Opioid Therapy for the Treatment of Refractory Pain in Children with Juvenile Rheumatoid Arthritis

Mark Connelly; Laura Schanberg


Nat Clin Pract Rheumatol. 2006;2(12):636-637. 

Juvenile rheumatoid arthritis (JRA) is a common chronic childhood disease.[1] Despite its wide prevalence and the recent availability of a range of new treatment options, empirical data informing treatment are limited. This limitation is particularly evident in the management of pain in patients with JRA.

Before the introduction of disease-modifying antirheumatic drugs (DMARDs) and biologic agents for treating chronic arthritis in children, early studies on pain associated with JRA suggested nearly half of those diagnosed with JRA continued to report at least mild pain up to 5 years after disease onset,[2] with a third of patients reporting severe pain as adults.[3] Despite the subsequent widespread use of DMARDs and biologic agents, recent studies have documented that pain remains poorly controlled in many patients with JRA. For example, we have shown that 25% of children receiving standard treatments for polyarticular arthritis still reported pain intensity in the highest ranges of pain measurement scales and 39% of children reported pain on a daily basis.[4]

The pervasiveness of persistent pain in children with arthritis is of particular concern, because it often contributes to poor physical and psychosocial outcomes. Increased daily symptoms of pain predict considerable functional disability, including significantly reduced participation in school, social and physical activities and augmented mood disturbance.[4]

Over the past 20 years there has been a surge of research interest in pediatric pain, resulting in significant treatment advances. Nevertheless, errant beliefs and myths about pediatric pain and its treatment remain, and include negative opinions about the use of opioid analgesics in children. Despite accumulating evidence and published guidelines indicating that opioids, when properly used, are a safe and efficacious means of treating chronic nonmalignant pain,[5] they are only infrequently used for pediatric chronic pain,[6] yet their use has dramatically increased in adults.[7] This infrequent use in children is due in large part to concerns about addiction, side effects, or even legal or regulatory action, rather than being based on empirical data. For example, 77% of pediatric rheumatologists responding to a survey of Children's Arthritis and Rheumatology Research Alliance members agreed that children with chronic arthritis continue to have 'clinically significant pain' despite adequate treatment, yet the majority (60%) disagreed with use of opioid analgesic treatment for these children and adolescents, primarily because of concerns about side effects and addiction.[8]

Concerns about addiction developing as a result of opioid use to treat pain in children are unfounded. The potential for physical dependence is often confused with the term addiction, which is a disorder characterized by the compulsive and chronic use of a substance despite associated physical, psychological, or social harm. Dependence, however, is a common physiologic response that occurs with prolonged use of many medications, including conticosteroids, antihypertensives, and antidepressants. Abrupt cessation of any of these medicines after chronic use is dangerous and the medications must be gradually tapered before discontinuation. There is absolutely no evidence, however, that children or adolescents are at a higher risk for developing an 'addiction' than the general population is when given opioids for the management of pain. On the basis of published information, we estimate that approximately 1 in 30,000 children are at risk for addiction secondary to long-term opioid use if there is no prior history of substance abuse, and less than 4% of children are at risk even if a prior history of abuse is present.[9,10] Moreover, addiction-like behavior develops iatrogenically when pain medications are withheld and adequate pain relief is not achieved.[9]

Concerns about opioid side effects should be viewed in the context of current treatments for JRA. For example, NSAIDs are often standard in the treatment of JRA. Although there is a paucity of research on the safety of NSAIDs in children, recent studies in the adult literature raise serious concerns over potential adverse effects, including increased cardiovascular and renal problems. Long-term use of other 'standard' medications for JRA, including methotrexate and tumor necrosis factor inhibitors, are known to cause serious adverse events, such as hepatic toxicity, possible increased risk of malignancy and increased risk of infection. Corticosteroids are particularly toxic and potential adverse events include irreversible growth impairment, bone loss leading to osteoporosis, mood disturbance, and weight gain with significant changes in body habitus and self image.[2] Such steroid side effects can have a dramatic short-term and long-term impact on the life of a child or adolescent, yet their use is justified by their relative benefits in managing symptoms of the disease. In comparison, potential side effects of chronic opioid use are reversible and short-term, including respiratory depression, sedation, nausea, constipation, and pruritis. Opioid side effects are manageable with proper monitoring, medications, dosage reduction, or opioid rotation. Complications such as respiratory depression can be avoided by starting at a low dose and titrating up, and a pre-emptive bowel regimen, including both a stool softener and stimulant, can prevent constipation. Adequate pain control through opioid use has the potential to improve quality of life, both through the immediate benefits of pain relief and through the long-term benefits of increased activity, increased participation in social activities and improved range of motion promoting improved musculoskeletal health.

Opioid analgesia certainly is not a cure for pain in children and adolescents with arthritis, and requires careful consideration and family education. Used wisely, opioids can form part of a comprehensive pain-management approach which should also include nonpharmacologic strategies, such as training for coping with pain. The management of pain in children with JRA is suboptimal due to unfounded concerns regarding the use of opioids and we recommend that treatment with opioids is considered for children with persistent JRA-related pain who fail 'standard' analgesia. We have used opioids to treat children with JRA primarily in two settings: in the short-term treatment of an acute flare in combination with anti-rheumatic therapy, and in the long-term treatment of refractory disease with persistent chronic pain. For acute pain, we use short-acting opioid preparations containing oxycodone or hydrocodone. For persistent pain, we use long-acting preparations, preferentially methadone, which can be superior to other drugs in its class for chronic use due to its excellent oral bioavailability, prolonged serum concentration, and relatively long duration of effective analgesia. Methadone is also available as a liquid preparation and can be carefully titrated even in small children. A conservative starting dose of 0.1 mg/kg twice daily is recommended, with subsequent slow titration and careful monitoring up to 1 mg/kg three times daily. In children, it is rarely necessary to dose more frequently than every 8-12 h. The benefits of opioid therapy are routinely evident in our patients and are sometimes profound, facilitating school attendance and decreasing physical and social limitations caused by pain. In our practice, chronic opioid therapy has been well-tolerated, there have not been any episodes of drug seeking, and children easily wean off the medication as their clinical condition improves.

More informed treatment of JRA pain is critical to debunking myths concerning opioid use and improving the quality of life of children and adolescents with arthritis. Poorly managed, persistent pain has both immediate and long-term consequences that can permanently disrupt development. Opioid analgesics are an important component of a comprehensive pain-management strategy and, in addition to nonpharmacologic strategies and aggressive treatment of the underlying disease, should be considered part of the symptomatic treatment of acute flares and persistent arthritis pain.

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