College of American Pathologists
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  Providing consults in support of the pain service


CAP Today




January 2012
Feature Story

Clinical Toxicology Testing—A Guide for Laboratory Professionals. It’s a new book out now 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, this month, is the final part of the chapter on supporting the pain service, by Catherine A. Hammett-Stabler, PhD, DABCC, and Dr. Magnani. In last month’s issue: the chapter’s sections on role of the lab in pain management and samples, analytes, and methods.

Clinical Pathology Consultations

There are occasions where the treating physician needs more help in test result interpretation than can be addressed by a simple e-mail or phone conversation. In those cases, a clinical pathology consultation may be warranted. When providing this service, the most appropriate CPT code is CPT 80502, comprehensive consult for a complex diagnostic problem with review of patient’s history and medical records.16* These consultations are also applicable for pharmacokinetic issues. A consultation should state the patient’s problem, list of medications, results of drug testing and an assessment of what the results mean (eg, compliant, noncompliant), and/or recommendations for further monitoring or testing (for an example of a clinical pathology consultation, see Fig. 3-2; for an example of a consultation template). Information derived from software programs about drug interactions may also be included and may be helpful to the ordering practitioner.

The metabolism of certain benzodiazepines and opioids often produce confusing reports since many metabolites are themselves prescription medications. Treating physicians may obtain results that appear inconsistent with the prescribed medication but are in fact consistent because the reported drug may be a metabolite of the prescribed medication. For example, a response to the question from the practitioner, “My patient’s report showed he took Serax (oxazepam) and I did not prescribe that” might be as follows:

Dr. Jones,
Regarding your patient’s results: the confirmation assay was positive for the benzodiazepine oxazepam (Serax). Please note that oxazepam is also a metabolite of temazepam (Restoril), clorazepate (Tranxene), and can sometimes be a minor metabolite of diazepam (Valium).
Please call me if you have any further questions.

This same scenario is very common with prescribed opiates. As previously stated, the opiate immunoassay is designed to detect primarily morphine. Semisynthetic or synthetic opioids may or may not be detected, depending on the assay used. The laboratory might need to set up additional immunoassay screens or confirmations, particularly for oxycodone and buprenorphine, because these analytes are easily missed with the traditional opiate immunoassay. Confirmations demonstrating the presence of hydrocodone and hydromorphone will be confusing if one is unaware that hydrocodone is metabolized to hydromorphone. Recently, studies have demonstrated that patients on high-dose morphine therapy for cancer pain have had small quantities of hydromorphone detected in their urine.17-19 The patient may be suspected of obtaining unauthorized hydromorphone if the treating physician is unaware of the metabolic conversions (Fig. 3-3). Investigations to date have shown hydromorphone to be less than 6% of the urinary morphine concentration in these cases, whereas higher percentages suggest administration of hydromorphone. Similarly, one may question whether oxycodone was spiked into the urine at collection or is being ingested by the patient as prescribed; the presence of the metabolite oxymorphone, particularly in conjunction with the parent compound oxycodone, is evidence that the patient is taking the drug (Table 3-5).

For patients given morphine or codeine who may have been previous heroin abusers, confusion may occur if the final report states that both morphine and 6-acetylmorphine (6-AM) are found. The treating physician expects morphine as a metabolite but is unsure of the metabolite 6-AM, thinking it may be an expected metabolite of either morphine or codeine; it is not, and in fact is only seen in patients abusing heroin, because heroin (diacetylmorphine) is first metabolized to 6-AM with subsequent conversion to morphine (Fig. 3-4). The window for detecting 6-AM is short: the average plasma half-life for heroin is 1 to 4 minutes and approximately 3 to 52 minutes for 6-AM.20 Given the short half-life, it is possible for heroin abusers to have morphine present in the urine, but not 6-AM. Conversely, there are some patients who may have 6-AM in the urine with little or no morphine present.21 It has been suggested that the illicit use of heroin by pain management patients could go undetected in approximately 23% of cases given current federal guidelines for heroin abuse detection,21 which state that the urine should be tested for the presence of 6-AM if the morphine concentration is greater than or equal to 2000 ng/mL.22 The more common metabolites of the opiates/opioids can be seen in Table 3-6. When providing consultations, it is imperative to be able to explain the metabolic pathways and metabolites.

Alternate Specimens and Issues
Occasionally a request may be received to use a biological specimen other than urine for testing. The drugs discussed in this book are measured in other specimens, such as blood, oral fluid, sweat, hair, and nails, but these should be used with an understanding of their limitations. The shortest windows of detection are seen with blood and oral fluid. As discussed previously, blood is not an optimal sample because many of the drugs for which testing is performed in the pain management setting have short half-lives and may be difficult to detect. Although the use of oral fluid as a specimen has gained favor recently, the pharmacokinetic profile for many of the drugs in this matrix parallel that of the drugs in blood. Sweat has been used primarily for monitoring abstinence, not compliance. The longest windows of detection can be seen using hair and nails, and although these have been used to detect use of a drug, neither is a good matrix for monitoring issues of compliance.

One of the few scenarios in which blood or oral fluid may be useful is in the testing of the patient with poor renal function. Another type of case in which serum measurements have been useful is that of the patient receiving fentanyl via a patch who has unexpectedly low fentanyl concentrations upon confirmation and who states that a new patch is needed more frequently than expected. A serum measurement at the end of the dosing cycle just before application of a new patch could confirm the patient’s report.

Summary and Conclusions
The expansion of pain management in the United States has increased the demand for urine drug testing and opened new opportunities for the clinical laboratories performing the testing, as well as for the pathologist and laboratory professional who may be called upon to provide expertise in the utilization of the tests and in interpretation of the results. To most effectively provide these services, the pathologist must couple a solid knowledge of the drugs’ pharmacokinetic and metabolic pathways with an understanding of the analytical methods.

*The 25 references provided at the end of this chapter are published in their entirety in this issue. None of the references were published in the December issue with the first part of this chapter.


1. Trescot AM, Helm S, Hansen H, et al. Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians’ (ASIPP) guidelines. Pain Physician. 2008;11:S5–S62.
2. Dubois MY, Gallagher RM, Lippe PM. Pain medicine position paper. Pain Med. 2009;10:972–1000.
3. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain?: a review. Clin J Pain. 1997;13:116–137.
4. Cone EJ, Caplan YH, Black DL, Robert T, Moser F. Urine drug testing of chronic pain patients: licit and illicit drug patterns. J Anal Toxicol. 2008;32:530–543.
5. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10:113–130.
6. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Validity of self-reported drug use in chronic pain patients. Clin J Pain. 1999;15:184–191.
7. Katz NP, Sherburne S, Beach M, et al. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth Analg. 2003;97:1097–1102.
8. Manchikanti L, Damron KS, McManus CD, Barnhill RC. Patterns of illicit drug use and opioid abuse in patients with chronic pain at initial evaluation: a prospective, observational study. Pain Physician. 2004;7:431–437.
9. Manchikanti L, Manchukonda R, Pampati V, et al. Does random urine drug testing reduce illicit drug use in chronic pain patients receiving opioids? Pain Physician. 2006;9:123–129.
10. Ives TJ, Chelminski PR, Hammett-Stabler CA, et al. Predictors of opioid misuse in patients with chronic pain: a prospective cohort study. BMC Health Serv Res. 2006;6:46.
11. Jung B, Reidenberg MM. Physicians being deceived. Pain Med. 2007;8:433–437.
12. Michna E, Jamison RN, Pham LD, et al. Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings. Clin J Pain. 2007;23:173–179.
13. Melanson S, Baskin L, Magnani BJ, Kwong TC, Dizon A, Wu A. Interpretation and utility of drug of abuse immunoassays: lessons from laboratory drug testing surveys. Arch Pathol Lab Med. 2010:134:735–739.
14. Ortho Clinical Instructions for Use: Opiates. Version 5.0, publication #J27320 [package insert]. Rochester, NY: Ortho Clinical Diagnostics; 2008.
15. Reisfield GM, Webb FJ, Bertholf RL, Sloan PA, Wilson GR. Family physicians’ proficiency in urine drug test interpretation. J Opioid Manag. 2007;3:333–337.
16. CPT 2011. Professional edition (CPT/Current Procedural Terminology). Chicago, IL: American Medical Association; 2010.
17. Cone EJ, Caplan YH, Moser F, Robert T, Black D. Evidence that morphine is metabolized to hydromorphone but not to oxymorphone. J Anal Toxicol. 2008;32:319–323.
18. Reisfield GM, Chronister CW, Goldberger BA, Bertholf RL. Unexpected urine drug testing results in a hospice patient on high-dose morphine therapy. Clin Chem. 2009:55;1765–1768.
19. Wasan AD, Michna E, Janfaza D, et al. Interpreting urine drug tests: prevalence of morphine metabolism to hydromorphone in chronic pain patients treated with morphine. Pain Med. 2008;9:918–923.
20. Rook EJ, Huitema AD, van den Brink W, et al. Pharmacokinetics and pharmacokinetic variability of heroin and its metabolites: review of the literature. Curr Clin Pharmacol. 2006;1:109–118.
21. Crews B, Mikel C, Latyshev S, et al. 6-Acetylmorphine detected in the absence of morphine in pain management patients. Ther Drug Monit. 2009;31:749–752.
22. Substance Abuse and Mental Health Services Administration, Department of Health and Human Services. Mandatory guidelines for federal workplace drug testing programs: Section 2.4. Laboratory analysis procedures (f) (1) Confirmatory drug test. Fed Reg. 2004;69(71):19659.
23. Substance Abuse and Mental Health Services Administration, Department of Health and Human Services. Mandatory guidelines for federal workplace drug testing programs. Fed Reg. 2008;73(228):71857–71907. Accessed February 2010.
24. Substance Abuse and Mental Health Services Administration, Department of Health and Human Services. Mandatory guidelines for federal workplace drug testing programs. Fed Reg. 2004;69(71):19644–19673. Accessed August 3, 2011.
25. Smith ML, Hughes RO, Levine B, Dickerson S, Darwin WD, Cone EJ. Forensic drug testing for opiates, VI: urine testing for hydromorphone, hydrocodone, oxymorphone, and oxycodone with commercial opiate immunoassays and gas chromatography-mass spectrometry. J Anal Toxicol. 1995;19:18–26.

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, a former chair of and 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.