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Cardiac autonomic modulation during methadone therapy among heroin users: A pilot study
Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 188–193
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Cardiac autonomic modulation during methadone therapy among heroin users: A pilot study Li-Ren Chang a, 1, Yu-Hsuan Lin a, b, 1, Terry B.J. Kuo b, c, Yen-Cheng Ho d, Shiuan-Horng Chen e, Hung-Chieh Wu Chang a, Chih-Min Liu a, Cheryl C.H. Yang b, c,⁎ a
Department of Psychiatry, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan Sleep Research Center, National Yang-Ming University, Taipei, Taiwan d Department of Psychiatry, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan e Department of Rehabilitation, Taipei City Hospital, Heping Branch, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 24 November 2011 Received in revised form 11 January 2012 Accepted 14 January 2012 Available online 21 January 2012 Keywords: Autonomic nervous system Heart rate variability Heroin Methadone Opioid
a b s t r a c t Background: Methadone therapy benefits heroin users in both the medical and psychosocial dimensions. However, both heroin and methadone have cardiac toxicity. Only limited information is available describing the changes in cardiac autonomic function of heroin users and effects of methadone therapy. We conduct the current study to explore the cardiac vagal function in heroin users as well as the impact of lapse and methadone therapy. Methods: 80 heroin users from a methadone therapy clinic were distributed into 31 compliant and 49 incompliant patients according to whether they lapsed into heroin use within 10 days. 40 healthy control subjects were recruited from the community. Participants underwent electrocardiographic recordings and the heroin users were further investigated before and after methadone therapy. Spectral analysis of heart rate variability (HRV) was computed for cardiac parasympathetic modulation (high-frequency power, HF) and cardiac sympathetic modulation (normalized low-frequency power, LF%). Results: The baseline HRV parameters found lower HF values for heroin users and lower RR interval values for patients with a recent lapse compared with the healthy control subjects. After 1 h of methadone administration, heroin users who had lapsed showed a significant increase in HF but the heroin users who had not lapsed did not. Conclusion: Our findings suggest that heroin users show decreased cardiac vagal activity and that methadone therapy immediately facilitates vagal regulation in patients with a recent lapse. The differential patterns of autonomic alteration under methadone between those with and without lapse might offer an objective measure of lapse. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Heroin misuse is a chronic medical illness with a high relapse tendency (McLellan et al., 2000). Drug overdose and trauma are the major contributors to the mortality (Degenhardt et al., 2009; Ravndal and Amundsen, 2010; Tagliaro et al., 1998). In addition,
Abbreviations: ANOVA, One-Way Analysis of Variance; ANS, Autonomic Nervous System; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision; ECG, Electrocardiogram; HF, High-Frequency Power; HRV, Heart Rate Variability; LF, Low-Frequency Power; LF%, Normalized Low-Frequency Power; OTI, Opiate Treatment Index; RR, R–R Interval Value; SOWS, Subjective Opiate Withdrawal Scale; TP, Total Power; VLF, Very-Low Frequency Power. ⁎ Corresponding author at: Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Li-Nong St., Taipei 11221, Taiwan. Tel.: + 886 2 28267058; fax: + 886 2 28273123. E-mail address: [email protected] (C.C.H. Yang). 1 Li-Ren Chang and Yu-Hsuan Lin contributed equally to this work. 0278-5846/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2012.01.006
serious cardiovascular diseases are believed to be associated with mortality among heroin users (Darke et al., 2010; Dettmeyer et al., 2009; Routsi et al., 2007). Methadone treatment refers to administration of this long-acting opioid in a controlled setting. This approach reduces opiate use, transmission of human immunodeficiency virus, hepatitis B and hepatitis C infection, criminal activity (Panel, 1998) as well as comorbid psychiatric symptoms (Gossop et al., 2006). Nevertheless, methadone also has cardiac toxicity (Chugh et al., 2008; Krantz et al., 2009; Peles et al., 2007) and reduces intrapartum fetal heart rate variability (Jansson et al., 2005; Ramirez-Cacho et al., 2006). The application of heart rate variability (HRV) analysis has recently gained popularity as a non-invasive approach to the quantification of autonomic nervous system (ANS) functioning (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Spectral analysis of HRV by Fourier transformation has been categorized into high-frequency (HF), low-frequency (LF), and very-low frequency powers. HF is considered
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to represent vagal control of the heart rate. Normalized LF (LF%) and the ratio LF/HF are considered by some investigators to reflect sympathetic modulations and to mirror the sympathovagal balance (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). However, the relationship between autonomic modulation and methadone therapy has only been partially explored (Jansson et al., 2005, 2007, 2009; Ramirez-Cacho et al., 2006). Jansson and colleagues found that methadone administration was associated with either suppression (Jansson et al., 2005, 2007), activation (Jansson et al., 2007), or no change of maternal vagal tone (Jansson et al., 2007, 2009). Such differential effects of methadone on autonomic modulation among heroin users remained unexplained. The cardiovagal activity as well as the immediate effect of methadone among chronic heroin users other than fetuses and pregnant women is not clear. Furthermore, while relapse rate of patients receiving methadone therapy is high (McLellan et al., 2000), previous studies did not investigate the additional impact of heroin lapse on their autonomic function (Jansson et al., 2005, 2007, 2009; Ramirez-Cacho et al., 2006). Though ethnicity is important consideration in psychopharmacological studies, there are still no related studies among patients of Asian ethnicity. The present study aims to test the hypotheses. First, whether patients who use heroin have significant cardiac vagal dysfunction? Second, whether such autonomic dysfunction can be restored by methadone treatment? Finally, are there differential patterns of autonomic alteration between those with and without lapse?
2. Methods and materials
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2.2. Subjective Opiate Withdrawal Scale (SOWS) The SOWS is a self-rating scale which has been shown to be a reliable and valid measure of the opiate withdrawal syndrome (Handelsman et al., 1987). This scale contains 16 symptoms whose intensity the patient rates on a 5-point scale. 2.3. Opiate Treatment Index (OTI) The OTI consists of 6 independent outcome domains that reflect the dimensions of treatment outcome, included drug use, HIV risktaking behavior, social functioning, criminality, health status, and psychological adjustment. The present research focuses on the drug use domain. It relies on recent behavior examined by collecting information on the last 3 days of drug use for each drug category. The intervals between days of drug use, and the amounts consumed on these days, are employed to estimate recent consumption. The data obtained on recent use involves eleven drug categories: heroin, other opiates, alcohol, cannabis, amphetamines, cocaine, tranquilizers, barbiturates, hallucinogens, inhalants, and tobacco (Darke et al., 1991, 1992). The data obtained from the subject is then used to calculate an estimate of the individual's recent consumption by the simple formula: Q = (q1 + q2)/(t1 + t2) where Q = average amount per day, q1 = amount consumed on the last use occasion, q2 = amount consumed on the second last use occasion, t1 = interval between the last day of drug use and the next to last day of use and t2 = interval between the second and third last days of drug use. The use of the Chinese version of OTI has also been validated (unpublished manuscript).
2.1. Participants
2.4. Heart rate variability
80 heroin users were recruited by advertisement from the outpatient methadone maintenance therapy clinics at the Department of Psychiatry, National Taiwan University Hospital, Yun-Lin Branch, Taiwan. All of them fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for opioid dependence, which is ascertained by a board-certified psychiatrist. They were distributed into 2 subgroups according to whether they lapsed back to heroin use within the last 10 days. There were 49 heroin users who lapsed (incompliant group) and 31 heroin users who did not lapse (compliant group). Both groups received methadone therapy in the morning (08:30–12:00) and were investigated by carrying out a 5-minute electrocardiogram (ECG) before and 1 h after methadone administration. They completed a questionnaire about methadone use and the Opiate Treatment Index (OTI) during the 1-hour break between ECGs. Neither smoking nor alcohol consumption was allowed before and during data collection. Their heart rate, body temperature, and respiratory rate were stably within normal range. None of them presented with overt opioid withdrawal symptoms during investigation. 40 healthy volunteers without illicit drug, alcohol or tranquilizer use were recruited by advertisement from the same community. Heroin users and healthy volunteers with history of major systemic or psychiatric diseases were excluded from this study. Participants' tobacco, tranquilizer or other illicit drug use were all recorded. Those taking other medication which is documented to influence heart rate variability were also excluded. Healthy volunteers were matched to heroin users on the basis of age, gender and body mass index (BMI) because each of these variables is associated with HRV (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Tobacco use was also controlled as possible. Informed written consent was obtained from all participants, and the experiment protocol was approved by the Ethics Committee of National Taiwan University Hospital, Yun-Lin Branch, Taiwan.
The procedure for HRV analysis was designed according to the standard method (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996), and has been described previously (Kuo et al., 1999). To put it briefly, a lead I ECG was taken for 5 min in the daytime when each subject sat quietly and breathed normally. ECG signal acquisition, storage and processing were done using a HRV analyzer (SS1C, Enjoy Research Inc., Taiwan). Signals were recorded using an 8-bit analog-to-digital converter with a sampling rate of 512 Hz. The digitized ECG Lead I signals were analyzed online, and were simultaneously stored on a hard disk for offline verification. The computer algorithm then recognized each QRS complex and rejected each ventricular premature complex or noise according to likelihood by using a standard QRS template. Normal and stationary R–R interval values (RR) were resampled and interpolated at a rate of 7.11 Hz to produce continuity in the time domain. This interpolation produced 2048 data points over 288 s, which was used for the following Fourier transformation. Power spectral analysis was performed using fast Fourier transformation (FFT). The baseline shift was deleted, and a Hamming window was used to attenuate the leakage effect (Kuo and Chan, 1993). For each time segment (288 s, 2048 data points), our algorithm estimated the power spectrum density based on the FFT. The resulting power spectrum was corrected for attenuation resulting from the Hamming window. The power spectrum was subsequently quantified into the standard frequency-domain measurements as reported previously (Kuo et al., 1999; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996), including variance (variance of RR-interval values), very lowfrequency power (VLF, 0.003–0.04 Hz), LF (0.04–0.15 Hz), HF (0.15–0.40 Hz), total power (TP) and LF/HF, normalized LF (LF%). LF% was calculated from LF/(total power-VLF) × 100. Variance, VLF, LF, HF, and LF/HF were logarithmically transformed to correct for skewed distributions (Kuo et al., 1999).
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2.5. Statistical methods The differential effects in terms of demographic data and HRV parameters among the healthy volunteers, the compliant heroin users and the incompliant heroin users were compared using one-way analysis of variance (ANOVA). Chi-square statistics were applied for categorical variables such as gender and smoking. Post hoc comparisons using Fisher's least significant difference test were applied for a posteriori comparison of the means as appropriate. We compared the clinical characteristics and OTI scores among the compliant and incompliant heroin user by independent t-test. Comparisons between the pre- and post-methadone treatment data for the same group were performed using the paired Student's t-test. Statistical significance was assumed for p b 0.05. Values are expressed as means± standard deviation.
3. Results The demographic data and Q scores from the OTI of each group, which means the amount or the frequency of substance use, are listed in Table 1. As expected, incompliant heroin users reported higher heroin scores than the compliant group. Heroin users were more likely to be tobacco smokers but the tobacco smoking score, as well as other drugs used other than heroin, demonstrated no significant difference between the incompliant and compliant group. There was also no significant difference in age, gender and BMI among the three groups. Compliant heroin users were not significantly different from the incompliant group based on various clinical characteristics, including current methadone dosage, maximal methadone dose, duration of methadone therapy, age at onset of heroin use and scores of SOWS. Table 2 and Fig. 1 show the group differences in HRV parameters. To demonstrate the long term effects of heroin on autonomic function, we compared the two groups of heroin users with the healthy control group by ANOVA. There were significant group differences in baseline HRV parameters, including TP (F = 10.264, p b 0.05), HF (F = 9.752, p b 0.05), and RR (F = 4.433, p b 0.05). In the post hoc comparison, we found that the baseline HRV parameters demonstrated lower variance, TP and HF for both groups of heroin users and a lower RR in patients with recent lapse compared to the healthy control subjects. Moreover, RR, variance, TP, HF and LF% demonstrated no difference between the compliant and incompliant groups (p = 0.172, 0.870, 0.816, 0.668 and 0.609, respectively). Our results revealed that heroin users showed a parasympathetic activity (HF) decrease, but that their sympathetic activity (LF%) remained unchanged in comparison with controls. Furthermore, to explore the immediate effect of methadone on cardiovascular autonomic function of the chronic heroin users, we compared blood pressure and the HRV parameters before and 1 h after methadone use in both groups of heroin users. Their sympathetic activity (LF%), systolic and diastolic blood pressures were not changed (Table 2). In both groups, the variance and TP increased significantly (Table 2, Fig. 1). Incompliant users showed a significant increase in HF and RR. In contrast, the compliant group demonstrated no significant change in these parameters (Table 2, Fig. 1). In addition, the RR, variance and TP of heroin users after methadone therapy approached that of the control group and showed no significant difference (p = 0.519, 0.516 and 0.155 respectively) from it. Among compliant and incompliant heroin users, the HF values were still significantly lower after methadone therapy than those of the control group (p = 0.002 and 0.029 respectively). The sympathetic function (LF%) was not changed. In summary, heroin users with or without recent lapses showed decreased cardiac vagal activity (HF) at baseline. Methadone increased vagal modulation in patients with a recent lapse, but their vagal activity was still lower than that of the controls. The achieved statistical power was also sufficient.
Table 1 Demographic data and Opiate Treatment Index (OTI) scores of the healthy control group, the compliant heroin users and the incompliant heroin users. Control Heroin users Group comparison (N = 40) Compliant Incompliant p value (N = 31) (N = 49) Age, year Gender, M/F Body mass index, kg/cm2 Smokers Current methadone dosage, mg/day Age at onset of heroin use, year Duration of methadone treatment, year Maximum dose of methadone, mg/day Subjective Opiate Withdrawal Scale Q score of OTI Heroin Other opiates Alcohol Cannabis Amphetamines Cocaine Tranquilizers Barbiturates Hallucinogens Inhalants Tobacco Total score
33.4 (7.20) 36/4 23.9 (3.67) 17
36.3 (7.03) 27/4 23.3 (3.59) 22 39.5 (21.6) 26.3 (7.08) 1.23 (0.829) 61.4 (68.0) 8.94 (8.92) 0.115 (0.393) 0.065 (0.359) 0.389 (1.27) 0 0.008 (0.033) 0.000 (0.000) 0.133 (0.443) 0.000 (0.000) 0.000 (0.000) 0.000 (0.000) 13.9 (9.54) 14.5 (10.3)
35.8 (7.66)
F = 1.674
0.192
2
43/6 23.0 (3.46)
X = 0.170 0.919 F = 0.772 0.465
29 31.673 (20.0) 26.9 (8.40)
X2 = 5.978 0.050 0.104
1.77 (3.18)
0.355
63.6 (67.8)
0.891
11.65 (11.34)
0.262
0.853 (1.18)⁎ 0.190 (0.754) 0.601 (3.12) 0 0.111 (0.467) 0.020 (0.143) 0.136 (0.332) 0.020 (0.143) 0.122 (0.726) 0.020 (0.143) 16.1 (10.2)
b 0.001
17.3 (11.2)
0.268
0.749
0.390 0.720 NA 0.128 0.430 0.969 0.430 0.351 0.430 0.325
Data are presented as mean (standard deviation). Compliant: heroin users without lapse. Incompliant: heroin users with lapse. ⁎ p b 0.05 vs. compliant group by t test.
4. Discussion It has long been a question posed as to what extent is there autonomic dysfunction in heroin users. The impact of methadone on vagal modulation of heroin users and its effect on those who have lapsed again into heroin during methadone treatment also remain uncertain. Our study is the first Asian study on the topic of autonomic modulation under methadone treatment with careful control for age, gender and BMI. This is also one of the most comprehensive studies to exclusively investigate influence of methadone treatment on ANS among chronic heroin users. Particularly, our study is pioneering in considering the high relapse rate among heroin users under methadone treatment and distributed heroin users into two groups, namely, those that have lapsed in last 10 days and those without lapse in last 10 days. Our findings support the first hypothesis proposed earlier that heroin users show significant cardiac vagal depression. The baseline HRV parameters demonstrated lower variance, TP and HF among heroin users compared with healthy subjects. Our findings also provide evidence that supports our second hypothesis whereby autonomic dysfunction can be restored by methadone treatment in short term. The
L.-R. Chang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 188–193 Table 2 Heart rate variability parameters and blood pressure of the healthy control group, the compliant heroin users and the incompliant heroin users. Control
Heroin users Compliant
RR, ms
Baseline After methadone therapy Variance, Baseline ln(ms2) After methadone therapy TP, Baseline ln(ms2) After methadone therapy VLF, Baseline 2 ln(ms ) After methadone therapy Baseline HF, ln(ms2) After methadone therapy LF%, Baseline nu After methadone therapy LF/HF, Baseline ln(ratio) After methadone therapy SBP, Baseline mm Hg After methadone therapy DBP, Baseline mm Hg After methadone therapy
778.3 (85.28) 758.0 (145.4) 777.1 (135.0)
Incompliant 709.1 (109.2)⁎ 751.7 (138.4)†
7.519 (0.807) 6.944 (0.948)⁎ 6.821 (1.182)⁎ 7.262 (0.980)† 7.369 (1.027)† 7.480 (0.848) 6.726 (0.969)⁎ 6.584 (1.053)⁎ 7.079 (1.045)† 7.174 (0.925)† 6.607 (0.872) 5.918 (1.048) 6.432 (1.046)
5.844 (1.101) 6.418 (0.968)
5.411 (1.123) 4.544 (1.249)⁎ 4.292 (1.274)⁎ 4.516 (1.253)⁎ 4.840 (1.265)⁎† 65.61 (13.14) 62.07 (19.43) 67.46 (14.94)
63.25 (16.84) 63.93 (17.26)
1.044 (0.610) 0.995 (0.967) 1.269 (0.789)
1.045 (0.793) 1.085 (0.837)
123.7 (14.31) 125.7 (13.17) 123.8 (13.92)
120.5 (12.14) 120.4 (12.87)
79.05 (11.59) 76.53 (11.03) 78.13 (11.40)
76.89 (9.488) 77.02 (10.74)
Data are presented as mean (standard deviation). Compliant: heroin users without lapse. Incompliant: heroin users with lapse. TP, total power; VLF, very low frequency; HF, high frequency; LF, low frequency; SBP, systolic blood pressure; DBP, diastolic blood pressure. †p b 0.05 vs. before methadone by paired t test. ⁎ p b 0.05 vs. control group by Fisher's least significant difference test.
variance and TP increase significantly in both groups of heroin users. Finally, there are differential patterns of autonomic alteration between the heroin users on methadone treatment with and without lapse.
191
While the compliant group demonstrated no significant change, the incompliant users showed significant increases in HF and RR. As expected, heroin users show a significant cardiac vagal depression. We found that heroin users, compared with an age, gender and BMI-matched healthy group, had lower HF. Since HF is an index of cardiac vagal regulation, our results indicate that chronic heroin users suffer from significant cardiac vagal depression. However, morphine and various opioids acutely repress the LF more than the HF, which presented a relatively parasympathetic dominance (Jeanne et al., 2009; Michaloudis et al., 1998). But long-term opioid use may cause up regulation of cyclic adenosine monophosphate, along with changes in gene transcription. Thus chronic opioid receptor activation results in molecular effects that are opposite to those of acute opioid administration (Cami and Farre, 2003). This phenomenon is in correspondence with the vagal depression detected among our participants who reported heroin use on average for 10 years; this was based on the interval between patients' current age and the onset age of heroin use. Consistent with our prediction, autonomic dysfunction can be restored after acute methadone treatment. This is consistent with previous findings that parasympathetic tone is increased among some pregnant women on a peak methadone dose compared with a trough dose (Jansson et al., 2007). In the short-term, methadone may be a cardiovascular protective for heroin users. One hour after methadone administration, there were different patterns of altered cardiovascular autonomic function depending on whether there had been a heroin use lapse within the last 10 days. While the compliant group demonstrated no significant change, the incompliant users showed significant increases in HF and RR. Thus methadone therapy is associated with improved HF in heroin users who have lapsed. This implies that methadone might be discriminately protective with respect to cardiovagal function among incompliant users but not among compliant users. This might partially contribute to the finding that there is reduction in mortality of 40% among patients on methadone maintenance therapy compared to the predicted mortality risk prior to the therapy (Clausen et al., 2008). In comparison, sympathetic activity of heroin users remained unchanged after 1 h of methadone administration. Past studies showed increased sympathetic activity at baseline (Barutcu et al.,
Fig. 1. Mean R–R interval (RR) parameters of heart rate variability among the health control group, the heroin users without lapse (compliant group) and the heroin users with lapse (incompliant group). TP, total power; HF, high-frequency power; LF%, normalized low-frequency power; values are means ± SD. *p b 0.05 vs. control group by Fisher's least significant difference test; †p b 0.05 vs. before methadone by paired t test.
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2005) or acutely (Manzano et al., 2011) among tobacco users. Acute ingestion of alcohol also caused sympathetic activation and vagal withdrawal (Bau et al., 2011). Our results partially support the fact that heroin users in our study did not smoke or drink alcohol during data collection. Heroin has a half-life of 30 min, but the duration of action is about 4 to 5 h due to the presence of active metabolites including morphine. Opioid withdrawal symptoms of heroin peak within 36 to 72 h and last for 7 to 10 days (Kosten and O'Connor, 2003). Although the scores of SOWS were low and had no difference between the two groups, it is conceivable that heroin users who lapse within 10 days may manifest more subtle symptoms and signs of opioid withdrawal. For example, the compliant and incompliant groups presented with significant different baseline heart rate despite the heart rate were within normal range. The half-life of methadone is approximately 22 h (Eap et al., 2002) so methadone is used as substitution therapy to treat opioid dependence. The effects of the methadone therapy were quite different in the two groups. It suggests short-term cardiovascular benefit for incompliant heroin users. Overall, 61.25% (49/80) of heroin users in our study had lapsed within the 10 days, and this is similar to previous studies that half of all heroin addicts during methadone treatment report lapse within the preceding 14-day period (Senbanjo et al., 2009). However, they may deny relapse due to various reasons. The differential patterns of autonomic alteration under methadone between heroin users with and without lapse might be used as an objective measure of lapse and allow individualized treatment for patients. There are several limitations in our study. First, heroin use is usually combined with poly-substance use. Cigarette and alcohol consumption are the most prevalent and might influence heart rate variability as discussed above. Although the Q scores for all substance use showed no significant difference between the two groups of heroin users, the decrease in vagal activity among heroin user might be attributable to some extent to multiple substance use. Second, whether heroin users had lapse within 10 days or not is based on self report. There may be recall bias among patients with drug dependence. Though we have provided reassurance for participants about answering the date of last heroin use, it would be better to perform continuous urine drug screening at an interval of 2–3 days to confirm it objectively. Third, there is a lack of more structured interview to confirm psychiatric comorbidities more firmly in our study. Unrecognized comorbidities among heroin users might be confounding. Fourth, our study is limited by crosssectional design and short-term intervention. A longitudinal follow-up study is necessary to explore the development of vagal impairment in heroin users and the long-term cardiovascular effect of methadone therapy. Fifth, the relatively small sample size in our pilot study limits the further interpretation of our results. In the future, larger sample size is needed to confirm our novel findings. In conclusion, heroin users show reduced cardiac vagal modulation and methadone therapy raised vagal activity directly in patients who had recently relapsed into heroin use. The differential patterns of autonomic response under methadone between heroin users with and without lapse might have the potential of becoming an objective and reliable measure of lapse. As a pilot study in this field, our results provide new insights into autonomic regulation of heroin users. We also pointed out difficulties in studying autonomic modulation among heroin users. More comprehensive study design is needed to validate the phenomenon and further explore the underlying mechanism. Author contributions Conceived and designed the experiments: LRC, YHL and CCHY. Performed the experiments: LRC and YHL. Analyzed the data: LRC, YHL, TBJK and YCH. Contributed reagents/materials/analysis tools: TBJK, YCH, SHC, HCWC and CML. Wrote the paper: LRC, YHL and CCHY.
Acknowledgments and disclosures This study was supported by a grant (NTUHYL.99N015) from the National Taiwan University Hospital, Yun-Lin Branch, and a grant (NSC-99-2627-B-010-005) from the National Science Council (Taiwan). We appreciate the valuable comments of Dr. Sun-Yuan Chou and Dr. Meng-Chuan Lai. We also thank Mr. Ying-Zai Chen, Mr. Chun-Ting Lai and Ms. Ying-Hua Huang for their technical assistance. The authors report no competing interests.
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Cardiac autonomic modulation during methadone therapy among heroin users: A pilot study Li-Ren Chang a, 1, Yu-Hsuan Lin a, b, 1, Terry B.J. Kuo b, c, Yen-Cheng Ho d, Shiuan-Horng Chen e, Hung-Chieh Wu Chang a, Chih-Min Liu a, Cheryl C.H. Yang b, c,⁎ a
Department of Psychiatry, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan Sleep Research Center, National Yang-Ming University, Taipei, Taiwan d Department of Psychiatry, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan e Department of Rehabilitation, Taipei City Hospital, Heping Branch, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 24 November 2011 Received in revised form 11 January 2012 Accepted 14 January 2012 Available online 21 January 2012 Keywords: Autonomic nervous system Heart rate variability Heroin Methadone Opioid
a b s t r a c t Background: Methadone therapy benefits heroin users in both the medical and psychosocial dimensions. However, both heroin and methadone have cardiac toxicity. Only limited information is available describing the changes in cardiac autonomic function of heroin users and effects of methadone therapy. We conduct the current study to explore the cardiac vagal function in heroin users as well as the impact of lapse and methadone therapy. Methods: 80 heroin users from a methadone therapy clinic were distributed into 31 compliant and 49 incompliant patients according to whether they lapsed into heroin use within 10 days. 40 healthy control subjects were recruited from the community. Participants underwent electrocardiographic recordings and the heroin users were further investigated before and after methadone therapy. Spectral analysis of heart rate variability (HRV) was computed for cardiac parasympathetic modulation (high-frequency power, HF) and cardiac sympathetic modulation (normalized low-frequency power, LF%). Results: The baseline HRV parameters found lower HF values for heroin users and lower RR interval values for patients with a recent lapse compared with the healthy control subjects. After 1 h of methadone administration, heroin users who had lapsed showed a significant increase in HF but the heroin users who had not lapsed did not. Conclusion: Our findings suggest that heroin users show decreased cardiac vagal activity and that methadone therapy immediately facilitates vagal regulation in patients with a recent lapse. The differential patterns of autonomic alteration under methadone between those with and without lapse might offer an objective measure of lapse. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Heroin misuse is a chronic medical illness with a high relapse tendency (McLellan et al., 2000). Drug overdose and trauma are the major contributors to the mortality (Degenhardt et al., 2009; Ravndal and Amundsen, 2010; Tagliaro et al., 1998). In addition,
Abbreviations: ANOVA, One-Way Analysis of Variance; ANS, Autonomic Nervous System; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision; ECG, Electrocardiogram; HF, High-Frequency Power; HRV, Heart Rate Variability; LF, Low-Frequency Power; LF%, Normalized Low-Frequency Power; OTI, Opiate Treatment Index; RR, R–R Interval Value; SOWS, Subjective Opiate Withdrawal Scale; TP, Total Power; VLF, Very-Low Frequency Power. ⁎ Corresponding author at: Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Li-Nong St., Taipei 11221, Taiwan. Tel.: + 886 2 28267058; fax: + 886 2 28273123. E-mail address: [email protected] (C.C.H. Yang). 1 Li-Ren Chang and Yu-Hsuan Lin contributed equally to this work. 0278-5846/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2012.01.006
serious cardiovascular diseases are believed to be associated with mortality among heroin users (Darke et al., 2010; Dettmeyer et al., 2009; Routsi et al., 2007). Methadone treatment refers to administration of this long-acting opioid in a controlled setting. This approach reduces opiate use, transmission of human immunodeficiency virus, hepatitis B and hepatitis C infection, criminal activity (Panel, 1998) as well as comorbid psychiatric symptoms (Gossop et al., 2006). Nevertheless, methadone also has cardiac toxicity (Chugh et al., 2008; Krantz et al., 2009; Peles et al., 2007) and reduces intrapartum fetal heart rate variability (Jansson et al., 2005; Ramirez-Cacho et al., 2006). The application of heart rate variability (HRV) analysis has recently gained popularity as a non-invasive approach to the quantification of autonomic nervous system (ANS) functioning (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Spectral analysis of HRV by Fourier transformation has been categorized into high-frequency (HF), low-frequency (LF), and very-low frequency powers. HF is considered
L.-R. Chang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 188–193
to represent vagal control of the heart rate. Normalized LF (LF%) and the ratio LF/HF are considered by some investigators to reflect sympathetic modulations and to mirror the sympathovagal balance (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). However, the relationship between autonomic modulation and methadone therapy has only been partially explored (Jansson et al., 2005, 2007, 2009; Ramirez-Cacho et al., 2006). Jansson and colleagues found that methadone administration was associated with either suppression (Jansson et al., 2005, 2007), activation (Jansson et al., 2007), or no change of maternal vagal tone (Jansson et al., 2007, 2009). Such differential effects of methadone on autonomic modulation among heroin users remained unexplained. The cardiovagal activity as well as the immediate effect of methadone among chronic heroin users other than fetuses and pregnant women is not clear. Furthermore, while relapse rate of patients receiving methadone therapy is high (McLellan et al., 2000), previous studies did not investigate the additional impact of heroin lapse on their autonomic function (Jansson et al., 2005, 2007, 2009; Ramirez-Cacho et al., 2006). Though ethnicity is important consideration in psychopharmacological studies, there are still no related studies among patients of Asian ethnicity. The present study aims to test the hypotheses. First, whether patients who use heroin have significant cardiac vagal dysfunction? Second, whether such autonomic dysfunction can be restored by methadone treatment? Finally, are there differential patterns of autonomic alteration between those with and without lapse?
2. Methods and materials
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2.2. Subjective Opiate Withdrawal Scale (SOWS) The SOWS is a self-rating scale which has been shown to be a reliable and valid measure of the opiate withdrawal syndrome (Handelsman et al., 1987). This scale contains 16 symptoms whose intensity the patient rates on a 5-point scale. 2.3. Opiate Treatment Index (OTI) The OTI consists of 6 independent outcome domains that reflect the dimensions of treatment outcome, included drug use, HIV risktaking behavior, social functioning, criminality, health status, and psychological adjustment. The present research focuses on the drug use domain. It relies on recent behavior examined by collecting information on the last 3 days of drug use for each drug category. The intervals between days of drug use, and the amounts consumed on these days, are employed to estimate recent consumption. The data obtained on recent use involves eleven drug categories: heroin, other opiates, alcohol, cannabis, amphetamines, cocaine, tranquilizers, barbiturates, hallucinogens, inhalants, and tobacco (Darke et al., 1991, 1992). The data obtained from the subject is then used to calculate an estimate of the individual's recent consumption by the simple formula: Q = (q1 + q2)/(t1 + t2) where Q = average amount per day, q1 = amount consumed on the last use occasion, q2 = amount consumed on the second last use occasion, t1 = interval between the last day of drug use and the next to last day of use and t2 = interval between the second and third last days of drug use. The use of the Chinese version of OTI has also been validated (unpublished manuscript).
2.1. Participants
2.4. Heart rate variability
80 heroin users were recruited by advertisement from the outpatient methadone maintenance therapy clinics at the Department of Psychiatry, National Taiwan University Hospital, Yun-Lin Branch, Taiwan. All of them fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for opioid dependence, which is ascertained by a board-certified psychiatrist. They were distributed into 2 subgroups according to whether they lapsed back to heroin use within the last 10 days. There were 49 heroin users who lapsed (incompliant group) and 31 heroin users who did not lapse (compliant group). Both groups received methadone therapy in the morning (08:30–12:00) and were investigated by carrying out a 5-minute electrocardiogram (ECG) before and 1 h after methadone administration. They completed a questionnaire about methadone use and the Opiate Treatment Index (OTI) during the 1-hour break between ECGs. Neither smoking nor alcohol consumption was allowed before and during data collection. Their heart rate, body temperature, and respiratory rate were stably within normal range. None of them presented with overt opioid withdrawal symptoms during investigation. 40 healthy volunteers without illicit drug, alcohol or tranquilizer use were recruited by advertisement from the same community. Heroin users and healthy volunteers with history of major systemic or psychiatric diseases were excluded from this study. Participants' tobacco, tranquilizer or other illicit drug use were all recorded. Those taking other medication which is documented to influence heart rate variability were also excluded. Healthy volunteers were matched to heroin users on the basis of age, gender and body mass index (BMI) because each of these variables is associated with HRV (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Tobacco use was also controlled as possible. Informed written consent was obtained from all participants, and the experiment protocol was approved by the Ethics Committee of National Taiwan University Hospital, Yun-Lin Branch, Taiwan.
The procedure for HRV analysis was designed according to the standard method (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996), and has been described previously (Kuo et al., 1999). To put it briefly, a lead I ECG was taken for 5 min in the daytime when each subject sat quietly and breathed normally. ECG signal acquisition, storage and processing were done using a HRV analyzer (SS1C, Enjoy Research Inc., Taiwan). Signals were recorded using an 8-bit analog-to-digital converter with a sampling rate of 512 Hz. The digitized ECG Lead I signals were analyzed online, and were simultaneously stored on a hard disk for offline verification. The computer algorithm then recognized each QRS complex and rejected each ventricular premature complex or noise according to likelihood by using a standard QRS template. Normal and stationary R–R interval values (RR) were resampled and interpolated at a rate of 7.11 Hz to produce continuity in the time domain. This interpolation produced 2048 data points over 288 s, which was used for the following Fourier transformation. Power spectral analysis was performed using fast Fourier transformation (FFT). The baseline shift was deleted, and a Hamming window was used to attenuate the leakage effect (Kuo and Chan, 1993). For each time segment (288 s, 2048 data points), our algorithm estimated the power spectrum density based on the FFT. The resulting power spectrum was corrected for attenuation resulting from the Hamming window. The power spectrum was subsequently quantified into the standard frequency-domain measurements as reported previously (Kuo et al., 1999; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996), including variance (variance of RR-interval values), very lowfrequency power (VLF, 0.003–0.04 Hz), LF (0.04–0.15 Hz), HF (0.15–0.40 Hz), total power (TP) and LF/HF, normalized LF (LF%). LF% was calculated from LF/(total power-VLF) × 100. Variance, VLF, LF, HF, and LF/HF were logarithmically transformed to correct for skewed distributions (Kuo et al., 1999).
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2.5. Statistical methods The differential effects in terms of demographic data and HRV parameters among the healthy volunteers, the compliant heroin users and the incompliant heroin users were compared using one-way analysis of variance (ANOVA). Chi-square statistics were applied for categorical variables such as gender and smoking. Post hoc comparisons using Fisher's least significant difference test were applied for a posteriori comparison of the means as appropriate. We compared the clinical characteristics and OTI scores among the compliant and incompliant heroin user by independent t-test. Comparisons between the pre- and post-methadone treatment data for the same group were performed using the paired Student's t-test. Statistical significance was assumed for p b 0.05. Values are expressed as means± standard deviation.
3. Results The demographic data and Q scores from the OTI of each group, which means the amount or the frequency of substance use, are listed in Table 1. As expected, incompliant heroin users reported higher heroin scores than the compliant group. Heroin users were more likely to be tobacco smokers but the tobacco smoking score, as well as other drugs used other than heroin, demonstrated no significant difference between the incompliant and compliant group. There was also no significant difference in age, gender and BMI among the three groups. Compliant heroin users were not significantly different from the incompliant group based on various clinical characteristics, including current methadone dosage, maximal methadone dose, duration of methadone therapy, age at onset of heroin use and scores of SOWS. Table 2 and Fig. 1 show the group differences in HRV parameters. To demonstrate the long term effects of heroin on autonomic function, we compared the two groups of heroin users with the healthy control group by ANOVA. There were significant group differences in baseline HRV parameters, including TP (F = 10.264, p b 0.05), HF (F = 9.752, p b 0.05), and RR (F = 4.433, p b 0.05). In the post hoc comparison, we found that the baseline HRV parameters demonstrated lower variance, TP and HF for both groups of heroin users and a lower RR in patients with recent lapse compared to the healthy control subjects. Moreover, RR, variance, TP, HF and LF% demonstrated no difference between the compliant and incompliant groups (p = 0.172, 0.870, 0.816, 0.668 and 0.609, respectively). Our results revealed that heroin users showed a parasympathetic activity (HF) decrease, but that their sympathetic activity (LF%) remained unchanged in comparison with controls. Furthermore, to explore the immediate effect of methadone on cardiovascular autonomic function of the chronic heroin users, we compared blood pressure and the HRV parameters before and 1 h after methadone use in both groups of heroin users. Their sympathetic activity (LF%), systolic and diastolic blood pressures were not changed (Table 2). In both groups, the variance and TP increased significantly (Table 2, Fig. 1). Incompliant users showed a significant increase in HF and RR. In contrast, the compliant group demonstrated no significant change in these parameters (Table 2, Fig. 1). In addition, the RR, variance and TP of heroin users after methadone therapy approached that of the control group and showed no significant difference (p = 0.519, 0.516 and 0.155 respectively) from it. Among compliant and incompliant heroin users, the HF values were still significantly lower after methadone therapy than those of the control group (p = 0.002 and 0.029 respectively). The sympathetic function (LF%) was not changed. In summary, heroin users with or without recent lapses showed decreased cardiac vagal activity (HF) at baseline. Methadone increased vagal modulation in patients with a recent lapse, but their vagal activity was still lower than that of the controls. The achieved statistical power was also sufficient.
Table 1 Demographic data and Opiate Treatment Index (OTI) scores of the healthy control group, the compliant heroin users and the incompliant heroin users. Control Heroin users Group comparison (N = 40) Compliant Incompliant p value (N = 31) (N = 49) Age, year Gender, M/F Body mass index, kg/cm2 Smokers Current methadone dosage, mg/day Age at onset of heroin use, year Duration of methadone treatment, year Maximum dose of methadone, mg/day Subjective Opiate Withdrawal Scale Q score of OTI Heroin Other opiates Alcohol Cannabis Amphetamines Cocaine Tranquilizers Barbiturates Hallucinogens Inhalants Tobacco Total score
33.4 (7.20) 36/4 23.9 (3.67) 17
36.3 (7.03) 27/4 23.3 (3.59) 22 39.5 (21.6) 26.3 (7.08) 1.23 (0.829) 61.4 (68.0) 8.94 (8.92) 0.115 (0.393) 0.065 (0.359) 0.389 (1.27) 0 0.008 (0.033) 0.000 (0.000) 0.133 (0.443) 0.000 (0.000) 0.000 (0.000) 0.000 (0.000) 13.9 (9.54) 14.5 (10.3)
35.8 (7.66)
F = 1.674
0.192
2
43/6 23.0 (3.46)
X = 0.170 0.919 F = 0.772 0.465
29 31.673 (20.0) 26.9 (8.40)
X2 = 5.978 0.050 0.104
1.77 (3.18)
0.355
63.6 (67.8)
0.891
11.65 (11.34)
0.262
0.853 (1.18)⁎ 0.190 (0.754) 0.601 (3.12) 0 0.111 (0.467) 0.020 (0.143) 0.136 (0.332) 0.020 (0.143) 0.122 (0.726) 0.020 (0.143) 16.1 (10.2)
b 0.001
17.3 (11.2)
0.268
0.749
0.390 0.720 NA 0.128 0.430 0.969 0.430 0.351 0.430 0.325
Data are presented as mean (standard deviation). Compliant: heroin users without lapse. Incompliant: heroin users with lapse. ⁎ p b 0.05 vs. compliant group by t test.
4. Discussion It has long been a question posed as to what extent is there autonomic dysfunction in heroin users. The impact of methadone on vagal modulation of heroin users and its effect on those who have lapsed again into heroin during methadone treatment also remain uncertain. Our study is the first Asian study on the topic of autonomic modulation under methadone treatment with careful control for age, gender and BMI. This is also one of the most comprehensive studies to exclusively investigate influence of methadone treatment on ANS among chronic heroin users. Particularly, our study is pioneering in considering the high relapse rate among heroin users under methadone treatment and distributed heroin users into two groups, namely, those that have lapsed in last 10 days and those without lapse in last 10 days. Our findings support the first hypothesis proposed earlier that heroin users show significant cardiac vagal depression. The baseline HRV parameters demonstrated lower variance, TP and HF among heroin users compared with healthy subjects. Our findings also provide evidence that supports our second hypothesis whereby autonomic dysfunction can be restored by methadone treatment in short term. The
L.-R. Chang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 188–193 Table 2 Heart rate variability parameters and blood pressure of the healthy control group, the compliant heroin users and the incompliant heroin users. Control
Heroin users Compliant
RR, ms
Baseline After methadone therapy Variance, Baseline ln(ms2) After methadone therapy TP, Baseline ln(ms2) After methadone therapy VLF, Baseline 2 ln(ms ) After methadone therapy Baseline HF, ln(ms2) After methadone therapy LF%, Baseline nu After methadone therapy LF/HF, Baseline ln(ratio) After methadone therapy SBP, Baseline mm Hg After methadone therapy DBP, Baseline mm Hg After methadone therapy
778.3 (85.28) 758.0 (145.4) 777.1 (135.0)
Incompliant 709.1 (109.2)⁎ 751.7 (138.4)†
7.519 (0.807) 6.944 (0.948)⁎ 6.821 (1.182)⁎ 7.262 (0.980)† 7.369 (1.027)† 7.480 (0.848) 6.726 (0.969)⁎ 6.584 (1.053)⁎ 7.079 (1.045)† 7.174 (0.925)† 6.607 (0.872) 5.918 (1.048) 6.432 (1.046)
5.844 (1.101) 6.418 (0.968)
5.411 (1.123) 4.544 (1.249)⁎ 4.292 (1.274)⁎ 4.516 (1.253)⁎ 4.840 (1.265)⁎† 65.61 (13.14) 62.07 (19.43) 67.46 (14.94)
63.25 (16.84) 63.93 (17.26)
1.044 (0.610) 0.995 (0.967) 1.269 (0.789)
1.045 (0.793) 1.085 (0.837)
123.7 (14.31) 125.7 (13.17) 123.8 (13.92)
120.5 (12.14) 120.4 (12.87)
79.05 (11.59) 76.53 (11.03) 78.13 (11.40)
76.89 (9.488) 77.02 (10.74)
Data are presented as mean (standard deviation). Compliant: heroin users without lapse. Incompliant: heroin users with lapse. TP, total power; VLF, very low frequency; HF, high frequency; LF, low frequency; SBP, systolic blood pressure; DBP, diastolic blood pressure. †p b 0.05 vs. before methadone by paired t test. ⁎ p b 0.05 vs. control group by Fisher's least significant difference test.
variance and TP increase significantly in both groups of heroin users. Finally, there are differential patterns of autonomic alteration between the heroin users on methadone treatment with and without lapse.
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While the compliant group demonstrated no significant change, the incompliant users showed significant increases in HF and RR. As expected, heroin users show a significant cardiac vagal depression. We found that heroin users, compared with an age, gender and BMI-matched healthy group, had lower HF. Since HF is an index of cardiac vagal regulation, our results indicate that chronic heroin users suffer from significant cardiac vagal depression. However, morphine and various opioids acutely repress the LF more than the HF, which presented a relatively parasympathetic dominance (Jeanne et al., 2009; Michaloudis et al., 1998). But long-term opioid use may cause up regulation of cyclic adenosine monophosphate, along with changes in gene transcription. Thus chronic opioid receptor activation results in molecular effects that are opposite to those of acute opioid administration (Cami and Farre, 2003). This phenomenon is in correspondence with the vagal depression detected among our participants who reported heroin use on average for 10 years; this was based on the interval between patients' current age and the onset age of heroin use. Consistent with our prediction, autonomic dysfunction can be restored after acute methadone treatment. This is consistent with previous findings that parasympathetic tone is increased among some pregnant women on a peak methadone dose compared with a trough dose (Jansson et al., 2007). In the short-term, methadone may be a cardiovascular protective for heroin users. One hour after methadone administration, there were different patterns of altered cardiovascular autonomic function depending on whether there had been a heroin use lapse within the last 10 days. While the compliant group demonstrated no significant change, the incompliant users showed significant increases in HF and RR. Thus methadone therapy is associated with improved HF in heroin users who have lapsed. This implies that methadone might be discriminately protective with respect to cardiovagal function among incompliant users but not among compliant users. This might partially contribute to the finding that there is reduction in mortality of 40% among patients on methadone maintenance therapy compared to the predicted mortality risk prior to the therapy (Clausen et al., 2008). In comparison, sympathetic activity of heroin users remained unchanged after 1 h of methadone administration. Past studies showed increased sympathetic activity at baseline (Barutcu et al.,
Fig. 1. Mean R–R interval (RR) parameters of heart rate variability among the health control group, the heroin users without lapse (compliant group) and the heroin users with lapse (incompliant group). TP, total power; HF, high-frequency power; LF%, normalized low-frequency power; values are means ± SD. *p b 0.05 vs. control group by Fisher's least significant difference test; †p b 0.05 vs. before methadone by paired t test.
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2005) or acutely (Manzano et al., 2011) among tobacco users. Acute ingestion of alcohol also caused sympathetic activation and vagal withdrawal (Bau et al., 2011). Our results partially support the fact that heroin users in our study did not smoke or drink alcohol during data collection. Heroin has a half-life of 30 min, but the duration of action is about 4 to 5 h due to the presence of active metabolites including morphine. Opioid withdrawal symptoms of heroin peak within 36 to 72 h and last for 7 to 10 days (Kosten and O'Connor, 2003). Although the scores of SOWS were low and had no difference between the two groups, it is conceivable that heroin users who lapse within 10 days may manifest more subtle symptoms and signs of opioid withdrawal. For example, the compliant and incompliant groups presented with significant different baseline heart rate despite the heart rate were within normal range. The half-life of methadone is approximately 22 h (Eap et al., 2002) so methadone is used as substitution therapy to treat opioid dependence. The effects of the methadone therapy were quite different in the two groups. It suggests short-term cardiovascular benefit for incompliant heroin users. Overall, 61.25% (49/80) of heroin users in our study had lapsed within the 10 days, and this is similar to previous studies that half of all heroin addicts during methadone treatment report lapse within the preceding 14-day period (Senbanjo et al., 2009). However, they may deny relapse due to various reasons. The differential patterns of autonomic alteration under methadone between heroin users with and without lapse might be used as an objective measure of lapse and allow individualized treatment for patients. There are several limitations in our study. First, heroin use is usually combined with poly-substance use. Cigarette and alcohol consumption are the most prevalent and might influence heart rate variability as discussed above. Although the Q scores for all substance use showed no significant difference between the two groups of heroin users, the decrease in vagal activity among heroin user might be attributable to some extent to multiple substance use. Second, whether heroin users had lapse within 10 days or not is based on self report. There may be recall bias among patients with drug dependence. Though we have provided reassurance for participants about answering the date of last heroin use, it would be better to perform continuous urine drug screening at an interval of 2–3 days to confirm it objectively. Third, there is a lack of more structured interview to confirm psychiatric comorbidities more firmly in our study. Unrecognized comorbidities among heroin users might be confounding. Fourth, our study is limited by crosssectional design and short-term intervention. A longitudinal follow-up study is necessary to explore the development of vagal impairment in heroin users and the long-term cardiovascular effect of methadone therapy. Fifth, the relatively small sample size in our pilot study limits the further interpretation of our results. In the future, larger sample size is needed to confirm our novel findings. In conclusion, heroin users show reduced cardiac vagal modulation and methadone therapy raised vagal activity directly in patients who had recently relapsed into heroin use. The differential patterns of autonomic response under methadone between heroin users with and without lapse might have the potential of becoming an objective and reliable measure of lapse. As a pilot study in this field, our results provide new insights into autonomic regulation of heroin users. We also pointed out difficulties in studying autonomic modulation among heroin users. More comprehensive study design is needed to validate the phenomenon and further explore the underlying mechanism. Author contributions Conceived and designed the experiments: LRC, YHL and CCHY. Performed the experiments: LRC and YHL. Analyzed the data: LRC, YHL, TBJK and YCH. Contributed reagents/materials/analysis tools: TBJK, YCH, SHC, HCWC and CML. Wrote the paper: LRC, YHL and CCHY.
Acknowledgments and disclosures This study was supported by a grant (NTUHYL.99N015) from the National Taiwan University Hospital, Yun-Lin Branch, and a grant (NSC-99-2627-B-010-005) from the National Science Council (Taiwan). We appreciate the valuable comments of Dr. Sun-Yuan Chou and Dr. Meng-Chuan Lai. We also thank Mr. Ying-Zai Chen, Mr. Chun-Ting Lai and Ms. Ying-Hua Huang for their technical assistance. The authors report no competing interests.
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