Upon conclusion of this article, students will be able to:
Understand the scope of prescription drug use and its effects on ED visits;
Understand the various routes of administration and effects of psychoactive narcotics;
Demonstrate knowledge of drug-drug interactions;
Understand commonly used substance detection strategies and drug screens.
Drug overdoses are routinely seen in trauma bays and emergency departments worldwide. The increasingly complex methods employed to develop and consume drugs make detection of side effects and potential interactions with other drugs difficult. Common substances of abuse are now being ingested in alternative, more hazardous ways, while designer drugs are being chemically modified to enhance their euphoric effects. These various modifications have rendered modern drug screening tests almost obsolete, placing medical professionals in a formidable position.
The purpose of this two-part review is to educate emergency medical personnel on trends in drug use and provide an overview of the physiologic effects associated with these substances, as well as touch on some of the potential adverse drug-drug interactions in order to allow for proper identification and treatment when patients present to the ED. January’s Part 1 covered alcohol, cocaine, and chemically modified/“designer” drugs; this second part looks at prescription drugs and drug interactions.
Prescription Drug Abuse
Illegal drugs are not the only culprits of drug-related intoxications and visits to the ED. A variety of readily available prescription medications have serious abuse potential. The opioid epidemic is widely acknowledged to be a public health crisis fueled by the misuse of prescription opioids. The heralding of pain as the fifth vital sign is often considered an inciting factor in the precipitation of this crisis, leading to relaxation of standards in prescription of opioid painkillers.1 It is estimated that two million people in the United States are affected by substance use disorders related to prescription opioid analgesics.2
There has also been a proposed link between introduction to opioids through prescription drugs and subsequent abuse of heroin.3,4 The public health ramifications are immense: increases in overdoses, spread of infectious diseases secondary to transition to intravenous administration, and enormous monetary and societal costs.2,5 Commonly abused prescription opioids include compounds containing morphine (MS Contin), oxycodone (Percocet), hydrocodone (Vicodin) and hydromorphone (Dilaudid).6
Along with the recognized abuse of these common substances, abuse of fentanyl, a synthetic opioid, has increased in recent years. Fentanyl is 50–100 times more powerful than morphine and is commonly combined with powdered heroin.7 It binds to opiate receptors in the brain, leading to the release of dopamine and subsequent sensations of euphoria and relaxation. It can be administered in many forms, including intravenous, transdermal patch, and lozenge, as well as in nontraditional ways such as insufflation and infusion with tea. ED presentation of fentanyl use includes feelings of euphoria, nausea, constipation, confusion, respiratory depression, loss of consciousness, coma, and death.7 Routine urine opioid screening does not detect synthetic opioids, but they can be detected with special add-on urine tests. Treatment involves administration of high doses of naloxone, an opiate receptor antagonist, to reverse the overdose.
Ironically, opioids designed to help treat opioid addiction, such as methadone, a full mu opioid receptor agonist, and buprenorphine-naloxone or Suboxone, a semisynthetic partial mu opioid agonist, have tremendous abuse potential.8 Interestingly, both methadone and Suboxone play important roles in pain management of critically ill patients to decrease risk of opioid-induced hyperalgesia and respiratory drive depression.9 The abuse potential for methadone is well-recognized, and it is tightly regulated.10
Suboxone is an alternative to methadone and, while more expensive, is more convenient for patients, as it is prescribed in the outpatient primary care setting and can be administered orally.10 Typically, sublingual or buccal forms of Suboxone are administered in treatment of opioid addiction; however, the potential for abuse via intravenous use can result in serious complications, especially when combined with alcohol. Various life-threatening infections, gangrene of extremities, and death have all been reported.8
The thin strips enable it to be easily hidden, rendering Suboxone a drug commonly abused in the prison setting, as it can be smuggled under stamps, envelope seals, or painted into pictures to evade prison security.11 Due to its risk of addiction and dangers of alternative consumption, Suboxone is highly regulated, and specific laws exist regarding its prescription. The Drug Addiction Treatment Act of 2000 permits only physicians with specific qualifications to prescribe Suboxone and institutes a 30-patient-per-physician limit.8
Both methadone and Suboxone can be detected via urine drug tests. In healthcare facilities methadone is often included in the panel of drugs routinely ordered on patients, while Suboxone detection requires a special add-on test.12 Overdose of methadone and/or Suboxone results in a clinical presentation similar to that of opioid overdose, and treatment involves providing airway and breathing support as well as immediate detoxification via intravenous naloxone administration.13
Given the availability of a myriad of prescription opioids, concerns over development of opioid addictions have made practitioners wary and curbed liberal prescribing of these substances. While it is necessary to be cautious in prescribing opioid analgesics, there is inevitably a concern of inadequate management of chronic pain patients. It needs to be acknowledged that the sufferings of these patients are not trivial and warrant appropriate treatment with opioids. The crackdown on opioid prescriptions has marginalized chronic pain patients, who face increasing difficulties in securing their medications and resent the suspicious attitudes they often encounter from providers and society.1,14 Therefore, it is essential that physicians validate the pain experienced by their patients and strive for an appropriate balance between prudence and addressing the needs of chronic pain patients.
Phenibut, while not approved for clinical use in the United States, most of Europe, or Australia, is marketed for medical use in Russia, Ukraine, Kazakhstan, and Latvia. It was introduced in Russia in the 1960s and has cognition-enhancing and anxiolytic effects.15 It is typically ingested orally, acts on GABA-B receptors, and has a strong hypothermic and sedative effect. Risk of acute phenibut toxicity is low, and it appears recent reports are associated with a sudden increase in dosage.16–20 Treatment of overdose involves mainly supportive care for agitation, delirium, and reduced metal status for 2–5 days in a critical care setting.21 Upon presentation, patients experiencing symptoms of acute phenibut toxicity were hematologically, biochemically, and on imaging unremarkable.
Drug Detection and Drug Interactions
Most patients presenting to the ED with signs of acute intoxication will undergo serum alcohol testing as well as urine drug testing. Alcohol detection, while possible with urine testing, is more commonly accomplished through serum measurement. Correlation between blood alcohol concentrations (BAC) and clinical presentation of intoxication may not be reliable, as chronic users will develop tolerance and may not exhibit some of the classic symptoms despite an elevated BAC.22 These correlations are broad generalizations and do not account for gender, body composition, metabolic rate, and other variables that can have a significant effect on the rate of metabolism of alcohol.
Standard urine drug screens are adopted at the discretion of the facility and can thus vary in coverage. A five-panel drug test checks for amphetamines, cocaine, marijuana, opiates (codeine, morphine), and PCP. A 10-panel drug test adds barbiturates, benzodiazepines, methadone, methaqualone, and propoxyphene.23 Specialized additional testing for different kinds of opiates is also available, with positive identification for heroin, hydrocodone, hydromorphone, and oxycodone.
It should be noted that the durations listed are approximate and that the presence of a metabolite in the urine is not necessarily indicative of an acute exposure to a particular substance. A positive result does not automatically denote the identified substance as the culprit, as the substance could be present in a physiologically inconsequential quantity. Therefore, it is imperative to always consider the clinical context, generate a thorough differential diagnosis, and not rely solely on the urine drug panel.
While the litany of adverse reactions alone is enough to induce alarm, the theoretical drug-drug interactions that can result when substances are combined is truly terrifying. Exacerbating this fear is the paucity of knowledge around many of these interactions, in part due to the uncertainty of the exact nature and mechanism of action of various substances. As a rule most drugs are metabolized in the liver by various cytochrome P450 enzymes, and the presence of any inhibitors or inducers of these enzymes can affect the metabolism and availability of drugs in the body.
Perhaps the most widely reported interactions are between alcohol and other drugs, likely due to the prevalence with which illicit substances are ingested with alcohol. Each drug class has numerous other extensively reported interactions, notably with antibiotics, antidepressants, antipsychotics, and benzodiazepines, to name a few.25
Each year millions of drug-related cases present in emergency departments across the United States, many due to drug abuse. Substance abusers are employing increasingly creative methods to modify chemical formulas and ingest in nontraditional ways in a bid to enhance their high. The physiological consequences can be life-threatening, especially given the perpetually outdated screening tests. It is thus essential for emergency personnel to maintain a high index of clinical suspicion to promptly identify symptoms of commonly abused drugs prior to initiating treatment.
1. National Institute on Drug Abuse. Commonly abused drugs charts, www.drugabuse.gov/drugs-abuse/commonly-abused-drugs-charts.
3. Stanford School of Medicine. Palliative Care, Equivalency Table, https://palliative.stanford.edu/opioid-conversion/equivalency-table/.
4. Compound Interest. A Brief Guide to Common Painkillers, www.compoundchem.com/2014/09/25/painkillers/.
5. National Institute on Drug Abuse. Fentanyl, www.drugabuse.gov/drugs-abuse/fentanyl.
6. Chua SM, Lee TS. Abuse of prescription buprenorphine, regulatory controls and the role of the primary physician. Ann Acad Med Singapore, 2006; 35(7): 492–5.
7. U.S. Drug Test Centers. Suboxone-Buprenorphine Drug Testing, www.usdrugtestcenters.com/suboxone-drug-testing.html.
8. UpToDate. Acute Opioid Intoxication in Adults, www.uptodate.com/contents/acute-opioid-intoxication-in-adults.
9. Owen DR, Wood DM, Archer JR, Dargan PI. Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity. Drug Alcohol Rev, 2016; 35(5): 591–6.
10. Joshi YB, Friend SF, Jimenez B, Steiger LR. Dissociative Intoxication and Prolonged Withdrawal Associated With Phenibut: A Case Report. J Clin Psychopharmacol, 2017; 37(4): 478–80.
11. O’Connell CW, Schneir AB, Hwang JQ, Cantrell FL. Clinical communication to the editor: phenibut, the appearance of another potentially dangerous product in the United States. Amer J Med, 2014; 127(8): e3–4.
12. Samokhvalov AV, Paton-Gay CL, Balchand K, et al. Phenibut dependence. Case Reports, 2013; bcr2012008381.
13. Högberg L, Szabó I, Ruusa J. Psychotic symptoms during phenibut (beta-phenylgamma aminobutyric acid) withdrawal. J Substance Use, 2013; 18(4): 335–8.
14. Downes MA, Berling IL, Mostafa A, et al. Acute behavioural disturbance associated with phenibut purchased via an internet supplier. Clinical Toxicology, 2015; 53(7): 636–8.
15 Villeneuve M. Chronic pain patients say opioid law creates new crisis. US News, 2017 Apr 22; www.usnews.com/news/best-states/maine/articles/2017-04-22/chronic-pain-patients-say-opioid-law-creates-new-crisis.
16. National Drug Screening, Inc. 10 Panel Drug Test, www.nationaldrugscreening.com/10-panel-drug-test.php.
17. Mayo Clinic. Drug testing: An overview of Mayo Clinic tests designed for detecting drug abuse. www.mayomedicallaboratories.com/test-info/drug-book/pod/DrugBook.pdf.
18. Hernandez-Lopez C, Farre M, Roset PN, et al. 3,4-Methylenedioxymethamphetamine (Ecstasy) and alcohol interactions in humans: Psychomotor performance, subjective effects, and pharmacokinetics. J Pharmacol Exp Ther, 2002; 300(1): 236–44.
19. Alcohol-related drug interactions. Pharmacist’s Letter/Prescriber’s Letter, 2008; 24(1): 240106.
20. Melton ST. Stirring the pot: Potential drug interactions with marijuana. Medscape, www.medscape.com/viewarticle/881059#vp_3.
22. UpToDate. Ethanol Intoxication in Adults, www.uptodate.com/contents/ethanol-intoxication-in-adults
23. Jansson-Nettelbladt E, Meurling S, Petrini B, Sjölin J. Endogenous ethanol fermentation in a child with short bowel syndrome. Acta Paediatr, 2006; 95(4): 502–4.
24. Dahshan A, Donovan K. Auto-brewery syndrome in a child with short gut syndrome: case report and review of the literature. J Pediatr Gastroenterol Nutr, 2001; 33(2): 214–5.
25. Welch BT, Coelho Prabhu N, Walkoff L, Trenkner SW. Auto-brewery Syndrome in the Setting of Long-standing Crohn’s Disease: A Case Report and Review of the Literature. J Crohns Colitis, 2016; 10(12): 1,448–50.
Michael J. Reihart, DO, FACEP, is a physician in the Department of Emergency Medicine at Penn Medicine Lancaster General Health, Lancaster, Pa.
Madison Morgan, BS, works in trauma services at Penn Medicine Lancaster General Health, Lancaster, Pa.
Tawnya M. Vernon, BA, is with the Penn Medicine Lancaster General Health Research Institute, Lancaster, Pa.
Shreya Jammula, MD, is a surgical resident with the Geisinger Health System, Danville, Pa.
Brian W. Gross, BS, is with the Robert Larner, MD, College of Medicine at the University of Vermont, Burlington, Vt.
Eric H. Bradburn, DO, MS, FACS, works in trauma services at Penn Medicine Lancaster General Health, Lancaster, Pa.
Frederick B. Rogers, MD, MS, FACS, works in trauma services at Penn Medicine Lancaster General Health, Lancaster, Pa. Contact him at firstname.lastname@example.org.