The medical letter issue 1137

Published by The Medical Letter, Inc. • 1000 Main Street, New Rochelle, N.Y. 10801 • A Nonprofit Publication TESTS FOR DRUGS OF ABUSE
Testing for drug use has become increasingly common, not only in health care, but also in drug rehabilitation, in the military, at the workplace, after accidents and in the criminal jus- Performance-enhancing drugs such as anabolic steroids, growth hormone (Genotropin, and others) and erythropoietin (Procrit, Epogen) are not discussed here.
ASSAYS — Assays can be categorized as preliminary (initial) or confirmatory tests. Prel-
iminary tests include immunological assays such as radioimmunoassay (RIA), homogenous enzyme immunoassay (EMIT), fluorescence polarization immunoassay (FPIA) and enzyme- linked immunoassay (ELISA). These assays tend to be highly sensitive, but they may be less specific than confirmatory tests. Confirmatory tests include high performance liquid chroma- tography (HPLC) gas chromatography and mass spectrometry; a combination of chromatogra- phy and mass spectrometry is considered the "gold standard" for confirmatory testing.
SPECIMENS − Urine is used most often to test for drugs because it is obtained easily and
concentrations of drugs in urine are relatively high Ingesting large quantities of liquids, taking diuretics or adding water or household bleach to a urine specimen can mask illicit drug use. Blood is useful for quantitative determinations, but
many abused substances leave the blood relatively quickly. Where there is a well-accepted relationship between blood concentrations and pharmacological effect, as with ethanol, blood testing can be helpful. Saliva may be particularly useful for assessing drugs taken too recent-
ly to be detectable in urine. Testing procedures may affect saliva concentrations; saliva is usually slightly more acidic than plasma, but when stimulated to collect sufficient volume for a sample, it may become more basic, which can alter the saliva-to-plasma (S/P) ratio. Smok- ing or eating can contaminate a saliva sample. Breath testing is useful for volatile sub-
stances, especially alcohol, because urine alcohol levels do not correlate well with blood al- cohol levels, while breath alcohol does. Sweat patches worn for 7 days have been used to
monitor patients in the criminal justice system or in drug treatment facilities. Environmental contamination can lead to false-positive results Hair gives a better long-term measure (1-6 months) of substance abuse than
urine because drugs stored in hair remain there as the hair grows out. The concentration of drugs in hair varies with hair color, hair structure and growth rates. Shampoos, bleaches or dyes can alter drug concentrations in hair. Volatile drugs like marijuana may adhere to hair EDITOR: Mark Abramowicz, M.D. DEPUTY EDITOR: Gianna Zuccotti, M.D., M.P.H., Weill Medical College of Cornell University
CONSULTING EDITOR: Martin A. Rizack, M.D., Ph.D., Rockefeller University ASSOCIATE EDITORS: Donna Goodstein, Amy Faucard ASSISTANT EDITOR: Susie Wong
CONTRIBUTING EDITORS: Philip D. Hansten, Pharm. D., University of Washington; Neal H. Steigbigel, M.D., New York University School of Medicine
ADVISORY BOARD: William T. Beaver, M.D., Georgetown University School of Medicine; Jules Hirsch, M.D., Rockefeller University; James D. Kenney, M.D., Yale University
School of Medicine; Gerhard Levy, Pharm.D., State University of N.Y. at Buffalo; Gerald L. Mandell, M.D., University of Virginia School of Medicine; Hans Meinertz, M.D.,
University Hospital, Copenhagen; Dan M. Roden, M.D., Vanderbilt School of Medicine; F. Estelle R. Simons, M.D., University of Manitoba
EDITORIAL FELLOWS: Elizabeth Stephens, M.D., Oregon Health Sciences University School of Medicine; Arthur M.F. Yee, M.D., Ph.D., Cornell University Medical Center
EDITORIAL ADMINISTRATOR: Marianne Aschenbrenner PUBLISHER: Doris Peter, Ph.D.
Founded 1959 by Arthur Kallet and Harold Aaron, M.D. Copyright 2002. (ISSN 1523-2859)
FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS FEDERAL DRUG TESTS — Federal drug testing programs require testing all specimens
for marijuana metabolites, cocaine metabolites, opiate metabolites, amphetamines and phen- cyclidine. Many multidrug screening assays also detect barbiturates and benzodiazepines in urine. The US Department of Health and Human Services (DHHS) specifies urine testing in their current Mandatory Guidelines for Federal Workplace Drug Testing Programs, but drafts of new guidelines include use of hair, sweat and oral fluidThe DHHS has established specific threshold concentrations for a positive finding in urine for the These concentrations were chosen for optimal sensitivity and specificity. The thresholds for other drugs, such as benzodiazepines, vary with the laboratory The length of time someone will test positive following drug ingestion depends on the drug, the dose, its elimination half-life, and the source of the specimen.
FEDERALLY MANDATED URINE TESTS FOR DRUGS OF ABUSE
drine, phenylephrine, am-phetamines, dextroamphe-tamine, methamphetamine,selegiline, chlorpromazine,trazodone, bupropion,desipramine, amantadine,ranitidine pin, fluoroquinolones, pop-py seeds, quinine in tonicwater 1. DHHS proposed new guidelines: 500 ng/ml2. DHHS proposed new guidelines: 150 ng/ml DRUGS — Blood and breath concentrations of alcohol correlate more closely than urine
concentrations with central-nervous-system impairment.
False-positive determinations are especially common with amphetamines.
second immunoassay to double-check positive results can reduce the number of false posi- tives. The exact substance present can be determined by confirmation testing.
Marijuana is converted into several metabolites; among these, ∆-9-tetrahydrocanna-
binol-9-carboxylic acid can be found in urine in high concentrations for the longest duration of time. Positive tests from passive inhalation of marijuana smoke or from consumption of hemp-containing foods found in health-food stores (such as nut butters or cold-pressed cook- Cocaine has a short half-life (about 1 hour); it is largely metabolized to benzoylecgonine,
which has an elimination half-life of about 7 The Medical Letter • Vol. 44 (Issue 1137) August 19, 2002 Benzodiazepine immunoassays are standardized to a single benzodiazepine, such as nor-
diazepam (a diazepam metabolite), and cross-reactivity to other benzodiazepines is variable.
If cross-reactivity to a benzodiazepine with a relatively short half-life, such as lorazepam (Ativan, and others), is low, and only a small dose of drug was taken, then the duration of a positive urine finding will be short compared to a longer half-life benzodiazepine with higher cross-reactivity, such as diazepam (Valium, and others).
Opiate immunoassays are highly sensitive for compounds showing structural similarity
to morphine, such as codeine, 6-acetylmorphine, and dihydrocodeine, but less sensitive to more structurally dissimilar opioids such as oxycodone (Oxycontin, and others) or meperidine CONCLUSION — The reliability of tests for drugs of abuse depends on the timing and the
assay. Use of confirmatory tests can reduce the number of false-positive results. Assays of hair can detect drugs used weeks before. Testing saliva, sweat and hair for abused drugs may circumvent the tampering that has weakened the reliability of urine specimens, but none of these sources are standardized as well as urine.
NEOTAME — A NEW ARTIFICIAL SWEETENER
Neotame (Neotame − NutraSweet Co.), an analog of aspartame (NutraSweet, and others), has been approved by the FDA for use as a nonnutritive sweetener and "flavor enhancer" in foods and beverages. Other non-caloric sweeteners available in the US include saccharin (Sweet’N Low, and others), acesulfame potassium (Sunette − Medical Letter, 1988; 30:116)and sucralose (Splenda − Medical Letter, 1998; 40:67). Neotame was approved for use in Aus-tralia and New Zealand in 2001.
PROPERTIES — Neotame is a water-soluble, non-caloric, white powder synthesized from
aspartame by addition of an N-alkyl group to yield N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester. It is about 7,000 to 13,000 times sweeter than table sugar and 30-60 times sweeter than aspartame, making it the sweetest artificial sweetener available.
Neotame is reported to have a "clean" sweet taste, similar to aspartame, without the markedly bitter, metallic aftertaste often associated with saccharin The new sweetener can also be advertised as a flavor enhancer because, in sub- sweetening doses, it increases the perception of flavors (such as strawberry), presumably by altering taste rather than any neural mechanism.
PHARMACOLOGY — About 50% of ingested neotame is absorbed from the GI tract. It
has a serum half-life of about 2 hours, is hydrolyzed by tissue and serum esterases to an aspartyl-phenylalanine derivative, and eliminated in urine and feces (C Nofre and J-M Tinti, Food Chem 2000; 69:245). The rest of the dose is mostly excreted intact. Only a small amount of the phenylalanine present in neotame is bioavailable, and these low levels do not pose a risk to patients with phenylketonuria.
ADVANTAGES — Neotame is more stable than aspartame at high temperatures and neu-
tral pH, making it suitable for use in some baked goods and hot beverages. The specification of "some" baked goods is not due to limitations on the stability of the sweetener, but rather to the use of sugar in some baked goods as a bulking agent. In clinical studies, neotame has had no effect on plasma glucose and insulin concentrations and can be used by patients with The Medical Letter • Vol. 44 (Issue 1137) August 19, 2002 diabetes. Animal experiments suggest that neotame, like other non-sugar sweeteners, does not contribute to development of dental caries.
SAFETY — Approval of neotame was based on the results of 113 unpublished studies in
both animals and humans presented to the FDA (Fed Reg 2002; 67:45300). The animal studies used doses up to 1000 times higher than the currently approved daily dose and assessed the effects of both short-term and chronic use.
A case-control study in rats found that the offspring of rats fed neotame 1000 mg/kg daily had reduced motor activity and ability to swim through a maze; the offspring of rats fed 100 mg/kg and 300 mg/kg daily were normal. Rever- sible increases in serum alkaline phosphatase developed in dogs fed more than 60 mg/kg of neotame daily for 52 weeks, but histopathological studies of the liver found no abnormalities.
Two rodent studies found a decrease in total body weight gain that appeared to be unrelated to food intake. A 104-week study in rats found no evidence of neotame-induced neoplasia at doses up to 1000 mg/kg daily. In human studies, neotame dosages of up to about 90-100 mg daily for 13 weeks were not associated with any clinical or laboratory abnormalities.
DOSAGE — Based on animal safety data, the FDA has recommended an acceptable daily
total neotame intake of 18 mg/day. One tabletop packet would contain about 0.9 mg of neo- tame. Because of its ability to enhance flavors, it is likely that small amounts of neotame will be blended with other sweeteners in food and beverages.
CONCLUSION — Neotame is a non-caloric sweetener that is more heat-stable than aspar-
tame, permitting use in cooked foods, and as a tabletop sweetener. Neotame is not yet used commercially in the US, and its range of uses remains to be defined. The drug’s long-term safety in humans is unknown, but it appears to be safe for patients with phenylketonuria.
A NEW PUBLICATION:
TREATMENT GUIDELINES FROM THE MEDICAL LETTER
Beginning September 1, 2002, The Medical Letter will launch a new publication called Treatment Guidelines from The Medical Letter. All of our subscribers will receive a free copy of the first issue, which will be on Drugs for Diabetes.
The new monthly publication will have something old, something new and something blue. The subject matter will be similar to the summary articles on drug classes that we have published in The Medical Letter from time to time and in our Drugs of Choice handbook. The main reason for the new publication is our wish to offer these summary articles on a regular basis, without having to push aside time-sensitive articles on individual new drugs. Most of the issues will be 6 or 8 pages long. What will be new is the format, which will be two columns per page, and the use of color (blue). We hope you like it.
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