Non-Opioid Pharmacology in Pediatric Pain Management

The Use of Membrane Stabilizers in Acute and Chronic Pain

By Galaxy Li, MD
Division of Pain Medicine, Department of Anesthesiology
Nemours Children’s Specialty Clinics
Jacksonville, Florida
and Pulsar Li, DO
Department of Anesthesiology and Perioperative Medicine
Division of Pediatric Anesthesiology
Loyola University
Chicago, Illinois

The management of pediatric acute and chronic pain has evolved over a half century from near denial of its existence to an era of its focus as the fifth vital sign to a more recent multimodal approach in the face of a national opioid epidemic.  Today, pharmacologic analgesia strategies are primarily based on opioids and nonopioids. Membrane stabilizers are among a prevalent group of non-opioids that have emerged in the management of pain in children, including certain anticonvulsants, local anesthetics, tricyclic antidepressants, and antiarrhythmics.  Many of these medications inhibit propagation of ectopic discharges at sodium or calcium channels that have been found in hyper-excited states at central and peripheral neurons, particularly in the presence of neuropathic pain. Membrane stabilizers known to act at sodium channels include lidocaine, amitriptyline, carbamazepine, oxcarbazepine, mexiletine, topiramate, and valproic acid; while those affecting calcium channels include gabapentin, pregabalin, and magnesium.

Adult clinical trials from the past two decades that supported gabapentin and pregabalin for fibromyalgia and some neuropathic pain conditions such as postherpetic neuralgia, painful diabetic neuropathy, and central neuropathic pain inspired exploration into their use for children.  A 2019 review of the efficacy and safety of these two medicines for pain in children and adolescents identified three studies investigating gabapentin as a prophylactic postsurgical analgesic; two exploring gabapentin and pregabalin for specific types of non-surgical pain, and two that were omitted due to unambiguous evidence of data fabrication.1  Although a 2016 randomized, double-blind, placebo-controlled 15-week study on gabapentin in 107 adolescents with fibromyalgia did not reveal an improvement in mean pain score over placebo at endpoint, there were improvements noted in secondary outcomes of change in pain score by week.2  A 2016 randomized controlled trial of amitriptyline versus gabapentin in 34 children with complex regional pain syndrome type 1 or a neuropathic pain condition led to significant reductions in pain after six weeks although there was not a statistically significant difference between the two groups.3 Furthermore, studies in mice with neuropathic pain suggest a synergistic antinociceptive effect when gabapentin and nortriptyline are administered together.4

Given that tricyclic antidepressants are among the most prescribed agents for anxiety and depression in inflammatory bowel disease, reports of their value in pain modulation surfaced for children with other abdominal pain conditions. A 2008 double-blinded, placebo-controlled trial of amitriptyline in 33 adolescents with irritable bowel syndrome showed significant quality of life improvement and periumbilical pain reduction over 10 weeks.5  A larger 2009 multicenter randomized, placebo-controlled trial of amitriptyline in 90 children with functional gastrointestinal disorders found that both amitriptyline and placebo were associated with excellent pain relief with no significant difference between each other after four weeks, and that both tended to be more effective in those with mild to moderate pain intensity.6 This prompted renewed discussion of pediatric placebo studies for these disorders.7  All of these experiments were captured in two 2017 Cochrane reviews that found insufficient data for analysis, as none of the studies reported primary outcomes of  >30% or >50% participant-reported pain relief.8,9

Intravenous lidocaine for children has been used both in long-standing cancer pain as well as in the perioperative arena. A 2016 case series highlights a participant-reported pain score reduction of 50% or more when 14 continuous lidocaine infusions were used for opioid-refractory pain in cancer patients at a children’s hospital.10 Half of the subjects were administered lidocaine infusions at the time of expiration, while another subject was discharged from the hospital on mexiletine because the pain relief was not sustained after discontinuation of the infusion. Of note, adverse events such as vision changes, paresthesia, and visual hallucinations occurred with 35% of the infusions that all either spontaneously resolved or after the infusion rate was decreased. To avoid potentially lethal lidocaine toxicity, this approach may benefit from regular serum concentration monitoring. Lidocaine has also been attributed to much more acute pain relief when dealing with pain upon injection of propofol for induction of general anesthesia. Countless adult studies have pointed towards potential analgesics that may alleviate pain on propofol injection, from lidocaine to remifentanil to sodium bicarbonate to ketamine. In the setting of research in adults, a 2017 meta-analysis of eleven randomized control trials found that lidocaine is effective in reducing propofol injection pain for pediatric patients.11

The Enhanced Recovery After Surgery (ERAS) group was established in 2001 in Europe to develop a protocol that would avoid complications, expedite postoperative recovery, and shorten hospital stay during the acute perioperative setting.12  The adaptation of multimodal analgesia aims to improve post-operative pain control, reduce surgical stress, and facilitate early oral diet and mobilization.13  Though early emphasis was placed on non-steroidal anti-inflammatory drug (NSAID) integration by ERAS program, concerns over adverse influence of NSAIDs on anastomotic integrity have ushered renewed interest in other non-opioid adjuncts, including gabapentin.

Encouraging results in the adult literature on membrane stabilizers lidocaine, magnesium, and gabapentin prompted their introduction into pediatric acute pain regimens.14,15  The use of non-opioid analgesia, including regional analgesia techniques, alpha‐2 agonists, ketamine, acetaminophen, NSAIDs, and neuropathic pain medications such as gabapentin or antidepressants was encouraged in a 2019 Society for Pediatric Anesthesia recommendation on perioperative pediatric opioid use.16 A 2017 meta-analysis found that intraoperative IV magnesium during osteotomy reduces pain scores, although two studies of its use during tonsillectomy and adenoidectomy produced no difference in pain scores, rescue analgesic requirement, nor emergence delirium.17  While no lidocaine nor pregabalin investigations met the inclusion criteria for this meta-analysis, two gabapentin studies did, but arrived at conflicting conclusions.

Proposed advantages of perioperative gabapentin include incorporation of non-opioid analgesia, decreased emergence delirium, and decreased postoperative nausea-vomiting.18  A 2019 randomized, controlled trial revealed that pediatric patients undergoing lower extremity surgery who received preoperative gabapentin 10mg/kg experienced superior pain reduction, more sedation in the operating room, less agitation in the postoperative period, and attenuated autonomic response to intubation.19  Older studies showed that repeated perioperative doses of gabapentin, but not a single preoperative dose, reduced opioid requirements following spinal fusion for idiopathic scoliosis.20  A 2014 randomized, controlled trial failed to show that a single 600mg preoperative dose of gabapentin resulted in a significant difference in opioid consumption or pain scores by adolescents undergoing scoliosis surgery.21

The perioperative addition of membrane stabilizers for pain is not without risk. A February 2020 Anesthesiology News article featuring a Canadian systematic review and meta-analysis concluded that perioperative use of gabapentin in adults yields no clinically significant analgesic effect, and comes with an increased risk for adverse events.22  These adverse effects include dizziness, visual disturbances, drowsiness, in addition to neurotoxicity and acute kidney injury secondary to rhabdomyolysis in those with advanced chronic kidney disease.  A 2020 randomized, controlled trial found that the combination of acetaminophen, gabapentin, ketamine, and lidocaine did not confer an improvement in the quality of recovery of adults undergoing spine surgery.23

As the opioid epidemic gains public awareness and ERAS becomes more prevalent, the role of non-opioid analgesic adjuncts is likely to grow.  Of these non-opioids, membrane stabilizers have attracted significant attention because of their diverse applications, synergistic effect, relatively favorable side effect profile, and encouraging research in the adult population.  Though membrane stabilizers have been adopted into acute, chronic, and palliative care pain regimens, further research is required to determine their safety, efficacy, and dosing in pediatric patients.

References

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