Pediatric Gabapentin Use in Postoperative Pain following Craniotomy: A Scoping Review

Introduction

A scoping review utilizes a systematic approach to identify and gather existing literature on specific topics with the aim of de- termining if there are gaps in evidence. In this study, a scop- ing review was conducted to determine the availability, or lack thereof, of research regarding the use of gabapentin in a pedi- atric postoperative setting, specifically post-craniotomy. During data collection from January 2022 through August 2022, the re- viewers sought to determine the possibility of Gabapentin being used in the pediatric population following neurological surgery, specifically craniotomies. The reviewers seek to emphasize the importance of the need for further research regarding the postop- erative use of gabapentin in a pediatric setting by presenting the topic of gabapentin being an alternative to opioids. This topic is supplemented by what is seen in the current literature regarding pediatric pain management.

Postoperative pain following craniotomy is managed in several ways and can be based on the attending physician's discretion. Treatment options utilized can be either conventional or uncon- ventional methods of pain management, some of which include the use of non-opioid-associated narcotics, narcotic medications, NSAIDs, as well as other management options. Gabapentin is one of the options that has been extensively used in acute post- operative settings due to its properties, such as its anticonvulsant effects and the ability to alleviate acute and chronic pain [1]. This is due to the increasing opioid crisis in the United States, as well as across the globe. The use case for moving towards a non-opioid medical management direction by using other op- tions will be a way to have a hopeful impact on this crisis. In contrast, gabapentin utilization in the pediatric population has been rarely used despite having shown to be an effective alterna- tive alone or in combination with narcotics as a strong analgesic option for post-operative pain [2].

While it has been well established in the adult population, the pediatric population seems to have increased benefits of stepping away from the opioid option and using alternative and effective pain management techniques. [LE1]. Furthermore, the reviewers observed the contribution of gabapentin in the pediatric popula- tion for postoperative nausea and vomiting [3]. Gabapentin is used in pediatric patients to manage postoperative pain after a variety of surgeries such as spinal fusion and corrective scoliosis surgeries (unfortunately, the literature did not provide instances where Gabapentin was used for post-operative pain in brain sur- geries) [4].

It effectively reduces postoperative pain and opioid consumption in pediatric patients, is well-tolerated, and has a low incidence of adverse effects in the pediatric population [4]. Postoperative pain management is a vital aspect of care for pe- diatric patients undergoing craniotomy. (The procedure is highly invasive as it involves removing a portion of the skull to access the brain) Despite continued advancements in medicine and pain management, the pain experienced by pediatric patients can be both acute and chronic following this procedure. Both forms of pain can negatively affect the recovery and quality of life of pa- tients [5]. Pain management in pediatric patients who have un- dergone craniotomy remains a challenge; the use of opioids for pain management is common. With alternative options to opi- oids and the implementation of effective pain management strat- egies, there can be better options to improve the quality of life of pediatric patients. Understanding the importance of reducing postoperative opioid usage while using an alternative effective pain management medication without opioid-related complica- tions is imperative in the progression of pain management, espe- cially in children.

Methods

During data collection from January 2022 through August 2022, the reviewers searched the literature for examples of Gabapen- tin used in pediatric populations following neurological surgery, specifically craniotomies. For this scoping review, the pediatric population age range is defined as zero days to 18 years old. Over eight months, reviewers characterized specific topics re- lated to gabapentin in the pediatric population and observed the occurrence of its use for postoperative pain management fol- lowing craniotomy. The databases utilized included Embase and PubMed. Search terms include: “Gabapentin,” “craniotomy,” “Decompressive Craniectomy,” and “Craniectomy.” (craniecto- my is utilized as a search term to broaden the literature search. Researchers are not examining postoperative craniectomy pain control, only craniotomy). Inclusion criteria included any arti- cle where gabapentin was utilized in patients aged 18 years and under who were to undergo or had undergone a craniotomy. The initial results yielded 33 publications organized using a Google Excel sheet. Medical Subject Headings (MeSH) terms were cre- ated to be used in the PubMed search and specific terms were selected for Embase (Table 1).

                                          Table 1: Search Terms for Each Database

Data retrieval used an approach that incorporated a three-stage method:

• Stage 1: Perform a limited search of relevant databases such as PubMed and Embase utilizing phrases such as “Gabapentin for postoperative craniotomy pain”, “Post-Operative Cranioto- my Pain Management”, “Gabapentin and craniotomy neurosur- gery”, “Alternative pain management in craniotomy”, and “Ga- bapentin and craniotomy”, “Decompressive Craniectomy”, and “craniectomy”. This examination prompted several questions. (A) What is currently used for postoperative pain management during craniotomy? B) Why is gabapentin an effective pain med- ication C) What are the reasons why gabapentin is used in the adult population but not in the pediatric population?

• Stage 2: Identify keywords and index terms that we wanted to utilize in the data collection and perform a detailed investigation of the databases listed above.

• Stage 3: Compile all the identified publications that met the following inclusion criteria: focus on pediatric patients, includ- ing references to gabapentin usage, postoperative pain manage- ment, and craniotomy. (Note: Articles were excluded if they fo- cused on the adult population or did not include gabapentin, or craniotomy).

Reviewers conducted the search strategy using several keywords related to the research question, "Why is Gabapentin not used in a pediatric setting for Postoperative pain of craniotomy.” A search was performed using Embase and MEDLINE databases. Search terms were created to select publications that depicted a relationship with the topic. The full process synopsis is outlined in the PRISMA flowsheet. (Figure) Reviewers synthesized the objectives and findings from two articles (Table 2) Research- ers did not feel there were limitations affecting the data yielded with respect to the search strategy implemented. This included, but was not limited to, restrictions associated with language or database function.

Figure: PRISMA Flow Diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

                                    Table 2: Articles Included After Complete Text Review

Results

Reviewers found a total of 229 articles for potential use. Af- ter further investigation, 37 remained. Of those 37 articles, 4 consisted of grey literature, which included materials beyond Embase and PubMed, such as Google Scholar. 14 consisted of Embase data, and of these results none met the inclusion criteria which included: any article gabapentin was utilized in patients under the age of 18 who were to undergo or had undergone a craniotomy. The remaining 19 articles from MEDLINE yielded only 2 articles which initially fit the inclusion criteria. These ar- ticles were as follows.

Article 1

Tsai et al, completed a study Gabapentin for Postoperative Vom- iting in Children Requiring Posterior Fossa tumour resection [8].

• Study Characteristics: The study examined two cases of gab- apentin use in pediatric patients for treatment in post-craniotomy vomiting of patients with posterior fossa tumors.

• Participant Demographics: An 11-year-old girl who under- went near-total excision of a medulloblastoma tumor in the fourth ventricle and a 4-year-old boy with near-total excision of a medulloblastoma tumor in the fourth ventricle.

• Main Findings: It found that the utilization of gabapentin was successful as an alternative antiemetic agent for recurrent vom- iting that was refractory to antiemetic agents.

• Research Gaps Identified: The study's gaps include a small sample size, a lack of understanding of gabapentin's mechanism of action for its antiemetic effects, and no comparison with other treatment options. Additionally, for the purposes of our scoping review found no discussion on pain management and gabapen- tin's effects in these cases were identified or present.

Misra et al, completed a study Gabapentin Premedication De- creases the Hemodynamic Response to Skull Pin insertion in Patients Undergoing Craniotomy [9].

Article 2

• Participant Demographics: 47 patients ranging from 18 to 60 years old were included in this study.

• Study Characteristics: This article conducted a comparative analysis of techniques used to attenuate stress responses during skull pin insertion in craniotomies in a group of patients under- going intracranial tumor surgery. Three treatment groups were utilized: one with placebo and 2% lidocaine, another with gab- apentin and normal saline, and the third with gabapentin and 2% lidocaine at pin insertion sites. Hemodynamic responses were evaluated to determine the effectiveness of each treatment in mitigating stress responses during the procedure.

• Main Findings: Gabapentin with 2% lidocaine was successful as a premedication to blunt the hemodynamic response of skull pin insertion, reducing the need for additional analgesia.

• Research Gaps Identified: The study’s gaps included a small sample size, without a head to head comparison of other aesthet- ic approaches. There is indication for more research to better understand mechanism of action from an analgesic and hemo- dynamic standpoint. For the purposes of our scoping review, the population tested was older than 18 even though they had undergone craniotomy, gabapentin was used in conjunction with another analgesic and was not used as the lone therapy for pain relief.

Unfortunately, neither article directly utilized Gabapentin for pain relief and were later excluded. This demonstrates the lack of research regarding the use of this medication in the use of pain management.

Discussion

This scoping review demonstrates that Gabapentin and opioids are frequently used in managing postoperative pain, but their use in treating pain following craniotomy in children is poor- ly documented. Supporting the potential use of Gabapentin, the researchers also compare this medication to other more main- stream medications that are widely used for postoperative crani- otomy pain management. Gabapentin is found to be used 83% of the time for off-label use [10]. This drug's conventional use is for epilepsy management, partial seizures, as well as post-her- petic neuralgia. However, gabapentin’s use goes beyond that; it can be used for bipolar disorder, neuropathic pain, diabetic neuropathy, complex regional pain syndrome, attention effect disorder, restless leg syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep, migraine and drug and alco- hol withdrawal seizures [11]. Gabapentin is a medication that features synergistic properties when combined with other drugs that exhibit CNS depression by inhibition of central voltage-gat- ed Calcium channels, lead to a reduction in levels of excitatory neurotransmitters such as glutamate, norepinephrine, and other contraceptive and neuroinflammatory neurotransmitters [12-14]. The varying pharmacological attributes and versatile properties of gabapentin contribute to its efficacy across a large therapeutic domain. Its intricate interactions in synergetic pharmacotherapy and its ability to feature such a spectrum and clinical practice and therapeutic modalities give it a unique characteristic that makes it so widely used.

Another modality for pain control is the Enhanced Recovery Af- ter Surgery (ERAS) pathways which are tailored for a multitude of different surgical procedures that incorporate evidence-based practices that are aimed to improve patient outcomes, reduction of opioid consumption, lower occurrences of post-operative nausea and vomiting (PONV), and a decrease in hospital length of stay, across a range of surgical interventions [15]. A study that looked at ERAS and gabapentin usage for patients after autologous breast reconstruction found that postoperative pain with gabapentin that was associated with a decrease in milligram morphine equivalent, found to reduce stress and return patients to homeostasis after surgery, reduction in postoperative opioid use, self-reported pain, and PONV [16]. While not pertaining to a neurological procedure, this study provides further importance to ERAS protocol that can integrate a successful modality, lead- ing to enhancing patient outcomes, and a notable reduction in postoperative opioid usage and most importantly the reduction of pain.

A key aspect in the management of pain is addressing what type of pain it is as well as its relation to trauma, surgery, progressive injury, and so forth. Depending on the mechanism attributed to the pain, pain management differs. Management can vary from nonpharmacological techniques such as rest, ice, compression, and elevation to pharmacologic agents differing in strength, starting with basic analgesics like NSAIDS and increasing to more potent agents such as Opioids [17]. Non-pharmacologic management of pain includes components of the RICE acronym. Resting after surgery helps with pain by promoting healing, re- ducing strain, inflammation, edema, and complications. Ice has less use in the immediate postoperative period; however, a cold towel applied to the area may have anti-inflammatory properties. However, caution is urged when utilized in the immediate post- operative period. Compression and elevation are not typically recommended in post-craniotomy patients due to complications from pressure placed onto unhealed sutures and a lack of ade- quate healing. The discretion of using these non-pharmacologic treatments should be left to the surgeon's discretion [18].

Nonsteroidal anti-inflammatory drugs (NSAIDs) consist of a wide variety of medications that act through the inhibition of cy- clooxygenase enzymes COX-1 and COX-2. COX-1 and COX-2 produce lipid molecules (prostaglandins) that are important in the perception of pain and inflammatory response. When these enzymes are inhibited, the number of prostaglandins produced is decreased, which results in a decrease in inflammation as well as pain. Examples of lower tier NSAIDs include over-the-counter medications Ibuprofen, Naproxen, Ketoprofen, and Diclofenac. Some of the more potent NSAIDs include Celecoxib, Meloxi- cam, prescription strength Ibuprofen/Diclofenac, Etodolac, and Toradol [19]. Gabapentin and opioids share multiple similarities in terms of their mechanism of action and capability of managing pain. There are also significant differences that must be addressed when considering gabapentin for postoperative pain manage- ment. Both the use of gabapentin and opioid-class pain medi- cations modulate the transmission of pain in the central nervous system. One mechanism of gabapentin is the ability to bind the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. This decreases the influx of calcium ions into neurons, which reduces the release of excitatory neurotrans- mitters, such as glutamate and substance P. Through decreased release of these neurotransmitters, gabapentin can help decrease the perception of pain. Gabapentin can also increase the pro- duction of GABA, which also causes an inhibitory effect on the nervous system, leading to decreased excitability and further po- tentiates the decreased release of neurotransmitters, decreasing pain [8]. The main mechanism of action of opioids is their ability to bind to and activate mu, delta, and kappa, which are opioid receptors in the brain and spinal cord. Once activated, they can inhibit the transmission of pain signals to the brain, leading to decreased pain and pain relief. Opioids can also activate opioid receptors in other parts of the body, which can cause other ef- fects, such as sedation, respiratory depression, and constipation [9].

Both methods of pain control could contribute to the produc- tion of analgesia and are effective in reducing pain. Still, opioids are favoured to be more potent with regard to pain relief. The natural higher potency of opioids leads to a higher risk of side effects. Some of these are the risk factors for addiction, respira- tory depression, constipation, nausea, and dizziness. Side effects of Gabapentin vary wildly depending on dosing and can range from rare serious side effects such as suicidality, depression, Steven-Johnson syndrome, angioedema, erythema multiforme, rhabdomyolysis, to more common side effects such as fever, fa- tigue, diarrhea, constipation, weight gain, dizziness, drowsiness, and confusion [20]. The main benefit of choosing gabapentin over opioid postoperative treatment is the decreased risk of addiction potential in comparison, complications, and delayed postoperative recovery associated with opioids [21]. Gabapentin has also been shown to decrease the need for postoperative opi- oids and contribute to a positive effect on recovery [2]. The cu- mulative benefits of utilizing gabapentin in the recovery period of postoperative surgery, as listed above, are grounds for explo- ration regarding the use of gabapentin in the pediatric population who undergo craniotomies.

In a study of patients who underwent lumbar laminectomy at Yavapai Regional Medical Centre, it was found that gabapentin effectively reduces postoperative pain and opioid consumption, is well tolerated, and appears to have a low incidence of adverse effects in the general population [2]. In contrast, a similar study found no significant difference in postoperative pain following craniotomies [22]. Further research specific to pain management in the acute postoperative patient would be useful in confirm- ing which of these conclusions are more accurate. The limited data available underscores the significant gap in research on gabapentin use in pediatric postoperative pain management fol- lowing craniotomies. This lack of data highlights an urgent need for well-designed clinical trials as well as observational studies focusing specifically on this patient population. Given the cur- rent opioid crisis and the potential benefits of gabapentin, inves- tigating the efficacy and safety in pediatric neurosurgery could lead to improved pain management strategies which minimize opioid use and its associated risks. Future research should aim to develop standardized protocols for including gabapentin ad- ministration in pediatric postoperative care, determine optimal dosing regimens, and evaluate long-term outcomes to ensure both efficacy and safety. Addressing these gaps are crucial in advancing pediatric pain management and enhancing the quality of care for young patients undergoing major surgical procedures like craniotomy.

Summary - Accelerating Translation

This scoping review outlines and demonstrates the lack of re- search and need to further evaluate the use of gabapentin in neurosurgical patients, particularly in pediatric patients who have undergone craniotomy for pain management. This review is aimed at emphasizing the importance of the need for further research regarding the postoperative use of gabapentin in a pe- diatric setting by presenting an alternative use of gabapentin to the traditional opioids.

However, the use of gabapentin for treating pain following cra- niotomy in children is poorly documented. Our scoping review addressed the lack of research on this unconventional method for postoperative pain management. An initial review of data collected through MEDLINE revealed 19 articles, including the use of gabapentin in some capacity; however, further review excluded 17 of these articles and included 2. An initial review of data collected through Embase revealed 14 articles that in- cluded the use of gabapentin in some capacity; however, 0 of these articles were included due to exclusion criteria. Thus, this review demonstrates the need for further research on gabapentin use in the pediatric population following craniotomy. A potential prospective study that included Gabapentin in the post-opera- tive management of pain in pediatric craniotomy patients may be able to evaluate the necessity for standard pain management versus optimization of decreased opioids in those who were also given gabapentin. Further research is needed prior to any defini- tive conclusions are able to be drawn [23].

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