To our knowledge, this study presents the most comprehensive analysis to date of cross-sectional comparisons and longitudinal trends in pregabalin use in the Israeli adult population. Our results showed an increase of 2.3-fold in pregabalin use among the adult population between 2010 and 2019, which is consistent with other studies [6, 27,28,29,30]. Several factors may have contributed to this trend. In part, it is possible that the perception that pregabalin poses a lower potential for abuse than opioids has prompted its consideration as an alternative to general pain management. This includes acute perioperative treatments and chronic pain management, aiming to reduce opioid consumption due to the sharp increase observed in the use of opioids, as previously reported in the USA, UK, and Europe [10, 28, 29, 31,32,33]. In this regard, between 2008 and 2018, the use of strong opioids in Israel increased two-fold among elderly patients without cancer and more than seven-fold among patients younger than 65 years old [34]. The Israeli health system is making efforts to control opioid consumption. As social and medical attitudes shift towards pain-intensive management, pregabalin has become more widely accepted and prescribed. The use of pregabalin to enhance analgesia has been observed in cases of chronic neuropathic pain caused by advanced cancer, which is being used alongside the primary treatment of opioids [35, 36]. Economic factors also likely contribute to this trend. Since 2012, pregabalin has become more affordable and economically accessible for patients due to its inclusion in the discount list of drugs provided as part of the complementary health insurance program, Clalit MUSHLAM. Removing the requirement for individual MUSHLAM approval for a discount has also enhanced pregabalin’s accessibility, allowing a wider range of patients to use it.

As observed in other countries, the vast majority of pregabalin prescriptions in our study were for neuropathic pain and pain indications in general [4, 29]. While pregabalin is also registered in Israel for the treatment of generalized anxiety disorder, it is not commonly used for this indication in practice, as shown by our results (0.2 and 0.09% prescriptions dispensed in 2010 and 2019, respectively). A German study also reported an uncommon use for generalized anxiety disorder within the corresponding years [29]. Pregabalin’s infrequent prescription for generalized anxiety disorder in Israel may be related to several factors; however, it is beyond the scope of the current study.

While pregabalin dispensing was most prevalent among the elderly population, a noticeable but non-statistically significant increase in pregabalin prescription rate was observed among young adults aged 18–34 years. Higher doses of pregabalin use were observed in males, patients with low socioeconomic status, patients aged 35–54 years (followed by those aged 55–74), and patients who used opioids, benzodiazepines, and/or Z-drugs. These trends were also noted in other studies; however, higher dose consumption was noted in a younger age group (18–29 years) [37, 38]. We did not find the trend of higher pregabalin doses among youngest group (aged 18–34 years), maybe due to the relatively small sample size of those ages during the study period. A higher pregabalin dose use by young adults may indicate clinical ineffectiveness, no need for dose adjustment in renal failure, which is common in elderly, as well as drug abuse and misuse among patients seeking psychoactive effects [37].

The upward trend in pregabalin use and pregabalin’s DDD was hypothesized to be more dominant among adults who also use opioids, benzodiazepines, and/or Z-drugs. This was based on studies suggesting pregabalin is also being utilized by individuals to enhance the psychoactive effects of these substances including enhanced sociability, euphoria, and, at higher doses, dissociation and sedation [39, 40]. Additionally, other studies have observed a rise in concurrent prescribing, further indicating coadministration potential [30, 41, 42]. This group of patients was found to have higher pregabalin doses, as we had expected. However, our findings suggest a decrease in same-year administration between 2010 and 2019. It is possible that this may be attributed in part to the effectiveness of Israeli policies concerning prescription drug monitoring programs for opioid use. This includes the use of prescription drug monitoring programs, limitations on days’ supply, and the need for special approvals for the long-term use of certain opioids. Therefore, despite the increase in pregabalin use in the past years, the number of same-year prescriptions remained steady or even decreased. In terms of benzodiazepines, the National Program for Quality Indicators in Community Healthcare (QICH) has made significant strides in addressing benzodiazepine use among individuals over 65 years old. The QICH data reveals a decrease in long-term benzodiazepine utilization within this age group, which might be reflected in our results [43, 44]. It is also imperative to acknowledge the unique circumstances of Holocaust survivors, who have been identified as prone to benzodiazepine overuse [45, 46]. Over time, their numbers have naturally decreased, potentially influencing the decline in same-year benzodiazepines and pregabalin prescriptions.

Our retrospective study had several limitations to consider. Due to the nature of our study, we were limited to analyzing prescriptions issued and could not take into account instances in which patients were not taking their prescribed medication as directed. Thus, purchased prescriptions may not always be equivalent to the ones that are actually consumed by patients.

Although several studies in the UK, the USA, and Australia have reported widespread off-label prescribing of pregabalin mostly for treating chronic pain [4, 30, 47], our findings indicate a minimal increase in off-label use. In most cases, CHS insurance covers drug therapy for labeled indications only. Off-label indications treatment is purchased outside the CHS services and data are not available in the CHS database. This fact explains the very low off-label pregabalin use in our study. In addition, prescription indications were derived from the medical history of the patients. It is therefore possible that some indications may be incorrectly classified due to inaccurate coding or outdated medical histories. In view of these limitations and assuming that there are some illegal pregabalin sales for recreational purposes, our findings may contain some inaccuracies.

Finally, we evaluated the purchase of benzodiazepines, Z-drugs, and opioids by pregabalin users. Same-year use was defined when the drug was purchased at least once during the relevant year. Consequently, our results cannot confirm coadministration, as it may be concurrent administration, drug substitution, or unrelated events.

Despite the previously mentioned limitations, this study is the first to examine pregabalin use trends over a 10-year period in Israel. It presents the most comprehensive analysis of cross-sectional comparisons and longitudinal trends in pregabalin use in the Israeli adult population to date. The analysis was based on databases maintained by CHS, the largest healthcare organization in Israel. The large CHS-insured population and its diversity make our findings generalizable to Israel’s adult population. The study results can serve as a foundation for further research in Israel aimed at providing a clear and precise depiction of pregabalin utilization patterns, particularly regarding high-intensity use, which may be at increased odds of misuse and abuse.