Overdose after detoxification: A prospective study

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1 Drug and Alcohol Dependence 89 (2007) Overdose after detoxification: A prospective study James D. Wines Jr. a,b,, Richard Saitz c,d, Nicholas J. Horton e, Christine Lloyd-Travaglini f, Jeffrey H. Samet c,g a Alcohol and Drug Abuse Research Center (ADARC), McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA b Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA c Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA d Department of Epidemiology and the Youth Alcohol Prevention Center, Boston, University School of Public Health, Boston, MA 02118, USA e Department of Mathematics and Statistics, Smith College, Northampton, MA 01063, USA f Data Coordinating Center, Boston University School of Public Health, Boston, MA 02118, USA g Department of Social and Behavioral Sciences, Boston University School of Public Health, Boston, MA 02118, USA Received 25 April 2006; received in revised form 28 November 2006; accepted 14 December 2006 Abstract Objective: The aim of this study was to determine predictors of non-fatal overdose (OD) among a cohort of 470 adults after detoxification from heroin, cocaine or alcohol. Methods: We examined factors associated with time to OD during 2 years after discharge from an urban detoxification unit in Boston, MA, USA using multivariable regression analyses. Separate analyses were performed for both the total sample and a subgroup with problem opioid use. Results: Lifetime prevalence for any OD was 30.9% (145/470) in the total sample and 42.3% (85/201) in patients with opioid problems. During the 2-year follow-up, OD was estimated to occur in 16.9% of the total sample and 26.7% of the opioid problem subgroup, with new-onset (incidence) OD estimated at 5.7% and 11.0%, respectively. Factors associated with an increased hazard of OD in both samples included white race, more depressive symptoms, and prior OD regardless of intent. Prior suicidal ideation or attempt was not associated with future OD. Conclusions: Findings underscore both the high prevalence of non-fatal OD among detoxification patients especially opioid users, and the potency of prior OD as a risk factor for future OD. Depressive symptoms, a modifiable risk factor, may represent a potential intervention target to prevent OD, including some unintentional ODs Elsevier Ireland Ltd. All rights reserved. Keywords: Overdose; Depressive symptoms; Opioids; Intent 1. Introduction In 2003, there were 28,700 fatal poisonings and 817,797 non-fatal poisonings in the US (CDC, 2006). Poisoning, which include overdoses (ODs) on illicit drugs, alcohol, and medications, is the leading cause of injury death for individuals age and the third leading cause of injury death overall, trailing motor vehicle accidents and firearmrelated deaths. Poisoning fatalities in 11 states increased 56% from 1990 to 2001, and unintentional poisonings, espe- Preliminary results were presented at the Complexities of Co-occurring Conditions Conference, June 23 25, 2004 in Washington, DC. Corresponding author at: McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. Tel.: ; fax: address: (J.D. Wines Jr.). cially opioid-related ODs, may be driving the increase (CDC, 2004). Opioid-related ODs have increased at an alarming rate in portions of the US (Ballesteros et al., 2003; Landen et al., 2003; Sanford, 2002; Sorg and Greenwald, 2002) and other countries (Darke and Hall, 2003; Warner-Smith et al., 2001), and OD has surpassed HIV infection as the primary cause of death for heroin users in some areas (Frischer et al., 1993). Not surprisingly, heroin is frequently associated with opioid-related ODs, both as a single drug and in combination with other substances (CDC, 2004; Darke et al., 1996a; Paulozzi, 2006; Paulozzi et al., 2006; Powis et al., 1999; Tobin and Latkin, 2003). Much of the current scientific literature regarding opioid-related OD is based on studies focused exclusively on intravenous heroin users conducted in Australia and Europe (Darke and Hall, 2003). The increased availability, misuse, abuse of and dependence on /$ see front matter 2007 Elsevier Ireland Ltd. All rights reserved. doi: /j.drugalcdep

2 162 J.D. Wines Jr. et al. / Drug and Alcohol Dependence 89 (2007) prescription opioids in the US (Compton and Volkow, 2006; Zacny et al., 2003) may limit the generalizability of these ODrelated findings from other countries to the US population and to populations abusing prescription opioids. Indeed, fatal drug poisonings related to prescription opioids now exceed heroinand cocaine-related poisoning deaths (Paulozzi, 2006; Paulozzi et al., 2006). Recently, leadership at the US National Institute on Drug Abuse (Compton and Volkow, 2006) stated,...the relationship of prescription opioid drugs to death is of increasing concern (p. 104). Unintentional OD and suicide contribute considerably to the increased mortality exhibited by heroin users (Davoli et al., 1997; Harris and Barraclough, 1997; Hser et al., 2001; Hulse et al., 1999; Oppenheimer et al., 1994; Quaglio et al., 2001). Although existing research clearly supports the notion that most opioid-related ODs are considered unintentional, the reported proportion of unintentional ODs with opioids ranges widely (e.g., from 99% (Darke et al., 1996a) to 51% (Neale, 2000) in some studies). Controversy also exists as to whether or not some unintentional ODs represent a type of hidden suicide (Darke and Ross, 2002; Kjelsberg et al., 1995; Ohberg and Lonnqvist, 1998). Fueling this debate are contradictory findings from some studies examining the relationship between suicidal behavior and OD (Best et al., 2000; Darke and Ross, 2001; Darke et al., 2004; Kosten and Rounsaville, 1988; Murphy et al., 1983; Neale, 2000; Ravndal and Vaglum, 1999; Rossow and Lauritzen, 1999; Vingoe et al., 1999). Several studies have also investigated the relationship between depressive symptoms and OD. Tobin and Latkin (2003) surveyed 729 opioid and cocaine users recruited from the community and found a strong association between elevated depressive symptoms and unintentional OD within the past year. In addition, researchers in Norway (Ravndal and Vaglum, 1999) interviewed 200 mixed drug users at entry into a therapeutic community and again after 5 years. Although opioids increased unintentional OD risk, no associations of this form of OD with psychopathology including depression were found. These results appear to contrast with the study (Tobin and Latkin, 2003) described above; however, the lack of an association between depression and unintentional OD may be explained by the use of different assessments for depression administered after a longer time interval (5 years) and perhaps by the samples selected (community versus treatment). Prospectively obtained data on non-fatal OD among subjects with diverse drug preferences are limited, especially in the US, despite steadily increasing OD rates. In addition to determining the prevalence and incidence of non-fatal OD in a cohort of patients initially admitted for detoxification from heroin, cocaine or alcohol, the purpose of this prospective study was to (1) improve our understanding of OD risk by drug type, (2) better characterize the magnitude of the risk of prior OD for future OD, (3) examine the role of depressive symptoms and OD, and (4) explore the relationship of intent and OD. The study s first hypothesis was that OD risk varies across drug categories. The second and third hypotheses were that prior OD and depressive symptoms would be associated with OD during follow-up. 2. Methods 2.1. Design and subjects Data for this prospective cohort study of OD were obtained from subjects enrolled in the HELP (Health Evaluation and Linkage to Primary care) study, a randomized clinical trial testing the effectiveness of a multidisciplinary health intervention to link individuals admitted for detoxification to primary medical care. The HELP study has been described in detail previously (Samet et al., 2003). Subjects in the HELP study were recruited from an inpatient detoxification unit in Boston, MA, which primarily treats uninsured or Medicaid-eligible patients. Eligible subjects were at least 18 years old; identified alcohol, cocaine, or heroin as their first or second drug of choice; and lacked a primary care physician. Exclusion criteria for the HELP study were as follows: (1) not English or Spanish speaking; (2) being pregnant; (3) living outside the Boston Medical Center catchment area; (4) significant cognitive impairment; (5) unable to provide three contacts for tracking purposes; and (6) specific plans to leave the Boston area within the next year. Subjects were scheduled for follow-up every 6 months for 2 years after study entry, and 85% (400/468) were assessed at least once during follow-up (two subjects died prior to follow-up). All subjects provided written informed consent prior to enrolling in the study, which was approved by the Institutional Review Board at Boston University Medical Center; subjects were also protected by a Certificate of Confidentiality from the National Institutes of Health Assessments Standardized interviews were administered by trained research personnel at study entry (after resolution of acute withdrawal symptoms) and during followup. Assessments for the current study included: age; gender; race/ethnicity; homelessness (defined as having lived on the street or in a homeless shelter at least one night during the previous 6 months); physical health status as measured by the Short Form Health Survey, Physical Component Summary (SF-36-PCS) (Ware, 1993); social support from friends and family assessed by the Perceived Social Support scale (PSS) (Procidano and Heller, 1983); sexual or physical abuse (Liebschutz et al., 2002); depressive symptoms as measured by the Center for Epidemiologic Studies Depression (CES-D) scale (Radloff, 1977); and the Addiction Severity Index (ASI) (McLellan et al., 1992). The ASI was used to construct indicator variables for suicidal ideation, suicide attempt, Problem Drug categories, and continuous variables for the total number of Problem Drugs and Drug Use as detailed below Lifetime suicidality assessed at detoxification (study entry). Lifetime suicidal ideation and lifetime suicidal attempt were assessed at study enrollment by two questions from the Addiction Severity Index (ASI): Have you ever attempted suicide? (include actual suicidal gestures or attempts) and Have you ever experienced serious thoughts of suicide? (patient seriously considered a plan for taking his/her life) Problem drug categories assessed at detoxification (study entry). In the absence of formal research assessment of drug diagnoses (abuse or dependence), frequency of drug use was used as a marker for excessive or heavy use, very likely problematic for people who met admission criteria for inpatient detoxification. Problem Drug categories were constructed from the drugs listed in the ASI at the index admission for detoxification (Wines et al., 2004). Problem Drug for a particular substance was defined as use 3 times per week (for alcohol use means to intoxication or 3 drinks) for a year or more, or 5 or more days of use in the past 30 days (definitions based on the ASI and outcome definitions used in treatment studies) (McLellan et al., 1992; O Malley et al., 1992; Volpicelli et al., 1992). Theoretical considerations were used to combine drugs with similar pharmacologic properties for analysis, creating four Problem Drug categories: alcohol; opioids (heroin, methadone and other opioids/analgesics); sedatives (barbiturates and sedatives/hypnotics/tranquilizers); and stimulants (cocaine and amphetamines). Indicator variables for each Problem Drug category were produced by combining the relevant drugs listed in the ASI. For example, if a subject met the Problem Drug definition for any of

3 J.D. Wines Jr. et al. / Drug and Alcohol Dependence 89 (2007) the three opioid drugs (heroin, methadone and other opioids/analgesics), then the subject would be considered to have problem opioid use (Opioid Problem Drug), an indicator of frequent use and a proxy for opioid abuse/dependence. In addition, the total number of the 11 drugs listed on the ASI fulfilling the Problem Drug criteria was used to create a continuous variable Drug Use after detoxification (follow-up). Drug Use was defined as the number of days used in the past 30 days as recorded by the ASI (range, 0 30 days) during follow-up (Wines et al., 2004). For Problem Drug categories consisting of more than one drug (i.e., opioids, sedatives, stimulants), the single most commonly used drug by the cohort at study entry (i.e., heroin, benzodiazepines, cocaine) was utilized to create four Drug Use variables. This one drug per category approach was taken in part to minimize ambiguity regarding the number of days used, as it cannot be determined from the ASI whether drugs used within a category are used on the same day or on different days (Wines et al., 2004). Specifically, Alcohol Use was defined as the number of days of any alcohol use; Heroin, Benzodiazepine, and Cocaine Use were defined as the number of days of each drug used. Also, as noted above, the total number of drugs used in the past 30 days was a continuous variable Outcome variables The main outcome variables for this study were lifetime OD ( prior OD ) assessed at the detoxification unit (study entry) and time to any OD during the 6-month intervals (6, 12, 18 and 24 months) after detoxification (followup). Lifetime OD ( prior OD ) was ascertained at study entry by the following question, Have you ever had a drug or alcohol OD requiring you to go to the emergency room (requiring medical attention right away)? OD during followup was defined similarly by asking subjects if they had an OD since their last assessment. To explore the role of intent, lifetime prior OD was divided into two groups based on intent. The first group, Prior Unintentional OD, was defined at study entry as a positive response to the Lifetime OD question above and a negative response to the suicide attempt question from the ASI. The second group, Prior Other OD, was defined at study entry as a positive response to the Lifetime OD question above and a positive response on the attempted suicide question. It should be noted that the No OD group contained only subjects without any history of OD, the Prior Unintentional OD group contained only individuals with a history of unintentional OD, and the Prior Other OD group could contain subjects with an unintentional (i.e., if past suicide attempt was not by OD) or intentional OD, or both types of OD Statistical analyses The extant scientific literature and clinical experience guided the selection of variables. Data from study entry were used to compare three groups according to OD history and intent (No OD, Prior Unintentional OD, and Prior Other OD) and to determine correlates of lifetime (prior) OD. Due to the increased lifetime (prior) OD risk from opioids, separate analyses were performed for both the total sample and the Opioid Problem Drug subgroup, which was constructed by limiting the sample to subjects meeting criteria for Opioid Problem Drug. For all analyses, age, SF-36-Physical Component Summary (PCS), Perceived Social Support (Family), Perceived Social Support (Friends), and depressive symptoms (CES-D) were treated as continuous variables. For the three group comparisons (No OD, Prior Unintentional OD, and Prior Other OD), continuous and categorical variables were analyzed using ANOVA and Chi-square, respectively (Tables 1 and 2). Post hoc tests (Duncan s method) were used to compare means of statistically significant continuous variables for the three group comparisons. The first hypothesis was tested in logistic regression models predicting lifetime (prior) OD (Section 3.2). The models contained the Problem Drug categories and potential confounders: age, gender, race, homeless status, SF- 36-Physical Component Summary (PCS), Perceived Social Support (Family), Perceived Social Support (Friends), history of physical or sexual abuse, and depressive symptoms (CES-D). Secondary analyses were conducted by replacing the Problem Drug categories with a single continuous variable representing the total number of drugs listed on the ASI fulfilling the Problem Drug criteria. Table 1 Characteristics of all subjects admitted for detoxification (total sample) Characteristic % (n)/mean (S.D.) No OD 69% (n = 325) Prior Unintent OD 19% (n = 89) Prior Other OD 12% (n = 56) Total (n = 470) Age ** 35.2 a (7.7) 38.1 b (7.7) 35.1 a (7.7) 35.8 (7.8) Male ** 74.5 (242) 89.9 (80) 66.1 (37) 76.4 (359) Race *** Black 55.7 (181) 27.0 (24) 23.2 (13) 46.4 (218) White 29.2 (95) 56.2 (50) 50.0 (28) 36.8 (173) Hispanic 8.9 (29) 11.2 (10) 21.4 (12) 10.9 (51) Other 6.2 (20) 5.6 (5) 5.4 (3) 6.0 (28) Homelessness *** 39.4 (128) 61.8 (55) 64.3 (36) 46.6 (219) Physical health status *** 49.3 a (10.6) 45.8 b (10.6) 44.3 b (10.6) 48.1 (10.8) Social support (family) * 7.3 a (4.7) 6.6 a,b (4.7) 5.5 b (4.7) 7.0 (4.7) Social support (friends) 6.8 (4.1) 6.8 (3.7) 5.8 (3.6) 6.7 (4.0) Depressive symptoms *** 30.7 a (11.9) 35.4 b (11.9) 41.5 c (11.9) 32.9 (12.5) Abuse history *** No abuse 32.8 (106) 20.7 (18) 10.9 (6) 28.0 (130) Physical abuse only 43.7 (141) 49.4 (43) 30.9 (17) 43.2 (201) Sexual abuse 23.5 (76) 29.9 (26) 58.2 (32) 28.8 (134) Problem drug Alcohol 83.4 (271) 92.1 (82) 91.1 (51) 86.0 (404) Opioids *** 35.7 (116) 60.7 (54) 55.4 (31) 42.8 (201) Sedatives *** 15.4 (50) 36.0 (32) 50.0 (28) 23.4 (110) Stimulants * 80.0 (260) 65.2 (58) 78.6 (44) 77.0 (362) OD = overdose. Mean (S.D.) for continuous variables age, physical health status, social support, and depressive symptoms. Means with a different letter (a, b, c) are significantly different in pairwise comparisons. As an example, the mean age of the No OD and Prior Other OD do not significantly differ from each other (since they both are listed with letter a), but the mean Prior Unintentional OD is significantly higher than either of the two other groups. p < 0.10; * p < 0.05; ** p < 0.01; *** p <

4 164 J.D. Wines Jr. et al. / Drug and Alcohol Dependence 89 (2007) Table 2 Characteristics of subjects with opioid problems admitted for detoxification (opioid subgroup) Characteristic % (n)/mean (S.D.) No OD 57.7 (n = 116) Prior Unintent OD 26.9 (n = 54) Prior Other OD 15.4 (n = 31) Total (n = 201) Age * 34.3 a (7.8) 37.9 b (7.8) 33.5 a (7.8) 35.1 (7.9) Male 72.4 (84) 85.2 (46) 67.7 (21) 75.1 (151) Race Black 35.3 (41) 24.1 (13) 16.1 (5) 29.4 (59) White 44.8 (52) 59.3 (32) 48.4 (15) 49.3 (99) Hispanic 13.8 (16) 11.1 (6) 32.3 (10) 15.9 (32) Other 6.0 (7) 5.6 (3) 3.2 (1) 5.5 (11) Homelessness ** 34.5 (40) 59.3 (32) 58.1 (18) 44.8 (90) Physical health status 46.5 (10.8) 45.7 (9.4) 45.0 (11.3) 46.1 (10.5) Social support (family) 7.1 (4.5) 6.6 (4.8) 5.8 (4.5) 6.8 (4.6) Social support (friends) 6.9 (4.0) 6.4 (3.8) 5.6 (3.8) 6.6 (4.0) Depressive symptoms *** 32.4 a (11.3) 35.6 a (11.3) 42.1 b (11.3) 34.8 (11.8) Abuse history * No abuse 35.7 (41) 28.9 (15) 12.9 (4) 30.3 (60) Physical abuse only 40.0 (46) 40.4 (21) 32.3 (10) 38.9 (77) Sexual abuse 24.4 (28) 30.8 (16) 54.8 (17) 30.8 (61) Problem drug Alcohol * 72.4 (84) 90.7 (49) 83.9 (26) 79.1 (159) Opioids 100 (116) 100 (54) 100 (31) 100 (201) Sedatives *** 31.0 (36) 55.6 (30) 74.2 (23) 44.3 (89) Stimulants 81.0 (94) 74.1 (40) 87.1 (27) 80.1 (161) OD = overdose. Mean (S.D.) for continuous variables age, physical health status, social support, and depressive symptoms. Means with a different letter (a, b, c) are significantly different in pairwise comparisons. As an example, the mean age of the No OD and Prior Other OD do not significantly differ from each other (since they both are listed with letter a), but the mean Prior Unintentional OD is significantly higher than either of the two other groups. p < 0.10; * p < 0.05; ** p < 0.01; *** p < Time-to-event (survival) models were constructed from statistically or clinically significant variables used in the cross-sectional, logistic regression analyses. OD rates during follow-up were based on Kaplan Meier estimates. The second and third hypotheses were tested using proportional hazards regression models predicting time to first new report of any OD during follow-up (Table 3). The longitudinal models contained Prior OD (or Prior Unintentional OD and Prior Other OD); two time-varying covariates, recent (past 7 days) depressive symptoms and recent (past 30 days) Drug Use; and potential confounders: age, gender, race, homeless status, and physical or sexual abuse. The reports of OD were interval censored (possible values were 6 months, 12 months, 18 months, 24 months, or censored at last observed timepoint). Secondary analyses were conducted by replacing the Drug Use variables with a single, continuous, timevarying, variable representing the total number of drugs with any use in the past 30 days. In additional secondary analyses, lifetime (prior) suicidal ideation and lifetime (prior) suicide attempt were added to the cross-sectional and longitudinal models. Finally, in order to assess the robustness of our findings related to depressive symptoms, several sensitivity analyses were performed: (1) timevarying variables were time lagged by one visit in order to assure the temporal ordering of depressive symptoms and OD; and (2) a binary variable for depressive symptoms using a CES-D cutoff score of 23 (Golub et al., 2004) was substituted for the continuous CES-D variable. Two-sided p < 0.05 was considered statistically significant and SAS/STAT software version 8.2 (Cary, NC) was used to perform all analyses. 3. Results 3.1. Lifetime overdose by intent assessed at detoxification (study entry) Characteristics of the total sample (n = 470) are depicted in Table 1. The three groups (No OD, Prior Unintentional OD, and Prior Other OD) significantly differed by age, gender, race, homeless status, physical health status, family social support, sexual/physical abuse, Problem Drug, and depressive symptoms (Table 1). Depressive symptoms were significantly elevated in both the Prior Other OD group and the Prior Unintentional OD group compared to the No OD group. Characteristics of the Opioid Problem Drug subgroup (n = 201) can be found in Table 2. Within the Opioid Problem Drug subgroup, the three groups also significantly differed by age, homeless status, sexual/physical abuse history, Problem Drug, and depressive symptoms (Table 2). Although the results were not statistically significant, gender, race, physical health status, and social support-family differences were also similar to those seen in the entire cohort. Depressive symptoms were elevated in both the Prior Other OD group and the Prior Unintentional OD group compared to the No OD group; however, the difference between the Prior Unintentional OD group and the No OD group was not statistically significant Lifetime overdose: prevalence and risk factors Lifetime prevalence for any OD ( prior OD ) was 30.9% (145/470) in the total sample and 42.3% (85/201) for the Opioid Problem Drug subgroup. In logistic regression analysis, factors associated with lifetime (prior) OD in the total sample included: male (OR: 2.99, 95% CI: ); white versus black race (OR: 1.97, 95% CI: ); Hispanic ethnicity versus black race (OR: 2.82, 95% CI: ); homelessness (OR: 2.21, 95% CI: ); sexual abuse versus no abuse (OR: 3.95,

5 Table 3 Factors associated with overdose during prospective follow-up after detoxification a J.D. Wines Jr. et al. / Drug and Alcohol Dependence 89 (2007) Characteristic HR (95% CI) Total sample (n = 397) Opioid subgroup (n = 169) W/ prior OD W/ prior OD by intent W/ prior OD W/ prior OD by intent Prior OD 6.19 ( ) *** NA 5.94 ( ) *** NA Prior Unintentional OD NA 7.07 ( ) *** NA 7.11 ( ) *** Prior Other OD NA 5.13 ( ) *** NA 4.05 ( ) ** Age 0.98 ( ) 0.98 ( ) 0.99 ( ) 0.98 ( ) Male 1.52 ( ) 1.44 ( ) 1.72 ( ) 1.57 ( ) Race White vs. black 3.89 ( ) *** 4.04 ( ) *** 2.97 ( ) * 3.13 ( ) * Hispanic vs. black 2.37 ( ) 2.45 ( ) 1.69 ( ) 2.01 ( ) Other vs. black 0.95 ( ) 0.94 ( ) 0.48 ( ) 0.45 ( ) Homelessness 0.85 ( ) 0.86 ( ) 0.68 ( ) 0.68 ( ) Depressive symptoms b 1.05 ( ) *** 1.06 ( ) *** 1.04 ( ) * 1.04 ( ) ** Physical abuse only vs. no abuse 1.34 ( ) 1.31 ( ) 1.06 ( ) 1.07 ( ) Sexual abuse vs. no abuse 2.63 ( ) * 2.77 ( ) * 1.66 ( ) 1.95 ( ) Drug Use b Alcohol 1.03 ( ) * 1.03 ( ) 1.02 ( ) 1.01 ( ) Heroin 1.03 ( ) 1.02 ( ) 1.03 ( ) 1.03 ( ) Benzodiazepines 1.02 ( ) 1.02 ( ) 1.02 ( ) 1.02 ( ) Cocaine 0.93 ( ) * 0.94 ( ) * 0.95 ( ) 0.95 ( ) HR = hazard ratio; CI = confidence interval. p < 0.10; * p < 0.05; ** p < 0.01; *** p < a Proportional hazards models control for all covariates above. b Time-varying covariates (depressive symptoms: past 7 days and Drug Use: # days past 30). 95% CI: ); physical abuse only versus no abuse (OR: 2.02, 95% CI: ); Stimulant Problem Drug (OR: 0.56, 95% CI: ); Opioid Problem Drug (OR: 2.21, 95% CI: ); and more depressive symptoms (OR: 1.04, 95% CI: ). Here the OR represents the change for each point increase in the CES-D score. In a secondary analysis, prior suicide attempt (OR: 3.20, 95% CI: ), but not prior suicidal ideation (OR: 1.35, 95% CI: ), was associated with OD when added to the model. The total number of drugs listed on the ASI that fulfilled the Problem Drug criteria was also associated with OD (OR: 1.15, 95% CI: ). In the Opioid Problem Drug subgroup, more depressive symptoms (OR: 1.03, 95% CI: ) and Sedative Problem Drug (OR: 2.27, 95% CI: ) were associated with lifetime (prior) OD. As in the total sample, secondary analysis showed that prior suicide attempt (OR: 2.80, 95% CI: ), not prior suicidal ideation (OR: 1.37, 95% CI: ), was associated with prior OD. The total number of Problem Drug categories was also associated with prior OD (OR: 1.20, 95% CI: ) Overdose after detoxification (follow-up) During the 2-year follow-up, Kaplan Meier method estimated that 16.9% (95% CI: ) of the total sample (n = 397, 60 individuals with at least 1 OD) and 26.7% (95% CI: ) of the Opioid Problem Drug subgroup (n = 169, 40 individuals with at least 1 OD) reported an OD. Among individuals with a prior OD, the KM estimate was that 43.5% (95% CI: ) of subjects in the total sample (n = 120) and 52.4% (95% CI: ) of the Opioid Problem Drug subgroup (n = 70), OD d again within 2 years after detoxification. Among individuals without a prior OD, the estimated 24-month incidence in the total sample (n = 277) and the 24- month incidence in the Opioid Problem Drug subgroup (n = 99) was 5.7% (95% CI: ) and 11.0% (95% CI: ), respectively. In the total sample, predictors of OD during the 2-year followup in the proportional hazards regression analysis included white race, past sexual abuse, less frequent cocaine use, more frequent alcohol use, recent depressive symptoms, and prior OD regardless of intent (Table 3). More frequent heroin use was marginally significant (p < 0.10). Interestingly, Prior Unintentional OD was the strongest predictor of future OD (HR: 7.07, 95% CI: ). Recent depressive symptoms were significantly associated with OD (HR 1.05, 95% CI: for each point increase in the CES-D score). When entered into the model, depressive symptoms 23 were associated with increased risk of OD (HR: 3.94, 95% CI: ). Time lagged analyses revealed similar results for depressive symptoms both as a continuous (HR: 1.07, 95% CI: ) and dichotomous variable (HR: 3.79, 95% CI: ), although limited power may have resulted in loss of statistical significance. A secondary analysis showed that neither prior suicide attempt (HR: 1.27, 95% CI: ) nor prior suicidal ideation (HR: 1.07, 95% CI: ) was significantly associated with future OD. Additional secondary analyses demonstrated that the

6 166 J.D. Wines Jr. et al. / Drug and Alcohol Dependence 89 (2007) total number of drugs with any use in the past 30 days was not significantly associated with OD (HR: 1.08, 95% CI: ). In the Opioid Problem Drug subgroup, white race, recent depressive symptoms, and prior OD regardless of intent (Table 3) predicted OD during follow-up. Although there were no statistically significant associations between frequency of recent Drug Use (heroin use was marginally significant) and OD, odds ratios were comparable to the Drug Use variables from the entire cohort. Prior Unintentional OD was again the strongest predictor of future OD (HR: 7.11, 95% CI: ). Recent depressive symptoms were significantly associated with OD (HR: 1.04, 95% CI: ). When entered into the model, depressive symptoms 23 were associated with increased risk of OD (HR: 2.33, 95% CI: ). Notwithstanding loss of statistical significance due to power limitations, time lagged analyses again demonstrated comparable findings for depressive symptoms both as a continuous (HR: 1.06, 95% CI: ) and binary predictor (HR: 4.89, 95% CI: ). Like the total sample, neither prior suicide attempt (HR: 0.89, 95% CI: ) nor prior suicidal ideation (HR: 0.89, 95% CI: ) was significantly associated with future OD. Finally, the total number of drugs with any use in the past 30 days was not significantly associated with OD (HR: 1.15, 95% CI: ). 4. Discussion Findings about these detoxification unit patients provide insight regarding OD as a leading cause of death among those with alcohol and other drug problems. Self-reports revealed the high prevalence of OD in detoxification patients (31%), especially problem opioid users (42%). Risk factors for OD were similar for the total sample and the Opioid Problem Drug subgroup, suggesting that some OD risk-identification efforts (e.g., screening for depressive symptoms) could apply universally to patients admitted for detoxification. This study extends previous research by demonstrating that prior OD among detoxification patients is a strong predictor of future OD. It is also noteworthy that the association of elevated depressive symptoms and OD, noted previously in a retrospective study of a community sample (Tobin and Latkin, 2003), was observed prospectively in our treatment population. Overall, these data suggest that some OD considered accidental may not be completely unintentional. OD is a common occurrence among detoxification patients in general (Ravndal and Vaglum, 1999) and opioid users in particular (Darke et al., 1996a; Gossop et al., 1996; Neale and Robertson, 2005; Ravndal and Vaglum, 1999; Seal et al., 2001). Our definition of OD, which can be applied to any drug with an OD risk, has face validity (Powis et al., 1999) and by requiring emergency medical treatment suggests that non-fatal OD results in considerable service utilization and healthcare cost. However, direct comparison to studies using other OD definitions (e.g., more drug-specific definitions (Darke et al., 1996a)) may be difficult. OD rates after detoxification in our study are similar to the study by Ravndal and Vaglum (1999), which also sampled patients with diverse drug preferences (17% over 2 years versus 29% over 5 years). Additionally, OD rates after discharge for the Opioid Problem Drug subgroup (27% over 2 years) are comparable to the estimated annual rates for non-fatal OD among heroin users in Australia, which range from 19% to 30% (Darke et al., 2003). While it should be emphasized that the degree to which risk factors for non-fatal and fatal OD overlap is currently unknown (Powis et al., 1999), the increased risk of OD from opioids is consistent with some toxicology studies of fatal OD (Coffin et al., 2003; Gossop et al., 2002). Opioids ability to depress the respiratory center in the brain is well known and most likely represents the mechanisms of action for opioid-related OD (White and Irvine, 1999). Prior suicide attempt is one of the strongest predictors of both future suicide attempt (Preuss et al., 2003; Wines et al., 2004) and completed suicide (Harris and Barraclough, 1997); however, less is known regarding quantifying the risk of prior non-fatal OD (elevated six-fold in our study) on future non-fatal OD. Results are consistent with a retrospective study of 312 injection drug users that found that each OD increased the risk of having another OD (Powis et al., 1999). Our finding of Prior Unintentional OD as the strongest predictor of OD was somewhat unexpected, but important, as it appears to reinforce both the preventable nature of OD and the need for effective interventions in high-risk individuals with a history of OD (Powis et al., 1999). The frequency of multiple drug use in our cohort and results from both the Problem Drug and Drug Use variables are generally consistent with the polydrug theory (Darke and Zador, 1996) of opioid-related OD and recent findings from a case-crossover study by Dietze et al. (2005). That stimulants may be associated with less risk should be interpreted with caution as stimulants like cocaine have been associated with both non-fatal (Kaye and Darke, 2004) and fatal OD (Coffin et al., 2003), and the effect measure (odds ratio) for stimulants in our study represents a relative comparison to other drugs, not a comparison to a no drug control. Our findings regarding the association of depressive symptoms and OD are very similar to the study by Tobin and Latkin (2003). Although depressive symptoms, a modifiable risk factor, may represent a potential intervention target to prevent OD, their exact role remains uncertain, as several explanations may account for the association between depressive symptoms and OD. Specifically, depressive symptoms may increase in the aftermath of an OD; however, several studies have shown that these symptoms actually improve after an intentional OD (Jack and Williams, 1991; Sarfati et al., 2003). Chronically elevated depressive symptoms may also form a trait-risk for OD, yet depressive symptoms were not increased among individuals with an OD that occurred more than a year previous (Tobin and Latkin, 2003). In addition, individuals may indulge in more risky drug use as an attempt to self-medicate dysphoric mood states (Chilcoat and Breslau, 1998; Khantzian, 1985; Wines et al., 2004), resulting from a mood disorder or other source (e.g., medical illness) (DSM-IV, 1994; Raimo and Schuckit, 1998). Conversely, drug use may cause the depressive symptoms (substance-induced depression) (Brown and Schuckit, 1988; Ries et al., 2001) leading to the OD (Preuss et al., 2003; Wines et al., 2004). Individuals relapsing after extended periods of abstinence may experience extreme guilt and hopelessness (abstinence violation effect) (Marlatt, 1985) that when coupled

7 J.D. Wines Jr. et al. / Drug and Alcohol Dependence 89 (2007) with decreased drug tolerance (Strang et al., 2003) may substantially enhance the risk of OD. Finally, acute life stressors (e.g., relationship disruptions) that have been associated with OD (Neale and Robertson, 2005) could conceivably be mediated by depressive symptoms (Hammen et al., 1986). Regardless of their cause, abrupt increases in depressive symptoms occurring just prior to the OD strongly argues that worsening dysphoria may lie on a causal pathway for OD and as such represent a prime intervention target. Determining whether these transient mood states can trigger an OD or if they are related to some other factor outside the causal pathway requires further research, perhaps using a case-crossover design which is capable of quantifying the impact of rapid mood shifts (Mittleman et al., 1995). In light of our study results, it is noteworthy that some investigators have argued that depression can be an implicit marker of intent for suicide (Rosenberg et al., 1988). In addition, several researchers (Farrell et al., 1996; Neale, 2000; Rossow and Lauritzen, 1999; Zador, 2005) have suggested that intent for OD may lie on a continuum, and we found some indirect support for this theory. In the Prior Unintentional OD group, the proportion of patients with a sexual abuse history, a well-known risk factor for suicidal behavior (Molnar et al., 2001), was higher than the No OD group, but lower than the Prior Other OD group, which almost certainly contained some subjects with intentional ODs. Depressive symptoms and perceived family support were similarly distributed. Notably, a definition of a suicide attempt commonly used in the US requires that the selfinjurious behavior occur with some nonzero level of intent to kill oneself (O Carroll et al., 1996). Given the importance of the accurate determination of intent, rigorously designed studies of individuals with severe opioid-related OD, using standardized suicide-related assessments are needed to further characterize drug-related OD, develop more sensitive intent scales, and explore the notion of a continuum of intent. Despite several strengths of our study including the longitudinal design utilizing a relatively large, diverse cohort and time-to-event analyses, there are some important limitations. First, our definition of OD has both disadvantages and advantages. It may have underestimated the true prevalence and incidence of OD as a substantial percentage of ODs (approximately 50% or more in some studies) do not result in emergency medical treatment (Darke et al., 1996b; Davidson et al., 2002; Powis et al., 1999). Furthermore, our findings may have been influenced by selecting individuals most likely to utilize medical services. At the same time as our OD definition likely sampled more severe ODs, it probably yielded more accurate effect estimates via improved specificity of the outcome. In order to more fully address these important issues, further methodological development and psychometric testing of differing outcome definitions used in OD research is warranted. Second, there is potential misclassification between the Prior Unintentional OD and Prior Other OD groups, in that some subjects in the Prior Other OD group may have had only an unintentional OD. Given the exploratory nature of the analyses pertaining to intent and suicidal behavior, results should be considered preliminary and in need of replication. Third, some standardized assessments used refer to overlapping but not identical time periods during follow-up (e.g., CES-D: past 1 week, ASI: past 1 month), making the exact sequencing of depressive symptoms and OD difficult to ascertain. Nonetheless, time lagged sensitivity analyses revealed comparable findings. Fourth, formal diagnostic instruments were not used to make specific substance use disorder and major depressive disorder diagnoses; however, subjects in our study almost certainly met substance dependence or abuse criteria given scores on addiction measurements like the ASI coupled with admission criteria for the detoxification unit. Fifth, not all subjects were observed at all follow-up timepoints, and we were only able to estimate time to new OD in 6-month intervals. Finally, results from our study of detoxification patients may not generalize to other populations (e.g., drug users not in treatment), yet the magnitude of OD risk from elevated depressive symptoms in our study was very similar (same adjusted HR and OR) to data from a community sample of drug users (Tobin and Latkin, 2003). In summary, the current study illustrates the high prevalence of OD in urban detoxification patients, the potency of prior OD as a risk factor for future OD, and the potential role of worsening depression in the etiology of OD. We also found preliminary evidence that some accidental ODs may not be completely unintentional. Regardless of whether or not an OD event is considered intentional, our data suggest that the effective treatment of depressive symptoms may hold potential for the prevention of OD. There is a striking lack of OD risk-recognition, prevention, and treatment efforts (Cook et al., 1998; Pollini et al., 2006). Addiction specialists, especially those in detoxification settings, could consider screening patients with a simple OD question, Have you ever overdosed? 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