There are few potent analgesic medications labeled for pediatric use. Tramadol is an atypical opioid structurally related to codeine whose unique mechanism of action involves both central inhibition of norepinephrine and serotonin reuptake coupled with a weak affinity of tramadol and its O-desmethyl metabolite for μ-opiate receptors (1–4). Since 1995, tramadol has been available in the United States in tablet form for use in adults. Based on worldwide experience in pediatric patients, tramadol has proven to be an effective and safe analgesic for postoperative, dental, and other pain (5–9). Little is known regarding the safety or efficacy of long-term use in children. We undertook this investigation to determine the safety profile of oral tramadol therapy for pain of 7–30 days’ duration in children. Efficacy measures were also assessed.
After obtaining IRB approval, informed parental consent, and patient assent, 7–16-yr-old children who were anticipated to require analgesics for 7–30 days, weighing >20 kg, and able to swallow tablets were enrolled. Children with a history of seizures, alcohol abuse, drug abuse, pregnancy, creatinine clearance <30 mL/min, or the use of CYP2D6 or CYP3A4 inhibitors (except amitriptyline, nortriptyline, and stable doses of selective serotonin reuptake inhibitors) were excluded from participation.
After a baseline medical history and physical examination, blood samples were obtained to determine serum alanine amino transferase, aspartate amino transferase, creatinine, blood urea nitrogen, sodium, potassium levels, hemoglobin, hematocrit, white blood cell count, and platelet count. Tramadol (50-mg scored tablets) 1 mg/kg orally every 4–6 h was started and increased if required (up to a maximum of 2 mg/kg per dose or 100 mg, not to exceed the lesser of 8 mg · kg−1 · d−1 or 400 mg/d). Parents recorded tramadol use on a diary card. Patients rated pain by using the Wong-Baker faces pain scale before, and 1 h after, dosing with tramadol, and recorded their scores on the diary card (10). Supplemental analgesics were permitted and prescribed at the discretion of the investigator if tramadol was inadequate to control pain.
Study compliance and adverse events (AEs) were assessed by telephone on day 3 and during a clinic visit on day 8. For patients continuing tramadol beyond 7 days, study compliance and AEs were assessed again by telephone on day 16 and during a final clinic visit after discontinuing tramadol therapy (no later than day 30 of therapy). During the final site visit, a physical examination and all laboratory evaluations were repeated, and the parents’ and the investigators’ overall assessment of drug efficacy was evaluated by using a 5-point scale (5-point scale: 1 = poor, 2 = fair, 3 = good, 4 = very good, and 5 = excellent). A final telephone interview was performed 2–4 days after the final site visit to assess AEs.
The sample size was based on evaluation of safety, and the trial was designed to ensure that at least 75 participants who completed 7 days of therapy and 8 participants who completed at least 14 days of therapy were enrolled. Efficacy was assessed by: the pain intensity difference calculated on days 1–8 (baseline pain score minus score 1 h postdosing); percentages of patients with less pain, no change, or more pain compared with baseline on days 1–8; percentages of subjects requiring supplemental analgesics; the total daily dose adjusted by body weight; and the parents’ and investigators’ overall assessment of tramadol as an analgesic. Safety and tolerability were assessed by summarizing all AEs by body system and by expressing all laboratory results and vital signs as change from baseline.
Safety and efficacy were evaluable in 113 of 114 patients enrolled. One subject was lost to follow-up. Twenty-three subjects withdrew before 7 days of therapy because of: resolution of pain (n = 11), AEs (n = 8), and patient choice (n = 4). Patient characteristics are provided in Table 1.
The average dose and mean duration of tramadol therapy were 3.0 ± 1.7 mg · kg−1 · d−1 and 11.2 ± 7.5 days, respectively. A total of 90, 28, and 9 patients completed 7, 14, and 30 days of tramadol therapy, respectively. Subjects completing 7 days of therapy discontinued tramadol because: an analgesic was no longer required (n = 60), completion of 29 days of therapy (n = 11), lack of efficacy (n = 6), subject or investigator choice (n = 6), AEs (n = 4), and subject required less potent analgesic (acetaminophen or ibuprofen, n = 3).
The mean Wong-Baker faces pain score before tramadol therapy on the first day of the study was 3.0 ± 1.3. However, almost all subjects were taking another analgesic medication at the time of enrollment and, therefore, this score does not represent the true baseline level of pain. On days 1–8, pain diminished 1 h after tramadol in 64%–78% of subjects (Table 2). The mean pain intensity difference by day ranged between 1.0 ± 1.1 to 1.4 ± 1.3 (Table 2). On at least one occasion during the study, 48% of subjects required supplemental analgesics. Tramadol was rated very good or excellent by 69% of parents and by 70% of investigators. The weighted κ of 0.658 (95% CI, 0.557–0.759) indicated good observer agreement among the parents/legal guardians and investigators.
There were no clinically important changes in vital signs. Changes in all serum chemistry and hematology variables were small and clinically insignificant. AEs were reported by 75 (66%) subjects and were similar regardless of length of therapy (Table 3). All AEs related to tramadol were rated as mild to moderate in severity. Only 12 subjects discontinued tramadol because of an AE.
The scarcity of approved potent analgesics labeled for children contributes to the under-treatment of pain in this age group. We have shown that tramadol was well tolerated by 7–16-year-old children with a variety of painful conditions for 7–30 days’ duration. AEs were generally considered to be mild or moderate in severity by investigators. The AE profile and, in particular, the incidence of nausea and vomiting observed, is similar to that reported in adult trials (11). Although the AE profile of tramadol is similar to that of other opioid analgesics, several reports indicate that respiratory depression is less severe with tramadol compared with other opiates (12–14). This may represent a significant advantage of tramadol in the treatment of pediatric pain.
In a previous companion trial, evidence for a dose response with tramadol in the treatment of pediatric postsurgical pain was established (15). A majority of subjects in the present study reported a reduction in pain within one hour of dosing, even though tramadol’s peak effect is not achieved until between two and three hours. The investigators decided that the pain assessment at one hour before the anticipated peak effect was necessary to accommodate the schedules of school-age children. The efficacy and safety of tramadol observed in this trial must be considered preliminary given the limitations of the open-label study design, the measures of efficacy used in this study, and absence of a comparator. Randomized, controlled trials are required to further clarify the analgesic efficacy and relative safety of tramadol compared with current alternatives and to explore the possible additive or synergistic effects of combination therapy with acetaminophen or nonsteroidal antiinflammatory drugs. In the meantime, the accumulating data about tramadol provide children with an important therapeutic option for treatment of pain.
Study concept and design: Medve, Schreiner, Lynn Schultz (RWJPRI); advisory board: Schmitz M, Finkel J, Walson P, Himelstein B, Rose J; acquisition of data, Tramadol-Peds-008 investigators: Rose J, Children’s Hospital of Philadelphia; Finkel J, Children’s National Medical Center, Washington, DC; Arguedas-Mohs A, Instituto Costarriccense De Investigaciones Costa Rica; Himelstein B, Children’s Hospital of Philadelphia; Jove M, Atlanta Knee and Sports Medicine; Goldsmith S, Clinical Studies Ltd., Florida; Thusu K, Lexington Biomedical Research, California; Luber S, Personal Practice, Washington; Rodarte A, Children’s Hospital of San Diego; Walson P, Columbus Children’s Hospital; Ostroc B, Hershey Medical Center; Nimityongkol P, University of South Alabama; McKinney R, Duke Children’s Hospital and Health Center; D’Sylva Y, Integrated Research Group, California; Mohyi L, Children’s Hospital of Orange County; Schmitz M, AR Children’s Hospital; Goldblatt E, Riverchase Clinical Research, Alabama; Perkins A, University of South Alabama; Bruce R, Emory University; Spencer C, Lutheran General Children’s Hospital; Malviya S, University of Michigan Health System; Simpser E, St. Mary’s Hospital for Children, New York; Phillips A, Health Advance, Medical Research Centers, Texas; Khalil S, University of Texas, Houston Health Science Center; Guinan E, Dana Farber Cancer Institute, Boston Children’s Hospital; and Leonard K, Hospital for Joint Diseases Orthopedic Institute, New York; drafting of the manuscript: Rose J; critical revision of the manuscript: Finkel, Schreiner, Rose, Himelstein; statistical expertise: Julia Wang (RWJPRI); administrative support: Meryl Polu (CCRI), Alice Poch (RWJPRI), Cheryl Impellizzeri (PAREXEL); study supervision: Schreiner, Medve.
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