The naturally occurring opiates (morphine, codeine, and thebaine) can be extracted from the opium poppy, Papaver somniferum, along with a number of other alkaloid compounds. The opiates, along with their semi-synthetic opioid derivatives (heroin, hydrocodone, hydromorphone, nalbuphine, oxycodone, oxymorphone) and the increasing number of completely synthetic opioids (propoxyphene, levorphanol, meperidine, diphenoxylate, butorphanol, methadone, fentanyl derivatives, tramadol, buprenorphine, tapentadol) have a long and checkered history in medicine. These drugs have been considered both a panacea for the ills and injuries of life and a path to self-destruction due to the rapid onset of tolerance and the potential for addiction. History is rife with examples of early promotion of a “new, non-addicting pain reliever” which was promoted to avoid the complications of the previous pain reliever (which had once been heralded the same way). Emergency Department physicians, surgeons, and others often withheld pain medication for fear of obscuring a progressive condition or interfering with clinical assessment. This was particularly true in the assessment of abdominal pain.
Pain as a “vital sign”
During the 1990s the recognition of the problem of undertreatment of patients with acutely painful conditions led the American Pain Society, the Veterans Administration, and others to promulgate pain as the “fifth vital sign” in an effort to increase physician attention to undertreated pain.1-3 Pain scales became the norm, and they have become a Joint Commission on Accreditation of Healthcare Organizations standard.4 These efforts have had unintended consequences, as it is now clear that over-prescription and inappropriate prescription of narcotics is a growing problem.5
Epidemiology of opioid use and abuse
Some statistics regarding opioid use in the U.S. are truly disturbing. While Americans comprise less than 5% of the world’s population, they account for more than 80% of the prescription opioid use worldwide, and more than 99% of the hydrocodone (e.g., Vicodin) use.5 The Monitoring the Future study (an annual telephone-based survey of more than 45,000 eighth, tenth, and twelfth graders in 400 private and public secondary schools throughout the U.S.) indicates that 8% to 10% of adolescents are using prescription opioids without a valid medical reason or prescription.6
It has often been said that although there is not a drug dealer on every corner of rural and suburban America, there is usually a pharmacy. Indeed, most of the non-prescribed use is accessed by being given (70%) or taking (22%) another person’s prescribed medication. The traditional “street dealer” is a source only 16% of the time. Recently, the ready availability of high dosage products and circumventable, controlled-release mechanisms has resulted in a significant increase in accidental fatal overdoses.7 Death rates vary greatly among states, with those that have higher nonmedical use also having both higher substance abuse treatment admission rates and death rates. In 2008, for the first time, deaths attributable to drugs (about half being opioid-related) equaled the number of traffic fatalities in the United States.8 Although all ages are affected, the increase in use of nonmedical analgesics is most prominent in teenagers and young adults, suggesting that the problem will continue to increase.9
Individual variability in response and toxicity
Individual genetic polymorphisms, with a population frequently as high as 10%, also come into play with opioid use.10,11 The conversion of codeine into its active opiate morphine is dependent on the activity of cytochrome P450 2D6 (CYP2D6). In those individuals with the poor metabolizer phenotype for CYP 2D6, codeine causes only nausea and vomiting and has no analgesic effects. On the other hand, in those individuals with ultra-functioning CYP2D6, excessive amounts of morphine may be generated by codeine metabolism, leading to altered mental status and respiratory depression.
The potential for significant opiate toxicity from the latter situation has led the U.S. Food and Drug Administration (FDA) to recommend caution in the use of codeine alone or in combination products for nursing mothers.12 An FDA review of codeine use in children following surgery (typically tonsillectomy and/or adenoidectomy) resulted in the issuing of a “black box warning” in February 201313 restricting use in that setting. This same genetic polymorphism can be an issue with oxycodone, which is partially metabolized by CYP2D6 into the even more potent opioid, oxymorphone. Genetic polymorphisms of multiple metabolic pathways are significant issues, particularly in the setting of the use of controlled-release preparations, such as slow-release tablets or dermal patches, where attempts to circumvent the controls or individual variability in metabolism can lead to toxicity.
Pharmacokinetic and pharmacodynamic aspects play a critical role in the likelihood of an individual developing opioid toxicity. Many opioids are manufactured as long-acting medications. In addition, since opioids slow gut motility, absorption may be altered. These pharmacokinetic parameters increase the likelihood of delayed and prolonged toxicity. Some patients take repeated doses of opioids when pain is not immediately relieved, resulting in cumulative toxicity, potentially enhanced by the metabolic pathways described earlier. In addition, tolerance to a given dose of any opioid can lead to a need for increased doses to achieve the same result within weeks of beginning therapy. While this would not be a problem for acute therapy for self-limited conditions, it becomes a central issue when opioids are used for the treatment of chronic pain.
Following interruption of the usual dosing regimen or withdrawal of the medication, tolerance wanes. This pharmacodynamic interaction of opioid medication and opioid receptor physiology leads to the potential for an inadvertent overdose when the usual dose is resumed. Additionally, large doses of opioids—adequately therapeutic for tolerant individuals—are now available for accidental ingestion by children naïve to opioids or via medication administration error, or to be misused by adolescents and others experimenting with “safe” pharmaceuticals. All of these problems are exacerbated in the setting of chronic opioid use.
An additional problem is also introduced with chronic opioid use: opioid-induced hyperalgesia. In this situation, there is enhanced pain perception partly related to enhancement of N-methyl-D-aspartate excitatory neurotransmission.14 Clinically, this is commonly seen as unusual pain sensitivity to minimal stimulus. This can contribute to difficulty in appropriate use and tapering of analgesics, as the fear of worsening pain leads to ongoing use, which itself leads to worsening pain.
Clinical presentation of opioid toxicity
The clinical presentation of opioid toxicity is fairly consistent, with decreasing levels of alertness followed by respiratory depression, leading to hypoxia (decreased blood oxygenation), hypercarbia (increased partial pressure of carbon dioxide in the blood), and hypotension. As respiratory arrest ensues, there is an outpouring of endogenous catecholamines, leading to pulmonary edema, cardiac arrest, and death. An early clinical finding is miosis (small pupils). This clustering of symptoms and signs is called the opioid toxidrome, and should serve to guide therapy. Some opioid analgesics alone (in particular meperidine and propoxyphene, no longer manufactured) or in combination with anticholinergic agents (some cough and cold preparations, the antidiarrheal agent diphenoxylate/atropine) do not result in miosis, but instead cause mydriasis (enlarged pupils), perhaps based on competing anticholinergic activity.15 When recognized, respiratory support and administration of an opioid antagonist such as naloxone reverses the respiratory and mental status depressing effects of all opioids, although the optimal role in reversing buprenorphine-induced respiratory depression has not been established.16,17
Some opioids result in additional signs of clinical toxicity. For example, most opioids result in some histamine release, resulting in pruritis (itching) and erythema of the skin overlying injection sites. Tramadol, meperidine, and recently other opioids have been implicated in a multisystem syndrome of altered mental status, autonomic abnormalities, and neuromuscular findings such as tremors, collectively termed serotonin syndrome. Tramadol, meperidine, and propoxyphene cause seizures either directly or through accumulation of metabolites. Propoxyphene causes sodium channel blockade, with prolongation of the QRS segment of the EKG and related increased risk for seizures, hypotension, and dysrhythmia. Methadone can cause repolarization abnormalities, with prolongation of the QT segment and a risk of a particular ventricular dysrhythmia called torsade de pointes.15
Laboratory analysis of opioids
The clinical picture of opioid toxicity is sufficiently specific and the need for a timely clinical response sufficiently acute that laboratory identification of opioids is not usually a critical feature of emergency care. The usual laboratory test for opioids is an immunoassay performed on urine. Historically, the epitope for opiate immunoassay antibody development was morphine 6-glucuronide, with cross-reactivity to morphine and codeine demonstrated. When generated in response to a need for workplace testing some 50 years ago, this opiate screen was considered a good match for the available opiates of the 1960s, in particular the detection of previous heroin use. Heroin (diacetyl-morphine) is deacetylated to 6-monoacetylmorphine (6-MAM) and then further deacetylated to morphine. Thus this assay allows detection of a heroin metabolite for >24 hours, while heroin itself would have cleared much earlier. Additional assays specific for 6-MAM have been developed to allow more specific attribution of a positive immunoassay to heroin.18
Use of an opiate immunoassay as a screening tool for past use of opiates is reasonable in ruling out recent use of heroin, morphine, and codeine. This is often important in the assessment of patients with mood and thought disorders, as concurrent substance abuse greatly complicates management. In addition, these tests can be important in the assessment of children with abnormal mentation or when there is concern about neglect or abuse. However, a negative opiate immunoassay in a child (or adult) with altered level of consciousness and small pupils should not be taken as diagnostic exclusion of the opioids. Cross-reactivity of a typical immunoassay for all semi-synthetic opioids is incomplete. To further complicate matters, false positive opiate assays have been seen in patients taking quinolone antibiotics.19 The American Association of Clinical Chemistry National Academy for Clinical Biochemistry Guidelines for the Poisoned Patient addressed this in recommendations to laboratory device manufacturers in 2003,20 and the cross-reactivity of assays has generally improved since then.21-23 Opioids that may not typically cross-react sufficiently to render an immunoassay positive may demonstrate positive tests in the setting of a clinically relevant overdose. For example, if an assay targeted at morphine has only 20% sensitivity for oxycodone at its reporting threshold, a more than 5-fold overdose may result in sufficient urinary drug concentration to trigger a positive result.
However, there is no structural similarity between the opiates and synthetic opioids; thus, there should be no expectation of cross-reactivity in the urine opiate immunoassay. More specific urine immunoassays are available for a number of synthetic opioids.24 As these assays have been developed, the need for proper utilization and interpretation have grown. Identifying legitimately prescribed opioids in a pre-placement workplace drug screen may raise questions about safety-sensitive performance in the workplace, but interpretation is hindered by the lack of correlation of the presence of a drug in urine with impairment, as well as the large variability in dosing and excretion of these compounds. As mentioned earlier, a number of opioids are metabolized into other opioids, which can further complicate the interpretation of laboratory results.
Confirmatory testing by chromatographic techniques (LC/MS, GC/MS) is also available at reference laboratories, and can assist in determining the importance of a finding on immunoassay testing. Expanded, tiered, or confirmatory testing should be employed when appropriate. In particular, an expanded opioid panel is useful in patient management in chronic pain clinics and treatment compliance programs.25 These tests can be used to check for compliance, diversion, and substitution of other opioids. Laboratorians and clinicians should discuss the composition of such panels to ensure that the necessary tests are ordered and the results interpreted correctly.
Public health steps
The recognition of the opioid abuse and accidental death epidemic has led to a number of proposals to deal with this public health issue. One of the most important aspects is an appreciation of the potential problem with diversion of opioids when provided unnecessarily. Associated with this is a need for better understanding of the role of opioids in painful conditions that become chronic, as well as instructions regarding safekeeping of these potent medications. In particular, if the decision is made to provide long-acting opioids or extended release formulations, the possibility for intentional or accidental exposure should be part of patient counseling.
Many advocacy groups have advanced the concept of outpatient use of naloxone by family members or bystanders, recognizing that reversal of the respiratory depression induced by these drugs may be lifesaving. Increasingly, state legislatures are introducing laws that exempt from penalties the use of a prescription medication (naloxone) by or for someone for whom it was not prescribed, and waive responsibility for adverse effects via Good Samaritan statutes.26 There are still issues that require resolution, such as pharmacy availability of nebulized forms of naloxone, appropriate education and instruction in recognition of the need, and evaluation of the outcome from use of naloxone to reduce prescription opioid deaths.
Risk management strategies
Oxycodone is an example of a semi-synthetic opioid, derived from the natural opiate thebaine. This drug has gained prominence and notoriety, both because of its potency and the availability of sustained-release preparations in large doses (10, 15, 20, 30, 40, 60, 80 mg, and previously 120 mg OxyContin, for example). When divided or crushed, these medications became immediate-release oxycodone sources. A number of deaths in adolescents experimenting with drug use led the manufacturer (Purdue Pharma) to change the formulation to decrease the ease of circumventing the sustained release characteristics of Oxycontin.27 The FDA conducted a number of educational and regulatory activities, including the initiation of REMS (Risk Evaluation and Mitigation Strategy) for extended release/long-acting (ER/LA) opioid analgesics.28 These programs require the manufacturer to provide educational material for patients and prescribers as a part of an effort to track and attempt to decrease diversion or misuse of these medications.
Almost all states have introduced some form of prescription drug monitoring programs. While these programs vary from state to state, they allow prescribers, pharmacists, law enforcement, and licensing agencies to access state-wide databases of patients’ and prescribers’ opioid prescriptions.29While some states have been reluctant to introduce these measures, citing a fear of decreased appropriate pain treatment, the experience to date has not supported those concerns.30 These programs are increasing in number and scope; it is incumbent upon medical professionals to be aware of them and evaluate their potential role in medical practice.31
Appropriate use of a variety of prescription opioids for both acute and chronic pain relief is a challenging area for prescribers, patients, and regulatory authorities. The current epidemic of prescription opioid addiction and unintentional overdose deaths has highlighted many problems with use, misuse, abuse, and diversion of opioids. Addressing the multifactorial prescription opioid problem will involve multiple steps in many areas. Efforts surrounding prescription opioids have begun with prescriber and patient education, changing drug formulations, restrictions in prescribing, and monitoring drug use patterns, and trialing various harm reduction strategies. For the individual patient, the clinical treatment of opioid overdose is primarily driven by recognition of the opioid toxidrome of altered mental status, miosis, and respiratory depression.
Laboratory testing for opioids has expanded from qualititative assessment of a few naturally occurring opiates to both qualitative and quantitative measurement of an ever-expanding array of synthetic opioids. Primary roles for laboratory testing lie in the areas of workplace drug screening, treatment program compliance issues, and evaluation of child endangerment. Development of an appropriate menu of testing options is best done by ongoing communication between assay developers, laboratorians, and clinicians.
- Veterans Health Administration, Geriatrics and Extended Care Strategic Healthcare Group, National Pain Management Coordinating Committee. Pain as the 5th Vital Sign Toolkit. October 2000. http://www.va.gov/PAINMANAGEMENT/docs/TOOLKIT.pdf . Accessed April 2, 2013.
- Mularski RA, White-Chu F, Overbay D, Miller L, Asch SM, Ganzini L. Measuring pain as the 5th vital sign does not improve quality of pain management. J Gen Intern Med. 2006;21(6):607-612.
- Lorenz KA, Sherbourne CD, Shugarman LR, Rubenstein LV, Wen L, et al. How reliable is pain as the fifth vital sign? J Am Board Family Med. 2009;22(3):291-298.
- Lanser P, Gesell S. Pain management: the fifth vital sign. Healthc Benchmarks. 2001;8(6):68-70.
- Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse and nonmedicinal use of opioids. Pain Physician. 2008;11(suppl 2):S63-S68.
- Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring the Future, National Results on Drug Use, 2012 Overview, Key Findings on Adolescent Drug Use. Ann Arbor: Institute for Social Research, The University of Michigan, National Institute on Drug Abuse; 2013. http://www.monitoringthefuture.org//pubs/monographs/mtf-overview2012.pdf. Accessed April 2, 2013.
- Paulozzi LJ, Jones CM, Mack KA, Rudd RA. Vital signs: overdose of prescription opioid pain relievers–United States, 1999-2008. MMWR. 2011;60(43):1487-1492.
- Warner M, Chen LH, Makuc DM, Anderson RN, Minino AM. Drug Poisoning Deaths in the United States, 1980-2008. NCHS Data Brief. 2011;No. 81. http://www.cdc.gov/nchs/data/databriefs/db81.pdf. Accessed April 2, 2013.
- Miech R, Bohnert A, Heard K, Boardman J. Increasing use of nonmedical analgesics among younger cohorts in the United States: a birth cohort effect. J Adolesc Health. 2013;52:35-41.
- Bernard S, Neville KA, Nguyen AT, Flockhart DA. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist. 2006;11(2):126-135.
- Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613-624.
- FDA warning on codeine use by nursing mothers. FDA News Release. August 17, 2007. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108968.htm. Accessed April 2, 2013.
- Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. FDA Drug Safety Communications, February 20, 2013. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf. Accessed April 2, 2013.
- Brush DE. Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia. J Med Toxicol. 2012;8(4):387-399.
- Levine M, Brooks DE, Truitt CA, Wolk BJ, Boyer EW, Ruha A-M. Toxicology in the ICU: general overview and approach to treatment; part 1. Chest. 2011;140(3):795-806.
- Sarton E, Teppema L, Dahan A. Naloxone reversal of opioid-induced respiratory depression with special emphasis on the partial agonist/antagonist buprenorphine. Adv Exp Med Biol. 2008;605:486-491.
- Geib A-J, Babu K, Burns EM, Boyer EW. Adverse effects in children after unintentional buprenorphine exposure. Pediatrics. 2006;118(4):1746-1751.
- Moeller MR, Mueller C. The detection of 6-monoacetylmorphine in urine, serum and hair by GC/MS and RIA. Forensic Sci Int. 1995;70(1-3):125-133.
- Baden LR, Horowitz G, Jacoby H, Eliopoulos GM. Quinolones and false-positive urine screening for opiates by immunoassay technology. JAMA. 2001;286:3115-3119.
- Wu AHB, McKay C, Broussard LA, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department. Clin Chem. 2003;49:357-379 (updated 2005). http://www.aacc.org/SiteCollectionDocuments/NACB/LMPG/toxicology/emergency_lmpg.pdf Accessed April 2, 2013.
- Smith ML, Hughes RO, Levine B. Forensic drug testing for opiates. VI. Urine testing for hydromorphone, hydrocodone, oxymorphone, and oxycodone with commercial opiate immunoassays and gas chromatography-mass spectrometry. J Analyt Toxicol. 1995;19(1):18-26.
- Triage® TOX drug screen product insert. Alere™ 2011. http://www.aleretoxicology.com/dloads/triage_tox.pdf. Accessed March 27, 2013.
- Bodor GS. The laboratory’s role in opioid pain medication monitoring. J Int Fed Clin Chem Lab Med. 2007;23(2):1-8.
- Milone MC. Laboratory testing for prescription opioids. J Med Toxicol. 2012;8(4):408-416.
- Reisfield GM, Bertholf R, Barkin RL, Webb F, Wilson G. Urine drug test interpretation: what do physicians know? J Opioid Manag. 2007;3(2):80-86.
- Burris S, Beletsky L, Castagna C, Casey C, Colin C, McLaughlin JM. Stopping an invisible epidemic: legal issues in the provision of naloxone to prevent opioid overdose. Drexel Law Review. 2009;1(2):273-339.
- FDA approves new formulation for OxyContin. FDA News Release. April 5, 2010. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm207480.htm. Accessed April 23, 2013.
- Timeline of selected FDA activities and significant events addressing opioid misuse and abuse. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm338566.htm. Accessed March 27, 2013.
- Prescription drug monitoring project. National Alliance for Model State Drug Laws. http://www.namsdl.org/presdrug.htm. Accessed March 27, 2013.
- Blumenschein K, Fink JL III, James K, Kirsh KL, Steinke DT, Talbert J. Review of prescription drug monitoring programs in the United States. University of Kentucky; 2010. http://chfs.ky.gov/NR/rdonlyres/85989824-1030-4AA6-91E1-7F9E3EF68827/0/KASPEREvaluationPDMPStatusFinalReport6242010.pdf. Accessed March 27, 2013).
- Perrone J, DeRoos FJ, Nelson LS. Prescribing practices, knowledge and use of prescription drug monitoring programs (PDMP) by a national sample of medical toxicologists, 2012. J Med Toxicol. 2012;8(4):341-352.