Analgesic medications are commonly prescribed in pediatrics, with prescribing practices frequently extrapolated from adult trials. Gabapentinoids (gabapentin and pregabalin) are widely used as analgesics but are labeled in pediatrics only for epilepsy. We aim to (1) define trends in pediatric gabapentinoid prescribing (label and off-label) over 7 years, and (2) evaluate use in chronic pain clinic (CPC) patients during 2018.
Retrospective data from a tertiary-care pediatric hospital were collected between 2013 and 2019. Annual numbers of gabapentinoid prescriptions were stratified by prescriber specialty. Additional information about gabapentinoid prescribing in the CPC was manually collected from initial clinic notes in 2018.
There were 15 808 outpatient prescriptions for gabapentinoids among 5172 patients over 7 years. Of these, 93% were gabapentin and 7% were pregabalin. Numbers of patients receiving gabapentin and pregabalin prescriptions increased by 1.4- and 1.3-fold, respectively, between 2013 and 2019. Few prescriptions were done for patients with a previous epilepsy diagnosis (in 2019, 16% for gabapentin and 13% for pregabalin). Approximately 28% of 650 CPC new patients were prescribed gabapentin or pregabalin before referral. Among those, 44% had discontinued the medication because of adverse events (35%), inefficacy (46%), or both (5%). Most side effects reported were mild to moderate. Diagnoses at first visit were diverse, not limited to neuropathic pain conditions, and did not differ between patients receiving or not receiving gabapentinoid prescriptions.
In our hospital, gabapentinoids are commonly prescribed off-label for diverse indications, including chronic pain. Future research is needed to evaluate gabapentinoid efficacy in these indications.
Pain is a complex experience with interactions between biological, cognitive, emotional, behavioral, and social factors.1,2 Moderate to severe chronic pain affects 5% to 8% of adolescents in the United States and has a high cost for their families and society.3–5 Multidisciplinary approaches encompassing physical therapy, cognitive behavioral therapy, and mindfulness-based stress reduction have proven to be effective in the management of chronic pain.6–10 A variety of medications are available for pain treatment, including nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants, and opioids, as well as muscle relaxants, sedatives, and anxiolytics.11 Analgesic medications are often prescribed to children on the basis of extrapolation from adult clinical trials and dosing guidelines.
Gabapentinoids (gabapentin, pregabalin) were first used as anticonvulsants; however, their use for neuropathic pain treatment in adults has become more widespread. Currently, the use of gabapentin as an analgesic adjuvant for the treatment of neuralgias, peripheral neuropathies, fibromyalgia, visceral neuropathy, and chronic daily headaches is a regular practice.12,13 Adult trials of gabapentinoids for neuropathic pain reveal small effect sizes relative to placebo.14 With concerns regarding opioid risks, and after aggressive marketing, gabapentinoids have become among the most widely prescribed drugs for adults.14,15 In adults, the US Food and Drug Administration (FDA) approved gabapentin for postherpetic neuralgia and pregabalin for diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. Gabapentinoids are also commonly used as a component of multimodal opioid-sparing regimens for the treatment of postoperative pain in adults and children, despite negative conclusions from recent meta-analyses.16,17 In children, these medications are approved as adjuvant therapy for partial seizures, but not for pain. In pediatrics, 2 systematic reviews17,18 revealed insufficient evidence for efficacy or harm of gabapentinoids for the treatment of either acute or chronic pain.17
The current study has 2 objectives. First, we evaluated overall trends in gabapentinoid prescribing practices (label and off-label) at a single pediatric institution over 7 years. Secondly, because most off-label uses of gabapentinoids are reported for chronic pain,19 we analyzed gabapentinoid-prescribing practices during patients' first chronic pain clinic (CPC) encounters in 2018.
We included all patients (<19 years old) with at least 1 outpatient gabapentinoid prescription between 2013 and 2019 at a tertiary-care pediatric hospital. Using an informatics platform that allows for querying and reporting clinical data managed by the Information Services Department, we extracted prescription date, epilepsy diagnosis (using International Classification of Diseases codes), and prescriber specialty. Annual counts and descriptive statistics are presented. We used linear regression models to evaluate whether there was a nonzero trend (slope) in annual gabapentinoid prescriptions over time.
We analyzed notes for patients’ initial CPC encounter during 2018, including previous and current gabapentinoid use, reasons for stopping (eg, ineffectiveness or adverse effects), and numbers of new prescriptions. In our clinic, as standard practice, we report analgesic medication tried before the encounter and reasons, if any, for discontinuation. If no gabapentinoid prescriptions were mentioned in notes or medication reconciliation, we assumed they had not been prescribed previously. Two reviewers extracted all data, and, when there was disagreement, the corresponding author made a final decision. Comparisons between patient groups were made by using χ2 tests. Analyses were performed by using R (R Foundation, Vienna, Austria). The study was approved by the institutional review board at our institution with a waiver of participant consent.
Over the past 7 years, our institution issued a total of 15 808 outpatient prescriptions for gabapentin and pregabalin for 5172 patients, median age 14.9 years (interquartile range [IQR] = 11.7–16.7), 69% girls. Among those prescriptions, 93% were gabapentin (n = 14 712) and 7% were pregabalin (n = 1096). Figure 1A reveals that the number of patients receiving gabapentin and pregabalin prescriptions increased by 1.4- and 1.3-fold, respectively, between 2013 and 2019. Over the study period, more prescriptions were seen in multiple clinics (Fig 1B and C). Most prescriptions were provided via CPC and the neurology clinic, with increments of gabapentinoid prescriptions of 1.3- and 1.4-fold, respectively. In 2019, the median number of days prescribed was 30 (IQR = 30–39), with a median of 3 (IQR = 1–5) refills. Days prescribed and number of refills did not change over time or by prescriber service. Prescriptions for patients with an epilepsy diagnosis, the only approved pediatric indication, account for a small percentage of all patients with gabapentinoid prescriptions (2013: 15% gabapentin, 9% pregabalin; 2019: 16% gabapentin, 13% pregabalin).
There were 650 first CPC encounters during 2018. Overall, 24% of patients had been previously treated with gabapentin, 1% with pregabalin and, 3% with both medications. Of those who had been treated with a gabapentinoid (n = 176), 56% were still taking the medication and 44% had stopped. The reasons for discontinuation were adverse events (35%), lack of efficacy (46%), or both (5%). Most side effects reported were mild to moderate (eg, dizziness, cloudiness, tiredness, and moodiness). No serious adverse events were reported. In only 2 (3%) cases, it was reported that the medication was discontinued because the pain was resolved. An additional 120 patients received a first gabapentinoid prescription at the first CPC encounter. Diagnoses at first visit did not differ between patients receiving or not receiving gabapentinoid prescriptions (Fig 2) (χ2 = 1.08, P value = .299).
Gabapentin and pregabalin are among the most widely prescribed drugs in the United States. In our analysis, prescriptions for patients with an epilepsy diagnosis were a small percentage of overall prescribing. Even among those patients with an epilepsy diagnosis, it is likely that gabapentinoids were prescribed for another indication, rather than seizures, especially neurologic irritability or pain. On the basis of the volume of prescribing among different clinics, eg, CPC, orthopedics, and Psychiatry (as revealed in Fig 1) it is probable that gabapentinoids are commonly prescribed as off-label medications for chronic pain and mode disorders, rather than as an adjuvant medication for epilepsy.
Along with marketing, several additional factors have fostered wider prescribing of gabapentinoids for chronic pain.20 In comparison with tricyclic antidepressants, gabapentinoids are regarded as simpler to prescribe because an electrocardiogram is not required and they may have a lower risk of death from overdose.
As noted in the introduction, a Cochrane review concluded that evidence is inconclusive regarding the efficacy of anticonvulsants and antidepressants for chronic pain management in pediatrics3,6 The term “neuropathic pain” was traditionally defined as pain arising from nerve injury or abnormal nerve excitability.21 It is often used broadly by some clinicians to include a range of conditions characterized by hyperalgesia, such as complex regional pain syndrome, irritable bowel syndrome, and fibromyalgia.21,22 The vague nature of the terminology used for gabapentinoid prescribing falsely suggests that this medication can be used for all types of pain, regardless of their etiology or mechanism.23
The FDA has not approved the use of gabapentin or pregabalin for chronic or acute pain in pediatrics. However, as revealed here, the number of prescriptions has increased over the years. Detailed analysis of prescribing patterns from patients referred to the CPC suggests several trends: (1) roughly 1 in 4 patients were already receiving gabapentin or pregabalin before a first CPC visit; (2) a majority of patients who received gabapentinoids before a first CPC visit continued to receive them afterward; and (3) diagnostic categories were similar among patients who received gabapentin or pregabalin prescriptions compared with those who did not.
In our analysis of the CPC, serious adverse events were not reported, although mild side effects were relatively common (40%) and the self-reported ineffectiveness was close to 50%. Given the study design, we cannot exclude the possibility that some patients experienced serious adverse events that were either not reported or recorded by CPC clinician at the first visit or that appear after the use of these medications for longer periods of time. In 2008, the FDA issued a label warning for the increased risk of suicidal thoughts and behaviors associated with the use of all antiepileptic drugs, including gabapentin.24 Given the potential of adverse effects, the common reports of mild to moderate side effects, and equivocal evidence for effectiveness in the management of pain in pediatrics, there is a need to re-evaluate prescribing of gabapentin and pregabalin in children and adolescents, both by prospective clinical trials and by pragmatic studies that attempt to understand factors associated with benefit or side effects in individual patients.
Our study was limited by the retrospective design and the use of data from a single tertiary-care pediatric hospital that may not represent prescription practices nationwide. There may be a recall bias for the information extracted from the notes and the previous use and reasons for discontinuation of the medication. The use of International Classification of Diseases codes and prescribers’ specialties is an indirect approach to understanding the indications, diagnoses, and prescribers’ rationale for the selection of these medications.
At our institution, prescribing gabapentin and, to a lesser extent, pregabalin, has markedly increased in the past few years. When prescribed for chronic pain, its use is not limited to fibromyalgia or narrowly defined neuropathic pain. Although specific trends in the prescribing of gabapentinoids have been identified at our institution, further research is needed to understand national trends. With the knowledge that analgesic clinical trials in pediatrics are challenging, especially for chronic pain, we recommend multicenter collaboration and consideration of innovative trial designs to better define appropriate indications for pediatric prescribing of gabapentin and pregabalin.
FUNDING: The Sara Page Mayo Endowment for Pediatric Pain Research provided financial support for this work (through Dr Berde).
Drs Donado and Berde conceptualized and designed the study, performed the initial analysis, and drafted and reviewed the manuscript; Dr Wangnamthip and Ms Nedeljkovic performed data gathering and revised the manuscript; Drs Solodiuk and Bourgeois critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.