Several prescription and nonprescription drugs are liable for abuse. However, oral hypoglycemic agents are among the most benign and low-risk drugs in terms of abuse liability. This commentary intends to raise awareness regarding the abuse of a particular type of oral hypoglycemic agent, namely sulfonylurea drugs, used to experience mental-altering effects for its euphoric “hypoglycemic rush.” Information is available on discussion fora online where people exchange their experiences. Moreover, several case reports have been published and described the liability for abuse of sulfonylurea drugs. This article intends to shed the light on this phenomenon in light of the available literature, attempting to explain the possible scientific basis for it. In addition, it highlights the need for health professional awareness and vigilance for this form of drug diversion. © 2019, Springer Nature Switzerland AG

Abushams, L

van Hout, MC

Wazaify, M

English

Van Hout, MC

LJMU Research Online (Liverpool John Moores University)

 Wazaify, M, Abushams, L and van Hout, MC Abuse of sulfonylureas: Is factitious hypoglycemia a cause for concern?http://researchonline.ljmu.ac.uk/id/eprint/10209/ArticleLJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. You may not engage in further distribution of the material or use it for any profit-making activities or any commercial gain.The version presented here may differ from the published version or from the version of the record. Please see the repository URL above for details on accessing the published version and note that access may require a subscription. For more information please contact researchonline@ljmu.ac.ukhttp://researchonline.ljmu.ac.uk/Citation (please note it is advisable to refer to the publisher’s version if you intend to cite from this work) Wazaify, M, Abushams, L and van Hout, MC (2019) Abuse of sulfonylureas: Is factitious hypoglycemia a cause for concern? International Journal of Clinical Pharmacy, 41 (3). pp. 3-5. ISSN 2210-7703 LJMU Research OnlineAbstract (word count 128) Several prescription and non-prescription drugs are liable for abuse. However, oral hypoglycemic agents are among the most benign and low risk drugs in terms of abuse liability.  This Commentary intends to raise awareness regarding the abuse of a particular type of oral hypoglycemic agent, namely sulfonylurea drugs, used to experience mental altering effects for its euphoric “hypoglycemic rush”.  Information is available on discussion fora online where people exchange their experiences.  Moreover, several case reports have been published and described the liability for abuse of sulfonylurea drugs. This article intends to shed the light on this phenomenon in light of available literature, attempting to explain the possible scientific basis for it. In addition, it highlights the need for health professional awareness and vigilance for this form of drug diversion.  Impact on practice:  Raising awareness of clinicians about the underestimated, under-researchedissue of hypoglycemic drug abuse. Explaining the potential abuse of hypoglycemic rush in light of published scientificliterature. Making recommendations to legislative authorities in some countries to limitaccess to sulfonylurea drugs to be available strictly on prescription.Abstract Click here to access/download;Manuscript (non-blinded);Abstract IJCP.docxClick here to view linked References1 Abuse of Sulfonylureas: Is Factitious Hypoglycemia a cause for concern? 1 2 Mayyada Wazaify,1 Leen Abushams,1 Marie Claire Van Hout23 4 1: Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The 5 University of Jordan 6 2: Public Health Institute, Liverpool John Moore’s University, United Kingdom 7 8 Address for correspondence and reprints:  9 Professor Mayyada Wazaify 10 Department of Biopharmaceutics and Clinical Pharmacy 11 E-mail:  m.wazaify@ju.edu.jo12 Telephone: +962795494923 13 ORCID #: orcid.org/0000-0001-8724-6027 14 15 16 17 18 19 20 Keywords: euphoria, factitious hypoglycemia, prescription drug abuse, sulfonylurea 21 22 23 Manuscript Click here to access/download;Manuscript (non-blinded);Non-Blinded OHA Commentary.docxClick here to view linked References2 Abuse of Sulfonylureas: Is Factitious Hypoglycemia a cause for concern? 24 25 26 The aim of writing this Commentary is to shed the light on a briefly reported and dated 27 form of intentional drug intoxication known as “factitious hypoglycemia” [1,2] which 28 appears to be re-emerging in recent times [1,3]. We refer to the phenomenon of abuse of 29 a particular type of oral hypoglycemic agents, namely sulfonylurea drugs, used to 30 experience mental altering effects for its euphoric “hypoglycemic rush” [1].  We utilize the 31 definition of abuse whereby intentional use of pharmaceutical medicines is for non-32 medical purposes, rather than accidental overdose [4]. Anecdotal web discussions  [5] 33 and case reports of Marchetti et al 1988 and Svirski and Edoute 1996 [6,7] center on the 34 use of sulfonylurea drugs to experience a “near coma” state, which users describe as 35 “joyful” or “euphoric”. [3,5] Such mind altering effects are caused by the deliberate 36 inducement of hypoglycemia or referred to as “factitious hypoglycemia” [6,7]. A narrative 37 review was conducted and designed to present a broad perspective on abuse or misuse 38 of oral hypoglycemic agents, and describe its history and development in terms of how 39 common it is and its public health implications. A structured literature search was 40 conducted based on the question; what is currently known about liability of sulfonylureas 41 to abuse? Search terms include sulfonylureas, oral hypoglycemic agents, glibenclamide, 42 glyburide, different brand names, and “euphoria”,“high”,“hypoglycemic rush”. There was 43 no restriction on date range, and all types of articles, including opinion pieces were 44 included. 45 In general, oral hypoglycemic agents are among the most benign and low risk 46 drugs in terms of potential abuse liability. However, on conducting this rapid review of 47 3  web discussions and extant literature, we wish to draw the readership’s attention to this 48 unique form of intoxicating and non-medical intentional use of sulfonylurea drugs. We 49 know that those interested in alternative ways of getting “high” are constantly in search 50 for new alternatives that are available, cheap and legal and replace those drugs which 51 are harder to obtain, more expensive illicit drugs. [8,9] For example, more unusual forms 52 of pharmaceutical medicinal diversion include those with little or no mental altering effects 53 such as bisoprolol, table salt or menthol vapor rubs [8-10]. Hence, we report here on the 54 case of abuse of sulfonylureas, whereby the reported intoxication effect is caused by 55 adrenaline release [11,12]. Adrenaline is responsible for the feeling of “rush” and 56 contribution to dependence type behavior [11,12].  57 Normally, the brain utilizes glucose as sole energy source, which makes it 58 particularly sensitive to any decrease in blood glucose level. When blood glucose levels 59 drop too low, the body tries to increase the amount of glucose available in the bloodstream 60 by releasing hormones such as glucagon and epinephrine (also called adrenaline) that 61 stimulate the release of glycogen from the liver [13]. Symptoms of hypoglycemia are 62 caused by a combination of adrenaline release and low glucose in the brain. Adrenaline 63 can cause anxiety, shaking, sweating, tachycardia, and emotional reactivity such as 64 irritability, anger and tears, “brain fog,” fatigue and insomnia [14]. These symptoms are 65 often called the “warning signs” of hypoglycemia [13].  Lack of glucose to the brain can 66 cause  difficulties in concentration, blurred vision, slurred speech, lack of coordination, 67 headaches, dizziness, and drowsiness. Hypoglycemia can also cause changes in 68 emotions and mood. Feelings of nervousness and irritability, becoming argumentative, 69 showing aggression, and crying are common, although some people experience euphoria 70 4  and giddiness [14]. “Factitious hypoglycemia” occurs secondary to the surreptitious use 71 of insulin or insulin secretagogues (sulfonylureas, meglitinides). It can be differentiated 72 from fasting hypoglycemia caused by hyperinsulinaemia or injection of insulin, by an 73 elevated (> 1.0) molar ratio of insulin to C-peptide [15]. When sulfonylurea preparations 74 are consumed, the only way of distinguishing factitious hypoglycemia from insulinoma is 75 by determining the drug in serum and urine [14]. 76  77 We conducted a rapid assessment of web discussions and review of extant literature 78 which describe this unique form of pharmaceutical medicinal abuse whereby consumers 79 deliberately ingest large doses of glibenclamide (also known as Glyburide) of up to 80 50mg at once to cause hypoglycemia and induce associated euphoric effects [6,7,16]. 81 We note that the maximum daily dose ranges between 12 mg (micronized form) to 20 82 mg (standard glibenclamide) [17]. Several cases of deliberate inducement of 83 hypoglycemia [6,7,16] described varied reasons for such excessive consumption, either 84 to experience drug induced euphoria [16], or in seeking attention caused by Munchasen 85 syndrome [18]. Of note are that case reporting occurs in the majority in medical 86 personnel, diabetics or members of their family [14,16].  There are several factors 87 contributing to such increased risk of drug abuse among medical personnel, such as 88 emotional stress at work and easy access to drugs. [19] In addition, healthcare 89 professionals’ over-confidence may lead them to believe that their medical competency 90 will prevent problems relating to acute intoxication and misuse of such drugs.. [19] A 91 survey of 60 adolescents (12-20 years old) with Type-1 diabetes mellitus revealed a 92 36.7% prevalence of substance (alcohol, tobacco, illicit drugs) use and 19% reported 93 5  insulin misuse. [20] In this study, self-harm intent was reported by one-third of insulin 94 misusers. Substance use and insulin misuse were not related to glycemic control or 95 diabetes self-management behaviors.[20] 96  97 Despite the low case reporting, web discussions register an interest in “factitious 98 hypoglycemia” as evidence by the following comments; “I like the feeling. until it starts 99 getting crazy intense, then it's like I guess I should do something about this”, “mild 100 hypoglycemia feels good to me. I feel like I have been day drinking”, “I know alot of 101 people describe having a hypo like being drunk, but at least you know why you're 102 drunk.” “I bet if there was a way to safely get your levels down to a hypo level and keep 103 them there people would use it as a drug.” [5]. 104 Hence we wish to draw attention to this unique form of pharmaceutical medicinal 105 abuse for intoxication purposes, and the need for health professional awareness of and 106 vigilance for this form of diversion and patient misuse of their drugs. In addition medical 107 and pharmacy practitioners are advised to be aware of  symptomatologies of “factitious 108 hypoglycemia” and the need for pharmacovigilance  109  110 Ethics Approval: N/A 111 Finding: N/A 112 Acknowledgements: N/A 113 6  References: 114 1. Suusman KE. The use and abuse of oral hypoglycemic agents. Rocky Mt Med J. 115 1967;64(2):56-9 116 2. Horwitz DL. Factitious and artifactual hypoglycemia. Endocrinol Metab Clin N  117 Am. 1989;18(1):203-10. 118 3. Brown A. Feeling euphoric on a low-carb diet? The effect on your brain is similar to an 119 illicit drug. In: The conversation website. 2017. http://theconversation.com/feeling-120 euphoric-on-a-low-carb-diet-the-effect-on-your-brain-is-similar-to-an-illicit-drug-76303.   121 Accessed 2 Jul 2018. 122 4. Hughes GF, McElnay JC, Hughes CM, McKenna P. Abuse/misuse of non-123 prescription drugs. Pharm World  Sci 1999; 21: 251-255. 124 5. Anonymous. Feeling some sort of high or euphoria from hypoglycemia. In: Reddit 125 website. 2016. 126 https://www.reddit.com/r/diabetes/comments/4snzwp/feeling_some_sort_of_hig127 h_or_euphoria_from/. Accessed 24 Jun 2018. 128 6. Marchetti P, Faloppa C, Zappella A, Navalesi R. A case of factitious hypoglycemia 129 with unusual presentation. Minerva Med. 1988;79(12):1101-3. 130 7. Svirski B, Edoute Y. Sulfonylurea-induced factitious hypoglycemia. 131 Harefuah. 1996;130(10):678-80. 132 8. Madae'en S, Bostamy B, Jaber D, Wazaify M. Death of a middle-aged man after long 133 term abuse of a combination anticholinergic, beta blockers and narcotic drugs: A 134 7  suspected Münchausen syndrome case report. J Addict Neuropharmacol. 135 2015;2(1):7-9 136 9. Jaber D, Al-Awwa I, Wazaify M. Multiple prescription drug abuse and salt craving in a 137 psychotic patient: A case report from a teaching hospital in Jordan. Int J High Risk 138 Behav Addict. 2015;4(3):e22449 139 10. Blackwood GW. 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Abuse of sulfonylureas: Is factitious hypoglycemia a cause for concern?

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Abuse of sulfonylureas: Is factitious hypoglycemia a cause for concern?

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