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9 Articles in Volume 6, Issue #2
Assessment and Treatment of Chronic Pain
Clinical Drug Testing for Pain Medicine
Epidural Indomethacin Alternative in Adult Onset Diabetics
Focus on Urine Drug Monitoring
Office-based Treatment of Opioid Physical Dependence
Oxycodone to Morphine Rotation
Pain Care at the End of Life
Tennant Blood Study—Summary Report
The Psychiatric Model of Treating Chronic Pain

Clinical Drug Testing for Pain Medicine

A Laboratory Perspective

The demand for clinical drug testing in the field of pain management has increased dramatically as clinicians, regulatory agencies and insurance payers seek objective measures to enhance and augment pharmacotherapy, monitor pharmacotherapeutic compliance, assess treatment efficacy, and identify individuals at risk following the use or misuse of illicit substances, prescription drugs, over the counter medications and herbals. Clinical Pharmacology/Toxicology is an evolving and complex discipline whereas many of the current methodologies were designed for non-clinical applications. As the demand for relevant, accurate, quantifiable, cost-effective technologies grows, the need to design, develop, validate, and perform assays that satisfy the requirements of clinicians must keep pace. In addition, the timely dissemination of scientifically sound information regarding laboratory science pertinent to the pain management field is essential.

Diagnostics are fundamental to western medicine and are an essential part of clinical decision making. The technologies that create and satisfy clinician and consumer demand must also be used intelligently to ensure a scientifically sound, clinically efficacious, and financially responsible healthcare system. Clinicians must have a sufficient understanding of, and have access to, the laboratory and its processes. Education at every level (College of American Pathologists, CAP; Clinical Laboratory Information Amendments, CLIA; Food and Drug Administration, FDA; Center for Medicare and Medicaid Services, CMS; Pain Associations; primary; and clinical medical education, etc.) is critical if we are to set realistic expectations and ensure proper utilization and interpretation of results and regulations.

The prevention, diagnosis, measurement, and the interventional and pharmacotherapeutic treatment of pain are difficult tasks. More specifically, the use of many pain medications can result in dependence, addiction, pseudoaddiction, tolerance, withdrawal, and over- or under-medication. Pain can be the result of a disease process, a disease itself, or the cause of other illness (e.g., depression, anxiety, etc.). Two essential elements common to these phenomena are the needs to identify and measure their critical aspects. These are the core functions of the medical laboratory. The methodical integration of laboratory medicine can lead to a diagnostic-based model for pain management, mental health and behavioral medicine (addiction medicine) and assist in improving patient care by objectifying outcomes.

Laboratory Objectives

The laboratory should strive to:

  • discover, develop, implement, standardize, and augment objective diagnostic procedures for the daily treatment of pain and its downstream effects (i.e., state-of-the-art analytical pharmacology/toxicology [drug testing], therapeutic drug management, quantitative analyses for chemistry, hematology, molecular diagnostics, virology, immunology, microbiology, [where appropriate], pharmacokinetic consulting, integrated training and technical support [access to pharmacologists, toxicologists, pharmacists, physicians, etc.],
  • develop and implement data systems that efficiently allow ordering, organizing, analyzing, reporting, billing, and archiving of every aspect of laboratory information, as well as assisting in data mining, bioinformatics applications, cost management, budgeting and patient trending,
  • assist in establishing scientific-based curricula for all educational programs pertinent to pain and addiction medicine, regulatory agencies, healthcare payers, and consumers,
  • build infrastructure for basic to clinical research and implement programs to obtain extramural funding, and
  • help establish the proper diagnostic criteria for objective outcome measurement (evidence-based medicine) and best-practice guidelines.

The type of drug testing used for the pain patient must satisfy many clinical and forensic requirements. Most importantly, the methodologies and their interpretations must always have the capacity to satisfy the clinical needs of the physician. There are many different analyses used for the isolation, identification, and quantification of drug substances. These procedures all have strengths and limitations and are certainly not equivalent. Historically, testing has been divided into two distinct categories: forensic (including workplace applications) and clinical testing. The first testing was performed using the more traditional techniques of chromatography and spectrometry. As the need for workplace testing increased and was driven by federal rules and regulations, rapid and inexpensive technologies became essential and so immunoassays became popular.

Immunoassays

Immunoassays are divided into clinical products (therapeutic drug monitoring/ TDM serum assays) and forensic (drugs of abuse/DAU urine assays). These distinct applications can differ in their design, technical capabilities and regulatory approval processes. Listed below are some fundamental general differences:

Therapeutic Drug Monitoring (TDM) Assays

  • TDM assays are designed to quantify a single analyte and/or parent drug and major metabolite in serum.
  • The therapeutic range is based upon many preclinical and clinical studies where the therapeutic level of compound necessary to produce the desired biological effect has been determined.
  • Dosing can be controlled by repeated peak and trough measurements and iterative adjustments to the frequency and amount of drug administered.
  • Performed in a fixed compartment model.

Drug of Abuse (DAU) Assays

  • DAU assays are designed to identify a single analyte and/or parent drug and metabolites, or congeners within a particular drug class in urine.
  • If quantifiable, they can be used to determine patient-specific drug elimination rates or trends following single/ intermittent usage, or steady state rates for compounds administered in a maintenance or chronic administration regimen if normalized for creatinine concentration.
  • They are not designed to measure specific, clinically relevant levels of drugs in urine.
  • They are performed in an open compartment model.

These differences can cause confusion, as these products can either adhere to very rigorous performance specifications or perform at minimal levels. The same can be said in general for chromatographic (e.g., thin layer chromatography, high pressure liquid chromatography, and gas chromatography) and coupled mass spectrometric techniques (e.g., gas/liquid chromatography/mass spectrometry).

Analytical Considerations

Minimally, for clinical purposes, the Analytical Reportable Range (ARR) and the Clinical Reportable Range (CRR) should overlap in the linear portion of the assays response curves and the assays should adhere to standards regarding accuracy, reproducibility, sensitivity, and selectivity.

In addition to multiple technical considerations during these analytical procedures, there are numerous factors that influence the absorption, distribution, metabolism and elimination of a drug including:

  • Route and rate of distribution
    - Membrane permeability
    - Blood perfusion of organs and tissues
  • Extent of Distribution
    ionizable molecules)
    - Plasma protein binding
    - Intracellular binding
  • Drug-Drug Interactions, Drug/Food-Herbal Interactions
  • Cytochrome P450 inhibitors and inducers, enzyme deficiencies or upregulation, multiple genes, polymorphisms
  • Enterohepatic Recycling
  • Renal and Hepatic function
  • Disease States
  • Body Weight, Surface Area, and Muscle Mass
  • Cardiac Output
  • Age

Therefore measurements from urine regarding the amount of drug and metabolite(s) and the time of their detection, should not be used to extrapolate backward and make specific determinations regarding proper dosing or, in some cases, the identity of the drug ingested. Software and laboratory products that have not been fully scientifcally validated and/or examined by agencies—including the FDA, CAP, CLIA, among other regulatory bodies—regarding all aspects of their functions and usage, may possibly put clinicians and patients at risk.

There is much information inherent in these assay results and their correct interpretation is critical. Since each patient is unique, the results and the testing regiment should be handled in the same patient-specific manner. Drug testing in this setting should be more appropriately performed as a clinical pharmacological assessment and in the context of pharmacotherapeutic management. The pharmacokinetic properties of the compounds of interest should dictate how the tests are to be performed and the results utilized. Therefore it is essential the laboratory have trained staff (e.g., Pharmacologist, Pharmacist, and PharmD) available for technical and clinical pharmacokinetic consultation and training. A new paradigm is emerging that addresses the specific testing of drug substance and that may identify proper adherence, abuse, or misuse. Both laboratorian and physician should be aware of each other’s capabilities and limitations if the patient is to be served efficiently and efficaciously.

Laboratory Documentation and Regulation

A major part of the diagnostic process involves the correct ordering, billing, and reporting of these tests. Laboratories are heavily regulated by national certifying agencies including CAP and CLIA, in addition to state and local agencies. They also are under the scrutiny of the Office of the Inspector General and can be audited by any of their payers including the CMS and any commercial or managed care agency. In addition, laboratories must perform and document daily quality control, regular proficiency testing, and have in place detailed Standard Operating Procedures for every aspect of their operations including an internal compliance committee.

Drug testing is a very specialized part of laboratory science and advances and new applications in technology are overwhelming the regulatory system. The need for the new and improved technology is greater than the system’s response capabilities. Therefore it is imperative that new inspection standards be put into effect, regulatory agencies must be responsive, current, and qualified. Laboratory personnel must be appropriately educated, trained, and certified. As the discipline of pain medicine evolves, it must include expert laboratory science and scientists.

The laboratory is held accountable for issues involving medical necessity, ordering procedures, and reimbursement. These are very complicated, multifactorial situations that need to be standardized and implemented as the demand for more and new assays continues. There must be an efficient, fair, and functioning reimbursement system that can create new and upgraded CPT codes as technology improves and the cost of analyses increases. The system must deliver payment in a timely fashion and audit appropriately and fairly.

It is clear that there is much work to do as the field of pain medicine evolves. Creating a system where the stakeholders can integrate and access information is vital during this evolution. Such stakeholders include:
· patients,
· treatment facilities,
· mental health clinics,
· payers (i.e., Medicaid, Medicare, state and county agencies, commercial carriers, worker’s compensation programs, etc.),
· Physicians (i.e., Pain Management specialists, Physicians prescribing pain medications, psychiatrists, Addiction Medicine physicians, Primary Care Networks, etc.)
· Pain Management Clinics and Associations,
· Educational facilities (i.e., Medical schools, universities, certification and accreditation programs, etc.)
· nurses,
· legal system,
· pharmaceutical companies,
· regulatory agencies,
· pharmacies, and
· pharmacy benefits management groups

The healthcare delivery system must have access to scientifically sound information, and research must be expedited regarding the basic biochemical, neurophysiological, and genetic mechanisms of pain. A current and continually expanding complement of pertinent diagnostics (e.g., clinical drug testing, pharmacokinetic interpretation, biomarkers for pain, neurophysiological testing, pharmacogenetic, and genomics, etc.) needs to be available. We must have quality control measures that identify the least and greatest possibility for error and minimize them. There must be an adequate understanding of laboratory procedures to ensure protection for the patient and the physician regarding the legitimate prescription and usage of opiates and other misused drugs when punitive and medical issues overlap. The development of CME programs and best practice guidelines must be developed that are accessible and instruct how to incorporate laboratory science practically into everyday medical practice is in progress.

Summary

The role of the healthcare system is to prevent, identify, and treat illness and drug testing should be used to augment pharmacotherapeutic treatment. Prescribing drugs to patients who need them and protecting a physicians’ practice need not be divergent issues. Sound monitoring, patient documentation, and complying with state and federal legal guidelines are essential. The discipline of Pain Medicine is growing rapidly and treating pain is complicated and technically challenging. The integration of every aspect of the healthcare system is necessary to ensure patient safety, clinical efficacy, fiscal responsibility, expediency, accuracy, and ethicality.

Future Reports

This article is the first in a series of reports that will describe the current state-of-the-art regarding laboratory science and examine the scientific and regulatory issues affecting clinical laboratories. The reports to follow will examine, in some detail, the current state of laboratory tools available to the Pain Medicine field, and the need to develop sound clinical diagnostics, including software, that address pertinent pharmacological issues that may drive the discovery, development and implementation of the next generation of diagnostic tools to assist in practical pain management. The reports will focus on diagnostics pertinent to the pain management field, including an overview of:

  1. current testing methodologies for detecting and identifying drugs (i.e.,colorometric, fluorometric chromatographic, spectrometric, etc.),
  2. Specimen processing, regulatory, legal and validation issues in laboratory medicine,
  3. pharmacokinetic principles as they relate to diagnostics issues (i.e., absorption, distribution, metabolism and excretion of drug substance),
  4. profiles of the different pain medications with pertinent information regarding testing for these compounds and their metabolic profiles,
  5. clinical issues that can be augmented by thorough tiered clinical pharmacological/toxicological analyses,
  6. future directions in the development and incorporation of existing and emerging technologies (e.g., lc/ms/ms, pharmacogenetics, biomarkers, point-of-care testing, etc.), and
  7. the need for a process and guidelines regarding the diagnostic needs of the pain management field.
Last updated on: January 26, 2012
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