Abuse liability assessment of hydrocodone under current draft regulatory guidelines

Journal of Pharmacological and Toxicological Methods

Volumn 75, Issue , 2015, Pages 118-129

  Gauvin, David V ^a   McComb, Margaret ^a   Code, Robert ^a   Dalton, Jill A ^a   Baird, Theodore J ^a  

^a MPI RESEARCH   (United States)

Author keywords

Abuse liability; Discontinuation syndrome; Drug dependence; Drug discrimination; Hydrocodone; Methods; Morphine; Oxycodone; Self administration; Withdrawal

Indexed keywords

HYDROCODONE; MORPHINE; OXYCODONE; NARCOTIC ANALGESIC AGENT;

ANIMAL BEHAVIOR; ANIMAL EXPERIMENT; ANIMAL MODEL; AROUSAL; ARTICLE; AUTONOMIC NERVOUS SYSTEM; CONTROLLED STUDY; DRUG DISCRIMINATION TEST; DRUG SELF ADMINISTRATION; FUNCTIONAL STATUS; MALE; NEUROMUSCULAR FUNCTION; NONHUMAN; OPIATE ADDICTION; QUALITATIVE ANALYSIS; QUANTITATIVE ANALYSIS; RAT; REWARD; SENSORIMOTOR FUNCTION; WITHDRAWAL SYNDROME; ANIMAL; COMPARATIVE STUDY; PATHOPHYSIOLOGY; PERCEPTIVE DISCRIMINATION; PRACTICE GUIDELINE; SPRAGUE DAWLEY RAT;

ANALGESICS, OPIOID; ANIMALS; DISCRIMINATION (PSYCHOLOGY); GUIDELINES AS TOPIC; HYDROCODONE; MALE; MORPHINE; OPIOID-RELATED DISORDERS; OXYCODONE; RATS; RATS, SPRAGUE-DAWLEY; SELF ADMINISTRATION; SUBSTANCE WITHDRAWAL SYNDROME;

EID: 84942552230     PISSN: 10568719     EISSN: 1873488X     Source Type: Journal    
DOI: 10.1016/j.vascn.2015.05.003     Document Type: Article

References (83)

1. Akera T., Brody T.M. The addiction cycle to narcotics in the rat and its relation to catecholamines. Biochemical Pharmacology 1968, 7:675-688.
2. Barnes R.H., Fiala G. Effects of the prevention of coprophagy in the rat. I. Growth studies. Journal of Nutrition 1958, 64:533-540.
3. Barnes R.H., Fiala G. Effects of the prevention of copraphagy in the rat. II. Vitamin B12 requirement. Journal of Nutrition 1958, 65:103-114.
4. Barnes R.H., Fiala G. Effects of the prevention of coprophagy in the rat. VI. Vitamin K. Journal of Nutrition 1959, 68:603-614.
5. Barnes R.H., Fiala G., McGehee B., Brown A. Prevention of coprophagy in the rat. Journal of Nutrition 1957, 63:489-498.
6. Batra V.R., Schrott L.M. Acute oxycodone induces the pro-emetic pica response in rats. Journal of Pharmacology & Experimental Therapeutics 2011, 33:738-745.
7. Beach H.D. Morphine addiction in rats. Canadian Journal of Psychology 1957, 11:104-112.
8. Beardsley P.M., Aceto M.D., Cook C.D., Bowman E.R., Newman J.L., Harris L.S. Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys. Experimental & Clinical Psychopharmacology 2004, 12:163-172.
9. Blasig J., Herz A., Reinhold K., Zieglgansberger S. Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia 1973, 33:19-38.
10. Boisse N.R., Okamoto M. Physical dependence to barbital compared to pentobarbital. III. Withdrawal characteristics. Journal of Pharmacology & Experimental Therapeutics 1978, 204:514-525.
11. Boisse N.R., Okamoto M. Physical dependence to barbital compared to pentobarbital. I. "Chronically equivalent" dosing method. Journal of Pharmacology & Experimental Therapeutics 1978, 204:497-506.
12. Testing drugs for physical dependence potential and abuse liability 1984, The Committee on Problems of Drug Dependence, Inc.; NIDA Research Monograph 52, US Govt Printing Office, Washington DC. J.V. Brady, S.E. Lukas (Eds.).
13. Briscoe R.J., Vanecek S.A., Vallett M., Baird T.J., Holloway F.A., Gauvin D.V. Reinforcing effects of caffeine, ephedrine, and their binary combination in rats. Pharmacology Biochemistry & Behavior 1999, 60:685-693.
14. Chan S., Edwards S.R., Wyse B.D., Smith M.T. Sex differences in the pharmacokinetics, oxidative metabolism and oral bioavailability of oxycodone in the Sprague-Dawley rat. Clinical and Experimental Pharmacology & Physiology 2008, 35:295-302.
15. Colpaert F.C. Discriminative stimulus properties of narcotic analgesic drugs. Pharmacology Biochemistry & Behavior 1978, 9:863-887.
16. Cone E.J., Darwin W.D., Gorodetzkey C.W., Tan T. Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. Drug Metabolism & Disposition 1978, 6:488-493.
17. Coon T.P., Miller M., Kaylor D., Jones-Spangle K. Rectal insertion of fentanyl patches: A new route of toxicity. Annals of Emergency Medicine 2005, 46:473.
18. Craft R.M., Howard J.L. Cue properties of oral and transdermal nicotine in the rat. Psychopharmacology 1998, 96:281-284.
19. Drug Enforcement Administration, Department of Justice Schedules of controlled substances: rescheduling of hydrocodone combination products from schedule III to schedule II (final rule). Federal Register 2014, August 22, Vol. 79:49661-49682. (Number 163 (Friday, August 22, 2014), FR Doc No: 2014-19922).
20. Eddy N.B., Halbach H., Braenden O.J. Synthetic substances with morphine-like effect: Relationship between analgesic and addiction liability, with a discussion of the chemical structure of addiction-producing substances. Bulletin of the World Health Organization 1956, 14:353-402.
21. Eddy N.B., Halbach H., Braenden O.J. Synthetic substances with morphine-like effect. Clinical experience: potency, side effects and addiction liability. Bulletin of the World Health Organization 1957, 17:595-600.
22. European Medicines Agency (EMeA) Evaluations of Medicines for Human Use, Committee for Medicinal Products for Human Use (CHMP) Guideline on the non-clinical investigation of the dependence potential of medicinal products 2006, 1-12. (EMEA/CHMP/SWP/94227/2004), (Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003360.pdf (Accessed February 8, 2015)).
23. European Monitoring Centre for Drugs and Drug Addiction Risk assessment of new psychoactive substances. Operating guidelines 2009, European Monitoring Centre and Drug Addiction (EMCDDA), Lisbon, (Available at: http://www.emcdda.europa.eu/attachements.cfm/att_100979_EN_RiskGuidelines2010.pdf (Accessed April 18, 2014)).
24. Fennessy M.R., Rattray J.F. Cardiovascular effects of intravenous morphine in the anaesthetized rat. European Journal of Pharmacology 1971, 14:1-8.
25. Fraser H.F. Methods for assessing the addiction liability of opioids and opioid antagonists in man. The addictive states 1968, 176-187. Williams and Wilkins, Baltimore. A. Wikler (Ed.).
26. Fraser H.F. 13. Methods for assessing the addiction liability of opioids and opioid antagonists in man. Research Publications - Association for Research in Nervous and Mental Disease 1968, 46:176-187.
27. Fraser H.F., Isbell H. Addiction liabilities of morphinan, 6-methyldi-hydromorphine and dihydrocodeinone. Journal of Pharmacology & Experimental Therapeutics 1950, 100:128-135.
28. Fuentes V.O., Hunt W.H., Crossland J. The production of morphine tolerance and physical dependence by the oral route in the rat. A comparative study. Psychopharmacology 1978, 59:65-69.
29. Garcia-Lecumberri C., Torres I., Martin S., Crespo J.A., Miguéns M., Nicanor C., et al. Strain differences in the dose-response relationship for morphine self-administration and impulsive choice between Lewis and Fischer 344 rats. Journal of Psychopharmacology 2011, 25:783-791.
30. Gauvin D.V., Criado J.R., Moore K.R., Holloway F.A. Potentiation of cocaine's discriminative stimulus effects by caffeine: A time-effect analysis. Pharmacology Biochemistry & Behavior 1990, 36:195-197.
31. Gauvin D.V., Dalton J.A., Baird T.J. Current strategies for abuse liability assessment of new chemical entities. A comprehensive to toxicology in preclinical drug development 2013, Elsevier Press, New York. 10.1016/B978-0-12-387815-1.00019.8. A. Faqi (Ed.).
32. Gauvin D.V., Harland R.D., Michaelis R.C., Holloway F.A. Caffeine-phenylethylamine combinations mimic the cocaine discriminative cue. Life Sciences 1989, 44:62-73.
33. Glennon R.A., Young R. Drug discrimination: Applications to medicinal chemistry and drug studies 2011, John Wiley and Sons, Inc., Hoboken, NJ.
34. Harland R.D., Gauvin D.V., Michaelis R.C., Carney J.M., Seale T.W., Holloway F.A. Behavioral interaction between cocaine and caffeine: A drug discrimination analysis in rats. Pharmacology Biochemistry & Behavior 1989, 32:1017-1023.
35. Huan L., Edwards S.R., Smith M.T. Comparison of the pharmacokinetics of oxycodone and noroxycodone in male dark agouti and Sprague-Dawley rats: Influence of streptozotocin-induced diabetes. Pharmaceutical Research 2005, 22:1489-1498.
36. International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use ICH Harmonised Tripartite Guideline Safety Pharmacology Studies For Human Pharmaceuticals, S7A Available at:, (Accessed February 5, 2015). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_Guideline.pdf.
37. International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. M3(R2) Available at:, (Accessed February 5, 2015). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2__Guideline.pdf.
38. Irwin S. Comprehensive observational assessment: 1a. A systematic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia 1968, 13:222-257.
39. Isbell H. Addiction liability of dihydrocodeinone (No. 154). Report of the 5th meeting of the Committee on Drug Addiction and Narcotics, National Academy of Sciences, National Research Council. Bulletin, Drug Addiction and Narcotics, Appendix: Report to the Committee on Drug Addiction and Narcotics by the Research Division U.S. Public Health Service Hospital, Lexington, Kentucky 1949, (p. 89 of report, p. 2 of Appendix A).
40. Iwomoto K., Klaassen C.D. First-pass effect of morphine in rats. Journal of Pharmacology & Experimental Therapeutics 1977, 200:236-244.
41. Järbe T.U.C. Perceptual drug discriminative aspects of the endocannabinoid signaling system in animals and man. Drug discrimination: Applications to medicinal chemistry and drug studies 2011, 241-286. John Wiley and Sons, Inc, Hoboken, NJ. R.A. Glennon, R. Young (Eds.).
42. Jasinski D.R. Assessment of abuse potential of morphine-like drugs (methods used in man. Drug Addiction 1977, Vol. 45:197-258. Springer, New York. W.R. Martin (Ed.).
43. Lelas S., Wegert S., Otton V., Sellers E.M., France C.P. Inhibitors of cytochrome P450 differentially modify discriminative stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys. Drug & Alcohol Dependence 1999, 54:239-249.
44. Lugo R.A., Kern S.E. Clinical pharmacokinetics of morphine. Journal of Pain & Palliative Care Pharmacotherapy 2002, 16:5-18.
45. March C.H., Elliott H.W. Distribution and excretion of radioactivity after administration of morphine-N-methyl C14 to rats. Proceedings of the Society for Experimental Biology and Medicine 1954, 86:484-497.
46. Meert T.F., Vermeirsch H.A. A preclinical comparison between different opioids: Antinociceptive versus adverse effects. Pharmacology Biochemistry & Behavior 2005, 80:309-326.
47. Mengs U., Mitchell J., McPherson S., Gregson R., Tigner J. A 13week oral toxicity study of senna in the rat with an 8week recovery period. Archives of Toxicology 2004, 78:269-275.
48. Mierzejewski P., Koroś E., Goldberg S.R., Kostowski W., Stefański R. Intravenous self-administration of morphine and cocaine: A comparative study. Polish Journal of Pharmacology 2003, 55:713-726.
49. Moser V.C., McCormick J.P., Creason J.P., MacPhail R.C. Comparison of chlordimeform and carbaryl using a functional observational battery. Fundamentals of Applied Toxicology 1988, 11:189-206.
50. Moser V.C., Ross J.F. US EPA/AIHC training video and reference manual for a functional observational battery 1996, US Environmental Protection Agency, Washington, D.C.
51. Mrvos R., Feuchter A.C., Katz K.D., Duback-Morris L.F., Brooks D.E., Krenzelok E.P. Whole fentanyl patch ingestion: A multicenter case series. Journal of Emergency Medicine 2012, 42:549-552.
52. Mucha R.F., Kalant H., Linseman M.A. Quantitative relationship among measures of morphine tolerance and physical dependence in the rat. Pharmacology Biochemistry & Behavior 1979, 10:397-405.
53. Mullis K.G., Perry D.C., Finn A.M., Stafford B., Sadée W. Morphine persistence in rat brain and serum after single doses. Journal of Pharmacology & Experimental Therapeutics 1979, 208:228-231.
54. Office of Technology Assessment, Congress U.S. Neurotoxicity: Identifying and controlling poisons of the nervous system 1990, US Government Printing Office, OTA-BA-436, Washington DC.
55. Okamoto M., Boisse N.R. Sedative-hypnotic tolerance and physical dependence. Trends in Pharmacological Sciences 1981, January, 9-13.
56. Okamoto M., Boisse N.R., Rosenberg H.C., Rosen R. Characteristics of functional tolerance during barbiturate physical dependence production. Journal of Pharmacology & Experimental Therapeutics 1978, 207:906-915.
57. Okamoto M., Hinman D.J., Aaronson L.M. Comparison of ethanol and barbiturate physical dependence. Journal of Pharmacology & Experimental Therapeutics 1981, 218:701-708.
58. Picker M.J., Doty P., Negus S.S., Mattox S.R., Dykstra L.A. Discriminative stimulus properties of U50,488 and morphine: Effects of training dose on stimulus substitution patterns produced by Mu and Kappa opioid agonists. Journal of Pharmacology & Experimental Therapeutics 1990, 254:13-22.
59. Prosser J.M., Jones B.E., Nelson L. Complications of oral exposure to fentanyl transdermal delivery system patches. Journal of Medical Toxicology 2010, 6:443-447.
60. Randich A., Robertson J.D., Willingham T. The use of specific opioid agonists and antagonists to delineate the vagally mediated antinociceptive and cardiovascular effects of intravenous morphine. Brain Research 1993, 603:186-200.
61. Rush C.R., Vansickel A.R., Stoops W.W. Human drug discrimination: Methodological considerations and application to elucidating the neuropharmacology of amphetamines. Drug discrimination: Applications to medicinal chemistry and drug studies 2011, 431-462. John Wiley and Sons, Inc., Hoboken, NJ. R.A. Glennon, R. Young (Eds.).
62. Sánchez-Cardoso P., Hguera-Matas A., Martin S., del Olmo N., Miguéns M., Garcia-Lecumberri C., et al. Modulation of the endogenous opioid system after morphine self-administration and during its extinction: A study in Lewis and Fischer 344 rats. Neuropharmacology 2007, 52:931-948.
63. Sánchez-Cardoso P., Hguera-Matas A., Martin S., Miguéns M., del Olmo N., Garcia-Lecumberri C., et al. Strain differences between Lewis and Fischer 344 rats in the modulation of dopaminergic receptors after morphine self-administration and during extinction. Neuropharmacology 2009, 57:8-17.
64. Sannerud C.A., Young A.M. Environmental modification of tolerance to morphine discriminative stimulus properties in rats. Psychopharmacology 1987, 93:59-68.
65. Schechter M.D. Transfer of state-dependent control of discriminative behavior between subcutaneously and intraventricularly administered nicotine and saline. Psychopharmacologia 1973, 32:327-335.
66. Schulteis G., Markou A., Gold L.H., Stinus L., Koob G.F. Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis. Journal of Pharmacology & Experimental Therapeutics 1994, 271:1391-1398.
67. Shannon H.E., Holtzman S.G. Evaluation of the discriminative effects of morphine in the rat. Journal of Pharmacology & Experimental Therapeutics 1976, 198:54-65.
68. Shannon H.E., Holtzman S.G. Further evaluation of the discriminative effects of morphine in the rat. Journal of Pharmacology & Experimental Therapeutics 1977, 201:55-66.
69. Sharp P.E., LaRegina M.C. The laboratory rat 1998, CRC Press, Boca Raton.
70. Stevenson J., Hume M.A. Concealed rectal opiates presenting as respiratory arrest: The importance of rectal administration in i.v. drug abusers. Scottish Medical Journal 1991, 36:148.
71. Thurston C.L., Starnes A., Randich A. Changes in nociception, arterial blood pressure and heart rate produced by intravenous morphine in the conscious rat. Brain Research 1993, 612:70-77.
72. Tomkins D.M., Otton S.V., Joharchi N., Li N.-K., Balster R.F., Tyndale R.F., et al. Effect of cytochrome P450 2D1 inhibition of hydrocodone metabolism and its behavioral consequences in rats. Journal of Pharmacology & Experimental Therapeutics 1997, 280:1374-1382.
73. U.S.Department of Health and Human Services, Food and Drug Administration Guidance for industry. Assessment of abuse potential of drugs Available at:, (Accessed February 5, 2015). http://www.fda.gov/cder/guidance/index.htm.
74. U.S.Drug Enforcement Administration Schedules of controlled substances: Placement of hydrocodone combination products into schedule II background, data, and analysis: eight factors determinative of control and findings pursuant to 21 U.S.C. 812(b) Available at:, (Accessed April 4, 2015). http://www.regulations.gov/#!documentDetail;D=DEA-2014-0005-0003.
75. U.S.Food and Drug Administration Controlled Substances Staff, CDER, PhRMA-FDA Dialogue Session: Abuse Potential Assessments Available at:, (Accessed February 5, 2015). http://www.fda.gov/Cder/Offices/CSS/presentations/CSS_PHRMA_FDA_Dialogue_Session%20FINAL%20022508.pdf.
76. United Nations Commission on Narcotic Drugs: The Single Convention on Narcotic Drugs; Schedules: E/CN.7/AC.3/9/Add.1 Available at:, (Accessed February 5, 2015). http://www.drugtext.org/National-Commission-on-Marihuana-Volume-III/the-international-drug-control-system.html.
77. van Ree J., Slangen J.L., de Wied D. Intravenous self-administration of drugs in rats. Journal of Pharmacology & Experimental Therapeutics 1978, 204:547-557.
78. Weeks J.R. Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rats. Science 1962, 138:143-144.
79. Weeks J.R., Collins R.J. Factors afflicting voluntary morphine intake in self-maintained addicted rats. Psychopharmacologia 1964, 6:267-279.
80. Weeks J.R., Collins R.J. Dose and physical dependence as factors in the self-administration of morphine by rats. Psychopharmacology 1979, 65:171-177.
81. Werner T.E., Smith S.G., Davis W.M. A dose-response comparison between methadone and morphine self-administration. Psychopharmacology 1976, 47:209-211.
82. World Health Organization World Health Organization technical report series No. 495: Opiates and their alternatives for pain and cough relief. Report of a WHO scientific Group 1972, (Geneva: Switzerland).
83. Yan-Hua R., Ji-Wang Z. Influence of tramadol on morphine discriminative behavior in rats. Acta Pharmacologica Sinica 2000, 10:924-926.