ReviewTreatment of toxicity from amphetamines, related derivatives, and analogues: A systematic clinical review☆
Introduction
The accidental or intentional overdose and abuse of over-the-counter, prescribed, and illicit amphetamine, its related derivatives, and analogues (ARDA) such as ephedrine, pseudoephedrine, methylphenidate, lisdexamfetamine, methamphetamine, cathinone (“khat”) and derivatives (“bath salts”), and 3,4-methylenedioxy-N-methylamphetamine (MDMA or “ecstasy”) is a growing problem. Based on the most recent United Nations World Drug Report (2012), there are an estimated 50 million ongoing users worldwide, which surpasses heroin and cocaine use combined. This does not include frequent use of naturally occurring compounds such as cathinone from the khat plant (Catha edulis) used in the horn of Africa and Middle East, and ephedrine and pseudoephedrine from Ephedra sinica, which are commonly ingested by inhabitants of East Asia.
In the United States, there were greater than 150,000 emergency department visits for toxicity from ARDA in 2011 based on data from the Substance Abuse and Mental Health Services Administration (SAMHSA, 2011). The Drug Enforcement Agency estimates there were 439,000 past-month methamphetamine users in 2011 (USDOJ, 2013). The number of first-time methamphetamine users ages 12 and older was 133,000 in 2011, which represents an increase from 97,000 in 2008 (SAMHSA, 2012). In 2011, 11% of children 4–17 years old (6.4 million) had at some point in their lives been diagnosed with attention deficit hyperactivity disorder (ADHD), and 3.5 million were taking ADHD medication (Visser et al., 2014). Illicit use of these prescribed medications among young adults without ADHD and of designer synthetic cathinones such as “bath salts” is also an increasing problem (Garnier et al., 2010, Lakhan and Kirchgessner, 2012, Wood, 2013). Over-the-counter decongestants and herbal products targeting weight loss may contain pseudoephedrine, ephedrine, and phenylpropanolamine and have been associated with morbidity and mortality even when taken at correct dosage (Gunn et al., 2001).
These patients frequently present to the emergency department for acute care and consume hospital resources at a higher than normal rate, including emergency, psychiatric, trauma, intensive care unit, and telemetry services (Cloutier et al., 2013, Hendrickson et al., 2008, Richards et al., 1999a, Swanson et al., 2007). Furthermore, they are rarely forthcoming about their illicit drug use, and treating clinicians must consider a wide spectrum of diagnoses during the initial face-to-face evaluation, such as acute psychosis, thyrotoxicosis, sepsis, pheochromocytoma, anticholinergic toxicity, alcohol, benzodiazepine and opioid withdrawals, serotonin and neuroleptic malignant syndromes, and intracranial hemorrhage. Debate exists regarding the best “antidote” and method of treating acute intoxication or overdose. Therefore inconsistencies may occur among different physicians, specialties, and regional hospitals in their approach to the ARDA-intoxicated patient.
Amphetamine, its related derivatives, and analogues increase concentrations of norepinephrine, dopamine, and serotonin through multiple mechanisms and are amphipathic molecules which can cross the blood–brain barrier and placenta (Panenka et al., 2013). Blockade of plasmalemmal and vesicular transporters results in elevated levels of monoamines in the cytoplasm and synapse, respectively, and also cause reverse transport of cytoplasmic monoamines across the cell membrane of the presynaptic neuron into the synaptic space. These drugs also disrupt vesicular storage of monoamines and inhibit the degradative enzymes monoamine oxidase A and B. The net effect is a precipitous rise in central nervous system (CNS) and serum catecholamines with sudden and unpredictable increase in heart rate (HR), systolic (SBP), and diastolic blood pressure (DBP; Fleckenstein et al., 2007). All ARDA have this potential hyperadrenergic effect, but with varying degrees based on the specific ARDA, route of administration, patient tolerance, and pharmacogenetics (de la Torre et al., 2012). Patients abusing ARDA may have serious consequences from this hyperadrenergic state.
Control of agitation and the hyperadrenergic state are top priorities to prevent acute coronary syndrome (ACS), stroke, pulmonary hypertension, acute heart and renal failure, and fetal/maternal morbidity and mortality (Ali et al., 2011, Bingham et al., 1998, Davis and Swalwell, 1994, Hawley et al., 2013, Johnson and Berenson, 1991, Kaye et al., 2007, Richards et al., 1999b, Stewart and Meeker, 1997, Sutamtewagul et al., 2014, Thompson, 2008, Turnipseed et al., 2003, Westover et al., 2007, Won et al., 2013). The half-lives of ARDA are several hours and vary with route of administration, increasing the potential for pathologic sequelae (Mendelson et al., 2006). The purpose of this review is to determine the current best evidence for treatment of (1) agitation/psychosis, and (2) the hyperadrenergic state caused by toxicity from ARDA, and any treatment-related adverse events.
Section snippets
Methods
All human trials, case series, or case reports of pharmacologic treatment of ARDA-related agitation, psychosis, and hyperadrenergic symptoms (hypertension, tachycardia) were considered in the literature search. Data was abstracted systematically from an extensive query of MEDLINE, PsycINFO, and the Cochrane Library from inception to September 20, 2014. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed (Supplement 11
Results
The search resulted in 6082 articles, of which 6001 were not relevant and excluded (Fig. 1). There were no prior systematic reviews regarding this topic. The gray literature search yielded no additional reports. A total of 81 treatment publications involving 835 human subjects were included (Table 1, Table 2). Because of the small number of high-quality (levels I, II) eligible studies, case series and case reports detailing treatments and outcomes were also included and discussed when
Discussion
As of September 2014, there were no published evidence-based systematic reviews regarding pharmacologic treatment of agitation, psychosis, and hyperadrenergic symptoms from ARDA. For control of agitation and psychosis from ARDA, butyrophenones and later-generation antipsychotics are a reasonable choice, with the understanding extrapyramidal side effects may occur. There were 287 patients receiving antipsychotics and 15 adverse extrapyramidal identified in this review. A position statement from
Role of funding source
Nothing declared.
Contributors
All authors (JRR, TEA, RWD, RAL, KRO, BZH) were involved in the conception and design of the work; JRR, TEA, RWD, BZH were involved in the acquisition and analysis of data; all authors interpreted the data; JRR, TEA, RWD, BZH wrote the manuscript; all authors revised the manuscript critically for important intellectual content and provided final approval of the version to be published.
Conflict of interest
No conflict declared.
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Supplementary material can be found by accessing the online version of this paper. See Appendix A for more details.