Thursday, January 21, 2010

Pitfalls of Urine Drug Monitoring in Pain Care

Editor’s Notebook Editorial Notes on Pain Topics of Interest & Importance.

Medical practitioners today often focus on objective assessments via diagnostic procedures for guiding patient care. However, relying on urine drug screening and testing for managing opioid-analgesic therapy in patients with pain is fraught with some important but unrecognized problems and challenges.

Numerous articles propose the need for drug monitoring in all patients prescribed opioid analgesics for chronic pain conditions [eg, Gourlay et al. 2006; Hammett-Stabler and Webster 2008; Moeller et al. 2008]. While the authors of such articles may be expert in applying the principles of urine screening and testing described, there have been many cases of patients being mistreated by healthcare providers less skilled in the interpretation of monitoring results. At least two small studies have found that practitioners ordering urine drug assays to monitor patients on long-term opioid therapy typically are not proficient in interpreting the results [Reisfield et al. 2007a, 2007c]. Certainly, improved healthcare provider education might be helpful but, considering the cost and limitations of urine monitoring for guiding treatment and achieving better outcomes, it could be time for a reassessment of such assessments.

Recent and widely accepted guidelines on opioid prescribing recommend urine drug screens to confirm adherence to prescribed therapy; however, the authors also concede that “…evidence on accuracy of urine drug screening to identify aberrant drug-related behaviors or diversion is lacking, and no evidence exists that demonstrates that screening improves clinical outcomes…” [Chou et al. 2009]. Meanwhile, proponents of urine monitoring as a component of opioid-analgesic therapy suggest a number of justifications [Hammett-Stabler and Webster 2008]:
  1. Verifying patient compliance with an agreed-upon treatment plan,

  2. identifying possible new or recurrent drug misuse,

  3. support medical decisions about opioid therapy,

  4. assist in substance misuse diagnosis (although it does not itself “diagnose” addiction),

  5. detect and deter illicit drug use and abuse,

  6. provide objective evidence of illicit-drug abstinence in high-risk patients,

  7. demonstrate to regulatory authorities prescribers’ efforts in monitoring patients.
While all of these are well-intended reasons, the interpretation of screening or testing results can be complicated and often misleading, leading to delays in therapy or mistreatment for pain, as well as spoiled patient-provider relationships [Reisfield 2009]. In some settings, screening and testing may end up being used or perceived by patients as a “lie detector” in a game of “gotcha” to detect and punish suspected therapeutic noncompliance or misbehavior.

Drug monitoring in pain practice is often a two-stage process [Leavitt 2005]:
  1. Preliminary Screening of patient-provided specimens, usually urine, at the point-of-care (POC) to detect the presence or absence of a limited number of prescribed and non-prescribed drugs of interest. The accuracy and reliability of relatively inexpensive POC screening assays are limited; although, more costly laboratory-performed assays can be of higher quality.

  2. Confirmatory Testing techniques, using high-quality methods (eg, GC-MS, LC-MS), are more expensive but highly accurate and reliable. A problem is that these methods sometimes can be too good, detecting small amounts of irrelevant agents or metabolites that are diagnostically unhelpful or confusing.
With either type of drug-monitoring assay, it often is unappreciated that “analytical” accuracy is not the same as “diagnostic” accuracy [Saah and Hoover 1997]. That is, due to the many complicating factors, merely detecting the true absence or true presence of a drug during screening or testing does not necessarily denote patient behavior: when (or if) the drug was taken, how much drug was taken, the source of the drug (licit or illicit), or even whether the drug in question actually was directly consumed by the patient (eg, marijuana or cocaine). In order to understand and properly interpret the many subtleties of assay results, practitioners must be knowledgeable of opioid pharmacokinetics (eg, metabolism), pharmacodynamics, pharmacogenetics, and limits of assay methods [Carlozzi et al. 2008; Chou et al. 2009].

While it would be presumptuous to caution against the use of urine drug monitoring, there are a number of potential pitfalls worth noting. Here are several common as well as less well-known considerations:
  • Detection cutoff-levels do not always take into account passive (innocent) exposure to marijuana or cocaine consumed by others, consumption of poppy seeds (natural opiate), and the use of OTC products that may cross-react with the assay to produce false results [Evans et al. 2009; Reisfield 2009].

  • A number of opioids are metabolized by liver (CYP450) enzymes: eg, codeine, hydrocodone, oxycodone, methadone, buprenorphine, tramadol, and fentanyl. Individual patients may have genetic variants of the enzymes, or may be taking inducer or inhibitor drugs, that strongly influence opioid metabolism and, hence, their detectable presence or absence in urine (or blood, or oral fluid if used) [see, Carlozzi et al. 2008; Smith 2009]. For example, the unexpected absence of one of the above opioid analgesics upon testing can be due to rapid metabolism in a patient rather than therapeutic noncompliance or drug diversion.

  • Morphine preparations typically contain low levels of codeine as an impurity, which may be detected by high-quality assays in patients who have not been prescribed codeine [Evans et al. 2009].

  • Patients prescribed high doses of oxycodone also may test positive for hydrocodone, which is believed to be present as an impurity; analytically this is a true positive, but diagnostically it is a false positive [Evans et al. 2009].

  • It has been clinically observed that unanticipated conversions between opioids going beyond common metabolic pathways may occur, and these can be detected by high-quality assays [Haddox 2005]. For example, patients prescribed only codeine might test positive for codeine and morphine, and also hydrocodone and hydromorphone. Patients taking only morphine might also test positive for hydrocodone and/or hydromorphone. While mechanism behind this metabolic phenomenon are not understood, such findings could falsely suggest that patients are taking unauthorized opioids.

  • Proprietary, computerized methods have been developed for quantifying the amount of opioid agents in testing samples; these have been based on controlled conditions examining carefully-selected patients [Couto et al. 2009] or pharmacologically adjusted values [Kell 1994, 1995]. Relying on quantitative tests to help determine whether a patient is properly taking the specifically prescribed dose of opioid can be questionable, especially in patients who do not fit typical patterns of metabolism or have other confounding factors. Due to their limitations, quantitative assessments have been eschewed by government agencies where the consequences of misinterpretation could be severe (eg, Drug Courts).

  • Even the most high-quality laboratory testing may not deter persons seeking opioids for illicit purposes — they know how to cheat. An entire industry has sprung up offering advice and products to “beat the test” (just insert that phrase into any search engine to see the myriad of solutions being promoted).

  • Case reports have noted false-negative results for opioids and cannabinoids in the presence of tolmetin, an NSAID, and for amphetamines due to interference by chlorpromazine (eg, Thorazine®) metabolites. The antifungal agent fluconazole may interfere with the detection of cocaine [Reisfield 2009]. Persons determined to “beat the test” may know about this.

  • A popular and effective way to beat the test is by substituting “untainted” urine for one’s own by carrying a concealed specimen into the bathroom. The only way to thwart this is by supervised urine collection (ie, a staff member observing urine leave the patient’s body and fill the cup). While this is required for forensic urine testing, it could be the ruin of a typical medical practice; it is upsetting for patients and demoralizing for staff.

  • To avoid the possibility of urine specimen substitution, oral fluid can be collected for use with screening devices employing technology similar to on-site, POC urine screens. Sensitivity and specificity of oral fluid screening and testing are acceptable, but subject to the same limitations of interpretation and confounding factors as urinalysis [Leavitt 2005].

  • Urinalysis is unhelpful for detecting alcohol misuse or abuse [Moeller et al. 2008], and alcohol can be more hazardous in combination with opioids than many other drugs.
The above list is certainly not all-inclusive [eg, also see, Carlozzi et al. 2008; Reisfield et al. 2007b]; however, in view of the many caveats, healthcare providers may want to reconsider what they expect to accomplish by drug monitoring as a component of pain care and if it will adequately serve them and their patients. Drug screening and testing are evolving fields and some aspects — metabolites and their concentrations and ratios, assay limitations, cross-reactive interferences — are complex and incompletely understood [Reisfield 2009].

At the least, drug assay results must be placed within the context of the total clinical picture and providers need to ask themselves in advance what they will do with results, which may or may not depict an accurate portrayal of the patient’s medication use or other drug-use behavior. Guidelines on opioid prescribing have observed that drug monitoring assays “do not suggest a definitive course of action, but rather should be interpreted in the context of individual patient circumstances” [Chou et al. 2009]. Healthcare providers need to be cautious about making decisions affecting patients’ lives based solely on laboratory reports; that is, applying test-guided treatment rather than being patient-centered. It must be recognized that placing too much reliance on drug screen or test results can depersonalize pain care to the point of working against all other aspects of sound clinical practice.

> Carlozzi AF, Fornari FA, Siwicki DM, et al. Urine drug monitoring: opioids [monograph]. Pain Medicine News. 2008(Dec) [
booklet PDF here]. Also see the companion website:
> Chou R, Fanciullo GJ, Fine PG, et al. APS/AAPM clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009(Feb);10(2) [
access full guidelines here].
> Couto JE, Webster L, Romney MC, Leider HL, Linden A. Use of an algorithm applied to urine drug screening to assess adherence to an OxyContin® regimen. J Opioid Manag. 2009;5(6):359-364 [
> Evans M, Kriger S, Gunn J, Schwilke E. Anomalous opiate detection in compliance monitoring. Practical Pain Manag. 2009;9(7):54-55 [
> Gourlay DL, Heit HA, Caplan YH. Urine drug testing in clinical practice: dispelling the myths & designing strategies. California Academy of Family Physicians. 2006 (Edition 3) [
article PDF here].
> Haddox JD. Presentation at the 2005 AAPM Scientific Meeting. In: Pembrook L. Urine drug screening may detect metabolic opioid conversion; judgment of abuse, addiction should not be based on urine test alone. Pain Medicine News. 2005(Dec);3(6) [
available with free registration].
> Hammett-Stabler CA, Webster LR. A clinical guide to urine drug testing: augmenting pain management & enhancing patient care. University of Medicine & Dentistry of New Jersey, Center for Continuing & Outreach Education. 2008(May) [
article PDF here].
> Kell MJ. Utilization of plasma and urine methadone concentration measurements to limit narcotics use in methadone maintenance patients: II. Generation of plasma concentration response curves. J Addict Dis. 1995;14(1):85-108 [
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> Leavitt SB. Substance-abuse monitoring in methadone maintenance treatment. Addiction Treatment Forum. 2005(Apr) [
article PDF available here]. Also see, “SAM Supplement” explaining principles and terminology used in drug screening and testing [available here].
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> Reisfield GM, Bertholf RL, Barkin RL, Webb F, Wilson G. Urine drug test interpretation: what do physicians know? J Opioid Manag. 2007a;3(2):80-85 [
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article PDF here].
> Reisfield GM, Webb F, Bertholf RL, Sloan PA, Wilson G. Family physicians’ proficiency in urine drug test interpretation. J Opioid Manag. 2007c;3(6):333-337 [
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> Saah AJ, Hoover DR. “Sensitivity” and “specificity” reconsidered: the meaning of these terms in analytical and diagnostic settings. Ann Intern Med. 1997;126:91-94 [
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> Smith HS. Opioid metabolism. Mayo Clin. Proc. 2009(Jul);84(7):613-624 [
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