Low back pain (LBP) is one of the most prevalent pain conditions and a leading cause of disability worldwide. Its complex pathophysiology may involve both nociceptive and neuropathic mechanisms, contributing to the heterogeneous nature of the condition. In 2020, LBP affected 619 million (95% uncertainty interval 554–694) people globally (GBD, 2021 Low Back Pain Collaborators, 2023).

In LBP, nociceptive pain results from activation of nociceptors that innervate ligaments, joints, muscles, fascia and tendons as a response to tissue injury or inflammation and biomechanical stress. Neuropathic back pain describes pain arising from injury or disease directly affecting the nerve roots that innervate the spine and lower limbs, and pathological invasive innervation of the damaged lumbar discs. Chronic LBP is increasingly considered to be a mixed pain syndrome consisting of both nociceptive and neuropathic components, and it has been suggested that neuropathic components in chronic LBP may be under-recognized and therefore undertreated (Baron et al., 2016).

This mixed pain condition is notoriously difficult to manage and resistant to treatments (Ghazisaeidi et al., 2023; Sharma and McAuley, 2022; Mák et al., 2021). Pain is also associated with a significant decline in quality of life and leads to both direct and indirect costs (Ghazisaeidi et al., 2023; Sharma and McAuley, 2022; Mák et al., 2021; Shetty et al., 2022). Studies suggest that nearly a quarter of individuals with LBP suffer from psychiatric comorbidities, such as depression and anxiety, which has led to advocate for psychiatric screenings in these patients (Dickson et al., 2023; Hu et al., 2022). Furthermore, the indirect costs of managing lumbar pain can reach up to 68% of total costs (Morera-Domínguez et al., 2010). Pharmacy costs alone may account for as much as 13% of the total expenses related to this condition while the cost of physical therapy account for up to 17% (Dagenais et al., 2008). Additionally, all the costs incurred, such as those resulting from reduced productivity at work, are significant, because LBP is the leading cause of disability in the United States and the main reason for absenteeism (Areias et al., 2023).

Current treatments for lower back pain, such as NSAIDs and opioids, often have significant drawbacks. NSAIDs, for instance, are associated with considerable health risks, including gastrointestinal toxicity, which can impose a substantial economic burden (Kikuchi et al., 2021). The majority of guidelines for the treatment of low back pain recommend paracetamol as the first-line option, with NSAIDs (that are readily accessible in various types and brands, both over-the-counter and by prescription) as a subsequent choice if paracetamol proves inadequate. While most NSAIDs are taken in oral preparations, topical formulations are also available to avoid systemic side effects, particularly in patients with allergies to specific medications, gastroesophageal reflux disease, and cardiac disease (Enthoven et al., 2016; Wang and Doan, 2024).

In addition, a Cochrane review noted by Cashin et al. (2023) found that opioids can lead to adverse events like nausea, headaches, constipation, and dizziness, which can severely affect a patient’s quality of life. The rapid escalation of the opioid epidemic reveals critical issues like addiction and dependency, complicating long-term treatment and management. This situation underscores the urgent need for alternative strategies to address these challenges effectively (Damiescu et al., 2021).

Although recent national guidelines have offered conflicting recommendations on the role of opioids in treating chronic LBP, opioids remain widely used in both Europe and North America. The prolonged use of opioids for chronic non-cancer pain has played a significant part in the opioid crisis in North America, contributing to a rise in opioid prescriptions, non-medical use, and the associated increase in mortality rates (Petzke et al., 2020). The guidelines from the European Medicines Agency and the American CDC highlight the need to assess physical dependence, abuse, and addiction in opioid trials, but these outcomes were not analyzed in the most systematic reviews for chronic LBP (Petzke et al., 2020).

For all these reasons, the need arose to seek more treatments that could be incorporated into clinical guidelines. Pregabalin emerges as treatment for neuropathic lumbar pain due to its ability to selectively bind to the α2-δ subunit of voltage-dependent calcium channels, inhibiting calcium influx, reducing excitatory neurotransmitter release and, as a consequence, reducing nerve impulse and pain sense (Taylor et al., 2007). This molecular action decreases pain signal transmission, alleviates symptoms, and enhances functionality, thus highlighting its potential in the management of LBP (Taylor et al., 2007).

Original studies on the pharmacological management of low back pain revealed mixed effectiveness across treatments. Robertson et al. (2019) favour gabapentin (GBP) for its minimal adverse effects and significant pain relief, whereas Sakai et al. (2015) and Mathieson et al. (2017) found no substantial benefits of pregabalin over opioids or placebo, respectively. Park et al. (2024) suggest that the choice between pregabalin and limaprost should be tailored to the individual, while Kalita et al. (2014) highlights amitriptyline’s superior functionality improvement.

Contrarily, Gammoh et al. (2021) report pregabalin as more effective than GBP, Romanò et al. (2009) see added benefits with pregabalin combined with celecoxib but only in cases where both nociceptive and neuropathic elements were present, and Saldaña et al. (2010a) note its cost-effectiveness in clinical practice.

Some previous meta-analyses, as noted by Wewege et al. (2023), did not specifically focus on pregabalin but considered a wider array of medications, complicating the isolation of variables that could influence outcomes. Another meta-analysis by Giménez-Campos et al. (2022) included only three randomised controlled trials (RCTs) for pregabalin, and they did not account for dosage, controls, and other confounding variables. Baron et al. (2010) concluded that “further work” was required to understand the potential of pregabalin in treating LBP. These insights underscore the necessity for a new meta-analysis aimed at objectively assessing the therapeutic value of pregabalin, addressing the gaps identified in earlier studies.

This meta-analysis addresses gaps by providing an up-to-date, focused synthesis of studies that evaluate both the efficacy and safety of pregabalin specifically in non-surgical LBP. Through rigorous inclusion criteria and the integration of recent data, this work aims to comprehensively assess the efficacy and safety of pregabalin in the management of LBP, addressing gaps in current research and providing clear, evidence-based insights to guide clinical practice.

Despite the development of multiple drugs targeting diverse mechanisms of action for predominantly nonspecific axial LBP syndromes, no therapy has been approved for neuropathic LBP conditions such as sciatica (Markman et al., 2018). Pregabalin has shown efficacy in several neuropathic and nociplastic pain conditions, including diabetic peripheral neuropathy (Zhang et al., 2015; Parsons et al., 2018) and fibromyalgia (Zareba, 2008; Migliorini et al., 2022). However, evidence remains inconsistent for other conditions, such as LBP, particularly in neuropathic subtypes like sciatica.

Pregabalin has demonstrated improvements in LBP at 4, 6, and 8 weeks, underscoring the importance of addressing the multidimensional nature of this condition, which can involve both neuropathic and nociceptive pain components. Notably, our meta-analysis indicates that the most pronounced effectiveness of pregabalin emerges from 4 weeks onward, which contrasts with findings for other compounds such as buprenorphine (Pota et al., 2012) or conventional care (Taguchi et al., 2015), where the onset of pain relief may differ. In addition to its analgesic effects, pregabalin has shown efficacy in improving reduction in sleep disturbance and anxiety symptoms, which are frequently associated with chronic LBP (Montaño et al., 2025). This psychiatric benefit may help explain the significant improvements in quality of life observed, even in the absence of marked changes in functional or disability scores. It is important to note that many of the included studies had relatively short follow-up durations (≤12 weeks), which may have limited the detection of changes in disability outcomes. Improvements in sleep quality associated with pregabalin may contribute to overall symptom relief, as a strong relationship between sleep quality and quality of life has been documented (Perotta et al., 2021).

In conditions such as sciatica and radiculopathy, pulsed radiofrequency has demonstrated efficacy in pain relief (Chao et al., 2008) both as a standalone treatment and when combined with steroid injection (Napoli et al., 2023). However, these approaches have not yet been specifically evaluated in combination with pregabalin for these indications. Interestingly, the combination of pregabalin with radiofrequency has been shown to improve sleep quality in patients with herpetic neuralgia, further supporting its beneficial effects on overall patient wellbeing (Chen et al., 2023). These findings suggest that exploring combined treatment approaches could be valuable for enhancing outcomes in patients with neuropathic pain conditions.

The heterogeneity of comparators in existing studies—including gabapentin (GBP), amitriptyline, limaprost, diphenhydramine, NSAIDs, and opioids—has limited the number of trials directly comparing pregabalin to individual agents, constraining robust conclusions. However, the literature indicates that pregabalin showed superiority over gabapentin in cancer-related neuropathic pain (Mishra et al., 2012) and over opioids for lower-limb symptoms in elderly patients with chronic LBP (Sakai et al., 2015).

In this meta-analysis, the combination of pregabalin with other pharmacological agents demonstrated a significant improvement in pain outcomes compared to active control or placebo. These findings suggest that adjunctive pregabalin may represent an optimal strategy for enhancing pain management in patients with lower back pain, particularly when a neuropathic component is present (Romanò et al., 2009). It is important to note that certain combinations, such as pregabalin with opioids, have been associated with increased risks of sedation and falls (Virnes et al., 2022) as well as dizziness, cognitive dysfunction, and respiratory depression (Hahn et al., 2022).

Another important question to address is regarding the comparative effectiveness and safety of higher doses of pregabalin versus alternative regimens. Future research should categorize pregabalin dosing (e.g., ≤150 mg, 150–300 mg, >300 mg) to better elucidate potential dose–response relationships. In our meta-analysis, only three studies explicitly reported mean doses above 300 mg; however, this does not necessarily indicate that all patients received doses exceeding 300 mg, but rather that the average dose within those studies was higher. Similarly, the initial starting dose did not appear to influence outcomes, as studies commencing pregabalin at 75 mg and those starting between 150 and 300 mg achieved comparable results, provided they reached the same final dose. Our analysis also did not demonstrate any clear differences in the incidence of adverse events across dosing regimens. Moreover, future studies should consider stratifying patients using validated tools such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) or the DN4 questionnaire to further clarify pregabalin’s role in individuals with prominent neuropathic features. For example, the study by Romano et al. found that pregabalin was particularly effective in patients with LANSS scores indicative of neuropathic pain, even when nociceptive components were also present (Romanò et al., 2009). The concept that pain with different mechanistic characteristics—nociceptive, neuropathic, or nociplastic—can coexist in the same patient, in any combination, has been further developed by Freynhagen et al. (2019) in their narrative review describing the phenomenon of ‘mixed pain.’ Given pregabalin’s demonstrated efficacy in both neuropathic and nociplastic pain models, it may be particularly well-suited for the management of these complex, overlapping pain phenotypes.

Pregabalin has demonstrated efficacy in spinal conditions beyond those included in the present meta-analysis. Specifically, pregabalin has been shown to be more effective than gabapentin in reducing pain associated with Failed Back Surgery Syndrome (Al-Ameri et al., 2024). Additionally, pregabalin has been associated with reductions in postoperative pain and opioid consumption following spinal fusion, highlighting its potential as an adjunct in postoperative pain management (Fujita et al., 2016). In line with these findings, the present meta-analysis revealed that pregabalin was associated with lower total costs compared to other interventions. This cost-effectiveness is further supported by evidence indicating that pregabalin’s efficacy in managing not only pain but also comorbid symptoms, such as anxiety and depression, contributes to a reduction in indirect costs, including loss of productivity and diminished quality of life, which are significant drivers of the economic burden in neurological disorders (Morera-Domínguez et al., 2010; Dagenais et al., 2008). These indirect costs are recognized as the most substantial component in the overall treatment burden for these conditions (Chodavadia et al., 2023).

Few meta-analyses have specifically examined the isolated effect of pregabalin for low back pain, which limits the ability to consistently analyze heterogeneity focused on pregabalin. For example, Wewege et al. (2023) reported only limited pain improvement with various medications, including pregabalin, and highlighted the low certainty of evidence for any pain reduction achieved with these agents. Similarly, Giménez-Campos et al. included pregabalin alongside gabapentin in their analysis, but only three studies specifically evaluated pregabalin. They found no evidence of efficacy for either drug in sciatica, with no benefit over placebo for pain relief and a worse safety profile, characterized by increased rates of dizziness and nausea/vomiting (Giménez-Campos et al., 2022). Consistent with these findings, Mascarenhas et al. (2023) observed that opioids provided greater pain relief than pregabalin in older adults with chronic nonspecific low back pain. Additionally, Shanthanna et al. (2017) found no benefit of pregabalin, even when used as an adjunct to opioids.

Pregabalin, whether administered as monotherapy or in combination with other treatments, has demonstrated efficacy in the management of LBP. Notable benefits include significant reductions in pain (observed from weeks four to eight of follow-up) as well as improvements in associated symptoms such as anxiety, depression, sleep disturbances, and overall quality of life. Additionally, pregabalin exhibited a safety profile comparable to that reported in existing literature and similar to other therapeutic alternatives, based on the adverse events analyzed. However, these findings should be interpreted with caution due to the overall limited and heterogeneous quality of the available evidence, particularly the inadequate reporting of pain etiology and symptom duration across studies. Several included trials enrolled mixed populations or did not clearly distinguish between neuropathic and non-neuropathic LBP, which limits the generalizability of the results and precludes robust subgroup analyses. Therefore, further well-designed, standardized studies are warranted to clarify pregabalin’s role across various LBP subtypes and to establish optimal dosing strategies.