Home Educatione-Learning Prescription Opiate Opioid Drug Abuse A New Epidemic
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Prescription Opiate Opioid Drug Abuse A New Epidemic

PCCSU Volume 25, Lesson 1

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Susan Y. Kim-Katz, PharmD; and Ilene B. Anderson, PharmD

Dr Kim-Katz is Professor of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, and Senior Toxicology Management Specialist, California Poison Control System, San Francisco, California. Dr Anderson is Clinical Professor of Pharmacy, Department of Clinical Pharmacy, University of California San Francisco; and Senior Toxicology Management Specialist, California Poison Control System, San Francisco, California.

Drs Kim-Katz and Anderson have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this lesson.

Objectives

  1. Delineate the epidemiology of prescription opioid drug abuse.
  2. Recognize the two prescription opioid agents most commonly abused in the United States within the last 10 years.
  3. Recall the typical clinical features of opioid intoxication.
  4. Understand the pharmacology of two drug-drug interactions involving opioids and other medications and the clinical consequences that may result when these drugs are combined.
  5. Describe the hallmarks of diagnosis and treatment of an opioid-intoxicated patient, including potential complications of treatment.

Key words: abuse; drug; opiate; opioids; prescription; trend

Abbreviations: CYP3A4 = cytochrome P450 3A4 isozyme; DAWN = Drug Abuse Warning Network; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; POA = prescription opiate/opioid abuse; SSRI = selective serotonin reuptake inhibitor

Abuse of prescription opiates and opioids has emerged as a key drug problem in all age groups but particularly among teenagers and young adults. The Sumerians first cultivated the opium poppy around 3400 BC and referred to it as Hul Gil, or the “joy plant.” Throughout the centuries, opium has been used for multiple medicinal purposes but primarily as a highly effective analgesic and, more recently, as an antitussive. However, opium’s psychoactive properties, adverse effects, and addictive properties have made opiate use problematic for thousands of years, too.

The term opiates refers to naturally occurring alkaloids, such as morphine, codeine, and thebaine (paraopium, a natural opiate used to produce certain other derivatives), that are derived from the opium poppy plant, Papaver somniferum. Semisynthetic opioids are chemically modified opiates, such as hydrocodone, hydromorphone, oxycodone, oxymorphone, and levorphanol. Overall, these semisynthetic opioids are closely related to morphine in chemical structure. In contrast, fully synthetic opioids produce opiate-like effects but are usually distinct from the classic opiate chemical structure. Examples of these agents include fentanyl, meperidine, methadone, propoxyphene, and tramadol. Although definitions vary, the term opioid is generally used to subsume all naturally occurring alkaloid opiates derived from the opium poppy plant as well as all semi-synthesized and fully synthesized agents that have opiate-like effects. Unless otherwise stated, throughout this lesson, prescription opiate/opioid abuse (POA) will refer to all prescription opiates and opioids because both groups of drugs are linked to well-known acute and chronic adverse medical and psychiatric effects. This lesson excludes heroin because it is not available legally in the United States, and heroin abuse events are epidemiologically distinct. We do, however, include the prescription opioid methadone. In addition, for the purposes of this lesson, drug abuse will be defined as the voluntary, nonmedical consumption of prescription drugs to temporarily produce desired physical and psychotropic effects (eg, intoxication, euphoria, mind-altering experiences, or prevention of withdrawal).

A trend of increased POA leading to morbidity and mortality in the United States has been noted in multiple reports.1-4 Surveys conducted from 1991 to 1992 and then from 2001 to 2002 showed an increasing prevalence of prescription sedative and opiate dependence and abuse (per the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] definition)5; the prevalence of opiate abuse specifically rose 236% between the two study periods.6 In rural Virginia, drug overdose deaths increased 300% from 1997 to 2003. Of these fatalities, prescription opiates were involved in 74% of the cases. Overall, deaths from prescription drug overdose were more prevalent than deaths from illicit drugs.4 This suggests that demographic factors (eg, rural vs urban, where the opposite pattern holds) can be important determinants of adverse health outcomes from drug abuse. In West Virginia, which experienced the nation’s largest increase in drug overdose mortality rates from 1999 through 2004, opiate analgesics were taken by 93% of the decedents, of whom only 44% had ever been prescribed these drugs by a licensed health-care provider.3 A subsequent study in West Virginia in 2006 found that people who died from methadone overdose were significantly younger, more likely to be men, and less likely to have had a prescription for methadone than the decedents from other opiates.7

Some data indicate that POA may be particularly prominent in rural, suburban, and smaller urban areas.8 In fact, the pejorative slang term “hillbilly heroin” was coined to reflect the increasing recreational use and diversion of oxycodone (OxyContin), a brand of sustained-release oxycodone, first reported in rural areas of the United States such as Appalachia. In reality, abuse of hydrocodone has the greatest prevalence in California, a state dominated by urban populations.9 As a response to widespread reports of OxyContin abuse, its manufacturer sponsored the development of a surveillance mechanism called Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System in 2003. By monitoring opiate abuse reported to eight US poison control centers, regional “signals” of potential prescription drug abuse outbreaks were identified in the United States using three-digit postal zip codes.9 Data from these geographically dispersed poison control centers estimated that the highest rates of abuse were for hydrocodone and oxycodone (3.75 and 1.81 per 100,000 persons per year, respectively).10

The Drug Abuse Warning Network (DAWN),11 a public health surveillance system that monitors drug-related morbidity and mortality, uses a probability sample of hospitals in select metropolitan areas to produce annual estimates of drug-related ED visits for the United States. Extrapolating data from these sample EDs, DAWN estimated that 741,425 ED visits involved nonmedical use of pharmaceuticals in 2006. Of these visits, 50% involved CNS agents and opiates accounted for the plurality of those cases (33%). The most frequently implicated opiates were oxycodone products (26% of opiates), hydrocodone products (23%), and methadone (18%). Compared with 2004 data, visits in 2006 involving opiate analgesics increased 43%, with hydrocodone products increasing 44% and oxycodone products increasing 56%.11 More recent DAWN data through 2008 show that all of these trends have continued, and indeed, magnified further, as illustrated by Figure 1.12


L25Fig1

Figure 1. Rates of ED visits per 100,000 population for nonmedical use of selected opioid analgesics, by type—United States, 2004-2008. From the Centers for Disease Control and Prevention.12
95% confidence interval.
§ Rate significantly less than the rate in 2008, by two-sided t test (P<.05).
Drug types include combination products (eg, combinations of oxycodone and aspirin).


A gender disparity was demonstrated in another study13 of POA in which women were more likely than men to report use of any prescription opiates (29.8% of women vs 21.1% of men) and abuse of any prescription opiates (15.4% of women vs 11.5% of men) in the past month. Analysis of data from the 2003 National Survey on Drug Use and Health showed that for women, but not men, first use of illicit drugs beginning at 24 years or older, serious mental illness, and cigarette smoking were associated with past-year nonmedical use of prescription opiates; this is one of the few studies analyzing covariate risk factors.14

POA among adolescents is of particular public health concern. Individuals who began using prescription drugs nonmedically at or before age 13 years have been shown to be more likely to develop prescription drug abuse and dependence vs those who began using at or after age 21 years; in fact, the relative odds of developing any lifetime prescription drug abuse was reduced by approximately 5% with each year nonmedical use was delayed.15 The 2008 Partnership for a Drug-Free America survey of 6,518 teenagers found that close to one in five (19%) reported abusing prescription medications.16 Disturbingly, 41% of those surveyed agreed that “using prescription drugs without a prescription is much safer to use than illegal drugs.” This belief likely fuels the latest trend in drug abuse called “pharming,” the practice of adolescents raiding medicine cabinets in search of finding drugs for abuse.17

Specifically for prescription opiates, the results from the survey of the National Institute on Drug Abuse, Monitoring the Future,18 showed that for OxyContin, the annual prevalence rate of abuse in 2007 was estimated to be 1.8%, 3.9%, and 5.2% for grades 8, 10, and 12, respectively. The rates for Vicodin (hydrocodone and acetaminophen) are considerably higher, with the comparable prevalence rates being 2.7%, 7.2%, and 9.6%, respectively.18 The 2007 National Survey on Drug Use and Health reported that 2.1% of those aged 12 years or older (an estimated 5.2 million people) reported POA in the past month. This trend of abuse varied by age, declining among youth aged 12 to 17 years (from 3.2% in 2002 to 2.7% in 2007), yet increasing among young adults aged 18 to 25 years (from 4.1% to 4.6%) and adults aged 26 or older (from 1.3% to 1.6%). Of particular note, among children aged 12 to 13 years, 4.9% in 2006 and 4.1% in 2007 reported a lifetime nonmedical use of pain medications.19 A popular form of POA, particularly among the hip-hop community in the southern United States, is mixing prescription strength cough medicine with ingredients such as Sprite soft drink and pieces of Jolly Rancher candy. While a concoction with codeine and promethazine (“purple drank”) is the most common, other narcotic cough syrups containing codeine or hydrocodone can be used. “Yellow syrup” is a blend of sustained-release hydrocodone and atropine or chlorpheniramine, and “pink syrup” is the Cheratussin AC brand of codeine and guaifenesin. In 2004, a University of Texas survey found that 8.3% of secondary school students had taken codeine syrup to get high.20 Finally, portending an ever-growing problem, recent media reports have highlighted high-profile deaths from suspected Suboxone (buprenorphine/naloxone) abuse among young adults.21

Clinical Effects

Abuse of prescription opiates/opioids is an important health problem not only because of the social implications but also because of the inherent toxicity of these substances and their associated medical and psychiatric adverse effects. Thus, it is important to review the potential medical effects of opioid toxicity from acute overdose, chronic abuse, or inadvertent drug-drug interactions. Table 1 summarizes the common and severe consequences of acute opioid overdose that can lead to multiorgan system failure, long-term morbidity, and death.


Table 1Summary of Acute Opioid Overdose Effects

Organ System Clinical Effects
CNS Sedation, euphoria, cognitive impairment, coma, seizures (seizures particularly with meperidine, propoxyphene, or fentanyl)
Pulmonary Respiratory depression and arrest, bronchospasm, aspiration pneumonitis, noncardiogenic pulmonary edema, truncal rigidity with decreased thoracic compliance (rigidity with fentanyl)
Cardiovascular Hypotension, bradycardia, ECG abnormalities (eg, QT prolongation and torsades de pointes with methadone; increased duration of the QRS complex and associated dysrhythmias with propoxyphene)
Metabolic Hypothermia, acidosis (metabolic and respiratory)
Musculoskeletal Rhabdomyolysis, muscle rigidity (fentanyl)
Dermatologic Flushing, pruritus
GI Nausea, vomiting, constipation
Ophthalmic Miosis
Renal Acute renal failure

Adapted from Ellenhorn and Barceloux.22


Drug-Drug Interactions
The toxic effects of opioids are exacerbated when they are ingested with other drugs that can lead to pharmacodynamic and/or pharmacokinetic interactions. For instance, coingestion of other sedatives or alcohols with opioids can result in additive or synergistic toxic effects, particularly among naive users or the elderly.23 In addition, many opioids (eg, codeine, fentanyl, methadone) are substrates for and are metabolized by the cytochrome P450 3A4 isozyme (CYP3A4) system, as are many other classes of pharmaceuticals, including widely prescribed antidepressants. Therefore, the risk of drug-drug interactions resulting in more potent or sustained effects from opioids is greatly enhanced.24 Methadone use, in particular, carries the potential for severe, life-threatening complications from drug interactions. For example, concurrent use of the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and sertraline along with methadone can result in increased plasma methadone levels because of the CYP3A4 inhibition by these SSRIs that retards the metabolism of methadone. The same can result from coingestion of methadone with erythromycin or ketoconazole.25 In addition, even at therapeutic doses methadone can produce QT prolongation, which can result in ventricular arrhythmias leading to sudden death. Consistent with this, coingestion of methadone with any other drug that also causes QT prolongation further increases the risk of arrhythmias. Unfortunately, many commonly used medications are associated with QT prolongation, including antibiotics (eg, ciprofloxacin, clarithromycin, and erythromycin), antidepressants (eg, amitriptyline, fluoxetine, and venlafaxine), and antipsychotics (eg, haloperidol and quetiapine).26 Tramadol, an analgesic that binds to opiate receptors and inhibits reuptake of norepinephrine and serotonin, can potentially interact with numerous drugs. Increased risk of seizures and serotonin syndrome (confusion, autonomic instability, muscle rigidity, severe hyperthermia) occurs when tramadol is combined with any drug that can increase synaptic concentrations of norepinephrine and serotonin, such as SSRIs and older tricyclic antidepressants.25

Chronic Effects
In addition to active use, withdrawal from opioids may also prompt the user to seek medical attention. The physical symptoms of opioid withdrawal, while generally not life threatening, are exceedingly uncomfortable: vomiting, diarrhea, severe abdominal cramping, insomnia, elevated blood pressure, tachycardia, diaphoresis, and a strong craving to use opioids again.27 Finally, an ancillary risk of opiate misuse is the potential for severe hepatotoxicity owing to the fixed combination of acetaminophen with many commonly prescribed opiates, particularly hydrocodone and oxycodone. In a study28 that combined data from 22 specialty medical centers in the United States, acetaminophen-related liver injury was the leading cause of acute liver failure for the years 1998 through 2003. The annual percentage of acetaminophen-related acute liver failure rose during the study from 28% in 1998 to 51% in 2003. Unintentional overdoses accounted for 131 cases (48%); 38% of these individuals took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Another population- based surveillance study29 of acute liver failure found that acetaminophen-related acute liver failure was the most common etiology in adults (41%) and the second most common in children (25%). Of these, unintentional acetaminophen overdose was the most common type (61%) of acetaminophen-related cause. In June 2009, the US Food and Drug Administration convened an advisory meeting to discuss the growing problem of acetaminophen-related hepatotoxicity, but to date, no formal changes to current practices have yet been recommended.

Diagnosis

The diagnosis of an opioid-intoxicated patient includes history or evidence of exposure (eg, IV needle track marks, confirmation of access to a prescription opioid by the presence of a labeled bottle or via pharmacy records), presentation of classic clinical symptoms (coma, apnea, and miosis) and rapid reversal of these symptoms with naloxone administration. A positive result from a urine drug screen for opiates, along with these findings, is diagnostic. However, laboratory testing in the opioid-intoxicated patient has many shortcomings. Many synthetic opioids (eg, methadone, meperidine, propoxyphene) are not routinely detected by the standard immunoassay-based urine opiate screens. These assays were developed based on the classic opiate structure, but because synthetically derived opioids have distinctly different structures, they are not routinely detected by this approach. Poppy seeds, which actually do contain morphine and codeine, will produce a positive result on the opiate screen when the standard level of detection is used; however, clinical effects do not occur with ingestion. Some nonopioid agents (eg, rifampin, ofloxacin, papaverine) may lead to a false-negative result on the opiate screen, even in the presence of agents that would otherwise be detected.

Other useful tests in the opioid-intoxicated patient include salicylate and acetaminophen blood levels (many opioids are formulated in combination with these agents), electrolytes, arterial blood gases, pulse oximetry, chest radiograph, and ECG. Lastly, it is important for clinicians to realize that there are several other agents or medical conditions that may mimic opioid intoxication. The differential diagnosis, primarily for patients presenting with miosis, can include intoxication with clonidine, imidazole derivatives (eg, tetrahydrozoline eye drops), cholinergic-active agents (including certain pesticides), phencyclidine, sedative-hypnotics (eg, benzodiazepines, barbiturates), other CNS depressants (including profound ethanol intoxication), phenothiazines, or structural CNS compromise (pontine infarct or subarachnoid hemorrhage).

Treatment

The most common cause of death in opioid-intoxicated patients is respiratory depression with resulting hypoxia (and, less commonly, noncardiogenic pulmonary edema). Therefore, supportive measures to ensure a patent airway, oxygen supplementation, and, if indicated, mechanical ventilation are of paramount importance. The hallmark of treatment is the administration of naloxone, a pure competitive opioid antagonist that rapidly reverses both the CNS and respiratory depression present in opioid intoxication. Close titration of naloxone administration in the opiate-dependent patient is advised because overadministration of naloxone may result in the abrupt reversal of opiate effects, precipitating withdrawal symptoms. This may lead to a highly agitated patient who can pose a management problem for the treating clinicians. Abrupt reversal of opioid effects is also associated with noncardiogenic pulmonary edema, especially for patients to whom catecholamines and large volumes of fluid have been coadministered. It is also important to note that patients intoxicated with select synthetic opioids (eg, propoxyphene, fentanyl, buprenorphine) may require much higher doses of naloxone (>10-20 mg) for reversal, and that naloxone does not reverse seizures or muscle rigidity associated with some opioids. For opioid overdoses requiring frequent, repeated naloxone dosing (eg, sustained release formulations, methadone), continuous naloxone infusion may be required. These patients should be monitored for at least 4 h after the cessation of the naloxone infusion to watch for recurrence of symptoms. Patients experiencing sodium-channel blockade effects of propoxyphene with resulting QRS interval prolongation and cardiac dysrhythmias should be treated with sodium bicarbonate.

A detailed discussion of treatment of opioid withdrawal symptoms is beyond the scope of this PCCSU lesson. However, treatment modalities include methadone and clonidine to reduce hyperadrenergic symptoms such as diaphoresis and piloerection, antinauseants, antispasmodics for GI pain and cramping, and sedatives for insomnia.

Summary

With its attendant financial, clinical, and personal costs, prescription opiate/opioid abuse is costly to society, yet escalating abuse continues to be reported in the United States as well as internationally. Occasional or long-term abuse is linked to serious adverse health effects that can be fatal or lead to long-term sequelae in survivors. The demographic profile of prescription opiate/opioid abusers differs from common street drug use, with far more female users, involvement of adolescents and even preadolescents, and a mix of urban, suburban, and rural cases. This means that such intoxication should be considered broadly with a high index of suspicion. Moreover, even though the presentation and management of these cases are often straightforward, it is important to maintain clinical vigilance for potential drug interactions and treatment complications.


References

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