Gabapentin for treatment of neonatal abstinence syndrome in patients with or without perinatal gabapentin exposure

doi:10.21203/rs.3.rs-1953785/v1

Download PDF

Article

Gabapentin for treatment of neonatal abstinence syndrome in patients with or without perinatal gabapentin exposure

https://doi.org/10.21203/rs.3.rs-1953785/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objective

To determine the effect of gabapentin on neonatal abstinence syndrome (NAS)-related neurologic and/or feeding symptoms.

Study Design:

Retrospective case series involving thirteen infants who received gabapentin for NAS

Result

Gabapentin 5 mg/kg every 8 to 12 hours was initiated, and three (23%) patients required dose escalation. Median time from initiation to discharge was 8 days (range: 2–15) and length of stay was 19 days (range: 13–45 days). Eight patients required gavage feeds, and showed oral feeding improvement. All patients were discharged home with gabapentin and weaned off in the outpatient setting.

Conclusion

Although there is limited experience with gabapentin for NAS, it may be beneficial for managing symptoms not controlled by other treatment modalities, regardless of prenatal exposure. No side effects were noted and oral feeding was improved. Prospective randomized studies are needed to confirm the efficacy and safety of gabapentin in the treatment of neonatal abstinence syndrome.

Neonatal abstinence syndrome (NAS) is a general term describing the constellation of symptoms that can occur when neonates are exposed in utero to medications or illicit substances. Opioid use disorder (OUD) in pregnancy is a leading cause of withdrawal in neonates, and has been more recently reclassified as Neonatal Opioid Withdrawal Syndrome (NOWS).^1,2 Although opioids are classically implicated in this disease, many neonates are exposed to non-opioid substances in conjunction with opioids .² Several prescribed medications may worsen NAS severity, including but not limited to psychiatric drugs (antidepressants, anti-psychotics, anti-anxiety, bipolar medications), psychiatric polypharmacy (≥ 2 psychiatric medications), benzodiazepines, and gabapentin.³ Length of stay is increased in babies whose mothers used opioid agonists (methadone or buprenorphine) concurrently with psychiatric medications compared to those exposed to opioid agonists alone.^3,4 Specifically, co-exposure with antidepressants can increase length of withdrawal treatment, while antiepileptics are linked to increase length of stay.⁵

Optimal treatment of NAS/NOWS remains unknown; however, there are many approaches including non-pharmacologic (eat-sleep-console), long-acting opioid agonists (methadone, buprenorphine), short-acting opioids (morphine), and non-opioid adjunctive medications (clonidine, phenobarbital).^1,6−9 Protocolized-based therapy, regardless of treatment type, is essential to improving outcomes, including decreased length of stay.^10,11 Gabapentin is an emerging therapy for neonatal hyperalgesia, where it is thought to work via reduced excitatory neurotransmitter release. There are sparse published reports describing gabapentin’s role in treatment of neonatal abstinence, especially in the absence of maternal gabapentin use.^12,13 We describe in this case series our use of gabapentin as adjunctive or primary treatment as part of a comprehensive NAS protocol that allows individualization of treatment modalities based on prenatal substance exposure and postnatal symptoms.

This study was a retrospective case review of neonates admitted between 2020 and 2021 who were treated with gabapentin for NAS at a community teaching hospital with a 48-bed level IV neonatal intensive care unit (NICU). Infants were only excluded if they received gabapentin for any indication other than NAS.

Our standard long-acting opioid withdrawal management pathway dictates postnatal observation of infants exposed to methadone or buprenorphine for at least five days, utilizing modified Finnegan scores to assess NAS symptoms. Pharmacologic treatment with methadone is initiated for three consecutive scores of eight to 11 or two consecutive scores of 12 or greater. There is a separate clinical pathway with a reduced observation period for infants exposed to short-acting opioids or non-opioid substances. Gabapentin may be initiated as an adjunctive medication if providers are unable to wean or capture the patient with methadone. It may also be initiated first-line or as adjunctive therapy for non-opioid or non-opioid withdrawal if the infant is presenting with predominantly neurologic and/or feeding-related symptoms. Descriptive statistics were used to analyze patients included in this case series.

Patient demographics, including maternal exposures and concomitant NAS treatment medications utilized are described in Table 1. Each patient’s gabapentin regimen is described in Table 2. Gabapentin initiation occurred at a median of 11 days after birth (range: 3 to 35 days), and the most common initial dose was 5 mg/kg by mouth every 8 hours. Three (23%) patients required dose escalation to achieve the desired therapeutic response, defined as improvement in NAS scores, oral feeding ability, and/or caregiver perception of symptoms. Most of the patients (n = 9) received gabapentin as adjunctive treatment to methadone +/- clonidine and phenobarbital. Three patients received gabapentin monotherapy, and gabapentin was started first-line in one patient. The median duration from gabapentin initiation to discharge from the hospital was eight days (range 2–15 days), whereas the median length of hospitalization was 19 days (range 13–45 days).

Table 1

Patient Demographics
Patient	GA (wk)	BW (kg)	Gender	Maternal Prescription Medications	Maternal Substances (non-prescription)	NAS Medications
1	37	2.86	Female	Methadone, lamotrigine, sertraline, gabapentin	Amphetamine, cocaine, tobacco	Methadone, clonidine, phenobarbital
2	39	2.79	Female	Methadone	--	N/A*
3	39	3.52	Male	Methadone, sertraline, aripiprazole	--	Methadone, clonidine, phenobarbital
4	37	2.515	Female	Methadone	Amphetamine, benzodiazepine, cocaine, fentanyl, heroin, methamphetamine	Methadone
5	39	3.21	Female	Buprenorphine	THC	Clonidine
6	37	1.86	Male	Methadone, fluoxetine	Amphetamine, opiates	N/A*
7	41	3.255	Female	Buprenorphine, phenytoin, lamotrigine, gabapentin	--	Clonidine
8	40	2.95	Female	Buprenorphine, gabapentin	Cocaine, THC	Methadone
9	40	3.2	Female	Clonidine	Heroin, fentanyl, THC, tramadol	Methadone, clonidine, phenobarbital
10	39	3.305	Female	--	Fentanyl, benzodiazepine	Clonidine
11	39	2.8	Male	Buprenorphine	Heroin	N/A*
12	36	3.03	Male	Sertraline, citalopram	Amphetamine, benzodiazepine, opiates	Methadone Clonidine, phenobarbital
13	40	3.555	Female	Buprenorphine	Amphetamine, heroin, methamphetamine, opiates	Methadone
*N/A: not applicable

Table 2

Gabapentin Regimen and Outcomes
Patient	Initial Dose	Maximum Dose	DOL Initiated	Concomitant NAS treatment weaned	Oral feeding % prior to initiation	Oral feeding % 48 hours after initiation	Days full oral feeds achieved after initiation
1	5 mg/kg q12h	7.5 mg/kg q8h	35	Yes	42	75	4
2	5 mg/kg q8h	5 mg/kg q8h	6	N/A*	26	12	14
3	5 mg/kg q12h	5 mg/kg q12h	25	Yes	100	100	N/A*
4	5 mg/kg q8h	5 mg/kg q8h	17	No	45	68	9
5	5 mg/kg q8h	5 mg/kg q8h	3	Yes	43	62	4
6	5 mg/kg q12h	5 mg/kg q12h	16	N/A*	100	100	N/A*
7	5 mg/kg q12h	7.5 mg/kg q8h	6	No	43	60	5
8	5 mg/kg q8h	5 mg/kg q8h	9	Yes	100	100	N/A*
9	5 mg/kg q12h	5 mg/kg q8h	12	Yes	100	100	N/A*
10	5 mg/kg q8h	5 mg/kg q8h	3	Yes	15	62	11
11	5 mg/kg q8h	5 mg/kg q8h	8	N/A*	28	65	5
12	2.5 mg/kg q8h	5 mg/kg q8h	13	Yes	31	52	5
13	5 mg/kg q8h	5 mg/kg q8h	11	No	100	100	N/A*
*N/A: not applicable

Weaning of the first-line agent within 24 hours was successful in seven (70%) of the patients receiving concomitant withdrawal medications prior to gabapentin initiation (n = 10). Seven patients were still undergoing NAS scoring with the modified Finnegan scale at the time of gabapentin initiation. The impact of gabapentin on median NAS scores 24 hours before and after initiation is represented in Fig. 1. Six patients were not undergoing modified Finnegan scoring at the time of gabapentin initiation. Gabapentin criteria for use in these patients included failure to capture the patient with other agents/inability to wean existing NAS medications (n = 3) or as monotherapy in patients with prenatal methadone exposure who did not reach treatment threshold for neonatal methadone initiation during the five-day NOWS screening period.

Eight patients were receiving a combination of gavage and oral feeds at the time of gabapentin initiation. Oral feeding percentage increased within 48 hours for seven (87.5%) of these patients, with a median increase of 67.7% from pre-treatment oral feeding intake. The median days to achieve full oral feeding after gabapentin initiation was 5 days. All patients were discharged home on gabapentin and successfully weaned off in the Special Infant Care Clinic, where a team consisting of neonatologists, developmental pediatricians, and advanced practice providers assessed each patient’s neurobehavioral status, feedings, and growth. Outpatient weans were completed once weekly to prevent symptom rebound seen in previously published reports. No infant experienced documented withdrawal attributed to gabapentin weaning.

Neonatal withdrawal results in dysregulation of neurobehavior after prenatal exposure to offending substances in conjunction with environmental and biologic risk factors. The neurochemical and hormonal disruptions lead to physiologic and behavioral dysregulation that can be divided into four domains: autonomic, motor/muscle tone, sleep/attentional state, and sensory processing/modulation.¹⁴ Some infants may require pharmacologic management based on severity of withdrawal symptoms or failure to respond to other non-medication treatment modalities. The majority of infants were exposed to poly-pharmacy in our case series, including psychiatric medications, which can increase risk of prolonged hospitalization and length of treatment.^3–5 Recent AAP recommendations for adjunctive NOWS pharmacotherapy suggest that phenobarbital should be used with caution given its potential for neuronal apoptosis.¹ For this reason, we have explored treatment options including gabapentin. The median length of stay in our patients was nearly three weeks; however, initiation of gabapentin prompted discharge readiness in approximately a week for most patients. The infants with longer length of stay were feeding less by mouth at the start of gabapentin but were able to achieve oral feeding autonomy within two weeks.

Gabapentin is structurally similar to gamma-amino-butyric acid (GABA) but does not bind to either GABA_A or GABA_B receptors. It appears to act on voltage-gated calcium channels in the dorsal horn ganglion neurons, which likely drives gabapentin’s ability to mediate spinal anti-nociception.¹⁵ Gabapentin has been used for alcohol withdrawal in adult patients, where its use is thought to reduce hippocampal excitability and normalization of stress-induced GABA activation in the amygdala.^16–18 Additionally, gabapentin has been shown to reduce certain symptoms of withdrawal including diarrhea, dysphoria, and muscle tension in adults being treated for OUD.¹⁸

Hyperactivity of noradrenergic neurons within the locus coeruleus appear to be responsible for some of the physiologic and behavioral activities associated with opioid withdrawal. There are data which suggest that glutamate is an important mediator in this process, where its presence within the locus coeruleus is associated with increased neuronal activity and the expression of opioid withdrawal behaviors.¹⁹ Glutamate induces withdrawal signs in opioid-dependent rat models, where infusion of naloxone causes increased extracellular fluid levels of glutamate in the locus coeruleus, highlighting the important role that the locus coeruleus region may play in withdrawal syndromes.²⁰ This phenomenon may also explain the benefit of alpha-agonists such as clonidine and dexmedetomidine in treatment of neonatal and infant withdrawal, where norepinephrine release and subsequent symptoms are dampened with alpha-2 adrenergic agonist administration.^21–22

Gabapentin has been described in neonates for hyperalgesia associated with neurologic dysfunction, abdominal defects, and cardiac surgery.^23–27 Increases in oral feeding and enteral feeding tolerance were noted in at least two of these case series. In our NAS patients, oral feedings tended to improve after initiation of gabapentin, which may be secondary to decreased neuronal hyperactivity allowing increased feeding coordination and neurobehavioral organization.

Gabapentin withdrawal in neonates prenatally exposed to gabapentin and opioids has been described.^12,28 Gabapentin crosses the placenta and is detectable in umbilical cord samples, where the ratio of cord to maternal plasma is close to two.²⁹ Symptoms specific to gabapentin withdrawal include tongue thrusting, wandering eye movements, back arching, and continuous extremity movements.¹² Infants were successfully treated with gabapentin in conjunction to standard NAS treatment algorithms. Decisions to utilize gabapentin included admitted prenatal use, failure to wean or escalation of methadone, and sustained behavioral changes. Rapid gabapentin weaning was associated with increased Finnegan scores and reemergence of abnormal neurologic behaviors.¹² Previously published duration of use for gabapentin was 42–47 days. Treatment duration was variable in our case series since every patient was discharged with an outpatient prescription and weaned in our follow-up clinic. Most patients were medically ready for discharge within weeks of gabapentin initiation.

This case series is one of the first to demonstrate short-term safety and efficacy of utilizing gabapentin for withdrawal symptoms in patients with or without prenatal gabapentin exposure. Larger randomized controlled trials are needed to determine what role gabapentin may serve in neonatal withdrawal, particularly in infants with poor oral feeding and those exposed to concomitant psychoactive medications.

Conflict of Interest: The authors declare no competing financial interests.

Ethics approval and consent to participate: This study was considered exempt from IRB evaluation based on WakeMed Health and Hospital’s QI/QA determination policy.

Funding: There was no funding source for this work.

Author Contributions: KO made substantial contributions to the conception and design of the work, acquisition, analysis, and interpretation of the data, drafting the work, and giving final approval of the version to be published. LE made substantial contributions of the conception of the work and interpretation of the data, as well as revising the manuscript for important intellectual content and giving final approval of the version to be published.

Patrick SW, Barfield WD, Poindexter BB. Committee on Fetus and Newborn, Committee on Substance Use and Prevention. Neonatal Opioid Withdrawal Syndrome. Pediatrics. 2020. 146(5): e2020029074. doi: 10.1542/peds.2020-029074.
Hudak, M, Tan RC, The Committee on drugs; The Committee on Fetus and Newborn. Neonatal Drug Withdrawal. Pediatrics 2012; 129(2): e540-560. doi: 10.1542/peds.2011=3212.
Wachman EM, Warden AH, Thomas Z, Thomas-Lewis JA, Shrestha H, Nikita FNU et al. Impact of psychiatric medication co-exposure on Neonatal Abstinence Syndrome severity. Drug Alcohol Depend. 2018; 192:45–50. doi: 10.1016/j.drugalcdep.2018.07.024.
Wachman EM, Newby PK, Vreeland J, Byun J, Bonzagni A, Bauchner et al. The relationship between maternal opioid agonists and psychiatric medications on length of hospitalization for neonatal abstinence syndrome. J Addict Med. 2011; 5(4): 293–299. doi: 10.1097/ADM.0b013e3182266a3a.
Morris E, Bardsley T, Schulte K, Seidel J, Shakib J, Buchi KF et al. Hospital outcomes of infants with neonatal opioid withdrawal syndrome in a tertiary care hospital with high rates of concurrent nonopioid (polysubstance) exposure. Doi: 10.1055/s-0040-1716490.
Grisham LM, Stephen MM, Coykendall MR, Kane MF, Maurer JA, Bader MY. Eat, sleep, console approach: a family-centered model for the treatment of neonatal abstinence syndrome. Adv Neonatal Care. 2019; 19(2): 138–144. Doi: 10.1097/ANC0000000000000581.
Blount T, Painter A, Freeman E, Grossman M, Sutton AG. Reduction in length of stay and morphine use for NAS with “Eat, Sleep, Console” method. Hosp Pediatr. 2019; 9(8): 615–623. Doi:10.1542/hpeds.2018-0238.
Hein S, Clouser B, Tamim MM, Lockett D, Brauer K, Cooper, L. Eat, Sleep, Console and adjunctive buprenorphine improved outcomes in neonatal opioid withdrawal syndrome. Adv Neonatal Care. 2021; 21(1): 41–48. Doi: 10.1097/ANC.0000000000000824.
McPherson C. Pharmacotherapy for neonatal abstinence syndrome. Neonatal Netw. 2016; 35(5): 314–320. Doi: 10.1891/0730-0832.35.5.314.
Gibson BL, Coe K, Bradshaw W. Pharmacologic management of neonatal abstinence syndrome using a protocol. Adv Neonatal Care. 2019; 19(6): 482–489. Doi: 10.1097/ANC. 0000000000000648.
Hall ES, Wexelblatt SL, Crowley M, Grow JL, Jasin LR, Klebanoff MA et al. Implementation of a neonatal abstinence syndrome weaning protocol: a multicenter cohort study. Pediatrics. 2015; 136(4): e803-810. Doi: 10.1542/peds.2015-1141.
Loudin S, Murray S, Prunty L, Davies T, Evans J, Werthammer J. An atypical withdrawal syndrome in neonates prenatally exposed to gabapentin and opioids. J Pediatr. 2017; 181:286–288. Doi: 10.1016/j.jpeds.2016.11.004.
Carrasco M, Rao SC, Bearer CF, Sundararajan S. Neonatal gabapentin withdrawal syndrome. Pediatric Neurol. 2015; 53(5): 455–477. Doi: 10.1016/j.pediatricneurol.2015.06.023.
Velez ML, Jordan CJ, Jansson LM. Reconceptualizing non-pharmacologic approaches to Neonatal Abstinence Syndrome (NAS) and Neonatal Opioid Withdrawal Syndrome (NOWS): A theoretical and evidence-based approach. Neurotoxicol Teratol. 88:107020. doi: 10.1016/j.ntt.2021.10702.
Sutton KG, Martin DJ, Pinnock RD, Lee K, Scott RH. Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurons. Br J Pharmacol. 2002; 135(1): 257–265. Doi: 10.1038/sj.bjp.0704439.
Clemmons KJ, Vendruscolo LF. Anxious to drink: gabapentin normalizes GABAergic transmission in the central amygdala and reduces symptoms of ethanol dependence. J Neurosci. 2008; 28 (37):9087–9089. Doi: 10.1523/JNEUROSCI.2928-08.2008.
Leung JG, Hall-Flavin D, Nelson S, Schmidt KA, Schak KM. The role of gabapentin in the management of alcohol withdrawal and dependence. Ann Pharmacother. 2015. 2–15; 49(8): 897–906. Doi: 10.1177/1060028015585849.
Toce MS, Chai PR, Burns MM, Boyer EW. Pharmacologic treatment of opioid use disorder: a review of pharmacotherapy, adjuncts, and toxicity. J Med Toxicol. 2018; 14(4):306–322. Doi: 10.1007/s13181-018-1.
Tokuyama S, Takahashi M, Yamamoto T. On the role of glutamate within the locus coeruleus during the development of opioid dependence and on the expression of withdrawal from dependence on opioids. Japanese Journal of Psyhcopharmacology 2000; 20(4): 141–147.
Tokuyama S, Zhu H, Wakabayashi H, Feng YZ, Ho IK. The role of glutamate in the locus coeruleus during opioid withdrawal and effects of H-7, a protein kinase inhibitor, on the action of glutamate in rats..J of Biomed Sci. 1998. 5:45–53. Doi: 10.1007/BF02253355.
Little PJ, Price RR, Hinton RK, Kuhn CM. Role of noradrenergic hyperactivity in neonatal opiate abstinence. Drug Alcohol Depend. 1996; 41(1):47–54. Doi: 10.1016/0376-8716(96)01236-7.
Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Lewis TR et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009; 123(5):e849-856. Doi: 10.1542/peds.2008-0978.
Sacha GL, Foreman MG, Kyllonen K, Rodriguez RJ. The use of gabapentin for pain and agitation in neonates and infants in the neonatal ICU. J Pediatr Pharmacol Ther. 2017; 22(3): 207–211. Doi: 10.5863/1551-6776-22.3.207.
Edwards L, DeMeo S, Hornik CD, Cotten CM, Smith PB, Pizoli C et al. Gabapentin use in the neonatal intensive care unit. J Pediatr. 2016; 169: 310–312. Doi: 10.1016/j.jpeds.2015.10.013.
Bruce AS, Davis AM, Baum CF, Chepolis D, Kolomensky A, Monagas J et al. Retrospective study of gabapentin for poor oral feeding in infants with congenital heart disease. Global Pediatric Health. 2015;2:2333794X15591565. Doi: 10.1177/2333794X15591565.
Burnsed JC, Heinan K, Letzkus L, Zanelli S. Gabapentin for pain, movement disorders, and irritability in neonates and infants. Dev Med Child Neurol. 2020; 62(3): 386–389. Doi: 10.111/dmcn.14324.
O’Mara KL, Islam S, Taylor JA, Solomon D, Weiss MD. Gabapentin improves oral feeding in neurologically intact infants with abdominal disorders. J Pediatr Pharmacol Ther. 2018; 23(1): 59–63. Doi: 10.5863/1551-6776-23.1.59.
Carrasco M, Rao SC, Bearer CF, Sundararajan S. Neonatal gabapentin withdrawal syndrome. Pediatric Neurol. 2015; 53(5): 455–477. Doi: 10.1016/j.pediatricneurol.2015.06.023.
Ohman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: does fetal accumulation occur during pregnancy? Epilepsia. 2005; 46:1621–1624. Doi: 10.1111/j.1528-1167.2005.00251.x.

There is NO conflict of interest to disclose.

Download PDF

Version 1

posted

You are reading this latest preprint version

Gabapentin for treatment of neonatal abstinence syndrome in patients with or without perinatal gabapentin exposure

Status:

Version 1

Abstract

Objective

Study Design:

Result

Conclusion

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1