American Association for Clinical Chemistry
Better health through laboratory medicine
June 2010 Clinical Laboratory News: Prescription for Pain Relief

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June 2010: Volume 36, Number 6

Prescription for Pain Relief
What Can Labs Do to Help Identify Misuse?

By Genna Rollins

Over the past decade, recognition of the deleterious effects pain can have on quality of life and healing has increased substantially. Physicians now are more attuned to the need to alleviate patients’ pain and are writing an ever-growing number of prescriptions for pain medications. Although this focus on pain management is positive, it has presented some challenges for clinicians in terms of balancing the legitimate benefits of prescription pain therapy with the potential for misuse of the drugs.

“We’re in a bit of a conundrum when it comes to this issue,” said Jeffrey Coben, MD, professor of emergency medicine and director of the Injury Control Prevention Center at West Virginia University in Morgantown. “Ten years ago, doctors were criticized fairly heavily for not providing adequate pain management, and there’s still concern in that regard. We’re trying to respond, but at the same time, we’ve seen an increase in abuse, misuse, and other sequellae.”

Because of their central role in detecting and monitoring drug use, laboratorians are in an excellent position to collaborate with physicians in achieving pain management targets while minimizing potential harms from the medications, according to Bill Clarke, PhD, MBA, DABCC, associate professor and director of therapeutic drug monitoring and toxicology in the department of pathology at Johns Hopkins University School of Medicine in Baltimore. “Clinicians are getting more lab savvy, but they still don’t have a sophisticated understanding of what we do and do not detect, and they’re desperate for answers,” he said. “They just want to know, is my patient doing what they’re supposed to be doing with a particular drug. That’s the bottom line for them.”

When a Good Drug Turns Bad

The prominence of prescription pain medications is clear: codeine and its combinations were the second most prescribed class of drugs in 2008 behind lipid regulators, and hydrocodone (Vicodin) by far was the single most prescribed drug (See Tables, below). But the potential for misuse is equally obvious. Approximately 52 million Americans age 12 or older—more than 20% of the population—reported a nonmedical use of prescription-type psychotherapeutic drugs, including opioids, at some point in their lifetimes, according to the 2008 National Survey on Drug Use and Health. The National Institute on Drug Abuse’s research report, Prescription Drugs: Abuse and Addiction, also found that opioids, depressants, and stimulants are the three most commonly abused drug classes.

Inappropriate use of these medications has negative consequences not only for the individuals taking them but also for society and the healthcare system. For example, people who abuse opioids have direct healthcare costs more than eight times those of nonabusers, according to the Centers for Disease Control and Prevention. New research conducted by Coben also indicates that hospitalizations for poisoning by prescription opioids, sedatives, and tranquilizers increased 65% between 1999–2006, double the rate for other drugs and substances (Am J Prev Med 2010;38:517–24). “We found that similar to fatality rates, there was tremendous escalation in serious but not fatal cases of prescription drug abuse or misuse ending up in hospitals across the country,” he said. “This further highlights the importance and magnitude of the problem.”

Top 10 Classes of Prescribed Therapeutic Drugs
Lipid Regulators
Codeine & Combinations
ACE Inhibitors
Beta Blockers
Proton Pump Inhibitors
Seizure Disorders
Thyroid Hormone Synthetic
Calcium Blockers
* Total prescriptions in millions
Source: IMS Health

Top 10 Prescribed Drugs
Levothyroxine Sodium
Amlodopine Besylate
* Total prescriptions in millions
Source: IMS Health

The Bottom Line

Helping clinicians determine whether patients are taking pain medications appropriately requires that laboratorians not only be well-versed in the analytical issues involved with their drug testing methods, but also that they communicate the nuances and limitations of those methods to physicians. To do that, labs first need to understand the prescription and abuse patterns in their communities. “It’s important to participate in grand rounds to know what kinds of medications are being prescribed, overdosed, or diverted,” explained Michael Wagner, PhD, associate professor at Indiana University School of Medicine and director of the Indiana State Department of Toxicology in Indianapolis. “You need to know whether or not your lab can test for those drugs, and whether your platform cross-reacts with the various opioids that are out there.”

For instance, if oxycodone is the most prescribed medication in a given community, it is likely to be the most misused—whether intentional or not—simply by virtue of the volume of the drug circulating in the community. However, most urine immunoassays that screen for opiates do not reliably detect oxycodone, which is a semisynthetic opioid. A separate screening assay specifically detects oxycodone and oxymorphone, but it is not widely used, according to Alan Wu, PhD, director of clinical chemistry and toxicology at the University of California San Francisco. “Many labs don’t know about this assay and they don’t use it, but it should be used,” he observed.

The Methadone Controversy

Wu also indicated that some labs lack a specific assay for methadone, which has become more popular as a pain management agent and is associated with proportionally more severe adverse outcomes than other opioids, sedatives, and tranquilizers. For instance, Coben and his colleagues found the largest percentage increase (400%) in hospitalization-related prescription drug poisonings between 1999 and 2006 was due to methadone.

About a decade ago, physicians started prescribing the drug for pain management but did not have a clear understanding of its potential toxicity, according to Lee Kral, PharmD, clinical pharmacy specialist at the University of Iowa Hospitals and Clinics’ Center for Pain Medicine in Iowa City. “A lot of providers had not been exposed to the pharmacokinetics and were using methadone just like any other opioid. But morphine-equivalent conversions to methadone are unusual in that the higher the morphine-equivalent dose per day translates as a percentage and you need less and less percentage as the daily dose of morphine equivalence increases,” Kral explained. For instance, a 50 mg morphine dose would translate to a 25% morphine-equivalent methadone dose of 12.5 mg. But to achieve a 1,000 mg morphine-equivalent dose of methadone would require just 5%, or a 50 mg dose.

Word now has spread about methadone’s narrow therapeutic range, so an analysis similar to Coben’s with data through 2009 might show an attenuation in adverse events associated with the drug, experts said. Still, labs and clinicians need to collaborate closely on therapeutic monitoring of this drug.

Where Labs Can Help

Wagner suggested that laboratorians may have more of an opportunity to educate physicians about the nuances of prescription drug detection in the inpatient setting. “In overdoses, the lab might be analyzing serial samples to make sure the patient is clearing the drug,” he explained. “In that situation, the lab is playing a more profound role.”

Conversely, labs’ sometimes diminished role in emergent situations may work against closer laboratorian-clinician dialogue when arguably it is needed the most. “In suspected overdoses, a lot of emergency physicians go straight to the counter-measure, naloxone, and it either works dramatically or it doesn’t work. Lab results in that situation may or may not be important. It depends on how fast the results are available, and on the drug in question. If we don’t have an oxycodone assay, the result will be negative even though it’s a clear opiate overdose, from the reversal with naloxone,” Wu explained. “In that situation, there may be a mistrust of the lab. Whose fault is that? Probably a combination of both the lab’s and the doctor’s.”

Is it Really Negative?

Labs also need to understand and effectively communicate numerous analytical issues related to urine drug screening immunoassays. The assays can cross-react with unrelated compounds such as quinolone antimicrobials, but at the same time they don’t react with all compounds in the opiate, sedative, and tranquilizer drug classes, or may do so but only at very high concentrations. This cross reactivity can vary across immunoassay format, vendor, and reagent lot. As an example, opiate immunoassays, which detect the natural opioids codeine and morphine, do not reliably detect semisynthetic compounds like hydrocodone, hydromorphone, and oxycodone, but may if they are present in high enough concentrations.

While laboratorians understand these cross-reactivity issues well, the same is not true of physicians. Without dialogue between the two, clinicians at the least could be confused about drug screening results, but far more concerning, they could make erroneous decisions. In either circumstance, there could be profound consequences for patients. “What would really be useful is if doctors called us up front and said, ‘I’ve got a need to measure drug X’,” said Loralie Langman, PhD, director of toxicology and the drug monitoring laboratory and associate professor of laboratory medicine and pathology at the Mayo Clinic. “If you’re looking for morphine and perform an opiate immunoassay screening test and due to the presence of hydrocodone a positive result is obtained, this is classified as a false positive. But if you’re looking for opiates as a drug class, the result will be classified as a “true positive.” That’s why I dislike using the terms “false-positive” and “false-negative” in the context of drug screening. It really depends on what you’re expecting the assay to do.”

Clarke agreed that laboratorian-physician communication is essential in enabling providers to make sound clinical decisions. “The doctor makes an assumption that our opiate assay is going to pick up a particular pain medication, when it won’t pick it up at all, or at least not until it’s present in the urine at a very high level. Or perhaps the drug is present but at a concentration lower than our cut off, so it comes back negative,” explained Clarke. “The clinician may take that information and just assume the patient is non-compliant and sever their relationship with the patient.” Kral has seen that very scenario play out. “We’ve had several patients who were fired from their pain management clinic because the toxicology screen came back negative, but they were taking methadone or fentanyl, so those drugs were not going to show-up on an opiate immunoassay,” she indicated.

Cross-reactivity analytics can pose challenges even for labs with high volumes of drug testing, like Clarke’s. “We had a problem with our opiate immunoassay. We were telling clinicians ‘no, it doesn’t cross-react with oxycodone,’ but then we found that’s not exactly true. If a patient is on a higher dose and they’re taking it regularly four or five times a day, their urine concentration may be high enough that they do turn the assay positive,” explained Clarke. “Now we give clinicians a qualified maybe.”

Because of the nuances related to cross-reactivity, cutoffs, and screening for drug classes rather than specific drugs, Kral suggested that labs would do well to provide interpretive comments with drug screening results. “They can be priceless, particularly for providers not well-versed with the assays,” she observed. “Just a paragraph that explains the abnormalities you might see in general terms can be helpful.”

Moving Into Mass Spec

Because of the limitations of urine immunoassays, many labs have implemented a two-step confirmation process involving initial screening followed by gas or liquid chromatography mass spectrometry (GCMS/LCMS) to identify the specific drug in the patient’s system. GCMS has been the chief means of confirmatory testing, but as more labs invest in LCMS and look for expanded applications for the technology, the latter is gaining currency in drug screening.

However, since LCMS is considerably more expensive than GCMS and requires significant technical expertise, it will not be an option for many labs. In addition, it would not be cost-effective to use either GCMS or LCMs for confirmation testing on every drug screening sample.

An Appeal to Manufacturers

Wagner suggested that as an alternative, smaller volume labs might consider multiplex platforms that enable analysis of several drug classes at once. “Instead of loading samples in one carousel to do antidepressants, another for opiates, and another for central nervous system depressants, they might be able to have a microchip array that screens multiple categories at one time,” he explained. “The biggest setback with that is the way companies cluster the various antibodies on the chip. They design the chips to maximize drug categories and to fit the right antibody with the right type of buffers, rather than producing one chip that screens for all opiates or antidepressants.”

Wu also appealed to manufacturers to update their assays to stay abreast of drug developments. “We need better tools,” he said. “LC mass spec is not going to be available everywhere, and especially in the emergency department where you need results quickly, there is a role for new immunoassays. But the lab can only work with the cut off tools they have.” Immunoassays are needed for fentanyl, tramadol, and some of the newer benzodiazepines, he suggested.

Drug PGx: Not There Yet

Pharmacogenomic testing holds more future potential than existing opportunity for labs to support physicians’ pain management strategies, experts agreed. “Unlike warfarin, the data isn’t there. It hasn’t been studied enough to make a definitive recommendation,” said Langman. “Pharmacogenomics also may not be as much of a factor because pain is a subjective end-point, and what’s excruciating for one person may be tolerable to another, and the dose that will bring it to a tolerable level in one person may not in another because of their different perceptions of pain.” The exception might be testing for the CYP2D6 gene in codeine and its derivatives (CLN 2009;35:8–10). Patients with more than two copies of this gene are considered ultrarapid metabolizers and can have considerably enhanced—and even fatal—effects from the drug.

In 2007, FDA required manufacturers of prescription codeine medicines to include information about codeine ultra-rapid metabolism in drug package inserts, but has not recommended CYP2D6 genotyping for patients taking these medications. For now, CYP2D6 genotyping is not ordered frequently, perhaps because of the complex interplay between genetics, pain perception, and the way other drugs affect opioid metabolism, as well as the availability of alternative medications. “Pharmacogenomic testing hasn’t been pushed a lot because there are many other options besides codeine and it is the medication you run into problems with,” Kral observed. “We encourage providers right out of the gate not to order it unless people tell you they’ve had codeine and it worked.”

Even as the science around pain management progresses and drug detection analytics improve, the need for strong laboratorian-clinician dialogue will not change, Clarke indicated. “Communication is the key. It’s a two-way street so that clinicians have an understanding of how to interpret the results and also so that the lab can understand the needs of the clinician.”