Research Article PTB Reports Analysis of Gabapentinoids Abuse-Reports in the Middle East and North Africa Region Utilizing the Food and Drug Administration Adverse Event Reporting System Mona Yaser Alsheikh, College of Pharmacy, Taif University, Taif, SAUDI ARABIA. Ali Mofleh Alshahrani, College of Pharmacy, Taif University, Taif, SAUDI ARABIA. Reem Dhayan Almutairi, Department of Pharmaceutical Business and Administrative Sciences, MCPHS University, Boston, MA, USA. Hana Abdulmohsen Althobaiti, College of Pharmacy, Chapman University, Irvine, California, US. Ahmed Ibrahim Fathelrahman, College of Pharmacy, Taif University, Taif, SAUDI ARABIA. Enrique Seoane-Vazquez, College of Pharmacy, Chapman University, Irvine, California, US. Moudi Mubarak Alasmari*, 1College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah, SAUDI ARABIA. 2 King Abdullah International Medical Research Center (KAIMRC), Jeddah, SAUDI ARABIA. ABSTRACT Objectives: The purpose of this study was to identify abuse-related post-marketing reports associated with gabapentinoids use in the Middle East and North Africa (MENA) region countries. Methods: A retrospective cross-sectional analysis of abuse-related adverse drug event (ADE) reports from the Middle East and North Africa (MENA) region. It was performed using the Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 2008 through June 2020. Abuserelated ADE reports for gabapentin and pregabalin were extracted from the FAERS database. Descriptive statistics were performed, and the proportional reporting ratio (PRR) was calculated to detect disproportional attribution of abuse-related ADEs for gabapentin versus pregabalin. Results: We identified 559 all-cause ADE reports for gabapentinoids, including 205 (36.7%) abuse-related ADE reports reported to FAERS in the period of analysis. FAERS included 139 (67.8%) pregabalin and 66 (32.2%) gabapentin abuse-related ADE reports. Among MENA region countries, Turkey (55, 39.6%) and Saudi Arabia (34, 23.7%) had the highest number of abuse-related ADE reports for pregabalin. The most pregabalin abuse-related ADE reports involved adult male patients. The PRR of pregabalin versus gabapentin abuse-related ADE reports was 1.11, indicating that the number of abuse-related events was higher for pregabalin compared to gabapentin. Conclusion: Over 200 cases of abuserelated gabapentinoids events were reported to FEARS from the MENA region in the study period. Further studies should assess risk factors and potential programs to reduce gabapentinoids abuse. Key words: Gabapentin, Pregabalin, Adverse drug events, MENA, FAERS, Abuse. INTRODUCTION Correspondence: Dr. Moudi M Alasmari, Pharm D, MSc College of Medicine, King Saud bin Abdulaziz University for Health Sciences, P.O Box 9515, Zip Code 21423, Jeddah, SAUDI ARABIA. Phone no: 00966 12 2245000 E-mail: alasmari_moudi@gmail.com Received: 21-10-2020; Accepted: 05-02-2021. Copyright: © the author(s),publisher and licensee Pharmacology, Toxicology and Biomedical Reports. This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. This is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License Access this article online WWW.ptbreports.org DOI: 10.5530/PTB.2021.7.2 PTB Reports, Vol 7, Issue 1, Jan-Apr, 2021 Gabapentinoids (pregabalin and gabapentin) are widely prescribed in neurology and psychiatry and often prescribed off-label for a range of clinical conditions, including alcohol and narcotic withdrawal states, non-neuropathic pain disorders, and attention deficit hyperactivity disorder. Gabapentinoids act as gammaaminobutyric acid (GABA) analogs, blocking alpha-2- delta subunit-containing voltagedependent calcium channels.1 Gabapentin was approved by the Food and Drug Administration (FDA) for post-herpetic neuralgia and epilepsy in 1993. Pregabalin was approved in 2004 for neuropathic pain, fibromyalgia, post-herpetic neuralgia, and seizures.2-5 In the United States, the prescription rates for gabapentinoids increased significantly between 2002 and 2015 and pregabalin was a top 10 best-selling medication in 2017.6,7 In Saudi Arabia, pregabalin was one of the top 10 sold drugs during 2010-2015.8 Recent systematic reviews documented gabapentinoid abuse-related adverse drug events (ADEs), including abuse, misuse, dependence, or overdose.9,10 Studies have also shown gabapentinoids are likely to be abused among individuals with opioid dependence syndrome.11-13 The abuse potential of gabapentinoids has been demonstrated in some clinical studies.9,10 In Saudi Arabia, a study found that 12.4% of participants used pregabalin without a prescription.14 Additionally, studies showed the potential risks for pregabalin misuse, abuse, and related harms in the United Arab Emirates and Jordan.15,16 A few case reports also described pregabalin abuse in Turkey and Lebanon.17-19 The abuse of gabapentinoids is a serious public health problem.6,13,14,16-20 There are some differences among countries in terms of gabapentinoids scheduling system. According to the United States Drug Enforcement Administration (DEA), pregabalin is classified as a Schedule V controlled substance, representing the least potential for abuse. In contrast, gabapentin is not classified as a controlled substance despite the evidence of abuse.4,5,13 On the other hand, In Saudi Arabia, in May 2015, pregabalin was classified as a controlled substance by (SFDA). However, gabapentin is still a prescribed medication (Saudi Food and Drug Authority). The Jordan Food and Drug Administration (JFDA) also included pregabalin preparations in the restricted drug list in 2017.21-23 On the other hand, gabapentinoids are not controlled medications in Turkey.17 Although gabapentinoids share many similar pharmacologic properties, such as interacting with the same binding site, renal excretion, comparable metabolic profiles, minimal protein binding, and negligible drug-drug interactions, they have significant absorption differences.24-27 Gabapentin is absorbed less rapidly than pregabalin, with maximum plasma concentrations attained within 3-4 hr instead of 1 5 Alsheikh MY, et al.: Analysis of Gabapentinoids Abuse-Reports in the Middle East and North Africa Region hr. Due to saturable absorption, gabapentin absorption drops from 68% to 36% after the dosage increases from 300mg to 1600 mg. In contrast, pregabalin’s absolute bioavailability maintains ≥90% despite increasing doses.24,26,28 That might explain why pregabalin is classified as a controlled medication while gabapentin is not. A recent study, which used the United States data from the 2012-2016 Food and Drug Administration Adverse Event Reporting System (FAERS) data; found that a total of 576 cases out of 10,038 (5.7%) abuserelated events were reported to FAERS for gabapentin, and 58 cases out of 571 (10.2%) ADEs related to abuse were identified for pregabalin.29 This study has been conducted to evaluate epidemiological information regarding the scope of gabapentinoids abuse utilizing the FAERS database not to assess their abuse trends. To the authors’ knowledge, there were no studies available at the time of this study that have identified abuse-related post-marketing reports associated with gabapentinoids (gabapentin and pregabalin) use in the Middle East and North Africa (MENA) region countries.This study aimed to identify abuse-related post-marketing reports associated with gabapentinoids (gabapentin and pregabalin) use in the MENA region countries reported to FAERS from January 2008 to June 2020. MATERIALS AND METHODS Data sources A retrospective analysis of gabapentinoids (gabapentin and pregabalin) ADE reports from the MENA region was performed using the FAERS (U.S. Food and Drug Administration). The FAERS database contains ADE reports, medication error reports, and product quality complaints resulting in adverse events submitted to the FDA. The database is designed to support the FDA’s post-marketing safety surveillance program for drug and therapeutic biological products. In other words, FAERS data play a significant role in identifying early safety signals.30-32 The dataset is publicly available online and de-identified on the FDA website. Thus, no institutional review board approval is required. All ADE reports for pregabalin and gabapentin reported to FAERS from January 2008 to June 2020 were identified by searching the active ingredient names, dosage forms, and spellings with no specific reaction or outcome criteria. The MENA region definition includes 23 countries: Afghanistan, Algeria, Bahrain, Djibouti, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Mauritania, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, Turkey, United Arab Emirates, Yemen. The MENA region reports were extracted by using International Organization for Standardization (ISO) 3166-1 alpha-2 codes.33-35 FAERS classifies the reports expedited (reports from the manufacturer submitted to the FDA within 15 days of a serious and unexpected ADE not included in product labeling) and non-expedited reports of serious and non-serious adverse events for new molecular entity (NME) products within the first three years following FDA approval.36 Serious outcomes include death, hospitalization, life-threatening, disability, congenital anomaly, and/or other serious outcomes. The primary sources of FAERS reports are categorized into healthcare professionals and consumers. Abuse-related ADE reports were defined as reports with drug abuse, drug dependence, drug tolerance, withdrawal syndrome, euphoric mood, overdose, intentional overdose, intentional product misuse, product use in unapproved indication, maternal use an illicit drug, loss of personal independence in daily activities, substance-induced psychotic disorder, and intoxication.25,29,37-39 The demographic characteristics of FAERS reports are limited. ADE reports were classified by patient gender (male, female) and age in years at the time of the report. Data analysisDescriptive statistics were performed, and the proportional reporting ratio (PRR) was calculated to detect a disproportional 6 attribution of ADEs for gabapentin versus pregabalin. The PRR was calculated using the following equation: PRR=[Pa/Pt]/[Ga/Gt], where Pa = number of ADEs reported for pregabalin abuse, Pt = total number of ADEs reported for all pregabalin, Ga = number of ADEs reported of gabapentin abuse, and Gt = total number of ADEs reported for all gabapentin. The null value for a PRR is one, which means the higher the PRR, the greater the strength of the signal of abuse.29,40 Descriptive statistical analyses, including frequencies and percentages, were performed using Microsoft Excel (2016 Version, Redmond, WA). RESULTS We identified 559 all-cause FAERS ADE reports for gabapentinoids from January 2008 to June 2020, including 366 (65.5%) pregabalin and 193 (34.5%) gabapentin reports. FAERS listed 66 (32.2%) abuse-related gabapentin ADE reports, of which 55 (83.3%) were reported by healthcare professionals, and 63 (95.5%) were expedited reports. There were 35 (53.0%) abuse-related ADEs reports of women patients. The mean patient age among abuserelated ADEs was 54.4±16.5 years (median=50). Among MENA region countries, Turkey (42, 63.6% of all MENA reports) had the greatest number of reports, followed by Iran (17, 25.8%) (Table 1). The most common gabapentin abuse-related ADEs reactions were for indications that are non-FDA approved, which were mentioned in 16 (23.2%) reports (Table 2). Other gabapentin abuse-related ADEs included 15 (21.7%) substance-induced psychotic disorder, 14 (20.3%) intoxication, 8 (11.6%) withdrawal syndrome and 8 (11.6%) maternal use of illicit drugs reactions. The outcomes reported for gabapentin abuse-related ADE included 6 (9.1%) death, 8 (12.1%) hospitalizations, and 46 (69.7%) other serious outcomes (Table 3). Moreover, from January 2008 to June 2020, FAERS listed 139 (67.8%) abuse-related pregabalin ADE reports. There were 106 (76.3%) cases were reported by healthcare professionals to the FAERS database, and 137 (98.6%) were expedited reports. There were 67 (48.2%) abuse-related ADEs reports of male patients. The mean patient age among abuserelated ADEs was (36.0 ± 19.1) years (median=28). Among MENA region countries, Turkey (55, 39.6%) had the greatest number of reports, followed by Saudi Arabia (34, 23.7%) and Jordan (19, 13.7%) (Table 1). Drug abuse was mentioned in 77 (39.1%) reports and was the most frequent pregabalin abuse-related ADE, followed by overdose (24, 12.2%), intentional overdose (12, 6.1%), and drug dependence reactions (12, 6.1%) (Table 2). The outcomes reported for pregabalin abuse-related ADE included 4 (2.9%) death, 24 (17.3%) hospitalizations, 2 (1.4%) congenital anomalies, and 103 (74.1%) other serious outcomes (Table 3). The PRR of pregabalin versus gabapentin abuse-related events was 1.11, indicating that the number of abuse-related ADEs and the strength of the signal of abuse were slightly higher for pregabalin than for gabapentin. DISCUSSION This study’s results indicate that most of the gabapentinoids abuserelated events reported in some of the MENA region countries in the study period were associated with pregabalin use. This finding could be due to the distinct pharmacokinetic advantages of pregabalin over gabapentin. These advantages have been linked to the superiority of pregabalin pharmacodynamic properties such as higher bioavailability, faster absorption, and rapid onset of action with higher potency than gabapentin, which may explain the higher addiction potential of pregabalin.24-28We also noted that Turkey, Saudi Arabia, and Jordan had the greatest number of pregabalin abuse-related ADE reports among MENA region countries. In most MENA region countries, gabapentinoids are prescribed as non-controlled medications.16,41 However, some of the MENA countries have taken serious actions to PTB Reports, Vol 7, Issue 1, Jan-Apr, 2021 Alsheikh MY, et al.: Analysis of Gabapentinoids Abuse-Reports in the Middle East and North Africa Region prevent the risk of gabapentinoids abuse. For instance, in Saudi Arabia, the SFDA classified pregabalin as a controlled substance in May 2015, but gabapentin has not been classified as a controlled substance yet (Saudi Food and Drug Authority). In Jordan, the JFDA added pregabalin to the restricted drug list in 2017.21-23Previous studies show that gabapentinoid abuse events seem to be more likely in young adults; however, data about gender differences are conflicting.10,29,39 Our study found that most of the gabapentin abuse-related ADE reports involved adult women patients, while the majority of pregabalin abuse-related ADE reports were for young adult male patients. Some MENA region countries did not report any gabapentinoids ADE to FAERS. This may be attributed to variations in policies and characteristics of reporting systems in the region because each country has its adverse event reporting system. For example, Saudi Adverse Event Reporting System (SAERS) was launched by SFDA in March 2009 to monitor the safety of post-marketed medications. Also, the Turkish Pharmacovigilance Center (TUFAM) was established in 2015.42The analysis also revealed that abuse-related ADEs were higher for pregabalin than gabapentin. This result confirms the findings by Evoy et al. 2019. Although this study did not assess the concomitant medications, Table 1: Characteristics of Gabapentinoids Abuse-Related ADEs Reported to FAERS (January 2008-June 2020). Table 2: Type of Gabapentinoids Abuse-related ADE Reactions Reported to FAERS (January 2008-June 2020). ADE Reactions Gabapentin n (%) Pregabalin n (%) 69 (25.9%) 197 (74.1%) - 77 (39.1%) 2 (2.9%) 24 (12.2%) TOTAL Drug Abuse Overdose Intentional Overdose - 12 (6.1%) Drug Dependence 4 (5.8%) 12 (6.1%) Withdrawal Syndrome 8 (11.6%) 10 (5.1%) Intentional Product Misuse - 9 (4.6%) Product Use in Unapproved Indication 16 (23.2%) 9 (4.6%) Intoxication 14 (20.3%) 8 (4.1%) Drug Tolerance 1 (1.4%) 6 (3.0%) Euphoric Mood 1 (1.4%) 4 (2.0%) - 4 (2.0%) Maternal use of the illicit drug 8 (11.6%) 8 (4.1%) Substance-Induced Psychotic Disorder 15 (21.7%) 14 (7.1%) Loss of Personal Independence in Daily Activities *Multiple reactions were listed for some cases Gabapentin n (%) Pregabalin n (%) Total 66 (32.2%) 139 (67.8%) Male 11 (16.7%) 67 (48.2%) Female 35 (53.0%) 37 (26.6%) Reactions Not Specified 20 (30.3%) 35 (25.2%) TOTAL Death 6 (9.1%) 4 (2.9%) 54.4 36.0 Hospitalization 8 (12.1%) 24 (17.3%) 50 28 Life-threatening 2 (3.0%) - Disability 1 (1.5%) - Characteristics Age Mean Median Standard Deviation ±16.5 ±19.1 Table 3: Outcomes of Gabapentinoids Abuse-related ADE Reported to FAERS (January 2008-June 2020). Gabapentin events n (%) Pregabalin events n (%) 66 (32.2%) 139 (67.8%) Type Congenital anomaly - 2 (1.4%) Expedited 46 (69.7%) 103 (74.1%) 3 (4.5%) 6 (4.3%) 63 (95.5%) 137 (98.6%) Other serious outcomes 3 (4.5%) 2 (1.4%) Non-serious outcomes Consumer 11 (16.7%) 33 (23.7%) Healthcare Professional 55 (83.3%) 106 (76.3%) Non-Expedited Source MENA Region Countries (Includes Only Countries with FAERS Reports) Algeria - 7 (5.0%) Bahrain - 1 (0.7%) Egypt 1 (1.5%) 3 (2.2%) Iran 17 (25.8%) 1(0.7%) Israel 2 (3.0%) 13 (9.4%) Jordan - 19 (13.7%) Lebanon 2 (3.0%) 3 (2.2%) Morocco - 1 (0.7%) 2 (3.0%) 33 (23.7%) Saudi Arabia Tunisia - 1 (0.7%) Turkey 42 (63.6%) 55 (39.6%) - 2 (1.4%) United Arab Emirates PTB Reports, Vol 7, Issue 1, Jan-Apr, 2021 Chiappini et al. 2016 and Evoy et al. 2019 studies found that most deaths occurred in patients who were also taken opioids.29,39 This study has some limitations. First, there is no certainty that the ADE reports were due to gabapentinoids themselves; it might be due to the concomitant medications. Second, since ADE reporting from consumers or healthcare professionals is voluntary, the FDA does not receive reports for every adverse event or medication error that occurs with a product. Therefore, FAERS data can detect safety signals but cannot be used to estimate the incidence of adverse events or medication errors. CONCLUSION Over 200 cases of abuse-related gabapentinoids events were reported to FEARS from the MENA region in the study period. Further studies should assess risk factors and potential programs to reduce gabapentinoids abuse. ACKNOWLEDGEMENT None 7 Alsheikh MY, et al.: Analysis of Gabapentinoids Abuse-Reports in the Middle East and North Africa Region Declarations of interest None Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. CONFLICT OF INTEREST The authors declare no conflict of interest. Ethical approval This study does not involve the use of any human or animal subjects. Data availability The data used to support the findings of this study will be available upon request. Authors contributions Mona Alsheikh: Writing- original draft preparation, methodology, data curation. Ali Alshahrani: Software, reviewing, and editing. Reem Almutairi: Conceptualization, reviewing, and editing. Hana Althobait: Methodology, investigation. Validation. Ahmed Ibrahim Fathelrahman: Editing and proofreading, Enrique Seoane-Vazquez: visualization, supervision, and editing. Moudi Alasmari: Writing- original draft, methodology, reviewing, and editing. REFERENCES 1. Patel R, Dickenson AH. Mechanisms of the gabapentinoids and α2δ-1 calcium channel subunit in neuropathic pain. Pharmacol Res Perspect. 2016;4(2):e00205. 2. Vadivelu N, Mitra S, Narayan D. Recent advances in postoperative pain management. Yale J Biol Med. 2010;83(1):11-25. 3. Imani F, Rahimzadeh P. Gabapentinoids: Gabapentin and pregabalin for postoperative pain management. Anesthesiol Pain Med. 2012;2(2):52-3. 4. Neurontin® [package insert]. Pfizer Inc. USA. 2020. http://labeling.pfizer.com/ ShowLabeling.aspx?format=PDF&id=630. 5. Lyrica® [package insert]. Pfizer Inc., USA. 2020. http://labeling.pfizer.com/ showlabeling.aspx?id=561. 6. Johansen ME. Gabapentinoid use in the United States 2002 through 2015. JAMA Intern Med. 2018;178(2):292-4. 7. Urquhart L. Market Watch: Top drugs and companies by sales in 2017. Nat Rev Drug Discov. 2018;17(4):232-3. 8. AlKhamees OA, AlNemer KA, Maneea MWB, AlSugair FA, AlEnizi BH, Alharf AA. Top 10 most used drugs in the Kingdom of Saudi Arabia 2010–2015. Saudi Pharm J. 2018;26(2):211-6. 9. Zaccara G, Gangemi P, Perucca P, Specchio L. The adverse event profile of pregabalin: A systematic review and meta-analysis of randomized controlled trials. Epilepsia. 2011;52(4):826-36. 10. Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017;77(4):403-26. 11. Grosshans M, Lemenager T, Vollmert C, Kaemmerer N, Schreiner R, Mutschler J, et al. Pregabalin abuse among opiate addicted patients. Eur J Clin Pharmacol. 2013;69(12):2021-5. 12. Bodén R, Wettermark B, Brandt L, Kieler H. Factors associated with pregabalin dispensing at higher than the approved maximum dose. Eur J Clin Pharmacol. 2014;70(2):197-204. 13. Peckham AM, Ananickal MJ, Sclar DA. Gabapentin use, abuse and the US opioid epidemic: The case for reclassification as a controlled substance and the need for pharmacovigilance. Risk Manag Healthc Policy. 2018;11:109-16. 14. Alosaimi FD, Alruwais FS, Alanazi FA, Alabidi GA, Aljomah NA, Alsalameh NS. Patient’s reasons for obtaining psychotropic medications without a prescription at retail pharmacies in Central Saudi Arabia. Neurosciences. 2016;21(4):338-44. 15. Alblooshi H, Hulse GK, ElKashef A, AlHashmi H, Shawky M, AlGhaferi H, et al. The pattern of substance use disorder in the United Arab Emirates in 2015: Results of a National Rehabilitation Centre cohort study. Subst Abuse Treat Prev Policy. 2016;11(1):19. 16. Al-Husseini A, Wazaify M, Hout MCV. Pregabalin Misuse and Abuse in Jordan: A Qualitative Study of User Experiences. Int J Ment Health Addict. 2018;16(3):642-54. 8 17. Yargic I, Ozdemiroglu FA. Pregabalin abuse: A case report. Klin Psikofarmakol Bul. 2011;21(1):64-6. 18. Aldemir E, Altintoprak AE, Coşkunol H. Pregabalin dependence: A case report. Turk Psikiyatr Derg. 2015;26(3):217-20. 19. Halaby A, Kassm SA, Naja WJ. Pregabalin dependence: A case report. Curr Drug Saf. 2015;10(2):184-6. 20. Grosshans M, Lemenager T, Vollmert C, Kaemmerer N, Schreiner R, Mutschler J, et al. Pregabalin abuse among opiate addicted patients. Eur J Clin Pharmacol. 2013;69(12):2021-5. 21. Saudi Food and Drug Authority (n.d.-a). 2020. Available at: https://www.sfda. gov.sa/ar/drug/circulations/DocLib/%D8%A5%D8%AC%D8%B1%D8%A7% D8%A1%D8%A7%D8%AA%20%D9%88%D8%B6%D9%88%D8%A7%D 8%A8%D8%B7%20%D8%B5%D8%B1%D9%81%20%D9%85%D8%B3 %D8%AA%D8%AD%D8%B6%D8%B1%D8%A7%D8%AA%20Pregabalin. pdf. 22. Saudi Food and Drug Authority (n.d.-b). 2020. Available at: https://www.sfda. gov.sa/ar/drug/drug_reg/DocLib/anti_drugs22.pdf. 23. Jordan Food and Drug Administration. Formal Statement About the restricted Dispensing of Pregabalin in Jordan. JFDA. 2013. http://www.jfda.jo/ EchoBusV3.0/SystemAssets/2f00f42e-427b-40ba-abf4 93adfb8c2ad6.jpg. 24. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661-9. 25. Schwan S, Sundström A, Stjernberg E, Hallberg E, Hallberg P. A signal for an abuse liability for pregabalin-results from the Swedish spontaneous adverse drug reaction reporting system. Eur J Clin Pharmacol. 2010;66(9):947-53. 26. Schifano F. Misuse and abuse of pregabalin and gabapentin: Cause for concern?. CNS Drugs. 2014;28(6):491-6. 27. Baird CRW, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: A survey among substance misusers. Eur Addict Res. 2014;20(3):115-8. 28. Papazisis G, Tzachanis D. Pregabalin’s abuse potential: A mini-review focusing on the pharmacological profile. Int J Clin Pharmacol Ther. 2014;52(8):709-916. 29. Evoy KE, Covvey JR, Peckham AM, Ochs L, Hultgren KE. Reports of gabapentin and pregabalin abuse, misuse, dependence, or overdose: An analysis of the Food and Drug Administration Adverse Events Reporting System (FAERS). Res Soc Adm Pharm. 2019;15(8):953-8. 30. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions current perspectives and future needs. J Am Med Assoc. 1999;281(9):824-9. 31. Throckmorton DC, Gottlieb S, Woodcock J. The FDA and the next wave of drug abuse - Proactive pharmacovigilance. N Engl J Med. 2018;379(3):205-7. 32. FDA Adverse Event Reporting System (FAERS) Public Dashboard. FDA, USA. 2019. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-eventreporting-system-faers/fda-adverse-event-reporting-system-faers-publicdashboard. 33. Fahed AC, El-Hage-Sleiman AKM, Farhat TI, Nemer GM. Diet, genetics, and disease: A focus on the Middle East and North Africa region. J Nutr Metab. 2012. 34. Chemaitelly H, Mahmud S, Kouyoumjian SP, Al‐Kanaani Z, Hermez JG, Abu‐ Raddad LJ. Who to Test for Hepatitis C Virus in the Middle East and North Africa?: Pooled Analyses of 2,500 Prevalence Measures, Including 49 Million Tests. Hepatol Commun. 2019;3(3):325-39. 35. International Organization for Standardization. Popular standards. ISO, Geneva. 2019 36. Reports Received and Reports Entered into FAERS by Year. FDA. Published 2015. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-eventreporting-system-faers/reports-received-and-reports-entered-faers-year 37. Gahr M, Freudenmann RW, Hiemke C, Kölle MA, Schönfeldt-Lecuona C. Pregabalin abuse and dependence in Germany: Results from a database query. Eur J Clin Pharmacol. 2013;69(6):1335-42. 38. Bossard JB, Ponté C, Dupouy J, Lapeyre-Mestre M, Jouanjus E. Disproportionality Analysis for the Assessment of Abuse and Dependence Potential of Pregabalin in the French Pharmacovigilance Database. Clin Drug Investig. 2016;36(9):735-42. 39. Chiappini S, Schifano F. A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency’s ‘Suspected Adverse Drug Reactions’ Database. CNS Drugs. 2016;30(7):647-54. 40. Evans SJW, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Harmacoepidemiol Drug Saf. 2001;10(6):483-6. 41. Wazaify M, Abood E, Tahaineh L, Albsoul-Younes A. Jordanian community pharmacists’ experience regarding prescription and nonprescription drug abuse and misuse in Jordan: An update. J Subst Use. 2017;22(5):463-8. 42. Ozcan G, Aykac E, Kasap Y, Nemutlu NT, Sen E, Aydinkarahaliloglu ND. Adverse Drug Reaction Reporting Pattern in Turkey: Analysis of the National Database in the Context of the First Pharmacovigilance Legislation. Drugs: Real World Outcomes. 2016;3(1):33-43. PTB Reports, Vol 7, Issue 1, Jan-Apr, 2021