Cardiovascular safety of gabapentinoids gabapentin & pregabalin: A systematic review

Materials & Methods

This systematic review was done as per the guidelines of PRISMA checklists, with the protocol registered with PROSPERO (CRD42024605979)¹⁰. We systematically searched databases like MEDLINE, Cochrane Central Register, Scopus, Embase and ClinicalTrials.gov, for research papers published till March 31, 2025. The search technique followed a Boolean methodology using the terms ‘gabapentin’ OR ‘pregabalin’ AND ‘cardiovascular’. References in the articles of interest were also scanned for any potential work fulfilling our inclusion and exclusion criteria. No separate approval was required for this systematic review as it did not analyse any data directly taken from patients and analysed data from prior published studies, which had respective ethical clearances.

Results

A total of 8770 and 5077 studies were found after an initial literature search with gabapentin and pregabalin, respectively (Fig. 1) from where 198 duplicates were removed. Following the screening of the titles and abstracts, the search was reduced to 216 studies and 118 articles for gabapentin and pregabalin, respectively, which were evaluated in detail. The search was finally down to six cohort studies and two RCTs. The two RCTs did not fulfil our inclusion and exclusion criteria and hence were excluded from analysis^16,17. The study by Peng et al¹⁸ looked at the healthcare utilisation between pregabalin and duloxetine in patients with fibromyalgia, which was excluded from analysis, as they did not examine cardiovascular outcomes. Finally, data from five cohort studies, which fulfilled all inclusion and exclusion criteria, were analysed in this systematic review^8,9,19-21.

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Fig. 1.

Flowchart elaborating on study retrieval and inclusion in this systematic review.

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The profile of the 10,85,488 patients in the five different cohort studies analysed in this systematic review is elaborated in table I. The average age of the study participants ranged from 51 to 75 yr (Table I). Nearly six out of every 10 patients analysed were females. The patients had a high baseline cardiovascular risk as evidenced by their age, high prevalence of obesity, diabetes and hypertension (metabolic syndrome; Table I). A considerable number of patients in these studies had preexisting established cardiovascular disease (Table I). The majority of the patients were on one or more cardiovascular medications (Table I). All studies were found to be of high quality as the NOS scores for all the analysed studies were more than 7 (Table II).

It is important to note the drugs received by the patients in the control group. In the study by Pan et al⁹, patients with fibromyalgia in the control group received duloxetine or milnacipran. In the study by Pan et al⁸, the control group consisted of patients with diabetic neuropathy who were not prescribed either gabapentin or pregabalin but were prescribed nortriptyline, topiramate, tapentadol, duloxetine, capsaicin, amitriptyline, carbamazepine, venlafaxine, or mexiletine. In the study by Corriere et al¹⁹, the control group received duloxetine, desvenlafaxine, levomilnacipran, milnacipran, and venlafaxine for managing non-cancer pain. In the study by Jermendy et al²¹, the control group received alpha-lipoic acid (ALA) for managing diabetic neuropathy instead of gabapentin/pregabalin²¹. In the study by Landaluce et al²⁰, the control group received analgesic opiate, alprazolam or diazepam.

Impact on primary outcomes:

MI

Gabapentinoids use was not associated with increased risk of MI after three months of clinical use [Hazard Ratio; HR 1.24 (0.92, 1.68); I²=69%; P=0.15; n=124,710; Fig. 2A]. However, their use was associated with increased risk of MI after one year [HR 1.31 (1.14, 1.52); I²=0%; P=0.0002; n=173,859; Fig. 2B]. The risk of MI was not increased after five years of clinical use [HR 1.46 (0.96, 2.24); I²=89%; P=0.08; n=31,882; Fig. 2C; approached statistical significance].

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Fig. 2.

Forest plot highlighting the impact of use of gabapentin/pregabalin on myocardial infarction at (A) three months; (B) one year; (C) five years. Stroke at (D) three months; (E): one year; (F) five years.

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Stroke

Gabapentinoids were not associated with increased risk of stroke after three months [HR 1.2 (0.83, 1.73); I²=90%; P=0.33; n=124,716; Fig. 2D], and one year [HR 1.08 (90.96, 1.23); I²=0%; P=0.21; n=173,855; Fig. 2E] of clinical use. However, their chronic use was associated with increased risk of stroke after five years of clinical use [HR 1.44 (1.04, 2.01); I²=86%; P=0.03; n=31,988; Fig. 2F].

Impact on secondary outcomes

Heart failure

Gabapentinoids were not associated with increased risk of HF after three months [HR 1.25 (0.94, 1.66); I²=95%; P=0.12; n=125, 288; Fig. 3A], one year [HR 1.10 (0.99, 1.23); P=0.08; n=58,166] and five years [HR 1.62 (0.87, 3.04); I²=98%; P=0.13; n=125,288; Fig. 3B] of clinical use.

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Fig. 3.

Forest plot highlighting the impact of use of gabapentin/pregabalin on heart failure at (A) three months; (B) five years. Peripheral vascular disease (PVD) at (C) three months; (D) five years. Stroke at (E) one year; (F) five years.

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PAD

Gabapentinoids were not associated with increased risk of PAD after three months of clinical use [HR 1.02 (0.71, 1.46); I²=88%; P=0.90; n=124,718; Fig. 3C]. However, their chronic use was associated with increased risk of PAD after one year [HR 1.41 (1.18, 1.67); P=0.0001; n=58, 430] and five years [HR 1.58 (1.16, 2.15); I²=83%; P=0.003; n=31, 978; Fig. 3D] of clinical use.

PTE

Gabapentinoids use was associated with increased risk of PTE after three months [HR 1.27 (1.09, 1.46); P=0.002; n=76,908], one year [HR 1.23 (1.01, 1.40); P=0.04; n=58,002], and five years [HR 1.86 (1.64, 2.09); I²=0%; P<0.0001; n=31,996; Fig. 3E] of clinical use.

DVT

Gabapentinoids use was associated with increased risk of DVT after three months [HR 1.37 (1.21, 1.55); P<0.00001; n=76,890], one year [HR 1.42 (1.15, 1.74); P=0.0009; n=58, 384], and five years [HR 1.78 (1.31, 2.40); I²=71%; P=0.0002; n=31,980; Fig. 3F] of clinical use.

AF

Anti-arrhythmic drugs initiation or initiation of anti-platelet/anti-coagulant medications were taken as a surrogate measure of AF. The initiation of anti-arrhythmia drugs [HR 4.32 (2.24, 8.32); P<0.0001; n=4587] and anti-platelet/anti-coagulant medications [HR 2.08 (1.50, 2.87); P<0.0001; n=4587] were significantly higher following initiation of gabapentinoids.

Discussion

Gabapentin and pregabalin are the two drugs which are most used for managing neuropathic symptoms across the globe²². Diabetes is the most common cause of neuropathy, and diabetes per se is associated with increased risk of cardiovascular events²³. Our analysis showed that short-term three month use of gabapentinoids in people with high baseline risk of cardiovascular events was, in general, safe from a cardiovascular point of view, without any increased occurrence of MI, stroke, HF or PAD. However, even three months of use of gabapentinoids was noted to be associated with increased occurrence of thrombotic events (DVT and PTE). Hence, the use of these medications may be avoided in people with a history of DVT or PTE.

The cardiovascular risks with the use of gabapentinoids increased with chronic use in people with a high risk of cardiovascular events. One year of use of these two drugs was associated with significantly higher risks of MI, PAD, DVT, and PTE. Five-year use of these drugs was associated with even higher risks of cardiovascular events, as evidenced by the odds ratios. Specifically, the occurrence of stroke, PAD, DVT, and PTE was increased after five years of use of gabapentinoids. It is important to consider that thrombotic complications (DVT and PTE) tend to occur earlier with the use of gabapentinoids (as early as three months use), and the increased risks persisted at one and five years of clinical use. It is important to consider that the increased risk of thrombotic events with gabapentinoids when used for managing neuropathic pains or fibromyalgia was noted in the context when the control group received serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, opioids or tri-cyclic anti-depressants.

Our systematic review raises important questions regarding the cardiovascular safety of long-term use of gabapentin and pregabalin, when used in people more than 50 years of age, with high baseline cardiovascular risk. These drugs should be used with caution in people with multiple risk factors for cardiovascular disease and may be avoided in people with established cardiovascular disease. There remains an urgent need for dedicated cardiovascular safety RCTs on gabapentinoid-based therapies in people with diabetic neuropathy and other types of neuropathies. Also, the risk of cardiovascular events with the use of gabapentinoids needs to be specifically evaluated in people with a low baseline risk of cardiovascular events. Till then, safer alternatives like SSRIs, SNRIs, TCAs, or opioid analgesics may be considered for managing neuropathic pain in people with high baseline cardiovascular risk.

There are several limitations of this systematic review. No RCTs were available for analysis. All included investigations were real-world cohort studies. Hence, gabapentin and pregabalin were used at the approved doses for clinical use. The exact dose used in each patient was not available for analysis. The current analysis is based on data obtained from a few ethnic groups and countries (USA, Hungary and Spain), and hence needs to be replicated in different populations across the globe. The presence of data heterogeneity also limits some of the observations of this study. The strength of this systematic review is the large number of patients analysed from diverse aetiologies of neuropathic pain or fibromyalgia. All analysed cohort studies were of high quality.

To conclude, it may be said that the use of gabapentin and pregabalin in people with a high baseline risk of cardiovascular events was associated with increased risks of thrombotic events as early as three months of use, with increased risk of cardiovascular events on prolonged use of more than a year duration.