM and treatment outcome (Eissenberg et al., 1997; Oliveto et al., 1998). Second, the impact of LAAM on cocaine use in a cocaine-abusing opioid-dependent population has not been systematically examined. Among individuals admitted to methadone maintenance programs, intravenous cocaine abuse is endemic and undermines both treatment effectiveness and the prevention of the HIV virus. Given that LAAM produces effects similar to methadone and is administered in the same milieu, it is conceivable that rates of cocaine use will be similar in cocaine abusers maintained on LAAM. Alternatively, the facilitation of cocaine use with LAAM may be less than that with methadone, in that LAAM is administered on a thriceweekly rather than daily basis. Clients will, therefore, attend the clinic less often, thereby reducing their exposure to cocaine in the clinic environment. Thus, the impact of LAAM maintenance on cocaine use is important to clarify. Third, behavioral interventions, notably contingency management procedures, have demonstrated some efficacy in facilitating illicit drug abstinence in methadone-maintained individuals (e.g., Griffith et al., 2000; Jones et al., 2001; Rawson et al., 2002; Rowan-Szal et al., 1994; Silverman et al., 1996, 1998), but have not been examined in LAAM-maintained individuals. Thus, this trial examined the efficacy of a high and low maintenance dose of LAAM with and without the application of contingency management procedures aimed at facilitating opioid and cocaine abstinence in opioid-dependent cocaine abusers. Our hypotheses were the following: (1) LAAM dose would have greater influence on the degree of opioid than cocaine use; (2) the contingency management procedures would affect the degree of cocaine use more than LAAM dose; (3) abstinence from both opiates and cocaine would be greatest in the high-dose LAAM group that received the contingency management procedure.
2. Methods 2.1. Subjects One hundred forty male and female cocaine-abusing, opioid-dependent individuals (ages 21–55, including 45 fe-
males, 39 African-Americans, 10 Hispanics, and 91 Caucasians) seeking opioid maintenance treatment were recruited from the greater New Haven area after giving informed consent to participate in this randomized clinical trial approved by the Yale Human Investigations Committee and the VA CT Human Studies Subcommittee. All participants met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for opioid and cocaine dependence, as determined from the Structured Clinical Interview for DSM-IV (SCID), and had urine toxicologies positive for both drugs. Exclusions included medical reasons contraindicating LAAM maintenance (e.g., pregnancy, respiratory condition such as asthma, abnormal liver enzyme levels, or use of medications that might interact with LAAM), a current diagnosis of other drug or alcohol physical dependence (other than tobacco), a history of major psychiatric disorder (psychosis, schizophrenia, bipolar), current suicidality, and an inability to read and understand the consent form. Women of childbearing age were included provided they had a negative urine pregnancy test, agreed to use adequate contraception to prevent pregnancy during the study, and agreed to monthly pregnancy tests. 2.2. Research design and procedures In this 12-week randomized, double blind, outpatient clinical trial, 140 patients were randomized by sex to one of the following treatment groups: low-dose LAAM (30, 30, 39 mg/MWF) with contingency management procedures (LC); low-dose LAAM (30, 30, 39 mg/MWF) without contingency management procedures (LY); high-dose LAAM (100, 100, 130 mg/MWF) with contingency management procedures (HC); high-dose LAAM (100, 100, 130 mg/MWF) without contingency management procedures (HY). During LAAM induction, patients received an initial dose of 20 mg of LAAM on Monday of week 1. This dose was increased by 10 mg at next dosing such that patients received 30 mg on Wednesday of week 1. The patients in the low-dose group then received their maintenance doses of LAAM (30 mg on Mondays and Wednesdays; 39 mg on Fridays), while subjects in the high-dose group continued to be inducted onto LAAM in 10 mg dose increments until they received their maintenance dose of 100 mg by Friday of week 4. All patients were then maintained on their respective maintenance dose of LAAM through week 12. If a subject missed one dose, he/she was administered their usual dose if they came to the clinic on the day of the next scheduled dose as it is well tolerated in most instances (LAAM labeling instructions, Biodevelopment Corporation). If a subject missed Monday–Wednesday consecutive doses or a Friday dose, he/she was discharged from the study. The reason for discharging a participant for missing the Friday dose was that adjusting the dose after five consecutive days without LAAM would have involved dose adjustments and therefore not kept the integrity of the fixeddose design.
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
The contingency management procedures used in this study were adapted from those developed by Higgins et al. (1991, 1993), which have been demonstrated to facilitate initial cocaine abstinence in nonopioid-dependent cocaine abusers. Supervised urines were collected thriceweekly (MWF) prior to being medicated in order to implement the contingency management procedures, which began during week 1 along with weekly group and weekly individual therapy sessions. For the contingency group, urines free from both opioids and cocaine resulted in a voucher worth a monetary value, such that the first urine was worth $3. Each consecutive, drug-free urine sample thereafter increased in monetary value by $1. If a urine sample was missed or contained cocaine or opioids, the value of the next drugfree urine reset back to $3. Patients in the contingency group who remained abstinent during the entire 12-week trial were able to earn goods and services worth a maximum of $738. For the yoked group, each patient was yoked to a person in the contingency group, such that the yoked person earned vouchers based on the contingency person’s performance, not their own. Each person in the yoked group was told that they would receive vouchers on a random basis. Feedback concerning urine results was given to patients in both groups at their weekly individual sessions, at which time vouchers were given as appropriate. Vouchers could be exchanged for mutually agreed upon goods and services at any time during the study. Typically, patients accumulated vouchers for larger goods or services than a day or week’s earnings would allow. The larger reinforcers were often obtained within one day of the request, but some items took up to 7 days to purchase. In addition to reviewing urine results and vouchers, each weekly individual session focused on identifying antecedents and consequences of drug-taking behavior during that week, discussing strategies to initiate or maintain abstinence, and discussing case management issues. Weekly group sessions were manual guided, based on an expanded version of the Group Drug Counseling Manual (Mercer et al., 1992). Patients were discharged from the study if they missed more than three consecutive therapy sessions. Assessments of treatment outcome included retention in treatment, illicit opioid and cocaine use, as measured by urine toxicologies and self-reported use, opiate withdrawal symptoms and depressive symptom severity. 2.3. Laboratory tests Urine samples were analyzed for the presence of opioids and cocaine metabolites upon submission of a urine sample on a thrice-weekly basis. This frequency of urine testing was employed in order to detect most opioid and cocaine use. Breath analysis for alcohol was performed on a random basis or when recent alcohol use had been suspected. If the breath alcohol level was >0.00 and <0.05, one-half the LAAM dose was administered. Breath alcohol levels ≥0.05 resulted in the LAAM being withheld on that day. Urines were also screened for barbiturates and benzodiazepines on a weekly basis. A
159
urine sample was rated positive if the quantity of opioids was greater than 200 ng/ml for opioids and quantity of other drugs or their metabolites was 300 ng/ml. Urine toxicology results were available the next day from the VA Clinical Laboratory. Blood chemistries (SMA 20, CBC) and electrocardiogram (ECG) as well as a general physical examination were performed during screening. 2.4. Psychosocial assessments Self-reported opioid and cocaine use, as well as opiate withdrawal symptoms, were assessed at baseline and weekly using instruments we have developed in previous studies (Kosten et al., 2003; Oliveto et al., 1999). Since medication hours were between 7 and 10 a.m., the time of day for these ratings was relatively standardized. Ratings were completed before LAAM dosing. At intake, the SCID interview was completed for DSMIV psychiatric diagnoses, including depression and substance use disorders (First et al., 1995). Substance-related problems and psychosocial functioning were assessed at intake using the addiction severity index (ASI), a 140-item structured clinical interview using both subjective and objective information to make severity ratings on 10-point scales in seven areas: alcohol and drug use, medical status, legal status, psychiatric symptoms, occupational functioning, and family/social functioning (McLellan et al., 1992). Depressive symptoms were measured at baseline and monthly using the Center for Epidemiological Studies Depression Inventory (CES-D) and at baseline only using the Hamilton Depression Scale. The CES-D inventory is a 20item self-report with item scores ranging from 0 to 3 and total scores ranging from 0 to 60. Means for the general population range from 8 to 9 and for depressed patients are 24 (Radloff, 1977). The Hamilton observer-rated scale covers 21 symptoms with a total score ranging from 0 to 62 and a cutoff of 15 for moderate depression. 2.5. Training of raters The raters had previous experience in clinical rating and interviewing and at least a Bachelors level education or its equivalent in experience. Under supervision, each rater received 1 month of training on the ASI, SCID and DSM-IV. Training included observation of interviews and ratings, corating, and interviewing with the supervisor present. In order to conduct interviews for this study, it was required that the rater complete three consecutive conjoint interviews on which DSM IV diagnoses are in complete agreement with those of more experienced raters. After training, reliability was periodically spot-checked. 2.6. Data analyses The intent to treat sample of 140 participants was used for the statistical analyses. The four treatment groups were com-
160
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
pared for baseline differences using Chi-square for categorical characteristics and analysis of variance (ANOVA) for continuous variables such as age, CES-D score and withdrawal symptoms. The amount of voucher reinforcement and overall urine results across groups were compared using Mann Whitney U tests, because the distributions were skewed. The primary outcome in the intent to treat sample was urine toxicology screening result. We compared the mean proportion of the three weekly urine samples that were opiatepositive, cocaine-positive, and negative from both each week ranging between 0 and 1 in a manner similar to that described previously (Kosten et al., 2003; Oliveto et al., 1999). In order to make analyses amenable to ordinal analysis, urinalysis data were first calculated as weekly mean proportion of urines positive for the target drug. Then zero reflected “no use,” proportions between 0 and 1 were recoded 1 for “some use,” and a proportion of 1 was recoded 2, reflecting “all use,” These data were entered into a 2 × 2 × 12 hierarchical linear modeling analyses with LA AM dose, contingency condition, and time as factors for these comparisons and present the odds ratio of drug-free urines to total urines as a measure of difference at week 12 (Bryk and Raudenbush, 1987; Gibbons et al., 1993). We used the MIXOR program of Hedeker (University of Chicago) for HLM analyses and SPSS for other statistics. These analyses yielded z tests that assessed the overall magnitude as well as that of the linear increase or decrease in data values over the course of the study as a function of LAAM dose and contingency management condition. In reporting significance levels, the HLM models included all interaction terms as well as the main factors. When the interaction among LAAM dose, contingency condition, and time was
significant, we also conducted statistical contrasts between each of the four groups and the other three groups. Because the ordinal data had a limited number of outcomes that was not normally distributed, we determined whether there were overall differences (i.e., not over time) among groups using the Kruskal–Wallace nonparametric test. Weekly self-reported opioid use, cocaine use, and CESD scores were analyzed using HLM similarly to the urine toxicology results. Opioid withdrawal ratings during the first half of the study were also analyzed using HLM. For all analyses, statistical significance was inferred by a p value less than 0.05.
3. Results 3.1. Baseline characteristics, treatment retention and reinforcement values The 140 subjects who were initially randomized and started on LAAM maintenance are compared in Table 1 on baseline and demographic comparisons among the four treatment conditions. These subjects showed no significant differences on demographics, drug and alcohol use, or depressive symptoms, except for net income in the month prior to study entry. The LY group had significantly greater income than the HC (z = −2.4, p = 0.02) and HY (z = 2.6, p = 0.009), but not LC (z = −1.0, p = 0.30) groups (Kruskal–Wallis χ = 11.1, p = 0.01). The LC group had significantly greater income than the HC (z = −2.0, p = 0.04) and HY (z = −2.1, p = 0.04) groups.
Table 1 Means (S.D.) on baseline measures for the four treatment groups Measure
Treatment groupsa HC
HY
LC
LY
N Age (years) Sex (no. of male/female) Race (no. of C/AA/H)b Education (nhs/hs/col+)c Net income ($/month)d Lifetime heroin use (years) Lifetime cocaine use (years) Heroin use (no. of days/month)e Cocaine use (no. of days/month)e Alcohol use (no. of days/month)e Rte for primary drug (no. of IV/IN/S)f CES-D Prior methadone treatment (%) Prior LAAM treatment (%) Current major depression (%)
35 36.8 (4.8) 23/12 25/8/2 7/27/1 373 (710) 8.6 (7.0) 9.6 (7.9) 29.2 (2.1) 12.5 (10.1) 2.3 (4.3) 18/16/1 16.9 (13.1) 45.7 8.6 8.6
35 37.7 (7.6) 20/15 25/8/2 11/22/2 319 (517) 11.5 (7.9) 11.4 (8.2) 28.6 (4.1) 15.9 (10.0) 1.5 (2.9) 20/14/1 21.8 (13.7) 68.6 5.7 20.0
35 36.6 (6.0) 27/8 19/13/3 9/26/0 579 (653) 10.1 (6.6) 9.6 (7.2) 27.6 (7.1) 13.4 (9.6) 3.3 (6.0) 19/4/2 20.1 (14.5) 57.1 8.6 22.9
35 34.9 (6.2) 25/10 22/10/3 6/29/0 947 (1065) 9.1 (7.2) 9.2 (7.8) 28.5 (5.0) 15.3 (9.1) 3.7 (7.8) 19/16/0 20.1 (12.9) 65.7 2.9 28.6
a
Treatment groups: HC, high-dose LAAM plus contingency; HY, high-dose LAAM plus yoked control; LC, low dose LAAM plus contingency; LY, low dose LAAM plus yoked control. b Race: C, Caucasian; AA, African–American; H, Hispanic. c Education: nhs, non-high school graduate; hs, high school graduate; col+, college graduate or more. d Net income ($/month) – dollars earned in the month prior to study entry. e No. of days/month – number of days used substance in the month prior to study entry. f Route for primary drug: IV, intravenous; IN, intranasal or inhaled; S, smoked. Bold values – significant difference among groups (p < 0.05).
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
161
Fig. 1. Weekly number of patients retained in each of the four treatment groups across the 12-week trial: high-dose LAAM with contingencies (HC, filled circles), high-dose LAAM without contingencies (HY, open circles), low-dose LAAM with contingencies (LC, filled squares), and low-dose LAAM without contingencies (LY, open squares).
The average length of retention was 9.1 ± 3.9 (mean ± S.D.) weeks with 74 completing the trial (53%), which did not differ among the four treatment groups, as shown in Fig. 1 (log rank = 2.7, p < 0.44). Reasons for premature termination from the study included leaving at the patient’s request (N = 6), non-compliance with the study protocol (N = 15), medical issues unrelated to study participation (N = 3), being jailed (N = l), lacking tolerance to the LAAM induction (N = 2), and missing medication on a consecutive Monday–Wednesday or on a Friday (N = 39). Although groups did not differ by LAAM dose on dropping out due to missed medication (log rank = 7.32, p = 0.06), two-thirds of those who missed medication were receiving low-dose LAAM. The mean weekly proportion of counseling sessions attended was 55% for weekly groups and 75% for weekly individual sessions, with no difference across the four treatment groups. The HC group earned a higher mean voucher amount ($138.34) than the LC ($49.86; z = −2.5, p = 0.01) and the LY ($62.11; z = −2.7, p = 0.007) groups. The HC group voucher amount did not differ from that of the HY group ($87.26; z = −1.5, p = 0.14), which also did not differ from the LC (z = −1.2, p = 0.25) and LY (z = −1.4, p = 0.16) groups. 3.2. Illicit opioid and cocaine use during the trial Opioid and cocaine use, as measured by urine toxicology tests, are shown in Fig. 2. There were no baseline differences across groups in opioid and/or cocaine negative urines. In terms of opioid use, the HC (52.0%) and HY (51.0%) groups overall had significantly greater urines negative for opioids relative to the LC (29.8%; z = −6.1, p < 0.001 and z = −6.1, p < 0.001, respectively) and LY (40.6%; z = −6.8, p < 0.001 and z = −6.9, p < 0.001, respectively) groups. Opi-
Fig. 2. Weekly proportion of urines free of opioids (top panel), cocaine (middle panel) and both opioids and cocaine (bottom panel) for the four treatment groups: high-dose LAAM with contingencies (HC, filled circles), high-dose LAAM without contingencies (HY, open circles), low-dose LAAM with contingencies (LC, filled squares), and low-dose LAAM without contingencies (LY, open squares) in 140 opioid- and cocaine-dependent patients maintained on LAAM for 12 weeks.
oid negative urines increased most rapidly over time in the HC group relative to the HY (z = 4.6, p = −0.00001), LC (z = 8.3, p < 0.00001) and LY (z = 5.5, p < 0.00001) groups (Fig. 2, top panel). Overall, the HC group had significantly greater urines negative for cocaine (51.0%) relative to the HY (33.7%;
162
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
z = −5.0, p < 0.001), LC (39.6%; z = −3.3, p = 0.001), and LY (37.5%; z = −3.7, p < 0.001) groups. Cocaine negative urines increased most rapidly over time in the HC and LY groups relative to the HY (z = 4.1, p = 0.00004 and z = 4.2, p = 0.00003, respectively) and LC (z = 2.3, p = 0.02 and z = 2.4, p = 0.02, respectively) groups (see Fig. 2, middle panel). Abstinence from both opiates and cocaine, as measured by urine toxicology tests, are shown in Fig. 2 (bottom panel). The HC (26.4%) group had significantly more urines negative for both opioids and cocaine than the HY (12.7%; z = −6.0, p < 0.0001), LC (13.1%; z = −4.2, p < 0.0001), and LY (15.1%; z = −4.1, p < 0.0001) groups. The rate at which urines negative for both opioids and cocaine increased most rapidly over time in the HC group relative to the HY (z = 2.6, z = 0.009) and LC (z = 3.8, p = 0.0001), but not LY (z = 1.0, p = 0.32) groups. The HC ($87.00) and HY ($87.00) groups reported significantly lessheroin use overall relative to LC ($104.00; z = −4.6, p < 0.001 and z = −4.1, p < 0.001, respectively) and LY ($148.00; z = −6.4, p < 0.001 and z = −6.0, p < 0.001, respectively) groups. The rate at which reported heroin use changed over time did not differ across groups (data not shown). The HC group reported significantly less cocaine use ($35.00) relative to the HY ($62.00; z = −4.9, p < 0.001) and LY ($67.00; z = −3.13, p = 0.002), but not LC ($36.00; z = −1.4, p = 0.15) groups. The LC group reported significantly less cocaine use relative to the HY (z = −3.8, p < 0.001) and LY (z = −2.0, p < 0.05) groups. The rate at which reported cocaine use changed overtime did not differ across groups (data not shown). 3.3. Withdrawal and depression symptoms At baseline, withdrawal symptoms did not differ across groups (HC 12.8; HY 15.1; LC 10.5; LY 13.3; z = 0.5, p = 0.68). During the first 6 weeks of the study, opioid withdrawal symptoms decreased most rapidly over time in the HC and HY groups relative to the LC (z = 2.4, p = 0.02 and z = 2.5, p = 0.01) and LY (z = −2.6, p = 0.01 and z = −2.7, p = 0.006, respectively) groups (Fig. 3). At baseline, severity of depressive symptoms did not differ across groups (F = 1.4, p = 0.25, see Table 1). Depressive symptom severity rating significantly decreased over time during the 12-week study (z = −5.1, p < 0.0001), but did not differ across groups (data not shown).
4. Discussion Consistent with our first hypothesis, the efficacy of LAAM in reducing opioid use was dose-related, with greater reductions in opioid-positive urines, self-reported opioid use and opioid withdrawal symptoms at the high than low dose. This is in agreement with the results of previous studies examining the efficacy of different LAAM (e.g., Eissenberg et
Fig. 3. Weekly mean opiate withdrawal scores over the first 6 weeks of the study for the four treatment groups: high-dose LAAM with contingencies (HC, filled circles), high-dose LAAM without contingencies (HY, open circles), low-dose LAAM with contingencies (LC, filled squares), and lowdose LAAM without contingencies (LY, open squares) in 140 opioid- and cocaine-dependent patients maintained on LAAM for 12 weeks.
al., 1997; Oliveto et al., 1998) as well as methadone (e.g., Johnson et al., 2000; Kosten et al., 1993; Ling et al., 1996) and buprenorphine (Johnson et al., 1995; Kosten et al., 1993; Schottenfeld et al., 1997) maintenance dose regimens. Opioid use was relatively unaffected by contingency management condition, except in the high-dose group where the addition of the contingency management procedure appeared to facilitate a more rapid reduction in opioid-positive urines over time. These findings suggest that, for opioid use, effective opioid agonist maintenance doses have greater efficacy in facilitating abstinence than contingency management procedures; however, at effective maintenance doses, contingency management procedures may facilitate a faster reduction in opioid use. Although we hypothesized that contingency management procedures would have a greater effect on cocaine use than LAAM dose, cocaine use, as measured by urine toxicologies, was reduced most only in the contingency management group that received high-dose LAAM. The reason for this finding is unclear. To our knowledge, this is the first study to examine the efficacy of contingency management procedures in a dually cocaine- and opioid-dependent population maintained at different doses of an opioid maintenance agent and so comparisons with other studies based on maintenance dose cannot be made. Nevertheless, the observation that contingency management procedures were not effective in reducing cocaine use at the low dose of LAAM may be related to the fact that the contingency management procedures targeted both opioid and cocaine use. For instance, a similar finding was observed in buprenorphine-maintained cocaine abusers receiving desipramine or placebo with or without contingency management procedures targeting both cocaine and opiates, such that the desipramine plus contingency man-
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
agement group showed the greatest efficacy in reducing cocaine use (Kosten et al., 2003). A 1–3 days delay in receiving feedback regarding urine results may also have decreased the impact of the contingencies relative to the opioid maintenance dose. In addition, the total magnitude of the vouchers, though similar to the Kosten et al. (2003) study, was less than that in other studies (e.g., Silverman et al., 1996). Be that as it may, the findings of the present study suggest that an efficacious opioid agonist maintenance dose is necessary in order for these contingency management procedures to be effective in a dually opioid- and cocaine-dependent population. Consistent with our third hypothesis, abstinence from both cocaine and opioids was greatest in the group receiving both the high LAAM dose and contingency management procedures. This is similar to the findings of Kosten et al., (2003) showing that the buprenorphine-maintained group receiving both desipramine and contingency management procedures had the greatest degree of abstinence from cocaine and opioids. However, the degree of abstinence from illicit opioids (51% negative urines), cocaine (49% negative urines) as well as from both (26% negative urines) was still quite low in the HC group. The reason for this is unclear, but may be due to several factors. For instance, the methodology of the present study had at least a 1-day delay in patients receiving feedback regarding their urine result, which may have reduced the impact of the reinforcement strategy. In addition, the lack of impressive abstinence rates may be due to the fact that the contingencies targeted both opioid and cocaine use, as opposed to just cocaine use. The results of the present study were similar to (Kosten et al., 2003) or better than (Downey et al., 2000) those in buprenorphinemaintained cocaine- and opioid-dependent patients receiving similar contingencies aimed at combined opioid and cocaine use, but much worse than those in cocaine-abusing methadone patients (e.g., Silverman et al., 1996, 1998, 1999), and primary cocaine-dependent patients (e.g., Higgins et al., 1991, 1993, 1994) receiving contingencies aimed only at cocaine use. These findings suggest that contingencies might be more effective when targeting one drug at a time. Indeed, a study employing contingencies aimed at multiple drugs in methadone-maintained poly-drug abusers showed outcomes similar to those in the present study (Piotrowsky et al., 1999). Although Correia et al. (2003) showed no differences in rates of cocaine abstinence in methadone-maintained cocaine abusers when contingencies targeted either cocaine alone or both cocaine and opiates, the brief intervention period (4 days) and large voucher value for abstinence ($200) make comparisons of this study with the present trial difficult. Nevertheless, Petry and Martin (2002) demonstrated that a low-cost alternative in which patients receive opportunities to earn small prizes contingent on urines negative for cocaine, opioids, or both cocaine and opioids might be very effective in achieving and sustaining abstinence from both cocaine and opioids in this population. Only 53% of participants remained in treatment for the entire 12 weeks. Although the level of retention observed
163
in the present study is similar to that observed in studies involving buprenorphine maintenance (e.g., Kosten et al., 2003; Johnson et al., 1992; Ling et al., 1996), LAAM maintenance has been associated with significantly less retention than methadone maintenance (e.g., Farre et al., 2002; Clark et al., 2004). Nevertheless, the rigidity of the dosing regimen in the present study may have accounted for the greater dropout observed, with 28% of participants being administratively discharged for missing either consecutive Monday and Wednesday doses or a Friday dose. This finding may suggest that a more flexible schedule would enhance retention. LAAM has been demonstrated to prolong the QT interval (Ingersoll et al., 2004; Kang et al., 2003), which is believed to contribute to a potentially life-threatening ventricular arrhythmia including torsades de pointes (Ben-David and Zipes, 1993). Due to reports of ventricular arrhythmias associated with LAAM maintenance (Deamer et al., 2001), a “black box” labeling for LAAM warning of QT prolongation and severe arrhythmia has been issued by the United States Food and Drug Administration (Schwetz, 1990). In the present study, the only study-related adverse events were a lack of tolerance to LAAM dosing (i.e., nausea and vomiting). Whether LAAM will reemerge as a primary pharmacotherapy for opioid dependence is unclear. Several reports have indicated that methadone (e.g., Gil et al., 2003; Krantz et al., 2003; Martell et al., 2003; Walker et al., 2003) also produces prolongation of the QT interval, particularly at high doses, suggesting that this may a side effect of opioid agonists in general. Overall these findings suggest that more research is necessary to determine the relative safety profiles of these agents and measures to limit harm while providing as many choices for opioid agonist maintenance treatment as possible. To our knowledge this was the first study to examine the interaction between opioid agonist maintenance and contingency management procedures aimed at facilitating illicit drug abstinence. Results demonstrate that an effective opioid agonist dose not only is more important than contingency management procedures in facilitating opioid abstinence, but also may be necessary for contingencies on cocaine use to be effective. As such, these finding suggest that employing an optimal opioid agonist maintenance dose strategy is a vital first step in treating dual opioid and cocaine dependence. More work is necessary to clarify how contingency management strategies aimed at facilitating different behavioral changes (e.g., cocaine abstinence vs. both opiate and cocaine abstinence) may interact with opioid agonist maintenance dose in treating this dually dependent population.
Acknowledgements This work was supported by the National Institute on Drug Abuse grants R01-DA09876 and K05-DA0454 (TRK). A preliminary report of this work was presented at the Annual Meeting of the College on Problems of Drug Dependence, Scottsdale, AZ, June 2001.
164
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165
References Ben-David, J., Zipes, D.P., 1993. Torsades de pointes and proarrhythmia. Lancet 341, 1578–1582. Black, J.L., Dolan, M.P., Penk, W.E., Robinowitz, R., DeFord, H.A., 1987. The effect of increased cocaine use on drug treatment. Addict. Behav. 12, 289–292. Bryk, A.S., Raudenbush, S.W., 1987. Application of hierarchical linear models to assessing change. Psychol. Bull. 101, 147–158. Bux, D.A., Lamb, R.J., Iguchi, M.Y., 1995. Cocaine use and HIV risk behavior in methadone maintenance patients. Drug Alcohol Depend. 37, 29–35. Clark, N., Lintzeris, N., Gijsbers, A., Whelan, G., Dunlop, A., Ritter, A., Ling, W., 2004. LAAM maintenance vs. methadone maintenance for heroin dependence (Cochrane review). In: The Cochrane Library, Issue 1. Wiley, Chichester, UK. Compton, W.M., Lamb, R.J., Fletcher, B.W., 1995. Results of the NIDA treatment demonstration grants’ cocaine workgroup: Characteristics of cocaine users and HIV risk behaviors. Drug Alcohol Depend. 37, 1–6. Correia, C.J., Dallery, J., Katz, E.C., Silverman, K., Bigelow, G., Stitzer, M.L., 2003. Single-versus dual-drug target: effects in a brief abstinence incentive procedure. Exp. Clin. Psychopharmacol. 11, 302–308. Deamer, R.L., Wilson, D.R., Clark, D.S., Pritchard, J.G., 2001. Torsades de pointes associated with high dose levomethadyl acetate (ORLAAM). J. Addict. Dis. 20, 7–14. Downey, K.K., Helmus, T.C., Schuster, C.R., 2000. Treatment of heroindependent poly-drug abusers with contingency management and buprenorphine maintenance. Exp. Clin. Psychopharmacol. 8, 176– 184. Eissenberg, T., Bigelow, G.E., Strain, E.C., Walsh, S.L., Brooner, R.K., Stitzer, M.L., Johnson, R.E., 1997. Dose-related efficacy of levomethadyl acetate for treatment of opioid dependence. A randomized clinical trial. JAMA 277, 1945–1951. Farre, M., Mas, A., Torrens, A., Moreno, V., Cami, J., 2002. Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis. Drug Alcohol Depend. 65, 283–290. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1995. Structured Clinical Interview for DSM-IV, Patient ed. American Psychiatric Press, Washington, DC. Gibbons, R.D., Hedeker, D., Elkin, I., Waternaux, C., Kraemer, H.C., Greenhouse, J.B., Shea, M.T., Imber, S.D., Sotsky, S.M., Watkins, J.T., 1993. Some conceptual and statistical issues in analyses of longitudinal psychiatric data. Arch. Gen. Psychiat. 50, 739–750. Gil, M., Sala, M., Anguerra, I., Chapinal, O., Cervantes, M., Guma, J.R., Segura, F., 2003. QT prolongation and Torsades de Pointes in patients infected with Human Immunodeficiency virus and treated with methadone. Am. J. Cardiol. 92, 995–997. Grella, C.E., Anglin, M.D., Wugalter, S.E., 1995. Cocaine and crack use and HIV risk behaviors among high-risk methadone maintenance clients. Drug Alcohol Depend. 37, 15–21. Griffith, J.D., Rown-Szal, G.A., Roark, R.R., Simpson, D.D., 2000. Contingency management in outpatient methadone treatment: a metaanalysis. Drug Alcohol Depend. 58, 55–66. Hartell, D.M., Schoenbaum, E.E., Selwin, P.A., Kline, J., Davenny, K., Klein, R.S., Friedland, G.H., 1995. Heroin use during methadone maintenance treatment: The importance of methadone dose and cocaine use. Am. J. Public Health 85, 83–88. Higgins, S.T., Budney, A.J., Bickel, W.K., Foerg, F., Donham, R., Badger, G., 1994. Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch. Gen. Psychiat. 51, 568– 576. Higgins, S.T., Budney, A.J., Bickel, W.K., Hughes, J.R., Foerg, F., Badger, G., 1993. Achieving cocaine abstinence with a behavioral approach. Am. J. Psychiat. 150, 763–769. Higgins, S.T., Delaney, D.D., Budney, A.J., Bickel, W.K., Hughes, J.R., Foerg, F., Fenwick, J.W., 1991. A behavioral approach to achieving initial cocaine abstinence. Am. J. Psychiat. 148, 1218–1224.
Hunt, D., Spunt, B., Lipton, D., Goldsmith, D., Strug, D., 1986. The costly bonus: cocaine-related crime among methadone-maintenance treatment clients. Adv. Alcohol Substance Abuse 6, 107–122. Ingersoll, G., Mooney, M., McQueen, K., Grabowski, J., 2004. An examination of adverse events in a sample of LAAM-maintained patients. In: Presented at the 2004 Annual Meeting of the College on Problems of Drug Dependence, San Juan, P.R. Jaffe, J.H., Schuster, C.R., Smith, B.B., Blachley, P.H., 1970. Comparison of acetylmethadol and methadone in the treatment of long-term heroin users – a pilot study. JAMA 211, 1834–1836. Jaffe, J.H., Senay, E.C., Schuster, C.R., Renault, P.F., Smith, B., DiMenza, S., 1972. Methadyl acetate vs. methadone. A double blind study in heroin users. JAMA 222 (4), 437–442. Johnson, R.E., Chutuape, M.A., Strain, E.C., Walsh, S.L., Stitzer, M.L., Bigelow, G.E., 2000. A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence. N Engl. J. Med. 343, 1290–1297. Johnson, R.E., Eissenberg, T., Stitzer, M.L., Strain, E.C., Liebson, I.A., Bigelow, G.E., 1995. A placebo-controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Depend. 40, 17–25. Johnson, R.E., Jaffe, J.H., Fudala, P.J., 1992. A controlled trial of buprenorphine treatment for opioid dependence. JAMA 267, 2750–2755. Jones, H.E., Haug, N., Silverman, K., Stitzer, M., Svikis, D., 2001. The effectiveness of incentives in enhancing treatment attendance and drug abstinence in methadone-maintained pregnant women. Drug Alcohol Depend. 61, 297–306. Kang, J., Chen, X.-L., Wang, H., Rampe, D., 2003. Interactions of the narcotic 1-a-acetalmethadol with human cardiac K+ channels. Eur. J. Pharmacol. 458, 25–29. Kosten, T.R., Oliveto, A., Feingold, A., Poling, J., Sevarino, K., McCanceKatz, E., Stine, S., Gonzalez, G., Gonsai, K., 2003. Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients. Drug Alcohol Depend. 70, 315–325. Kosten, T.R., Rounsaville, B.J., Kleber, H.D., 1987. A 2.5 year follow-up of cocaine use among treated opioid addicts. Arch. Gen. Psychiat. 44, 281–284. Kosten, T.R., Rounsaville, B.J., Kleber, H.D., 1988. Antecedents and consequences of cocaine abuse among opioid addicts – a 2.5 year followup. J. Nerv. Mental Dis. 176, 176–181. Kosten, T.R., Schottenfeld, R., Ziedonis, D., Falcioni, J., 1993. Buprenorphine versus methadone maintenance for opioid dependence. J. Nerv. Mental Dis. 181, 358–364. Krantz, M.J., Kutinsky, I.B., Robertson, A.D., Mehler, P.S., 2003. Doserelated effects of methadone on QT prolongation in a series of patients with torsade de pointes. Psychopharmacology 23, 802–805. Ling, W., Klett, J., Gillis, R.D., 1978. A cooperative clinical study of methadyl acetate I. Three-times-a-week regimen. Arch. Gen. Psychiat. 35, 345–353. Ling, W., Wesson, D.R., Charuvastra, C., Klett, C.J., 1996. A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch. Gen. Psychiat. 53, 401–407. Martell, B.A., Arnsten, J.H., Beevash, R., Gourevitch, M.N., 2003. Te impact of methadone induction on cardiac conduction in opiate users. Ann. Int. Med. 139, 154–155. McLellan, A.T., Alterman, A.I., Cacciola, J., Metzger, D., O’Brien, C.P., 1992. A new measure of substance abuse treatment. Initial studies of the treatment services review. J. Nerv. Mental Dis. 180, 101–110. Meandzija, B., O’Connor, P., Fitzgerald, B., Rounsaville, B.J., Kosten, T.R., 1994. HIV infection and cocaine use in methadone-maintained and untreated drug users. Drug Alcohol Depend. 36, 109–113. Mercer, D., Carpenter, G., Daley, D., Patterson, C., Volpicelli, J., 1992. Group Drug Counseling Manual. University of Pennsylvania/Philadelphia VAMC Center for Studies on Addiction, Philadelphia, PA.
A. Oliveto et al. / Drug and Alcohol Dependence 79 (2005) 157–165 Oliveto, A.H., Farren, C., Kosten, T.R., 1998. Effects of LAAM dose on opiate use in opioid-dependent patients: A pilot study. Am. J. Addict. 7, 272–282. Oliveto, A., Feingold, A., Schottenfeld, R., Jatlow, P., Kosten, T.R., 1999. Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs. methadone. Arch. Gen. Psychiat. 56, 812– 820. Petry, N.M., Martin, B., 2002. Low-cost contingency management for treating cocaine- and opioid-abusing methadone patients. J. Consult. Clin. Psychol. 70, 398–405. Piotrowsky, N.A., Tusel, D.J., Sees, K.L., Reilly, P.M., Banys, P., Meek, P., Hall, S.M., 1999. Contingency contracting with monetary reinforcers for abstinence from multiple drugs in a methadone program. Exp. Clin. Psychopharmacol. 7, 399–411. Radloff, L.S., 1977. A CES-D Scale: A self-report depression scale for research in the general population. Appl. Psychol. Meas. I, 385– 401. Rawson, R.A., Huber, A., McCann, M., Shoptaw, S., Farabee, D., Reiber, C., Ling, W., 2002. A comparison of contingency management and cognitive-behavioral approaches during methadone maintenance treatment for cocaine dependence. Arch. Gen. Psychiat. 59 (9), 817–824. Rowan-Szal, G., Joe, G.W., Chatham, L.R., Simpson, D.D., 1994. A simple reinforcement system for methadone clients in a community-based treatment program. J. Substance Abuse Treat. 11 (3), 217–223. Schottenfeld, R.S., Pakes, J.R., Oliveto, A.H., Ziedonis, D., Kosten, T.R., 1997. Buprenorphine vs. methadone maintenance treatment for con-
165
current opioid dependence and cocaine abuse. Arch. Gen. Psychiat. 54, 713–720. Schwetz, B.A., 1990. Labeling changes for ORLAAM. JAMA 285, 2705. Senay, E.C., Dorus, W., Renault, P.F., 1977. Methadyl acetate and methadone: an open comparison. JAMA 237, 138–142. Silverman, K., Chutuape, M.A., Bigelow, G.E., Stitzer, M.L., 1999. Voucher-based reinforcement of cocaine abstinence in treatmentresistant methadone patients: effects of reinforcement magnitude. Psychopharmacology 146, 128–138. Silverman, K., Higgins, S.T., Brooner, R.K., Montoya, I.D., Cone, E.J., Schuster, C.R., Preston, K.L., 1996. Sustained cocaine abstinence in methadone-maintained patients through voucher-based reinforcement therapy. Arch. Gen. Psychiat. 53, 409–415. Silverman, K., Wong, C.J., Umbricht- Schneiter, A., Montoa, I.D., Schuster, C.R., Preston, K.L., 1998. Broad beneficial effects of cocaine abstinence reinforcement among methadone patients. J. Consult. Clin. Psychol. 66 (5), 811–824. Sorenson, J.L., Hargreaves, W.A., Weinberg, J.A., 1982. Withdrawal from heroin in three or six weeks – comparison of methadyl acetate and methadone. Arch. Gen. Psychiat. 39, 167–171. Walker, P.W., Klein, D., Kasza, L., 2003. High dose methadone and ventricular arrhythmias: a report of three cases. Pain 103, 321–324. White, J.M., Danz, C., Kneebone, J., La Vincente, S.F., Newcombe, D.A.L., Ali, R.L., 2002. Relationship between LAAM-methadone preference and treatment outcomes. Drug Alcohol Depend. 66, 295–301.