Introduction

Neuropathic pain involves damage to neural tissues and can develop from a variety of conditions, such as fibromyalgia, headache syndromes, complex regional pain syndrome, orofacial pain, and neuralgias.^1,2 Neuropathic pain is less common in childhood, and epidemiologic studies have not been conducted to characterize its true prevalence; however, juvenile primary fibromyalgia syndrome may account for 25% to 40% of pediatric chronic pain syndromes.³ Additionally, neuropathic pain and complex regional pain syndrome may account for up to 40% of referrals to pediatric pain clinics.^4,5 Research has also demonstrated the interplay of chronic pain and psychiatric disorders. Anxiety and depression are two common psychiatric problems in pediatric patients with chronic pain.⁶ The underlying mechanism of neuropathic pain syndromes in children and adolescents is not fully known; however, injury from competitive sports, dance, trauma, and cancer are known risk factors for the development of neuropathic pain. The presentation of neuropathic pain may differ between adults and children; however, common symptoms can include burning, tingling, and allodynia.⁷ For a further in-depth discussion of pain syndromes in the pediatric pain population, please refer to the review by Walker.⁸

The management of neuropathic pain for children is largely based on adult treatment guidelines. There is a paucity of well-designed, randomized, controlled studies and Food and Drug Administration (FDA)–approved medications for all pediatric age groups. Children and adolescents often present with rare conditions that differ from adult patients regarding level of acuity, presentation, and comorbid states.⁹ Therefore, extrapolation of adult data may not appropriately fit the pediatric population. These gaps in knowledge often lead to delayed diagnosis and inadequate evaluation.¹⁰ Suboptimal treatment of pediatric pain syndromes can have substantial implications for the treatment of psychiatric disorders.^11-13 Children with chronic pain commonly experience delayed psychosocial development, loss of physical function, absence from school, and increased visits to the emergency department and pain clinic. Thus, there is a need to critically evaluate the management of neuropathic pain for these vulnerable patients.

A multimodal treatment approach that combines medications with synergistic mechanisms of action is needed to address the unique aspects of neuropathic pain. Several adjuvant analgesics have been used effectively in adult patients, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, and anticonvulsants. Opioids are not preferred for long-term management of these conditions because neuropathic symptoms generally respond poorly to this class of medication. Patients and parents frequently discontinue opioids secondary to side effects of sedation, dependence, abuse risk, and exacerbation of certain types of neuropathic pain.¹⁴

The tricyclic antidepressants have a longer history of use in pediatric pain management but are limited by their histaminergic, adrenergic, and cholinergic side effects.¹⁵ The dose response range for tricyclic antidepressants in neuropathic pain is wide, and it may take several weeks to titrate to analgesic effect. Experience with SSRIs has been limited in pediatric analgesia.^16-18 Serotonin-norepinephrine reuptake inhibitors may have advantages in pain syndromes over SSRIs because of the added inhibition of norepinephrine reuptake. Noradrenergic models, and to a lesser extent serotonergic models, have been shown to reduce painlike behavior in preclinical populations.¹⁹ The serotonin-norepinephrine reuptake inhibitor duloxetine has been used successfully for managing neuropathic pain syndromes, including fibromyalgia, in adult patients.^20,21 To date, no trials have demonstrated the efficacy of duloxetine in childhood neuropathic pain.

Currently, there are 3 case reports published on the safe and effective use of off-label duloxetine in children and adolescents ages 10 to 17 years for the management of chronic neuropathic pain.^22-24 These reports document a total of 4 pediatric patients with varying comorbid disease states where pain was successfully controlled with duloxetine. We aim to describe the use and outcomes of duloxetine in a pediatric population through a series of cases seen in our clinic.

Methods

Here, we report our experience initiating duloxetine for the management of neuropathic pain in 5 consecutive pediatric patients treated in the multidisciplinary pain clinic at the Children's Hospital of Michigan in the Detroit Medical Center during a 6-month period in 2013 (Table 1). Although exact conditions varied across our patient cases, each patient had a neuropathic component to his or her chronic pain condition. Demographic data, etiology of pain symptoms, clinical presentation, causes of symptoms, prior treatments, pain response (Faces Pain Scale-Revised [FPS-R]), medication changes, and adverse effects were documented before and after exposure to duloxetine, which is standard for patient documentation in our clinic. Data, including changes in pain scores (FPS-R), were collected for each patient at baseline and at 6- and 12-week follow-up visits.

TABLE 1:  Patients treated with duloxetine for neuropathic pain conditions

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Results

Discussion

We have described the off-label use of duloxetine for neuropathic pain in an adolescent population. Each case resulted in discontinuation of duloxetine because of either adverse effects, lack of efficacy, or both. The primary adverse effect of nausea was not improved with altered administration times or coadministration with food, yet resolved after discontinuation of duloxetine. To date, only 3 reports exist describing cases of duloxetine use for pediatric pain.^7-9 Briefly, a case series by Meighen²⁴ reported the successful use of duloxetine in adolescent females with comorbid chronic pain and depression. A second report by Desarkar et al²³ described the successful use of duloxetine for a pediatric patient with depression, severe pain, and dissociative symptoms. The third case, by Kachko et al,²² reported the successful use of duloxetine in a female pediatric patient with femoral neuropathy and “reactive depression” with conversion symptoms. Although each report described the successful use of duloxetine (summarized in Table 2), to date there have been no prospective trials looking at the efficacy of duloxetine for pediatric neuropathic pain management. Although our case series reports a lack of efficacy and side effects with duloxetine's use, our population is different from each of the other case reports, making comparisons difficult. Clinicians must bear in mind that a modest decrease in pain score may appear insignificant; however, for a neuropathic pain condition, a decrease of 30% may indicate clinical effectiveness.²⁵

TABLE 2:  Previous reports of duloxetine for pediatric neuropathic pain

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Overall, nausea is the most common side effect of duloxetine therapy compared with placebo.^26-28 The mechanism of duloxetine-induced nausea is not completely understood but may be related to its mechanism of action at the serotonin and norepinephrine receptors. Nausea is also a common side effect of the other SSRIs; however, it may be more common in duloxetine compared with other SSRIs.²⁷ Compared with adults treated with venlafaxine, nausea is reported more frequently by adolescents.^29-31

Many potential barriers to pediatric medication adherence have been identified, and furthermore, adherence has been linked to health outcomes in this population.^32-34 Thus, potentially troubling side effects, like nausea, can substantially inhibit the efficacy of promising agents, like duloxetine, for neuropathic pain. Additionally, duloxetine, like all antidepressants, carries an FDA boxed warning about increased suicidal thinking and behavior for children, adolescents, and young adults, which can increase both patient and parental anxiety regarding medication use. Self-monitoring plans enhance the effectiveness of pain therapy and minimize the risk of serious side effects, such as increased suicidal thoughts and behaviors.²⁶

Finally, duloxetine is now available in a generic formulation, which aids in affordability. Because it is a moderate inhibitor of cytochrome P450 2D6, it has the potential for drug-drug interactions; therefore, adequate examination of the patient's medication profile during drug therapy changes is necessary.

Conclusion

Off-label use of duloxetine continues to be an option for relief of neuropathic pain syndromes in adolescents despite the lack of prospective evidence. Because chronic pain often occurs with depression (present in every case report to date), it can be difficult to fully elucidate the underlying etiology of the disorders because they are interrelated and likely interdependent. Thus, serotonin-norepinephrine reuptake inhibitors are attractive options to address both depressive and pain symptoms with a single medication; however, it is essential that appropriate monitoring and precautions be taken prior to prescribing duloxetine. Monitoring and screening must be initiated before prescribing this agent to this vulnerable population because the risks can outweigh the benefits. Education on side effects and the importance of adherence is key, especially for adolescents. Based on our experience of using duloxetine in a pediatric population with neuropathic components to their pain, we suggest considering its use only after failure of other agents. We believe that pharmacotherapeutic options, such as gabapentin, tricyclic antidepressants, or transdermal lidocaine, may be more appropriate, depending on patient-specific factors. If these options fail, we then would consider a trial of duloxetine after considerable patient education and careful, slow titration of the drug. Overall, the best management, in our opinion, of a pediatric patient's pain condition is likely accomplished through a combination of pharmacotherapy and nonpharmacotherapy interventions.