انقراض واکنش پذیری به مواد مخدر در افراد وابسته به متامفتامین

Abstract Conditioned responses to drug-related environmental cues (such as craving) play a critical role in relapse to drug use. Animal models demonstrate that repeated exposure to drug-associated cues in the absence of drug administration leads to the extinction of conditioned responses, but the few existing clinical trials focused on extinction of conditioned responses to drug-related cues in drug-dependent individuals show equivocal results. The current study examined drug-related cue reactivity and response extinction in a laboratory setting in methamphetamine-dependent individuals. Methamphetamine cue-elicited craving was extinguished during two sessions of repeated (3) within-session exposures to multi-modal (picture, video, and in-vivo) cues, with no evidence of spontaneous recovery between sessions. A trend was noted for a greater attenuation of response in participants with longer (4–7 day) inter-session intervals. These results indicate that extinction of drug cue conditioned responding occurs in methamphetamine-dependent individuals, offering promise for the development of extinction- based treatment strategies.

Introduction Consistent with a Pavlovian conditioning theory, cues associated with drug using (e.g. paraphernalia, locations where drug is used) acquire the capacity to elicit conditioned responses, such as craving, as a consequence of repeated pairings between the cues and the central nervous system effects of the drug (i.e., activation of reward pathways in the brain; Pavlov, 1927). This conditioned association has been systematically examined in human laboratory settings using paradigms in which participants are exposed to cues related to the use of nicotine (LaRowe et al., 2007, McClernon et al., 2007 and Tiffany et al., 2000), alcohol (Glautier and Drummond, 1994, Monti et al., 1993 and Szegedi et al., 2000), heroin (Moring and Strang, 1989, Sell et al., 2000 and Yu et al., 2007), and cocaine (Avants et al., 1995, Robbins et al., 1999 and Saladin et al., 2006), and subjective, behavioral, and physiological responses are recorded. Several studies have shown that craving is related to relapse to drug-taking behavior (Back et al., 2006, Brady et al., 2006, Cooney et al., 1997, Drummond and Glautier, 1994, Killen and Fortmann, 1997 and Rohsenow et al., 1994), and conditioned responses to drug cues play a critical role in relapse during abstinence, when craving is likely to be elevated (Childress et al., 1988, O’Brien et al., 1998 and Sinha et al., 2000). While craving and reactivity to cocaine-associated cues is reliable and robust (Coffey et al., 2002, Robbins et al., 1999, Saladin et al., 2006 and Sinha et al., 2000), relatively little attention has been given to methamphetamine (METH), a related psychostimulant with high abuse and dependence liability. Emerging evidence suggests that craving to METH cues can be reliably measured in METH-dependent individuals (Bruehl et al., 2006, Newton et al., 2006 and Tolliver et al., 2010) and cue-elicited craving is a strong predictor of subsequent METH use (Hartz, Frederick-Osborne, & Galloway, 2001). Accordingly, cue-elicited METH craving should be viewed as a clinically important phenomenon. Animal models demonstrate that repeated exposure to drug-associated cues in the absence of drug administration leads to the extinction of conditioned responses (Barr et al., 1983, Neisewander et al., 1996 and See, 2002). Early work applying these principles to drug-dependent clinical populations showed promise in reducing reactivity to drug-associated cues and improving drug-use related outcomes (e.g. Childress et al., 1986 and O’Brien et al., 1990). Nevertheless, the limited number of studies employing such techniques in clinical settings have had mixed results (e.g. Cooney et al., 1997, Drummond and Glautier, 1994, Monti et al., 1993 and Rohsenow et al., 2001). Recent studies of experimentally-controlled acquisition, extinction, and renewal of conditioned appetitive responses have elucidated nuances of extinction and renewal, including the importance of context and expectation (Thewissen et al., 2006 and Van Gucht et al., 2008); however, if and how to integrate these subtleties into treatment-oriented extinction paradigms is not yet clear. A recent review of the use of cue extinction paradigms in drug-dependent clinical populations (Conklin & Tiffany, 2002) discussed the disconnect between the theoretical promise of this type of intervention and the use of extinction training in clinical practice. The authors cited the lack of clear optimal parameters for conducting cue extinction studies as one possible contribution to the inconsistent results. In addition, the time course and parameters influencing extinction may differ across substances, as use patterns tend to vary across classes of drugs of abuse. Thus, further research to characterize drug cue extinction is warranted. The purpose of this study is to explore extinction of craving response to METH-related cues following repeated exposure in METH-dependent individuals.

Results Twenty-eight subjects were enrolled in the study; four subjects dropped out and multiple cue-sequence extinction data was collected for 24 of subjects. The descriptive and clinical data for the participants are listed in Table 1. The participants had a mean age of 32.1 (±7.4) years and were mostly female (79.2%). The majority of the participants smoked cigarettes (83.3%) and were currently in drug treatment (79.2%); less than 1/3 of the subjects were currently employed full-time (29.2%). Baseline craving values represent the mean of the two craving ratings taken 20 & 5 min prior to cue presentation. The two baseline craving ratings for session 1 were not statistically different from one another (20 min: 1.75 ± 2.40, 5 min: 1.96 ± 2.69; p = 0.375). Table 1. Demographic and clinical characteristics for >all subjects and dichotomized by METH craving status at study baseline. Demographics and characteristicsc All subjects Baseline non-cravers Baseline cravers P value and n Mean Std Err n Mean Std Err n Mean Std Err Age (yrs) 24 32.1 1.5 14 31.4 1.7 10 33.2 2.8 0.58 HR at Baseline (BPM) 22 79.2 2.7 14 80.4 3.8 8 77.2 3.6 0.87 Skin Cond at Baseline (μS) 24 2.5 0.3 14 2.6 0.3 10 2.4 0.6 0.34 Craving at Baseline 24 1.9 0.5 14 0 0 10 4.5 0.6 <0.01 % Male 24 20.8 14 7.1 10 40.0 0.12 % Smoker 24 83.3 14 78.6 10 90.0 0.62 % Currently Employed 24 29.2 14 21.4 10 40.0 0.39 % High School Edu 24 37.5 14 21.4 10 60.0 0.07 % in Treatment 24 79.2 14 85.7 10 70.0 0.62 % Craving At Baseline 24 41.7 NA NA a P value for difference between baseline cravers and non-cravers. b Continuous variables were compared by use of the Wilcoxon 2-sample test statistic and categorical variables were compared by use of the 2-sided fisher exact test statistic. c Continuous variables are listed as mean and standard deviation while categorical variables are listed as percentages. Table options To establish that the selected METH-related cues activated craving, the change in craving scores before and after exposure to the initial cue sequence was evaluated. The participants reported a mean craving score at baseline of 1.85 ± 0.51, and following cue sequence 1 reported a craving level of 4.03 ± 0.65 (p < 0.001). The mean craving (and standard deviations) for the two session 2 baselines were 0.67 ± 2.04 and 0.54 ± 1.89, which are not significantly different p = 0.75. The averaged session 2 baseline craving score was 0.60 (±0.39), which was significantly lower than the session 1 baseline (p = 0.031). To assess extinction of cue-elicited responses after repeated exposure, the within-subject effect of cue sequence (6 sequences over 2 sessions) was assessed. The main effect of sequence was significant (F(5,21) = 7.82, p < 0.001), indicating a decrease in craving response to the cues at an average rate of 0.65 per sequence ( Fig. 1). There was a decrease from 4.03 ± 0.65 following sequence 1 to 0.85 ± 0.35 following sequence 6. Twenty of the 24 participants reported craving for METH following the initial cue sequence (response >0). Of these 20 participants, the mean % change in craving score through the end of the last cue sequence was −84.4% and 11 (of the 20) participants reported no craving at the end of sequence 6. Mean craving score by sequence across session 1 and session 2 for all subjects ... Fig. 1. Mean craving score by sequence across session 1 and session 2 for all subjects and dichotomized by METH craving status at study baseline. The solid line represents the overall mean (n = 24). Figure options Similar analyses were run on the physiologic data (heart rate and skin conductance) and no significant changes were identified. Neither the heart rate nor the skin conductance patterns mirrored those seen for craving ratings. Baseline cravers vs. non-cravers Following the primary full-cohort analysis, the participants were grouped according to their initial baseline craving. The groupings consisted of 14 participants who had no baseline craving for METH and 10 participants who reported craving at baseline (4.45 ± 0.58). The two groups did not differ with respect to age (non-cravers 31.4 ± 1.7 vs. cravers 33.2 ± 2.8; p = .58), baseline heart rate (80.4 ± 3.8 vs. 77.2 ± 3.6; p = 0.87), baseline skin conductance (2.6 ± 0.3 vs. 2.4 ± 0.6; p = 0.34), percent current smokers (78.6% vs. 90.0%; p = 0.62), or percent currently in treatment (85.7% vs. 70.0%; p = 0.62). The participants that failed to crave at baseline (0 ± 0) reported a minimal response to the initial cue (1.8 ± 0.44; p = 0.002) while those that did crave METH at baseline rated their craving at 7.1 ± 0.62 following cue sequence 1, an increase of 2.6 ± 0.73 (p = 0.012). Of the ten participants who reported craving at session 1 baseline, only 3 reported craving at the session 2 baseline. Of the 14 participants who reported no craving at session 1 baseline, all continued to report a lack of craving at the session 2 baseline. The effect of baseline craving groups, sequences, and the interaction of the two were examined for statistical significance. The interaction of sequence and craving group was not significant (F(5,21) = 1.65; p = 0.190). The overall effect of sequence in the model remained significant (F(5,21) = 10.34; p < 0.001) as did the effect of the grouping (F(1,21) = 15.19; p <0.001), which was to be expected due to the dichotomization on the craving at baseline. Extinction of the conditioned craving response to METH cues was then analyzed independently for those individuals who did and did not report baseline craving. There was a significant effect of sequence (F(5,8) = 11.34; p = 0.001) in the group of baseline cravers, in which craving response to the cues decreased at an average rate of 1.12 per cue exposure sequence (decreasing from 7.13 ± 0.62 to 1.60 ± 0.75). Similarly, those who did not crave at baseline showed a significant decrease in cue-elicited craving over the course of the six cue exposure sequences (F(5,65) = 2.69; p = 0.028) with an average decrease of 0.32 per sequence (decreasing from 1.81 ± 0.44 to 0.31 ± 0.21; see Fig. 1). Effect of inter-session interval Each subject was assigned an inter-session interval (ISI) between 1 and 7 days (median = 2 days). Extinction rates of the individuals with ≤3 days between cue exposure sessions (n = 17) were compared with those that had ≥ 4 days between sessions (n = 7). Mean baseline craving values did not differ between the ISI Groups (1.79 ± 0.62 for ≤3 days vs. 2.00 ± 1.00 for ≥ 4 days; p = 0.86), nor did their rate of response extinction (F(5,21) = 1.95; p = 0.13). There was also no significant difference in craving response between the two ISI groups (F(1,21) = 0.07; p = 0.796). However, in an unadjusted non-parametric (Wilcoxon Rank Sums) analysis of the total decline in craving from sequence 1 to sequence 6, a trend toward significance was found (p = 0.06), showing a slightly greater average decrease in conditioned craving in the group with >4 days between session 1 and session 2 (See Table 2). Table 2. Inter-session interval group craving scores (mean ± SE) during session 1 baseline, session 1 and 2 by sequence, as well as the absolute change from baseline to the last cue sequence. Group Change From BL Baseline Session 1 Session 2 S1 S2 S3 S1 S2 S3 ≤3 Days 2.43 ± 0.67 1.79 ± 0.62 3.55 ± 0.78 3.25 ± 0.71 2.31 ± 0.61 1.73 ± 0.62 1.49 ± 0.54 1.12 ± 0.48 ≥4 Days 5.00 ± 1.12 2.00 ± 1.00 5.19 ± 1.18 4.10 ± 1.47 2.33 ± 1.20 1.00 ± 0.74 0.33 ± 0.22 0.19 ± 0.12 P-Value a 0.06 0.86 0.23 0.64 0.99 0.30 0.13 0.16 a 2-sample wilcoxon rank sums test p value.