Drugs-of-abuse testing and therapeutic-drug monitoring

March 1, 2011


here are two models of drug abuse testing — the forensic or legal model and the therapeutic model.
Drug-abuse screening originates from the forensics model and continues to be prevalent as a monitoring tool to identify illicit or criminal use of substances.
The second model — therapeutic drug testing — has evolved from forensics into a monitoring tool to help physicians ensure safety, proper care, and best treatment options for their patients.

Forensics model

Drug-abuse testing was originally implemented using a forensics model. Law-enforcement and criminal-justice constituents are concerned with the detection of illegal or banned drug use. Examples of forensic drug-abuse screening include court-mandated drug testing; law-enforcement drug testing to determine if drugs of abuse were contributing factors in an accident or the commission of a crime; and in the criminal-justice system both drug-abuse screening in the prison environment, and to meet parole and probation requirements.

From the forensics model, drug-abuse testing traditionally refers to the practice of testing for the illicit drugs commonly known as the NIDA Five.1 NIDA, or the National Institute of Drug Abuse, lists these drugs or drug classes as 1) amphetamines (methamphetamine), 2) cocaine, 3) marijuana (THC), 4) opiates (morphine), and 5) phencyclidine (PCP).

Over the years, the forensic model of drug-abuse testing has expanded beyond the legal and criminal-justice system to industry in the form of workplace testing for drugs of abuse, to sports/athletic screening, to the military, and to schools. In all of these arenas, the forensic model, usually urine drug testing (UDT), is concerned with identifying individuals who are taking illicit drugs or non-prescribed medications.

Therapeutic model

The second UDT model is therapeutic. The goal of therapeutic UDT is to help physicians provide the best treatment to their patients by monitoring the presence of substances in their bodies. The primary difference between the forensics model and the therapeutic model is the expectation of a positive (therapeutic) vs. negative (forensic) result. As such, therapeutic UDT must use more specific methods to provide confirmations of drug presence at extremely low levels. The therapeutic model seeks to identify drugs rather than prove their absence and is, therefore, uniquely utilitarian in the pain-management space.

Over the past 20 years, significant changes have occurred in 1) the recognition of pain as a condition that should be medically treated and 2) the medications available to physicians for its treatment.2,3 The primary drugs used for the treatment of pain are the opioids oxycodone, hydrocodone, and oxymorphone.2,3 In addition to pain control, these drugs induce euphoria and, therefore, are highly addictive. The number of prescriptions written for opioids has increased tenfold since 1990 and has similarly resulted in a tenfold increase in the number of deaths from these medications.4,5 Pain patients suffer from a complex disease and require compassionate care that includes the use of medications with abuse potential.6 Laboratories assist physicians who prescribe controlled substances for the treatment of pain and many patient comorbidities by providing confirmation of drugs used by their patients, potentially reducing patient danger.

Doctors treating pain patients use UDT to establish compliance with prescribed medications and to identify illicit drug use or the use of non-prescribed medications, as well as the use of alcohol.7,8 The risk of a patient becoming dependent on their medications is a major concern for pain physicians.6 This is compounded by the potential for morbidity due to abuse or misuse of the opioid medications, which can cause serious drug-drug interactions.2,3 These combined factors necessitate that pain physicians receive detailed and highly accurate information about the patients' use of licit and illicit drugs.9-11

Therapeutic-drug monitoring

When monitoring for opioid medication compliance, the testing method should be able to differentiate between codeine, morphine, hydrocodone, norhydrocodone, and hydromorphone. The test should also be able to differentiate between oxycodone, noroxycodone, and oxymorphone. This allows the physician to determine that the opiate the patient is taking is, in fact, the one being prescribed and that the patient is metabolizing the medication properly.9

Urine is the biological fluid of choice for drug-testing purposes because specimen collecting is non-invasive and large quantities are available for analysis. Oral fluid, however, is gaining in popularity for drug testing because sample collection can be easily monitored.12

Urine drug testing is most often carried out first by point-of-care (POC) devices (e.g., a CLIA-waived collection cup or strip) and by hospital laboratories.13 The tests designed for use in hospital laboratories are geared toward the emergency-medicine service, which is concerned with determining drug overdose. These tests detect classes of drugs such as opiates and benzodiazepines for which there are antidotes. The cutoffs used on these tests are set to detect high concentrations of abused drugs.14,15 These cutoffs are appropriate for emergency units, where the correlation between the patient's condition and the presence of high concentrations of drugs enable the treating physician to decide on the appropriate supportive care.

Because of the high cutoff levels, the POC devices and hospital laboratories do not adequately serve the physician treating chronic pain whose concerns are 1) whether the prescribed drug is present, not how much of it is there; 2) whether a non-prescribed drug is present, even in low quantities; and 3) whether any illicit drug is present, not necessarily in overdose quantities.15,16

Furthermore, POC devices utilize immunoassay test strips combined with a urine specimen cup and are sufficient to capture many of the usually prescribed drugs; however, they do not provide sufficient detail or accuracy to define which drugs in a drug class the patients are actually taking15; nor do they provide doctors with information about metabolism or concentration of drug in a patient's specimen.15 (Laboratory testing cannot determine patient compliance with drug dosage.) Reference laboratories provide the most extensive analysis available to physicians who treat pain and, therefore, many of them send a portion of the urine specimen taken for the POC, or in-office immunoassay, to a reference laboratory where mass-spectrometry techniques (e.g., liquid chromatography, mass spectrometry [LC-MS/MS]) are used.9,15 LC-MS/MS can accurately identify drugs within a drug class and can do so at very low concentrations.

Additionally, these analytical methods can quantify the amount of drug in a specimen. Of the two common analytical methods that employ mass spectrometry, LC-MS/MS is the preferred method over gas chromatography-mass spectrometry, or GC-MS). LC-MS/MS requires less sample volume, less preparation, and has fewer interferences.17 This quantification or confirmation of results is required to give the doctor confidence when counseling a patient.

A partial list of abused drugs include stimulants of the amphetamine class (MDMA, Ritalin, methamphetamine), sedative hypnotics (barbiturates) and psychotropic agents (Spice),18,19 and the classic abused drug, alcohol (ethanol).6 Because of the wide variety of abused drugs, physicians often have to make a best guess as to which of these drugs their patients are at risk of abusing. POCT devices or forensics laboratories may not be able to test for all of them.

A similar case can be made for the testing of benzodiazepines. The method should be able to detect at low concentrations and differentiate between alphahydroxalprazolam,7-aminoclonazepam, lorazepam, nordiazepam, temazepam, and oxazepam.14,16 This will allow the doctor to see that the patient is taking the prescribed benzodiazepine and allay any concerns about the patient's possible doctor shopping. The best way to accomplish this is by analyzing the urine specimens with mass spectrometry.


Given the widespread prevalence of drug use and abuse,20 there is a great need for laboratories to provide identification of prescribed, non-prescribed, and illicit drug use. While the forensics model of drug-abuse testing continues to help provide society protection from criminal behavior, the therapeutic model of drug screening is preferred in the healthcare setting as these laboratories can provide important information to physicians to aid in their diagnosis and help them better protect their patients.

Amadeo Pesce, PhD, D(ABCC), is a principal investigator at the Millennium Research Institute,
Laboratory Director at Millennium Laboratories and adjunct professor in the Department of Pathology and Laboratory Medicine at the University of California-San Diego School of Medicine.
Cameron West, PhD, is a researcher at the Millennium Research Institute and a New York Times best-selling author.


  1. Federal Register – Mandatory Guidelines and Proposed Revisions to Mandatory Guidelines for Federal Workplace Drug Testing Programs. Substance Abuse and Mental Health Services Administration. Rockville, MD: Department of Health and Human Services. 2004;69(71).
  2. Trescot AM, Boswell MV, Atluri SL, Hansen HC, et al. Opioid guidelines in the management of chronic non-cancer pain. Pain Physician. 2006;9(1):1-40.
  3. Chou R, Fanciullo GJ, Fine PG, Adler JA, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.
  4. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med. 2010;363(21):1981-1985.
  5. Kuehn BM. Opioid prescriptions soar: Increase in legitimate use as well as abuse. JAMA. 2007;297(3):249-251.
  6. Webster LR, Dove B. Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners. North Branch, MN: Sunrise River Press, 2007.
  7. Michna E, Jamison RN, Pham LD, Ross EL, et al. Urine toxicology screening among chronic pain patients on opioid therapy: Frequency and predictability of abnormal findings. Clin J Pain. 2007;23(2):173-179.
  8. Harmful interactions: Mixing alcohol with medicines. National Institute on Alcohol Abuse and Alcoholism. Bethesda, MD: National Institutes of Health, 2007.
  9. Cone EJ, Caplan YH, Black DL, Robert T, et al. Urine drug testing of chronic pain patients: Licit and illicit drug patterns. J Anal Toxicol. 2008;32(8):530-543.
  10. Crews B, Latyshev S, Mikel C, Almazan P, et al. Improved detection of ethyl glucuronide and ethyl sulfate in a pain management population using high-throughput LC-MS/MS. J Opioid Manag. 2011;submitted.
  11. Crews B, West R, Gutierrez R, Latyshev S, et al. An improved method of determining ethanol use in a chronic pain population. J Opioid Manag. 2011;in press.
  12. Cone EJ, Huestis MA. Interpretation of oral fluid tests for drugs of abuse. Ann N Y Acad Sci. 2007;1098(1):51-103.
  13. Amedica Drug Screen Test Cup. Hayward, CA: Amedica Biotech Inc.
  14. Mikel C, Almazan P, West R, Crews B, et al. LC-MS/MS extends the range of drug analysis in pain patients. Ther Drug Monit. 2009;31(6):746-748.
  15. Pesce A, Rosenthal M, West R, West C, et al. An evaluation of the diagnostic accuracy of liquid chromatography-tandem mass spectrometry versus immunoassay drug testing in pain patients. Pain Physician. 2010;13(3):273-281.
  16. West R, Pesce A, West C, Crews B, et al. Comparison of clonazepam compliance by measurement of urinary concentration by immunoassay and LC-MS/MS in pain management population. Pain Physician. 2010;13(1):71-78.
  17. Mikel C, Pesce A, West C. A tale of two drug testing technologies: GC-MS and LC-MS/MS. Pain Physician. 2010;13(1):91-92.
  18. Vardakou I, Pistos C, Spiliopoulou C. Spice drugs as a new trend: Mode of action, identification and legislation. Toxicol Lett. 2010;197(3):157-162.
  19. Sobolevsky T, Prasolov I, Rodchenkov G. Detection of JWH-018 metabolites in smoking mixture post-administration urine. Forensic Sci Int. 2010;200(1-3):141-147.
  20. National Survey on Drug Use and Health: Detailed Tables — Prevalence Estimates, Standard Errors, P Values, and Sample Sizes. Substance Abuse and Mental Health Services Administration. Rockville, MD: Department of Health and Human Services, 1995-2006.