Illicit gamma-hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem®): Differences in characteristics and misuse

Drug and Alcohol Dependence

Volumn 104, Issue 1-2, 2009, Pages 1-10

  Carter, Lawrence P ^a   Pardi, Daniel ^b   Gorsline, Jane ^c   Griffiths, Roland R ^d  

^a UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^b JAZZ PHARMACEUTICALS   (United States)

^c Frank and Gorsline Associates   (United States)

^d JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Abuse; Dependence; GHB; Narcolepsy; Sodium oxybate; Xyrem

Indexed keywords

4 HYDROXYBUTYRIC ACID; ILLICIT DRUG; OXYBATE SODIUM;

AUSTRALIA; CATAPLEXY; DRUG ABUSE; DRUG BLOOD LEVEL; DRUG DOSE INCREASE; DRUG FATALITY; DRUG FORMULATION; DRUG INTOXICATION; DRUG MISUSE; DRUG OVERDOSE; DRUG PURITY; EUROPE; EVENING DOSAGE; FIBROMYALGIA; HUMAN; NONHUMAN; POSTMARKETING SURVEILLANCE; PREVALENCE; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; REVIEW; RISK ASSESSMENT; RISK MANAGEMENT; SCIENTIFIC LITERATURE; SEXUAL CRIME; TOXICOKINETICS; UNITED STATES;

CHEMISTRY, PHARMACEUTICAL; HUMANS; NARCOLEPSY; RAPE; RISK MANAGEMENT; SODIUM OXYBATE; STREET DRUGS; SUBSTANCE-RELATED DISORDERS;

EID: 67651093919     PISSN: 03768716     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.drugalcdep.2009.04.012     Document Type: Review

References (104)

1. Abanades S., Farré M., Barral D., Torrens M., Closas N., Langohr K., Pastor A., and de la Torre R. Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users. J. Clin. Psychopharmacol. 27 (2007) 625-638
2. Abanades S., Farré M., Segura M., Pichini S., Barral D., Pacifici R., Pellegrini M., Fonseca F., Langohr K., and De La Torre R. Gamma-hydroxybutyrate (GHB) in humans: pharmacodynamics and pharmacokinetics. Ann. N.Y. Acad. Sci. 1074 (2006) 559-576
3. Anderson I.B., Kim S.Y., Dyer J.E., Burkhardt C.B., Iknoian J.C., Walsh M.J., and Blanc P.D. Trends in gamma-hydroxybutyrate (GHB) and related drug intoxication: 1999 to 2003. Ann. Emerg. Med. 47 (2006) 177-183
4. Arfken C.L., Schuster C.R., and Johanson C.E. Postmarketing surveillance of abuse liability of sibutramine. Drug Alcohol Depend. 69 (2003) 169-173
5. Australian Institute of Health and Welfare, 2008. 2007 National Drug Strategy Household Survey: first results. Drug Statistics Series number 20.Cat. no. PHE 98. Canberra: AIHW. (accessed 8.10.08.).
6. Barker J.C., Harris S.L., and Dyer J.E. Experiences of gamma hydroxybutyrate (GHB) ingestion: a focus group study. J. Psychoactive Drugs. 39 (2007) 115-129
7. Bellis M.A., Hughes K., Bennett A., and Thomson R. The role of an international nightlife resort in the proliferation of recreational drugs. Addiction 98 (2003) 1713-1721
8. Borgen L.A., Okerholm R.A., Lai A., and Scharf M.B. The pharmacokinetics of sodium oxybate oral solution following acute and chronic administration to narcoleptic patients. J. Clin. Pharmacol. 44 (2004) 253-257
9. Bronstein A.C., Spyker D.A., Cantilena L.R., Green J., Rumack B.H., and Heard S.E. 2006 Annual Report of the American Association of Poison Control Centers' National Poison Data System. Clin. Toxicol. 45 (2007) 815-917
10. Bronstein A.C., Spyker D.A., Cantilena J.R., Louis R., Green J.L., Rumack B.H., and Heard S.E. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin. Toxicol. 46 (2008) 927-1057
11. Broughton R., and Mamelak M. The treatment of narcolepsy-cataplexy with nocturnal gamma-hydroxybutyrate. Can. J. Neurol. Sci. 6 (1979) 1-6
12. Caldicott D.G., Chow F.Y., Burns B.J., Felgate P.D., and Byard R.W. Fatalities associated with the use of γ-hydroxybutyrate and it analogues in Australasia. Med. J. Aust. 181 (2004) 310-313
13. Carter L.P., Flores L.R., Wu H., Chen W., Unzeitig A.W., Coop A., and France C.P. The role of GABAB receptors in the discriminative stimulus effects of γ-hydroxybutyrate in rats: time course and antagonism studies. J. Pharmacol. Exp. Ther. 305 (2003) 668-674
14. Carter, L.P., Griffiths, R.R., Mintzer, M.Z., 2007. Psychomotor, subjective, and cognitive effects of GHB and triazolam in healthy volunteers. Presented at the 69th Annual Meeting of the College on Problems of Drug Dependence. (accessed 17.07.08.).
15. Carter L.P., Koek W., and France C.P. Behavioral analyses of GHB: receptor mechanisms. Pharmacol. Ther. 121 (2009) 100-114
16. Carter L.P., Richards B.D., Mintzer M.Z., and Griffiths R.R. 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 (2006) 2537-2551
17. B receptor agonists. J. Pharmacol. Exp. Ther. 313 (2005) 1314-1323
18. Centers for Disease Control. Multistate outbreak of poisonings associated with illicit use of gamma hydroxy butyrate. JAMA 265 (1991) 447-448
19. Chin M.Y., Kreutzer R.A., and Dyer J.E. Acute poisoning from γ-hydroxybutyrate in California. West. J Med. 156 (1992) 380-384
20. Chin R.L., Sporer K.A., Cullison B., Dyer J.E., and Wu T.D. Clinical course of gamma-hydroxybutyrate overdose. Ann. Emerg. Med. 31 (1998) 716-722
21. Couper F.J., Thatcher J.E., and Logan B.K. Suspected GHB overdoses in the emergency department. J. Anal. Toxicol. 28 (2004) 481-484
22. Craig K., Gomez H.F., McManus J.L., and Bania T.C. Severe gamma-hydroxybutyrate withdrawal: a case report and literature review. J. Emerg. Med. 18 (2000) 65-70
23. Degenhardt L., Copeland J., and Dillon P. Recent trends in the use of "club drugs": an Australian review. Subst. Use Misuse 40 (2005) 1241-1256
24. Degenhardt L., Darke S., and Dillon P. GHB use among Australians: characteristics, use patterns and associated harm. Drug Alcohol Depend. 67 (2002) 89-94
25. Degenhardt L., Darke S., and Dillon P. The prevalence and correlates of gamma-hydroxybutyrate (GHB) overdose among Australian users. Addiction 98 (2003) 199-204
26. Degenhardt L., and Dunn M. The epidemiology of GHB and ketamine use in an Australian household survey. Int. J. Drug Policy 19 (2008) 311-316
27. Dietze P.M., Cvetkovski S., Barratt M.J., and Clemens S. Patterns and incidence of gamma-hydroxybutyrate (GHB)-related ambulance attendances in Melbourne. Victoria Med. J. Aust. 188 (2008) 709-711
28. 14C] butyrate by rat brain: relationship to the Krebs cycle and metabolic compartmentation of amino acids. J. Neurochem. 30 (1978) 1305-1309
29. Dupont P., and Thornton J. Near-fatal gamma-butyrolactone intoxication-first report in the UK. Hum. Exp. Toxicol. 20 (2001) 19-22
30. Dyer J.E. γ-Hydroxybutyrate: a health-food product producing coma and seizurelike activity. Am. J. Emerg. Med. 9 (1991) 321-324
31. Dyer J.E., Roth B., and Hyma B.A. Gamma-hydroxybutyrate withdrawal syndrome. Ann. Emerg. Med. 37 (2001) 147-153
32. ElSohly M.A., and Salamone S.J. Prevalence of drugs used in cases of alleged sexual assault. J. Anal. Toxicol. 23 (1999) 141-146
33. European Monitoring Centre for Drugs and Drug Addiction, Annual report 2007: the state of the drugs problem in Europe. Luxembourg: Office for Official Publications of the European Communities. (accessed 17.07.08.).
34. European Monitoring Centre for Drugs and Drug Addiction, Annual report 2008: the state of the drugs problem in Europe. Luxembourg: Office for Official Publications of the European Communities. (accessed 6.02.09.).
35. Ferrara S.D., Tedeschi L., Frison G., and Rossi A. Fatality due to gamma-hydroxybutyric acid (GHB) and heroin intoxication. J. Forensic Sci. 40 (1995) 501-504
36. Frucht S.J., Houghton W.C., Bordelon Y., Greene P.E., and Louis E.D. A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor. Neurology 65 (2005) 1967-1969
37. Fuller D.E., Hornfeldt C.S., Kelloway J.S., Stahl P.J., and Anderson T.F. The Xyrem risk management program. Drug Saf. 27 (2004) 293-306
38. Galloway G.P., Frederick S.L., Staggers Jr. F.E., Gonzales M., Stalcup S.A., and Smith D.E. Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 92 (1997) 89-96
39. Glasper A., McDonough M., and Bearn J. Within-patient variability in clinical presentation of gamma-hydroxybutyrate withdrawal: a case report. Eur. Addict. Res. 11 (2005) 152-154
40. Goodwin A.K., Froestl W., and Weerts E.M. Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons. Psychopharmacology 180 (2005) 342-351
41. Goodwin A.K., Griffiths R.R., Brown P.R., Froestl W., Jakobs C., Gibson K.M., and Weerts E.M. Chronic intragastric administration of gamma-butyrolactone produces physical dependence in baboons. Psychopharmacology 189 (2006) 71-82
42. Griffiths R.R., Bigelow G.E., and Ator N.A. Principles of initial experimental drug abuse liability assessment in humans. Drug Alcohol Depend. 70 Suppl. 3 (2003) S41-54
43. Griffiths R.R., and Johnson M.W. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J. Clin. Psychiatry 66 Suppl. (2005) 31-41
44. Hawaii Revised Statute, Chapter 329 - Uniformed Controlled Substances Act. (accessed 1.10.08.).
45. Hillebrand, J., Olszewski, D., Sedefov, R., 2008. EMCDDA Thematic Papers-GHB and its precursor GBL: an emerging trend case study. European Monitoring Centre for Drugs and Drug Addiction. (accessed 17.07.08.).
46. Johnston, L.D., O'Malley, P.M., Bachman, J.G., Schulenberg, J.E., 2008. Various stimulant drugs show continuing gradual declines among teens in 2008, most illicit drugs hold steady, University of Michigan News Service: Ann Arbor, MI. (accessed 23.01.09.).
47. Juhascik M.P., Negrusz A., Faugno D., Ledray L., Greene P., Lindner A., Haner B., and Gaensslen R.E. An estimate of the proportion of drug-facilitation of sexual assault in four U.S. localities. J. Forensic Sci. 52 (2007) 1396-1400
48. Kim S.Y., Anderson I.B., Dyer J.E., Barker J.C., and Blanc P.D. High-risk behaviors and hospitalizations among gamma hydroxybutyrate (GHB) users. Am. J. Drug Alcohol Abuse 33 (2007) 429-438
49. Kim S.Y., Barker J.C., Anderson I.B., Dyer J.E., Earnest G., and Blanc P.D. Systematic assessment of gamma hydroxybutyrate (GHB) effects during and after acute intoxication. Am. J. Addict. 17 (2008) 312-318
50. Knudsen K., Greter J., and Verdicchio M. High mortality rates among GHB abusers in Western Sweden. Clin. Toxicol. (Phila) 46 (2008) 187-192
51. Lai M.W., Klein-Schwartz W., Rodgers G.C., Abrams J.Y., Haber D.A., Bronstein A.C., and Wruk K.M. 2005 Annual Report of the American Association of Poison Control Centers' National Poisoning and Exposure Database. Clin. Toxicol. 44 (2006) 803-932
52. LeBeau M.A., Miller M.L., and Levine B. Effect of storage temperature on endogenous GHB levels in urine. Forensic Sci. Int. 15 (2001) 161-167
53. LeBeau M.A., Montgomery M.A., Morris-Kukoski C., Schaff J.E., and Deakin A. Further evidence of in vitro production of gamma-hydroxybutyrate (GHB) in urine samples. Forensic Sci. Int. 169 (2007) 152-156
54. LeBeau M.A., Montgomery M.A., Morris-Kukoski C., Schaff J.E., Deakin A., and Levine B. A comprehensive study on the variations in urinary concentrations of endogenous gamma-hydroxybutyrate (GHB). J. Anal. Toxicol. 30 (2006) 98-105
55. Lettieri J., and Fung H. Improved pharmacological activity via pro-drug modification: comparative pharmacokinetics of sodium γ-hydroxybutyrate and γ-butyrolactone. Res. Commun. Chem. Pathol. Pharmacol. 22 (1978) 107-118
56. Litovitz T.L., Klein-Schwartz W., Rodgers G.C., Cobaugh D.J., Youniss J., Omslaer J.C., May M.E., Woolf A.D., and Benson B.E. 2001 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 20 (2002) 391-452
57. Maitre M. The γ-hydroxybutyrate signaling system in brain: organization and functional implications. Prog. Neurobiol. 51 (1997) 337-361
58. Marwick C. Coma-inducing drug GHB may be reclassified. JAMA 277 (1997) 1505-1506
59. Mason P.E., and Kerns II W.P. Gamma hydroxybutyric acid (GHB) intoxication. Acad. Emerg. Med. 9 (2002) 730-739
60. Maxwell J.C., and Spence R.T. Profiles of club drug users in treatment. Subst. Use Misuse 40 (2005) 1409-1426
61. McDaniel C.H., and Miotto K.A. Gamma hydroxybutyrate (GHB) and gamma butyrolactone (GBL) withdrawal: five case studies. J. Psychoactive Drugs 33 (2001) 143-149
62. Miotto K.A., Darakjian J., Basch J., Murray S., Zogg J., and Rawson R. Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal. Am. J. Addict. 10 (2001) 232-241
63. National Drug Intelligence Center U.S. Department of Justice, 2008. National Drug Threat Assessment 2009. (accessed 23.01.09.).
64. Nevada Administrative Code, Chapter 453 - Controlled Substances. (accessed 1.10.08.).
65. Nicholson K.L., and Balster R.L. GHB: a new and novel drug of abuse. Drug Alcohol Depend. 63 (2001) 1-22
66. Office of Diversion Control, 2008. National Forensic Laboratory Information System: Year 2007 Annual Report. Washington, DC: U.S. Drug Enforcement Administration. http://www.deadiversion.usdoj.gov/nflis/index.html (accessed 6.02.09.).
67. Palatini P., Tedeschi L., Frison G., Padrini R., Zordan R., Orlando R., Gallimberti L., Gessa G.L., and Ferrara S.D. Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers. Eur. J. Clin. Pharmacol. 45 (1993) 353-356
68. Palmer R.B. Gamma-butyrolactone and 1,4-buandiol: abused analogues of gamma-hydroxybutyrate. Toxicol. Rev. 23 (2004) 21-31
69. Pardi D., and Black J. Gamma-hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs 20 (2006) 993-1018
70. Price G. In-patient detoxification after GHB dependence. Br. J. Psychiatry 177 (2000) 181
71. Russell I.J., Perkins A.T., Michalek J.E., and Oxybate SXB-26 Fibromyalgia Syndrome Study Group. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 60 (2009) 299-309
72. Scharf M.B., Brown D., Woods M., Brown L., and Hirschowitz J. The effects and effectiveness of gamma-hydroxybutyrate in patients with narcolepsy. J. Clin. Psychiatry 46 (1985) 222-225
73. Scharf M.B., Lai A.A., Branigan B., Stover R., and Berkowitz D.B. Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients. Sleep 21 (1998) 507-514
74. Slaughter L. Involvement of drugs in sexual assault. J. Reprod. Med. 45 (2000) 425-430
75. Strickland R.M., Felgate P., and Caldicott D.G. Survival of massive gamma-hydroxybutyrate/1,4-butanediol overdose. Emerg. Med. Australas. 17 (2005) 281-283
76. Strom, K.J., Wong, L., Fornnarino, L., Eicheldinder, C., Bethke, A., Ancheta, J., Rachal, V., 2003. The National Forensic Laboratory Information System: 2002 Annual Report. Washington, DC: U.S. Drug Enforcement Administration. (accessed 17.07.08.).
77. Strom, K.J., Wong, L., Fornnarino, L., Eicheldinger, C., Bethke, A., Ancheta, J., Rachal, V., 2004. The National Forensic Laboratory Information System: 2003 Annual Report. Washington, DC: U.S. Drug Enforcement Administration. (accessed 17.07.08.).
78. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2008a. Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-30, DHHS Publication No. (SMA) 08-4339, Rockville, MD. (accessed 6.02.09.).
79. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2008b. Results from the 2007 National Survey on Drug Use and Health: National Findings. NSDUH Series H-34, DHHS Publication No. (SMA) 08-4343, Rockville, MD. (accessed 6.02.09.).
80. Sumnall H.R., Woolfall K., Edwards S., Cole J.C., and Beynon C.M. Use, function, and subjective experiences of gamma-hydroxybutyrate (GHB). Drug Alcohol Depend. 92 (2008) 286-290
81. Tarabar A.F., and Nelson L.S. The gamma-hydroxybutyrate withdrawal syndrome. Toxicol. Rev. 23 (2004) 45-49
82. Thai D., Dyer J.E., Benowitz N.L., and Haller C.A. Gamma-hydroxybutyrate and ethanol effects and interactions in humans. J. Clin. Psychopharmacol. 26 (2006) 524-529
83. Thai D., Dyer J.E., Jacob P., and Haller C.A. Clinical pharmacology of 1,4-butandiol and gamma-hydroxybutyrate after oral 1,4-butanediol administration in healthy volunteers. Clin. Pharmacol. Ther. 81 (2007) 178-184
84. The National Forensic Laboratory Information System, 2001. Year 2000 Annual Report. U.S. Drug Enforcement Administration, Office of Diversion Control. Washington, D.C. (accessed 17.07.08.).
85. The National Forensic Laboratory Information System, 2002. Year 2001 Annual Report. U.S. Drug Enforcement Administration, Office of Diversion Control. Washington, D.C. (accessed 17.07.08.).
86. U.S. Controlled Substances Act. Title 21, U.S.C. 802(34). http://www.deadiversion.usdoj.gov/21cfr/21usc/802.htm#34 (accessed 4.09.08.).
87. U.S. Xyrem Multi-Center Study Group. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J. Toxicol. Clin. Toxicol. 41 (2003) 131-135
88. Van Sassenbroeck D.K., De Neve N., De Paepe P., Belpaire F.M., Verstraete A.G., Calle P.A., and Buylaert W.A. Abrupt awakening phenomenon associated with gamma-hydroxybutyrate use: a case series. Clin. Toxicol. (Phila) 45 (2007) 533-538
89. Varela M., Nogue S., Oros M., and Miro O. Gamma hydroxybutirate use for sexual assault. Emerg. Med. J. 21 (2004) 255-256
90. ®): abuse, misuse, dependence, and diversion. J. Clin. Sleep Med, in press.
91. Watson W.A., Litovitz T.L., Rodgers G.C., Klein-Schwartz W., Reid N., Youniss J., Flanagan A., and Wruk K.M. 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 23 (2005) 589-666
92. Watson W.A., Litovitz T.L., Rodgers G.C., Klein-Schwartz W., Youniss J., Reid N., Rouse W.G., Rembert R.S., and Borys D. 2003 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 22 (2004) 335-404
93. Watson W.A., Litovitz T.L., Rodgers G.C., Klein-Schwartz W., Youniss J., Rose S.R., Borys D., and May M.E. 2002 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 21 (2003) 353-421
94. Wedin G.P., Hornfeldt C.S., and Ylitalo L.M. The clinical development of γ-hydroxybutyrate (GHB). Curr. Drug Safety 1 (2006) 99-106
95. Weerts E.M., Goodwin A.K., Griffiths R.R., Brown P.R., Froestl W., Jakobs C., and Gibson K.M. Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons. Psychopharmacology 179 (2005) 678-687
96. Weimer, B.J., Peters, D., Sannerud, C., Eicheldinger, C., Ancheta, J., Strom, K., Rachal, V., 2007. The National Forensic Laboratory Information System: 2006 Annual Report. Washington, DC: U.S. Drug Enforcement Administration. (accessed 17.07.08.).
97. Weimer, B.J., Wong, L., Sannerud, C., Eicheldinger, C., Ancheta, J., Strom, K., Rachal, V., 2006. The National Forensic Laboratory Information System: 2005 Annual Report. Washington DC: U.S. Drug Enforcement Administration. (accessed 17.07.08.).
98. Weimer, B.J., Wong, L., Strom, K., Forti, A., Eicheldinger, C., Bethke, A., Ancheta, J., Rachal, V., 2004. The National Forensic Laboratory Information System: Year 2004 Annual Report. Washington, DC: U.S. Drug Enforcement Administration. (accessed 17.07.08.).
99. Williams S.R. Gamma-hydroxybutyric acid poisoning. West. J. Med. 168 (1998) 187-188
100. Winickoff J.P., Houck C.S., Rothman E.L., and Bauchner H. Verve and Jolt: deadly new internet drugs. Pediatrics 106 (2000) 829-830
101. Wojtowicz J.M., Yarema M.C., and Wax P.M. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review. CJEM 10 (2008) 69-74
102. Wood D.M., Warren-Gash C., Ashraf T., Greene S.L., Shather Z., Trivedy C., Clarke S., Ramsey J., Holt D.W., and Dargan P.I. Medical and legal confusion surrounding gamma-hydroxybutyrate (GHB) and its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD). QJM 101 (2008) 23-29
103. Xyrem Prescribing Information, 2008. Jazz Pharmaceuticals, Inc. (accessed 17.07.08.).
104. Zvosec D.L., Smith S.W., McCutcheon J.R., Spillane J., Hall B.J., and Peacock E.A. Adverse events, including death, associated with the use of 1,4-butandiol. New Engl. J. Med. 544 (2001) 87-93