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Medical Outcomes Associated with Nonmedical Use of Methadone and Buprenorphine
The Journal of Emergency Medicine, Vol. 45, No. 2, pp. 199–205, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2012.11.104
Selected Topics: Toxicology
MEDICAL OUTCOMES ASSOCIATED WITH NONMEDICAL USE OF METHADONE AND BUPRENORPHINE Samantha Lee, PHARMD, Wendy Klein-Schwartz, PHARMD, MPH, Christopher Welsh, MD, and Suzanne Doyon, MD University of Maryland School of Medicine and School of Pharmacy, Baltimore, Maryland Reprint Address: Suzanne Doyon, MD, University of Maryland School of Medicine and School of Pharmacy, 220 Arch Street, Office Level 1, Baltimore, MD 21201
, Abstract—Background: There exists a significant amount of misinformation regarding methadone and buprenorphine, and a belief that toxicity associated with nonmedical use of methadone and nonmedical use of buprenorphine is similar in severity and outcomes. Objective: The objective of this study is to compare outcomes associated with nonmedical use of methadone vs. nonmedical use of buprenorphine in patients presenting to the Emergency Department (ED) and reported to poison centers. Methods: This was a retrospective cohort study using data from the American Association of Poison Control Centers from January 1, 2003 to December 31, 2009 (7 years). Inclusion criteria were nonmedical use of methadone or buprenorphine (or buprenorphine/naloxone) as a single substance by history, age 18 years or older, ingestions only, evaluated in an ED. Outcome measures were clinical effects, treatments, disposi-
tion, and final medical outcomes. Results: Of 1,920 cases, 1,594 were in the methadone group and 326 were in the buprenorphine group. Frequently reported clinical effects were lethargy, 59.2% vs. 29.4%, and respiratory depression, 28.7% vs. 2.5%, for methadone and buprenorphine groups, respectively. Hospitalization rates were 67.4% in the methadone group and 32.2% in the buprenorphine group. Half of all patients in the methadone group were admitted to the intensive care unit (ICU) vs. only 15% of all the patients in the buprenorphine group. Twenty-six patients in the methadone group died vs. no deaths in the buprenorphine group. There were significant differences in the distribution of clinical effects, disposition, and medical outcomes (p < 0.001). Conclusions: Patients who use methadone nonmedically have higher hospitalization rates, greater ICU utilization rates, and considerably worse medical outcomes when compared with patients who use buprenorphine nonmedically. Ó 2013 Elsevier Inc.
Disclaimer: The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country’s 57 poison centers. Case records in this database are from self-reported calls: they reflect only information provided when the public or health care professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure), or request information or educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures might go unreported to poison centers and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).
, Keywords—nonmedical use; methadone; buprenorphine
INTRODUCTION Drug overdose fatalities are on the rise in the United States (US) and prescription medications, particularly prescription opioids, account for most of the increase (1). In 2008, prescription medications caused 20,044 deaths and prescription opioids were involved in 14,800 (73.8%) of them (1). In 2009, 1.2 million Emergency Department (ED) visits were associated with the nonmedical use of pharmaceuticals (mostly opioids), a number that
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exceeded the number of ED visits associated with the use of illicit drugs, such as heroin and cocaine (2). Current medical literature rarely offers an examination of this pharmacoepidemic beyond medical examiner data, surveillance reports, and description of patterns (1–4). Methadone is a synthetic full m-receptor agonist with inhibition at the N-methyl-D-aspartate receptor, which might make it a better analgesic than morphine (5–7). Buprenorphine is a semi-synthetic partial m-receptor agonist and k-receptor antagonist (8–10). It has a relatively low intrinsic activity as a partial agonist at the m-receptor, resulting in a ceiling effect for respiratory depression at higher doses. Buprenorphine has a high affinity for and slow dissociation from the m-receptor, which contribute to its long duration of action, comparable to that of methadone. Unlike methadone, buprenorphine has the potential to induce opioidwithdrawal symptoms if other opioids are present (5,8). Pharmacologic investigations indicate that opioids, including methadone and buprenorphine, have the potential to be misused, abused, used nonmedically, and diverted (11,12). Many authors have compared methadone to buprenorphine, despite their different pharmacology, different US Food and Drug Administration (FDA) indications, and different prescribing regulations (13–20). In one case series of hospitalized patients, the authors concluded that the toxicities of methadone and buprenorphine were indistinguishable from one another (13). Others have studied diversion rates, comparing patient populations that were prescribed methadone with patient populations that were prescribed buprenorphine, overlooking the fact that these two populations might be different (methadone can only be prescribed legally for pain) (20–30). As a result, there exists a significant amount of misinformation and a belief that, because of similar toxicities and similar diversion rates, nonmedical use of methadone and nonmedical use of buprenorphine are, at a minimum, comparably hazardous (31–34). An examination of the immediate and short-term health effects resulting from nonmedical use of methadone and buprenorphine is necessary. The study null hypothesis is that the nonmedical use of methadone and buprenorphine results in similar medical outcomes.
METHODS This is a retrospective review of poison center data. The American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) receives data from all poison centers serving the entire US population, including its territories. NPDS is an electronic database. Cases are called in to poison centers from multiple
sources and information is collected by specialists in poison information (SPI) in real time and sent electronically to NPDS. NPDS data collection and reporting process are further explained elsewhere (35,36). The University of Maryland Baltimore Institutional Review Board (IRB) determined that the study did not require IRB review (not human subject research status). AAPCC NPDS was queried for cases from January 1, 2003 through December 31, 2009 (7 years) involving oral preparations of buprenorphine (alone or buprenorphine and naloxone) and methadone. Inclusion criteria were nonmedical use of buprenorphine or methadone as a single substance by history; age 18 years and older; ingestion only; and managed in the ED or other health care facility (HCF). Nonmedical use was defined as either ‘‘intentional abuse’’ or ‘‘intentional misuse’’ as the reason for exposure. The term buprenorphine group refers to patients who ingested either buprenorphine or buprenorphine/naloxone preparations. SPI collect data on the presence of precoded clinical effects (i.e., symptoms, signs, or laboratory abnormalities). Because of overlap in clinical effects, a datamining algorithm (Boolean algorithm) for opioid withdrawal was used. Opioid withdrawal was defined as the absence of naloxone administration and the presence of at least three of the following six clinical effects: tachycardia, agitation and irritability, vomiting and diarrhea, diaphoresis, tremor, or mydriasis (37). Naloxone was identified as a confounding variable. Outcomes measures included treatment(s) received, disposition, and poison center coding of final medical outcomes. Treatments included administration of naloxone, endotracheal intubation, use of antiemetics, and use of sedatives. Disposition included treated and released from the ED, admitted to a general medical or surgical unit, admitted to an intensive care unit (ICU), or admitted to a psychiatric unit (35). Poison center coding of medical outcomes included no effect, minor effect, moderate effect, major effect, and death. Moderate effect was defined as clinical effects that are more pronounced, more prolonged, or more systemic, and usually some form of treatment is indicated. Major effect was defined as signs or symptoms that were life threatening or resulted in significant residual disability or disfigurement (38). These medical outcomes were determined and coded by the SPI when the cases were closed. Cases were excluded if the final medical outcomes were not known. Deidentified data were received in NPDS in Microsoft Access 2007 format and reports were generated using Crystal Reports 2008. Data were analyzed for age, sex, substance ingested, clinical effects, management sites, treatments, and final medical outcomes. Geographic data were not obtained.
Medical Outcomes from Nonmedical Use of Methadone and Buprenorphine Table 1. Clinical Effects after Nonmedical Use of Methadone or Buprenorphine Methadone (n = 1,594) Clinical Effects Respiratory Cyanosis Respiratory depression Respiratory arrest Pneumonitis Cardiovascular Cardiac arrest Hypotension Neurological Drowsiness/ lethargy Coma Agitation/ irritable Ocular Miosis Gastrointestinal Abdominal pain Vomiting Miscellaneous CPK elevation Diaphoresis
Buprenorphine (n = 326)
n
%
n
%
p Value*
52 458
3.3 28.7
0 8
2.5
0.002 <0.001
97
6.1
0
<0.001
20
1.3
0
NS
22 138
1.4 8.7
0 7
2.1
NS <0.001
943
59.2
96
29.4
<0.001
377 91
23.7 5.7
7 76
2.1 23.3
<0.001 <0.001
128
8.0
12
3.7
0.008
7 111
0.4 7.0
18 42
5.5 12.9
<0.001 <0.001
59 18
3.7 1.1
4 23
1.2 7.1
0.034 <0.001
CPK = creatine phosphokinase; NS = not significant. * c2 with Yates correction.
Quantitative data were summarized by medians and ranges and categorical data by frequencies and percentages. c2 with Yates correction for continuity was used to compare selected clinical effects, treatments, dispositions, and medical outcomes. To compare medical outcomes, major effect and death were combined because of the small numbers in the buprenorphine group. Analyses were performed with SigmaStat 3.1.1 (Point Richmond, CA) and all reported p values are two-sided. Statistical significance was defined as p < 0.05.
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in 377 (23.7%) and 97 (6.1%), respectively, of patients in the methadone group and 7 (2.1%) and 0 (0%), respectively, of patients in the buprenorphine group (p < 0.001). Agitation/irritability, vomiting, and diaphoresis were present in 91 (5.7%), 111 (7%), and 18 (1.1%), respectively, of the methadone cases, and in 76 (23.3%), 42 (12.9%), and 23 (7.1%), respectively, of the buprenorphine cases (p < 0.001). In the subset of patients who did not receive naloxone, 10 of 559 (1.9%) patients in the methadone group and 19 of 292 (6.5%) patients in the buprenorphine group fit the diagnostic criteria for opioid withdrawal (p < 0.001). Finally, 101 (6.3%) patients in the methadone group were asymptomatic compared with 34 patients (10.4%) in the buprenorphine group (p = 0.012). Patients in the methadone group were more likely to receive naloxone and endotracheal intubation than those in the buprenorphine group (p < 0.001) (Table 2). Patients in the buprenorphine group more often received benzodiazepines and antiemetic therapy (p < 0.001). Five hundred and nineteen (32.5%) patients in the methadone group and 221 (67.8%) in the buprenorphine group were treated and released from the ED (Table 3). There were 1,075 (67.4%) patients hospitalized in the methadone group compared with 105 (32.2%) in the buprenorphine group. The ICU admission rates were 49.5% in the methadone group and 15% in the buprenorphine group. There were 26 fatalities in the methadone group and none in the buprenorphine group. Comparing methadone and buprenorphine, the distributions of dispositions and medical outcomes were significantly different (p < 0.001). DISCUSSION Nonmedical use of methadone and buprenorphine reported to poison centers was compared with Drug Abuse Warning Network (DAWN) weighted estimates of ED visit mentions of nonmedical use of buprenorphine and
RESULTS The AAPCC NPDS search yielded 1,990 cases that met inclusion criteria. Of these, 56 patients in the methadone and 14 in the buprenorphine group left against medical advice, without complete treatment or known medical outcomes. Of the remaining 1,920 patients, 1,594 were in the methadone and 326 in the buprenorphine group. Median age was 33 years in both the methadone group (range 18–85 years) and in the buprenorphine group (range 18–78 years). The majority were men; 56.9% and 61.1% in the methadone and buprenorphine groups, respectively. Table 1 presents the frequency of clinical effects. Coma and life-threatening respiratory arrest were present
Table 2. Treatments Received after Nonmedical Use of Methadone or Buprenorphine Methadone (n = 1,594)
Buprenorphine (n = 326%)
Treatments Received
n
%
n
%
p Value*
Naloxone Intubation Benzodiazepine Antiemetic i.v. fluids Vasopressors
1,035 187 93 37 683 44
64.9 11.7 5.8 2.3 42.8 2.8
34 8 75 28 83 1
10.4 2.5 23.0 8.6 25.5 0.3
<0.001 <0.001 <0.001 <0.001 NS NS
NS = not statistically significant. * c2 with Yates correction.
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Table 3. Disposition and Final Medical Outcomes after Nonmedical Use of Buprenorphine or Methadone Methadone Buprenorphine (n = 1,594) (n = 326) Disposition and Outcomes Emergency Department disposition Discharged Admitted to non critical care unit Admitted to critical care unit Admitted to psychiatric care facility Final medical outcome No effect Minor effect Moderate effect Major effect Death
n
%
n
%
p Value* <0.001
519 242
32.5 15.2
221 44
67.8 13.5
790
49.6
48
14.7
43
2.7
13
4.0
101 411 748 308 26
6.3 25.8 47.0 19.3 1.6
34 170 112 10 0
10.4 52.1 34.4 3.1 0
<0.001
* c2 with Yates correction.
methadone over time (Figure 1). AAPCC NPDS is a poisoning surveillance system that collects data on exposures to substances and reports in near real time from 57 US poison centers. NPDS includes exposures and produces case counts. DAWN is a public health surveillance system designed to monitor national and local trends in drug-related ED visits and drug-related deaths by collecting data from a representative sample of US hospitals. DAWN includes ‘‘mentions’’ and produces estimates (2). Despite markedly different methodologies and their
inherent shortcomings, trends in poison center data closely followed those found in DAWN. Strengths of NPDS data include early tracking of buprenorphine starting in 2004 and nationwide reporting of case counts, not estimates. Central nervous system and respiratory depression were most frequently encountered in the methadone group and gastrointestinal symptoms were most frequently present in the buprenorphine group (Table 1). The opioid withdrawal algorithm was more frequently observed in the buprenorphine group than in the methadone group (5.8% vs. 1.9%, respectively). These findings are consistent with previous reports of buprenorphine diversion, where commonly stated reasons for nonmedical use of buprenorphine were to treat opioid withdrawal or for detoxification (39,40). Patients who used methadone nonmedically were more likely to fare worse on all measures of health outcomes. They were more likely to have received naloxone or endotracheal intubation, to be admitted to the ICU, and were more likely to die (Table 2). There were 26 deaths in the methadone group. The risks associated with nonmedical use of buprenorphine were much less severe, as exemplified by the fact that patients in the buprenorphine group were more likely to be treated with antiemetics and benzodiazepines, and the great majority of them were treated and released from the ED (67%). Importantly, there were no deaths in the buprenorphine group (Table 3). These data support the conclusion that nonmedical use of buprenorphine, although rising, is associated with
Figure 1. Comparison of poison control center (PCC) annual cases vs. Drug Abuse Warning Network (DAWN) weighted annual estimates of methadone and buprenorphine nonmedical use.
Medical Outcomes from Nonmedical Use of Methadone and Buprenorphine
markedly better medical outcomes than nonmedical use of methadone. A small but significant proportion of patients who used buprenorphine nonmedically sought medical attention because they were in opioid withdrawal. Nonmedical use of methadone is a much more serious problem. In addition to increased number of deaths and worsening of all measurable medical outcomes, increased health care costs are another potential societal burden posed by nonmedical use of methadone. This burden is not negligible, as it includes increases in procedures, higher admission rates, and greater utilization of the ICU (41). Additional research is needed in this area in order to better understand the impact of nonmedical use of all prescription opioids on health outcomes, length of hospital stay, health care costs, and deaths. Limitations Findings might not be generalizable to all ED patients. Patients younger than 18 years of age were excluded from the study. Exposures are under-reported in NPDS. Methadone and buprenorphine were not routinely screened in urine toxicology. Cases with co-ingestants were excluded. Cases not followed to a known outcome, refusal of referral to an HCF, or left an HCF against medical advice were also excluded. Dose information was not evaluated in the study because doses were not available for all cases, nor was information on whether the event occurred in an opioid-naı¨ve or opioid-dependent individual. Information on whether the buprenorphine was used sublingually or swallowed was not available. The retrospective design and undercoding of certain clinical effects might have affected the results of the algorithmic analysis for opioid withdrawal. CONCLUSIONS Nonmedical use of methadone was associated with serious clinical effects, such as respiratory arrest, coma, and death. The majority of patients had complicated clinical courses characterized by the use of naloxone or endotracheal intubation, and a 50% admission rate to the ICU. Nonmedical use of buprenorphine was most often associated with milder clinical effects or clinical effects of opioid withdrawal, a more benign clinical course, and most (67%) were treated and discharged from the ED. There were no deaths associated with nonmedical use of buprenorphine. These findings can help physicians determine the appropriate triage and disposition of patients presenting to the ED with nonmedical use of methadone and buprenorphine. Future research might include an assessment of outcomes in other populations, such as adolescents or populations that use benzodiazepines nonmedically along with opioids.
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Medical Outcomes from Nonmedical Use of Methadone and Buprenorphine
ARTICLE SUMMARY 1. Why is this topic important? Nonmedical use of prescription opioids is responsible for the majority of 1.2 million Emergency Department (ED) visits per year associated with nonmedical use of pharmaceuticals. Nonmedical use of methadone and buprenorphine is on the rise. Many authors purport that methadone and buprenorphine are similar in severity and outcomes. 2. What does this study attempt to show? Because of different pharmacology, different outcomes can be expected to be observed after nonmedical use of methadone and buprenorphine. 3. What are the key findings? There were 26 deaths in the methadone group vs. 0 deaths in the buprenorphine group. Admission rate to the intensive care unit (ICU) was 50% in the methadone group vs. 15% in the buprenorphine group. Most of the patients in the buprenorphine group were treated and released from the ED. 4. How is patient care impacted? These findings can help in triage and disposition of patients presenting with nonmedical use of these opioids. Nonmedical use of methadone is more likely to require a higher level of care in the ED than buprenorphine. Nonmedical use of methadone is more likely to require admission to ICU than nonmedical use of buprenorphine.
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http://dx.doi.org/10.1016/j.jemermed.2012.11.104
Selected Topics: Toxicology
MEDICAL OUTCOMES ASSOCIATED WITH NONMEDICAL USE OF METHADONE AND BUPRENORPHINE Samantha Lee, PHARMD, Wendy Klein-Schwartz, PHARMD, MPH, Christopher Welsh, MD, and Suzanne Doyon, MD University of Maryland School of Medicine and School of Pharmacy, Baltimore, Maryland Reprint Address: Suzanne Doyon, MD, University of Maryland School of Medicine and School of Pharmacy, 220 Arch Street, Office Level 1, Baltimore, MD 21201
, Abstract—Background: There exists a significant amount of misinformation regarding methadone and buprenorphine, and a belief that toxicity associated with nonmedical use of methadone and nonmedical use of buprenorphine is similar in severity and outcomes. Objective: The objective of this study is to compare outcomes associated with nonmedical use of methadone vs. nonmedical use of buprenorphine in patients presenting to the Emergency Department (ED) and reported to poison centers. Methods: This was a retrospective cohort study using data from the American Association of Poison Control Centers from January 1, 2003 to December 31, 2009 (7 years). Inclusion criteria were nonmedical use of methadone or buprenorphine (or buprenorphine/naloxone) as a single substance by history, age 18 years or older, ingestions only, evaluated in an ED. Outcome measures were clinical effects, treatments, disposi-
tion, and final medical outcomes. Results: Of 1,920 cases, 1,594 were in the methadone group and 326 were in the buprenorphine group. Frequently reported clinical effects were lethargy, 59.2% vs. 29.4%, and respiratory depression, 28.7% vs. 2.5%, for methadone and buprenorphine groups, respectively. Hospitalization rates were 67.4% in the methadone group and 32.2% in the buprenorphine group. Half of all patients in the methadone group were admitted to the intensive care unit (ICU) vs. only 15% of all the patients in the buprenorphine group. Twenty-six patients in the methadone group died vs. no deaths in the buprenorphine group. There were significant differences in the distribution of clinical effects, disposition, and medical outcomes (p < 0.001). Conclusions: Patients who use methadone nonmedically have higher hospitalization rates, greater ICU utilization rates, and considerably worse medical outcomes when compared with patients who use buprenorphine nonmedically. Ó 2013 Elsevier Inc.
Disclaimer: The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country’s 57 poison centers. Case records in this database are from self-reported calls: they reflect only information provided when the public or health care professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure), or request information or educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures might go unreported to poison centers and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).
, Keywords—nonmedical use; methadone; buprenorphine
INTRODUCTION Drug overdose fatalities are on the rise in the United States (US) and prescription medications, particularly prescription opioids, account for most of the increase (1). In 2008, prescription medications caused 20,044 deaths and prescription opioids were involved in 14,800 (73.8%) of them (1). In 2009, 1.2 million Emergency Department (ED) visits were associated with the nonmedical use of pharmaceuticals (mostly opioids), a number that
RECEIVED: 13 March 2012; FINAL SUBMISSION RECEIVED: 18 June 2012; ACCEPTED: 6 November 2012 199
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exceeded the number of ED visits associated with the use of illicit drugs, such as heroin and cocaine (2). Current medical literature rarely offers an examination of this pharmacoepidemic beyond medical examiner data, surveillance reports, and description of patterns (1–4). Methadone is a synthetic full m-receptor agonist with inhibition at the N-methyl-D-aspartate receptor, which might make it a better analgesic than morphine (5–7). Buprenorphine is a semi-synthetic partial m-receptor agonist and k-receptor antagonist (8–10). It has a relatively low intrinsic activity as a partial agonist at the m-receptor, resulting in a ceiling effect for respiratory depression at higher doses. Buprenorphine has a high affinity for and slow dissociation from the m-receptor, which contribute to its long duration of action, comparable to that of methadone. Unlike methadone, buprenorphine has the potential to induce opioidwithdrawal symptoms if other opioids are present (5,8). Pharmacologic investigations indicate that opioids, including methadone and buprenorphine, have the potential to be misused, abused, used nonmedically, and diverted (11,12). Many authors have compared methadone to buprenorphine, despite their different pharmacology, different US Food and Drug Administration (FDA) indications, and different prescribing regulations (13–20). In one case series of hospitalized patients, the authors concluded that the toxicities of methadone and buprenorphine were indistinguishable from one another (13). Others have studied diversion rates, comparing patient populations that were prescribed methadone with patient populations that were prescribed buprenorphine, overlooking the fact that these two populations might be different (methadone can only be prescribed legally for pain) (20–30). As a result, there exists a significant amount of misinformation and a belief that, because of similar toxicities and similar diversion rates, nonmedical use of methadone and nonmedical use of buprenorphine are, at a minimum, comparably hazardous (31–34). An examination of the immediate and short-term health effects resulting from nonmedical use of methadone and buprenorphine is necessary. The study null hypothesis is that the nonmedical use of methadone and buprenorphine results in similar medical outcomes.
METHODS This is a retrospective review of poison center data. The American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) receives data from all poison centers serving the entire US population, including its territories. NPDS is an electronic database. Cases are called in to poison centers from multiple
sources and information is collected by specialists in poison information (SPI) in real time and sent electronically to NPDS. NPDS data collection and reporting process are further explained elsewhere (35,36). The University of Maryland Baltimore Institutional Review Board (IRB) determined that the study did not require IRB review (not human subject research status). AAPCC NPDS was queried for cases from January 1, 2003 through December 31, 2009 (7 years) involving oral preparations of buprenorphine (alone or buprenorphine and naloxone) and methadone. Inclusion criteria were nonmedical use of buprenorphine or methadone as a single substance by history; age 18 years and older; ingestion only; and managed in the ED or other health care facility (HCF). Nonmedical use was defined as either ‘‘intentional abuse’’ or ‘‘intentional misuse’’ as the reason for exposure. The term buprenorphine group refers to patients who ingested either buprenorphine or buprenorphine/naloxone preparations. SPI collect data on the presence of precoded clinical effects (i.e., symptoms, signs, or laboratory abnormalities). Because of overlap in clinical effects, a datamining algorithm (Boolean algorithm) for opioid withdrawal was used. Opioid withdrawal was defined as the absence of naloxone administration and the presence of at least three of the following six clinical effects: tachycardia, agitation and irritability, vomiting and diarrhea, diaphoresis, tremor, or mydriasis (37). Naloxone was identified as a confounding variable. Outcomes measures included treatment(s) received, disposition, and poison center coding of final medical outcomes. Treatments included administration of naloxone, endotracheal intubation, use of antiemetics, and use of sedatives. Disposition included treated and released from the ED, admitted to a general medical or surgical unit, admitted to an intensive care unit (ICU), or admitted to a psychiatric unit (35). Poison center coding of medical outcomes included no effect, minor effect, moderate effect, major effect, and death. Moderate effect was defined as clinical effects that are more pronounced, more prolonged, or more systemic, and usually some form of treatment is indicated. Major effect was defined as signs or symptoms that were life threatening or resulted in significant residual disability or disfigurement (38). These medical outcomes were determined and coded by the SPI when the cases were closed. Cases were excluded if the final medical outcomes were not known. Deidentified data were received in NPDS in Microsoft Access 2007 format and reports were generated using Crystal Reports 2008. Data were analyzed for age, sex, substance ingested, clinical effects, management sites, treatments, and final medical outcomes. Geographic data were not obtained.
Medical Outcomes from Nonmedical Use of Methadone and Buprenorphine Table 1. Clinical Effects after Nonmedical Use of Methadone or Buprenorphine Methadone (n = 1,594) Clinical Effects Respiratory Cyanosis Respiratory depression Respiratory arrest Pneumonitis Cardiovascular Cardiac arrest Hypotension Neurological Drowsiness/ lethargy Coma Agitation/ irritable Ocular Miosis Gastrointestinal Abdominal pain Vomiting Miscellaneous CPK elevation Diaphoresis
Buprenorphine (n = 326)
n
%
n
%
p Value*
52 458
3.3 28.7
0 8
2.5
0.002 <0.001
97
6.1
0
<0.001
20
1.3
0
NS
22 138
1.4 8.7
0 7
2.1
NS <0.001
943
59.2
96
29.4
<0.001
377 91
23.7 5.7
7 76
2.1 23.3
<0.001 <0.001
128
8.0
12
3.7
0.008
7 111
0.4 7.0
18 42
5.5 12.9
<0.001 <0.001
59 18
3.7 1.1
4 23
1.2 7.1
0.034 <0.001
CPK = creatine phosphokinase; NS = not significant. * c2 with Yates correction.
Quantitative data were summarized by medians and ranges and categorical data by frequencies and percentages. c2 with Yates correction for continuity was used to compare selected clinical effects, treatments, dispositions, and medical outcomes. To compare medical outcomes, major effect and death were combined because of the small numbers in the buprenorphine group. Analyses were performed with SigmaStat 3.1.1 (Point Richmond, CA) and all reported p values are two-sided. Statistical significance was defined as p < 0.05.
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in 377 (23.7%) and 97 (6.1%), respectively, of patients in the methadone group and 7 (2.1%) and 0 (0%), respectively, of patients in the buprenorphine group (p < 0.001). Agitation/irritability, vomiting, and diaphoresis were present in 91 (5.7%), 111 (7%), and 18 (1.1%), respectively, of the methadone cases, and in 76 (23.3%), 42 (12.9%), and 23 (7.1%), respectively, of the buprenorphine cases (p < 0.001). In the subset of patients who did not receive naloxone, 10 of 559 (1.9%) patients in the methadone group and 19 of 292 (6.5%) patients in the buprenorphine group fit the diagnostic criteria for opioid withdrawal (p < 0.001). Finally, 101 (6.3%) patients in the methadone group were asymptomatic compared with 34 patients (10.4%) in the buprenorphine group (p = 0.012). Patients in the methadone group were more likely to receive naloxone and endotracheal intubation than those in the buprenorphine group (p < 0.001) (Table 2). Patients in the buprenorphine group more often received benzodiazepines and antiemetic therapy (p < 0.001). Five hundred and nineteen (32.5%) patients in the methadone group and 221 (67.8%) in the buprenorphine group were treated and released from the ED (Table 3). There were 1,075 (67.4%) patients hospitalized in the methadone group compared with 105 (32.2%) in the buprenorphine group. The ICU admission rates were 49.5% in the methadone group and 15% in the buprenorphine group. There were 26 fatalities in the methadone group and none in the buprenorphine group. Comparing methadone and buprenorphine, the distributions of dispositions and medical outcomes were significantly different (p < 0.001). DISCUSSION Nonmedical use of methadone and buprenorphine reported to poison centers was compared with Drug Abuse Warning Network (DAWN) weighted estimates of ED visit mentions of nonmedical use of buprenorphine and
RESULTS The AAPCC NPDS search yielded 1,990 cases that met inclusion criteria. Of these, 56 patients in the methadone and 14 in the buprenorphine group left against medical advice, without complete treatment or known medical outcomes. Of the remaining 1,920 patients, 1,594 were in the methadone and 326 in the buprenorphine group. Median age was 33 years in both the methadone group (range 18–85 years) and in the buprenorphine group (range 18–78 years). The majority were men; 56.9% and 61.1% in the methadone and buprenorphine groups, respectively. Table 1 presents the frequency of clinical effects. Coma and life-threatening respiratory arrest were present
Table 2. Treatments Received after Nonmedical Use of Methadone or Buprenorphine Methadone (n = 1,594)
Buprenorphine (n = 326%)
Treatments Received
n
%
n
%
p Value*
Naloxone Intubation Benzodiazepine Antiemetic i.v. fluids Vasopressors
1,035 187 93 37 683 44
64.9 11.7 5.8 2.3 42.8 2.8
34 8 75 28 83 1
10.4 2.5 23.0 8.6 25.5 0.3
<0.001 <0.001 <0.001 <0.001 NS NS
NS = not statistically significant. * c2 with Yates correction.
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Table 3. Disposition and Final Medical Outcomes after Nonmedical Use of Buprenorphine or Methadone Methadone Buprenorphine (n = 1,594) (n = 326) Disposition and Outcomes Emergency Department disposition Discharged Admitted to non critical care unit Admitted to critical care unit Admitted to psychiatric care facility Final medical outcome No effect Minor effect Moderate effect Major effect Death
n
%
n
%
p Value* <0.001
519 242
32.5 15.2
221 44
67.8 13.5
790
49.6
48
14.7
43
2.7
13
4.0
101 411 748 308 26
6.3 25.8 47.0 19.3 1.6
34 170 112 10 0
10.4 52.1 34.4 3.1 0
<0.001
* c2 with Yates correction.
methadone over time (Figure 1). AAPCC NPDS is a poisoning surveillance system that collects data on exposures to substances and reports in near real time from 57 US poison centers. NPDS includes exposures and produces case counts. DAWN is a public health surveillance system designed to monitor national and local trends in drug-related ED visits and drug-related deaths by collecting data from a representative sample of US hospitals. DAWN includes ‘‘mentions’’ and produces estimates (2). Despite markedly different methodologies and their
inherent shortcomings, trends in poison center data closely followed those found in DAWN. Strengths of NPDS data include early tracking of buprenorphine starting in 2004 and nationwide reporting of case counts, not estimates. Central nervous system and respiratory depression were most frequently encountered in the methadone group and gastrointestinal symptoms were most frequently present in the buprenorphine group (Table 1). The opioid withdrawal algorithm was more frequently observed in the buprenorphine group than in the methadone group (5.8% vs. 1.9%, respectively). These findings are consistent with previous reports of buprenorphine diversion, where commonly stated reasons for nonmedical use of buprenorphine were to treat opioid withdrawal or for detoxification (39,40). Patients who used methadone nonmedically were more likely to fare worse on all measures of health outcomes. They were more likely to have received naloxone or endotracheal intubation, to be admitted to the ICU, and were more likely to die (Table 2). There were 26 deaths in the methadone group. The risks associated with nonmedical use of buprenorphine were much less severe, as exemplified by the fact that patients in the buprenorphine group were more likely to be treated with antiemetics and benzodiazepines, and the great majority of them were treated and released from the ED (67%). Importantly, there were no deaths in the buprenorphine group (Table 3). These data support the conclusion that nonmedical use of buprenorphine, although rising, is associated with
Figure 1. Comparison of poison control center (PCC) annual cases vs. Drug Abuse Warning Network (DAWN) weighted annual estimates of methadone and buprenorphine nonmedical use.
Medical Outcomes from Nonmedical Use of Methadone and Buprenorphine
markedly better medical outcomes than nonmedical use of methadone. A small but significant proportion of patients who used buprenorphine nonmedically sought medical attention because they were in opioid withdrawal. Nonmedical use of methadone is a much more serious problem. In addition to increased number of deaths and worsening of all measurable medical outcomes, increased health care costs are another potential societal burden posed by nonmedical use of methadone. This burden is not negligible, as it includes increases in procedures, higher admission rates, and greater utilization of the ICU (41). Additional research is needed in this area in order to better understand the impact of nonmedical use of all prescription opioids on health outcomes, length of hospital stay, health care costs, and deaths. Limitations Findings might not be generalizable to all ED patients. Patients younger than 18 years of age were excluded from the study. Exposures are under-reported in NPDS. Methadone and buprenorphine were not routinely screened in urine toxicology. Cases with co-ingestants were excluded. Cases not followed to a known outcome, refusal of referral to an HCF, or left an HCF against medical advice were also excluded. Dose information was not evaluated in the study because doses were not available for all cases, nor was information on whether the event occurred in an opioid-naı¨ve or opioid-dependent individual. Information on whether the buprenorphine was used sublingually or swallowed was not available. The retrospective design and undercoding of certain clinical effects might have affected the results of the algorithmic analysis for opioid withdrawal. CONCLUSIONS Nonmedical use of methadone was associated with serious clinical effects, such as respiratory arrest, coma, and death. The majority of patients had complicated clinical courses characterized by the use of naloxone or endotracheal intubation, and a 50% admission rate to the ICU. Nonmedical use of buprenorphine was most often associated with milder clinical effects or clinical effects of opioid withdrawal, a more benign clinical course, and most (67%) were treated and discharged from the ED. There were no deaths associated with nonmedical use of buprenorphine. These findings can help physicians determine the appropriate triage and disposition of patients presenting to the ED with nonmedical use of methadone and buprenorphine. Future research might include an assessment of outcomes in other populations, such as adolescents or populations that use benzodiazepines nonmedically along with opioids.
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Medical Outcomes from Nonmedical Use of Methadone and Buprenorphine
ARTICLE SUMMARY 1. Why is this topic important? Nonmedical use of prescription opioids is responsible for the majority of 1.2 million Emergency Department (ED) visits per year associated with nonmedical use of pharmaceuticals. Nonmedical use of methadone and buprenorphine is on the rise. Many authors purport that methadone and buprenorphine are similar in severity and outcomes. 2. What does this study attempt to show? Because of different pharmacology, different outcomes can be expected to be observed after nonmedical use of methadone and buprenorphine. 3. What are the key findings? There were 26 deaths in the methadone group vs. 0 deaths in the buprenorphine group. Admission rate to the intensive care unit (ICU) was 50% in the methadone group vs. 15% in the buprenorphine group. Most of the patients in the buprenorphine group were treated and released from the ED. 4. How is patient care impacted? These findings can help in triage and disposition of patients presenting with nonmedical use of these opioids. Nonmedical use of methadone is more likely to require a higher level of care in the ED than buprenorphine. Nonmedical use of methadone is more likely to require admission to ICU than nonmedical use of buprenorphine.
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