The Lab’s Role in Monitoring Pain Medication

Approximately 30% of the US population (~100 million people) are affected by chronic pain.1,2 Those who seek help may receive drug therapy for their condition that consists of either NSAIDs or of narcotic analgesics according to the WHO 3-step analgesic protocol3.

The most commonly used narcotic analgesics are the opiates (natural or modified compounds of the poppy plant) or opioids (synthetic chemicals that act on opiate receptors). While opiates and opioids are excellent analgesics, they can also have significant side effects that include respiratory depression and coma leading to death.

Tolerance, physical dependence and addiction (psychological dependence) are other severe side effects of opioid use. Tolerance and physical dependence, when they develop, will require successively higher doses of the drug to achieve the desired analgesic effect.

Addiction, on the other hand, is characterized by drug-seeking behavior that can lead to criminal activity to obtain the drug. Additional signs of addiction are dysfunctional opioid use and the concurrent use of more than one narcotics, including illicit ones.

Finally, tolerance can also be lost if the opioid drug is discontinued even for a few days. Resuming treatment at the previously tolerated dose after a hiatus could lead to opioid overdose with occasional fatal outcome.

To prevent fatal drug overdose, monitor appropriate medication use and asses the possibility of addiction. Laboratory measurement of opioid drug concentration is necessary using appropriate laboratory methods. When we test for opiates we assess the patient’s compliance with prescription and we look for the presence of non-prescribed or illicit opioids.

Confirmed absence of the prescribed drug is interpreted as “diversion” or the illegal sale of prescription medication, while the presence of non-prescribed drugs may be a sign of addiction, and either one can lead to discharge from the treatment program. Compliance with treatment guidelines is only proven if the patient has the prescribed drug in his/her body while he/she does not have any non-prescribed narcotics on board.

Detection Obstacles
Several factors complicate accurate laboratory detection of opioids. The natural opiates (morphine and codeine) have somewhat similar chemical structures and can be modified chemically to gain semi-synthetic opiates (hydrocodone, hydromorphone, oxycodone, oxymorphone, naloxone) or can be converted into illegal narcotics (heroin). The patient may also receive synthetic opioids (fentanyl, meperidine, methadone, propoxyphene) that are chemically dissimilar to natural opiates. Metabolites of natural and semi-synthetic opiates may have the exact chemical structure as a different prescription medication, further complicating interpretation of results (Figure 1).

Urine Opiate Immunoassays
The most commonly used urine opiate immunoassays were developed to be used for workplace drug testing; therefore they are optimized to detect morphine and codeine, but they may also detect some of the semi-synthetic opiates. Those immunoassays that cross-react with semisynthetic opiates show variable sensitivity for those chemicals and their reactivity is brand dependent.

Unfortunately none of the “traditional” opiate immunoassays detect the synthetic opioids. Immunoassays are available for detection of synthetic opioids, but a comprehensive assessment of the patient’s compliance with prescription, and ruling out of illicit use of non-prescribed narcotics would require a panel of multiple immunoassays.

Another drawback of the urine opiate assays is that they don’t have the analytical sensitivity required for monitoring therapy. Workplace drug testing standards mandate either 2,000 ng/mL or 300 ng/mL cutoff concentrations but these are above what would be seen in urine of patients on low-dose medication. Urine is inherently suboptimal specimen for therapeutic drug monitoring because urine drug concentrations don’t correlate with serum or blood opiate concentrations although analgesic effect is closely related to blood or serum drug concentration. Urine testing, therefore, can’t provide information regarding how much of the drug is taken. Finally, adulteration of urine is easy to achieve if one wants to cover up signs of addiction.

Point-of-care devices are available for urine opiate testing but very little is known about the true sensitivity and cross-reactivity of these devices. As they are also dependent on antigen-antibody reactions, they have the basic limitations of automated immunoassays.

Mass Spectrometry
The optimal test for opioid measurement should be able to detect and identify the commonly prescribed natural and semi-synthetic opiates, the synthetic opioids and their metabolites. This test should have low analytic sensitivity to detect occasional use, too. The only technology available today to satisfy all these criteria are chromatography-based separation coupled with mass spectrometry detection.

Commonly applied systems use gas chromatography mass spectrometry (GC-MS), or high performance liquid chromatography (LC) coupled to tandem mass spectrometry (MSMS) or time of flight mass spectrometry (TOF). These techniques can be easily adapted to both urine and blood testing by using sample-specific extraction procedures. Because mass spectrometry based methods can simultaneously detect and quantitate parent drugs and metabolites they can also be used to detect adulteration of the specimen by uningested prescription drug, often used to hide drug diversion.

Laboratory Standards
The testing laboratory that performs opiate measurement must list each drug that is detected by its method and must provide the minimum detectable concentration for the parent drug and metabolites. Drugs that are not detected by the particular assay should be listed also. Negative results can only be accepted as true negative (and used as proof of diversion) if the analytic sensitivity for that drug is known.

The clinician who orders these tests must also demand the above information if he or she wants to be conscientious to his or her patients. A recently published practice guideline by Peppin et al. attempts to provide framework for ordering, analyzing and interpreting opioid test results.4

Similar standards must be adopted by clinicians and laboratories. A study by Levy et al. demonstrated that clinicians have difficulty interpreting pain medication results5; therefore laboratory personnel must be able to assist with interpretation of opiate results to prevent further harm to the patient.


  1. Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education: Relieving Pain in America, A Blueprint for Transforming Prevention, Care, Education and Research. The National Academies Press, 2011.
  2. National Centers for Health Statistics, Chartbook on Trends in the Health of Americans 2006, Special Feature: Pain.
  3. The management of chronic pain in patients with breast cancer. The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Canadian Society of Palliative Care Physicians. Canadian Association of Radiation Oncologists. CMAJ, 1998. 158 Suppl 3: p. S71-81.
  4. Peppin JF, et al., Recommendations for Urine Drug Monitoring as a Component of Opioid Therapy in the Treatment of Chronic Pain. Pain Med, 2012.
  5. Levy, S., et al., Drug testing of adolescents in ambulatory medicine: physician practices and knowledge. Arch Pediatr Adolesc Med, 2006. 160(2): p. 146-50.

Geza S. Bodor is professor of Pathology, University of Colorado Denver, section chief of Chemistry and Toxicology, Pathology and Laboratory Medicine, VA Eastern Colorado Health Care System, Denver.