Table 1.
Clinical and epidemiological studies
| Drug | Study, year | Time period | Country | Study design | Data source | Study population | Results |
|---|---|---|---|---|---|---|---|
| Pharmacovigilance studies | |||||||
| Pregabalin and gabapentin | Vickers-Smith et al., 2020 [16] | 2005–15 | USA | Post-marketing surveillance system study using pregabalin and duloxetine as controls | FDA adverse event reporting system (FAERS) | 99,977 all-cause ADEs were reported for gabapentin, 97,813 for pregabalin, and 73,977 for duloxetine | 22.9% (n = 22,929) of all reports were related to abuse for gabapentin, 26.1% (n = 25,554) for pregabalin: 25,554 reports and 29.3% (n = 21,689) for duloxetine |
| Pregabalin and gabapentin | Evoy et al., 2019 [17] | 2012–16 | USA | Post-marketing surveillance system study | FDA adverse event reporting system (FAERS) | 571 all-cause ADEs were reported for pregabalin and 10,038 all-cause ADEs for gabapentin | 10.2% (n = 58) of all reports were related to abuse for pregabalin and 5.7% (n = 576) for gabapentin |
| Pregabalin and gabapentin | Chiappini and Schifano, 2016 [18] | 2004–15 | Globally | Post-marketing surveillance system study | EMA’s adverse event reporting system (Eudravigilance) | 115,616 reports concerned pregabalin and 90,166 gabapentin |
Proportion of all reports related to abuse: Pregabalin 6.6% (n = 7639 including 27 deaths) Gabapentin 4.8% (n = 4301 including 86 deaths) |
| Pregabalin | Bossard et al., 2016 [19] | 2010–15 | France | Post-marketing surveillance system study using clonazepam and amitriptyline as controls | French adverse event reporting system (FPVD) | Of 184,310 reports, 521 were reports on abuse or dependency |
Proportion of all reports related to abuse: Pregabalin 1.5% (n = 8) Clonazepam 3.5% (n = 18) Amitriptyline 0% (n = 0) |
| Pregabalin | Gahr et al., 2013 [20] | 2008–12 | Germany | Post-marketing surveillance system study | German adverse event reporting system | 1552 all-cause ADRs concerned pregabalin |
Proportion of all reports related to abuse: pregabalin 3.5% (n = 55) |
| Pregabalin | Schwan et al., 2010 [21] | 1980–2009 | Sweden | Post-marketing surveillance system study | Swedish adverse event reporting system (SWEDIS) | 82,714 all-cause ADRs were reported. Of these, 198 reports concerned abuse or addiction | Proportion of reports on abuse related to pregabalin: 8.1% (n = 16) |
| Register-based studies | |||||||
| Pregabalin | Crossin et al., 2019 [22] | 2012–17 | Australia | Retrospective analysis of patient records Ambulance attendance due to misuse of pregabalin | Patient records | A total of 1201 pregabalin misuse-related ambulance attendances were included |
Proportion of attendances related to abuse related to pregabalin sales: 0.28 cases per 100,000 inhabitants during the first 6 months in 2012 3.32 cases per 100,000 inhabitants during the last 6 months in 2017 |
| Pregabalin and gabapentin | Piper et al., 2018 [23] | 2016 | USA | Open observational cohort study | Arrests reported to Maine Diversion Aalert Program (DAP) | 2368 arrested individuals | Of 181 arrests involved non-scheduled drug, 22.7% (n = 41) concerned gabapentin and 1.7% (n = 3) pregabalin |
| Gabapentin | Buttram et al., 2017 [24] | 2002–15 | USA | Quarterly survey of prescription drug diversion reported to law enforcement by means of a brief questionnaire | Drug diversion program of the Researched Abuse, Diversion and Addiction-Related Surveillance System (RADARS) | Data from a national survey |
In total, 407 cases of gabapentin diversion were reported during the period. Diversion rate: 0 during the first 2 quarters in 2002 0.027 per 100,000 inhabitants during the fourth quarter in 2015 |
| Pregabalin and gabapentin | Molero et al., 2019 [25] | 2006–13 | Sweden | Population-based cohort study | Prescription drug register | New users of gabapentin or pregabalin, in total 191,973 people | Treatments were associated with increased suicidal behavior or death from suicide 5.2% (n = 10,026), 8.9% (n = 17,144) had an unintentional overdose, 36.7% (n = 70,522) presented with head/body injuries, and 4.1% (n = 7984) were arrested for a violent crime Pregabalin was associated with higher hazards of all outcomes compared with gabapentin |
| Pregabalin and gabapentin | Driot et al., 2019 [26] | 2006–14 | France | Controlled cohort study | General sample of beneficiaries | New users of pregabalin (8692), gabapentin (1963), and duloxetine (3214) |
Proportion of patients where misuse was considered: 12.8% (n = 1112) for pregabalin 6.6% (n = 130) for gabapentin and 9.7% (n = 313) for duloxetine |
| Pregabalin | Cairns et al., 2019 [27] | 2012–17 | Australia | Population-based retrospective cohort study | Australian pharmaceutical benefits scheme, poison information centers, Australian toxicology service database, coronial records | 122,572 people dispensed pregabalin | Of 1158 reports of intentional poisonings, 88 pregabalin-related deaths were recorded 14.7% was considered to be at high risk of misuse according to an analysis of those prescribed pregabalin between March 2016 and February 2017 (n = 58,921) |
| Gabapentin | Peckham et al., 2018 [28] | 2013–15 | USA | Cross-sectional cohort study | Commercial insurance database |
44,148 patients treated with gabapentin 15,335 treated with gabapentin and opioids |
2.0% (n = 881) of patients with sustained overdose treated with gabapentin and no opioids 11.7% (n = 1,789) of patients treated with gabapentin and opioids |
| Pregabalin and gabapentin | Lyndon et al., 2017 [29] | 2004–15 | UK | Multidisciplinary, register-based study | Trends in drug-related deaths and prescription data | Data on prescription and death. Pregabalin and gabapentin prescriptions increased from 1 to 10.5 million over the period |
The number of deaths involving gabapentinoids increased from fewer than one per year before 2009 to 137, in 2015 79% of the deaths involved opioids Death < 1/million prescriptions to 13/million prescriptions from 2009 to 2015 |
| Pregabalin | Abrahamsson et al., 2017 [30] | 2005–12 | Sweden | Retrospective register-based open cohort study | Swedish Prescribed Drug Register linked to cause of death register, and the national inpatient register | All individuals aged 18–50 years dispensed methadone or buprenorphine as maintenance treatment for opioid dependence (n = 4501) heroin abusers | 22.2% had a pregabalin prescription Pregabalin was associated with overdose deaths, HR 2.82 (95% CI 1.79–4.43) |
| Pregabalin | Asomaning et al., 2016 [31] | 2004–9 | UK | Observational drug utilization study of prescription data | Prescription data | In total 13,480 subjects with a prescribed pregabalin including dosing information |
Proportion of patients prescribed pregabalin > 600 mg/day: 1% (n = 136) Of these, 18.4% (n = 25) had a history of substance abuse vs 14.0% (n = 1884) of the entire population |
| Pregabalin | Schjerning et al., 2016 [32] | 2004–13 | Denmark | Observational drug utilization study | Drug utilization nationwide registers | 42,520 pregabalin users were identified |
Proportion of patients prescribed pregabalin > 600 mg/day: 9.6% (n = 4090) for 6 months or more 6.5% (n = 2765) for 12 months or more |
| Pregabalin | Bodén et al., 2014 [33] | 2006–9 | Sweden | Prospective observational cohort study | Prescription drug register | 48,550 patients were dispensed pregabalin |
Proportion of patients prescribed pregabalin > 600 mg/day: 8.5% (n = 4130) |
| Surveys | |||||||
| Gabapentin | Stein et al., 2020 [34] | 2018–19 | USA | Sample of cohort of patients with opioid user disorders in withdrawal program | Survey interview | 401 of 472 patients with opioid user disorders admitted | 47% (n = 264) of 401 patients had used gabapentin, of them only non-prescribed gabapentin |
| Pregabalin | Al-Husseini et al., 2018 [35] | 2016–17 | Jordan | Structured interview with all customers | – | Requests for pregabalin at 14 community pharmacies in Amman, 77 customers | 45% (n = 35) with suspected abuse |
| Pregabalin | Al-Husseini et al., 2018 [36] | 2017 | Jordan | Semi-structured interviews | - | 11 users of pregabalin at two addiction centers | 91% (n = 10) of users with a previous history of substance abuse |
| Gabapentin | Vickers Smith et al., 2017 [37] | 2015 | USA | Semi-structured interview and focus group discussions | - | 33 recent users of gabapentin among non-medical users in Kentucky identified in two cohort studies | 67% (n = 22) reported use of prescription opioids, 15% reported use of gabapentin to get high |
| Pregabalin | Snellgrove et al., 2017 [38] | 2012–13 | Germany | Cross-sectional study Structured questionnaire and urine samples | – | 253 patients admitted to the detoxification ward for illicit drugs | 56% (n = 142) of patients used pregabalin, of these 92% had acquired it illegally |
| Gabapentin | Bastiaens et al., 2016 [39] | NA | USA | Structured questionnaire | – | 250 patients participating in the community correctional centers treatment program | 58% (n = 145) with an opioid use disorder, of these 26% (n = 37) used gabapentin vs 4% (n = 4) in the remaining 105 patients |
| Pregabalin | Alblooshi et al., 2016. [40] | 2015 | UAE | Structured questionnaire | – | 250 SUD patients at the national rehabilitation center and a control group of 239 individuals from a family register |
14% (n = 35) of patients used pregabalin The mean dose of 8.3 capsules a day, either alone or in combination with other drugs |
| Pregabalin and gabapentin | Wilens et al., 2015. [41] | 2013 | USA | Self-report questionnaire | – | 196 patients admitted to a public detoxification program: 162 opioid-dependent patients and 72 alcohol-dependent patients |
Proportion of the opioid patients misused gabapentin: 22% (n = 36) Proportion of the opioid patients misused pregabalin: 2% (n = 3) |
| Pregabalin and gabapentin | Baird et al., 2014. [42] | 2011–12 | Scotland | Questionnaire-based survey | – | 129 patients at 6 substance misuse clinics |
19% (n = 25) of the patients misused gabapentin 3% (n = 4) of the patients misused pregabalin: 7% (n = 9) were prescribed gabapentin and 1.5% (n = 2) pregabalin |
ADE adverse drug events, ADRs adverse drug reactions, CI confidence interval, EMA European Medicines Agency, FDA US Food and Drug Administration, HR hazard rate, NA not available, SUD substance use disorder, UAE United Arab Emirates