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“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”

Paracelsus (1493-1541)

INTRODUCTION

 

Toxicology is a branch of biology, chemistry, and medicine (more specifically pharmacology), concerned with the study of the adverse effects of chemicals on living organisms. It also studies the harmful effects of chemical, biological and physical agents in biological systems that establishes the extent of damage in living organisms. The relationship between dose and its effects on the exposed organism is of high significance in toxicology. Factors that influence chemical toxicity include the dosage (and whether it is acute or chronic), the route of exposure, the species, age, sex, and environment.

There are two distinct disciplines in analytical toxicology concerned with human biological matrices, namely clinical and forensic toxicology. Both fields use similar analytical techniques designed to detect and quantify drugs, chemicals, and poisons in fluids or tissues. In clinical toxicology, analytical results help to specify the appropriate treatment of a poisoned or intoxicated patient. In forensic toxicology, the results often play a vital role in determining the possible impairment or behavioral changes in an individual, or the contribution of drugs or poisons to death in a medico-legal investigation.

Drug tests identify a chemical compound – a "drug" – in body fluids or tissues. A test is “positive” if the specific compound is present in the sample at a concentration at or above the cutoff for that compound. The identification of a drug in a drug test provides evidence of exposure to that drug. In many settings drug testing also includes alcohol testing.

Drugs of abuse are chemicals that produce specific effects in the user’s brain, particularly in the reward circuitry of the brain. In general, drugs of abuse either produce good feelings (positive reward) or relieve bad feelings (negative reward) within seconds to minutes after administration.

Drugs can be administered by many routes, including inhalation (breathing, smoking); nasal insufflation ("snorting"); oral (buccal or sublingual) absorption; oral ingestion; subcutaneous, intramuscular or intravenous injection; and, by transdermal, vaginal or rectal absorption.

Experienced drug users generally prefer routes of administration that produce the most rapidly rising brain concentrations of drugs, especially smoking, snorting and intravenous injection. While the specific circuits of brain reward are the targets of all drugs of abuse, drugs are distributed throughout the body and are metabolized into breakdown products (primarily by the liver), facilitating their elimination (mostly in urine and feces).

The drug metabolites may be present in biological matrices in higher concentrations and for longer periods of time than the parent drugs themselves, and thus, when they are analyzed in drug testing, can sometimes serve as specific and superior markers of drug use.

Drug tests do not detect drug use “in general.” Instead, drug tests identify specific drugs or drug classes as well as drug metabolites in biological matrices that are represented in particular test panels. Drugs can be identified in any matrix; the most common matrices for typical testing purposes include urine, blood, oral fluid, hair, nails, sweat and breath.

However, because of the distinctive physicochemical characteristics of each drug (and its metabolites), its concentration may vary greatly among these matrices. With the growing use of synthetic cannabinoids (e.g. “K2” or “spice”), synthetic cathinones (known as “bath salts”), and other novel compounds, drug testing has become even more challenging. The range of widely misused non-traditional drugs has dramatically increased in recent years, in part to evade detection by drug tests. These new synthetic drugs are commonly called "designer drugs" because they are designed to produce psychoactive effects similar to compounds familiar to drug users and to also elude drug tests and drug laws.

FORENSIC VS. CLINICAL DRUG TESTING

 

In forensic drug testing, safeguards are in place so that every result can stand up to legal challenges. False positives are a serious concern so properly constructed forensic testing programs are designed to virtually eliminate such results.

Standards for federally-mandated workplace forensic testing address specimen chains of custody, split specimens, confirmation of all presumptive positive or non-negative test results in laboratories certified by the Department of Health and Human Services (DHHS)/Substance Abuse and Mental Health Services Administration (SAMHSA), review of test results by a Medical Review Officer, as well as other issues.

Unlike forensic drug testing where the test results must be able to meet rules of evidence in administrative, civil or criminal proceedings, clinical drug testing is part of a patient examination performed by a clinician with whom the patient is in a therapeutic relationship.

Clinical testing is used for the purposes of diagnosis, treatment, and the promotion of long-term recovery. Clinical drug test results must meet the established standards of medical practice and benefit the therapeutic relationship, rather than meeting the formal legal requirements of forensic testing.

Drug testing in medicine employs the same sound procedures, safeguards, and systems of information management that are used for all other health-related laboratory tests, tests on which life-and death medical decisions are commonly made.

The majority of drug testing done today includes elements of forensic and clinical drug testing. For example, one might assume that drug testing of individuals on probation or parole in the criminal justice system is performed according to the requirements of forensic testing; however, this drug testing does not follow the rigorous federal standards for workplace drug testing programs and is not forensic in nature.

The most important challenge in drug testing today is not the identification of every drug that we are technologically capable of detecting, but to do medically necessary and accurate testing for those drugs that are most likely to impact clinical decisions.

Choices of technology should be based on the clinical situation and patient risk. Cost must also be considered in the choice of drug testing in balance with the clinical goals for each patient.

THE EVOLUTION OF DRUG TESTING

 

The contemporary history of drug testing can be divided into three overlapping generations of technology, the details of which are described below.

The history of drug testing in the United States provides a useful background for understanding how drug testing is conducted today and the future opportunities for drug testing.

Drug testing was first widely used in the U.S. in the 1950’s in hospital emergency rooms in order to rapidly diagnose and guide the treatment of patients who had overdosed. Testing was also important in death investigations. In cases of poisoning, the testing was appropriately referred to as toxicology testing (thus, the phrase “tox screens”).

Most of this early drug testing used blood as the testing matrix. Not until the 1960’s, with the development of thin layer chromatography, did testing for drugs of abuse in urine become feasible in large populations.

In the 1970’s, the development of sensitive and automated immunoassay (IA) technologies conducted in laboratories permitted large scale urine drug testing in addiction treatment and in the criminal justice system. IA technology is widely used today in some circumstances as a stand-alone technique either through laboratory or point-of-collection (POC) options. Immunoassay methodologies were the first drug testing technology to be automated, permitting high volume testing and lower costs per test.

Particularly, in addiction treatment and corrections settings, further analysis or “confirmation” of presumptive positive IA test results was seldom performed because the pre-test probability of positive results was usually high, tests were performed serially, and severe consequences generally did not ensue as a result of a single positive test.

In the 1970’s, drug testing became routine in methadone maintenance treatment (MMT), provided by opioid treatment programs (OTP). Drug testing validated a program's success in reducing opioid and other nonmedical drug use. The rate of negative drug test results, a marker for cessation of drug use, became a central quality measure in assessing treatment outcomes in methadone-based OTP’s developed under the regulatory authority of the Food and Drug Administration (FDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), and Drug Enforcement Administration (DEA).

The second generation of drug testing, IA testing with presumptive positive results confirmed by gas chromatography-mass spectrometry (GC-MS), was introduced in the military in the early 1980’s and shortly thereafter adopted by private industry, the federal government, and federally regulated industries (e.g. commercial drivers). Workplace drug testing remains the most widespread model for forensic drug testing.

In the 1980’s, in the context of the cocaine epidemic in the U.S., drug testing became widespread in the civilian workforce to discourage drug use that could impair workforce productivity and safety.

The introduction of drug testing into the workplace produced controversy over privacy issues, leading to two Supreme Court decisions. The controversy was intense because the consequence of a single confirmed positive test was often termination or denial of employment.

Prescribed controlled substances were becoming increasingly common in the workplace and thus, needed to be addressed in order to balance legitimate medical treatment with workplace safety concerns.

These challenges led to mandatory federal workplace drug testing guidelines enforced by explicit action of the U.S. Congress for interstate truck drivers regulated by the federal Department of Transportation (DOT) under 49 CFR Part 40 in the Code of Federal Regulations.

These guidelines specified every aspect of drug testing, including 1) the panel of five drugs (or drug classes) to be tested (the “SAMHSA-5”), 2) the confirmation of all presumptive positive IA results with highly specific and sensitive GC-MS testing, and 3) the use of Medical Review Officers (MRO) to evaluate all confirmed positive test results.

Clinicians hoping to use drug testing in health care were sometimes frustrated because commercial laboratories oftentimes steered them to the very limited testing panel employed by the Department of Transportation.

In the first decade of the 21st century, drug testing became increasingly widespread in highway safety, as drug testing was added to alcohol testing for drivers arrested for being impaired and drivers involved in serious and fatal accidents. Promoting the increased use of drug testing now is part of a new national effort, led by the Office of National Drug Control Policy and the Department of Transportation.

Within the past decade an additional confirmation testing option has become available, liquid chromatography-mass spectrometry (LC-MS) or tandem mass-spectrometry (LC-MS/MS). LC-MS/MS is increasingly utilized as an alternative to GC-MS to identify specific drugs or metabolites that are present in a specimen through a POC or laboratory IA test. GC-MS and LC-MS/MS tests "confirm" drugs that were identified on the initial IA test, and are newly referred to as “definitive” tests by LC-MS.

Testing for drugs of abuse in medical practice today is rapidly increasing in the area of pain management because the increased use of opioids to treat chronic pain is paralleled by increases in opioid and other drug diversion, as well as morbidity and mortality related to the misuse of these drugs. The problem of prescription drug abuse and resulting overdose deaths was labeled an "epidemic" by the U.S. Centers for Disease Control and Prevention.

The relatively recent dramatic rise in the misuse and diversion of prescription medications, as well as in rates of addiction and overdose deaths, prompted increases in drug testing, which are now spreading into other areas of medicine outside addiction treatment and pain management.

DRUG METABOLISM

 

Drug metabolism is the chemical alteration of a drug by the body. See also, “Appendix A: Drugs and their Metabolites.”

The substances that result from metabolism (metabolites) may be inactive, or they may be similar to the original drug in therapeutic activity or toxicity.

Some medications, called prodrugs, are administered in an inactive form, which is metabolized into an active form. The resulting active metabolites produce the desired therapeutic effects. Metabolites may also be metabolized further instead of being excreted from the body. However, subsequent metabolites are then excreted. Excretion involves elimination of the drug from the body, for example, in the urine or bile.

Most drugs pass through the liver, which is frequently the primary site for drug metabolism. Once in the liver, enzymes convert prodrugs to active metabolites or convert active drugs to inactive forms. The liver’s primary mechanism for metabolizing drugs is via a specific group of cytochrome enzymes. The level of these cytochrome enzymes controls the rate at which many drugs are metabolized, and differs from patient to patient.

The capacity of the enzymes to metabolize is limited, so they can become overloaded when blood levels of a drug are high. Many substances such as drugs and foods, affect the cytochrome enzymes. If these substances decrease the ability of the enzymes to break down a drug, then that drug's effects (including side effects) are increased. If the substances increase the ability of the enzymes to break down a drug, then that drug's effects are decreased.

Because metabolic enzyme systems are only partially developed at birth, newborns have difficulty metabolizing certain drugs. As people age, enzymatic activity decreases, so that older people, like newborns, cannot metabolize drugs as well as younger adults and children do. Consequently, newborns and older people often need smaller doses per pound of body weight than do young or middle-aged adults.

CLINICAL IMPLICATIONS OF METABOLIC PATHWAYS

Most opioids are metabolized via CYP-mediated oxidation and have substantial drug interaction potential.

The exceptions are morphine, hydromorphone, and oxymorphone, which undergo glucuronidation. In patients prescribed complicated treatment regimens, physicians may consider initiating treatment with an opioid that is not metabolized by the CYP system.

However, interactions between opioids that undergo CYP-mediated metabolism and other drugs involved with this pathway often can be addressed by careful dose adjustments, vigilant therapeutic drug monitoring, and prompt medication changes in the event of serious toxicity.

PRODUCTION OF ACTIVE METABOLITES

Some opioids produce multiple active metabolites after administration. Altered metabolism due to medical comorbidities, genetic factors, or drug-drug interactions may disrupt the balance of metabolites, thereby altering the efficacy and/or tolerability of the drug. Moreover, opioids that produce metabolites chemically identical to other opioid medications may complicate the interpretation of urine toxicology screening.

ADHERENCE MONITORING: THE IMPORTANCE OF ACTIVE METABOLITES

Opioids that produce active metabolites structurally identical to other opioid medications can complicate efforts to monitor patients to prevent abuse and diversion.

Thus, in a patient prescribed oxycodone, both oxycodone and oxymorphone metabolites will appear in urine toxicology results, but these results will not determine whether the patient took the prescribed oxycodone alone or also self-medicated with oxymorphone (Opana).

Patients treated with codeine will have both codeine and morphine in urine samples. If too much morphine is present, the patient may be taking heroin or ingesting morphine in addition to codeine. CYP2D6 rapid metabolizers may have an unusually high morphine-to-codeine ratio, making interpretation of the morphine-to-codeine ratio challenging. However, in patients taking only codeine, the codeine-to-morphine ratio is typically less than 6, even in rapid metabolizers. Additionally, morphine alone may be detectable in the urine 30 hours after ingestion of a single dose of codeine.

The urine of patients treated with morphine may contain small amounts of hydromorphone (≤2.5% of the morphine concentration). Similarly, those treated with hydrocodone may test positive for both hydrocodone and hydromorphone, making it difficult to determine whether the parent opioid was taken as prescribed or a second opioid is being abused.

Clinicians may find it easier to monitor patients for adherence and abuse if the opioid prescribed does not produce metabolites similar to other opioid medications. If abuse is suspected, choosing opioids such as fentanyl, hydromorphone, methadone, or oxymorphone may simplify monitoring.

Sometimes an inactive metabolite provides a more reliable test of adherence than does the parent opioid. Urinary concentrations of methadone depend not only on dose and metabolism but also on urine pH. In contrast, the concentration of an inactive metabolite of methadone (via N-demethylation), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, is unaffected by pH and is therefore preferable for assessing adherence to therapy.

POPULATION PHARMACOKINETICS

Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of a drug into, through, and out of the body--the time course of its absorption, bioavailability, distribution, metabolism, and excretion.

Opioid metabolism differs with individual opioids in populations stratified according to age, sex, and ethnicity among other environmental factors. Reduced clearance of morphine, codeine, fentanyl, and oxymorphone has been reported in older patients.

Oxycodone concentrations may be approximately 25% higher in women than in men after controlling for differences in body weight, making it important for physicians to consider the patient's sex when prescribing this opioid.

A BRIEF INTRODUCTION TO CLINICAL TOXICOLOGY

Chinese patients may have higher clearance and lower concentrations of morphine. Similarly, codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Morphine concentrations were shown to be reduced in Chinese patients treated with codeine, providing confirmation of altered morphine metabolism in this large population.

Altered opioid metabolism in ethnic populations is also a byproduct of allelic variants of the gene encoding CYP2D6, particularly in African populations.

Clearance Mechanisms for the Top 200 Drugs Prescribed in the United States Metabolism is a listed clearance mechanism for three quarters of the top 200 prescribed drugs in the United States. Whereas, glucuronidation is a clearance mechanism for approximately 1 in 10 drugs in the top 200.

APPENDIX A:

 

DRUGS AND THEIR METABOLITES TESTED FOR BY SWL

CITATIONS

 

Intro to the Toxicology Market

i. North America Toxicology Laboratories Market is Anticipated to Increase to US$ 198.2 Mn by 2022, Owing to Growing Demand for Toxicity Testing of Controlled Substances http://www.persistencemarketresearch.com/mediarelease/north-america-toxicology-laboratories-market.asp
ii. North America Market Study on Toxicology Laboratories: Increasing Usage of Toxicology Testing Services in Crime Investigation is Expected to Drive the Growth of Toxicology Laboratories http://www.persistencemarketresearch.com/market-research/north-america-toxicology-laboratories-market.asp
iii. Toxicology Laboratories Market: Global Industry Analysis and Forecast 2015 – 2021 http://www.persistencemarketresearch.com/market-research/toxicology-laboratories-market.asp
iv. Toxicology Laboratories Market: New Market Research Report https://www.medgadget.com/2017/05/toxicology-laboratories
v. Toxicology Laboratories: Market Research Report https://www.ibisworld.com/industry-trends/specialized-market--research-reports/life-sciences/laboratory-services/toxicology-laboratories.html

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