Gabapentinoid Use is Associated With Increased Risk of Drug Poisoning, Study Finds

According to study authors of research published in PLOS Medicine, gabapentinoids, such as gabapentin, appeared to be associated with an increased risk of drug poisoning. The authors emphasize that close monitoring throughout the treatment journey is necessary for drug poisoning, particularly at the initial phase of treatment.¹

What Research Preceded This Study?

In an email interview with Pharmacy Times, study author Kenneth Man, BSc, MPH, PhD, University College London School of Pharmacy, explained that gabapentinoid prescribing has been increased substantially in many countries, an indication that it is being used across multiple on- and off-label indications, such as neuropathic pain.¹

Supporting this is a retrospective, serial cross-sectional study published in Drug and Alcohol Dependence that the prescription of gabapentin has increased in substance use disorder (SUD) treatment settings, despite a lack of strong evidence for its utility. Specifically, gabapentin was prescribed to approximately 5.9% of this study’s sample (206,161 urine drug tests), increasing from 3.9% in 2016 to 7.6% in 2023; however, the use of gabapentin without a prescription—which was identified in 11.3% of the sample—had decreased from 15.2% in 2016 to 9.9% in 2023.²

“…much of the existing literature on poisoning or overdose has focused on gabapentinoids when they are used together with opioids, or in selected high-risk populations. What we wanted to address was whether gabapentinoid treatment itself is associated with an increased risk of drug poisoning in routine clinical practice, and how that risk changes over time before and after treatment initiation,” study author Kenneth KC Man, BSc, MPH, PhD, University College London School of Pharmacy, explained in an email interview with Pharmacy Times. “While pharmacovigilance and mortality studies had raised safety signals, population-level evidence on gabapentinoids as an independent medication class, and in combination with opioids or benzodiazepines remained limited.”

What Did the Study Investigate?

For this within-individual study, the investigators utilized data from the UK Clinical Practice Research Datalink Aurum database linked to the Hospital Episode Statistics and Office for National Statistics. Participants aged 18 years or older who were prescribed gabapentinoids and had an incident all-cause drug poisoning event between January 1, 2010, and December 31, 2020, were included in the analysis. Additionally, a self-controlled case series (SCCS) design was used for this study to assess the risk of drug poisoning incidence in predefined risk periods: 90 days prior to treatment initiation; first 28 days, days 29 through 56; days 57 through 84; and the remaining treatment time. Concomitant use with opioids and benzodiazepines was also evaluated.¹

“The major strength of a within-individual design is that each patient serves as their own control. This means we can automatically account for all characteristics that do not change over time within the same person, such as genetics, sex, socioeconomic background, and long-term health characteristics that may not be fully captured in routine healthcare databases,” Man explained. “This is particularly relevant to gabapentinoid research, as individuals prescribed gabapentinoids often differ substantially from those who are not. They may have chronic pain, psychiatric comorbidities, a history of substance use, or other clinical vulnerabilities.”

Further, the investigators calculated adjusted incidence rate ratios (aIRRs) using conditional Poisson regression, and a case-case-time-control (CCTC) analysis was also conducted, with an adjusted odds ratio (aOR) calculated to validate the findings from the main SCCS analysis. All analyses were adjusted for key time-varying confounders (eg, age, season, concomitant use of opioids), antiseizure medications, psychotropic medications, and nonsteroidal anti-inflammatory drugs.¹

“The design also allows us to examine how risk changes over time. By examining the risk before treatment, immediately after initiation, and later during treatment, we can understand the corresponding risk across the whole period rather than producing a single estimate,” Man said.

A total of 16,827 individuals were included in the SCCS analysis. The investigators observed that, compared with the reference periods, the risk of drug poisoning increased during the first 28 days of treatment (aIRR = 1.81 [95% CI, 1.66–1.99; p < .001), eventually dropped (aIRR: 1.11 [95% CI, 1.05–1.17]; p < .001) in the remainder of the treatment period. Notably, the risk was doubled during the 90-day prior to treatment initiation (aIRR = 2.09 [95% CI, 1.98–2.21]; p <.001).¹

Further, coadministration with opioids was shown to elevate the risk by approximately 30%, whereas benzodiazepines increased it two-fold. For these reasons, Man and his coauthors emphasized that concomitant use should be avoided. The CCTC analysis also detected an increased aOR of about 1.36 (95% CI, 1.12–1.65; p = .002) when receiving gabapentinoid treatment within 30 days before a drug-poisoning event.¹

“Clinically, this finding suggests that gabapentinoids are often initiated during a period when patients are already vulnerable. The conditions that lead to gabapentinoid prescribing, such as worsening neuropathic or chronic pain, anxiety, insomnia, or other mental health conditions, may themselves be associated with a higher risk of drug poisoning. In other words, much of the elevated preinitiation risk likely reflects the conditions that prompted the prescription, rather than being attributable to gabapentinoids themselves,” Man noted. “That said, the risk did not immediately return to the nontreatment reference level after gabapentinoid treatment began. It remained elevated during treatment, especially in the first 28 days. Therefore, the interpretation should be balanced: the strong pretreatment signal suggests substantial underlying patient vulnerability, but the persistent elevation during treatment also supports the need for caution and close monitoring after gabapentinoids are initiated.”

What Should Pharmacists Take Away From These Findings?

In the interview, Man emphasized that the most important takeaway to the study is that the period around gabapentinoid initiation appears to be a high-risk window, meaning that prescribers should not view the prescription as an isolated event. Instead, the broader clinical context (eg, pain severity, mental health status, substance misuse history, prior poisoning events) as well as concurrent medications must be taken into consideration.

Pharmacists are crucial in identifying high-risk medication combinations. They are health care professionals who must pay close attention to patients who are receiving gabapentinoids alongside opioids or benzodiazepines, as those classes may increase the risk of sedation, respiratory depression, misuse, and drug poisoning, according to Man. Additionally, pharmacists should check whether medication combinations are clinically justified, whether the doses are appropriate, whether there has been recent initiation or dose escalation, and whether the patient has risk factors (eg, prior overdose, SUD, severe mental health conditions, respiratory disease, older age). Communication between the pharmacist and other members of the patient’s care team is essential and necessary.

“Patient counseling is also important. Patients or carers should be reminded to take the medicines only as prescribed, avoid taking extra doses, avoid combining them with alcohol or nonprescribed sedatives, and seek urgent medical attention if they experience extreme sleepiness, confusion, shallow breathing, or unresponsiveness,” emphasized Man.

Future Directions In This Space

In the interview, Man explained that the study findings support strengthening existing prescribing and monitoring practices, including careful risk assessment prior to treatment, early follow-up after treatment initiation, review of concomitant central nervous system depressants, patient counseling on overdose symptoms, and avoiding—or minimizing—concurrent opioid or benzodiazepine use where possible.

“Future research may validate these findings in other health care systems and populations, including settings with different prescribing practices, opioid use patterns, and health care access. It would also be useful to conduct studies with richer clinical data to better understand why the risk rises before the initiation of gabapentinoid.”

Further work may also examine dose-response relationships, the impact of dose escalation, treatment duration, discontinuation (including risks during and following withdrawal, where current evidence remains limited), and whether risk differs between gabapentin and pregabalin in specific patient groups…” concluded Man. “…we may also consider intervention-focused research…studies could evaluate whether pharmacist-led medication review, structured risk assessment before initiation, early follow-up after prescribing, alerts for high-risk coprescribing, naloxone provision for selected patients on opioids, or de-prescribing interventions can reduce drug poisoning events in real-world practice.”

REFERENCES

1. Yuen ASC, Chen B, Chan AYL, et al. Association between gabapentinoid treatment, concurrent use with opioid or benzodiazepine and the risk of drug poisoning: A self-controlled case series study. PLOS Med. 2026;23(4):e1005035. doi:10.1371/journal.pmed.1005035

2. McGovern G. Data Show Significantly Higher Gabapentin Use in SUD Treatment Settings. Pharmacy Times. March 13, 2026. Accessed May 11, 2026. https://www.pharmacytimes.com/view/data-show-significantly-higher-gabapentin-use-in-sud-treatment-settings