Pediatr Drugs DOI 10.1007/s40272-014-0092-2

THERAPY IN PRACTICE

Pharmacological Treatment of Chronic Non-Cancer Pain in Pediatric Patients Eapen Mathew • Eugene Kim • Kenneth R. Goldschneider

 Springer International Publishing Switzerland 2014

Abstract Chronic pain in children and young adults occurs frequently and contributes to early disability as well as personal and familial distress. A biopsychosocial approach to evaluation and treatment is recommended. Within this approach, there is a role for pharmacologic intervention. A variety of medications are used for chronic pain conditions in pediatric patients. Medication classes include anticonvulsants, muscle relaxants, antidepressants, opioids, local anesthetics, and anti-inflammatory drugs. Data is sparse, and most medications are used without condition-specific approval by national regulatory agencies such as the Food and Drug Administration in the US and the European Medicines Agency. In the absence of evidence on which to base practice, optimal drug therapy decisions rest on understanding proposed mechanisms of pain conditions, extrapolation from adult data—when such exists, and empirical and experiential knowledge. Drug delivery systems have evolved, and practitioners have to decide amongst not only medication classes, but also routes of delivery. Opioids are not recommended for use by nonpain specialists for the treatment of pediatric chronic pain, and even then the issues are more complex than can be addressed here. This article reviews the major medications used for pediatric chronic pain conditions.

Electronic supplementary material The online version of this article (doi:10.1007/s40272-014-0092-2) contains supplementary material, which is available to authorized users. E. Mathew
E. Kim
K. R. Goldschneider (&) Pain Management Center, Department of Anesthesiology, L # 2001, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA e-mail: [email protected]

Key Points Medication management is an important though modest component of multidisciplinary treatment of pediatric chronic pain. There is sparse evidence to support medications used in pediatric chronic pain, and many are used ‘offlabel’. Choosing a particular medication is generally based upon knowledge of pain mechanisms and drug pharmacology, extrapolation from adult data, and expert consensus. It is recommended that opioid prescription be limited when possible to those experienced in management of chronic painful conditions in children.

1 Introduction Chronic pain in children and young adults is a frequent problem and one that has impact on the daily function of those affected [1–3]. Optimal treatment is multidisciplinary in nature and is based upon a biopsychosocial approach. Cognitive behavioral therapies (CBT) and physical therapies are well accepted cornerstones to treatment of most pediatric chronic pain conditions. Medication treatment features as a much requested, often used part of the therapeutic plan. However, the amount and quality of evidence supporting the use of any particular drug is disappointing [4]. Practitioners see a variety of pain conditions, including abdominal pain, back pain, headaches, musculoskeletal pain, fibromyalgia, and neuropathic pain (which for this discussion will include complex regional pain syndrome

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[CRPS], traumatic and metabolic neuropathies, and phantom limb pain) [5]. Several hereditary or congenital syndromes are associated with pain, such as sickle cell disease [6], cerebral palsy [7], muscular dystrophy [8, 9], and hypermobility syndromes [10]. It should be noted that there is no precise definition of chronic pain, as the processes underpinning a particular subtype can be seen immediately or after weeks or months. For purposes of discussion the following conceptualization may be helpful. Chronic pain ‘‘persists beyond…expected healing time (arbitrarily defined as [3–6 months) and develops into a chronic persistent or recurrent pain syndrome. Chronic pain in children is the result of a dynamic integration of biological processes, psychological factors, and sociocultural factors considered within a developmental trajectory’’ [11]. In treating chronic pain in children and young adults, practitioners face several barriers. One barrier is the lack of randomized controlled trials in pediatric populations. Stemming from this, approval by national medicine regulatory agencies for use in specific conditions for pediatric patients is often lacking. The majority of the medications discussed herein either lack indication from national or international drug regulatory bodies for the pain condition, or lack it for the pediatric age range, even if indicated in adults. Thus, medication choices are often best made on three bases. First, medication treatment may be chosen ‘‘based on all available data, thoughtful consideration, presumed mechanism, pharmacology, and expert consensus’’ [12]. Second, extrapolation from adult data and practice can be useful in young adults and older children when the problem under treatment can be reasonably assumed to have a similar mechanism. Examples of that include sciatica related to a herniated disc or pain related to CRPS. Hence, the reader will note frequent references to adult data, which form the basis for extrapolation to pediatric practice in the common event that no pediatric data exist. The third basis for decision making is to match the understood mechanism of action of a medication with the best known pathophysiology of the pain condition. None of these decision-making processes are optimal. Walco et al. [13] cited the sparse literature on pediatric neuropathic pain treatment in recommending that great care be taken in extrapolating from adult practice to avoid potentially dangerous results. Use of particular medicines for pain is also difficult to explain to patients and families when the relationship to pain is tenuous or theoretical in nature. Explaining that adding amitriptyline to CBT for migraine headaches is worth doing because it has good data [14] to support the practice is one thing. Suggesting it be used for abdominal pain when the data is contradictory, negative or absent is another [15, 16], even when it has been a standard practice for many years. The opposite holds true for opioids. It can be challenging to steer

patients away from something they know to be a fast-acting and effective acute pain treatment, when the literature does not support use for chronic pain states [17, 18]. The purpose of this review is to highlight the major medications used in the treatment of a variety of common pediatric pain conditions. Two caveats must be noted. First, local practice and individual experience may lead to differing conclusions regarding the application or utility of a given drug. This may relate to differences in populations with attendant variations in pharmacogenetic responses, availability of specific preparations, personal experiences with side effects and ability to monitor and treat such effects, and local consensus from meetings and discussion with colleagues. Until evidence is generated, such variability in practice is to be expected and opinion on the use of any particular medication may be subject to debate. Second, when underlying pathology exists (e.g., inflammatory arthritis), treatment of the underlying condition is a primary component of pain management. All medications and treatments presented herein presume separate treatment of the primary disorder when one is present. Medications are organized by route of administration, to promote thinking about how drugs are used in addition to why and when. Diagrams are interspersed to illustrate how medications discussed in the text are used within archetypal treatment protocols for several common pediatric chronic pain categories, though detailed discussion of treatment protocols for each specific diagnosis extends beyond the scope of this presentation. An appendix of drug dosing is available in the electronic supplementary material and serves as a starting guide, but is limited by available data, as discussed in the text.

2 Medications by Route of Administration 2.1 Oral Administration 2.1.1 NSAIDs and Acetaminophen Nonsteroidal anti-inflammatory drugs (NSAIDs) have become a widely accepted and reliable first-line treatment for a variety of disease states in adults. Commonly used non-selective NSAIDs include ibuprofen, ketorolac, diclofenac, and naproxen. NSAIDs are commonly used for musculoskeletal pains (see Table 1) and are considered first-line abortive therapy for migraine headaches [19, 20]. Currently, the evidence for long-term therapy of NSAIDs in the pediatric population is found in patients with juvenile idiopathic arthritis. NSAIDs are considered firstline therapy and, although incompletely studied, their long-term use has been shown to be safe [21]. The general side effect profile is the same for children as adults;

Pharmacologic Treatment of Pediatric Chronic Pain Table 1 Example musculoskeletal pain care diagram

Evaluaon •History, Physical Exam, Review of labs, imaging, prior findings •Establish diagnosis •Begin educaon process

Treatment •Educaon connues (chronic pain vs. acute) •Cognive Behavioral Therapy (primary treatment based on evidence) •Physical therapy (land-based or aquac; home exercise program; aerobic condioning when possible; Transcutaneous Electrical Nerve Smulaon [TENS]) •Medicaon •Integrave Medicine (acupuncture, Yoga, meditaon, maral arts, etc.)

Medicaon opons •Inflammatory condions; general musculoskelatal pain - NSAIDs, (includes COX-2 inhibitors when indicated) •Muscular contracon condions - Cyclobenzaprine, zanidine, methocarbamol, baclofen •Widespread and non-specific pain - Tricyclic andepressants, gabapenn, pregabalin - Selecve serotonin and norepinephrine reuptake inhibitor •Localized pain (confirmed or suspected inflammatory type) - Topical NSAIDs, iontophorec steroids •Neurodegenerave and stac neuromuscular condions (e.g. Muscular dystrophy, cerebral palsy) - Cyclobenzaprine, zanidine, methocarbamol, baclofen - NSAIDs, (includes COX-2 inhibitors when indicated) - Opioids

gastrointestinal, renal, and bleeding disorders have been described [22, 23]. Selective cyclooxygenase-2 (COX-2) inhibitors offer advantages of decreased incidence of gastrointestinal ulcers as well as inhibition of platelet aggregation. Several small studies have shown their use in juvenile rheumatoid arthritis with favorable results and good tolerance [24–26]. Pediatric dosing and pharmacokinetic data of celecoxib are available [27]. Acetaminophen exhibits minimal anti-platelet and antiinflammatory properties but rather exerts its mechanism via proposed inhibition of prostaglandin synthesis and serotonergic descending pain pathways [28]. Acetaminophen is widely used for fever reduction and in the treatment of pain, either by itself or in combination with opioids. Hepatic injury can result and adherence to maximum total daily dosing is paramount with careful consideration paid to patients with liver disease. Practitioners are advised to watch for combination products containing acetaminophen in addition to taking care to remain within dosing limits when acetaminophen is used as a sole agent [29].

2.1.2 Opioids Opioids are a frequently requested set of medications. Use of them for chronic pain is not supported by either adult or pediatric literature except in limited circumstances as part of a structured treatment plan [11, 30] with high levels of screening and monitoring [31, 32]. Research needs have been published for this set of analgesics in adults [18] and certainly more is needed in children as well. Chronic opioid treatment should be limited to pain clinics set up to screen and monitor patients for side effects, diversion, and abuse or done in collaboration with such clinics. For disorders such as sickle cell disease, where recurrent acute pain is superimposed on chronic, opioids play a more prominent role. Use of patient-controlled analgesia pump-delivered opioids has been used for many years (e.g., [33]), though studies have been logistically difficult to conduct [34] and treatment usually requires adjuncts such as ketamine and ketorolac, which also have variable efficacy [35, 36]. We recommend early collaboration with the hematology team, who will often prescribe hydroxyurea as part of the global treatment regimen. Hydroxyurea shows efficacy in reducing

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the number of hospitalizations in children [37] and of painful vasoocclusive episodes in adults [38]. Tramadol is a weak l-opioid receptor agonist and norepinephrine and serotonin reuptake inhibitor. Long-term safety and efficacy have only been studied to 30 days of use in children but side effects during that time were considered only mild to moderate [39]. Similarly, tapentadol has l-opioid receptor activity as well as norepinephrine reuptake inhibitor qualities. Although no pediatric studies have been performed to date, randomized trials in adults have shown that both immediate and extended release forms have equianalgesic properties to oxycodone with fewer gastrointestinal side effects [40–42]. Standard l-agonists are readily available, though they must be used judiciously. Morphine offers several advantages in its convenience to be flexible in route of administration as well as offer both immediate and extended release versions. Morphine’s active metabolites, morphine6-glucuronide and morphine-3-glucuronide, are renally excreted, which is relevant in patients with chronic renal dysfunction. Codeine is an orally administered prodrug of morphine. It undergoes conversion via the cytochrome P450 system CYP2D6 enzyme to morphine. Unfortunately, population heterogeneity for this enzyme’s activity results in codeine showing a range of effect from no analgesia to toxicity [43]. For this reason, both the US FDA and the European Medicines Agency (EMA) have issued warnings to not use codeine for postoperative analgesia in pediatric patients having undergone tonsillectomy, though the age cutoffs differ between the two sets of recommendations [44, 45]. Codeine is frequently combined with acetaminophen (also true for oxycodone and hydrocodone). Thus, chronic use and inadvertent overuse may result in hepatotoxicity. A primary role for these medications is to aid patients in performing physical therapy or to help manage severe flare-ups of a chronic underlying condition, with very little use for ongoing therapy of chronic pain. Methadone is a long-acting opioid agonist and Nmethyl-D-aspartate (NMDA) receptor antagonist. Several small studies have found success with its use in the treatment of pediatric cancer pain as well as for weaning children off long-term opioid use, such as in the intensive care unit setting [46–48]. Its pharmacokinetics are highly variable, and side effects, including respiratory depression and cardiac conduction abnormalities, can have a significantly delayed onset. For these reasons, it is recommended that only experienced pediatric pain specialists prescribe methadone in children [49]. 2.1.3 Anticonvulsants Antiepileptic drugs have long been used to treat chronic neuropathic pain. This class of medications also plays a

role in the medical treatment of fibromyalgia, most notably gabapentin and pregabalin [50–52]. There has been a small but measurable increased risk of suicidal ideation in patients using anticonvulsants. Patients treated with any antiepileptic drug should be educated about and monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior [53, 54]. Gabapentin and pregabalin are hypothesized to work via modulation of voltage-gated calcium channels. They have been shown to be effective in treatment of diabetic neuropathy [55, 56] and postherpetic neuralgia [57, 58], which are predominantly adult conditions; pregabalin alone has also been supported by evidence as a treatment of central neuropathic pain and fibromyalgia [59]. Their side effect profile is generally favorable, most commonly including dizziness, drowsiness, and peripheral edema. They require titration when initiating and discontinuing therapy. Given their overall safety profile and moderate effectiveness, these two anticonvulsants are among the most frequently used for pediatric neuropathic pain conditions. Moderate level evidence supports the use of oxcarbazepine in the treatment of diabetic neuropathy, and it does not have significant efficacy in treatment of radicular pain [60]. Moreover, adverse effects leading to its discontinuation are not uncommon which may include dizziness, fatigue, and hyponatremia. Carbamazepine has also been extensively studied; however, these studies are limited by brief duration of follow-up, wide range of doses used, and variation in results [61, 62]. Regular monitoring is necessary for the possible adverse effects of aplastic anemia and hepatic impairment. Levetiracetam has been targeted as a potential improvement over other antiepileptic medicines used for chronic pain since it has a comparably favorable pharmacokinetic profile. A small, randomized placebo-controlled trial demonstrated the benefit of levetiracetam therapy in multiple sclerosis patients [63] and a small study of spinal cord injury patients revealed lack of benefit [64]. Investigation of levetiracetam in prophylaxis of migraine headache in the pediatric population has borne some promising data [65], but further larger scale studies are needed. Studies of lamotrigine for all-cause neuropathic pain did not provide any convincing evidence that it plays a role in treatment of neuropathic pain [66]. Topiramate has also been empirically used for neuropathic pain, but good quality studies of this medicine have only addressed neuropathic pain resulting from diabetes. Analgesic effects were no different from placebo, and the side effect profile was significantly worse [67]. Topiramate has been studied rigorously in management of chronic migraine headache in the pediatric population and serves as a good agent in prophylaxis as a single drug and in concert

Pharmacologic Treatment of Pediatric Chronic Pain Table 2 Example sickle cell pain care diagram

Evaluaon •History, Physical Exam, Review of labs, imaging, prior findings •Establish diagnosis (chronic and acute) e.g. vasoocclusive episode, avascular necrosis, splenic infarcon, neuropathic, leg ulceraon •Begin collaboraon with Hematology team and family early in life when possible to begin lifelong educaon

Treatment •Educaon connues (chronic pain vs. acute) •Cognive Behavioral Therapy •Physical therapy for chronic pain and dysfuncon (land-based or aquac; home exercise program; aerobic condioning when possible; Transcutaneous Electrical Nerve Smulaon [TENS]) •Medicaon: vary by acute or chronic diagnosis; hydroxyurea per Hematology •Injecon therapy (acute pain) •Integrave Medicine (acupuncture, Yoga, meditaon, maral arts, etc.)

Medicaon opons •Acute - opioids (consider PCA) - NSAIDs - Consider regional anesthesia if localized or for acute chest syndrome in paents old enough to have procedure done awake - consider ketamine •Chronic - As for other muscloskeletal pain disorders (see Table 1)

with other medicines [68]. Valproic acid has good evidence for prophylaxis of migraine headaches in adults [69] and conflicting evidence in children [70]. Weight gain and possible bone marrow and hepatic toxicities are of concern. In summary, antiepileptic medications play a role in pediatric pain for conditions analogous to those for which they are used in adults (see Table 2). Gabapentin and pregabalin are used most often, with topiramate and valproic acid used for migraine headaches and oxcarbazepine for peripheral neuropathies and less often for more general hypersensitivity states. Lamotrigine and levetiracetam are used infrequently, after other medications have been tried. 2.1.4 Antidepressants Tricyclic antidepressants (TCAs) are commonly used medications for a variety of pediatric pain conditions. They have long been used as a component of multidisciplinary treatment of complex regional pain syndrome [71], with an emphasis on facilitating the highly indicated physical and psychological interventions [72, 73]. A multicenter, randomized placebo-controlled trial of amitriptyline in 90

children with functional gastrointestinal pain showed no statistical difference from placebo [15]. A small study of 33 adolescents newly diagnosed with irritable bowel syndrome (IBS) and randomized to receive weight-based doses of amitriptyline or placebo showed improvement of quality of life, bowel function, and pain scores [74]. However, it was limited by sample size and potential sources of bias [74]. Its role in treatment of neuropathic pain is limited by quality of studies—small, brief studies demonstrate significantly more favorable results than larger studies of longer duration [75]. In conjunction with CBT, amitriptyline has evidence supporting its use for pediatric migraine headaches [14]. Nortriptyline has shown some benefit as a sole agent in a small study of low back pain [76] and as a combination treatment with gabapentin for neuropathic pain [77]. Owing to their ability to prolong the QT duration, a baseline electrocardiogram evaluation should be strongly considered prior to initiating therapy with tricyclic antidepressants [78] and interpreted by a pediatric cardiologist since automated readings may not correctly calculate required parameters [79]. Pharmacogenetic variations in TCA metabolism can be seen which would require appropriate dose adjustments [80].

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Duloxetine is a balanced serotonin and norepinephrine reuptake inhibitor (SNRI). Moderate-quality evidence from multiple trials supports its use in treatment of diabetic neuropathic pain [81]. It is also well supported as a treatment of fibromyalgia [82, 83], though further study is necessary to elucidate analgesic mechanism of action— some data point to buoying of mental symptoms as the reason for its efficacy, while other data suggest improvement in somatic pain as well [82]. Nausea and sleep disturbance are the main adverse effects. Milnacipran is a relatively new SNRI used for treatment of fibromyalgia in adults. Both SNRIs should be titrated to the target dose over several weeks of initiation and weaned off at discontinuation. Target dosing for pediatric patients has not been established. In a randomized placebo-controlled trial of more than 1,000 patients, the milnacipran group experienced significantly better pain symptoms, global status, and physical function [84]. Its effect is likely supraspinally mediated [85]. Quality of evidence could be limited by certain data imputation methods [86]. Long-term therapy of 3 years or longer does not seem to be affected by extinction of response to milnacipran [87]. Fluoxetine has been used in juvenile fibromyalgia in a small open-label trial with good symptom relief, albeit among the small proportion of patients who completed the study without protocol deviation [88]. Selective serotonin reuptake inhibitors (SSRIs) have had mixed effects at best in adults with IBS [89, 90] and are not considered first-line treatments for pain in children. Increased risks for suicidal ideation in adolescents taking SSRIs for depression (at least in the first 1–2 months) led to regulatory agencies issuing a warning regarding antidepressants in the pediatric age range [91]. Close follow-up and patient/family education about mood changes and suicidal ideation are important when prescribing antidepressants for pain in pediatric patients. The mechanism of action of trazodone has not been clearly elucidated, but it has some properties of serotonin reuptake inhibition. It may have moderate, evidence-based utility in treatment of chronic headache in children [92, 93]. Antidepressants as a class are frequently prescribed for the treatment of functional abdominal pain conditions (e.g., IBS). A systematic review that included 15 studies of antidepressants treating over 900 patients demonstrated a statistically significant benefit of TCAs and SSRIs compared with placebo; subgroup analysis suggested SSRIs were a more effective treatment of global function, while TCA treatment was more specific to abdominal pain and symptoms [94]. Chiou and Nurko [95] present a nice overview of the treatment of functional abdominal pain in children, noting the role for medications as a small component of therapy (see Table 3).

2.1.5 Muscle Relaxants This class of medications finds use as part of treatment plans for musculoskeletal pain. There is adult data supporting the use of several of them for back pain [96], but pediatric data is lacking. Fibromyalgia has also been treated with muscle relaxation with some efficacy [96]. No single oral muscle relaxant has been shown to be superior to others. Choice may be guided by side effect profile. For instance, the sedation caused by cyclobenzaprine and tizanidine can be utilized for patients with the insomnia and nocturnal spasm often seen with fibromyalgia and back pain. Baclofen is a gamma-aminobutyric acid B (GABA-B) receptor agonist often used to treat conditions of spasticity and may also be used to treat muscle spasm pain. Tolerance does not seem to limit its effectiveness in long-term use. A randomized placebo-controlled study of 200 patients with acute low-back pain demonstrated significant benefit of this medicine in the subset of patients experiencing severe pain at baseline. Function measured by straight leg raise and range of motion was also significantly improved in those taking baclofen [97]. Tizanidine is an a2-agonist with antispasmodic properties that is very sedating, making it useful at bed time for patients with poor sleep related to pain and spasm. It causes hepatocellular damage in a small minority of patients, and liver enzyme levels should be followed in the first 6 months of treatment, or as indicated clinically. Interestingly, there is some evidence that it may have some gastroprotective effects and mitigate the potential harm of NSAIDs when used together [98]. Three high-quality trials demonstrate superiority of tizanidine plus analgesics versus placebo plus analgesics [96]. Diazepam is a benzodiazepine with properties of skeletal muscle relaxation, as well as being an anxiolytic, hypnotic, and antiepileptic. It has a role for the treatment of acute muscle spasm, but the development of tolerance and CNS side effects preclude its chronic use. Cyclobenzaprine is a muscle relaxant that works supraspinally and has anticholinergic effects. A meta-analysis of cyclobenzaprine treatment of fibromyalgia included five randomized placebo-controlled trials; there were statistically significant improvements in global function and amelioration of sleep disturbances [99], although the included studies universally suffered from high dropout rates. There have been case reports of serotonin syndrome when cyclobenzaprine was taken with other serotonergic medicines [100]. Metaxolone and methocarbamol are muscle relaxants without a well understood mechanism of action; they may act via central nervous system depression. High-quality

Pharmacologic Treatment of Pediatric Chronic Pain Table 3 Example neuropathic pain care diagram

Evaluaon •History, Physical Exam, Review of labs, imaging, prior findings •Establish diagnosis •Begin educaon process

Treatment •Educaon connues (chronic pain vs. acute) •Cognive Behavioral Therapy (primary treatment based on evidence) •Physical therapy (land-based or aquac; home exercise program; aerobic condioning when possible, TENS) •Medicaon •Integrave Medicine (acupuncture, Yoga, meditaon, maral arts, etc.)

Medicaon opons •First line - Gabapenn, tricyclic andepressant - Lidocaine patch •Second line - Pregabalin, oxcarbazepine; Selecve serotonin and norepinephrine reuptake inhibitor •Third line - Capsaicin, ketamine - Other anconvulsant - Intervenonal therapy (e.g. sympathec chain blockade, epidural)

studies of these agents are lacking. They are often used when non-sedating agents are preferred. 2.1.6 Antihypertensives b-blockers and calcium channel blockers have seen use in migraine headache prophylaxis. Evidence is modest at best, with many trials being small or uncontrolled [93]. Propranolol was found to have efficacy equivalent to amitriptyline [101] and valproic acid [102]; however, study design weaknesses, including lack of placebo control, limit interpretation. 2.1.7 Ketamine Ketamine is a versatile medicine used in many settings. It is a phencyclidine analog and NMDA receptor antagonist acting at multiple sites; it also has l-receptor agonist and local anesthetic properties. As an oral agent, ketamine has found use in a variety of ways. In a pilot study, 12 children with chronic pain were given ketamine 0.25–1.5 mg/kg orally three times per day for 14 days; doses above 1 mg/

kg were not tolerated, five children experienced improvement of pain and two experienced complete resolution lasting greater than 1 month beyond the study period [103]. It has also been used specifically as an analgesic during dressing changes for epidermolysis bullosa [104]. Overall, the role of ketamine in pediatric chronic pain is unclear. 2.1.8 Triptans The triptans are a group of serotonin agonists best known for treatment of migraine and cluster headaches. Migraine symptom relief has been quite positive in adults; pediatric studies have been fraught with significant placebo effect, and superiority of triptans compared with placebo has been difficult to demonstrate [19, 105]. They are nonetheless frequently recommended [20] and prescribed for acute treatment of migraine headaches (see Table 4). 2.1.9 Nutraceuticals A full review of herbal supplements is not possible here. However, peppermint oil in enteric-coated capsules been

E. Mathew et al. Table 4 Example abdominal pain care diagram

Evaluaon •History, Physical Exam, Review of labs, imaging, prior findings •Establish diagnosis •Begin educaon process

Treatment •Educaon connues (chronic pain vs. acute) •Cognive Behavioral Therapy (primary treatment based on evidence) •Medicaon (secondary treatment based on evidence) •Dietary modificaons as indicated •GI intervenons (e.g. fiber, molity agents) as indicated •Integrave Medicine (acupuncture, Yoga, meditaon, etc.)

Medicaon opons •First line - Amitriptyline, nortriptyline - Peppermint oil capsules (if IBS) - Topiramate (if abdominal migraine) - Cyproheptadine (if younger child) •Second line - Gabapenn - Other tricyclic andepressants •Third line - Intravenous lidocaine in combinaon with adjuncts - Oxcarbazepine or other anepilepc - Selecve norepinephrine serotonin reuptake inhibitor

studied for IBS in adolescents and adults. While the literature is mixed, overall there is positive evidence for this low-risk intervention in general [106] and in pediatric patients [107]. The proposed mechanism is a spasmolytic effect in the bowel [108]. Coenzyme Q10 is used for pediatric migraines; an early study [109] showed effect in patients deficient in the substance, whereas as no lasting difference was found in a later study [110] in which patients received a full multidisciplinary treatment protocol. Low magnesium (Mg2?) levels has been shown to be associated with migraine headache in both pediatric and adult populations [111, 112]. Studies of intravenous Mg2? as abortive therapy in adults were not promising [113, 114]. A pediatric study had sample sizes too small to show relationship although minimal side effects are noted [115]. Prophylactic use is modestly supported by small studies of oral Mg2? in children [116, 117] (Table 5). 2.2 Transdermal Delivery Systems 2.2.1 NSAIDs Topical NSAIDs, particularly diclofenac, have been shown to be better than placebo in reducing adult chronic

musculoskeletal pain, although no difference was found between it and oral NSAID use. The topical formulation was associated with a higher incidence of local skin reactions with a lower frequency of gastrointestinal side effects [118]. 2.2.2 Steroids For localized pain related to presumed or known inflammatory processes, applying potent corticosteroids can be helpful. Iontophoresis is a process by which electrical current drives charged medications through the skin to the target area. This modality is well tolerated and is helpful in adults for local musculoskeletal pain such as epicondylitis [119] and has been used in arthritic temporomandibular pain in children [120]. 2.2.3 Local Anesthetics Applying local anesthetics topically allows for targeted delivery and safer administration by avoiding cardiac and central nervous system toxicity. In addition, patches provide barrier protection against the sensitive area of the skin in cases of allodynia. The most commonly applied topical is lidocaine, which has been shown to be effective in the treatment of neuropathic pain disorders such as

Pharmacologic Treatment of Pediatric Chronic Pain Table 5 Example headache pain care diagram

Evaluaon •History, Physical Exam, Review of labs, imaging, prior findings •Establish diagnosis •Begin educaon process

Treatment •Educaon connues •Cognive Behavioral Therapy •Headache lifestyle counseling (sleep, hydraon, caffeine, exercise) •Medicaon (secondary treatment based on evidence) •Injecon therapy (terary treatment, for subtypes of headache) •Integrave Medicine (acupuncture, Yoga, meditaon, etc.)

Medicaon opons •First line prophylaxis - Amitriptyline, nortriptyline - Topiramate - Cyproheptadine (younger children) - Coenzyme Q10 if deficient •Second line prophylaxis - Other tricyclic andepressant, trazodone - Valproic acid, gabapenn, leveracetam - Beta blocker or calcium channel blocker •Third line prophylaxis - Gabapenn or other anepilepc •First line Aborve treatment (along with hydraon) - Ibuprofen or other NSAID •Second line aborve - Triptan - Intranasal butorphanol •Third line aborve (status migrainosus) - Dihydroergotamine - Intravenous valproic acid

postherpetic neuralgia [121]. One small trial found efficacy and minimal systemic absorption in pediatric patients with post-burn neuropathic pain [122]. Although systemic absorption was shown to be very limited in adult trials [123], care should be taken applying these to smaller children.

seen what dosages are required to attain measurable benefit [124]. Until further studies are done, the risks of toxicity in children outweigh the potential benefits from compounded creams containing multiple agents.

2.2.4 Compounded Mixtures

Capsaicin has had mixed results in the treatment of chronic pain in adults. A recent Cochrane review found that lowconcentration capsaicin patches were unlikely to have any benefit [125]. Higher concentration patches (30–90 min of 8 % capsaicin preceded by topical anesthetic for better tolerance, repeated every 12 weeks) were found to be beneficial in the treatment of postherpetic neuralgia and HIV neuropathy, providing relief for up to 12 weeks [126]. Practically, children have difficulty tolerating the initial

Compounded mixtures have grown in popularity recently due to their customizability, allowing for several different medications in varying concentrations to be applied to the skin overlying affected areas. The combination of ketamine and amitriptyline has been shown in adults to be effective in long-term pain score reductions with minimal side effects and systemic absorption. However, it remains to be

2.2.5 Capsaicin

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burning, and use is therefore somewhat limited in pediatric practice. 2.3 Intravenous/Injection 2.3.1 Local Anesthetics Lidocaine is a short-acting amide local anesthetic with a wide array of uses. Its central effects are likely mediated through increases in acetylcholine, muscarinic receptor binding, glycine receptor inhibition, and endogenous opioid release [127]. Comorbidities including cardiac disease and hepatic dysfunction should be carefully considered prior to initiation of intravenous lidocaine therapy. A small retrospective case series of 15 adolescent patients undergoing lidocaine intravenous infusions for chronic pain revealed that the protocol was well tolerated and conferred a modest but statistically significant reduction in pain [128]. A case report of erythromelalgia in a child describes pain refractory to many other treatments responding well to intravenous lidocaine [129]. While used very infrequently compared with adult practice, injection of local anesthetic and often a depotform of steroid has a place in pediatric pain practice. Local anesthetics are injected into trigger points for myofascial pain [130], into the celiac plexus for foregut pathology such as chronic pancreatitis, as occipital nerve blocks for post-concussive headache, and into the lumbar sympathetic chain for lower extremity CRPS. Epidural local anesthetics have been used in children for refractory pain in sickle cell disease [131]. Steroids are often used for acute disc herniation with sciatica. Evidence for all injection therapies in pediatric practice is either modest or extrapolated from adult practice (see Szabova et al. [132, 133], for review). 2.3.2 Dihydroergotamine and Triptans By the mid-20th century, ergot alkaloids and dihydroergotamine were used to treat migraine headache. They were supplanted as the mainstay of abortive therapy by triptans in the 1990s [134]. Two adverse events most limit their use—ergot overuse headaches and ergotism, which is a syndrome of gastrointestinal distress, seizures, and possibly dry gangrene resulting from vasoconstriction. Though no longer the first-line agent of choice in treatment of migraine headache, they remain an option for refractory and severe headaches. 2.3.3 Ketamine Short-term ketamine infusions may play a role in long-term management of chronic pain states including central and peripheral neuropathic pain, phantom limb pain, CRPS,

malignancy pain, and possibly fibromyalgia [135]. Lowdose ketamine infusions had mixed results in a case series of five pediatric patients with sickle cell disease and vasoocclusive pain [35]. Intravenous regional blockade has been used for chronic pain, based largely on anecdotal experience. A small prospective, randomized, doubleblinded crossover trial of adults with CRPS compared intravenous lidocaine regional blockade with varying doses of ketorolac supplementation. No condition provided any analgesia lasting longer than a day, and the evidence did not support intravenous regional blockade for CRPS [136]. A case series of two pediatric patients with CRPS did support use of intravenous regional blockade with lidocaine and ketorolac [137]. 2.4 Intranasal 2.4.1 Butorphanol and Triptans Butorphanol is an opioid agonist-antagonist that has been used intranasally for acute migraine [138]. Though it was initially released as an unscheduled medication in the early 1990s, reports of abuse and dependence arose among headache patients and it was re-released as a schedule IV narcotic. It can be considered a third-line rescue therapy for acute migraine headache. Triptans have been used via a number of routes in the treatment of acute migraine headaches. The intranasal route provides rapid blood levels and relative rapid relief in adults [139, 140], and can be considered for relief of acute migraine episodes in adultsized patients.

3 Discussion There is a large range of medications used in pediatric pain management. Data supporting the use of many of them is sparse. There have been calls for research over the years [4, 141], but progress has been slow. Impediments to studying analgesics in pediatric pain include both ethical and practical matters [30]. Concerns and recommendations of pharmacologic studies in children have been clearly delineated [142]. Informed consent is an issue for pediatric patients, who constitute a vulnerable population. Use of placebos is of concern in some instances, where continued pain might be expected for which there might be a known remedy that is not included in the trial. Adults may consent to take this risk, but the same cannot be expected of children. Chronic pain is relatively common in children [1, 2], but the number of patients with any given diagnosis tends to be small. This small sample size poses challenges for study design. Some have proposed ‘n of 1’ trials, or other less-used trial designs as a way to approach this issue, at

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least in acute pain studies [30]. Outcome domains have been proposed for pediatric chronic pain trials to aid in uniformity of interpretation [143]. Among these, long-term chronic pain trials would also need to assess the effects of medications on the developing nervous system, which is an issue uniquely seen in the pediatric population.

4 Conclusion For the time being, the medications discussed in this review remain among the more commonly used analgesics in the treatment of pediatric chronic pain. There is decent evidence for some medications, and conflicting, negative, or no evidence for the use of other drugs. Extrapolation from adult practice and literature is common, though the evidence in the adult literature is often lacking as well. While extrapolating from adult use is supported for some medications, at least for short-term use [30], use for longer term problems is less clear. Further, classes of medications such as anticonvulsants and antidepressants lack data regarding effects on the nervous system when used for extended periods of time. As evidence is developed to better target pharmacologic treatment of pediatric pain, one must bear in mind that the current evidence supports multidisciplinary treatment in the biopsychosocial model with medications being a component, but not the central feature, of that approach. Conflict of interest E. Mathew, E. Kim and K. R. Goldschneider declare no relevant conflicts of interest. No sources of funding were used to support the writing of this manuscript.

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