This article originally appeared in the ASRA News, Volume 17, Issue 3, pp 13-16 (August 2017).
Floria E. Chae, MD
Section Editor: Andrea Nicol, MD
The International Association for the Study of Pain (ISAP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” The American Pain Society defines chronic pain in children as “the result of dynamic integration of biological processes, psychological factors and social/cultural context considered within a developmental trajectory.” It is important to note that according to these definitions, tissue damage does not need to be present in order for one to experience pain and that there is an affective component to pain.
The most common pediatric chronic pain conditions include headache, functional abdominal pain, and musculoskeletal pain, including back pain.[4-5] Chronic pediatric pain has a negative impact on the child’s activities of daily life, emotional well-being, and health care system. Groenewald et al obtained information from 149 adolescents (ages 10-17) who went for evaluation and treatment at pain clinics across the United States. Parents reported on health service use and productivity losses due to their child’s chronic pain retrospectively over 12 months. The cost on the health care system is estimated to be $19.5 billion annually in the US. The following is a brief overview of selected nonpharmacologic and pharmacologic therapies for the management of chronic pain in a pediatric population.
Therapies outside mainstream medicine have been called by many different terms, such as complementary, alternative, and integrative medicine. The National Center for Complementary and Integrative Health (NCCIH) defines complementary as a non-mainstream practice used together with conventional medicine, while alternative as a non-mainstream practice used in place of conventional medicine. The NCCIH prefers to use the term complementary health approaches as most non-mainstream approaches are used in conjunction with conventional treatments. The term integrative health is used when complementary approaches are incorporated into mainstream health care. 
Most complementary health approaches can be divided into natural products or mind and body practices. Natural products include herbs, vitamins and minerals, and probiotics. Mind and body practices include a large and diverse array of procedures or techniques, such as yoga, meditation, massage therapy, acupuncture, relaxation techniques (breathing exercises, guided imagery, progressive muscle relaxation), tai chi, healing touch, hypnosis, and movement therapies. The goal of mind and body practices is to integrate mind processes with body function and experience in order to promote health. Active distraction techniques, such as imagery, release endorphins, increase activity of descending inhibiting pathways, decrease nociception, and thus modulate pain.
Hypnosis has been used alone and with analgesics in a variety of painful situations such as burns, fractures, recurrent abdominal pain, migraines, and sickle cell disease.  Many studies demonstrate the efficacy of hypnosis in alleviating pain and anxiety during needle-related procedures and reducing chemotherapy related nausea and vomiting. 
Massage therapy has been investigated in children and adults with acute and chronic pain conditions. Studies have shown pain reduction in children with burns,  decreased stress hormones (cortisol and norepinephrine), increased quiet sleep, and increased cytotoxic capacity in children with juvenile rheumatoid arthritis. A Cochrane review on pre-term infants and massage showed improved infant weight gain, improved infant behavior responses, deceased length of hospitalization, improved performance on developmental scales, decreased postnatal complication scores, decreased length of stay, and improved caregiver health and satisfaction.
There are many active areas of research looking at the mechanism of acupuncture. Three main theories are the release of endogenous endorphins, physiologic changes in electrical resistance at acupoints,[20-21] and changes in brain flow and normalization of activity in limbic system. [22-24] Acupuncture can be used to treat headache, abdominal pain, fibromyalgia, juvenile arthritis, complex regional pain syndrome, cancer pain, chemotherapy-related nausea, and perioperative pain. Adams et al reviewed the safety of acupuncture in pediatric population and concluded that acupuncture is safe when preformed by appropriately trained practitioners.
Acetaminophen (APAP) works by inhibiting cyclooxygenase enzymes in the central nervous system (CNS), which leads to an inhibition of prostaglandin synthesis and suppresses central and peripheral neuronal excitability.[27-28] APAP is commonly used for both acute and chronic pain and is generally well-tolerated. Rectal APAP has variable absorption, and may lead to toxicity. Oral and intravenous routes of administration have more predicable uptake. Due to an immature hepatic system, APAP metabolism is decreased in newborns and young children as compared to adolescents and adults.
Aspirin (ASA) was historically commonly used for children but due to concerns of Reyes Syndrome, it is no longer recommended for use, and has been replaced by nonsteroidal anti-inflammatory drugs (NSAIDs) and APAP. Choline magnesium trisalicylate is sometimes used for pediatric cancer patients, as it does not affect bleeding time or platelet aggregation tests.
NSAIDs inhibit cyclooxygenase and decrease prostaglandin production. NSAIDs have analgesic and anti-inflammatory properties that are useful for chronic pain associated with inflammation. Most NSAIDs are nonselective COX-1 (found constitutively in platelets, kidneys, GI tract, and other tissues) and COX-2 (kidneys and CNS) inhibitors. As these agents differ in chemical composition and structure, patients may respond differently to each agent; therefore if a patient does not respond to one, consider trying another agent. There is a ceiling effect, and thus these are often used in conjunction with other classes of medications. NSAIDs are the mainstay of treatment for pain in pediatric rheumatic diseases (such as juvenile idiopathic arthritis). Potential adverse effects, especially with chronic use, include dyspepsia, bleeding, peptic ulcer, platelet inhibition, renal dysfunction, liver damage, bronchospastic NSAID exacerbated respiratory disease, and pseudoporphyria (in chronic use).
Opioids are commonly used analgesics, often in conjunction with non-opioid analgesics, to manage cancer pain and potentially non-cancer pain, such as postoperative pain. Opioids act on mu, kappa, and delta opioid receptors resulting in membrane hyperpolarization and analgesia. The adverse effects of opioids (such as constipation) can be blocked by low-dose naloxone infusions or oral naloxone. The cytochrome P450 system, which metabolizes opioids, does not mature until 3 years of age. Caution should be used in patients with liver or kidney disease, as metabolism and clearance will be delayed, leading to accumulation of the drug. Side effects may include sedation, respiratory depression, pruritus, nausea, and constipation. Opioids are available in immediate- and extended-release formulations. Although there are many types of opioids (such as morphine, hydromorphone, fentanyl, and methadone which can be used for moderate to severe pain), codeine and tramadol deserve further discussion in regards to pediatric pain management.
Codeine is a pro-drug and needs to be converted to morphine by CYP2D6 in order to have an analgesic effect. Due to genetic polymorphisms, about 10% of the population are poor metabolizers, 10% are intermediate metabolizers, 78% are extensive metabolizers, and 2% are ultra-rapid metabolizers. Tramadol, a synthetic opioid with weak mu receptor opioid agonist and norepinephrine/serotonin reuptake inhibitor, is also metabolized by CYP2D6 and thus is subjected to variable metabolism as well.
Koren et al. reported a case where a newborn infant, whose mother was taking codeine 30 mg twice a day, died two weeks after breastfeeding. The mother was an ultra-rapid metabolizer and the morphine concentration in her breast milk was about 8 times higher than normal for someone taking that amount of codeine. On postmortem exam, the infant had 35 times the levels of serum morphine than expected of breastfed infants by mothers receiving codeine. 
In a safety announcement on April 20, 2017, the FDA stated “codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12 yrs” and “breastfeeding is not recommended when taking codeine or tramadol medicines due to the risk of serious adverse reactions in breastfed infants.”
Gabapentin and pregabalin are calcium-channel alpha-2-delta ligands and decrease presynaptic release of pain neurotransmitters glutamine, norepinephrine, and substance P. These agents work best for neuropathic and central pain conditions, such as phantom limb pain, neuropathic cancer pain, peripheral neuropathies, and chronic spinal cord injury. As with most medications, adult studies have been extrapolated to the pediatric population. In an open label study of 30 pediatric patients with cancer pain, use of pregabalin resulted in significant improvement in pain with minimal adverse effects. Side effects of these agents include dizziness, somnolence, ataxia, fatigue, peripheral edema, myalgias, and impaired concentration.
Carbamazepine, a voltage-dependent sodium channel blocker, is effective for neuropathic pain from nerve root injury. Due to less favorable side effect profile and need for hematologic monitoring, this is not often used as a first line treatment. Side effects include aplastic anemia, agranulocytosis, dysrhythmias, sedation, ataxia, slurred speech and hepatitis.
Tricyclic antidepressants (TCA) inhibit the reuptake of serotonin, norepinephrine in the CNS and are used for neuropathic pain. Nortriptyline has less anticholinergic effects than amitriptyline and comes in liquid form. Common side effects include sedation, dry mouth, orthostatic hypotension, constipation, urinary retention, and tachycardia. A baseline EKG should be obtained prior to starting TCAs to rule out arrhythmias and after dose escalation as there is a risk of sudden death due to dysrhythmia. Other antidepressants can be used for neuropathic pain, such as serotonin and norepinephrine reuptake inhibitors (duloxetine and venlafaxine).
N-methyl-D-aspartate (NMDA) receptors play a role in management of hyperalgesia and chronic pain. NMDA receptor blockers include ketamine, methadone, memantine, dextromethorphan, and amantadine. Ketamine is an NMDA receptor blocker, opioid receptor agonist, and a serotonin/norepinephrine reuptake inhibitor. Sub-anesthetic doses can be useful for neuropathic pain and attenuation of opioid induced hyperalgesia.  Other NMDA receptor blockers such as dextromethorphan and memantine have not been commonly used in pediatric and studies thus far are equivocal.[42-44]
Local anesthetics have a membrane stabilizing effect by blocking sodium channels. Lidocaine, a nonselective sodium channel blocker, has been used for surgical pain, cancer pain, and neuropathic pain. [45-46] There are few case reports of use of lidocaine infusion for pediatric neuropathic pain. Massey et al. reported excellent pain relief in a 5-year-oldchild with terminal cancer using lidocaine infusion and Nathan et al. reported significant pain relief and improved function of an 11-year-old child with multiple daily painful episodes due to erythromelalgia after administration of lidocaine infusion and then transitioned to oral mexiletine, an oral analog of lidocaine. 
In summary, chronic pain involves complex interactions of biological, psychological, and social factors. Untreated pain during infancy and childhood leads to hypersensitivity to pain through a “rewiring” of the peripheral as well as central nervous system leading to long changes in pain perception.[49-50] Failure to control pain can have lifelong implications including poor coping strategies.
Pediatric chronic pain management requires a comprehensive, multidisciplinary approach. This includes both non-pharmacologic and pharmacologic treatment as necessary, with a team of pain management physicians, integrative health specialists, child life specialists, physical therapists, psychologists, social workers, and acupuncturists.