The National Academy of Clinical Biochemistry Presents LABORATORY MEDICINE PRACTICE GUIDELINES Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients EDITED BY: Loralie J. Langman (Chair) Paul J. Jannetto (Vice Chair) Committee Members: Loralie J. Langman Paul J. Jannetto Department of Laboratory Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN Pathology, Mayo Clinic, Rochester, MN Catherine A. Hammett-Stabler Nancy Bratanow Department of Pathology and Laboratory Midwest Comprehensive Pain Care, Medicine, University of North Carolina School of Wauwatosa, WI Medicine, Chapel Hill, NC Robin J. Hamill-Ruth William A. Clark Department of Anesthesiology, University of Department of Pathology, Johns Hopkins Virginia Health System, Charlottesville, VA University School of Medicine, Baltimore, MD Stacy E. Melanson Gwendolyn A. McMillin Department of Pathology, Brigham and Department of Pathology, University of Utah, Women’s Hospital, Boston, MA Salt Lake City, UT Marilyn A. Huestis Cheryl A. Kassed National Institute on Drug Abuse, Baltimore, Comparative Health Prespectives, LLCSilver MD Spring, MD Tim J. Lamer Department of Anesthesiology, Mayo Clinic, Rochester, MN Table of Contents I. Preamble II. Introduction III. Chapter 1: Testing for common classes of relevant over-the-counter, prescribed, and non- prescribed drugs and illicit substances abused by pain management patients IV. Chapter 2: Specimen types and detection times V. Chapter 3: Qualitative/semi-quantitative screening assays VI. Chapter 4: Quantitative or definitive assays VII. Chapter 5: Urine adulterant testing VIII. Chapter 6: Pharmacogenomic considerations IX. Chapter 7: Reporting, interpretation, and communication of laboratory test results with clinicians X. Appendix XI. References I. Preamble: The National Academy of Clinical Biochemistry (NACB) has developed numerous laboratory medicine practice guidelines (LMPGs). The NACB LMPGs are documented practice recommendations created using evidence-based approaches to address specific questions regarding the appropriate use of diagnostic laboratory testing in a defined scientific and/or clinical discipline. LMPGs include recommendations intended to improve the use of diagnostic laboratory tests in a manner that optimizes patient care based on practice recommendations informed by a systematic review of evidence. These guidelines were developed to address, incorporate, and/or conform to the standards stated in the 2011 Institute of Medicine (IOM) reports (Clinical Practice Guidelines We Can Trust[1] and Finding What Works in Health Care[2]) and followed the standard operating procedure for preparing, publishing, and revising NACB LMPGs. (https://www.aacc.org/~/media/files/nacb/nacb_lmpg_sopc_jan_2014.pdf?la=en, last accessed 4-6-16) The creation of the guideline was designed to fulfill the methodological quality criteria of the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument. (Appraisal of Guidelines for Research & Evaluation II. AGREE II instrument. The AGREE Next Steps Consortium, May 2009, 56 p. http://www.agreetrust.org/resource-centre/agree-ii, last accessed 5-15-16) Table 1. Process of Preparing and Publishing a Laboratory Medicine Practice Guideline: Step Process 1 Define topic, scope, and target audience 2 Select multidisciplinary LMPG committee and establish clinical collaborations 3 Define key PICO(TS) questions 4 Conduct a systematic review of the evidence 5 Formulate and evaluate the quality and strength of each recommendation 6 Public presentation of key LMPG information 7 Public posting of LMPG 8 Incorporation of comments and preparation of second draft 9 Internal/external review and approval of final draft 10 Publication of final LMPG The process of preparing and publishing this laboratory medicine practice guideline (Table 1): Step 1: Define the topic, scope, and target audience: The scope and purpose of this guideline was to compile evidence-based recommendations for the use of laboratory and point-of-care (POC) urine drug tests for relevant over-the-counter medications, prescribed and non-prescribed drugs, and illicit substances in pain management patients. Current published recommendations from the World Health Organization (WHO) and other medical societies recommend pharmacotherapy using opioids as the mainstay therapy for moderate and severe pain. Unfortunately, these medications pose the risk of addiction and abuse, so monitoring of patients for compliance, or lack thereof, is commonplace. In addition, clinicians in the United States are mindful of the Drug Enforcement Administration’s (DEA’s) efforts to crack down on the growing abuse and deaths related to pain management medications. Therefore, numerous professional organizations, including the Centers for Disease Control and Prevention (CDC), have published recommendations that include the use of urine drug tests to document compliance or assess possible diversion of pain medications. This guideline specifically reviewed the literature to assess and define recommendations regarding the clinical utility and use of urine and alternative specimen types, assorted assay formats (laboratory-based vs. POC), different assay types (screening vs. definitive), inclusion of specimen validity testing and pharmacogenomics testing, as well as the reporting, communication, and interpretation of test results back to clinicians. The intention of this guideline was to provide evidence-based recommendations on how urine drug testing for pain management patients should be performed. Alternatively, in the absence of evidence or only weak evidence, recommendations were based on consensus expert opinion. In the end, the target audience for this guideline was both the laboratories and laboratorians who perform pain management testing and the clinicians who order, use, and interpret these tests. Step 2: Select a multidisciplinary LMPG committee and establish clinical collaborations: The guideline committee included representatives of key stakeholders to whom the recommendations were meant to apply. As a result, the committee was made up of clinical laboratory professionals, clinicians practicing in pain management, and other relevant stakeholders, healthcare professionals, or clinical experts. The experts on the committee are listed in the guideline and represented the National Academy of Clinical Biochemistry (L.J. Langman, P.J. Jannetto); Clinical and Laboratory Standards Institute, which was jointly preparing an expert opinion guideline on laboratory testing for pain management (C.A. Hammett-Stabler, L.J. Langman, G.A. McMillin); College of American Pathologists (S.E. Melanson); Evidence Based Laboratory Medicine Committee (W.A. Clark); clinical laboratories performing pain management testing (L.J. Langman, P.J. Jannetto, C.A. Hammett-Stabler, G.A. McMillin, S.E. Melanson); American Association of Clinical Chemistry (C.A. Kassed); American Academy of Pain Medicine (T.J. Lamer, R.J. Hamill-Ruth, N. Bratanow); active pain management clinicians (T.J. Lamer, R.J. Hamill-Ruth, N. Bratanow); and the National Institute of Drug Abuse (M.A. Huestis). While all the members of the guideline committee were from the United States, where laboratory testing for pain management has become a major public health focus, the perspectives and views of other international organizations representing broader laboratory and clinical professionals, as well as other potential stakeholders (e.g., patients, policy makers, regulatory bodies, and health insurance companies) will be taken into account during the public-consultation process (steps 7 and 8; Figure 1). The guideline committee received no sponsorship, honoraria, or other direct funding related to the development of this guideline. AACC supported the development of the guideline process by providing funds to cover the expenses of meetings and provided administrative support. All authors who contributed to the development of this guideline have also declared any financial, personal, or professional relationships that might constitute conflicts of interest with this guideline and will be published on the AACC website. Step 3: Define key PICO(TS) questions: Prior to a systematic literature search, the LMPG committee defined all the key questions that would be addressed in the guideline using the PICO(TS) strategy for construction of the questions. PICO(TS) stands for the (P)atient population, (I)ntervention, (C)omparator, (O)utcome, (T)ime period, and (S)etting. In this guideline, the patient population was acute and/or chronic pain management patients, and the interventions were the laboratory tests (screening or definitive) that were compared with other clinician tools (e.g., physician interview, medical record review, prescription monitoring programs, screener and opioid assessment for patients with pain). Outcomes included adherence, diversion, emergency department visits, and others. Appendix 1 lists all terms used for the PICO(TS) style questions and systematic literature search. The time period was from January 2000-February 2015 in outpatient, inpatient, and community settings. The PICO(TS) questions were defined at a face-to-face meeting and finalized after numerous conference calls. Step 4: Systematic literature search for relevant key publications that address the PICO(TS) questions: A Mayo Clinic librarian (P. Erwin) performed the systematic literature search using the inclusion and exclusion criteria defined by the LMPG committee. The inclusion and exclusion criteria are shown in Tables 2 and 3. It should be noted that the original literature search only included publications up to December 2013 (when the committee finalized the PICO(TS) questions), but the literature search was updated again in February 2015 to capture any additional publications (January 2014-February 2015) to keep the document current during the lengthy and time-consuming guideline process and followed the same process outlined above. Table 2: Systematic Literature Search Inclusion Criteria: Publication dates 2000-2013 originally, then expanded to February 2015 Language English Species Human Age group All Sex All Journal subset All Article types Clinical Trial (phase I-IV), Case Reports, Clinical Conference, Comparative Study, Consensus Development Conference, Evidence-based Practice, Guideline, Journal Article, Legal Cases, Legislation, Meta-Analysis, Multicenter Study, Patient Education Handout, Practice Guidelines, Randomized Controlled Trial, Research Support, Review, Systematic Reviews Table 3: Systematic Literature Search Exclusion Criteria: Publication dates Prior to 2000 Language Non-English Species Non-Human Age group None Sex None Journal subset None Article type Others not listed in table 1 The following databases were searched: PubMed, the National Library of Medicine; Cochrane Database of Systematic Reviews, which includes the full text of regularly updated systematic reviews of the effects of healthcare prepared by the Cochrane Collaboration; the National Guideline Clearinghouse (an initiative of the Agency for Healthcare Research and Quality), a public resource for evidence-based clinical practice guidelines; EMBASE, which emphasizes drug-related literature and toxicology; CINAHL, which covers nursing and allied health disciplines and includes journal articles, healthcare books, nursing dissertations, selected conference proceedings and standards of professional practice; SCOPUS; Web of Science; and Psych Info. The combined literature search from 2000-2015 resulted in 7,647 articles being identified. Each abstract was assigned to two committee members for review. Using the DistillerSR software to document the entire review process, each abstract was then independently reviewed to determine if it was relevant to the PICO(TS) key questions and could proceed to the next phase of review (full text review). However, if either reviewer determined that the article should not undergo a full text review, they had to document the reason (e.g., publication out of scope) in the software. Both reviewers had to agree to move a publication from the abstract review phase to the full text review phase. Any discordance between the two reviewers was then resolved by either the chair or co-chair, who cast the third and tie-breaking vote. Of the 7,647 abstracts reviewed, 2,352 were selected for the full text review phase. An electronic version of all the remaining articles was then retrieved and divided up among the entire committee for review. Committee members then assessed each article and documented the answers to 32 questions in the DistillerSR software, which covered everything from the author’s declarations, study aims, and objectives to their conclusions. The articles were again reviewed for appropriateness, and, of the 2,352 articles that had a full text review, 562 of them were ultimately used to formulate the recommendations for the guideline. Step 5: Formulate and evaluate the strength of each recommendation: Committee members worked in teams, with each member taking the lead on a different section of the guideline to formulate recommendations for their assigned PICO(TS) questions. The strengths of each recommendation were evaluated and graded using an approach described in the 2011 IOM report. The approach was a modification of the US Preventive Services Task Force system. The strength of each recommendation was determined to be A, B, C, or I, while the grading of the quality of the evidence was either a I, II, or III (Table 4). Table 4: Strength and Grading of the Recommendations: A. The NACB strongly recommends adoption; there is good evidence that it improves important health outcomes, and it concludes that benefits substantially outweigh harms. B. The NACB recommends adoption; there is at least fair evidence that it improves important health outcomes, and it concludes that benefits outweigh harms. Strength of Recommendation C. The NACB recommends against adoption; there is evidence that it is ineffective or that harms outweigh benefits. I. The NACB concludes that the evidence is insufficient to make recommendations; evidence that it is effective is lacking, of poor quality, or conflicting, and the balance of benefits and harms can’t be determined. I. Evidence includes consistent results from well- designed, well-conducted studies in representative populations. II. Evidence is sufficient to determine effects, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; Grading of the Quality of the generalizability to routine practice; or indirect nature Evidence of the evidence. III. Evidence is insufficient to assess the effects on health outcomes because of the limited number of power studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information. Step 6: Public presentation of LMPG recommendations: The Pain Management LMPG guidelines were first presented in February 2016 at the AAPM annual meeting to pain management clinicians for public review and feedback. Emailed suggestions were taken into account and the modified guideline will be presented again at the August 2016 AACC annual meeting for additional review and feedback. Comments submitted by the AACC website or email will be reviewed and discussed by the committee. Additionally, the document will be directly circulated to a number of experts in the field for additional comments. Step 7: Public posting of the first draft of the LMPG document: The draft guideline will also be posted on the AACC website for a minimum of 30 days for public comment. Comments made during the online documentation process will also be reviewed and addressed by the LMPG committee. This process will document the comment receipt and final resolution. Step 8: Incorporation of comments and preparation of second draft: After all public presentations and postings, the LMPG will review and address all comments. Any necessary updates will then be incorporated into the second draft of the guideline. Step 9: Internal/external review and endorsement of final draft: The final LMPG will then be submitted to EBLMC for review and approval before being presented to the NACB Board of Directors and AACC Board of Directors for final approval. The submission will contain the LMPG committee response, clarification, and explanation of their reply to each and every comment provided by the other reviewers of the draft guideline. Other external organizations (CAP, AAPM, etc.) will also get time to review and endorse the final guidelines. Step 10: Publication of final LMPG: The final, approved guideline will then be published in Clinical Chemistry or another relevant clinical specialty journal for the clinical topic. II. Introduction: Background: Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. International Association for the Study of Pain, 1979 Once thought to be a necessary part of human existence due to a lack of scientific understanding and deep roots in philosophical and religious traditions, pain is now recognized as a complex clinical problem. The great, often challenging, variation in response across individuals to a painful stimulus arises from a combination of biological, psychological, environmental, and societal factors. Equally challenging is the range of responses in treating pain. Many of the early attempts to control pain—for example, through the use of trephination or bleeding—may seem quite barbaric and cruel, but for many years pain was seen as a necessary part of the human condition, and to violate this was considered unethical. Each person experienced pain in order to experience life and to instill various concepts of order and behavior. Debates along these lines continued well into modern times. For much of history, the ill and injured, as well as their caretakers, relied upon plant-derived products to ease pain. In fact, the use of opium as a tincture or soak (on sponges) is documented in the medical and lay literature of ancient Egypt, Greece, and China[3]. Nitrous oxide was discovered by the English chemist Joseph Priestley in 1772; his work attracted early interest, but soon the use of ether, chloroform, and other compounds become more prevalent[4]. In 1806, the compound responsible for opium’s sedative and anesthetic properties was isolated by Friedrich Sertürner. He named this compound morphine, after Morpheus, the god of dreams[3]. Another milestone of the 1800s was the mass production of various pharmaceutical agents. Pain relief could now more easily be purchased from the local pharmacist. The end of the century saw the introduction of diacetyl morphine (heroin) as a cough remedy and acetylated salicylic acid (aspirin) for both analgesia and antipyresis. The pharmaceutical regulations under which we currently operate did not exist at this time—patients and non-patients self-medicated. Physicians and citizens expressed concerns about the growing “morphine habit,” leading Congress to enact laws governing the sale and use of narcotics (the 1914 Harrison Narcotic Tax Act[5] and 1956 Narcotic Control Act[6]). It would be another 20 years before additional issues related to safe manufacturing practices for drugs and cosmetics, particularly in response to the deaths attributed to the presence of diethylene glycol in elixir sulfanilamide, led to the enactment of the Food, Drug, and Cosmetic Act of 1938[7], which set into motion the creation of the Food and Drug Administration of today. The 1970s saw the creation of the first programs in the US to specifically treat patients with chronic pain. And although cancer pain has been treated through the years with opioid medications, it was in the 1990s that opioids began to be used more frequently in non-cancer pain. It was thus somewhat of a surprise when surveys conducted in the 1990s suggested that many patients reported unresolved pain during hospitalizations[8]. In response to these reports and pressure from numerous advocacy groups, the Department of Veterans Affairs and the Joint Commission on Accreditation of Healthcare Organizations adopted pain as the “5th vital sign.” The mandate was designed not only to recognize a patient’s pain sooner, but also to initiate treatment. In 2000, Congress declared 2000-2010 to be the “Decade of Pain Control and Research.” Pain management became a major public health focus with resources targeting research, interventions, and education[9]. The consequences of this action and the events of the ensuing years are mixed. Much has been learned of the mechanisms of pain—its genetics, evolution, and complexity. Advancements have been made in treatment, though not as greatly as one would have hoped. Opiates remain the mainstay of drug therapy. A 2014 National Institutes of Health workshop reported about one-third of the US population experiences chronic pain, with a quarter of these individuals limited in daily activities as a result. The report also estimates the economic impact of chronic pain at $560 billion to $630 billion per year. (https://prevention.nih.gov/docs/programs/p2p/ODPPainPanelStatementFinal_10-02-14.pdf, accessed 12-24-2015) The CDC released data from a 2012 National Health and Nutrition Examination Survey showing that although there was not an increase in the percentage of adults (6.9%) who reported using an opioid analgesic from 2003 to 2012, those using an opioid stronger than morphine increased from 17% to 37%. (http://www.cdc.gov/drugoverdose/, accessed 12-24-2015)[10] Misuse and abuse of pain management medications: While pain remains an issue, data show a significant rise in abuse and misuse. Sadly, the concerns raised a hundred years earlier related to opiate addiction have been magnified[11-14]. (https://prevention.nih.gov/docs/programs/p2p/ODPPainPanelStatementFinal_10-02-14.pdf, accessed 12-24-2015; http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts- figures.pdf, accessed 12-24-2015) In a study assessing the amount of opioids dispensed from 1999 to 2008, Brady et al.[12] found the amount of opiates dispensed (as morphine milligram equivalents) increased progressively until 2007, at which time the volume stabilized and even trended slightly downward, possibly in response to broader use of prescription drug monitoring programs. Over the same timeframe, it was found that non-medical use of opioids resulted in a 111% increase in emergency department visits [DAWN reports] and the number of overdose deaths tripled[12]. The medical world has responded to the precipitous rise in overdose deaths by emphasizing more rigorous adherence to best practices for safe opioid prescribing. There are many ways this is manifested—in day-to-day clinical care and also the development of guidelines. There are not as many formal research laboratory studies in terms of compliance (evidence-based medicine), but there are common features to almost every guideline that has been developed that include the understanding of the risk of misuse, abuse, and diversion of prescribed medication. Certain patients are at risk, perhaps genetically, of developing addiction. Periodic urine drug testing for monitoring of compliance and for screening for abuse of drugs is recognized to be an objective way to try to assess this. The frequency of