Urine Toxicology Testing in Chronic Pain Management

Global reprints distributed only by Postgraduate Medicine USA. No part of Postgraduate Medicine may be reproduced or transmitted in any form without written permission from the publisher. All permission requests to reproduce or adapt published material must be directed to the journal office in Berwyn, PA, no other persons or offices are authorized to act on our behalf. Requests should include a statement describing how material will be used, the complete article citation, a copy of the figure or table of interest as it appeared in the journal, and a copy of the new (adapted) material if appropriate CLINICAL FEATURES Urine Toxicology Testing in Chronic Pain Management Edward J. Cone, PhD 1 Yale H. Caplan, PhD 2 1 Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD; 2 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD Correspondence: Edward J. Cone, PhD, 441 Fairtree Dr., Severna Park, MD 21224. Tel: 410-315-8643 Fax: 410-315-9067 E-mail: edward.cone@comcast.net Abstract: Treatment guidelines for chronic noncancer pain recommend opioids for carefully selected, closely monitored patients. However, many primary care physicians have a limited understanding of urine toxicology testing, which is the standard for monitoring opioid therapy. This article describes the technical aspects of urine toxicology testing and provides recommendations for monitoring patients to maximize the safety of opioid therapy. Articles were identified in PubMed, Medline, and EMBASE (January 1980 November 2008) using the search term opioid in combination with the terms urine toxicology, compliance monitoring, abuse, and diversion. Articles characterizing the pharmacology of individual opioids and practice guidelines for the management of chronic pain were also identified. Articles selected for inclusion discussed technical aspects of urine toxicology testing, clinical aspects of monitoring, and issues related to abuse and diversion. Urine tests can detect prescribed and illicit substances that are present above a specific threshold, but they provide limited data about the source, dose, or route of administration of substances detected. Effective monitoring requires careful test selection, an understanding of pharmacologic and metabolic factors influencing test results, and awareness of methods by which patients who are substance abusers may tamper with test specimens to escape detection. All patients prescribed opioids, not just those considered at risk for abuse, should undergo urine toxicology testing. Given its inherent complexities, effective urine testing requires close collaboration between the primary care physician and a reliable laboratory to develop an appropriate test protocol for each patient and to interpret test results. Keywords: opioids; chronic pain; urine drug testing; compliance monitoring Introduction Opioids have a well-established role in the management of postoperative 1 and cancer pain 2 4 and are now recommended therapies in the treatment of noncancer pain, including chronic pain in the elderly, 5 acute and chronic back pain, 6 osteoarthritis pain, 7 and other chronic pain that does not respond to other therapies. Despite guidelines supporting judicious use of opioids, the potential risks of abuse, addiction, and diversion have led to reluctance on the part of some physicians to prescribe them. 8,9 To reduce these risks, recent American Pain Society (APS)/American Academy of Pain Medicine (AAPM) guidelines recommend careful monitoring of any patient prescribed an opioid for an extended period (eg, 30 days) for the use of opioids in patients with chronic noncancer pain. 10 Monitoring methods include routine assessment of pain, function, and adverse events. Abuse-monitoring methods include patient self-report, behavioral monitoring, and drug testing. However, patient self-report is often unreliable, 11,12 and behavioral monitoring also frequently fails to detect misuse. 13 Drug testing can be performed using different types of biologic specimens, including blood, urine, saliva, hair, and sweat. Of these, urine testing is the most standardized and widely used method. The APS/AAPM guidelines include a strong recommendation Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260 91 71508e

Edward J. Cone and Yale H. Caplan for routine urine drug testing in patients who have a history of substance abuse or are otherwise considered to have a heightened risk of abuse. The guidelines further state that clinicians should consider periodic testing in patients who have no known history of substance abuse and no known risk factors, but the current evidence does not support a strong recommendation in this population. 10 Urine testing is noninvasive, is amenable to simple point-of-care and laboratory methods, and allows detection of many drugs and metabolites over a relatively long period. 14 Despite its utility, few physicians conduct urine toxicology testing in their opioid-treated patients 8 or are adept at interpreting results. 15,16 Given the increasing use of opioids, it is essential that clinicians know how to effectively monitor their patients compliance with therapy, and can detect abuse or diversion. To that end, this article provides clinicians with a basic understanding of the necessity, rationale, methodology, application, and interpretation of urine drug testing for all patients with chronic pain treated with opioid analgesics. We also discuss the potential benefits of routine urine drug testing in any patient receiving chronic opioid therapy as opposed to solely in patients with a history of or risk factors for abuse. Articles included in the review were identified in PubMed, Medline, and EMASE (January 1980 November 2008) using the search terms opioid, urine toxicology, compliance monitoring, abuse, and diversion. Additional references cited in the articles identified were also reviewed. Emphasis is placed on articles addressing technical aspects of urine toxicology testing, clinical aspects of effective patient monitoring, or issues related to opioid abuse and diversion. Articles on the pharmacology of individual opioids, opioid metabolism, and practice guidelines for the management of chronic pain are also selected for inclusion. Which Patients Require Urine Drug Testing? Careful Patient Selection Versus a Universal Precaution Approach The prevalence of chronic pain in the United States has been estimated at between 10% 17 and 25%, 18 with the rate increasing with age. At the same time, an estimated 19.5 million (8.3%) individuals aged > 12 years are current illicit drug users; this figure declines to 3% in persons aged 55 years. 19 Although the prevalence of substance abuse tends to decrease with age, chronic pain prevalence increases, resulting in substantial overlap of the 2 populations. In a recent systematic review, 1% of patients in opioid clinical trials with history of substance abuse as an exclusion criteria showed evidence of substance abuse or addiction during treatment. 20 However, in studies without this exclusion criteria, 5% showed evidence of abuse or addiction, and in studies reporting urine toxicology results, suspicious findings for opioids were reported in 20% of patients, and 11.5% of patients showed signs of nonopioid drug-related abuse. 20 These results suggest that clinical trials with carefully selected patient populations do not reflect the extent of abuse in the general population of patients treated with opioids, and urine screening may detect inappropriate use that is not identified by other means. Although sparse, clinical data suggest that urine testing may reduce the occurrence of substance abuse in patients receiving long-term opioid therapy. In a prospective study, 21 500 consecutive patients on stable doses of morphine, oxycodone, methadone, or hydrocodone underwent random urine drug testing to screen for opioids, oxycodone, methadone, cocaine, amphetamines, methamphetamines, cannabinoids, benzodiazepines, barbiturates, and phencyclidine. The prevalence of illicit drug use was found to be 16%, representing a 27% reduction from the 22% prevalence reported in a population of chronic pain patients evaluated in an earlier study by the same investigators. 22 In a second prospective study, 23 500 consecutive patients on stable doses of opioids were monitored using a more comprehensive protocol that included urine testing in conjunction with pill counts, periodic review of medications, and review of patient-provided medication information with treating physicians and pharmacists. In this cohort, prescription drug abuse was apparent in 9% of patients, a 50% reduction relative to the 18% prevalence reported in populations in 2 earlier studies by the same investigators. 24,25 The evident overlap between the populations of patients with chronic pain and individuals who abuse substances, coupled with the inherent difficulties in identifying at-risk patients using patient interviews and behavioral assessments 13,26 suggest that greater vigilance is needed to monitor patients treated with opioids. Given the potential to reduce abuse with routine monitoring as demonstrated in clinical trials, 21,23 we believe that urine drug testing should be standard practice for all patients treated with opioids for a prolonged period ( 30 days). This universal precaution approach to urine drug testing may not only reduce risk but also protect physicians from accusations of discrimination and prevent monitored patients from feeling stigmatized as having an exceptional risk profile. 92 Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260

Urine Toxicology Testing in Chronic Pain Management Urine Drug Testing Defined The term drug testing can be misleading because it implies that an individual is being tested for the presence of all drugs. 27 In fact, urine tests only target specific drugs or drug classes and are designed to detect substances only when they are present above predetermined thresholds. The term drug screening can also be misleading because it is used somewhat inappropriately to describe all types of drug testing, whereas screening is used in forensic toxicology to describe use of immunoassay tests to distinguish specimens that test negative for a drug and/or metabolite from positive specimens. Drug testing is frequently conducted by the federal government, employers, and the courts to detect common drugs of abuse. Federal drug testing usually focuses on 5 drug categories: marijuana, cocaine, opiates (eg, heroin), phencyclidine, and amphetamines (amphetamine/methamphetamine). 28 Employer-mandated testing in the private sector may extend these federal 5 drugs to include methadone, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, meperidine, propoxyphene, benzodiazepines, barbiturates, and other selected drugs. Detection thresholds for federal, employer, and forensic drug testing panels are set high enough to detect concentrations suggesting abuse, but they do not always detect therapeutic concentrations. For example, the threshold for opiates in federally mandated workplace drug screening is 2000 ng/ml. 29 The usual threshold for opiates in clinical monitoring is 300 ng/ml. 30 Thus, drug tests used for workplace applications may be inadequate for compliance monitoring in patients with chronic pain. How to Select the Appropriate Urine Drug Tests Point-of-Care Tests Point-of-care tests are single-use disposable devices employing immunoassay technologies that provide rapid detection and an opportunity for rapid clinical action. In most test kits, a color change indicates the presence of a drug and/or metabolite in the urine specimen. Usually, this is a nonquantitative all or none response, indicating only that the target chemical is present in the specimen at a concentration greater than a specified threshold. A survey of 5 point-of-care immunoassay devices found that each had a false negative rate for opioids 1% and a false positive rate 0.25%. 31 Immunoassay tests provide fast and convenient drug detection but lack specificity for individual opioids. Many are sensitive for morphine or codeine but show limited cross-reactivity for semisynthetic opioids such as oxycodone or oxymorphone and will not detect synthetic opioids such as meperidine or fentanyl. 30,32,33 These tests may be applied for verifying compliance when patients are prescribed morphine and codeine, but they have limited use in screening for opioid abuse. Some point-of-care immunoassays are available that are specifically designed to detect semisynthetic (eg, oxycodone, buprenorphine) or synthetic (eg, fentanyl, propoxyphene, meperidine, methadone) opioids. 30 The conclusiveness of immunoassay findings and need for laboratory confirmation tests will depend on the opioid prescribed and the immunoassay tests performed. Careful selection of a panel of immunoassays to detect frequently abused drugs will often be sufficient to deter or detect abuse. However, the limitations of point-of-care immunoassay tests must be taken into consideration. For example, codeine and hydrocodone cannot be distinguished by point-of-care tests but can be readily differentiated by laboratory tests despite having closely related chemical structures and identical molecular weights. Similarly, oxycodone-sensitive immunoassay tests will not distinguish oxycodone from oxymorphone. In contrast, many of the immunoassays for synthetic opioids such as methadone are quite specific and generally provide reliable results. Because of the inherent risk of false positives with all immunoassays, questionable results should be verified by laboratory confirmation tests. Laboratory Tests A good laboratory can provide an invaluable service to those who wish to conduct and interpret urine drug tests. The laboratory should be accredited to state and federal requirements, use good laboratory practices, comply with analytical toxicology guidelines and standards, maintain rigorous procedures and documentation, and follow appropriate forensic protocols. Knowledgeable staff (eg, board-certified toxicologists) should be available to help select appropriate test panels, detection thresholds, and interpret results. Laboratory testing is more accurate than point-of-care testing and provides specific and quantitative information on what drugs and/or metabolites are present. When specimens arrive at a laboratory for drug testing, they are logged in and assigned unique identification codes to allow recording and tracking of each specimen throughout its existence and to report and store all test results associated with the specimen Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260 93

Edward J. Cone and Yale H. Caplan for years. Laboratories typically employ immunoassay tests performed on high-volume clinical analyzers for initial testing. Such tests allow rapid separation of negative specimens from those that require confirmation testing for specific drugs and/or metabolites. Confirmation tests involve either liquid chromatography (LC) or gas chromatography (GC) in combination with mass spectrometry (MS) for detection and measurement of drugs and metabolites in biological specimens. Tandem mass spectrometry (MS/MS) is a more sensitive form of MS that consists of 2 MS systems positioned in series. The combination of LC or GC, for separation of specimens into component molecules, with MS systems, for identification and measurement of unique structural features, provides a laboratory with the ability to identify and measure drugs and/or metabolites in biological fluids at low concentrations. Laboratory testing should be performed as a confirmation test after ambiguous positive immunoassay results, but can also be used periodically (or randomly) as a first-line technique to detect drugs that may escape detection by immunoassays or be present at concentrations lower than the minimum threshold of available immunoassays. 33 Specimen Validity Tests Substance-abusing patients may be highly motivated to falsify or tamper with a urine test to avoid detection of abuse or diversion. Specimen validity tests are performed to ensure that the urine specimen has not been diluted, substituted, or adulterated to conceal drug abuse. 34,35 Dilution by drinking large amounts of fluid before producing the specimen or by adding a liquid to the specimen may be attempted to lower the concentration of any present drug below the test threshold. Substitution involves switching the specimen with another individual s urine or a fluid resembling urine. Adulteration is the addition of a chemical to the specimen that interferes with the testing process. 34,36,37 Ensuring specimen integrity begins during collection in the physician s office, with an inspection of the specimen s color, clarity, and foaming characteristics. Urine is typically yellow; a lack of yellow pigment might indicate dilution. Freshly voided urine should be clear, and foam on urine should be the same color as the rest of the specimen. 35 The temperature of urine should be taken and recorded within 4 minutes of specimen collection and should be between 90 F and 100 F. 35 Many collection cups contain a temperature strip that indicates if the specimen is at the correct temperature. Temperature is an effective validity test because it is difficult for patients to keep a substituted urine specimen at body temperature, even when techniques such as bringing the substitute specimen in a condom taped to the thigh are used. Specimens with temperatures out of range cannot be accepted as valid. Protocols for government-mandated testing, such as those for truck drivers 38 or nuclear facility workers, 39 mandate that a cold specimen must be replaced with a witnessed collection specimen. In the clinical setting, this further test needs to be discussed with the patient, unless a treatment agreement is already in place with consent to a witnessed collection follow-up of aberrant results. Failure to record the specimen temperature accurately within 4 minutes of micturition obviously thwarts the value of this test. Urine ph is typically between 4.5 and 8, although bacterial infection can result in a ph level 8, or even 9. ph can be assessed easily at the point of collection using a ph electrode, colorimetric test, or test strip. 40 Tests are also available to detect various adulterants such as glutaraldehyde, nitrite, chromate, and other oxidizing agents. Specimen dilution results in a low creatinine level and low specific gravity. 41 The most broadly used guidelines for identifying dilute and substituted specimens are those employed in the federal workplace program. 42 A dilute specimen is defined as containing creatinine in the range of 2 to 20 mg/dl. A substituted specimen is defined as containing creatinine 2 mg/dl and a specific gravity 1.0010 or 1.0200. Dilute urine can occur as a result of overhydration by water-loading or medical conditions. Thus, the occurrence of a dilute specimen may in some cases be suspicious but in others may be the expected result. The occurrence of a substituted specimen should be viewed as the equivalent of a failed drug test. Interpreting Urine Drug Test Results What Urine Tests Tell You Positive urine test results indicate that the prescribed opioid is present above a preselected threshold. A positive result for additional opioids must represent either the known metabolites of the prescribed compound, or the presence of licit or illicit opioids obtained from another source. Unexpected positive tests for nonopioid drugs, licit or illicit, require appropriate follow-up. Negative findings indicate that the target drug is not present in the sample but do not allow for determining the reason for its absence. Patients may not comply with prescribed therapies for clinical reasons, such as a reduced need for analgesia or adverse events. Noncompliance may also 94 Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260

Urine Toxicology Testing in Chronic Pain Management represent drug diversion. Alternatively, the specimen may have been adulterated or substituted, or the physician may have ordered a test panel or threshold incapable of detecting therapeutic levels of the target drug. For prescribed opioids, negative findings will require appropriate follow-up with the patient. When screening for drugs of abuse, faith in negative urine test results depends on an assurance of sample validity. What Urine Tests Do Not Tell You Specialized immunoassay tests are generally required for detection of opioids other than morphine and codeine. 30,32,33,43,44 When positive immunoassay tests are reflexed to confirmation testing, the test panel will include only the drugs identified by the immunoassay. Confirmation tests provide quantitative values of absolute and relative concentrations of drugs and metabolites, but the dose taken and the time at which it was taken cannot be determined reliably. Many factors influence urine drug concentrations, including the timing of the dose, fluid intake, and individual differences in metabolism and excretion rates. Confirmation tests are helpful in detecting abuse and diversion, but will not detect patients who abuse their prescription by hoarding and binging, obtaining additional quantities of drugs illegally, or selling most of their medication but keeping some to take just before their urine test. Differentiating Which Opioid Was Taken Many opioids produce metabolites chemically identical to other prescription opioids (Table 1). Determining whether the patient is illicitly taking one of the metabolites of the prescribed opioid as a discrete drug can be challenging even for those experienced in test interpretation. Positive urine tests for opioids that are not metabolites of the prescribed opioid indicate abuse. Because the synthetic opioids oxycodone, fentanyl, and tramadol are not produced as metabolites of any other opioid, positive results for these drugs indicate that they were ingested. Conversely, morphine, oxymorphone, hydrocodone, and hydromorphone are produced as metabolites of other opioids, and the presence of one of these opioids in a urine specimen may not indicate abuse if (and only if) the prescribed opioid is known to produce one of them as a metabolite. The metabolism of one opioid to another commercial opioid affects the interpretation of urine test results, as illustrated in the following examples. Table 1. Opioid Metabolites Opioid Metabolites Identical to Pharmaceutical Opioids Metabolites That are Not Pharmaceuticals Morphine Hydromorphone (minor) Morphine-3-glucuronide Morphine-6-glucuronide Hydromorphone Dihydromorphine Hydromorphone-3-glucuronide Hydrocodone Hydromorphone Norhydrocodone Dihydrocodeine Codeine Morphine Norcodeine Hydrocodone (minor) Oxycodone Oxymorphone Noroxycodone Oxycodol Oxymorphone None Oxymorphone-3-glucuronide Oxymorphol Fentanyl None Norfentanyl Tramadol None O-desmethyl-tramadol Nortramadol Butorphanol None Hydroxybutorphanol Norbutorphanol Propoxyphene None Norpropoxyphene Methadone None 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine 2-Ethyl-5-methyl-3,3-diphenylpyrroline Buprenorphine None Norbuprenorphine Norbuprenorphine-3-glucuronide Buprenorphine-3-glucuronide Heroin Morphine Codeine (contaminant) 6-Monoacetylmorphine Reproduced with permission from Mayo Clin Proc. 111 Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260 95

Edward J. Cone and Yale H. Caplan Morphine, Codeine, or Heroin The metabolism of codeine, morphine, and heroin is illustrated in Figure 1. Morphine produces only small quantities of hydromorphone as a metabolite. If a patient prescribed morphine tests positive for hydromorphone, confirmatory tests quantifying the relative levels of these drugs are needed to determine whether the hydromorphone was taken as a discrete entity. 45 47 Sometimes different opioids will produce a common metabolite. Both codeine and heroin produce morphine as a metabolite. When morphine and codeine are present in the urine of a patient prescribed codeine, quantitation of the relative levels is essential to determine whether the patient is taking codeine alone, codeine plus morphine, or heroin. If more morphine than codeine is present, the patient is likely taking heroin or morphine separately in addition to codeine. 48 Although heroin use is confirmed if either heroin or its 6-monoacetylmorphine (6-MAM) metabolite is identified, the short half-lives of heroin (3 5 min) and 6-MAM (25 30 min) limit their utility for confirming heroin use to a few hours. 49,50 Oxycodone and Oxymorphone Oxycodone is metabolized by cytochrome P450 (CYP) 3A4 to noroxycodone and by CYP2D6 to oxymorphone. 51 A patient prescribed oxycodone who tests positive for oxymorphone needs a quantitative analysis to confirm that the relative quantity of oxycodone is greater than oxymorphone. Only at late stages of excretion can the oxymorphone level exceed oxycodone. 33 Nonetheless, urine toxicology results cannot absolutely confirm that a patient took only his prescribed oxycodone and not some additional oxymorphone. Urine drug testing for patients prescribed oxymorphone is easy to interpret because oxymorphone does not produce any metabolites that can be mistaken for another prescribed opioid. Although oxymorphone tablets may contain up to 1% oxycodone as a manufacturing byproduct, this minute quantity of oxycodone should not be detectable on urine testing. Urine testing for oxymorphone via liquid chromatography coupled with MS/MS should reveal a single opioid ( 99% oxymorphone). 52 Figure 1. Metabolism of codeine, morphine, and heroin. 45 48,55 Codeine Heroin Hydrocodone Morphine 6-MAM If codeine to hydrocodone ratio < 10, codeine is not the sole source If codeine to morphine ratio < 6, codeine is likely not the sole source Source can only be heroin Hydromorphone Level generally lower than its hydrocodone source and below detection if only codeine was ingested Abbreviation: 6-MAM, 6-monoacetylmorphine. 96 Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260

Urine Toxicology Testing in Chronic Pain Management Hydrocodone Hydrocodone is the most commonly prescribed opioid analgesic in the United States. 53 Hydrocodone is metabolized to dihydrocodeine and hydromorphone, 33,54 and codeine may produce hydrocodone as a minor metabolite. 55 Hydrocodone levels generally exceed hydromorphone levels except at late stages of excretion. 33 Although a patient prescribed codeine may have hydrocodone present in the urine at a concentration as high as 11% of the codeine, 55 this small quantity of hydrocodone is highly unlikely to produce a detectable level of hydromorphone, even though hydromorphone is the chief metabolite of hydrocodone. The presence of hydromorphone in a patient prescribed codeine suggests that hydromorphone was taken separately. Although codeine produces hydrocodone as a metabolite, hydrocodone does not produce codeine as a metabolite; hence, the presence of codeine in a patient prescribed hydrocodone indicates that the codeine was taken as a discrete entity. It is important to remember that, even if a patient is prescribed codeine, the presence of codeine and hydrocodone can mean that either codeine alone or both drugs were taken. The metabolism of codeine shows substantial interpatient variability, 56 meaning that the ratio of hydrocodone to codeine in urine provides limited information about whether the patient took codeine alone or both drugs. Similarly, in a patient prescribed hydrocodone, the presence of hydrocodone and hydromorphone can mean that either hydrocodone alone or both drugs were taken. Communication with patients about their urine test results 57 and behavioral monitoring 58 can augment the objective finding of urine tests to distinguish appropriate use from abuse. Nonopioid Drugs of Abuse Patients who abuse opioids may abuse other controlled substances (eg, marijuana, amphetamines, cocaine, benzodiazepines) to enhance or counter opioid effects or to serve as substitutes when a preferred opioid (eg, heroin) is not available. 59 65 The majority of emergency department visits in the United States for illicit drug use involve concurrent alcohol use. 19 It is not uncommon for alcoholism to be present in patients requiring opioids for serious conditions, 66 and a substantial percentage of opioid-related fatalities also test positive for alcohol. 59 62 Patients must be advised that opioids can be expected to have additive effects when used in conjunction with alcohol and that the product labeling for most opioids advises against concurrent alcohol consumption. 51,67 70 Benzodiazepines Immunoassays reliably identify most benzodiazepines, 71 with a few exceptions such as clonazepam. 72 False-positive immunoassay results may occur in patients treated with the nonsteroidal anti-inflammatory drugs fenoprofen, flurbiprofen, indomethacin, ketoprofen, or tolmetin. 73 Amphetamine/Methamphetamine Interpretation of positive immunoassay results for amphetamine and methamphetamine is problematic as a result of their structural similarity to a wide range of prescription and over-the-counter products, including ephedrine, 74 trazodone, 75 selegiline, 76 and bupropion. 77 Laboratory confirmation tests are necessary to identify a specific drug. Well-informed drug abusers may claim to have used an over-the-counter product to account for a positive immunoassay result, but stereospecific chromatography tests conducted by a laboratory can differentiate amphetamine and methamphetamine from the medications that resemble them. 78,79 Cocaine Immunoassays are sensitive for cocaine and its principal metabolites, benzoylecgonine and ecgonine methylester, showing little cross-reactivity for other compounds. Although cocaine is a legal schedule II drug approved for use as a topical anesthetic, it is so very rarely used in clinical practice that a positive finding for cocaine should essentially always be interpreted as suggesting abuse. Marijuana Marijuana is easily detected by immunoassay. Contrary to popular myth, passive exposure to marijuana smoke does not explain positive urine test results. 80,81 However, delta-9-tetrahydrocannabinol (THC) is approved in the United States for the treatment of nausea in cancer patients undergoing chemotherapy, and as an appetite stimulant in AIDS patients (Marinol ). Thus, a positive immunoassay for THC may not indicate abuse. Moreover, the antiretroviral efavirenz 82 or the proton pump inhibitor pantoprazole 83 can produce false-positive immunoassay results. False-positive results for marijuana have also been reported following ingestion of foods containing hemp seed oil, but this is considered highly unlikely. 84 87 Confirmation testing for marijuana metabolites may be required to rule out falsepositive immunoassays. Alcohol Alcohol typically remains in the body for 12 hours, making use of blood tests or the standard hand-held breath devices (breathalyzers) necessary, but often impractical, for effective alcohol monitoring. However, the minor alcohol metabolite Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260 97

Edward J. Cone and Yale H. Caplan ethyl glucuronide remains in urine for several days 88,89 and can be tested using recently developed tests. 90,91 These tests are highly sensitive but may produce false-positive results in patients with incidental exposure to alcohol in cough medicines, mouthwashes, certain foods, communion wine, or even nonalcoholic beer. For this reason, the appropriate threshold for ethyl glucuronide is still not clear. 92 Red-Flag Findings Signs of Specimen Tampering Specimen tampering (cold samples; diluted, adulterated, or substituted samples) is a clear indication of abuse and necessitates confirmatory testing using witnessed specimen collection. 35 The Prescribed Opioid or its Metabolites are Absent from the Urine Specimen Absence of the prescribed opioid or its metabolites in the urine may indicate drug diversion or trafficking. It also may indicate that the patient is using his or her medications intermittently or only for severe episodes or that the patient experienced increased pain and consumed his or her supply earlier than anticipated. It may indicate that the patient is an ultra-fast metabolizer or has induced enzyme levels and clears the drug too rapidly to allow detection. For example, coadministration of antiretrovirals, which are CYP3A4 inducers, can decrease methadone levels, leading to withdrawal symptoms. 93 Absence of the prescribed opioid may indicate that an inappropriate test was performed. As stated previously, immunoassays may not detect synthetic or semisynthetic opioids, and immunoassays designed for abuse screening may have thresholds set too high to detect therapeutic levels. When ordering confirmation tests, instructions to the laboratory may not have included the prescribed drug or a request for appropriate detection thresholds. The Prescribed Opioid and its Metabolites are Identifi ed in Suspicious Relative Proportions Presence of the prescribed opioid does not exclude the possibility of abuse. Because urine testing cannot determine the dose taken, it cannot exclude the possibility that a patient who is prescribed an opioid is taking additional unprescribed quantities of the same opioid. As discussed previously, morphine, codeine, hydromorphone, hydrocodone, and oxymorphone can be present as metabolites of other opioids, and disproportionate metabolite levels can indicate that the prescribed opioid is not the only source. Urine test results must be considered in the context of the overall clinical picture, including history of abuse, positive findings for other drugs, and drug-seeking behaviors. Unprescribed Opioids, Unprescribed Licit Drugs, Illicit Drugs, or Alcohol are Detected Positive immunoassay tests for unprescribed licit drugs or illicit drugs require confirmation testing. Although guidelines state that a history of abuse or addiction does not preclude access to effective pain therapy, 94 concurrent abuse of drugs or alcohol presents an unacceptable risk of potentially lethal interactions with opioid pain therapy. Procedural Considerations in Urine Drug Testing Establish a Treatment Agreement at the Outset of Therapy Recommendations for conducting urine drug testing in patients receiving opioids for chronic pain are summarized in Table 2. When initiating opioid therapy, a signed treatment agreement between physicians and opioid-treated patients is helpful for setting expectations and boundaries, 95 making it easier to identify and intervene if signs of misuse are present. Drug testing should be a condition of opioid therapy in any treatment agreement with patients and should include opioids, other licit and illicit drugs, and drugs of abuse. A patient who is unwilling to undergo drug testing should not be prescribed opioids, and unwillingness in a patient who had previously consented to testing is a red flag for abuse or diversion. Treatment agreements should stipulate that testing will be random if there are no signs of abuse or diversion or unless patient function does not permit it, but more frequent testing will be needed when abuse or diversion is suspected. Agreements should also specify that evidence suggestive of sample tampering would necessitate follow-up with witnessed specimen collection. Finally, it should be agreed that testing would be at frequent regular intervals after any change in therapy or in selected patients receiving multiple medications. Assess Patients for Psychiatric Comorbidity and Addiction History or Risk All patients should be evaluated for previous abuse or addiction history as well as psychiatric comorbidities (eg, personality disorders, depression, anxiety, major mental illness) that may predispose to substance abuse. 96 98 Screening questionnaires such as the Opioid Risk Tool, 99 Current Opioid Misuse Measure, 100 or the revised Screener and Opioid Assessment for Patients with Pain 101 may be of value for identifying patients with increased risk of abuse. Screening tools and urine drug testing should be discussed with patients to assure them that monitoring does not indicate a lack 98 Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260

Urine Toxicology Testing in Chronic Pain Management Table 2. Recommendations for Urine Toxicology Testing Employ urine testing as part of a universal precaution approach to risk management Assess patients for psychiatric comorbidity or history of abuse/addiction before starting treatment Obtain informed consent from the patient Enter into a signed treatment agreement with the patient Urine testing should be A condition of opioid therapy Inclusive of other common drugs of abuse Random if there are no signs of abuse or diversion More frequent if abuse or diversion is suspected More frequent after changes in therapy More frequent in patients receiving multiple medications Evaluate patient pain and function before and during opioid therapy Monitor patient behavior, adverse events, and affect during treatment To prevent specimen dilution, substitution, or adulteration, implement a procedure for measuring Specimen appearance Temperature ph Creatinine levels Specifi c gravity Adulterants Follow-up aberrant results (ie, unexpected positive or negative results) Conduct confi rmatory tests Communicate with the patient Consider interruption or discontinuation of opioid therapy If necessary, refer patient to addiction specialist or treatment facility of trust but rather is a universal precaution taken with all patients treated with opioids. Thorough patient assessment is also an opportunity to direct patients exhibiting abuse to appropriate interventions. Evaluate Preintervention and Postintervention Pain and Function Pain is subjective, making it difficult to determine whether a patient s complaints are legitimate or a pretense. Careful evaluation of medical history and objective tests of function can support or undermine the veracity of a patient s expressed pain level. Physicians must help patients maintain realistic expectations about potential benefits and risks of treatment. Patients with unrealistic expectations about the benefits of treatment (eg, accepting reduction vs absence of pain) may engage in drug seeking, unrelated to addiction or abuse, in an effort to obtain a level of relief that may not be possible given their medical condition. Physicians should regularly assess adverse effects, aberrant behavior, and patient affect. 102,103 Aberrant behaviors include reports of lost or stolen medication, consumption in excess of the prescribed dosage, unscheduled visits or frequent phone calls to the physician s office, and claims of multiple drug intolerances requiring medication change. The last behavior allows for recreational use or diversion of the opioid that has been replaced. Altered affect can be a sign of abuse or that the opioid has unwanted effects, requiring the patient to be switched to another drug. 104 A request to switch opioids can suggest either abuse or a legitimate clinical need. Physicians need to consider the patient s overall clinical profile to distinguish these possibilities. Managing patient expectations in relation to treatment risks begins with clear definitions of tolerance, dependence, and addiction. Tolerance necessitating dosage escalation is a natural occurrence with ongoing therapy, and opioid withdrawal symptoms are expected after abrupt discontinuation or dose reduction. These processes should not be confused with addiction, which has been defined as a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. 104 Carefully Document All Results Urine drug testing procedures and results should be carefully documented. This is important not only medicolegally, but also to avoid misunderstanding between the physician and patient. When patients are compliant, documentation can reinforce positive behaviors. Implement a Protocol to Follow-up Aberrant Results Follow-up of any suspicious positive or negative urine test result should include confirmatory tests and frank communication between the physician and patient. Laboratories can help select appropriate tests to confirm suspicious but inconclusive findings. Although patient self-reports of drug use can be unreliable, one study found that self-report agreed with urine drug test results in 90% of cases when the interview was conducted after the drug test was administered. 57 This study highlights the way in which urine drug testing can foster good communication between physicians and patients because patients are more likely to be forthcoming when the physician presents them with concrete evidence of aberrant drug use. Although addiction is defined as a disease, physicians must bear in mind that the effective treatment of this disease requires the physician to set and uphold strict boundaries and limits and also requires the patient to accept the consequences of his or her actions. Confrontation of a substance abusing patient in a supportive, motivational context can be an effective first step to recovery. 105 107 Moreover, physicians must consider the safety, ethics, and legality of continuing to prescribe opioids in the face of evidence of abuse or diversion. Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN 0032-5481, e-issn 1941-9260 99

Edward J. Cone and Yale H. Caplan Conclusion Although opioid therapy is accompanied by a risk of addiction or abuse, a number of researchers have concluded that the risk of addiction in patients with chronic pain does not differ significantly from that of the general population. Moreover, patients with a history of substance abuse may be eligible for pain management with opioid medications if monitored closely. 108,109 The APS and AAPM maintain that a history of addiction should not prohibit the judicious use of opioids in patients with chronic noncancer pain who are not responsive to other treatments. 110 In any opioid-treated patient, urine drug testing can help ensure compliance, deter diversion, and detect abuse of prescribed opioids and other drugs, thereby preventing harm to the patient, the prescriber, and society. 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