College of American Pathologists
Printable Version

  Pain service—nuts and bolts of lab support


CAP Today




December 2011
Feature Story

Clinical Toxicology Testing—A Guide for Laboratory Professionals. It’s a book due out in early January and coming from the CAP Toxicology Resource Committee and CAP Press. Its four editors (Barbarajean Magnani, PhD, MD, Michael G. Bissell, MD, PhD, MPH, Tai C. Kwong, PhD, DABCC, and Alan H.B. Wu, PhD, DABCC) and many contributors have laid out what’s needed and expected from a clinical toxicology service. In the book are chapters on supporting the emergency department, methods and test menus, the autopsy, workplace drug testing, and a range of agents—cocaine, amphetamines, barbiturates, opioids, phencyclidine, and others. Here, to give you a taste of what awaits, is part of the chapter on supporting the pain service, by Catherine A. Hammett-Stabler, PhD, DABCC, and Dr. Magnani. In next month’s issue: the chapter’s section on clinical pathology consultations.


In the United States, an estimated 50 million people experience chronic pain and 25 million experience acute pain despite the $100 billion spent annually on pain care.1* An additional, seldom-discussed toll lies in the economic impact related to lost productivity from absenteeism and the patient’s inability to carry out normal work assignments. These costs are estimated to reach $60 billion annually. Furthermore, societal costs related to the impact on family and others may be even higher. All of these are important motivators for providing our patients with good pain control.2 Unfortunately, the treatments for chronic pain remain less than optimal, and the major drugs used for this purpose have a high potential for abuse or misuse. Drugs typically employed in the treatment of patients with chronic pain are seen in Table 3-1 (PDF, 897 KB) and include opioids (and opiates), as well as anti-inflammatory drugs and drugs used in the treatment of neuropathic pain. Furthermore, many of these patients become depressed and then require treatment with benzodiazepines and antidepressants, including selective serotonin reuptake agents, which also have some potential for misuse.3 One comprehensive study characterized the prevalence and patterns of both prescribed and nonprescribed licit drugs as well as illicit drugs of abuse in more than 10,000 urine samples obtained from patients in pain clinics in six states.4 Approximately 78% of all specimens required confirmation as a result of a positive screening. Confirmation demonstrated single-drug use in about 62% of positives, while the remainder constituted specimens with multiple drugs present. The frequency of illicit drug use (cannabis, cocaine, and ecstasy) was almost 11%.

Treatment of chronic pain is likely to extend over weeks to months. Clinical guidelines for the use of long-term opioid therapy in chronic noncancer pain have been published in an effort to provide the practitioner with recommendations, for example, on patient selection and risk stratification, opioid management plans, dose escalations, and high-dose opioid therapy.1,5 One of the major focuses of these guidelines and a concern of many pain management practitioners is the identification of patients who have an aberrant, drug-related behavior or who may be at risk of developing such a behavior. When multiple studies revealed that few practitioners were able to predict which of their patients fall into this category on the basis of demographics or behavior, other tools were sought.6-12

From these studies it has become clear that a personal or family history of alcohol or drug abuse is the one factor that is most predictive of drug abuse or misuse in patients on long-term opioid therapy.5,10 Other important factors include a history of certain psychological disorders (eg, depression, attention-deficit disorder, obsessive-compulsive disorder, bipolar disorder, and schizophrenia), age (16 to 45 years), and preadolescent sexual abuse. Consequently, pain management practitioners are turning to formal screening surveys to assist in their assessment of patients. In addition, there is an increase in the use of written contracts or treatment agreements that outline specific expectations to which the patient agrees to adhere during treatment. These include agreements for medication refills, pharmacy restrictions, no sharing of medications, no diversion or selling of medications, and submission to urine drug testing. This chapter will focus on the role the pathologist and clinical laboratory can expect to play in the care of these patients and will also address commonly encountered questions or issues.

Role of the Clinical Laboratory in Pain Management

The high potential for misuse and/or diversion of opioids, in particular, has given the clinical laboratory a key role in chronic pain management as pain management practitioners have come to rely on urine drug testing as a key tool to detect misuse or abuse. In fact, most clinical laboratories will find that these clinics represent their largest customer base for these tests and the ancillary tests that often accompany them, namely, testing for adulteration. Fig. 3-1 (PDF, 897 KB) shows the rise of such testing in one major medical center laboratory, where more than a doubling in the number of orders for urine drug testing has been seen due to the development of pain clinics within the health care system.

The pain management services will bring an interesting variety of issues and concerns that may be challenging for some laboratories, beginning with the simple questions of which analytes to include in the testing menu, which cutoffs to use, and whether to perform confirmation testing. It is critical that the pathologist have a clear understanding of the analytical capabilities and limitations of each method, which will be discussed in greater detail in this chapter. Turnaround times are important because the clinics must frequently decide if a patient is misusing the prescribed medication or abusing another. A determination that misuse or abuse is indeed the case may result in a patient’s dismissal from the program. The desire to discuss results with the patient at the time of their visit is one reason screening immunoassays continue to be the first line of testing, because these can be provided on a stat basis when needed. The pain service may inquire about the use of point-of-care devices for this reason as well. In either case, it is important that the pathologist be prepared to discuss the limitations of the methods used, as well as the concepts of screening versus confirmatory testing. Some clinics may request automatic confirmation of screening results. Still others may wish to pursue alternate samples. Although challenging, each of these scenarios should be viewed as opportunities for the pathologist to provide consultation and direction to the clinic. In addition, the laboratory must be poised to offer new tests as assays become available for specific drugs.

There are also numerous opportunities for the pathologist to interact with the primary care providers ordering the tests, particularly with respect to utilization and interpretation. Many ordering physicians will not fully understand or appreciate the limitations of the total testing process unique to drug testing—that is, from collection to reporting—and it may be surprising to find that many do not have a clear understanding of the pharmacology of the drugs for which testing is requested. The laboratory and the pathologist will thus be challenged constantly with requests for drug tests not performed in house, and they will also find themselves to be the experts on drug pharmacology. Without a doubt, successful use of urine drug testing in this setting begins with a good understanding of the drugs that are of concern, the implementation of best practices for minimizing preanalytical issues (for example, adulteration), and selection of methods that best meet both the analytical and clinical needs.

Samples, Analytes, and Methods

Most testing is performed using a randomly collected urine sample, largely as a spin-off from the availability of rapid screening methods used in the emergency department or in workplace drug testing. The sample is relatively “easy” to collect, and the analytes of interest are somewhat concentrated in the matrix. Furthermore, the sample is relatively “clean,” requiring minimal preanalytical preparation for testing. Unfortunately, a urine sample does have some limitations. First, and foremost, the sample reflects a single point in time, usually during a scheduled clinic visit that the patient may be expecting. The compounds detected or measured are typically metabolic by-products, and their presence may not relate to the patient’s clinical presentation. This is more often an issue with samples collected from patients being seen in the emergency department, rather than the pain clinic, because samples collected from emergency department patients are used to confirm or support clinical findings, whereas those collected from pain clinic patients are used to confirm compliance with drug treatment programs. In either case, questions are likely when an illicit drug is detected, yet the patient did not appear intoxicated with that drug. What is detected in the sample will be dependent upon both the dose and the patient’s pharmacokinetic profile, for example, how readily the drug was absorbed, metabolized, and excreted. Excretion will depend not only on the patient’s renal function, but also on hydration state and urinary pH.

Many practitioners call the laboratory regarding urine sample collection. There are concerns that the patient may have adulterated the urine or cannot produce a specimen while in the clinic. It is often asked if blood wouldn’t be a superior specimen. A blood specimen is not recommended because urine provides more information regarding drugs taken over a longer period of time and provides information via metabolites of drugs that may have already cleared the bloodstream. Generally, blood samples are best for assessing an acute administration. Despite the fact that the testing is being conducted for clinical purposes, some laboratories or clinics may need to implement collection practices similar to those used in the workplace setting. These may include the restriction of water access, use of colored agents in the toilet, and the prohibition of coats, briefcases, or purses. In some cases, adulterant testing may be warranted. When such testing is performed, it is advisable to use the criteria established for forensic applications (see Table 3-2 (PDF, 196 KB)).

No single testing menu meets the needs of all pain clinics, and few laboratories can perform all drug assays in house. Other chapters within this book describe the drugs of interest in more detail, but those that should be considered as part of the testing menu are shown in Table 3-3 (PDF, 196 KB). When selecting the menu, it is useful to work directly with the pain clinic or with rehabilitation physicians to optimize the menu. For example, it may not be necessary to include testing for specific drugs of abuse that are not widely abused in the geographic area. One such example is phencyclidine, a drug that is not seen in the authors’ geographic areas (metropolitan Boston, MA; Chapel Hill, NC) but is reported in other parts of the country. Others may need to offer testing for fentanyl routinely in order to best serve their clinics. Selection will also include consideration of the laboratory’s instrumentation and whether or not the available devices have open channels for methods not supported by the platform’s manufacturer.

When selecting methods, it is advisable to consider that the laboratory’s perspective of a good test may differ from the perspective of the treating physician. Whereas the laboratory professional judges an assay on the basis of its analytical and clinical performance, the treating physician judges it on the basis of the reliability of the result for answering the question of whether or not the patient is taking the prescribed medication appropriately, or another drug inappropriately. In some cases, the laboratory is locked into the assays available for a specific analytical platform; however, if a choice is possible, it is desirable to use an assay with well-documented specificity at the lowest threshold, or cutoff, possible.

The cutoffs used in the workplace setting have little relevance in the clinical setting, where concentrations below the established cutoffs may have significance. This is another aspect that is not always in sync with the clinical perspective because many pain specialists want laboratories to be able to measure to zero. Analytically, that is not feasible, regardless of the technique used for either screening or confirmation. Screening cutoffs tend to be established by the manufacturer and are set at a higher concentration. Because confirmation testing involves a method of greater analytical sensitivity, its concentration cutoffs are typically lower than those for screening methods.

Metabolites, rather than parent compounds, are often selected to determine the use of a given drug. In cases of large drug classes, such as the opiates or the benzodiazepines, often a single metabolite or parent compound is used to represent the entire class. This means the antibody developed for the immunoassay will target this compound and structurally related compounds. In addition, calibration and quality control are typically based upon this compound. The compound chosen may represent the most commonly encountered agent of the class or may afford the longest window of detection.

Because most screening is performed using immunoassays, antibody specificity or cross-reactivity is important, especially for the assays that are used for large drug classes, and again the opiates and benzodiazepines best illustrate this issue. The immunoassays available for each of these two groups are quite different from each other in terms of what is, or is not, detected. Opiate screening assays, for example, were originally developed to detect the use of heroin, a drug that is rapidly metabolized to morphine. For this reason, morphine was the logical antigen to be detected. These assays also readily detect codeine because of its structural similarity, but they may fall short in their ability to detect other opioids that are clinically important today, such as hydrocodone, hydromorphone, and oxycodone. This is likely even when using the 300 ng/mL cutoff, as revealed in an analysis of the College of American Pathologists Urine Drug Screen (UDS) proficiency testing survey results from 2003 to 2004.13 This review found most opiate immunoassays unable to detect oxycodone at concentrations of 1500 and 7500 ng/mL on the basis of only 2.5% and 17%, respectively, of laboratories reporting opiate present at the two concentrations. Although almost all of the participants using enzyme immunoassays (EIAs) with a cutoff of 300 ng/mL detected the opiate hydromorphone at 1000 ng/mL, the vast number of participants using fluorescent immunoassays (FIAs) and microparticle immunoassays (MIAs, such as kinetic interaction of microparticles in solution [KIMS]) did not (Table 3-4 (PDF, 177 KB)).13 One should also bear in mind that cross-reactivity will change across lots or generations of a specific assay. Currently, for example, the cross-reactivity reported for the Vitros opiate immunoassay toward oxycodone is 22%; previous generations of the immunoassay were less likely to detect oxycodone because of cross-reactivities of approximately 14%.14 A similar statement regarding cross-reactivity can be made for hydrocodone and hydromorphone.

Opiate immunoassays typically do not detect fentanyl or methadone, which are nonopiate opioids, and while this may make sense to the laboratory professional, it often does not to the health care provider. A similar story is seen for the heterogeneous benzodiazepine class, where there is often the misconception that benzodiazepine immunoassays detect all drugs of this class or their primary metabolites. This type of information is important for laboratories to have at hand. The laboratory professional should provide information to the medical staff regarding the methods used, including the cutoff concentrations and cross-reactivity to structurally similar compounds. This information may be shared either electronically through hospital web-based programs or via hard-copy laboratory testing handbooks. As assays or platforms are changed, it is important to review and update the information for the medical staff, as well as for laboratory personnel who provide customer service or technical advice. It is also important to remember that health care providers will often turn to the Internet for information, which may be outdated or unrelated, before calling the laboratory.15

Although most laboratories report urine drug screening results as positive when at or above the cutoff or negative when below the cutoff, some clinical laboratories report results as “>” or “<” the respective cutoff. A laboratory may choose to do this if they find that the medical staff consider “negative” to mean the drug of interest was not present. For a tetrahydrocannabinol (THC) method with a cutoff of 20 ng/mL, negative results are reported as <20 ng/mL, whereas positive results are reported as >20 ng/mL. Reports should also include a statement indicating that the results are for screening purposes and that more definitive testing (ie, confirmation testing) may be necessary.

A screening result less than the cutoff has the following three potential interpretations:

  1. The drug is not present (true negative).
  2. The drug is present but at a concentration below the cutoff (false negative).
  3. The assay does not detect the drug. In this case, the drug is present but not recognized by the antibody.

A screening result greater than or equal to the cutoff has the following two interpretations:

  1. A drug or metabolite belonging to the class has been detected and is present (true positive).
  2. Another structurally similar compound has been detected (false positive).

If the results are inconsistent (either positive or negative) with the clinical findings or medication history, then confirmation testing should be obtained if clinically necessary. Unexpected positive results, particularly in class assays or those assays with considerable cross-reactivity for other drugs and chemicals, should have confirmation testing to validate the presence of the compounds. In many cases, it is important to confirm the absence of a drug or drugs because this is used as an indicator of prescription diversion.

Confirmation testing should be performed using an analytical principle of better specificity and sensitivity than the method used for screening. Gas chromatography/mass spectrometry is considered the “gold standard” in forensic toxicology and is an excellent choice in the clinical setting. Liquid chromatography/tandem mass spectrometry is gaining use, although the libraries for drug identification are currently not as well developed as for gas chromatography/mass spectrometry. Many clinical laboratories do not have the equipment or staff to perform this testing in house, but nevertheless the testing should be available through their reference laboratory.

Results from confirmation testing may also need clarification, as some of the previously mentioned issues of analytical specificity and sensitivity apply. The reports should clearly note the compounds detected and the cutoff for each compound, according to the method used. Compounds present below the cutoff should be reported as such, and those present at or above the cutoff may be quantified.

Again, the laboratory professional should be cognizant that the treating health care provider may not be familiar with the analytical characteristics of the method or a drug’s metabolic pathway. For example, some health care providers have assumed that because methadone or fentanyl was not listed, these drugs were not present, when in fact the drugs were not part of the analysis. It should be clear that most opiate immunoassays do not detect all opioids. In another situation, cocaine confirmation in response to an unexpected screening result reveals the presence of benzoylecgonine without parent cocaine. This is a fairly common occurrence in the pain clinic setting, given the short half-life of cocaine. Unfortunately, some health care providers have interpreted this incorrectly, namely, that cocaine was not used.

Dr. Hammett-Stabler, a contributing author, is professor of pathology and laboratory medicine and director of the core laboratory, McLendon Clinical Laboratories, University of North Carolina School of Medicine, Chapel Hill. Dr. Magnani, advisor to the Toxicology Resource Committee, is chair and pathologist-in-chief, Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston.

Drs. Hammett-Stabler and Magnani refer the reader of this chapter to other chapters and to appendices for additional information. Those references to other sections of the book have been removed.

To order the book (Pub 220, $80 for CAP members, $95 for others), call the CAP at 800-323-4040, option 1.