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13 Articles in Volume 11, Issue #4
Diagnosing and Managing Hand Osteoarthritis
Difficult Migraine Patient
Electromagnetic Applications In Biology and Medicine
Excerpt from the Book Avoiding Opioid Abuse While Managing Pain
Hormone Therapies: Newest Advance in Pain Care
Make the Family Your Best Friend
Medications for Chronic Pain—Opioid Analgesics
Nonpharmacologic Remedies for Back Pain During Pregnancy
Reconsidering and Revising Evidence-Based Practice in Pain Medicine: Steps Toward Sustaining the Profession?
The Value of Blood Analysis for Compliance Monitoring
Treatment of Neuropathic Pain: The Role of Unique Opioid Agents
Understanding Potential Complications Of Epidural Steroid Injections
Unmasking Post-traumatic Headache

The Value of Blood Analysis for Compliance Monitoring

Obtaining opioid blood concentrations can help clinicians document medication compliance and opioid tolerance.
Editor's Note: I and other Board Members of Practical Pain Management have long believed in the clinical value of urine and blood testing. While the value of urine testing for compliance is now well known, the same is not true for blood testing. Although urine testing remains the standard for abuse and compliance monitoring, there are occasions and situations wherein blood testing should be done. To this end, I asked the toxicologists at AIT Laboratories to prepare this article as this laboratory has been one of the pioneers in opioid blood testing in pain patients. Practical Pain Management recognizes financial interest and wishes to always disclose it, but there are instances in which a pecuniary interest may also produce the best science. This paper represents such an intersection.

In the field of compliance monitoring, blood testing offers an effective means for providing physicians with information that is not available through urine drug testing (UDT).1 UDT is still the mainstay for identifying illicit or nonprescribed drug use for many reasons2,3 and is ideal for establishing recent drug exposure; however, it provides no information regarding the ingested dose.

Although this is not an issue for illicit or nonprescribed drugs, estimating the dose of prescribed medications may mitigate the risks associated with diversion and “doctor shopping.” In this regard, blood testing provides several advantages not possible with urine testing. Only by obtaining a steady-state (SS) blood concentration is a healthcare provider able to evaluate whether medication is being taken in accordance with the prescribed regimen. Routine blood testing also provides the physician with a documented SS blood concentration—a crucial piece of information for patients taking moderate- to high-dose opioids that can protect not only the prescriber but also patients and their families.

Table 1. Attributes of Urine Testing

Advantages of UDT

Urine is the most common biological fluid for determining recent drug use and offers several distinct advantages over blood for this purpose (see Table 1). Because of the concentrating ability of the kidneys, urine drug concentrations are typically much higher than those in corresponding blood (serum) samples. Higher urinary drug concentrations afford a longer window of detection than blood, thus increasing the probability of detecting substances ingested in the days just prior to collection.2,3 This is a crucial advantage of urine, as many drugs only remain detectable in blood for several hours, thus narrowing the window of opportunity for detecting noncompliant drug use. Analy-

tical advantages of urine include ease in obtaining larger specimen volumes and simple extraction and/or analysis technique, as urine is devoid of protein and cellular constituents.

Table 2. Reasons to Test Patients Taking High-dose Opioids

Limitations of UDT

Utilizing urine for compliance monitoring offers several distinct advantages, yet there are also key limitations regarding its use. For instance, urine toxicology results cannot provide evidence of therapeutic effect and cannot be used to estimate dose. Multiple variables associated with drug disposition in the body, such as pharmacogenetics, metabolism, absorption and elimination rates, urinary pH, state of hydration, drug formulation, and coadministered medications, induce highly variable drug/metabolite concentrations from a given dose. Simply put, the presence of a drug in the urine only indicates use in recent days.

This limitation does not present a significant problem when illicit or nonprescribed drugs are detected, as dose estimation of these substances most often is not required. Providers primarily wish to establish whether or not these drugs have been used. Thus, the benefit of the longer detection window afforded by urine is crucial. Recently, however, the inability to correlate urine drug concentrations with a dose of prescribed medication has become a commonly encountered frustration for healthcare providers.

Certain patients choose to divert some of their medication or obtain additional prescriptions from multiple providers. As long as such patients have taken a dose of their prescription medication in recent days, their urine will likely test positive for the appropriate drug and/or metabolite. Consequently, compliance will be assumed based on the positive urine specimen, when in fact patients may not have taken their medication in accordance with the caregiver’s instructions. This enables patients to undermedicate, divert the majority of their medication, and still test positive because of the extended period of time that drugs and their metabolites remain in the urine following ingestion.

This also enables patients to overmedicate by obtaining multiple prescriptions from different providers. In such cases, patients will almost certainly test positive for appreciable amounts of the appropriate drug and/or metabolite, and the urine test alone will provide no indication that the patient may be taking more medication than indicated. It is in these instances when the lack of dosing information from urine means that noncompliance will go undetected. In light of this, many physicians wish to evaluate patient compliance with respect to the prescription medication in addition to illicit drugs or nonprescribed pharmaceuticals.

Thus, although urine will continue to be the matrix of choice when the primary concern is illicit or nonprescribed drug use, if the primary concern involves how the prescription medication is being taken, physicians should perform routine blood analysis.

Blood Testing: An Effective Tool

Unlike urine testing, blood testing provides pivotal information pertaining to how a medication is being taken (see Table 2). The theoretical application of blood analysis for compliance monitoring is simple: Patients taking daily doses of opioids for the treatment of pain should have SS blood concentrations that reflect the ingested dose. Patients taking infrequent doses to pass a urine drug test will have blood concentrations below their expected SS range. Patients obtaining additional medication and taking more than prescribed will have blood concentrations above their expected SS range.

The pharmacokinetic equations used in calculating SS concentration ranges are available in multiple publications and text references and require know-

ledge of the relevant pharmacokinetic parameters for a given drug. At a minimum, the specific information that ties the calculation to an individual is the patient’s weight, dose, and dose frequency; however, other more complex calculations may require the patient’s age, gender, and possibly a list of any coadministered medications.

Other required information, derived from clinical investigations, includes pharmacokinetic parameters, such as the drug’s volume of distribution, rates of absorption and elimination, and time to peak concentration. Obviously, these parameters vary between individuals; thus, it is appropriate to apply the broadest possible ranges in order to optimize fair treatment of patients. These calculations are complex and may require consultation with a qualified professional, such as a toxicologist or pharmacologist.

Testing Tolerant Pain Patients

In the case of tolerant pain patients, routine blood testing to determine SS blood ranges may provide crucial information in the event of a patient’s unexpected death. Following repeated administration of opioid medications, receptors often become desensitized, and more medication may be needed to achieve the same clinical effect. Although this issue of tolerance is well understood in the medical community, it can complicate postmortem investigations. Tolerant pain patients are often able to function with opioid blood concentrations well above what is considered “therapeutic,” “toxic,” or even “lethal” in naïve, nontolerant patients. Therapeutic ranges are most commonly determined during clinical trials involving healthy patients taking low to moderate doses. Whereas these ranges may be appropriate for patients initiating opioid therapy, they do not necessarily apply to tolerant pain patients.

Unfortunately, the issue of tolerance may not always be considered in postmortem investigations, and elevated concentrations of opioids in postmortem specimens can be misleading when evaluating the cause of death. This is largely because postmortem blood concentrations are often evaluated with respect to “therapeutic ranges,” and elevated concentrations may indicate overdose.

Again, this may be an accurate assessment in a naïve, nontolerant patient. However, chronic pain patients who die for unforeseen reasons may have drug concentrations above what is considered therapeutic, even though their drug concentrations may be merely incidental to the cause of death.

The paucity of antemortem blood data in tolerant subjects on high doses of opioids makes it difficult for forensic investigators to evaluate postmortem drug concentrations.1 Ideally, tolerance should be evaluated in postmortem investigations by reviewing medical and prescription history along with antemortem drug concentrations when available. Physicians should consider periodically drawing blood on all patients who take opioids on a regular basis for the purpose of documenting tolerance and protecting themselves from possible investigation in the unfortunate event of a patient’s death.


Although urine testing is the standard for compliance monitoring, it has significant limitations in that it cannot indicate the presence of opioid tolerance or whether a patient is under- or overmedicating. Obtaining opioid blood concentrations for patients with pain will assist the practitioner in documenting clinical opioid tolerance, dose correlation, and potential comparison with postmortem blood concentrations. For these reasons, it would benefit healthcare providers to collect blood specimens every 6 to 12 months from any patient suffering from constant pain and requiring around-the-clock opioid administration.

Last updated on: September 13, 2011
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