Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions

Edward J. Cone, Reginald V. Fant, Jeffrey M. Rohay, Yale H. Caplan, Mayra Ballina, Robert F. Reder, J. David Haddox

Research output: Contribution to journalArticle

Abstract

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin® (oxycodone HCl controlled-release) Tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple-drug-induced deaths compared to single (OXC only)-drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple-drug-induced deaths, OxyContin identified, 0.93 μg/mL (N = 167); multiple-drug-induced deaths, OxyContin not identified, 0.73 μg/mL (N = 579); single (OXC)-drug-induced deaths, OxyContin identified, 1.55 μg/mL (N = 12); and single (OXC)-drug-induced deaths, OxyContin not identified, 1.70 μg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC)-drug-induced, drug-abuse deaths > multiple-drug-induced drug-abuse deaths > drug-related drug-abuse deaths ≈ deaths unrelated to drug abuse; and deaths in which OxyContin was identified ≈ deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple-drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple-drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 μg/mL (N = 90) as compared to 1.64 μg/ml (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple-drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple-drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.

Original languageEnglish (US)
Pages (from-to)616-624
Number of pages9
JournalJournal of Analytical Toxicology
Volume28
Issue number7
StatePublished - Oct 2004
Externally publishedYes

Fingerprint

Drug interactions
Oxycodone
Poisons
Drug Interactions
Substance-Related Disorders
drug
Blood
Toxicity
Pharmaceutical Preparations
Body fluids
Gas chromatography
Drug products
Mass spectrometry
Assays
Animals
Alcohols
Tissue
drug abuse
cause of death
Opioid Analgesics

ASJC Scopus subject areas

  • Analytical Chemistry
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Cone, E. J., Fant, R. V., Rohay, J. M., Caplan, Y. H., Ballina, M., Reder, R. F., & Haddox, J. D. (2004). Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions. Journal of Analytical Toxicology, 28(7), 616-624.

Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions. / Cone, Edward J.; Fant, Reginald V.; Rohay, Jeffrey M.; Caplan, Yale H.; Ballina, Mayra; Reder, Robert F.; Haddox, J. David.

In: Journal of Analytical Toxicology, Vol. 28, No. 7, 10.2004, p. 616-624.

Research output: Contribution to journalArticle

Cone, EJ, Fant, RV, Rohay, JM, Caplan, YH, Ballina, M, Reder, RF & Haddox, JD 2004, 'Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions', Journal of Analytical Toxicology, vol. 28, no. 7, pp. 616-624.
Cone EJ, Fant RV, Rohay JM, Caplan YH, Ballina M, Reder RF et al. Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions. Journal of Analytical Toxicology. 2004 Oct;28(7):616-624.
Cone, Edward J. ; Fant, Reginald V. ; Rohay, Jeffrey M. ; Caplan, Yale H. ; Ballina, Mayra ; Reder, Robert F. ; Haddox, J. David. / Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions. In: Journal of Analytical Toxicology. 2004 ; Vol. 28, No. 7. pp. 616-624.
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AU - Cone, Edward J.

AU - Fant, Reginald V.

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AU - Caplan, Yale H.

AU - Ballina, Mayra

AU - Reder, Robert F.

AU - Haddox, J. David

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N2 - Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin® (oxycodone HCl controlled-release) Tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple-drug-induced deaths compared to single (OXC only)-drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple-drug-induced deaths, OxyContin identified, 0.93 μg/mL (N = 167); multiple-drug-induced deaths, OxyContin not identified, 0.73 μg/mL (N = 579); single (OXC)-drug-induced deaths, OxyContin identified, 1.55 μg/mL (N = 12); and single (OXC)-drug-induced deaths, OxyContin not identified, 1.70 μg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC)-drug-induced, drug-abuse deaths > multiple-drug-induced drug-abuse deaths > drug-related drug-abuse deaths ≈ deaths unrelated to drug abuse; and deaths in which OxyContin was identified ≈ deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple-drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple-drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 μg/mL (N = 90) as compared to 1.64 μg/ml (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple-drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple-drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.

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