ORIGINAL RESEARCH
Abuse and Intentional Misuse of Promethazine Reported to US Poison Centers: 2002 to 2012 M. Ellen Tsay, PharmD, Gabrielle Procopio, PharmD, Bruce D. Anderson, PharmD, DABAT, and Wendy Klein-Schwartz, PharmD, MPH
Objective: Promethazine abuse has been reported. The objective was to investigate promethazine abuse/misuse in the United States. Methods: An 11-year retrospective review was conducted of promethazine abuse and intentional misuse cases without co-ingestants in persons 10 years and older reported to the National Poison Data System. Data were stratified by product (promethazine-alone [PA] or co-formulation [PC]) and evaluated for demographics, toxicity, management sites, and outcomes. Results: There were 354 single product abuse or misuse exposures— 95 PA and 259 PC. Over the 11-year timeframe, the annual exposure rate per 100,000 population doubled. Exposures were most prevalent among 10 to 19 years old and young adults (20s), accounting for 69.5% of PA and 57.5% of PC cases. Clinical effects due to PA included drowsiness (43.2%), tachycardia (7.4%), agitation (13.7%), confusion (13.7%), slurred speech (12.6%), hallucinations (7.4%), dizziness (7.4%), and hypertension (5.3%). Drowsiness (53.4%) and tachycardia (20.8%) were more frequent with PC. There were significant differences between PA and PC in management site (P = 0.0078). Management sites for PA and PC, respectively, were emergency department (37.9%, 55.6%), non–health care facility (33.7%, 14.7%), critical care unit (8.4%, 11.2%), non–critical care unit (7.4%, 7.3%), psychiatry (2.1%, 4.2%), and other/unknown (10.5%, 7.0%). Outcomes for PA and PC, respectively, were no effect (21.0%, 12.4%), From the Maryland Poison Center (MET, BDA, WKS), University of Maryland School of Pharmacy, Baltimore, MD; and Department of Pharmacy (GP), Johns Hopkins Hospital, Baltimore, MD. Received for publication July 23, 2014; accepted February 1, 2015. 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 (PCs). 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 (eg, an ingestion, inhalation, or topical exposure) or request information/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 may go unreported to PCs, and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s). The authors have no conflicts of interest or funding disclosures. Send correspondence and reprint requests to Wendy Klein-Schwartz, PharmD, MPH, Maryland Poison Center, University of Maryland School of Pharmacy, 220 Arch St, Room 01–108, Baltimore, MD 21201. E-mail: [email protected]. C 2015 American Society of Addiction Medicine Copyright ISSN: 1932-0620/15/0903-0233 DOI: 10.1097/ADM.0000000000000124
minor (58.9%, 53.7%), moderate (17.9%, 32.0%), and major effects (2.1%, 1.9%). Conclusions: Promethazine-alone abuse/misuse most frequently resulted in minor outcomes, and less than 20% required medical admission. Abuse/misuse of PC resulted in a higher frequency of health care facility treatment and a trend toward more moderate outcomes. These differences are most likely attributed to the co-formulate. Key Words: abuse, nonmedical use, promethazine, toxicity (J Addict Med 2015;9: 233–237)
P
romethazine, a phenothiazine derivative, was made available to the United States market in 1946. Mechanistically, it acts primarily as an H1 receptor antagonist but may also interact with muscarinic, dopaminergic, alpha-adrenergic, and serotonin receptors, giving the medication its sedative and antiemetic properties (Adolph et al., 2012). It is used therapeutically in individuals 2 years of age or older for the treatment of allergic reactions, as an adjunct to procedural sedation and as an antiemetic. Promethazine is available alone or in combination with other drugs, including codeine, dextromethorphan, and/or expectorants. Although the abuse potential of promethazine is largely unknown, it is believed that the combined use with opioids will provide additional sedation and a lower amount of opioid required to achieve this effect (Clatts et al., 2010). Promethazine misuse and abuse have been documented in certain areas in the United States and internationally. Promethazine had been detected in the urine samples of 26% of methadone maintenance patients in San Francisco despite only 15% of those patients having an active promethazine prescription. Up to 17% of injection drug users in San Francisco reported the use of promethazine in a month period (Shapiro et al., 2013). Promethazine was detected in the serum in 14.2% of methadone fatality cases in Kentucky (Shields et al., 2007). A majority (75%) of surveyed intravenous heroin users in Vietnam reported the use of promethazine to supplement a lower amount of heroin, to treat withdrawal, or due to its legal availability and price (Clatts et al., 2010). The objective of this study was to evaluate national poison center data on promethazine abuse and misuse in the United States and to document clinical effects and medical outcomes due to promethazine exposures.
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METHODS
RESULTS
A retrospective review was conducted of intentional misuse or abuse promethazine exposures in persons 10 years of age and older reported to the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) from January 2002 to December 2012. The National Poison Data System comprise data that are collected from all US poison centers. Poison centers provide consultations to both the general public and health care professionals regarding exposures (both accidental and intentional) to medications, chemicals, or to toxins in the environment. During the consultation, poison specialists collect data, which are then uploaded electronically to NPDS in real time. Coded data include age, sex, reason for exposure, product, clinical effects, treatments, management site, and medical outcomes. Abuse is defined as improper or incorrect use of a substance where the victim was likely attempting to gain a high, euphoric effect or some other psychotropic effect. Intentional misuse is improper or incorrect use of a substance for reasons other than the pursuit of a psychotropic effect. In this report, these reasons are considered nonmedical use. Only clinical effects coded as related to the exposure are included. Management sites are non–health care facility (managed on site), emergency department (treated/evaluated and released), critical care unit, non–critical care unit, psychiatric care facility, no show/left against medical advice, and other site. Poison center coding of known medical outcomes related to the exposure includes no effect, minor, moderate, major, and death. Patients with minor outcomes have some minimally bothersome signs or symptoms as a result of the exposure. Moderate outcomes include signs or symptoms that were more pronounced, more prolonged, or more systemic than minor symptoms, and usually some form of treatment is indicated. Major outcomes exhibit signs or symptoms that were life threatening or resulted in significant residual disability or disfigurement. The medical outcome is determined at the end of the case and is dependent on the types of clinical effects and treatment administered that were coded. Exposures due to promethazine were identified from NPDS by utilizing the AAPCC product codes for all promethazine-containing medications available in the United States. Intentional misuse and abuse cases were included. Information calls and exposures not followed to a known medical outcome were excluded. The data were separated into 2 categories—exposures to promethazine alone (PA) or single product exposures to promethazine in a co-formulation with other medications (PC). Promethazine-containing products may include codeine, dextromethorphan, and/or an expectorant. The data for PA and PC exposures were evaluated for demographics, state, management site, and medical outcomes. Clinical effects coded as related to promethazine were evaluated. The Pearson χ 2 test was run to determine whether there is a statistical significant difference between PA and PC in the categories of outcome, disposition, and age. The procedure PROC MULTTEST (SAS v 9.4) with the sequential Bonferroni procedure was used to adjust for the multiple comparisons. This study was granted exempt status by the University Institutional Review Board.
There were 4434 PA and PC exposures reported to poison centers, including 2106 single product and 2328 polysubstance cases in persons 10 years of age and older. Of these, 630 (14.2%) were due to abuse or intentional misuse. There were 276 abuse or misuse polysubstance exposures (involving mostly psychotherapeutic drugs and opioids) that were excluded. The study cohort included 95 PA and 259 PC cases. The most frequent co-formulates in PC products (alone or with other drugs) were codeine (n = 126, 48.4%) and dextromethorphan (n = 118, 45.6%). Table 1 displays the breakdown of co-formulates in PC products. Males accounted for 51.6% of PA and 61.4% of PC cases. Table 2 provides age breakdowns. There was a significant difference in age between PA and PC (χ 2 = 78.78, adjusted P < 0.0001). The age group with the highest proportion of cases was 10 to 19 years for PA (46.3%) and PC (37.1%). Figure 1 compares the rates of PA and PC cases per 100,000 US population with rates of total exposures (all substances) per 100,000 US population reported to poison centers over the study period. From 2003 to 2008, the rate of PA cases was relatively flat, increased in 2009 to 2010 and then decreased in 2011 to 2012. Similarly, from 2006 to 2011, the rate of PC cases increased and then showed a decline in 2012. The rate of national poison center exposures started to decline after 2009. States with the largest number of cases were California (n = 59), Texas (n = 35), New Jersey (n = 23), Ohio (n = 16), Arizona (n = 15), Florida (n = 14), Virginia (n = 14), and Louisiana (n = 12). Clinical effects from nonmedical use of PA include drowsiness (n = 41, 43.2%), agitation (n = 13, 13.7%), confusion (n = 13, 13.7%), slurred speech (n = 12, 12.6%), tachycardia (n = 7, 7.4%), dizziness (n = 7, 7.4%), hallucinations
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TABLE 1. Co-Formulates Involved in Nonmedical Use of PC Total (n = 259)
Co-Formulates Codeine Codeine + phenylephrine Codeine + expectorant Dextromethorphan Dextromethorphan + expectorant Expectorant Phenylephrine Aspirin + pseudoephedrine or caffeine Decongestant
92 (35.5%) 9 (3.5%) 25 (9.6%) 98 (37.8%) 20 (7.7%) 8 (3.1%) 4 (1.5%) 2 (0.8%) 1 (0.4%)
TABLE 2. Age Breakdown by Product Type* Age (y)
Promethazine Alone (n = 95)
Promethazine Containing† (n = 259)
44 (46.3%) 22 (23.2%) 2 (2.1%) 5 (5.3%) 7 (7.4%) 8 (8.4%) 7 (7.4%)
96 (37.1%) 53 (20.5%) 34 (13.1%) 28 (10.8%) 21 (8.1%) 22 (8.5%) 5 (1.9%)
10-19 20-29 30-39 40-49 50-59 60+ Unknown
*Significant difference between PA and PC (P < 0.0001). †Promethazine with co-formulates. C
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Abuse and Misuse of Promethazine
department (37.9%). Promethazine co-formulation exposures were mostly managed in the emergency department (55.6%) or were admitted (22.8%). The majority of nonmedical users of PA and PC experienced minor effects (58.9% and 53.7%, respectively). There was a trend toward nonmedical users of PC experiencing moderate outcomes (32.0%) more often than nonmedical users of PA (17.9%), but it was not significant. There were no reported deaths due to PA or PC abuse or misuse.
DISCUSSION
FIGURE 1. Trends in promethazine abuse and misuse compared with total national poison center exposures.
(n = 7, 7.4%), vomiting (n = 6, 6.3%), hypertension (n = 5, 5.3%), ataxia (n = 4, 4.2%), and dystonia (n = 2, 2.1%). Exposure to promethazine alone rarely caused more serious effects, but respiratory depression (n = 2, 2.1%) and hypotension (n = 1, 1.0%) were observed. Clinical effects from nonmedical use of PC were similar to those from promethazine alone, but the extent to which they were due to the co-formulate could not be ascertained with coded data only. Drowsiness (53.4%) and tachycardia (20.8%) were more frequent with PC. Although serious clinical effects were also rare with nonmedical use of PC, they included hyperthermia (n = 5, 1.9%), hypotension (n = 5, 1.9%), seizures (n = 4, 1.5%), and coma (n = 3, 1.2%). The 4 cases with seizures were due to exposures to promethazine and codeine products. There was a significant difference between PA and PC in management site (χ 2 = 20.17, adjusted P = 0.0078) but not outcome (χ 2 = 8.87, adjusted P = 0.0932). Table 3 displays a breakdown of management sites and outcomes by product type. Promethazine-alone exposures were mostly treated in a non–health care facility (33.7%) or managed in the emergency TABLE 3. Outcomes and Management Sites by Product Type
Outcome† No effect Minor effect Moderate effect Major effect Death Management sites‡ Non-HCF ED CCU Non-CCU Psychiatric care No show/AMA Other
Promethazine Alone (n = 95)
Promethazine Containing* (n = 259)
20 (21.0%) 56 (58.9%) 17 (17.9%) 2 (2.1%) 0
32 (12.4%) 139 (53.7%) 83 (32.0%) 5 (1.9%) 0
32 (33.7%) 36 (37.9%) 8 (8.4%) 7 (7.4%) 2 (2.1%) 10 (10.5%) 0
38 (14.7%) 144 (55.6%) 29 (11.2%) 19 (7.3%) 11 (4.2%) 17 (6.6%) 1 (0.4%)
*Promethazine with co-formulates. †P = 0.0932; ‡P = 0.0078 AMA, leave against medical advice; CCU, critical care unit; ED, emergency department; non-HCF, non–health care facility. C
Promethazine has been abused or misused to achieve a state of delirium and/or sedation (Erowid Experience Vaults, May 8, 2006; Erowid Experience Vaults, May 10, 2006; Erowid Experience Vaults, August 9, 2007). Users have also reported on online forums that promethazine can be combined with opioids to prevent opioid-induced nausea, to supplement the opioid-induced euphoria so that a lower dose of opioids can be taken, or to self-medicate drug withdrawal (Erowid Experience Vaults, January 12, 2007; Erowid Experience Vaults, August 9, 2007; Erowid Experience Vaults, October 10, 2009). Recent data have shown that promethazine can act as a noncompetitive antagonist to the N-methyl-D-aspartate receptor, which may contribute to its sedative properties and the potential to act as an analgesic (Adolph et al., 2012). The rate per 100,000 population of promethazine exposures from abuse or intentional misuse reported to US Poison Control Centers peaked in 2011 for PC and 2010 for PA and then declined. This may be due to reporting bias; as this exposure became more common, both health care practitioners and the lay public became more familiar with expected clinical effects so did not contact poison centers. Interestingly, the rate per 100,000 population of all exposure calls to US Poison Control Centers also started to decrease after 2009 (Mowry et al., 2013). Therefore, this decline may reflect lower reporting rates rather than lower abuse and misuse rates. In a case series of promethazine overdoses (both promethazine alone or with a co-ingestant) in Australia (where promethazine is available over the counter), the mean age of patients exposed to promethazine alone was 22 years (range: 3-70, n = 57). Common clinical effects experienced by those patients included tachycardia (58%) with no reported dysrhythmias or ECG changes, delirium (42%), and mild to moderate central nervous system depression (56%). Hypotension or myoclonus rarely occurred, and there were no reports of dystonia, neuroleptic malignant syndrome, seizures, or death. A small percentage of the study population experienced seizures (1%) but ingested promethazine with a co-ingestant. All patients in this case series were managed in the emergency department or were admitted to the hospital (Page et al., 2009). Common clinical effects of PA exposures seen in our study were similar to those previously described but occurred at a lower frequency. Although this may reflect a lower capture rate of clinical effects from promethazine, it may also be attributed to the inclusion of less serious cases managed outside a health care facility. The majority of nonmedical users of PA and PC in this study were preteens, teenagers, or adults in their 20s. Overall, PC users were older with almost a fourth of the cases reported
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in adults in their 30s and 40s. Promethazine co-formulation users required a higher level of medical care than PA users. A third of PA cases were managed outside a health care facility compared with close to 15% for PC cases. Approximately 80% of PC cases were treated in the emergency department or admitted. The most common co-formulates were codeine with or without phenylephrine or an expectorant (48.6%) and dextromethorphan with or without an expectorant (45.6%). The clinical presentation of dextromethorphan toxicity is dose dependent. Smaller amounts of dextromethorphan may result in euphoria, tachycardia, hypertension, and other minor symptoms. Larger doses of dextromethorphan can lead to hallucinations and ataxia. With extreme toxicity patients can seem agitated and experience hyperthermia and metabolic acidosis (Burns and Boyer, 2013). The clinical effects of promethazine and dextromethorphan abuse are not well documented in literature. Codeine, well documented for its abuse potential, may lead to a sense of euphoria. Some signs and symptoms of codeine toxicity include somnolence, respiratory depression, hypotension, bradycardia, and in severe cases cardiac arrest and even death. Opioids, including codeine, may aggravate hypoxia-induced seizures, and promethazine may lower seizure threshold (Burns and Boyer, 2013). Four patients with PC who were noted to have seizure also had codeine as a co-formulate. It is possible that the combination effect puts these patients at higher risk of seizure. Promethazine-induced alpha-adrenergic blockade, particularly in combination with other medications, may lead to hypotension as occurred in 5 cases due to PC. Promethazine abuse and misuse have been documented in the abuse of cough syrups containing promethazine and codeine. Promethazine and codeine have been commonly referred to as “purple drank,” “sizzurp,” “lean,” “barre,” or “drank” when mixed with a soft drink and candy (Agnich et al., 2013). This concoction started to gain popularity in the 1990s among African American teenagers in the Houston, Texas, rap scene (Peters et al., 2003; Agnich et al., 2013), also referred to as “screw music” (Peters et al., 2007). This form of music can be described as a form of hip-hop that utilizes a slower beat (Peters et al., 2007). A survey of middle and high school students in Houston, Texas, implicated that the rise in popularity of codeine/promethazine came from media influences and the euphoric effect achieved by the syrup. Addiction and repeated use of codeine/promethazine in these students have developed and occurred soon after first time use (Peters et al., 2003). Another survey of college-aged adults in Houston, Texas, reported that the initiation of codeine/promethazine cough syrup abuse came from peer pressure or curiosity and continued because of the produced euphoric effect. Males were more likely than females to habitually abuse codeine/promethazine as a coping mechanism (Peters et al., 2007). Users also reported common access to cough syrup by obtaining a prescription before selling the syrup illicitly or by diverting the medication from a pharmacy. Withdrawal, addiction, and peer pressure were identified as common barriers to quitting codeine/promethazine abuse (Peters et al., 2007). Although this survey was conducted on student participants in a histor-
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ically African American college campus, other studies have implicated that codeine/promethazine abuse may occur outside of the Houston, Texas, area and in other racial groups (ie, Native Americans and Hispanics) (Agnich et al., 2013). Our study found that PA and PC abuse occurred in most states with highest numbers in California, Texas, and New Jersey. Other identifiers to codeine/promethazine abuse may include individuals living in an urban setting or individuals that identify as LGBT (lesbian, gay, bisexual, or transgender) (Agnich et al., 2013). There were 276 cases excluded from the study because of co-ingestants. These cases had higher frequencies of moderate (36%) and major (7%) effects and intensive care unit (21%) and medical admissions (11%) compared with PA and PC alone. There were 3 deaths. Although clinicians should anticipate more serious consequences when other substances are involved, it is not possible to discern from these data whether this is related to additive effects or interactions with promethazine or due primarily to the inherent toxicity of the other substances. There were limitations to our study—information obtained is based on reported exposures. As reporting to poison centers is voluntary these data do not capture cases not reported. Also, because data are based on hospital or caller reports, the severity of some clinical effects may not be reflected in the coded data. Data coding was performed by specialists in poison information and poison information providers at approximately 57 poison centers, leading to the potential for variability in coding or the potential for incorrect or incomplete coding, despite a coding manual to assist staff in coding uniformly and standard coding procedures adopted by all poison centers. Promethazine-alone or PC exposures can only be determined through patient history or clinical presentation due to the fact that promethazine blood levels are not readily analyzed in the laboratories of most treating institutions. Finally, this study excluded multisubstance exposures; therefore, the results are not generalizable to nonmedical use of PA or PC with other substances.
CONCLUSIONS This study provided a nation-wide insight to the nonmedical use of promethazine alone and promethazine combination products. These data find that nonmedical use is increasing compared with 11 years ago. Abuse or intentional misuse of promethazine alone most frequently resulted in minor clinical effects. The majority of promethazine only exposures were cared for in the emergency department. Abuse or intentional misuse of PC had more serious consequences with a higher frequency of treatment at a health care facility and a trend toward a higher frequency of moderate outcomes. These differences are most likely attributed to toxicity associated with the co-formulate in PC products as opposed to promethazine alone.
ACKNOWLEDGMENTS We thank Larry Gonzales, BS, senior IT specialist at the Maryland Poison Center, for his assistance with data analysis C
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and Yolande Tra, PhD, for her assistance with statistical analysis. REFERENCES Adolph O, K¨oster S, Georgieff M, et al. Promethazine inhibits NMDA-induced currents—new pharmacological aspects of an old drug. Neuropharmacology 2012;63:280–291. Agnich LE, Stogner JM, Miller BL, et al. Purple drank prevalence and characteristics of misusers of codeine cough syrup mixtures. Addict Behav 2013;38:2445–2449. Burns JM, Boyer EW. Antitussives and substance abuse. Subst Abuse Rehabil 2013;4:75–82. Clatts M, Giang LM, Goldsamt L, et al. Nonmedical use of promethazine hydrochloride among heroin injectors in Vietnam: unrecognized risks and unintended consequences. Subst Use Misuse 2010;45:515–527. Erowid Experience Vaults. I felt happy and sedated (ID 30807). Available at: https://www.erowid.org/experiences/exp.php?ID=30807. Published May 8, 2006. Accessed July 8, 2014. Erowid Experience Vaults. Floating inside a marshmallow: an experience with promethazine & codeine (ID 47183). Available at: https://www.erowid.org/ experiences/exp.php?ID=47183. Published May 10, 2006. Accessed July 8, 2014. Erowid Experience Vaults. Just another medicine: promethazine (ID 58712). Available at: https://www.erowid.org/experiences/exp.php?ID= 58712. Published January 12, 2007. Accessed July 8, 2014.
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Erowid Experience Vaults. Few rewards + major side effect: promethazine (ID 63928). Available at: https://www.erowid.org/experiences/exp.php?ID= 63928. Published August 9, 2007. Accessed July 8, 2014. Erowid Experience Vaults. I’m entranced: hydrocodone (Vicoden), oxycodone (Endocet) & promethazine (Phenergan) (ID 61268). Available at: https: //www.erowid.org/experiences/exp.php?ID=61268. Published October 10, 2009. Accessed July 8, 2014. Mowry JB, Spyker DA, Cantilena LR, et al. 2012. Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol 2013;51:949–1229. Page CB, Duffull SB, Whyte IM, et al. Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. Q J Med 2009;102:123–131. Peters R Jr, Kelder SH, Markham CM, et al. Beliefs and social norms about codeine and promethazine hydrochloride cough syrup (CPHCS) onset and perceived addiction among urban Houstonian adolescents: An addiction trend in the city of lean. J Drug Educ 2003;33(4):415–425. Peters R Jr, Yacoubian GS, Rhodes WR, et al. Beliefs and social norms about codeine and promethazine hydrochloride cough syrup (CPHCS) use and addiction among multi-ethnic college students. J Psychoactive Drugs 2007;39(3):277–282. Shapiro BJ, Lynch KL, Toochinda T, et al. Promethazine misuse among methadone maintenance patients and community-based injection drug users. J Addict Med 2013;7:96–101. Shields LBE, Hunsaker JC, Corey TS, et al. Methadone toxicity fatalities: a review of medical examiner cases in a large metropolitan area. J Forensic Sci 2007;52(6):1389–1395.
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Abuse and Intentional Misuse of Promethazine Reported to US Poison Centers: 2002 to 2012 M. Ellen Tsay, PharmD, Gabrielle Procopio, PharmD, Bruce D. Anderson, PharmD, DABAT, and Wendy Klein-Schwartz, PharmD, MPH
Objective: Promethazine abuse has been reported. The objective was to investigate promethazine abuse/misuse in the United States. Methods: An 11-year retrospective review was conducted of promethazine abuse and intentional misuse cases without co-ingestants in persons 10 years and older reported to the National Poison Data System. Data were stratified by product (promethazine-alone [PA] or co-formulation [PC]) and evaluated for demographics, toxicity, management sites, and outcomes. Results: There were 354 single product abuse or misuse exposures— 95 PA and 259 PC. Over the 11-year timeframe, the annual exposure rate per 100,000 population doubled. Exposures were most prevalent among 10 to 19 years old and young adults (20s), accounting for 69.5% of PA and 57.5% of PC cases. Clinical effects due to PA included drowsiness (43.2%), tachycardia (7.4%), agitation (13.7%), confusion (13.7%), slurred speech (12.6%), hallucinations (7.4%), dizziness (7.4%), and hypertension (5.3%). Drowsiness (53.4%) and tachycardia (20.8%) were more frequent with PC. There were significant differences between PA and PC in management site (P = 0.0078). Management sites for PA and PC, respectively, were emergency department (37.9%, 55.6%), non–health care facility (33.7%, 14.7%), critical care unit (8.4%, 11.2%), non–critical care unit (7.4%, 7.3%), psychiatry (2.1%, 4.2%), and other/unknown (10.5%, 7.0%). Outcomes for PA and PC, respectively, were no effect (21.0%, 12.4%), From the Maryland Poison Center (MET, BDA, WKS), University of Maryland School of Pharmacy, Baltimore, MD; and Department of Pharmacy (GP), Johns Hopkins Hospital, Baltimore, MD. Received for publication July 23, 2014; accepted February 1, 2015. 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 (PCs). 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 (eg, an ingestion, inhalation, or topical exposure) or request information/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 may go unreported to PCs, and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s). The authors have no conflicts of interest or funding disclosures. Send correspondence and reprint requests to Wendy Klein-Schwartz, PharmD, MPH, Maryland Poison Center, University of Maryland School of Pharmacy, 220 Arch St, Room 01–108, Baltimore, MD 21201. E-mail: [email protected]. C 2015 American Society of Addiction Medicine Copyright ISSN: 1932-0620/15/0903-0233 DOI: 10.1097/ADM.0000000000000124
minor (58.9%, 53.7%), moderate (17.9%, 32.0%), and major effects (2.1%, 1.9%). Conclusions: Promethazine-alone abuse/misuse most frequently resulted in minor outcomes, and less than 20% required medical admission. Abuse/misuse of PC resulted in a higher frequency of health care facility treatment and a trend toward more moderate outcomes. These differences are most likely attributed to the co-formulate. Key Words: abuse, nonmedical use, promethazine, toxicity (J Addict Med 2015;9: 233–237)
P
romethazine, a phenothiazine derivative, was made available to the United States market in 1946. Mechanistically, it acts primarily as an H1 receptor antagonist but may also interact with muscarinic, dopaminergic, alpha-adrenergic, and serotonin receptors, giving the medication its sedative and antiemetic properties (Adolph et al., 2012). It is used therapeutically in individuals 2 years of age or older for the treatment of allergic reactions, as an adjunct to procedural sedation and as an antiemetic. Promethazine is available alone or in combination with other drugs, including codeine, dextromethorphan, and/or expectorants. Although the abuse potential of promethazine is largely unknown, it is believed that the combined use with opioids will provide additional sedation and a lower amount of opioid required to achieve this effect (Clatts et al., 2010). Promethazine misuse and abuse have been documented in certain areas in the United States and internationally. Promethazine had been detected in the urine samples of 26% of methadone maintenance patients in San Francisco despite only 15% of those patients having an active promethazine prescription. Up to 17% of injection drug users in San Francisco reported the use of promethazine in a month period (Shapiro et al., 2013). Promethazine was detected in the serum in 14.2% of methadone fatality cases in Kentucky (Shields et al., 2007). A majority (75%) of surveyed intravenous heroin users in Vietnam reported the use of promethazine to supplement a lower amount of heroin, to treat withdrawal, or due to its legal availability and price (Clatts et al., 2010). The objective of this study was to evaluate national poison center data on promethazine abuse and misuse in the United States and to document clinical effects and medical outcomes due to promethazine exposures.
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METHODS
RESULTS
A retrospective review was conducted of intentional misuse or abuse promethazine exposures in persons 10 years of age and older reported to the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) from January 2002 to December 2012. The National Poison Data System comprise data that are collected from all US poison centers. Poison centers provide consultations to both the general public and health care professionals regarding exposures (both accidental and intentional) to medications, chemicals, or to toxins in the environment. During the consultation, poison specialists collect data, which are then uploaded electronically to NPDS in real time. Coded data include age, sex, reason for exposure, product, clinical effects, treatments, management site, and medical outcomes. Abuse is defined as improper or incorrect use of a substance where the victim was likely attempting to gain a high, euphoric effect or some other psychotropic effect. Intentional misuse is improper or incorrect use of a substance for reasons other than the pursuit of a psychotropic effect. In this report, these reasons are considered nonmedical use. Only clinical effects coded as related to the exposure are included. Management sites are non–health care facility (managed on site), emergency department (treated/evaluated and released), critical care unit, non–critical care unit, psychiatric care facility, no show/left against medical advice, and other site. Poison center coding of known medical outcomes related to the exposure includes no effect, minor, moderate, major, and death. Patients with minor outcomes have some minimally bothersome signs or symptoms as a result of the exposure. Moderate outcomes include signs or symptoms that were more pronounced, more prolonged, or more systemic than minor symptoms, and usually some form of treatment is indicated. Major outcomes exhibit signs or symptoms that were life threatening or resulted in significant residual disability or disfigurement. The medical outcome is determined at the end of the case and is dependent on the types of clinical effects and treatment administered that were coded. Exposures due to promethazine were identified from NPDS by utilizing the AAPCC product codes for all promethazine-containing medications available in the United States. Intentional misuse and abuse cases were included. Information calls and exposures not followed to a known medical outcome were excluded. The data were separated into 2 categories—exposures to promethazine alone (PA) or single product exposures to promethazine in a co-formulation with other medications (PC). Promethazine-containing products may include codeine, dextromethorphan, and/or an expectorant. The data for PA and PC exposures were evaluated for demographics, state, management site, and medical outcomes. Clinical effects coded as related to promethazine were evaluated. The Pearson χ 2 test was run to determine whether there is a statistical significant difference between PA and PC in the categories of outcome, disposition, and age. The procedure PROC MULTTEST (SAS v 9.4) with the sequential Bonferroni procedure was used to adjust for the multiple comparisons. This study was granted exempt status by the University Institutional Review Board.
There were 4434 PA and PC exposures reported to poison centers, including 2106 single product and 2328 polysubstance cases in persons 10 years of age and older. Of these, 630 (14.2%) were due to abuse or intentional misuse. There were 276 abuse or misuse polysubstance exposures (involving mostly psychotherapeutic drugs and opioids) that were excluded. The study cohort included 95 PA and 259 PC cases. The most frequent co-formulates in PC products (alone or with other drugs) were codeine (n = 126, 48.4%) and dextromethorphan (n = 118, 45.6%). Table 1 displays the breakdown of co-formulates in PC products. Males accounted for 51.6% of PA and 61.4% of PC cases. Table 2 provides age breakdowns. There was a significant difference in age between PA and PC (χ 2 = 78.78, adjusted P < 0.0001). The age group with the highest proportion of cases was 10 to 19 years for PA (46.3%) and PC (37.1%). Figure 1 compares the rates of PA and PC cases per 100,000 US population with rates of total exposures (all substances) per 100,000 US population reported to poison centers over the study period. From 2003 to 2008, the rate of PA cases was relatively flat, increased in 2009 to 2010 and then decreased in 2011 to 2012. Similarly, from 2006 to 2011, the rate of PC cases increased and then showed a decline in 2012. The rate of national poison center exposures started to decline after 2009. States with the largest number of cases were California (n = 59), Texas (n = 35), New Jersey (n = 23), Ohio (n = 16), Arizona (n = 15), Florida (n = 14), Virginia (n = 14), and Louisiana (n = 12). Clinical effects from nonmedical use of PA include drowsiness (n = 41, 43.2%), agitation (n = 13, 13.7%), confusion (n = 13, 13.7%), slurred speech (n = 12, 12.6%), tachycardia (n = 7, 7.4%), dizziness (n = 7, 7.4%), hallucinations
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TABLE 1. Co-Formulates Involved in Nonmedical Use of PC Total (n = 259)
Co-Formulates Codeine Codeine + phenylephrine Codeine + expectorant Dextromethorphan Dextromethorphan + expectorant Expectorant Phenylephrine Aspirin + pseudoephedrine or caffeine Decongestant
92 (35.5%) 9 (3.5%) 25 (9.6%) 98 (37.8%) 20 (7.7%) 8 (3.1%) 4 (1.5%) 2 (0.8%) 1 (0.4%)
TABLE 2. Age Breakdown by Product Type* Age (y)
Promethazine Alone (n = 95)
Promethazine Containing† (n = 259)
44 (46.3%) 22 (23.2%) 2 (2.1%) 5 (5.3%) 7 (7.4%) 8 (8.4%) 7 (7.4%)
96 (37.1%) 53 (20.5%) 34 (13.1%) 28 (10.8%) 21 (8.1%) 22 (8.5%) 5 (1.9%)
10-19 20-29 30-39 40-49 50-59 60+ Unknown
*Significant difference between PA and PC (P < 0.0001). †Promethazine with co-formulates. C
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Abuse and Misuse of Promethazine
department (37.9%). Promethazine co-formulation exposures were mostly managed in the emergency department (55.6%) or were admitted (22.8%). The majority of nonmedical users of PA and PC experienced minor effects (58.9% and 53.7%, respectively). There was a trend toward nonmedical users of PC experiencing moderate outcomes (32.0%) more often than nonmedical users of PA (17.9%), but it was not significant. There were no reported deaths due to PA or PC abuse or misuse.
DISCUSSION
FIGURE 1. Trends in promethazine abuse and misuse compared with total national poison center exposures.
(n = 7, 7.4%), vomiting (n = 6, 6.3%), hypertension (n = 5, 5.3%), ataxia (n = 4, 4.2%), and dystonia (n = 2, 2.1%). Exposure to promethazine alone rarely caused more serious effects, but respiratory depression (n = 2, 2.1%) and hypotension (n = 1, 1.0%) were observed. Clinical effects from nonmedical use of PC were similar to those from promethazine alone, but the extent to which they were due to the co-formulate could not be ascertained with coded data only. Drowsiness (53.4%) and tachycardia (20.8%) were more frequent with PC. Although serious clinical effects were also rare with nonmedical use of PC, they included hyperthermia (n = 5, 1.9%), hypotension (n = 5, 1.9%), seizures (n = 4, 1.5%), and coma (n = 3, 1.2%). The 4 cases with seizures were due to exposures to promethazine and codeine products. There was a significant difference between PA and PC in management site (χ 2 = 20.17, adjusted P = 0.0078) but not outcome (χ 2 = 8.87, adjusted P = 0.0932). Table 3 displays a breakdown of management sites and outcomes by product type. Promethazine-alone exposures were mostly treated in a non–health care facility (33.7%) or managed in the emergency TABLE 3. Outcomes and Management Sites by Product Type
Outcome† No effect Minor effect Moderate effect Major effect Death Management sites‡ Non-HCF ED CCU Non-CCU Psychiatric care No show/AMA Other
Promethazine Alone (n = 95)
Promethazine Containing* (n = 259)
20 (21.0%) 56 (58.9%) 17 (17.9%) 2 (2.1%) 0
32 (12.4%) 139 (53.7%) 83 (32.0%) 5 (1.9%) 0
32 (33.7%) 36 (37.9%) 8 (8.4%) 7 (7.4%) 2 (2.1%) 10 (10.5%) 0
38 (14.7%) 144 (55.6%) 29 (11.2%) 19 (7.3%) 11 (4.2%) 17 (6.6%) 1 (0.4%)
*Promethazine with co-formulates. †P = 0.0932; ‡P = 0.0078 AMA, leave against medical advice; CCU, critical care unit; ED, emergency department; non-HCF, non–health care facility. C
Promethazine has been abused or misused to achieve a state of delirium and/or sedation (Erowid Experience Vaults, May 8, 2006; Erowid Experience Vaults, May 10, 2006; Erowid Experience Vaults, August 9, 2007). Users have also reported on online forums that promethazine can be combined with opioids to prevent opioid-induced nausea, to supplement the opioid-induced euphoria so that a lower dose of opioids can be taken, or to self-medicate drug withdrawal (Erowid Experience Vaults, January 12, 2007; Erowid Experience Vaults, August 9, 2007; Erowid Experience Vaults, October 10, 2009). Recent data have shown that promethazine can act as a noncompetitive antagonist to the N-methyl-D-aspartate receptor, which may contribute to its sedative properties and the potential to act as an analgesic (Adolph et al., 2012). The rate per 100,000 population of promethazine exposures from abuse or intentional misuse reported to US Poison Control Centers peaked in 2011 for PC and 2010 for PA and then declined. This may be due to reporting bias; as this exposure became more common, both health care practitioners and the lay public became more familiar with expected clinical effects so did not contact poison centers. Interestingly, the rate per 100,000 population of all exposure calls to US Poison Control Centers also started to decrease after 2009 (Mowry et al., 2013). Therefore, this decline may reflect lower reporting rates rather than lower abuse and misuse rates. In a case series of promethazine overdoses (both promethazine alone or with a co-ingestant) in Australia (where promethazine is available over the counter), the mean age of patients exposed to promethazine alone was 22 years (range: 3-70, n = 57). Common clinical effects experienced by those patients included tachycardia (58%) with no reported dysrhythmias or ECG changes, delirium (42%), and mild to moderate central nervous system depression (56%). Hypotension or myoclonus rarely occurred, and there were no reports of dystonia, neuroleptic malignant syndrome, seizures, or death. A small percentage of the study population experienced seizures (1%) but ingested promethazine with a co-ingestant. All patients in this case series were managed in the emergency department or were admitted to the hospital (Page et al., 2009). Common clinical effects of PA exposures seen in our study were similar to those previously described but occurred at a lower frequency. Although this may reflect a lower capture rate of clinical effects from promethazine, it may also be attributed to the inclusion of less serious cases managed outside a health care facility. The majority of nonmedical users of PA and PC in this study were preteens, teenagers, or adults in their 20s. Overall, PC users were older with almost a fourth of the cases reported
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Tsay et al.
in adults in their 30s and 40s. Promethazine co-formulation users required a higher level of medical care than PA users. A third of PA cases were managed outside a health care facility compared with close to 15% for PC cases. Approximately 80% of PC cases were treated in the emergency department or admitted. The most common co-formulates were codeine with or without phenylephrine or an expectorant (48.6%) and dextromethorphan with or without an expectorant (45.6%). The clinical presentation of dextromethorphan toxicity is dose dependent. Smaller amounts of dextromethorphan may result in euphoria, tachycardia, hypertension, and other minor symptoms. Larger doses of dextromethorphan can lead to hallucinations and ataxia. With extreme toxicity patients can seem agitated and experience hyperthermia and metabolic acidosis (Burns and Boyer, 2013). The clinical effects of promethazine and dextromethorphan abuse are not well documented in literature. Codeine, well documented for its abuse potential, may lead to a sense of euphoria. Some signs and symptoms of codeine toxicity include somnolence, respiratory depression, hypotension, bradycardia, and in severe cases cardiac arrest and even death. Opioids, including codeine, may aggravate hypoxia-induced seizures, and promethazine may lower seizure threshold (Burns and Boyer, 2013). Four patients with PC who were noted to have seizure also had codeine as a co-formulate. It is possible that the combination effect puts these patients at higher risk of seizure. Promethazine-induced alpha-adrenergic blockade, particularly in combination with other medications, may lead to hypotension as occurred in 5 cases due to PC. Promethazine abuse and misuse have been documented in the abuse of cough syrups containing promethazine and codeine. Promethazine and codeine have been commonly referred to as “purple drank,” “sizzurp,” “lean,” “barre,” or “drank” when mixed with a soft drink and candy (Agnich et al., 2013). This concoction started to gain popularity in the 1990s among African American teenagers in the Houston, Texas, rap scene (Peters et al., 2003; Agnich et al., 2013), also referred to as “screw music” (Peters et al., 2007). This form of music can be described as a form of hip-hop that utilizes a slower beat (Peters et al., 2007). A survey of middle and high school students in Houston, Texas, implicated that the rise in popularity of codeine/promethazine came from media influences and the euphoric effect achieved by the syrup. Addiction and repeated use of codeine/promethazine in these students have developed and occurred soon after first time use (Peters et al., 2003). Another survey of college-aged adults in Houston, Texas, reported that the initiation of codeine/promethazine cough syrup abuse came from peer pressure or curiosity and continued because of the produced euphoric effect. Males were more likely than females to habitually abuse codeine/promethazine as a coping mechanism (Peters et al., 2007). Users also reported common access to cough syrup by obtaining a prescription before selling the syrup illicitly or by diverting the medication from a pharmacy. Withdrawal, addiction, and peer pressure were identified as common barriers to quitting codeine/promethazine abuse (Peters et al., 2007). Although this survey was conducted on student participants in a histor-
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ically African American college campus, other studies have implicated that codeine/promethazine abuse may occur outside of the Houston, Texas, area and in other racial groups (ie, Native Americans and Hispanics) (Agnich et al., 2013). Our study found that PA and PC abuse occurred in most states with highest numbers in California, Texas, and New Jersey. Other identifiers to codeine/promethazine abuse may include individuals living in an urban setting or individuals that identify as LGBT (lesbian, gay, bisexual, or transgender) (Agnich et al., 2013). There were 276 cases excluded from the study because of co-ingestants. These cases had higher frequencies of moderate (36%) and major (7%) effects and intensive care unit (21%) and medical admissions (11%) compared with PA and PC alone. There were 3 deaths. Although clinicians should anticipate more serious consequences when other substances are involved, it is not possible to discern from these data whether this is related to additive effects or interactions with promethazine or due primarily to the inherent toxicity of the other substances. There were limitations to our study—information obtained is based on reported exposures. As reporting to poison centers is voluntary these data do not capture cases not reported. Also, because data are based on hospital or caller reports, the severity of some clinical effects may not be reflected in the coded data. Data coding was performed by specialists in poison information and poison information providers at approximately 57 poison centers, leading to the potential for variability in coding or the potential for incorrect or incomplete coding, despite a coding manual to assist staff in coding uniformly and standard coding procedures adopted by all poison centers. Promethazine-alone or PC exposures can only be determined through patient history or clinical presentation due to the fact that promethazine blood levels are not readily analyzed in the laboratories of most treating institutions. Finally, this study excluded multisubstance exposures; therefore, the results are not generalizable to nonmedical use of PA or PC with other substances.
CONCLUSIONS This study provided a nation-wide insight to the nonmedical use of promethazine alone and promethazine combination products. These data find that nonmedical use is increasing compared with 11 years ago. Abuse or intentional misuse of promethazine alone most frequently resulted in minor clinical effects. The majority of promethazine only exposures were cared for in the emergency department. Abuse or intentional misuse of PC had more serious consequences with a higher frequency of treatment at a health care facility and a trend toward a higher frequency of moderate outcomes. These differences are most likely attributed to toxicity associated with the co-formulate in PC products as opposed to promethazine alone.
ACKNOWLEDGMENTS We thank Larry Gonzales, BS, senior IT specialist at the Maryland Poison Center, for his assistance with data analysis C
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