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Benzodiazepine co-dependence exacerbates the opiate withdrawal syndrome
Drug and Alcohol Dependence 76 (2004) 31–35
Benzodiazepine co-dependence exacerbates the opiate withdrawal syndrome Cornelis de Wet a , Laurence Reed a , Anthony Glasper c , Paul Moran d , Jennifer Bearn a,b,∗ , Michael Gossop a,b a
Wickham Park House, South London & Maudsley NHS Trust Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent BR3 3BX, UK b National Addiction Centre, Institute of Psychiatry, 4 Windsor Walk, London SE5 8AF, UK c Drug Dependency Unit, St. George’s Hospital, Clare House, Cranmer Terrace, Tooting, London, UK d Health Services Research Department, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK Received 9 September 2003; received in revised form 23 March 2004; accepted 5 April 2004
Abstract Patients seeking treatment for opiate withdrawal are commonly also dependent on benzodiazepines, although the interactions between benzodiazepine and opiate dependence and withdrawal syndromes have been subject to little systematic investigation. This is the first study comparing type, severity and course of opiate withdrawal symptoms between opiate dependent patients with, and without, concurrent benzodiazepine dependence. Patients dependent only on opiates (n = 39), and patients dependent on both opiates and benzodiazepines (n = 22), were recruited from consecutive admissions to an in-patient drug treatment unit. Quantity and duration of prior opiate use was similar for both groups. Patients completed daily self-ratings of opiate withdrawal (SOWS) for the duration of a standard in-patient detoxification treatment. Co-dependent patients were detoxified from benzodiazepines and opiates concurrently. Co-dependent patients reported a more severe withdrawal symptoms than patients withdrawing from opiates alone. Co-dependent patients had significantly more severe opiate withdrawal symptoms. Concurrent benzodiazepine withdrawal exacerbates opiate specific withdrawal symptoms. Possible psychological and neurophysiological mechanisms for the observed sensitisation are discussed. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Benzodiazepine; Opiate; Withdrawal; Dependence; Detoxification
1. Introduction Despite its high prevalence (Bleich et al., 1999; Gossop et al., 1998; Rooney et al., 1999; San et al., 1993), the influence of benzodiazepine co-dependence on the clinical course and outcome of the treatment of opiate withdrawal has received little attention. Benzodiazepine abuse and dependence are frequently included as outcome measures of the efficacy of methadone maintenance programmes (Bleich et al., 1999; Shaffer and La Salvia, 1993) but are seldom considered in clinical efficacy trials of opiate detoxification treatments. Of 20 methadone detoxification treatment trials reviewed in the Cochrane Database Systematic Review ∗ Corresponding author. Tel.: +44 208 776-4114; fax: +44 208 776 2026. E-mail address: [email protected] (J. Bearn).
(Amato et al., 2002) only two studies specifically exclude benzodiazepine co-dependent patients. Yet there are no systematic clinical studies of the influence of benzodiazepine co-dependence on efficacy, clinical course or outcome of opiate detoxification treatment, or of the opiate withdrawal syndrome during detoxification from both opiates and benzodiazepines. The opiate and benzodiazepine withdrawal syndromes are understood to have distinct clinical symptoms, driven by discrete neurobiological mechanisms: noradrenergic activity in the locus coeruleus (LC) for opiate withdrawal (Rasmussen et al., 1990), and ␥-aminobutyric acid (GABA-ergic) for benzodiazepine withdrawal. However, there is also a substantial symptom overlap between the withdrawal syndromes. Overlapping symptoms include anxiety, irritability, insomnia and general malaise, which may be related to interactions between these neurochemical pathways.
0376-8716/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2004.04.002
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C. de Wet et al. / Drug and Alcohol Dependence 76 (2004) 31–35
Benzodiazepine compounds attenuate the opiate withdrawal syndrome (Drummond et al., 1989; Sugerman et al., 1971) by promoting inhibitory GABA-ergic input to the locus coeruleus (Gray, 1996). Benzodiazepine withdrawal might diminish the inhibitory GABA-ergic input to the LC, and exacerbate opiate withdrawal symptoms, although this has not been investigated in animals or humans. Concurrent withdrawal from both opiates and benzodiazepines might be predicted to selectively exacerbate specific symptoms common to both withdrawal syndromes, influence both the pattern and course of the opiate withdrawal syndrome, and short-term treatment outcome. The present study compares the type, severity and course of opiate withdrawal symptoms between opiate dependent patients with, and without concurrent benzodiazepine dependence, during in-patient detoxification treatment. This is the first systematic clinical evaluation of the opiate withdrawal syndrome during detoxification from both opiates and benzodiazepines. The study uses a naturalistic treatment setting to maximise the generalisability of our findings to other treatment settings.
2. Methods 2.1. Patients All patients consecutively admitted for in-patient methadone detoxification treatment on a dedicated drug dependence unit over a 6-month period were screened for the study. On admission, all patients underwent a comprehensive clinical and diagnostic interview by an experienced psychiatrist, physical examination, routine blood tests and urine drug screen. Eligible patients had a current DSM-IV diagnosis of opiate dependence alone (O), or concurrent diagnoses of both opiate dependence and benzodiazepine dependence at admission (OB). Subjective reports of opiate and benzodiazepine use were corroborated by urine testing for a range of drugs of misuse. Exclusion criteria were (1) any additional diagnosis of alcohol, cocaine or amphetamine dependence, (2) medical or other conditions that would require non-standard detoxification treatment, e.g. severe hepatic impairment, (3) severe mental illness, (4) pregnancy and (5) discharge within the first 3 days of admission, and prior to the start of the detoxification regimen. The South London & Maudsley NHS Trust Ethics Committee approved the study, and all subjects provided written informed consent to participate. 2.2. Standard clinical treatment The in-patient treatment programme lasted for up to 4 weeks and included a medical detoxification, and a structured individual and group relapse prevention programme, within a rigorous drug-free environment maintained by frequent random urine testing. Patients reported
subjective withdrawal symptoms daily (as described below), for research purposes only. Drug-free status was confirmed by random urine testing at least three times a week. On admission all patients underwent an initial 3-day stabilisation period, whereby methadone was titrated against objective and subjective withdrawal symptoms, guided by estimates of prior total daily opiate use. One gram of local illicit heroin was estimated as equivalent to 60 mg methadone (Department of Health, 1999). Over the 3-day period patients were titrated to a stabilisation dose, a proxy measure of severity of opiate dependence. Co-dependent patients (OB) underwent a concurrent 3-day diazepam stabilisation by titration against withdrawal symptoms. Following stabilisation all patients underwent a linear methadone dose reduction on a sliding scale from their initial methadone stabilisation dose over a period of about 10 days (mean 10.7 days, S.D. 3.0 days; 10.3 days for the O alone group, and 11.5 days for the OB group, t = 1.4, P = 0.17). Co-dependent patients (OB) underwent a simultaneous linear diazepam dose reduction over mean 12.9 (S.D. 3.6) days, depending on their diazepam stabilisation dose. 2.3. Measures Patients completed the short opiate withdrawal scale (SOWS) daily for up to 28 days, at approximately 9:00 a.m. after morning medication. The SOWS has established psychometric properties and provides a sensitive measure of withdrawal severity and changes in withdrawal severity (Gossop, 1990). The SOWS items are: feeling sick, stomach cramps, muscle spasms/twitching, feelings of coldness, heart pounding/racing, muscle tension/feeling tense, aches and pains, yawning, runny eyes, and insomnia/sleeping problems. Items were rated as none, mild, moderate or severe, accordingly scored from zero to three, and summated to yield a score out of a maximum of 30. Mean total withdrawal scores and daily mean scores for individual SOWS items were calculated for comparison between groups. 2.4. Statistical analysis Basic demographic data and withdrawal scores were coded using validation functions and random repeat encoding to detect and reduce transcription errors. Data were analysed using the Statistical Package for Social Sciences for Windows® version 10. Categorical and continuous variables were compared using the Chi-square and t-tests, respectively, where appropriate. Where indicated, multiple regression analysis was performed to control for candidate confounding variables in the association between benzodiazepine co-dependence and mean SOWS scores. Item-by-item analysis of SOWS items was subjected to Bonferroni correction by multiplying each P-value by 10 (the number of items tested).
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Table 2 Mean detoxification SOWS symptom scores of opiate dependent (O) and opiate-benzodiazepine co-dependent (OB) subjects (score range 0–3)
3. Results 3.1. Sample characteristics The study sample comprised 61 participants: 39 opiate dependent (O), and 22 opiate/benzodiazepine co-dependent patients (OB). Mean age was 34.9 years (range 20–57 years, S.D. 8.4). There were no group differences in respect of age, gender, or duration and amount of prior opiate use (Table 1). Patients returned 88.0% of the SOWS ratings (89.3% for O group and 85.4% for OB group, t = 1.2, P = 0.22). Patients had been using heroin for a mean of 12.3 years (range 1.7–30.5), since mean age 22.4 (range 14–39). Thirty-six patients (59%) were intravenous drug users, and a further 15 (25%) had previously injected. Prior to admission 52 patients (85%) were receiving opiate replacement therapy. Patients reported mean daily opiate use equivalent to 56.9 mg of methadone (S.D. 28.7). 3.2. Stabilisation and detoxification The patients dependent only on opiates (O) were stabilised on a mean methadone dose of 47.4 mg. Patients who were dependent on both opiates and benzodiazepines (OB) were stabilised on similar methadone doses (53.9 mg, t = 1.3, P = 0.21) and a mean diazepam stabilisation dose of 30.3 mg (S.D. 12.7, range 6–60 mg), with no association between benzodiazepine and methadone stabilisation doses (Table 1). Reported pre-admission opiate use correlated with methadone stabilisation dose, as expressed in methadone equivalence (r = 0.4, P = 0.001), suggesting adequate dose titration during the stabilisation period. 3.3. Symptom severity Co-dependent patients (OB) reported significantly higher opiate withdrawal scores for the detoxification period (t = 2.88, P = 0.006) (Table 1). SOWS scores were significantly
Item
O (n = 39)
OB (n = 22)
t
P-valuea
Feeling sick Stomach cramps Muscle spasm Feelings of coldness Heart pounding Muscle tension Aches and pains Yawning Runny eyes Insomnia
0.98 0.94 0.96 1.21 0.70 1.05 1.32 1.14 0.90 1.57
1.44 1.62 1.60 1.74 1.02 1.76 1.91 1.52 1.31 2.06
2.30 3.46 3.03 2.87 1.60 3.07 2.80 1.99 2.24 2.32
0.25 0.01 0.04 0.06 1.0 0.03 0.07 0.51 0.29 0.24
a Bonferroni corrected by multiplying P-value by 10 (number of items tested).
greater (P < 0.05) on days 3 and 4, days 11–14, and day 16, 17, and 19 of detoxification, peaking on day 13. The peak SOWS score for OB patients was 19.4 (day 13), and peak SOWS score for O patients was 11.6 (day 10). There was a trend for OB patients to report higher SOWS at baseline, during the initial stabilisation period, but the difference between groups was not statistically significant (t = 1.95, P = 0.06). When the higher baseline (mean stabilisation SOWS) was controlled for, the effect of benzodiazepine co-dependence remained significant (F = 4.0, P < 0.05). Individual symptom withdrawal scores were compared between groups for the withdrawal period (Table 2): OB patients scored higher on all SOWS items. When subjected to Bonferroni correction there were statistically significant differences for stomach cramps, muscles spasm and muscle tension (P < 0.05). Neither stabilisation nor withdrawal SOWS scores were significantly predicted by methadone stabilisation dose (r = 0.17, P = 0.2, and r = 0.23, P = 0.8), nor were SOWS scores related to diazepam stabilisation dose, or duration of drug use.
Table 1 Patient characteristics
Male gender Age (years) Age of first heroin use (years) Prior opiate use (mean daily methadone equiv.) Prior benzodiazepine use (mean daily diazepam equiv.) History of treatment for depression History of anxiety disorder Methadone stabilisation dose (n = 39) Diazepam stabilisation dose (n = 22) Mean stabilisation SOWS Mean withdrawal SOWS
Opiate only dependent (O) (N = 39)
Opiate-benzodiazepine co-dependent (OB) (N = 22)
P-value (t-test/2 -test)
27 (69%) 34.6 (S.D. 8.2) 22.5 (S.D. 5.8) 58.5 mg (S.D. 32.7)
11 (50%) 35.5 (S.D. 8.7) 22.3 (S.D. 6.9) 53.9 mg (S.D. 18.8)
0.14 0.66 0.90 0.57
32.2 mg (S.D. 20.3)
0.005
9 (40.9%) 3 (13.6%) 53.9 mg (S.D. 18.8) 30.3 mg (S.D. 12.7) 14.2 (S.D. 6.8) 15.8 (S.D. 6.7)
0.33 0.25 0.21 N/A 0.56 0.006
7.1 mg (S.D. 12.3) (n = 7) 21 (53.9%) 2 (5.1%) 47.4 mg (S.D. 19.2) N/A 10.6 (S.D. 6.5) 10.7 (S.D. 6.5)
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3.4. Length of stay The median length of stay for the whole sample was 19 days (mode 28 days). Mean lengths of stay were 20.8 days for the O group, and 16.7 days for OB group (t = 2.0, P = 0.51). Co-dependent patients were less likely to complete the medical phase of detoxification than those undergoing only an opiate detoxification (41% versus 85%, P < 0.001).
4. Discussion This naturalistic study is the first to examine the clinical impact of benzodiazepine co-dependence on opiate withdrawal severity. The results show exacerbation of opiate withdrawal symptoms associated with benzodiazepine co-dependence, and a lower detoxification completion rate in co-dependent patients. 4.1. Exacerbation of opiate withdrawal symptoms The observed findings may be explained by a number of mechanisms. Withdrawal severity may be related to anxiety (Phillips et al., 1986), and higher symptom ratings in the co-dependent group may reflect that individuals belonging to this group may have more anxious personality, or anxiety-related rebound phenomena. Psychological trait and state are both important potential confounders to be considered when interpreting subjective symptom reports, and may in themselves be psycho-behavioural manifestations of the withdrawal syndrome. In this study, patients with major mental illness were excluded, and the relatively mild levels of psychopathology did not differ between groups. There was no difference in withdrawal symptom scores before detoxification between the opiate only and the co-dependent group, suggesting no psychological confounding at baseline level. When the non-significant difference in baseline scores was controlled for, the SOWS score in OB subjects remained higher than for the O subjects. The more severe opiate withdrawal symptoms may be due to heightened perceptual sensitivity resulting from benzodiazepine withdrawal, leading to more severe subjective experience and rating of symptoms, or anxiety as a withdrawal symptom per se. Rebound anxiety and depression might be expected to occur later, and be more protracted than benzodiazepine withdrawal symptoms. However, in the co-dependent subjects symptom severity appears to rise and decay over less than 21 days, suggesting a specific withdrawal related exacerbation. The symptom pattern and duration of opiate withdrawal symptoms appear to be broadly comparable to those seen in trials of opiate and ␣-adrenergic detoxification treatments (Bearn et al., 1996), and co-dependence does not appear to extend the duration of the opiate withdrawal syndrome. In the present study, withdrawal scores were collected only for the first 28 days after admission. It is possible that some rebound effects may occur after this time, which
might be detected by a study with a longer measurement period. Exacerbation of the opiate withdrawal syndrome may reflect neurophysiological sensitisation induced by concurrent benzodiazepine dependence. Substantial evidence implicates the locus coeruleus (LC) in opiate-withdrawal symptoms. Increased activity and noradrenaline release in the LC neurones correlate with withdrawal symptoms, destruction of the LC reduces opiate withdrawal, and clonidine, an ␣2-adrenergic agonist, suppresses LC activity, noradrenaline release and many opiate withdrawal symptoms (Rasmussen et al., 1990). The major inputs mediating the opiate-withdrawal response in the locus coeruleus originate from the nucleus paragigantocellularis (PGi) in the rostral ventrolateral medulla, and comprise both excitatory (glutamate) and inhibitory (GABA) components (Ennis and Aston-Jones, 1988). Opiate withdrawal is associated with increased excitatory glutamate release from the PGi leading to increased LC activation. Benzodiazepine withdrawal leads to reduced GABA-ergic and increased glutamatergic output (Nutt, 1990). When this occurs concurrent with opiate withdrawal it may reduce the inhibitory and increase the excitatory input from the PGi to LC, and enhance noradrenaline release, thereby exacerbating opiate withdrawal symptoms. Clarification of this hypothesis requires further animal micro-dialysis studies. The present study measured a limited range of individual symptoms during medically assisted withdrawal. The full-blown syndrome is attenuated, and specific, clinically important differences in symptoms between groups, particularly behavioural and affective symptoms, may have been obscured by treatment. These withdrawal symptoms are significantly exacerbated in the co-dependent group, especially stomach cramps, and muscle tension and spasm. The reason for differential exacerbation of symptoms is unclear, but the most severe symptoms are relatively specific to opiate withdrawal, and seem unlikely to be directly related to anxiety, or to be driven by benzodiazepine withdrawal. Further research measuring a greater range of both objective and subjective withdrawal symptoms, as well as informative biological markers known to be associated with opiate withdrawal e.g. plasma cortisol levels (Bearn et al., 2001), may be worthwhile. 4.2. Treatment of co-dependence The results suggest that during concurrent opiate and benzodiazepine withdrawal, patients may suffer not only benzodiazepine-specific withdrawal phenomena, but also experience exacerbated opiate withdrawal symptoms. Co-dependent patients were less likely to complete medical treatment, and as such left treatment at a time when they were highly vulnerable to relapse. The poorer completion rates by co-dependent patients should, however, be interpreted in context. Although length of stay is similar between groups, the diazepam tapering schedules used in
C. de Wet et al. / Drug and Alcohol Dependence 76 (2004) 31–35
this study are slightly longer than opiate withdrawal schedules, and premature discharge is not simply the result of withdrawal symptom severity. Our results suggest that concurrent opiate and benzodiazepine detoxification may not be the optimal management strategy for co-dependence, and imply a case for sequential detoxification, or benzodiazepine reduction (Bleich et al., 2002; McDuff et al., 1993; Stitzer et al., 1982). Further research could be carried out to determine if this is more effectively done prior to opiate detoxification, or subsequent to it. Also, future clinical studies may show some detoxification treatments to be more efficacious than others in the treatment of co-dependent patients. Our findings are derived from an in-patient sample, and direct extrapolation to the opiate maintenance setting is speculative. It is nevertheless interesting to consider the possibility that co-dependent opiate maintenance patients may experience more severe intermittent opiate withdrawals between treatment administrations, with concurrent benzodiazepine withdrawal, especially if co-dependent benzodiazepine use is erratic (Strang et al., 1994). This may in turn augment the risk of additional drug use (Bleich et al., 1999). Benzodiazepine use may also complicate known risks associated with co-dependence, e.g. seizures and overdose (Oliver and Keen, 2003; Reynaud et al., 1998). Studies of the relationship of residual withdrawal symptoms and instability of treatment response to opiate replacement are required to explore this further. 4.3. Conclusion This naturalistic study of patients receiving medical detoxification treatments provides preliminary evidence that concurrent benzodiazepine dependence exacerbates opiate withdrawal. Our analyses suggest that the exacerbation is not simply due to benzodiazepine-related anxiety, and does not result from a protracted benzodiazepine rebound phenomenon. Future studies should include longitudinal measures of anxiety and affective state.
Acknowledgements We are grateful to patients and staff on Wickham Park House for their support and commitment to this study. This study was supported by internal funds only.
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Benzodiazepine co-dependence exacerbates the opiate withdrawal syndrome Cornelis de Wet a , Laurence Reed a , Anthony Glasper c , Paul Moran d , Jennifer Bearn a,b,∗ , Michael Gossop a,b a
Wickham Park House, South London & Maudsley NHS Trust Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent BR3 3BX, UK b National Addiction Centre, Institute of Psychiatry, 4 Windsor Walk, London SE5 8AF, UK c Drug Dependency Unit, St. George’s Hospital, Clare House, Cranmer Terrace, Tooting, London, UK d Health Services Research Department, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK Received 9 September 2003; received in revised form 23 March 2004; accepted 5 April 2004
Abstract Patients seeking treatment for opiate withdrawal are commonly also dependent on benzodiazepines, although the interactions between benzodiazepine and opiate dependence and withdrawal syndromes have been subject to little systematic investigation. This is the first study comparing type, severity and course of opiate withdrawal symptoms between opiate dependent patients with, and without, concurrent benzodiazepine dependence. Patients dependent only on opiates (n = 39), and patients dependent on both opiates and benzodiazepines (n = 22), were recruited from consecutive admissions to an in-patient drug treatment unit. Quantity and duration of prior opiate use was similar for both groups. Patients completed daily self-ratings of opiate withdrawal (SOWS) for the duration of a standard in-patient detoxification treatment. Co-dependent patients were detoxified from benzodiazepines and opiates concurrently. Co-dependent patients reported a more severe withdrawal symptoms than patients withdrawing from opiates alone. Co-dependent patients had significantly more severe opiate withdrawal symptoms. Concurrent benzodiazepine withdrawal exacerbates opiate specific withdrawal symptoms. Possible psychological and neurophysiological mechanisms for the observed sensitisation are discussed. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Benzodiazepine; Opiate; Withdrawal; Dependence; Detoxification
1. Introduction Despite its high prevalence (Bleich et al., 1999; Gossop et al., 1998; Rooney et al., 1999; San et al., 1993), the influence of benzodiazepine co-dependence on the clinical course and outcome of the treatment of opiate withdrawal has received little attention. Benzodiazepine abuse and dependence are frequently included as outcome measures of the efficacy of methadone maintenance programmes (Bleich et al., 1999; Shaffer and La Salvia, 1993) but are seldom considered in clinical efficacy trials of opiate detoxification treatments. Of 20 methadone detoxification treatment trials reviewed in the Cochrane Database Systematic Review ∗ Corresponding author. Tel.: +44 208 776-4114; fax: +44 208 776 2026. E-mail address: [email protected] (J. Bearn).
(Amato et al., 2002) only two studies specifically exclude benzodiazepine co-dependent patients. Yet there are no systematic clinical studies of the influence of benzodiazepine co-dependence on efficacy, clinical course or outcome of opiate detoxification treatment, or of the opiate withdrawal syndrome during detoxification from both opiates and benzodiazepines. The opiate and benzodiazepine withdrawal syndromes are understood to have distinct clinical symptoms, driven by discrete neurobiological mechanisms: noradrenergic activity in the locus coeruleus (LC) for opiate withdrawal (Rasmussen et al., 1990), and ␥-aminobutyric acid (GABA-ergic) for benzodiazepine withdrawal. However, there is also a substantial symptom overlap between the withdrawal syndromes. Overlapping symptoms include anxiety, irritability, insomnia and general malaise, which may be related to interactions between these neurochemical pathways.
0376-8716/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2004.04.002
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C. de Wet et al. / Drug and Alcohol Dependence 76 (2004) 31–35
Benzodiazepine compounds attenuate the opiate withdrawal syndrome (Drummond et al., 1989; Sugerman et al., 1971) by promoting inhibitory GABA-ergic input to the locus coeruleus (Gray, 1996). Benzodiazepine withdrawal might diminish the inhibitory GABA-ergic input to the LC, and exacerbate opiate withdrawal symptoms, although this has not been investigated in animals or humans. Concurrent withdrawal from both opiates and benzodiazepines might be predicted to selectively exacerbate specific symptoms common to both withdrawal syndromes, influence both the pattern and course of the opiate withdrawal syndrome, and short-term treatment outcome. The present study compares the type, severity and course of opiate withdrawal symptoms between opiate dependent patients with, and without concurrent benzodiazepine dependence, during in-patient detoxification treatment. This is the first systematic clinical evaluation of the opiate withdrawal syndrome during detoxification from both opiates and benzodiazepines. The study uses a naturalistic treatment setting to maximise the generalisability of our findings to other treatment settings.
2. Methods 2.1. Patients All patients consecutively admitted for in-patient methadone detoxification treatment on a dedicated drug dependence unit over a 6-month period were screened for the study. On admission, all patients underwent a comprehensive clinical and diagnostic interview by an experienced psychiatrist, physical examination, routine blood tests and urine drug screen. Eligible patients had a current DSM-IV diagnosis of opiate dependence alone (O), or concurrent diagnoses of both opiate dependence and benzodiazepine dependence at admission (OB). Subjective reports of opiate and benzodiazepine use were corroborated by urine testing for a range of drugs of misuse. Exclusion criteria were (1) any additional diagnosis of alcohol, cocaine or amphetamine dependence, (2) medical or other conditions that would require non-standard detoxification treatment, e.g. severe hepatic impairment, (3) severe mental illness, (4) pregnancy and (5) discharge within the first 3 days of admission, and prior to the start of the detoxification regimen. The South London & Maudsley NHS Trust Ethics Committee approved the study, and all subjects provided written informed consent to participate. 2.2. Standard clinical treatment The in-patient treatment programme lasted for up to 4 weeks and included a medical detoxification, and a structured individual and group relapse prevention programme, within a rigorous drug-free environment maintained by frequent random urine testing. Patients reported
subjective withdrawal symptoms daily (as described below), for research purposes only. Drug-free status was confirmed by random urine testing at least three times a week. On admission all patients underwent an initial 3-day stabilisation period, whereby methadone was titrated against objective and subjective withdrawal symptoms, guided by estimates of prior total daily opiate use. One gram of local illicit heroin was estimated as equivalent to 60 mg methadone (Department of Health, 1999). Over the 3-day period patients were titrated to a stabilisation dose, a proxy measure of severity of opiate dependence. Co-dependent patients (OB) underwent a concurrent 3-day diazepam stabilisation by titration against withdrawal symptoms. Following stabilisation all patients underwent a linear methadone dose reduction on a sliding scale from their initial methadone stabilisation dose over a period of about 10 days (mean 10.7 days, S.D. 3.0 days; 10.3 days for the O alone group, and 11.5 days for the OB group, t = 1.4, P = 0.17). Co-dependent patients (OB) underwent a simultaneous linear diazepam dose reduction over mean 12.9 (S.D. 3.6) days, depending on their diazepam stabilisation dose. 2.3. Measures Patients completed the short opiate withdrawal scale (SOWS) daily for up to 28 days, at approximately 9:00 a.m. after morning medication. The SOWS has established psychometric properties and provides a sensitive measure of withdrawal severity and changes in withdrawal severity (Gossop, 1990). The SOWS items are: feeling sick, stomach cramps, muscle spasms/twitching, feelings of coldness, heart pounding/racing, muscle tension/feeling tense, aches and pains, yawning, runny eyes, and insomnia/sleeping problems. Items were rated as none, mild, moderate or severe, accordingly scored from zero to three, and summated to yield a score out of a maximum of 30. Mean total withdrawal scores and daily mean scores for individual SOWS items were calculated for comparison between groups. 2.4. Statistical analysis Basic demographic data and withdrawal scores were coded using validation functions and random repeat encoding to detect and reduce transcription errors. Data were analysed using the Statistical Package for Social Sciences for Windows® version 10. Categorical and continuous variables were compared using the Chi-square and t-tests, respectively, where appropriate. Where indicated, multiple regression analysis was performed to control for candidate confounding variables in the association between benzodiazepine co-dependence and mean SOWS scores. Item-by-item analysis of SOWS items was subjected to Bonferroni correction by multiplying each P-value by 10 (the number of items tested).
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Table 2 Mean detoxification SOWS symptom scores of opiate dependent (O) and opiate-benzodiazepine co-dependent (OB) subjects (score range 0–3)
3. Results 3.1. Sample characteristics The study sample comprised 61 participants: 39 opiate dependent (O), and 22 opiate/benzodiazepine co-dependent patients (OB). Mean age was 34.9 years (range 20–57 years, S.D. 8.4). There were no group differences in respect of age, gender, or duration and amount of prior opiate use (Table 1). Patients returned 88.0% of the SOWS ratings (89.3% for O group and 85.4% for OB group, t = 1.2, P = 0.22). Patients had been using heroin for a mean of 12.3 years (range 1.7–30.5), since mean age 22.4 (range 14–39). Thirty-six patients (59%) were intravenous drug users, and a further 15 (25%) had previously injected. Prior to admission 52 patients (85%) were receiving opiate replacement therapy. Patients reported mean daily opiate use equivalent to 56.9 mg of methadone (S.D. 28.7). 3.2. Stabilisation and detoxification The patients dependent only on opiates (O) were stabilised on a mean methadone dose of 47.4 mg. Patients who were dependent on both opiates and benzodiazepines (OB) were stabilised on similar methadone doses (53.9 mg, t = 1.3, P = 0.21) and a mean diazepam stabilisation dose of 30.3 mg (S.D. 12.7, range 6–60 mg), with no association between benzodiazepine and methadone stabilisation doses (Table 1). Reported pre-admission opiate use correlated with methadone stabilisation dose, as expressed in methadone equivalence (r = 0.4, P = 0.001), suggesting adequate dose titration during the stabilisation period. 3.3. Symptom severity Co-dependent patients (OB) reported significantly higher opiate withdrawal scores for the detoxification period (t = 2.88, P = 0.006) (Table 1). SOWS scores were significantly
Item
O (n = 39)
OB (n = 22)
t
P-valuea
Feeling sick Stomach cramps Muscle spasm Feelings of coldness Heart pounding Muscle tension Aches and pains Yawning Runny eyes Insomnia
0.98 0.94 0.96 1.21 0.70 1.05 1.32 1.14 0.90 1.57
1.44 1.62 1.60 1.74 1.02 1.76 1.91 1.52 1.31 2.06
2.30 3.46 3.03 2.87 1.60 3.07 2.80 1.99 2.24 2.32
0.25 0.01 0.04 0.06 1.0 0.03 0.07 0.51 0.29 0.24
a Bonferroni corrected by multiplying P-value by 10 (number of items tested).
greater (P < 0.05) on days 3 and 4, days 11–14, and day 16, 17, and 19 of detoxification, peaking on day 13. The peak SOWS score for OB patients was 19.4 (day 13), and peak SOWS score for O patients was 11.6 (day 10). There was a trend for OB patients to report higher SOWS at baseline, during the initial stabilisation period, but the difference between groups was not statistically significant (t = 1.95, P = 0.06). When the higher baseline (mean stabilisation SOWS) was controlled for, the effect of benzodiazepine co-dependence remained significant (F = 4.0, P < 0.05). Individual symptom withdrawal scores were compared between groups for the withdrawal period (Table 2): OB patients scored higher on all SOWS items. When subjected to Bonferroni correction there were statistically significant differences for stomach cramps, muscles spasm and muscle tension (P < 0.05). Neither stabilisation nor withdrawal SOWS scores were significantly predicted by methadone stabilisation dose (r = 0.17, P = 0.2, and r = 0.23, P = 0.8), nor were SOWS scores related to diazepam stabilisation dose, or duration of drug use.
Table 1 Patient characteristics
Male gender Age (years) Age of first heroin use (years) Prior opiate use (mean daily methadone equiv.) Prior benzodiazepine use (mean daily diazepam equiv.) History of treatment for depression History of anxiety disorder Methadone stabilisation dose (n = 39) Diazepam stabilisation dose (n = 22) Mean stabilisation SOWS Mean withdrawal SOWS
Opiate only dependent (O) (N = 39)
Opiate-benzodiazepine co-dependent (OB) (N = 22)
P-value (t-test/2 -test)
27 (69%) 34.6 (S.D. 8.2) 22.5 (S.D. 5.8) 58.5 mg (S.D. 32.7)
11 (50%) 35.5 (S.D. 8.7) 22.3 (S.D. 6.9) 53.9 mg (S.D. 18.8)
0.14 0.66 0.90 0.57
32.2 mg (S.D. 20.3)
0.005
9 (40.9%) 3 (13.6%) 53.9 mg (S.D. 18.8) 30.3 mg (S.D. 12.7) 14.2 (S.D. 6.8) 15.8 (S.D. 6.7)
0.33 0.25 0.21 N/A 0.56 0.006
7.1 mg (S.D. 12.3) (n = 7) 21 (53.9%) 2 (5.1%) 47.4 mg (S.D. 19.2) N/A 10.6 (S.D. 6.5) 10.7 (S.D. 6.5)
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3.4. Length of stay The median length of stay for the whole sample was 19 days (mode 28 days). Mean lengths of stay were 20.8 days for the O group, and 16.7 days for OB group (t = 2.0, P = 0.51). Co-dependent patients were less likely to complete the medical phase of detoxification than those undergoing only an opiate detoxification (41% versus 85%, P < 0.001).
4. Discussion This naturalistic study is the first to examine the clinical impact of benzodiazepine co-dependence on opiate withdrawal severity. The results show exacerbation of opiate withdrawal symptoms associated with benzodiazepine co-dependence, and a lower detoxification completion rate in co-dependent patients. 4.1. Exacerbation of opiate withdrawal symptoms The observed findings may be explained by a number of mechanisms. Withdrawal severity may be related to anxiety (Phillips et al., 1986), and higher symptom ratings in the co-dependent group may reflect that individuals belonging to this group may have more anxious personality, or anxiety-related rebound phenomena. Psychological trait and state are both important potential confounders to be considered when interpreting subjective symptom reports, and may in themselves be psycho-behavioural manifestations of the withdrawal syndrome. In this study, patients with major mental illness were excluded, and the relatively mild levels of psychopathology did not differ between groups. There was no difference in withdrawal symptom scores before detoxification between the opiate only and the co-dependent group, suggesting no psychological confounding at baseline level. When the non-significant difference in baseline scores was controlled for, the SOWS score in OB subjects remained higher than for the O subjects. The more severe opiate withdrawal symptoms may be due to heightened perceptual sensitivity resulting from benzodiazepine withdrawal, leading to more severe subjective experience and rating of symptoms, or anxiety as a withdrawal symptom per se. Rebound anxiety and depression might be expected to occur later, and be more protracted than benzodiazepine withdrawal symptoms. However, in the co-dependent subjects symptom severity appears to rise and decay over less than 21 days, suggesting a specific withdrawal related exacerbation. The symptom pattern and duration of opiate withdrawal symptoms appear to be broadly comparable to those seen in trials of opiate and ␣-adrenergic detoxification treatments (Bearn et al., 1996), and co-dependence does not appear to extend the duration of the opiate withdrawal syndrome. In the present study, withdrawal scores were collected only for the first 28 days after admission. It is possible that some rebound effects may occur after this time, which
might be detected by a study with a longer measurement period. Exacerbation of the opiate withdrawal syndrome may reflect neurophysiological sensitisation induced by concurrent benzodiazepine dependence. Substantial evidence implicates the locus coeruleus (LC) in opiate-withdrawal symptoms. Increased activity and noradrenaline release in the LC neurones correlate with withdrawal symptoms, destruction of the LC reduces opiate withdrawal, and clonidine, an ␣2-adrenergic agonist, suppresses LC activity, noradrenaline release and many opiate withdrawal symptoms (Rasmussen et al., 1990). The major inputs mediating the opiate-withdrawal response in the locus coeruleus originate from the nucleus paragigantocellularis (PGi) in the rostral ventrolateral medulla, and comprise both excitatory (glutamate) and inhibitory (GABA) components (Ennis and Aston-Jones, 1988). Opiate withdrawal is associated with increased excitatory glutamate release from the PGi leading to increased LC activation. Benzodiazepine withdrawal leads to reduced GABA-ergic and increased glutamatergic output (Nutt, 1990). When this occurs concurrent with opiate withdrawal it may reduce the inhibitory and increase the excitatory input from the PGi to LC, and enhance noradrenaline release, thereby exacerbating opiate withdrawal symptoms. Clarification of this hypothesis requires further animal micro-dialysis studies. The present study measured a limited range of individual symptoms during medically assisted withdrawal. The full-blown syndrome is attenuated, and specific, clinically important differences in symptoms between groups, particularly behavioural and affective symptoms, may have been obscured by treatment. These withdrawal symptoms are significantly exacerbated in the co-dependent group, especially stomach cramps, and muscle tension and spasm. The reason for differential exacerbation of symptoms is unclear, but the most severe symptoms are relatively specific to opiate withdrawal, and seem unlikely to be directly related to anxiety, or to be driven by benzodiazepine withdrawal. Further research measuring a greater range of both objective and subjective withdrawal symptoms, as well as informative biological markers known to be associated with opiate withdrawal e.g. plasma cortisol levels (Bearn et al., 2001), may be worthwhile. 4.2. Treatment of co-dependence The results suggest that during concurrent opiate and benzodiazepine withdrawal, patients may suffer not only benzodiazepine-specific withdrawal phenomena, but also experience exacerbated opiate withdrawal symptoms. Co-dependent patients were less likely to complete medical treatment, and as such left treatment at a time when they were highly vulnerable to relapse. The poorer completion rates by co-dependent patients should, however, be interpreted in context. Although length of stay is similar between groups, the diazepam tapering schedules used in
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this study are slightly longer than opiate withdrawal schedules, and premature discharge is not simply the result of withdrawal symptom severity. Our results suggest that concurrent opiate and benzodiazepine detoxification may not be the optimal management strategy for co-dependence, and imply a case for sequential detoxification, or benzodiazepine reduction (Bleich et al., 2002; McDuff et al., 1993; Stitzer et al., 1982). Further research could be carried out to determine if this is more effectively done prior to opiate detoxification, or subsequent to it. Also, future clinical studies may show some detoxification treatments to be more efficacious than others in the treatment of co-dependent patients. Our findings are derived from an in-patient sample, and direct extrapolation to the opiate maintenance setting is speculative. It is nevertheless interesting to consider the possibility that co-dependent opiate maintenance patients may experience more severe intermittent opiate withdrawals between treatment administrations, with concurrent benzodiazepine withdrawal, especially if co-dependent benzodiazepine use is erratic (Strang et al., 1994). This may in turn augment the risk of additional drug use (Bleich et al., 1999). Benzodiazepine use may also complicate known risks associated with co-dependence, e.g. seizures and overdose (Oliver and Keen, 2003; Reynaud et al., 1998). Studies of the relationship of residual withdrawal symptoms and instability of treatment response to opiate replacement are required to explore this further. 4.3. Conclusion This naturalistic study of patients receiving medical detoxification treatments provides preliminary evidence that concurrent benzodiazepine dependence exacerbates opiate withdrawal. Our analyses suggest that the exacerbation is not simply due to benzodiazepine-related anxiety, and does not result from a protracted benzodiazepine rebound phenomenon. Future studies should include longitudinal measures of anxiety and affective state.
Acknowledgements We are grateful to patients and staff on Wickham Park House for their support and commitment to this study. This study was supported by internal funds only.
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