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Psychopharmacology

, Volume 232, Issue 5, pp 871–883 | Cite as

Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential

  • Chad J. ReissigEmail author
  • Joseph A. Harrison
  • Lawrence P. Carter
  • Roland R. GriffithsEmail author
Original Investigation

Abstract

Rationale

Infrahuman and human studies suggest that a determinant of the abuse potential of a drug is rate of onset of subjective effects.

Objectives

This study sought to determine if the rate of onset of subjective effects and abuse potential of alprazolam would be increased when administered via inhalation vs. the oral route.

Methods

Placebo, inhaled alprazolam (0.5, 1, and 2 mg), and oral alprazolam (1, 2, and 4 mg) were administered under double-blind, double-dummy conditions using a crossover design in 14 healthy participants with histories of drug abuse. Participant and observer ratings and behavioral and cognitive performance measures were assessed repeatedly during 9-h sessions.

Results

Both routes of administration produced orderly dose and time-related effects, with higher doses producing greater and longer-lasting effects. Onset of subjective effects following inhaled alprazolam was very rapid (e.g., 2 vs. 49 min after 2 mg inhaled vs. oral). On measures of abuse potential (e.g., liking and good effects), inhaled alprazolam was more potent, as evidenced by a leftward shift in the dose–response curve. Despite the potency difference, at the highest doses, peak ratings of subjective effects related to abuse potential (e.g., “drug liking”) were similar across the two routes. On other measures (e.g., sedation and performance), the routes were equipotent.

Conclusions

The inhaled route of administration modestly increased the abuse potential of alprazolam despite significantly increasing its rate of onset. If marketed, the reduced availability and increased cost of inhaled alprazolam may render the societal risk of increased abuse to be low.

Keywords

Alprazolam Oral Inhalation Staccato® Abuse potential Liking Performance Drug abusers Humans 

Notes

Acknowledgments and disclosures

Conduct of this research was supported by Alexza Pharmaceuticals, Inc. and NIH grant T32DA07209. Manuscript preparation was supported in part by NIH grant R01DA03889. We thank Janna Steinberg and Jill Griffith for serving as assistant session monitors, John Yingling for technical assistance, and Linda Felch for statistical assistance. The study was conducted in compliance with US laws. Dr. Carter is an employee of Jazz Pharmaceuticals, Inc. and has received stock and stock options for shares of Jazz Pharmaceuticals plc. Dr. Reissig is an employee of the US Food and Drug Administration (FDA), however, the views presented in this article do not necessarily reflect those of the FDA and no official support or endorsement of this article by the FDA is intended or should be inferred.

Supplementary material

213_2014_3721_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 34 kb)
213_2014_3721_MOESM2_ESM.docx (33 kb)
ESM 2 (DOCX 33 kb)

References

  1. Abreu ME, Bigelow GE, Fleisher L, Walsh SL (2001) Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans. Psychopharmacol (Berl) 154:76–84CrossRefGoogle Scholar
  2. Alexza Pharmaceuticals (2014a) Investigator’s brochure for study AZ-002Google Scholar
  3. Alexza Pharmaceuticals (2014b) Product Website frequently asked questions (FAQ). Available online at: http://www.alexza.com/products/faq. Accessed 30 May 2014
  4. Alexza Pharmaceuticals (2014c) Product Website frequently asked questions (FAQ). Available online at: http://www.alexza.com/products/faq. Accessed on June 26, 2014
  5. Avram MJ, Henthorn TK, Spyker DA, Krejcie TC, Lloyd PM, Cassella JV, Rabinowitz JD (2007) Recirculatory pharmacokinetic model of the uptake, distribution, and bioavailability of prochlorperazine administered as a thermally generated aerosol in a single breath to dogs. Drug Metab Dispos 35:262–267CrossRefPubMedGoogle Scholar
  6. Avram MJ, Spyker DA, Henthorn TK, Cassella JV (2009) The pharmacokinetics and bioavailability of prochlorperazine delivered as a thermally generated aerosol in a single breath to volunteers. Clin Pharmacol Ther 85:71–77CrossRefPubMedGoogle Scholar
  7. Avram MJ, Spyker DA, Kehne JH, Cassella JV (2013) The pharmacokinetics and pharmacodynamics of zaleplon delivered as a thermally generated aerosol in a single breath to volunteers. J Clin Pharmacol 53(2):140–150CrossRefPubMedGoogle Scholar
  8. Balster RL, Schuster CR (1973) Fixed-interval schedule of cocaine reinforcement: effect of dose and infusion duration. J Exp Anal Behav 20:119–129CrossRefPubMedCentralPubMedGoogle Scholar
  9. Carter LP, Richards BD, Mintzer MZ, Griffiths RR (2006) Relative abuse liability of GHB in humans: a comparison of psychomotor, subjective, and cognitive effects of supratherapeutic doses of triazolam, pentobarbital, and GHB. Neuropsychopharmacology 31:2537–2551CrossRefPubMedGoogle Scholar
  10. Carter LP, Griffiths RR, Mintzer MZ (2009) Cognitive, psychomotor, and subjective effects of sodium oxybate and triazolam in healthy volunteers. Psychopharmacol (Berl) 206:141–154CrossRefGoogle Scholar
  11. de Wit H, Bodker B, Ambre J (1992) Rate of increase of plasma drug level influences subjective response in humans. Psychopharmacol (Berl) 107:352–358CrossRefGoogle Scholar
  12. de Wit H, Dudish S, Ambre J (1993) Subjective and behavioral effects of diazepam depend on its rate of onset. Psychopharmacol (Berl) 112:324–330CrossRefGoogle Scholar
  13. Evans SM, Funderburk FR, Griffiths RR (1990) Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability. J Pharmacol Exp Ther 255:1246–1255PubMedGoogle Scholar
  14. Fischman MW, Schuster CR (1984) Injection duration of cocaine in humans. Fed Poc 43:570Google Scholar
  15. Gorelick DA (1998) The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. Adv Pharmacol 42:995–997CrossRefPubMedGoogle Scholar
  16. Greenblatt DJ, Wright CE (1993) Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 24:453–471CrossRefPubMedGoogle Scholar
  17. Griffiths RR, McLeod DR, Bigelow GE, Liebson IA, Roache JD (1984) Relative abuse liability of diazepam and oxazepam: behavioral and subjective dose effects. Psychopharmacol (Berl) 84:147–154CrossRefGoogle Scholar
  18. Griffiths RR, Lamb RJ, Ator NA, Roache JD, Brady JV (1985) Relative abuse liability of triazolam: experimental assessment in animals and humans. Neurosci Biobehav Rev 9:133–151CrossRefPubMedGoogle Scholar
  19. Kato S, Wakasa Y, Yanagita T (1987) Relationship between minimum reinforcing doses and injection speed in cocaine and pentobarbital self-administration in crab-eating monkeys. Pharmacol Biochem Behav 28:407–410CrossRefPubMedGoogle Scholar
  20. Macleod DB, Habib AS, Ikeda K, Spyker DA, Cassella JV, Ho KY, Gan TJ (2012) Inhaled fentanyl aerosol in healthy volunteers: pharmacokinetics and pharmacodynamics. Anesth Analg 115:1071–1077CrossRefPubMedGoogle Scholar
  21. Marsch LA, Bickel WK, Badger GJ, Rathmell JP, Swedberg MD, Jonzon B, Norsten-Hoog C (2001) Effects of infusion rate of intravenously administered morphine on physiological, psychomotor, and self-reported measures in humans. J Pharmacol Exp Ther 299:1056–1065PubMedGoogle Scholar
  22. McLeod DR, Griffiths RR, Bigelow GE, Yingling J (1982) An automated version of the digit symbol substitution test (DSST). Behav Res Methods & Instrum 14:463–466CrossRefGoogle Scholar
  23. Mumford GK, Evans SM, Fleishaker JC, Griffiths RR (1995a) Alprazolam absorption kinetics affects abuse liability. Clin Pharmacol Ther 57:356–365CrossRefPubMedGoogle Scholar
  24. Mumford GK, Rush CR, Griffiths RR (1995b) Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects. J Pharmacol Exp Ther 272:570–580PubMedGoogle Scholar
  25. Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, Henningfield JE, Schuster CR, Contoreggi C, Gorelick DA (2006) Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans. Drug Alcohol Depend 82:19–24CrossRefPubMedGoogle Scholar
  26. Neubauer DN (2010) ZolpiMist: a new formulation of zolpidem tartrate for the short-term treatment of insomnia in the US. Nat Sci Sleep 2:79–84CrossRefPubMedCentralPubMedGoogle Scholar
  27. Oldendorf WH (1992) Some relationships between addiction and drug delivery to the brain. NIDA Res Monogr 120:13–25PubMedGoogle Scholar
  28. Rabinowitz JD, Wensley M, Lloyd P, Myers D, Shen W, Lu A, Hodges C, Hale R, Mufson D, Zaffaroni A (2004) Fast onset medications through thermally generated aerosols. J Pharmacol Exp Ther 309:769–775CrossRefPubMedGoogle Scholar
  29. Rabinowitz JD, Lloyd PM, Munzar P, Myers DJ, Cross S, Damani R, Quintana R, Spyker DA, Soni P, Cassella JV (2006) Ultra-fast absorption of amorphous pure drug aerosols via deep lung inhalation. J Pharm Sci 95:2438–2451CrossRefPubMedGoogle Scholar
  30. Reissig CJ, Carter LP, Johnson MW, Mintzer MZ, Klinedinst MA, Griffiths RR (2012) High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens. Psychopharmacol (Berl) 223:1–15CrossRefGoogle Scholar
  31. Roset PN, Farre M, de la Torre R, Mas M, Menoyo E, Hernandez C, Cami J (2001) Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males. Drug Alcohol Depend 64:285–298CrossRefPubMedGoogle Scholar
  32. Rush CR, Frey JM, Griffiths RR (1999) Zaleplon and triazolam in humans: acute behavioral effects and abuse potential. Psychopharmacol (Berl) 145:39–51CrossRefGoogle Scholar
  33. Smith RB, Kroboth PD, Vanderlugt JT, Phillips JP, Juhl RP (1984) Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration. Psychopharmacol (Berl) 84:452–456CrossRefGoogle Scholar
  34. Spyker DA, Munzar P, Cassella JV (2010) Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers. J Clin Pharmacol 50:169–179CrossRefPubMedGoogle Scholar
  35. Wakasa Y, Takada K, Yanagita T (1995) Reinforcing effect as a function of infusion speed in intravenous self-administration of nicotine in rhesus monkeys. Nihon Shinkei Seishin Yakurigaku Zasshi 15:53–59PubMedGoogle Scholar
  36. Woolverton WL, Wang Z (2004) Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine. Eur J Pharmacol 486:251–257CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Pharmacology and ToxicologyUniversity of Arkansas for Medical SciencesLittle RockUSA

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