Misuse of Pregabalin and Gabapentin: A Second Systematic Review Update

Abstract

Background

A 2017 systematic review and 2021 update identified 114 studies regarding gabapentinoid (gabapentin and pregabalin) misuse, dependence, or overdose.

Objective

We aimed to update previous systematic reviews and describe new insights regarding gabapentinoid misuse.

Methods

PubMed was searched from 1 September, 2020 to 24 January, 2025 using the following four searches: “gabapentin [MeSH] OR pregabalin [MeSH] OR gabapentinoid AND” one of the following four substance misuse-related terms: “substance-related disorders [MeSH],” “overdose,” “abuse,” or “misuse.” Additional research was identified by reviewing papers cited by included studies. Studies presenting novel data regarding gabapentinoid misuse, dependence, or overdose were included. Non-English articles, review articles, and animal studies were excluded.

Results

One hundred studies (87 observational, 13 case reports/series) were included, from North America (33), Europe (39), Asia (20), Australia (7), and Africa (1). Sixteen studied gabapentin, 20 pregabalin, and 51 both medications. These studies corroborated previous findings that gabapentinoids are misused both for therapeutic and non-therapeutic purposes, often in conjunction with opioids or other substances, and commonly in people with substance use disorders and psychiatric conditions. Recent research built on the previous systematic review, providing more robust evidence that concomitant use with opioids or benzodiazepines increases overdose risks. New studies also highlight a growing body of evidence regarding misuse within the Middle East and North Africa, among adolescents, and in patients with chronic pain.

Conclusions

Newly published evidence demonstrated that gabapentinoid misuse remains a significant concern, including in several populations not often highlighted in previous research. It provides more compelling evidence that gabapentinoids increase overdose risk, particularly when used with opioids or benzodiazepines.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40265-026-02342-w.

Key Points

This systematic review corroborated previous findings that gabapentinoids are increasingly misused for therapeutic and non-therapeutic purposes, often with opioids, and among individuals with substance use disorders and psychiatric conditions.

Building on the previous systematic review, recent research has provided more robust evidence that gabapentinoids significantly increase overdose risk, particularly when used with opioids or benzodiazepines.

Recent evidence highlighted growing misuse trends in additional groups, including adolescents, those living within or immigrating from the Middle East and North Africa, and in patients with chronic pain.

Introduction

Gabapentin and pregabalin (collectively, gabapentinoids) were approved by the US Food and Drug Administration (FDA) in 1993 and 2004, respectively, for partial-onset seizures and post-herpetic neuralgia [1, 2]. Gabapentin has also gained approval for restless leg syndrome and pregabalin has additional indications for diabetic peripheral neuropathy, spinal cord injury, and fibromyalgia. However, both are frequently used off-label for a multitude of neuropathic pain or psychiatric conditions such as anxiety or alcohol use disorder [3, 4]. This is in part owing to their general perception as relatively safe, well-tolerated medications with limited misuse or overdose potential compared with alternative analgesics and anxiolytics [3, 4]. While pregabalin is classified within the lowest-risk controlled substance category (Schedule V) by the US Drug Enforcement Administration, gabapentin is not a controlled substance at the federal level [1, 2].

Since 2010, a growing body of evidence has demonstrated a concerning misuse liability for both gabapentinoids, including therapeutic misuse for self-treatment of various pain, substance use disorder (SUD), or psychiatric conditions, as well as non-therapeutic misuse to achieve euphoria or dissociation or to enhance the desirable effects of other drugs, particularly opioids [3–104]. This increased awareness of misuse and harm potential has led multiple US states to schedule gabapentin as a controlled substance or mandate its tracking within their prescription drug monitoring programs. It also prompted the FDA to issue a warning regarding gabapentinoid-related respiratory depression risk, particularly when used alongside opioids [52, 105]. Worldwide, more than ten additional countries have added additional gabapentinoid prescribing regulations in the past decade [106]. Thus, when considering prescribing gabapentinoids, it is important to weigh the risks of this increased misuse potential against their potential benefits, particularly for off-label uses with limited efficacy data [107, 108].

In 2017, we conducted a systematic review (SR) summarizing gabapentinoid misuse, dependence, and overdose reports published to date [3]; in 2021, we subsequently developed an update to that SR to highlight newly published evidence [4]. Since that time, the number of published reports on this topic have nearly doubled, continuing to provide important new insights into this topic. This present SR was conducted as an update to these previous reviews, compiling new information regarding gabapentinoid misuse, dependence, and overdose risk published over the last 5 years.

Methods

This SR followed a similar Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-guided research protocol as our previously published SRs [3, 4] to compile new research published since the previous 2021 update, presenting a narrative review of the novel insights gleaned from this research.

Data Sources and Searches

On 24 January, 2025, PubMed was searched from 1 September, 2020 (the end date of the previously published SR) to 24 January, 2025 using the following search criteria: “gabapentin [MeSH] OR pregabalin [MeSH] OR gabapentinoid AND substance-related disorders [MeSH]”. The same search was repeated three additional times on the same day, substituting “substance-related disorders [MeSH]” with each of the following three substance misuse-related terms: “overdose,” “abuse,” or “misuse.” Clinicaltrials.gov and the Cochrane Library database were also searched to identify relevant studies or SRs. Additional research was identified by hand-reviewing papers cited by included studies.

Study Selection, Data Extraction, and Quality Assessment

Any article reporting original human research regarding gabapentinoid misuse, withdrawal, dependence, overdose, or non-prescribed obtainment (e.g., “diversion”) was included. Misuse was defined to include non-prescribed use or use in a manner other than prescribed, either for therapeutic (self-treatment for medical reasons) or non-therapeutic (for euphoric or desirable effects [i.e., “recreation”]) reasons. Articles that assessed prescribed use were included if they provided insight into overdose, withdrawal, or dependence risks or assessed gabapentinoid use within a SUD population. Animal or in vitro research, manuscripts published in a non-English language, review articles, and studies already included in one of our previous SRs [3, 4] were excluded.

After the initial literature search, titles and abstracts were reviewed to screen articles clearly not meeting inclusion criteria. Those deemed potentially relevant received a full-text review from the lead author and at least one other author. Exclusion of articles identified as non-relevant was determined by consensus, with the lead author making the final decision if consensus was not reached after discussion. Three authors separately extracted key study information with the lead author providing a second review of each article and compiling this extracted information. Study limitations, potential sources of bias, and remaining literature gaps were qualitatively assessed when extracting study data and after a holistic review of the included literature and are summarized in Sect. 4.7 and Table 1 in the Electronic Supplementary Material (ESM).

Data Analysis

Key findings related to gabapentinoid misuse, withdrawal, dependence, or overdose risks from the included studies were summarized qualitatively, focusing on the most important takeaways related to gabapentinoid misuse and novel insights from the medical literature published since the 2021 SR [4]. This included focusing on the extent, risk factors, and patterns of gabapentinoid misuse; effects experienced or sought through misuse; potential harms, and insights for healthcare professionals and policymakers.

Results

In total, 319 studies were initially identified, and 100 were included [5–104]. Figure 1 summarizes study selection. Thirty-three studies occurred in North America (32 from the USA [13, 19, 20, 23, 27, 32–35, 45, 46, 52, 54, 60, 64–66, 70, 74, 75, 79, 80, 85, 86, 88, 90, 97, 101–103]), 39 in Europe (including multiple studies from the UK (16) [9, 14, 21, 22, 29, 37, 39, 40, 44, 50, 51, 57, 67–69, 87], Germany (8) [15–18, 36, 37, 72, 73], France (6) [30, 37, 38, 61, 96, 104], Finland (4) [58, 59, 62, 63], and Spain (3) [37, 82, 83]), 20 in Asia (including multiple from Turkey (7) [5, 53, 55, 56, 77, 84, 98], Saudi Arabia (3) [6, 8, 100], and India (3 [11, 42, 78]), 7 in Australia [12, 24, 25, 43, 48, 71, 99], and one in Africa [7].

Fig. 1.

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) diagram for a summary of the evidence search and selection. SR systematic review.

Adapted from Page MJ, et al. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71. Available under CC BY 4.0.

Eighty-seven original research studies met inclusion criteria [6–10, 12–25, 27–46, 48, 50–60, 62–71, 73–77, 79–86, 88–90, 92, 93, 96–104]. Among these, 16 studies assessed gabapentin, 20 pregabalin, and 51 both. These studies are summarized in Table 1 in the ESM. Additionally, 13 case reports/series were identified, ten describing misuse/dependence and two acute overdose fatalities [72, 94]. Nine involved pregabalin, three gabapentin, and one both. The case reports/series are summarized in Table 2 of the ESM.

Discussion

Table 1 provides a high-level summary of major findings, which are explored in greater depth in this section.

Table 1.

Summary of major findings

Area	High-level findings
Extent of misuse	First estimate of gabapentinoid misuse prevalence amongst US general population was published Continued evidence to suggest higher rates of gabapentinoid misuse among patients with SUD and OUD High regional variability in misuse likely based on local prescribing patterns and product availability
Effects experienced	Continued evidence of euphoric, dissociative, and self-medicating effects of gabapentinoids as motivators for use Patients seeking SUD treatment may see gabapentinoids as a form of harm reduction, albeit still seeking psychoactive effects
Risk factors and patient characteristics	Increase in evidence of gabapentinoid misuse highlighted from new areas globally, including the Middle East and North Africa Increase in evidence detailing gabapentinoid misuse among adolescent populations, often for non-therapeutic reasons Continued evidence suggesting untreated/uncontrolled pain and psychiatric diagnoses as risk factors for gabapentinoid misuse
Misuse patterns	Continued evidence on preference for oral route, although snorting and injection also reported Sourcing of gabapentinoids remain diverse, including healthcare professionals, family/friends, illicit markers, and forgeries/theft Evidence suggests gabapentinoid misuse as a common issue within prison systems, although screening is limited Gabapentinoid misuse most commonly co-occurs with other substances, including opioids, benzodiazepines, and to a lesser extent, stimulants, although dosing and frequency are highly variable
Harms associated	Continued evidence identifying gabapentinoids in port-mortem toxicology analyses of overdose deaths Gabapentinoid-only overdoses generally only fatal in combination with other substances Growing body of evidence providing a more robust case that overdose mortality increases when gabapentinoids are used concurrently with opioids and/or benzodiazepines Abrupt discontinuation of gabapentinoids (particularly at supratherapeutic misuse doses) is associated with withdrawal
Roles of healthcare professionals and policymakers	Healthcare professionals have concerns that that supply-side mitigation efforts to curtail gabapentinoid misuse may be ineffective Greater support was seen for information sharing, education, improved healthcare access, and reduced stigma

OUD opioid use disorder, SUD substance use disorder

Extent of Misuse

Research in our previous SRs largely highlighted gabapentinoid misuse in the USA and Europe, with much more limited data from other regions [3, 4]. They included several studies within SUD populations, but identified limited data regarding general population prevalence. Studies included in this SR filled these gaps and identified that the problem continued to grow over time. While a 2013 UK general population survey had identified 1.1% and 0.5% lifetime gabapentin and pregabalin misuse prevalence, respectively [109], a similarly conducted 2019 study identified lifetime gabapentinoid misuse in 6.6% of a representative US general population sample, including 2.1% and 1.5% specifically reporting non-therapeutic gabapentin and pregabalin misuse, respectively [35]. This was the first to estimate gabapentinoid misuse prevalence in a representative US general population sample; the higher rates may be indicative of increasing misuse in recent years or higher US versus UK misuse rates. In Spain, among those who had ever used gabapentinoids, 20% reported lifetime misuse, with pregabalin misuse more common than gabapentin [37]. Within a Spanish spontaneous prescription drug misuse reporting system, gabapentinoids were also among the highest drug class reported, trailing only benzodiazepines and opioids, and were particularly highly reported in people aged under 25 years [82].

As in previous research, higher misuse rates were observed among people with SUD, particularly opioid use disorder (OUD). Among US individuals receiving opioid maintenance therapy (OMT) for OUD, 9.3% reported past-month gabapentin misuse; based on the large sample size and study methodology, this may represent one of the most accurate assessments of current gabapentin misuse among US OUD treatment-seeking individuals [32]. In a separate study of US OMT patients, 43.2% reported lifetime gabapentin misuse [33]. This is higher than reported in the previous literature regarding gabapentin (15–22%), though a few European studies have identified higher pregabalin misuse rates among OUD populations [3, 4]. The majority (64.1%) of those misusing gabapentin also endorsed methadone or buprenorphine misuse [33]. United Arab Emirate and French data also identified considerable gabapentinoid misuse. Among United Arab Emirate patients seeking OUD treatment, pregabalin was the most common non-opioid misused (64.9%) [31], while the number of people in French SUD treatment facilities reporting pregabalin misuse increased 12-fold from 2008 to 2022 [38]. The number reporting pregabalin as the first substance leading to dependence also grew significantly (1.2% from 2008 to 2018 vs 10.4% from 2019 to 2022, p < 0.005) [38]. Conversely, within a German detoxification facility, gabapentinoids were rarely the primary substance leading to SUD treatment but typically involved in polysubstance use [15]. However, about half of those misusing gabapentinoids did meet on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition dependence criteria. Overall, evidence supports an increasing global awareness of gabapentinoid misuse.

Research continued to show regional differences in which gabapentinoids are more commonly misused, likely based on local prescribing patterns and greater local availability of one gabapentinoid versus another [8, 25]. While pregabalin was among the most misused substances in Saudi Arabia prior to its rescheduling as a controlled substance, following this reclassification, a sharp drop in pregabalin prescribing was observed and coincided with a significant gabapentin prescribing increase [6, 8]. A subsequent survey of Saudi Arabian pharmacists revealed gabapentin misuse was perceived as more common than pregabalin [100]. Thus, this effort to curtail pregabalin misuse may result in a transition to increased misuse of non-controlled gabapentin, akin to the much greater gabapentin prescribing and misuse in the USA compared with Europe [3, 4, 6, 8, 35, 70].

Effects Experienced

The previous SRs described gabapentinoid misuse for euphoric, dissociative, and self-medicating effects and also to enhance effects of other substances, particularly opioids [3, 4]. New studies included in this SR largely corroborated these findings [6, 34, 35]. Within a representative US general population sample, the proportion reporting lifetime therapeutic and non-therapeutic gabapentinoid misuse were the same (2.1%), indicating that approximately half of those misusing gabapentinoids do so to self-treat medical conditions (primarily pain and mental health) versus seeking euphoric effects [35].

This may differ in patients seeking SUD treatment. A survey of US patients seeking OUD treatment identified reasons for gabapentin misuse included: “high” seeking (38.6%); self-management of pain (33.3%), OUD (including sometimes when the person loses access to their OUD treatment [22.2%]), anxiety (15.8%), sleep (7%), or non-opioid substance use (3.5%); and for increased energy (3.5%) [34]. Qualitative research also described the popularity of gabapentin among patients in US SUD treatment programs, with study participants noting broad awareness of the euphoric effects of gabapentin and that it is one of the most misused substances in SUD treatment settings because it is easy to obtain, unlikely to be detected, and considered by some to be a “free lapse” during treatment (i.e., justifying misuse of a prescribed medication as a means of staying “sober”) [19]. These patients primarily misused gabapentin to elicit desirable psychoactive effects, though some did report it helping to mitigate opioid withdrawal symptoms.

Risk Factors and Patient Characteristics

Previous research indicated that individuals who misuse gabapentinoids tend to be younger with a history of SUD (especially OUD) and psychiatric comorbidities [3, 4]. This SR corroborated these findings [15, 19, 31–35, 38] but also highlighted potential concerns in several populations not as routinely highlighted in previous research, including adolescents, people from the Middle East and North Africa (MENA) region, and those living with chronic pain. Furthermore, a longitudinal study of French patients with SUD reporting pregabalin misuse indicated that the typical demographic profile may be changing in recent years [38]. Compared with reports from 2008 to 2018, persons observed misusing pregabalin from 2019 to 2022 displayed higher rates of incarceration, low socioeconomic status, dependence/withdrawal, and underground market obtainment and also consumed higher doses. They observed more people reporting pregabalin as the first substance leading to dependence and more adolescent cases as well.

This was one of several studies discussing adolescent pregabalin misuse, indicating this may be a growing concern [5, 30, 38, 44, 77, 96–98]. Among pregabalin misuse reports to the French spontaneous adverse event reporting system in 2019, 22.3% occurred in adolescents [96]. Similarly, among 94 adolescent recreational pregabalin misuse cases reported to French poison control centers from 2004 to 2020, 91% occurred from 2018 to 2020 [30]. Furthermore, 24% of adolescent cases involved non-therapeutic misuse versus only 3.6% of the adult cases. Most of the adolescents were male (5.3:1 ratio), median age 15 years (range 11–17.8 years), and 81% of the adolescent non-therapeutic misuse cases were among unhoused individuals or those living in migrant shelters. This trend was also observed in Turkey. Within a pair of Turkish studies, adolescents accounted for 10.2% (13/128) of non-prescribed pregabalin use [77] and 6% of pregabalin-involved post-mortem cases (29/487) [98]. A separate case series described three Turkish adolescents misusing pregabalin, with one teen noting that many of her friends use heroin and pregabalin [5].

Certain medical conditions, particularly if under-treated, likely also increase misuse risk. Several studies highlighted uncontrolled pain [25, 32, 34, 37, 56, 84, 92] or psychiatric diagnoses [5, 26, 42, 48, 49, 61, 72, 78, 84, 87, 91, 94–96] as factors contributing to misuse. A Spanish study identified uncontrolled pain was the most commonly cited reason for gabapentinoid misuse [37]. Among Turkish patients prescribed gabapentinoids for neuropathic pain, 17.9% reported non-therapeutic misuse, 5.7% therapeutic misuse, and 2.9% dependence; those with higher doses or longer use duration and those using pregabalin versus gabapentin were more likely to report misuse [56]. These rates were even higher among Turkish patients prescribed gabapentinoids for neuropathic pain related to spinal cord injury, with pregabalin and gabapentin use disorder (based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria) identified in 81.9% and 69.7% of patients, respectively [84]. More specifically, 60.6% and 42.4% were diagnosed as severe gabapentinoid use disorder. Longer disease duration and higher symptom score were associated with misuse. Other risk factors included younger age, living alone, and a higher Beck Depression Inventory score. This was one of many studies highlighting psychiatric diagnoses as another potential risk factor [5, 26, 42, 48, 49, 61, 72, 78, 84, 87, 91, 94–96]. Overall, evidence suggests that healthcare professionals should recognize that gabapentinoid misuse may be driven, in part, by patient-directed self-treatment of conditions where the effects of the medication may provide temporary relief.

While early gabapentinoid misuse research primarily came from Europe and the USA, and many studies continue to highlight misuse in these regions, it was also commonly reported from other areas among studies in this SR, indicating gabapentinoid misuse is becoming more widespread or increasingly recognized in different parts of the world. Among the studies included in this SR, gabapentinoid misuse was documented from several countries with no or very few cases reported in previous research (e.g., Serbia, Sudan, United Arab Emirates, Iran, Japan, Slovenia, Israel) [7, 10, 14, 31, 49, 81, 94]. Most notably though, a considerable number of recent studies reported concerns regarding gabapentinoid misuse in the MENA region and among migrants from that area [3, 6, 31, 49, 53, 70, 77, 81, 84, 92, 93, 100]. In a small Saudi general population sample, nontherapeutic pregabalin and gabapentin misuse were reported in 4.6% and 2.7% of respondents, respectively, with pregabalin the most commonly reported misused drug (23.6% of those reporting substance misuse) [6]. Notably, more than half of those reporting substance use did not specify which substances, so the proportion misusing pregabalin was likely under-reported. Gabapentinoids were also the most commonly reported drug class Saudi pharmacists perceived to be misused by their patients [100]. Similar results were observed among Iraqi pharmacists [93]. This increased misuse has caused some providers in the region to reduce their gabapentinoid prescribing in favor of alternative agents [53]. Several studies also reported growing concern regarding pregabalin misuse among migrants, particularly from the MENA region [10, 30, 73, 92]. Among a sample of MENA migrants in Belgium, pregabalin misuse was described as a means to cope with difficult living situations, trauma, and social hardships associated with difficult immigration paths, limited income, and lack of healthcare access for pain and mental health conditions [92]. They also noted that pregabalin was easily accessible and considered lower risk (in terms of adverse effects and potential legal trouble) versus benzodiazepines or tramadol. Additionally, some justified their use because it is a prescription medication versus an illicit substance [92], as was documented among US patients seeking SUD treatment [19].

This trend in the region seems to stem, at least in part, from limited regulation in obtaining gabapentinoids [6–8]. In a Saudi study, half the patients who misused a gabapentinoid obtained it from the pharmacy without a prescription [6]. Pregabalin was subsequently reclassified to further regulate its non-prescribed use, but gabapentin was not [6]. After this rescheduling, pregabalin prescribing in Saudi Arabia dropped sharply, but a corresponding increase in gabapentin use was observed, with no impact on tramadol, duloxetine, or amitriptyline, indicating that rescheduling likely just shifted use to gabapentin [8]. One report noted gabapentin is still easily obtainable without a prescription, and half of those reporting gabapentin misuse after the rescheduling was announced had previously misused pregabalin [6]. Similarly, most pharmacists surveyed in Sudan perceived pregabalin misuse to be a growing problem (86%) [7]. While the authors noted that pregabalin is considered a prescription-only medication in Sudan, these rules are weakly enforced.

Misuse Patterns

Previous research indicated that gabapentinoids are often misused via the oral route, and typically at supratherapeutic doses or with other substances to achieve desired effects [3, 4]. Recent research continued to identify oral ingestion as the most common [10], but other routes, including snorting and injection were reported [10, 37, 81]. Reported doses for non-therapeutic use ranged from commonly prescribed doses to over 12,000 mg per day [11, 35, 42, 47, 49, 61, 78, 96]. Research regarding the frequency with which people misuse gabapentinoids continues to vary as well [35, 38].

Similar to previous research [3, 4], while gabapentinoids seem to be most commonly obtained from healthcare professionals or family/friends [35], recent studies indicated gabapentinoids are widely available and often obtained from the underground market [10, 14, 61, 73, 92, 96], with studies in Europe [73], France [38, 96], Spain [83], Germany [15], and Israel [81] detailing obtainment from illicit markets, forged prescriptions, theft, or doctor shopping. In 2019, pregabalin was the most reported drug among forged prescriptions in France (23.8% of suspicious prescriptions), a considerable increase from 2.6% in 2017 [96]. Furthermore, in an analysis of doctor shopping in France, pregabalin observed the greatest increase from 2010 to 2019, among more than 200 drugs assessed [104]. In SUD treatment facilities, people may report false symptoms in order to obtain gabapentin prescriptions or “cheek” the medication, hiding single doses provided during treatment in their cheek to take at a later time in higher doses or via alternative routes [19].

Though gabapentinoid misuse in prisons has been reported in previous research [3, 4], both gabapentinoids were identified among drug-impregnated papers in English prisons, highlighting a newly documented method to obtain these substances [9]. Most prison and forensic medicine physicians surveyed from several European countries noted increased pregabalin misuse and pregabalin withdrawal among their patients, while 55% noted they do not prescribe pregabalin as a result of its significant misuse potential in prison medicine [73]. However, only 37.6% routinely included pregabalin in routine admission drug screening in their prisons, so it is likely often not detected. Gabapentin and pregabalin seizures by US law enforcement increased by 242% and 18%, respectively, from 2011 to 2019, with three states observing a more than 1000% increase in gabapentin seizures [70]. By the end of the study period, gabapentin was among the top 25 most seized drugs. Several studies reported on the median price paid for gabapentinoids in the illicit market, noting it was about €10 in Spain, while pregabalin could be obtained for about €1 per capsule in France and Belgium [37, 92, 96].

Gabapentinoids are commonly misused alongside other substances, particularly opioids, but also other sedatives and, to a lesser extent, stimulants [3, 4]. While concurrent gabapentinoid and opioid use has continued to be frequently reported, a growing number of studies have highlighted concomitant benzodiazepine use or misuse with gabapentinoids [10, 14, 30, 35, 81, 92, 94, 99]. Studies among the US general population [35], French adolescents, German detoxification clinic patients [15], Israeli OMT patients [81], and Serbian poison control center reports [10] all identified high rates of concomitant benzodiazepine use. Among 128 patients testing positive for non-prescribed pregabalin use in Turkey, pregabalin was the only substance detected in 38.7–53.2% of the cases; interestingly, stimulants were the most common concomitant substance identified (22.8–46.9% vs 1.3–4.1% for opioids), which the authors attribute to local substance use patterns in Turkey favoring stimulants over opioids [77]. A few small studies identified gabapentinoid use with synthetic cannabinoids or kratom [5, 15, 57, 72, 98]. While this does not seem to be commonly reported at this time, it may be an interesting trend to monitor, as these substances have gained popularity in recent years [110–112].

Harms Associated

Recent studies have built on emerging evidence highlighted in the previous SR [4] to provide a more robust assessment of the impact of gabapentinoids on overdose risks. It is important to note that many of these used population-level healthcare data and thus focused on prescribed gabapentinoid use, though it can be reasonably assumed that gabapentinoid misuse would likely confer even greater risk. The available evidence continued to indicate that gabapentinoid-only overdoses are typically relatively benign, with rare reports of seizures, coma, or death; most fatal overdose cases involving gabapentinoids result from polysubstance use involving opioids, benzodiazepines, and, to a lesser extent, stimulants or alcohol [10, 25, 39, 48, 50, 59, 64, 89, 90]. In several studies, gabapentinoids were implicated in a number of intentional overdoses [25, 30, 44, 48], which may signal a need for cautious prescribing among patients at risk of self-harm.

Many recent studies assessed the relative impact of gabapentinoids on drug overdose risks, consistently showing concomitant gabapentinoid use increases opioid and polysubstance overdose risk and opioid-related mortality [12, 21, 29, 39, 45, 54, 66, 71, 85, 86, 97, 103]. Several studies specifically highlighted risks regarding concomitant gabapentinoids and benzodiazepines [12, 22, 24, 41, 44, 60, 99]; concurrent gabapentinoid, benzodiazepine, and opioid prescriptions further increase mortality versus receipt of opioids alone or benzodiazepine and opioid combinations [12, 41, 60]. New in this SR were several studies suggesting concomitant gabapentinoid and opioid use within hospital settings may increase inpatient overdose/oversedation risk as well, which may be an important consideration for hospital-based clinicians managing acute pain [27, 45, 66]. The reasons for these risks are likely multifactorial. Studies included in this SR have provided several hypotheses, including pharmacodynamic interactions between gabapentinoids and opioids, and gabapentinoids reducing opioid tolerance or naloxone (the opioid overdose reversal agent) effectiveness [50, 65]. Previous research has postulated that pharmacokinetic (e.g., prolonged gastrointestinal transit increasing gabapentinoid concentrations) and pharmacodynamic (e.g., increased respiratory depression) interactions with opioids, mischaracterization of the relative risk of gabapentinoids from healthcare professionals and people who use them, and delayed gabapentinoid onset versus injected opioids may also play a role [3, 4].

Several studies specifically assessed gabapentinoid-related risks associated with OMT [12, 29, 39, 71]. In the UK, non-fatal overdose risk was increased when gabapentinoids were concurrently prescribed with methadone or buprenorphine (weighted rate ratio 2.22, 95% confidence interval [CI] 1.77–2.79), which was numerically higher than the risk observed with benzodiazepines (1.45, 95% CI 1.26–1.67), Z-drugs (1.60, 95% CI 1.31–1.96), or additional opioids (1.28, 95% CI 1.02–1.60) [29]. Among Australians with OUD, gabapentinoid use was found to increase all-cause mortality (adjusted hazard ratio 1.57, 95% CI 1.37–1.79). This risk was worse when gabapentinoids were used concurrently with opioids (1.78, 95% CI 1.37–2.31), benzodiazepines (2.73, 95% CI 2.06–3.60), and opioids plus benzodiazepines (6.10, 95% CI 4.11–9.06) [12]. However, all-cause mortality related to these gabapentinoid combinations was significantly lower while the patient was receiving OMT, which could result from more regular clinic visits and medication reviews, early adverse effect identification, and more integrated care plans [12]. Though they did not study overdoses, another Australian study identified a significantly less risk of gabapentinoid urine drug screen detection among patients receiving long-acting injectable buprenorphine versus sublingual buprenorphine (0% vs 9.9%, p = 0.031), potentially indicating that improved OMT adherence might reduce concurrent gabapentinoid misuse as well [71]. A large Scottish study showed similar results, with gabapentinoid prescribing during OMT associated with a significantly increased fatal overdose risk (adjusted hazard ratio 2.18, 95% CI 1.92–2.46) [39]. However, this study did not identify differing risk when patients were on versus off OMT. Utilizing a case-crossover design, one study determined that within-person adjusted analyses did not show an increased overdose risk when gabapentin and buprenorphine were used together, despite a considerable increase noted in non-adjusted analyses, and concluded that the increased overdose risk observed in studies may be confounded by indication, with patients prescribed gabapentinoids having more severe underlying medical conditions [33].

Several studies assessed blood concentrations following gabapentinoid poisonings. Among Serbian poison control center data, the highest pregabalin plasma concentration identified was 76.2 mg/L on admission (which the authors noted was the highest recorded in a living patient in the medical literature), 3 hours after an unknown dose was ingested [10]. Several other drugs screened positive, including alcohol and therapeutic levels of diazepam, zolpidem, citalopram, mirtazapine, and acetaminophen. This patient was comatose, with hypotension and low oxygen saturation. With intubation, mechanical ventilation, and supportive care, the patient recovered 6 days after hospital admission. Previous research indicated that therapeutic gabapentin and pregabalin blood concentrations were approximately 2–6 mg/L and 2.8–8.3 mg/L, respectively, and postulated that post-mortem pregabalin blood concentrations ≥25 mg/L increased the risks of significant harm, though much higher blood concentrations have been observed [3, 4]. It is important to note that comparisons of post-mortem data are complicated by fluctuating blood concentrations dependent on how much time elapsed between ingestion and sample measurement and most cases involving polysubstance use [3, 4, 44]. Gabapentinoids continue to be increasingly identified and implicated in post-mortem drug overdose analyses [14, 28, 50, 59, 62, 69, 90, 97, 99]. Among studies involving primarily polysubstance fatalities, median post-mortem blood concentrations reported in included studies ranged from 9.5 to 35 mg/L for gabapentin and from 7.6 to 18.5 mg/L for pregabalin [25, 44, 50, 59, 94, 99]. In Northern Ireland, limiting the sample to only cases in which pregabalin was considered the primary cause of death (though still typically polysubstance cases), the median concentration was 26 mg/L [44]. Among four fatalities in which gabapentinoids were the only substance identified, the post-mortem concentrations reported for gabapentin were 17 (drawn 39 hours after admission) and 240 mg/L and for pregabalin 17.7 and 30.1 mg/L [44, 50, 59].

Previous evidence was conflicting as to whether gabapentinoid-associated overdose risks are dose dependent [3, 4]. Newly compiled evidence in this SR points towards dose-dependent risks but there was still some incongruence [41, 67, 89, 103]. Among pregabalin-only poisonings reported to a Dutch poison control center, a significantly higher mean dose was observed among moderate-severity poisonings versus low-severity cases [89]. The authors concluded that pregabalin-only ingestions below 20 mg/kg typically result in only mild poisonings and can likely be triaged without sending the patient to the hospital, though underlying diseases that increase risk should be considered.

Withdrawal and dependence continued to be reported in cases where gabapentinoids are discontinued abruptly, especially if misused at supratherapeutic doses [11, 35, 38, 47, 49, 78, 92]. Among 291 patients reporting pregabalin misuse, 47.8% endorsed having experienced pregabalin withdrawal [38]. Similarly, within French adverse event reports regarding pregabalin misuse, 19% requested or were referred to SUD treatment, and 26.5% had previously tried to quit pregabalin use unsuccessfully [96]. Withdrawal symptoms may include delirium, hallucinations, anxiety, depression, insomnia, amnesia, loss of appetite, tremors, cold sweats, restlessness, dyspnea, head/body aches, chest tightness, chills, diarrhea, palpitations, cravings, and, in worst case, seizures [4, 11, 47, 92]. When misusing supratherapeutic doses, withdrawal effects may develop quickly. One case report described a patient experiencing intense cravings and withdrawal the day after discontinuing the 2250 mg/day of pregabalin they had been taking [78]. Interestingly, this patient had co-occurring alcohol use disorder and was successfully treated with chlordiazepoxide and N-acetyl cysteine. While previous reports indicated benzodiazepines may not be effective for gabapentinoid withdrawal, several cases highlighted successful gabapentinoid withdrawal management with benzodiazepines [3, 11, 61, 78]. One case managed withdrawal with 2 mg of lorazepam three times daily plus 0.25 mg of haloperidol once daily, tapered over 5 days [11]. However, another paper anecdotally suggested clonidine may be a better alternative, as benzodiazepines carry their own misuse risk, though these two treatment options were not directly compared [61]. As recommended in previous research, several other reports indicated re-initiating the previously misused gabapentinoid can be effective, though slow tapers (in one case, 18 months) or additional medications to treat underlying psychiatric or pain conditions may be needed [3, 4, 26, 47, 61, 91, 95]. Given rising gabapentinoid misuse concerns, clinical research to compare treatment options and develop standardized gabapentinoid withdrawal treatment protocols is warranted [61].

Role of Healthcare Professionals and Policymakers

Polysubstance use is a key factor in the current “fourth wave” of the opioid overdose epidemic [85]. Despite the robust evidence presented here and in previous research, the best approach to mitigating these misuse concerns is unclear, particularly given their widespread use and efficacy in treating several common medical conditions [108].

US healthcare professionals and drug policy experts voiced mixed opinions in interviews regarding how best to mitigate gabapentinoid misuse [23]. Most felt gabapentinoids were over-prescribed, largely because they pose less risks than opioid analgesics. Some believed gabapentin should be re-classified as a controlled substance because it poses similar misuse liability as pregabalin, but others worried this would further reduce access to effective analgesia for patients living with chronic pain (especially in settings where advanced practice providers have controlled substance prescribing limitations) and might not significantly curtail misuse. At least seven US states have re-classified gabapentin as a controlled substance [53], although it is unclear how these supply reduction-focused interventions have impacted patient outcomes. Following re-scheduling as a controlled substance in England, no meaningful decrease in gabapentinoid prescribing was observed among general practitioners [51]. Additionally, there is concern that supply-focused solutions may lead some to seek gabapentinoids from higher-risk sources or result in more individuals experiencing SUD-related legal troubles [23]. In an Australian study, after implementing a real-time prescription drug monitoring program system, pregabalin-related poisonings fell but there was a significant increase in poisonings related to non-prescribed pregabalin use [43].

There appeared to be more agreement regarding other mitigation measures, such as mandatory gabapentin prescription drug monitoring program reporting to help inform safer prescribing (a change that has been implemented in at least 15 US states [53]), education for healthcare professionals and patients regarding gabapentinoid misuse risks, and systematic changes to healthcare and social support systems [10, 23, 30, 53, 73, 92]. Importantly, these include improved access to therapy for underlying conditions people use gabapentinoids to self-treat [23] and improved access to services for migrant populations to limit the desire to self-medicate [10, 30, 73, 92]. One study included in this SR found that a brief educational intervention for OMT patients significantly increased their knowledge regarding pregabalin risks [81]; unfortunately, such counseling is not routinely provided when gabapentinoids are prescribed [113]. Education regarding gabapentinoid misuse liability geared towards veterinarians may also be helpful as most veterinarians regularly prescribe gabapentin for pets but do not recognize its misuse potential in humans or take precautions to limit prescription refills [88]. Other suggested means of reducing gabapentinoid-associated overdose risks have included more judicious prescribing (e.g., not assuming gabapentinoids are safe and effective for all pain conditions), development of risk stratification tools to identify patients at greater risk, and implementation of electronic medical record alerts to help reduce high-risk prescribing [103, 108]. However, another study suggested that efforts to limit gabapentinoid prescribing with opioids may not affect overdose rates as much as expected, given that illicit opioids are now primarily driving the increased overdose deaths involving gabapentinoids [85], and no change in US gabapentinoid-associated deaths has been observed following the 2019 FDA warning regarding gabapentinoids increasing respiratory depression risk [86]. Thus, it is important to not only assess for concomitant opioid and gabapentinoid prescribing but also to routinely ask patients about substance use and create a non-stigmatizing environment in which patients feel comfortable disclosing such information. Including gabapentinoids in routine urine drug screens during clinical practice, particularly in SUD treatment settings, and post-mortem toxicology screenings is likely also warranted [19, 77, 90]. While recent evidence seemed to indicate that this is becoming more common, it still does not appear to be standard practice and may lead to under-reporting of the issue or delayed treatment [42, 90, 91]

Study Limitations

Current evidence largely comprises retrospective observational data, and case reports with inherent bias concerns. Many studies utilized healthcare databases, which may not accurately reflect the full spectrum of risks associated with gabapentinoid misuse, particularly where it involves illegal activity. Other sources of information (e.g., patients, law enforcement) are valuable but are subject to social desirability bias. Reporting bias may also be possible, especially as awareness of this subject has greatly increased in recent years and gabapentinoids are now commonly studied as a potential risk factor in drug overdose research. The included studies are quite heterogeneous in design, outcomes reported, and location conducted, limiting the ability to compare findings across studies. Furthermore, some research specifically assessed only one of the two gabapentinoids and studying both collectively assumes study observations are class effects, which may not always be accurate. However, given their similarities in mechanism of action, clinical use, and misuse trends reported in previous research, studying both drugs collectively is reasonable and provides a greater evidence base to help overcome inherent limitations of many of the included studies. However, as the body of evidence continues to grow, compiling new research to build upon our two previously published SRs provides a more robust understanding of gabapentinoid misuse and associated risks.

Conclusions

A highly diverse and extensive body of literature exists regarding gabapentinoid misuse. Recently published literature indicated misuse continues to grow and may be expanding in new locations, demographics, and risk factors. With growing misuse and increasingly robust evidence that gabapentinoids can significantly increase polysubstance overdose risk, it is important that healthcare professionals and policymakers act to mitigate this important public health concern.

Supplementary Information

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Funding

No funding was received for the preparation of this article.

Declarations

Conflict of interest

Kirk E. Evoy, Daija Drain, Justin Pedigo, Jordan R. Covvey, and Olivia Ramey have no conflicts of interest that are directly relevant to the content of this article.

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Authors’ contributions

KE: conceptualization, methodology, data curation, writing (original draft), writing (editing and reviewing), supervision, project administration; DD: data curation, writing (original draft), writing (editing and reviewing); JP: data curation, writing (original draft), writing (editing and reviewing); JC: writing (editing and reviewing), visualization; OR: data curation, writing (original draft), writing (editing and reviewing). All authors have read and approved the final version.