PEDIATRICS Vol. 108 No. 2 August 2001, pp. 482-484

EXPERIENCE AND REASON:
Treatment of Pain With Gabapentin in a Neonate

Gabapentin (GBP) is a gamma-aminobutyric acid (GABA) analog approved for the treatment of partial seizures with and without generalization in patients 12 years of age and older. The precise mechanism of action for GBP in the central nervous system is not known. Although it was originally designed to mimic the effects of GABA, it has been found to be inactive at GABA binding sites.¹ Recently, GBP has been shown to be effective in the treatment of neuropathic pain in adults² and children.³ We report the case of a neonate with amyoplasia congenita resulting in severe contractures and dislocated joints who was successfully and safely treated with GBP to relieve pain.

	CASE REPORT

D. L. was a 3-week-old male born at 36 5/7 weeks' gestation and weighing 2475 g to a 20-year-old G₁/P₀ mother who received late prenatal care. The pregnancy was remarkable for oligohydraminos and substance abuse including marijuana, tobacco, alcohol, crack cocaine, and ecstasy, the mother's self-reported drug of choice. The neonatal toxicology screen was positive for marijuana (9-THC) and opiates. The infant received routine resuscitation at birth and the Apgar scores were 4 and 7, respectively. At birth the infant was noted to have an extended neck and contractures of the extremities. Radiographs were remarkable for cervical spine in severe extension contracture, bilateral shallow acetabula with probable dislocated hips, bilateral clubfeet, fingers with severe flexion contractures, and dysplastic shoulders with probable dislocation. A head ultrasound obtained on day of life (DOL) 2 was unremarkable. Physical therapy was also instituted on DOL 2. Although the infant was noted to lie peacefully at rest, the slightest movement produced significant pain associated with a loud, shrill high-pitched cry. The infant was initially started on as needed acetaminophen (10 mg/kg) which was quickly converted to a regular (Q4 hour) dosing interval.

Symptomatic assessment on DOL 4 illustrated apparent failure of acetaminophen, which prompted its discontinuation and the initiation of ibuprofen therapy (ibuprofen oral suspension) at a dose of 10 mg/kg every 6 hours. At this same time, an electromyeolgram was performed. It revealed that the neurologic problems were axonal in nature and represented a static process. The Genetics Department was consulted and initial results indicated a pericentric inversion of chromosome 8. Additionally, consultation from the Orthopaedic Surgery Service was obtained, which recommended mobilization of muscle tissue as opposed to surgical intervention or the use of braces/splints. During this time, the diagnosis was refined to amyoplasia congenita, a sporadic abnormality most likely caused by hypotension in the developing fetal spinal cord at a time when anterior horn cells are susceptible to insults.⁴

The Clinical Pharmacology Service was consulted on DOL 19 to make recommendations for long-term analgesic therapy required to prepare the infant for discharge to a medical foster home and to facilitate necessary physical therapy. The physical examination at this time revealed a small infant with an extended neck and distal extremity contractures who would cry at the slightest movement including small flexion and extension of the wrist. Additionally, the infant was unable to be soothed by a pacifier and would not accept it. Serum electrolytes, blood urea nitrogen, creatinine, and a complete blood count were all within normal limits. A decision was made to discontinue the ibuprofen consequent to concerns over potential adverse effects. Therapy was then started with an extemporaneous oral liquid formulation of GBP at a dose of 7.0 mg/kg once daily. Additionally, acetaminophen (15.0 mg/kg orally) was ordered to be administered as needed 60 to 90 minutes before a scheduled event that required vigorous manipulation of the infant (eg, physical therapy).

	METHODS AND RESULTS

A review of the medical literature failed to reveal any guidance regarding the selection of GBP dose for a neonate. As well, GBP plasma concentrations were not available from our patient. Thus, pharmacokinetic modeling was used to project an average steady state plasma concentration of approximately 2.0 mg/L; a value previously associated with effective seizure control in infants.⁵ The following equation⁶ was used: Where F is the estimated fraction of an oral dose absorbed; Css, the desired average steady state plasma concentration; Kel, the apparent first order elimination rate constant; VDss, the apparent steady state volume of distribution; and , the desired dosing interval. Average values of F (ie, 50%-60%⁷) and VDss (ie, 58-61 L⁸) were assumed for GBP from the literature. The value for Kel was corrected for the average normal value for the glomerular filtration rate in a 3-week-old infant (ie, 54 mL/min/1.73 m²)⁹ using a standard pharmacokinetic equation previously derived for this purpose.¹⁰

To assess the potential efficacy of GBP, both subjective and objective techniques were used. The objective method consisted of a semiquantitative infant pain scale that was applied on a periodic basis by neonatal nurse practitioners trained in its use and dedicated to the care of the infant. This modified neonatal pain scale is currently being validated and combines elements of Barrier's postoperative pain scale¹¹ and the neonatal faces coding system. The scale, depicted in Table 1, consists of 10 areas of behavioral data scored on a scale from 0-1. Subjective measurements consisted of routine vital signs and regular nursing assessments of the infant's status.

The average values from repeated application of the neonatal pain scale over approximately 200 hours are depicted in Fig 1. As illustrated by these data, the pain score reached its nadir by 72 hours after the initiation of GBP therapy, a time which corresponded to approximately 3 times the estimated elimination half-life of 24 hours for GBP in this infant. By this time, the infant was noted to be much calmer, was not sedated, readily accepted a pacifier, and engaged in nonnutritive sucking. The patient was able to tolerate more extensive, both in duration and vigor, physical therapy with passive range of motion exercise to all joints without the production of severe pain as evidenced by a decrease in crying response and acceptance of physical contact. Most importantly, after 72 hours of GBP therapy, the infant could be swaddled and held in a rocking chair without the production of apparent pain and/or discomfort.

View larger version (40K): [in this window] [in a new window]   Fig. 1.   Mean value from infant pain scale versus time in a neonate treated with GBP.

The GBP dose was increased to 10 mg/kg once daily after 5 days of therapy, just before discharge. At follow-up in clinic 3 days later, the foster mother noted that she was able to play with the infant and change the diaper without causing cries of pain. Additionally, she reported a desire to transition the infant from nasogastric to bottle feeding because of the infant's strong suck on the pacifier. Finally, she reported that the infant did not seem sedated (an anticipated adverse effect from GBP therapy) and was very alert during the day. Application of the neonatal pain score at this time revealed a value of zero (Fig 1). Regular follow-up was scheduled to determine the need for subsequent GBP dose changes to compensate for increasing renal maturity and body weight.

	DISCUSSION

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Over the past decade there has been an increased awareness of pain in the neonate with research aimed at finding safe and effective treatments. Most of this research has concentrated on the treatment of acute onset pain such as that associated with medical procedures (eg, circumcision and lumbar punctures). In contrast, there has been little work on the treatment of chronic pain in neonates or young infants. Indeed, a recent review of pain in the neonate discusses only the use of opiates and acetaminophen, while giving a general statement of prohibition concerning the use of nonsteroidal antiinflammatory agents (eg, ibuprofen).¹²

In the case of our patient, the use of traditional pharmacologic analgesic agents (eg, codeine, morphine, acetaminophen) did not appear appropriate. Patient symptoms suggested that monotherapy with acetaminophen administered on either an as needed or fixed schedule was insufficient. Although there is neonatal dosing information for this drug and existing data demonstrate its safety at doses <40 to 50 mg/kg/d for a relatively short duration of treatment, it is an analgesic agent of only moderate potency.¹³ Two opiate analgesics, morphine and fentanyl, indicated for the treatment of severe pain, have been reasonably well-studied in neonates and young infants with regard to their safety/efficacy profile and pharmacokinetic profile.¹² Although these agents may well have been effective for short-term, episodic treatment of pain in our patient, issues pertinent to long-term use of these drugs (eg, upregulation of opiate pain receptors, potential impact on respiration, the risks of physiologic dependence, control/ease of outpatient therapy) precluded their selection. Despite the fact of an established dose and effect profile for codeine in young children,¹⁴ it was not selected for use consequent to the young age of our patient and the previous demonstration of developmentally compromised CYP2D6 activity in neonates between 2 and 3 weeks' postnatal age.¹⁵ CYP2D6 is the cytochrome P450 isoform responsible for the bioactivation of codeine to morphine and thus, the activity of this enzyme is a major determinant for the analgesic action of codeine in young infants.

As noted above, ibuprofen therapy was discontinued consequent to concerns over the potential for adverse effects associated with its long-term use in a neonate. In addition to the well-described adverse effects of ibuprofen and other nonsteroidal antiinflammatory agents (eg, platelet dysfunction, gastrointestinal hemorrhage, reductions in effective renal plasma flow)¹⁶ there is a potential protein binding interaction between ibuprofen and bilirubin resulting in a marked increase in the free fraction of bilirubin.¹⁷ Indeed, this infant required phototherapy until DOL 8, which, may have been related in part to ibuprofen use. Finally, ibuprofen is a substrate for CYP2C9, a polymorphically expressed enzyme in human beings that is the primary determinant of ibuprofen plasma clearance and has low activity during the first 2 to 4 weeks of life.¹⁵

GBP is a relatively new anticonvulsant agent approved by the US Food and Drug Administration for the treatment of partial seizures, with and without generalization, in patients 12 years of age and older.¹⁸ The precise mechanism of action for this drug in the central nervous system is currently, poorly understood. It has been found to be inactive at GABA binding sites¹⁸ and thus, may not derive its action through direct GABA receptor interaction. Recent attention has been focused on the use of GBP to treat pain symptoms of neuropathic origin¹⁹ and also, as an adjunctive agent to traditional analgesic drugs used for treatment of moderate to severe pain.²⁰ Specifically, the drug has been used with considerable success in the treatment of pain associated with trigeminal neuralgia, diabetic neuropathy, and Fabry disease.²¹ In the field of rheumatology, GBP is now considered by many to represent the drug of choice for the chronic treatment of neuropathic pain.²² Recently, GBP has recently been found effective for both postoperative pain²³ and inflammatory pain.²⁴ Indeed, the drug is quickly gaining popularity because of its mild side effect profile (eg, somnolence), apparent lack of drug-drug interactions, predominant renal route of excretion, and the ability to escalate doses quickly in an attempt to achieve control of either pain or seizure activity.

In children aged 2 to 16 years, GBP doses up to 100 mg/kg/d have been well-tolerated during its use as an anticonvulsant agent.²⁵ The most common side effects associated with therapy have been somnolence, dizziness, fatigue, ataxia, nystagmus, and weight gain.²⁶ There have been a few case reports of behavior changes at higher doses mainly consisting of moodiness, oppositional behavior, and outbursts of anger.²⁷ At a GBP dose of 10 mg/kg/d, no apparent adverse effects (including somnolence) were noted in our patient. In view of this finding and the apparent dramatic analgesic response associated with GBP treatment (Fig 1), a decision was made to continue treatment with repeated assessment of both efficacy and apparent adverse effects. As well, plans were made for future revision of the dose based on the impact of expected, normal development on renal function (ie, increased glomerular filtration rate with age), and increases in patient weight.

	CONCLUSIONS

Top Introduction Discussion Conclusion References

Given that arthrogryposis per se can have a neuropathic component affecting the brain and spinal cord or peripheral nerves,²⁸ neuropathic pain represents a likely complication of these severe disorders. As reflected by the subjective and objective assessment of our patient, therapy with GBP appeared to be both effective and safe, obviating the need for adjunctive analgesic treatment. The use of published pharmacokinetic data enabled us to model a starting dose for the initiation of GBP therapy using, as a guide, a level of drug exposure (ie, a desired steady state plasma concentration) that had been previously associated with effective anticonvulsant treatment in infants. Although the relatively short period of observation in our patient precludes our ability to address with certainty the long-term therapeutic implications of GBP use outside of the neonatal period, the example of apparent therapeutic success is evidenced by our case. Given the limited nonopiate therapeutic options available for treating neuropathic pain in the neonate, future evaluation of GBP in neonates and young infants is warranted.

	ACKNOWLEDGMENTS

The work was supported in part by Grant 1 U01 HD31313-07 (to G.L.K.) Network of Pediatric Pharmacology Research Units, National Institute of Child Health and Human Development, Bethesda, Maryland.

The comments and insights provided by Drs William E. Troug and Robert J. Rinaldi are sincerely appreciated. Also, we gratefully acknowledge the exemplary care provided by the neonatal intensive care nurses.

Martin O. Behm, MD^*
* Department of Pediatrics
New York University
New York, NY 10016

Gregory L. Kearns, PharmD^{, §,}
 Division of Pediatric Pharmacology and Toxicology
Children's Mercy Hospital and Clinics
Kansas City, MO 64108
Departments of ^§ Pediatrics and  Pharmacology
University of MissouriKansas City
Kansas City, MO 64108

	FOOTNOTES

Received for publication Sep 13, 2000; accepted Jan 3, 2001.

Reprint requests to (G.L.K.) Division of Pediatric Pharmacology and Toxicology, Department of Pediatrics, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108. E-mail: gkearns{at}cmh.edu

	ABBREVIATIONS

GBP, gabapentin; GABA, gamma-aminobutyric acid; DOL, day of life.

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