Prescribing of antiepileptic drugs for the treatment of pain

doi:10.21203/rs.3.rs-5192451/v1

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Prescribing of antiepileptic drugs for the treatment of pain

https://doi.org/10.21203/rs.3.rs-5192451/v1

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Background

Antiseizure medications (ASMs), particularly gabapentinoids like pregabalin, are increasingly prescribed for pain management. Despite their growing use, evidence of their effectiveness for pain is mixed. This highlights the need for a clearer understanding of the prevalence and prescribing patterns of ASMs in pain management.

Aims

To investigate the initiation of ASMs in people with and without pain or epilepsy diagnoses and to explore the concurrent use of opioids.

Method

This cross-sectional study used deidentified primary care data from 542 general practices in Victoria, Australia. Descriptive statistics were used to analyze ASM prevalence, concurrent opioid use, and prescribing patterns by age and gender.

Results

We identified 171,619 primary care patients who initiated an ASM between January 1, 2018, and May 31, 2023, of whom 80.1% had pain without epilepsy. Pregabalin was the most commonly initiated ASM, particularly among older adults with pain diagnoses, while sodium valproate, lamotrigine, levetiracetam, and carbamazepine were more commonly initiated for epilepsy. We also found high rates of opioid use preceding ASM initiation, particularly among patients with pain but not epilepsy.

Conclusion

Given the widespread off-label use of gabapentinoids and the potential for serious harm, further research is warranted to better understand their clinical and safety outcomes.

The findings highlight the need for clearer clinical guidelines to address the growing off-label use of ASMs for pain management.
The study reveals significant variations in ASM initiation by age and gender, with younger women more likely to receive lamotrigine or levetiracetam for epilepsy.
Findings show a high rate of opioid use preceding ASM initiation, suggesting the need for careful monitoring due to the increased risk of overdose.

Antiseizure medications (ASMs) are indicated for the management of epilepsy and other seizure disorders. Some ASMs may also be effective for pain management [1], and are prescribed for pain [2]. For instance, gabapentinoids (pregabalin and gabapentin), which were originally developed as ASMs, are now widely prescribed for various pain syndromes [3, 4].

In the US, gabapentin is predominantly prescribed for off-label uses, with one study finding over 95% of gabapentinoids were prescribed for patients without diagnoses that aligned with the approved conditions [5]. In Australia, gabapentinoids are only subsidised by the Pharmaceutical Benefits Scheme (PBS) for cases of refractory neuropathic pain or epilepsy [6, 7]. Between 2020 and 2021, more than 4 million gabapentin and pregabalin prescriptions, were subsidised under the PBS [6]. Due to the risk of central nervous system depression, caution is advised when prescribing gabapentinoids in combination with opioids, which are commonly used to manage pain conditions.

A systematic review assessed gabapentinoids, and other ASMs (e.g. valproate, lamotrigine, levetiracetam, and carbamazepine) for managing pain after spinal cord injury and found pregabalin showed moderate effectiveness in improving neuropathic pain, but evidence supporting the effectiveness of valproate and levetiracetam for treating pain was lacking [8]. The same review found lamotrigine reduced neuropathic pain in patients with incomplete lesions, while carbamazepine was effective for the treatment of moderate to intense pain. Contrary to this, a recent Cochrane review showed limited evidence supporting the efficacy of lamotrigine in treating neuropathic pain [9], while another Cochrane review concluded that there was insufficient evidence to support the use of valproic acid for neuropathic pain and fibromyalgia [10].

Given the increased use of ASMs for pain management, combined with mixed evidence on clinical outcomes, there is a need to understand the prevalence and patterns of ASM use for pain. Our study aims to investigate the initiation of ASMs in people with and without pain or epilepsy diagnoses in Australian primary care settings. Given safety concerns with overdose, we will also explore the concurrent use of opioids in this population.

This cross-sectional study used deidentified primary health data from general practices in Victoria, Australia (Monash University Ethics approval: 24139).

Data source and setting

These deidentified data, owned by and extracted with Primary Health Networks (PHNs) permission via the Population Level Analysis and Reporting (POLAR) primary care database, contains routinely collected data from electronic health records. Data on patient demographics, diagnoses and prescription medications were examined from 542 general practitioner (GP) practices, across three of the six Victorian PHNs. These PHNs were located in South East Victoria, which includes parts of metropolitan Melbourne and rural Victoria, representing 48% of the Victorian population. Additional information about data has been published elsewhere [11].

Participants

Eligible participants were a minimum of 14 years old at database cohort entry (January 1, 2017) and had newly initiated an ASM between January 1, 2018 to May 31, 2023. ASMs was identified using the Anatomical Therapeutic Chemical (ATC) code class N03 (epilepsy) and N02BF (gabapentinoids) (Table S1).

Outcomes and analysis

The primary outcome examined was the prevalence of pain and/or epilepsy diagnoses in people initiating ASMs.

Initiation was defined as a new prescription of an ASM, with no prescriptions in the 12 months prior. Inclusion criteria required that patients had at least one GP activity (e.g., consultations, prescriptions or vaccinations) by any participating GP practice within the 12 months before starting ASMs, reflecting their ongoing status/attendance.

Concurrent opioid use was examined by identifying prescription of opioids during the 12 months prior to the ASM initiation (inclusive). All opioid analgesics marketed in Australia were identified using the ATC code class N02A (opioids). Opioids for cough or opioid dependence treatment were excluded.

We used descriptive statistics to present the number and proportion of ASMs at the time of initiation. The prevalence of pain, and epilepsy diagnoses (derived from SNOMED CT codes) and opioid use in the 12 months prior to the ASM initiation by type of diagnoses were examined. We classified diagnoses into four categories: (1) pain diagnosis without an epilepsy diagnosis, (2) pain and epilepsy diagnoses, (3) epilepsy diagnosis without a pain diagnosis, and (4) no pain or epilepsy diagnoses. The prevalence of the eight most frequently prescribed ASMs, which represented 95% of all ASMs, was reported by diagnosis category and further stratified by age and sex groups at the time of initiation. The reporting of this study conforms to the STROBE statement.

We identified 171,619 primary care patients who initiated an ASM between January 1, 2018, and May 31, 2023, consisting of 99,751 females (58.5%), with 43.1% aged ≥ 65 years. The most commonly initiated ASMs were pregabalin (58.2%), sodium valproate (7.3%), pregabalin (6.9%), clonazepam (6.7%), topiramate (5.8%), lamotrigine (3.9%), levetiracetam (3.5%) and carbamazepine (3.5%) The year trend of ASM type at initiation are described in the Supplemental Figure S1.

Most (n = 137,528, 80.1%) had a documented diagnosis of pain without epilepsy. Few (n = 3,970, 2.3%) had a documented diagnosis of epilepsy without pain.

Pregabalin was more frequently initiated for patients with a documented pain diagnosis only (without an epilepsy diagnosis), particularly among those aged 65 years and older, regardless of gender (Table 1). Among younger patients (14–49 years old) with a pain diagnosis without epilepsy, males were more likely to receive pregabalin at initiation compared to females.

Table 1

Types of ASMs at initiation by age group, sex, and the presence of pain and/or epilepsy diagnoses.
Antiseizure medication use in people with and without pain and epilepsy diagnoses
	Men			Women
	14–49 (n = 23,105 32.5%)	50–64 (n = 18,382, 25.8%))	65+ (n = 29,533, 41.6%)	14–49 (n = 30,999, 31.1%)	50–64 (n = 25,762, 25.8%)	65+ (n = 42,990, 43.1%)
Pain diagnosis without an epilepsy diagnosis (n = 137, 528)
N (%)	15261 (28.1)	14296 (26.3)	24823 (45.7)	23027 (27.8)	21568 (26.1)	38128 (46.1)
Pregabalin	9655(63.3)	10207 (71.4)	16984(68.4)	11685 (50.7)	14145 (65.6)	26753(70.2)
Sodium valproate	1365 (8.9)	748 (5.2)	876 (3.5)	1218 (5.3)	814 (3.8)	1094 (2.9)
Gabapentin	1072 (7.0)	1013(7.1)	1531 (6.2)	1829 (8.0)	2038 (9.5)	2813 (7.4)
Clonazepam	670 (4.4)	564 (4.0)	2488 (10.0)	1045 (4.5)	759 (3.5)	3357 (8.8)
Topiramate	851 (5.6)	420 (2.9)	243 (1.0)	4112 (17.9)	1906 (8.8)	666 (1.8)
Lamotrigine	625 (4.1)	273 (1.9)	166 (0.7)	1881 (8.2)	476 (2.2)	256 (0.7)
Levetiracetam	150 (1.0)	201 (1.4)	652 (2.6)	159 (0.7)	164 (0.8)	552 (1.5)
Carbamazepine	321 (2.1)	309 (2.2)	609 (2.5)	546 (2.4)	538 (2.5)	974 (2.6)
Pain and epilepsy diagnoses (n = 9,394)
N (%)	1917 (41.3)	1109 (23.9)	1619 (34.9)	1992 (42.2)	1118 (23.7)	1611 (34.1)
Pregabalin	125 (6.2)	93 (8.4)	113 (7.0)	139 (6.5)	122 (10.9)	167 (10.4)
Sodium valproate	658 (34.3)	291 (26.2)	329 (20.3)	333 (16.7)	226 (20.2)	322 (20.0)
Gabapentin	35 (1.8)	13 (1.2)	27 (1.7)	36 (1.8)	29 (2.6)	33 (2.1)
Clonazepam	48 (2.5)	42 (3.8)	47 (2.9)	43 (2.2)	44 (3.9)	85 (5.3)
Topiramate	68 (3.6)	36 (3.3)	23 (1.4)	207 (10.4)	90 (8.1)	42 (2.6)
Lamotrigine	212 (11.1)	85 (7.7)	81 (5.0)	405 (20.3)	93 (8.3)	112 (7.0)
Levetiracetam	375 (19.6)	248 (22.4)	584 (36.1)	470 (23.6)	209 (18.7)	448 (30.3)
Carbamazepine	239 (12.5)	205 (18.5)	217 (13.4)	203 (10.2)	211 (18.9)	196 (12.2)
Epilepsy diagnoses without a pain diagnosis (n = 3,970)
N (%)	1442 (65.8)	465 (21.2)	285 (13.0)	1172 (67.6)	318 (18.4)	244 (14.1)
Pregabalin	12 (0.7)	5 (1.1)	7 (2.5)	15 (1.1)	7 (2.2)	5 (2.1)
Sodium valproate	544 (38.7)	126 (27.1)	64 (22.5)	222 (18.9)	69 (21.7)	52 (21.3)
Gabapentin	4 (0.3)	2 (0.4)	3 (1.1)	9 (0.8)	3 (0.9)	5 (2.1)
Clonazepam	25 (1.7)	12(2.6)	9 (3.2)	18 (1.5)	4 (1.3)	10 (4.1)
Topiramate	63 (4.4)	16 (3.4)	6 (2.1)	76 (6.5)	11 (3.5)	14 (5.7)
Lamotrigine	165 (11.4)	48 (10.3)	17 (5.9)	255 (21.8)	52 (16.4)	17 (7.0)
Levetiracetam	312 (21.6)	110 (23.7)	98 (34.4)	360 (30.7)	66 (20.8)	67 (27.5)
Carbamazepine	195 (13.5)	96 (20.7)	41 (14.4)	129 (9.7)	75 (23.6)	34 (13.9)
No pain or epilepsy diagnoses (n = 20,727)
N (%)	4485 (45.8)	2512 (25.6)	2806 (28.6)	4808 (45.5)	2758 (26.1)	3007 (28.4)
Pregabalin	1832(40.9)	1344 (53.5)	1343(47.9)	1711(35.6)	1367 (49.6)	1545 (51.4)
Sodium valproate	903 (20.1)	350 (13.9)	258 (9.2)	546 (11.4)	240 (8.7)	194 (6.5)
Gabapentin	253 (5.4)	137 (5.5)	144 (5.1)	320 (6.7)	260 (9.4)	189 (6.3)
Clonazepam	361 (8.1)	195 (7.8)	510 (18.2)	394 (8.2)	211 (7.7)	553 (18.4)
Topiramate	174 (3.9)	56 (2.2)	25 (0.9)	579 (12.0)	188 (6.8)	43 (1.4)
Lamotrigine	379 (8.5)	75 (3.0)	24 (0.9)	769 (16.0)	116 (4.2)	34 (1.1)
Levetiracetam	143 (3.2)	96 (3.8)	172 (6.1)	115 (2.4)	81 (2.9)	113 (3.8)
Carbamazepine	195 (4.4)	101 (4.0)	120 (4.3)	168 (3.5)	121 (4.4)	123 (4.1)
Note: Column totals do not sum to 100% as only the eight most frequently prescribed ASMs are listed.

The type of ASM that was initiated varied by epilepsy diagnosis. Pregabalin and gabapentin were significantly less commonly initiated for those without an epilepsy diagnosis. Additionally, in those aged 14–49 with a documented epilepsy diagnosis, women were twice as likely as men to be prescribed topiramate and lamotrigine at initiation, whereas prescription rates for both genders were similar in the 50 and older age groups. Among patients without a diagnosis of pain or epilepsy, nearly half of those over 50 years old were prescribed pregabalin at initiation, with similar rates for both genders. Women < 50 years were more likely to initiate topiramate and lamotrigine compared to men of the same age.

Opioid use during the12-months preceding ASM initiation was significantly more prevalent among patients with a documented pain diagnosis without epilepsy diagnosis with 40–50% of patients in this group prescribed opioids within the 12 months prior to their ASM initiation. This rate was nearly ten times higher for patients diagnosed with epilepsy without a pain diagnosis (Table 2).

Table 2

Opioid prescription within the 12 months prior to ASM initiation
	Opioid prescription within the 12 months prior to ASM initiation (N, %)
	Men			Women
Diagnosis	14–49	50–64	65+	14–49	50–64	65+
Pain diagnosis without an epilepsy diagnosis	5976 (39.2)	6317 (44.2)	10983 (44.3)	8756 (38.0)	9224 (42.8)	18178 (47.7)
Pain and epilepsy diagnoses	251 (13.1)	233 (21.0)	348 (21.5)	360 (18.1)	257 (23.0)	441 (27.4)
Epilepsy diagnoses without a pain diagnosis	49 (3.4)	20 (4.3)	23 (8.1)	46 (3.9)	17 (5.4)	18 (7.4)
No pain or epilepsy diagnoses	817 (18.2)	653 (26.0)	896 (31.9)	906 (18.8)	635 (23.0)	958 (31.7)

Our study indicates that pain is the primary driver of gabapentinoid initiation, particularly pregabalin. However, the initiation of sodium valproate, lamotrigine, levetiracetam and carbamazepine were more prevalent among patients with a recorded an epilepsy diagnosis. Opioid use preceding ASM initiation was highest in those with pain but not an epilepsy diagnosis.

Pregabalin appears commonly used for neuropathic pain in those who have not responded to other medications like opioids, and is used as a second-line medication for partial seizures. Pregabalin gained PBS-subsidy status for neuropathic pain in March 2013, leading to an immediate and sustained increase in prescribing [12, 13]. In 2020, pregabalin was the most frequently supplied analgesic in the country [13]. In early 2020, following mandatory implementation of prescription drug monitoring in Victoria, an increase in the initiation of pregabalin was observed [14]. It was hypothesized that clinicians might initiate a non-monitored medicine, like pregabalin, instead of prescribing monitored medications such as opioids for pain [15]. While pregabalin is effective in reducing pain associated with neuropathic pain, recent studies have failed to find clinical benefits from pregabalin in a chronic pain cohort, irrespective of neuropathic pain status [16]. Increased harms including death and misuse [17, 18] associated with global increased gabapentinoid prescribing, combined with widespread off-label use of gabapentinoids for non-neuropathic pain, reinforces the need for a more detailed understanding of the use of these medications, including clinical outcome data. The relative common concomitant prescribing of opioids and ASMs is also a trend that warrants further monitoring given the increased risk of overdose documented with this combination of medicines [19, 20].

Findings from this study also suggested that valproate, lamotrigine, levetiracetam, and carbamazepine are predominantly used for the treatment of epilepsy rather than pain, with valproate being more commonly initiated for younger (< 50 years old) male patients, while female patients of the same age are more likely to initiate treatment with lamotrigine or levetiracetam. This may be because lamotrigine or levetiracetam are considered more effective as a first-line treatment of epilepsy for girls and women of reproductive age[21].

Limitation

There are limitations to acknowledge; 1) The primary care dataset represents prescribed medications, whether these medications were subsequently dispensed by pharmacists or used by patients is not known; 2) We examined recorded diagnoses, but the indication for specific prescriptions is not recorded, so it is not possible to confirm if the medication was prescribed for those diagnoses, nor whether use was clinically appropriate.

This is one of the first population-level studies to examine ASM use for pain in Australia. We found gabapentinoids like pregabalin are commonly used in Australia for pain management in primary care. ASMs like sodium valproate, lamotrigine, and levetiracetam were more commonly initiated in patients with epilepsy, with clear gender and age differences noted in initiating, consistent with best practice. The findings of high rates of concurrent gabapentinoids and opioid prescribing for pain conditions should be carefully monitored.

Funding

This work was supported by the Australian National Health and Medical Research Council (NHMRC, GNT2002193). SN and LP are recipients of NHMRC Investigator Grants (# 2025894 and #2016909).

Acknowledgments

The de-identified data supplied is owned by PHNs and was sourced from contributing general practices by Outcome Health (via the POLAR platform) on behalf of Eastern Melbourne PHN, Gippsland PHN and South Eastern Melbourne PHN.

Competing Interests

All authors report no conflicts of interest.

Data Availability

Researchers interested in accessing POLAR data should contact Outcome Health ([email protected]).

Author Contributions

SN and JI conceived the study. TX cleaned the data and performed the analysis. TX took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

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Prescribing of antiepileptic drugs for the treatment of pain

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Abstract

Impact statements

Introduction

Methods

Data source and setting

Participants

Outcomes and analysis

Result

Discussion

Limitation

Conclusion

Declarations

References

Supplementary Files

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