Non-Opioid Pharmacology in Pediatric Pain Management

The Potential of Psychotropic Medications for Alleviating Pain in Children and Young Adults

By R. Blake Windsor, MD, FAAP, DABMA
Chief, Division of Pediatric Pain Medicine
Clinical Assistant Professor of Pediatrics and Anesthesiology
University of South Carolina School of Medicine
Greenville, South Carolina
and Elaine Kerr, MD
University of South Carolina School of Medicine
Greenville, South Carolina

Children and adolescents with chronic pain are a complex and heterogeneous population. Psychiatric comorbidities are frequent, active-ongoing disease may co-occur, and evidence supporting pharmacologic interventions for pediatric chronic pain is limited. Recommendations for the treatment of psychiatric conditions in this patient population is beyond the scope of this article. This will provide an overview of the analgesic, and related physiologic, effects of medications traditionally classified as psychotropic in nature. For the sake of brevity, mood stabilizing agents were not included due to their overlap with anticonvulsant medications.

Tricyclic Antidepressants
Tricyclic antidepressants (TCA) are multi-mechanistic agents with good evidence supporting their use as analgesics in adults. As a class, TCAs possess serotonergic and noradrenergic reuptake inhibition, NMDA antagonism, sodium, and calcium channel inhibition, kappa, and delta opioid receptor agonism, and anti-inflammatory activity via prostaglandin and TNF-alpha modulation (1, 2). The anti-inflammatory effects of TCAs may contribute to the enhanced benefits seen in adult patients with rheumatologic disease such as rheumatoid arthritis or ankylosing spondylitis.

Despite frequent use in pediatrics, the evidence supporting amitriptyline use is not very strong. In pediatric functional abdominal pain, amitriptyline has shown improved quality of life, reduced right lower quadrant pain (but not other locations of abdominal pain), and reduced anxiety. Patients with mild-moderate pain responded better than those with severe pain. Like other pediatric studies, large placebo effects were seen across these studies (3).
Similarly, several recent analyses cast doubt on the efficacy of amitriptyline for adolescent migraine. The CHAMPS trial performed a multi-center, randomized, double-blind, placebo-controlled crossover study of amitriptyline, topiramate, and placebo and found no evidence of benefit over placebo (4). Later meta-analysis supported this conclusion (5).

In adults, amitriptyline demonstrated efficacy in migraine, functional abdominal pains (particularly functional dyspepsia), fibromyalgia, chronic low back pain, and neuropathic pains. Most evidence supports adult dose ranges from 25-30mg with little evidence supporting additional benefit from higher doses (6).

TCAs are notable for being anti-cholinergic, anti-alpha-1 adrenergic, and anti-histaminic that can be counterproductive in cases of chronic constipation, orthostatic dizziness, and obesity. They are metabolized by CYP2D6 and prone to risks from hyper-metabolizers and under-metabolizers, including QTc prolongation. They are also prone to interactions with CYP2D6 inhibitors, most notably fluoxetine, bupropion, cannabidiol, sertraline, and duloxetine which can all increase amitriptyline levels and contribute to adverse effects.

Selective Serotonin Reuptake Inhibitors 
Selective serotonin reuptake inhibitors (SSRIs) are defined by their high selectivity for serotonin reuptake inhibition. They are similar, but not interchangeable, and evidence supporting their use does not generalize across the class. Fluoxetine (Prozac) and escitalopram (Lexapro) are the only SSRIs that are FDA approved to treat depression and anxiety disorders in children > 12. Fluoxetine also has anti-sodium channel activity and is notable for having a long half-life that improves tolerability. SSRI studies in children are complicated by similarly high placebo response rates seen in pediatric analgesic studies for chronic pain.

SSRIs have not been well studied for pediatric and adolescent chronic pain due to the evidence of only modest benefit in adults for the treatment of neuropathic pain and fibromyalgia. The analgesic effects of SSRIs for adult pain conditions are independent of effects on anxiety or depression.

The existing evidence supporting SSRI use for pediatric chronic pain is primarily centered on the use of citalopram (Celexa) for childhood functional abdominal pain. Two trials demonstrated benefit above placebo with doses of 20-40mg/day (3). One of the advantages of SSRI therapy for abdominal pain is that they tend to have pro-motility effects that may enhance their outcomes in treating chronic abdominal pain related to constipation. They are typically well tolerated but carry the same FDA black box warning on suicidal ideation in adolescents as TCAs and alpha 2-delta ligands. Citalopram also has a warning on doses >40mg/day due to significant QTc prolongation.

Serotonin and Norepinephrine Reuptake Inhibitors
Serotonin and norepinephrine reuptake inhibitors (SNRIs) are commonly accepted as efficacious in treating most adult chronic pain conditions. Unlike TCAs, they are relatively effective antidepressants and anxiolytic agents. Commonly used medications include duloxetine, venlafaxine, and milnacipran. Newer agents such as desvenlafaxine (Pristiq) and levomilnacipran (Fetzima) have not been well studied for pain. SNRIs have significant within class variability. They generally share dose-dependent reuptake inhibition of serotonin (low doses) and norepinephrine (higher doses) with correlating effects. For instance, at low doses, side effects tend to be like SSRIs (e.g. nausea and headache) and at higher doses are adrenergic (e.g. dry mouth, hypertension) and activating (e.g. increased energy, insomnia, and restlessness).

Venlafaxine (Effexor) is highly serotonergic and has a 30-fold increased affinity for 5HT receptors compared to NE. Venlafaxine also has some interesting interactions with opioids that are being elucidated with one preclinical study showing a lack of antidepressant activity in opioid receptor knockout mice. Other clinical studies have suggested attenuated benefits from venlafaxine in adults receiving chronic opioid therapy (6, 7). It is effective in adults for treating various neuropathic pain states, migraine, and fibromyalgia. It is used off-label for ADHD in adults with some limited evidence to support this in pediatrics.

Generally, analgesia occurs in adults with doses between 75-225mg/day. Upward titration occurs faster than with SSRIs or TCAs. Nausea and activation can become dose-limiting for some patients, but they are generally well tolerated. Extended-release venlafaxine (Effexor XR) has superior tolerability compared to immediate-release formulations.

Duloxetine (Cymbalta) is FDA approved for fibromyalgia, chronic musculoskeletal pains (particularly chronic low back pain), and painful diabetic neuropathy. There is limited data in pediatrics, but one placebo-controlled trial evaluation of duloxetine for juvenile fibromyalgia showed no statistically significant improvements in their primary outcomes (reduced average pain scores). However, secondary analysis showed an increased likelihood of achieving 30% and 50% reductions in pain. Duloxetine also demonstrated efficacy in adult trials evaluating chemotherapy-induced neuropathy and that duloxetine is superior to venlafaxine for this indication. This benefit was postulated to be due to its central noradrenergic activity, but duloxetine also reduces intracellular inflammatory messaging via MAPK and NF-kB pathways that are thought to mediate platinum-induced neural toxicity (8).

Generally, the analgesic activity of duloxetine in adults does not occur below doses of 60mg, but it is unclear if higher doses are more effective. The COMBO-DN trial evaluated duloxetine non-responders at 60mg and found that combination therapy with 300mg/day of pregabalin was slightly superior to high dose monotherapy (120mg) suggesting that there may be some dose-response interaction. Short term notable side effects include nausea, weight loss, and headache, with more long-term effects including mild elevations in HR (~3bpm) and weight gain.
Milnacipran (Savella) is only FDA approved for fibromyalgia in adults. It has a 1:1 ratio of 5HT:NE. It has a relatively short half-life requiring twice daily dosing with rapid up-titration to goal dosing of 50mg BID. There are no completed pediatric trials, but a study that was terminated early due to poor enrollment showed modest improvement in pain and quality of life during the initial open-label portion of the study.

Miscellaneous Anti-depressants
Bupropion (Wellbutrin) is a second-generation anti-depressant with specific noradrenergic and weak dopaminergic reuptake activity. It has been studied primarily for neuropathic pain in adults and results are generally favorable with doses from 150-300mg with anti-hyperalgesic benefits and some preclinical studies showing anti-inflammatory effects (9, 10). It has also shown reduced morphine tolerance and dependence. Though it is effective for smoking cessation, it is not particularly effective in managing opioid use disorders (11). Bupropion has the distinction of being one of the few psychotropic medications that is not associated with weight gain. Its notable side effects tend to be activation (e.g. increased energy, restlessness, insomnia) and lowered seizure threshold.

Mirtazapine (Remeron) is an alpha-2 antagonist (contrasted with clonidine’s alpha-2 agonism) that produces increased central serotonin and noradrenergic levels. It also inhibits multiple 5-HT receptors allowing for enhanced serotonin interaction with the 5-HT1 receptors that are thought to mediate its antidepressant effects. It is potently antihistamine (H1) and has moderate alpha-1 and anti-muscarinic antagonism. Its primary use is for major depressive disorder, particularly with sleep disruption or anxiety. It is used off label with some success for chronic tension type headache. Recently it was shown to improve early satiety, increase nutrient intake and weight, and overall symptoms in an adult sample of non-anxious, non-depressed patients with functional dyspepsia. These benefits did not correlate with any peripheral physiologic changes. Its effects suggest some possible utility in adolescent functional abdominal pain associated with weight loss that is suggestive of Avoidant/Restrictive Food Intake Disorder (12). 

Buspirone (Buspar) is a less commonly used adjunctive therapy for generalized anxiety disorder. It acts primarily on 5HT1A receptors. It is largely ineffective for adult or pediatric pain, but recent studies have contributed to growing interest as a gastric neuromodulator. It improved gastric accommodation, early satiety, and overall reduction of symptoms in a cohort of adults with functional dyspepsia independent of effects on anxiety (12).

Antipsychotics
Antipsychotics are a heterogeneous class with little evidence supporting their use for adult or pediatric chronic pain, though they are more commonly used by adult and pediatric palliative care specialists for delirium, nausea, and other symptoms. Atypical antipsychotics share many mechanisms that may modulate pain, including actions on multiple 5HT receptors, alpha-1 adrenergic, anticholinergic, and antihistaminic activity.

Of the various small studies, olanzapine (Zyprexa) has the most consistent positive results for fibromyalgia and migraine, followed by quetiapine (Seroquel) for fibromyalgia (13-15). One recent retrospective study on the use of olanzapine in adolescents in the Emergency Room with agitation, headache, or GI complaints,  showed that only 9% of adolescents with acute headache required rescue analgesic and 14% of adolescents with GI complaints required rescue analgesic or anti-emetic therapy, and the treatments were generally well tolerated.

The results suggest olanzapine as a potentially helpful therapy for acute headache or GI pain refractory to other interventions in the hospital setting (16). Chronic use is associated with significant side effects including weight gain, dyslipidemia, hypertension, galactorrhea and menstrual abnormalities, and hepatic dysfunction.

Conclusions
Psychotropic medications have many possible therapeutic benefits in children with pain independent of treatment effects for psychiatric conditions, but there is scant pediatric-specific data. Because of the relative lack of evidence, these medications are probably best used in a multi-specialty setting with co-treatment for psychiatric conditions. With a working knowledge of the pain-relevant physiologic effects of these medications, the pediatric pain specialist is well placed to help tailor a cohesive pharmacologic regimen.

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