Addressing challenges of clinical trials in acute pain: The Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study.

BACKGROUND/AIMS: Neuropathic pain is a known component of vaso-occlusive pain in sickle cell disease; however, drugs targeting neuropathic pain have not been studied in this population. Trials of acute pain are complicated by the need to obtain consent, to randomize participants expeditiously while optimally treating pain. We describe the challenges in designing and implementing the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study (NCT01954927), a phase II, randomized, double-blind, placebo-controlled trial to determine the effect of gabapentin for vaso-occlusive crisis. METHODS: In the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study, we aim to assess the analgesic effect of gabapentin during vaso-occlusive crisis. Difficulties we identified included avoiding delay of notification of study staff of potential participants which we resolved by automated notification. Concern for rapid randomization and drug dispensation was addressed through careful planning with an investigational pharmacy and a single liquid formulation. We considered obtaining consent during well-visits to avoid the time constraints with acute presentations, but the large number of patients and limited duration that consent is valid made this impractical. RESULTS: In all, 79% of caregivers/children approached have agreed to participate. The trial is currently active, and enrollment is at 45.8% of that targeted (76 of 166) and expected to continue for two more years. Maintaining staff availability after-hours remains problematic, with 8% of screened patients missed for lack of available staff. LESSONS LEARNED: Lessons learned in designing a trial to expedite procedures in the acute pain setting include (1) building study evaluations upon a standard-of-care backbone; (2) implementing a simple study design to facilitate consent and data capture; (3) assuring ample, well-trained study staff; and (4) utilizing technology to automate procedures whenever possible. CONCLUSION: This study design has circumvented many of the logistical barriers usually associated with acute pain trials and may serve as a prototype for future studies.

Comparison of pain outcomes between two anti-GD2 antibodies in patients with neuroblastoma.

BACKGROUND: Addition of anti-GD2 antibody ch14.18 to the treatment of neuroblastoma has improved outcomes. The most common side effect of ch14.18 is neuropathic pain, which may in part be complement-mediated. Hu14.18K322A is a humanized anti-GD2 antibody designed to diminish complement activation and induce less pain. We compare the pain outcomes in patients treated with ch14.18 and those treated with hu14.18K322A, and explore dose-dependent relationships between pain scores, opioid requirements, and complement levels in patients treated with hu14.18K322A. PROCEDURE: Opioid (morphine equivalent mg/kg) and anxiolytic requirements during course 1 (4 days) in patients treated with hu14.18K322A and ch14.18 were reviewed. Correlations between antibody dose and pain scores, opioid requirements, and complement levels were examined for patients receiving hu14.18K322A. RESULTS: Patients treated with hu14.18K322A (n = 19) had lower opioid requirements than those who received ch14.18 (n = 9). The differences in median opioid requirements (mg/kg) were statistically significant for the overall course (1.57 vs. 2.41, P = 0.019) as well as for Days 3 (0.34 vs. 0.65, P = 0.005), and 4 (0.32 vs. 0.64, P = 0.010). No difference in anxiolytic use was observed between the two groups. In the group treated with hu14.18K322A, we found a positive correlation between antibody dose administered and pain scores, but no correlation between antibody dose and opioid requirements or changes in complement levels. CONCLUSIONS: In this retrospective analysis, hu14.18K322A induced less pain than ch14.18 based on opioid requirements. Pediatr Blood Cancer 2015;62:224-228. © 2014 Wiley Periodicals, Inc.

The Safety and Effectiveness of Patient-controlled Analgesia in Outpatient Children and Young Adults With Cancer: A Retrospective Study.

BACKGROUND: Patient-controlled analgesia (PCA) is safe and effective in hospitalized children; however, data regarding its use for outpatients are limited. The aims of the study are to determine the safety of outpatient PCA and to compare the standard and proxy PCA groups. METHODS: All patients receiving outpatient PCA over 54 months were included in this retrospective study. Data regarding age, sex, diagnosis, PCA initiation/discontinuation circumstances, patient versus proxy-authorized PCA type, opioid doses, pain scores, and complications were collected. Nonparametric tests (Wilcoxon-Mann-Whitney test for comparing 2 groups or Kruskal-Wallis rank-sum test for comparing >2 groups) were used to compare duration of PCA use, opioid doses, pain scores, and circumstances of initiation and discontinuation of outpatient PCA. RESULTS: Forty-five patients used 69 outpatient PCAs. The complication rate was 0.36%. The starting mean MED (mg/kg/d) was 1.67 when initiation was for an outpatient and 4.04 for those discharged from the hospital with PCA; this difference was not statistically significant (P=0.13). The analysis of mean opioid doses in relationship to the circumstances for the discontinuation of the outpatient PCA revealed a significantly higher dose (mg/kg/d) in the group of patients who died (19.54) than in the group with a change of status to inpatient or transfer to another hospital or hospice (3.70) and in the group in which PCA was discontinued because pain management no longer required a PCA (1.19). The mean opioid daily doses and pain scores were significantly higher at the end of life (P<0.0001). CONCLUSIONS: Outpatient PCA use for children and young adults with cancer is safe.

Opioid misuse behaviors in adolescents and young adults in a hematology/oncology setting.

OBJECTIVE: To describe the occurrence and psychosocial correlates of aberrant opioid-associated behavior (AOB) in adolescent and young adult (AYA) hematology and oncology patients prescribed opioid therapy. METHODS: Structured retrospective chart reviews were conducted for AYA patients (N = 398) accepted for active treatment at a large pediatric hematology/oncology institution over a 17-month period. Opioid therapy was documented in the records of 94 out of the 398 patients. The records of those 94 patients were further reviewed to identify documented AOB and documented correlates of AOB. RESULTS: Of the 94 patients prescribed opioid therapy, 11.7% exhibited AOB. At least one psychosocial risk factor was identified in 90.9% of patients with AOB. Concurrent use of multiple opioids was significantly associated with AOB (p = .003). CONCLUSIONS: Hematology/oncology AYA patients may exhibit AOB despite a legitimate clinical indication for opioid therapy. Clinicians should consider young patients' psychosocial risk factors when using opioid therapy.

Neuropathic pain referrals to a multidisciplinary pediatric cancer pain service.

Neuropathic pain (NP) in children with cancer is not well characterized. In a retrospective review of patient data from a 3.5-year period, we describe the prevalence of NP and the characteristics, duration of follow-up, and interventions provided for NP among patients referred to a pediatric oncology center's pain management service. Fifteen percent (66/439) of all referrals to our pain service were for NP (56/323 patients [17%]; 34 male, 22 female). The NP patient group had 1,401 clinical visits (778 inpatient visits [55.5%] and 623 outpatient visits [44.5%]). Patients with NP had a significantly greater mean number of pain visits per consultation (p = .008) and significantly more days of pain service follow-up (p < .001) than did other patients. The most common cause of NP was cancer treatment rather than the underlying malignancy. Pharmacologic management of NP was complex, often comprising three medications. Nonpharmacologic approaches were used for 57.6% of NP referrals. Neuropathic pain is less frequently encountered than non-NP in children with cancer; nevertheless, it is more difficult to treat, requiring longer follow-up, more clinical visits, complex pharmacologic management, and the frequent addition of nonpharmacologic interventions.

Prospective randomized crossover evaluation of three anesthetic regimens for painful procedures in children with cancer.

OBJECTIVE: To identify the most effective sedation regimen for bone marrow aspiration and lumbar puncture procedures with a prospective trial of 3 combinations of sedation/analgesia. STUDY DESIGN: In this double-blind crossover study, we randomly assigned 162 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to receive fentanyl 1 mcg/kg, fentanyl 0.5 mcg/kg, or placebo, in addition to propofol and topical anesthetic for 355 procedures. RESULTS: We found no significant differences among the 3 regimens in the frequency of pain (pain score > 0) or severe pain (pain score ≥ 5) during recovery, or a >20% increase in hemodynamic/respiratory variables during anesthesia. Treatment with fentanyl 1 mcg/kg was associated with a lower frequency of movement during procedure compared with treatment with fentanyl 0.5 mcg/kg (P = .0476) or treatment with placebo (P = .0545). The placebo group required longer time to recover (median, 18 minutes) compared with the fentanyl 0.5 mcg/kg group (median, 9 minutes) (median difference 2.0, P = .007) and the fentanyl 1 mcg/kg (median 8 minutes), (median difference 2.0, P = .15). The placebo group also required larger total dose of propofol (median 5 mg/kg) compared with that of the fentanyl 1 mcg/kg group (median, 3.5 mg/kg) and the fentanyl 0.5 mcg/kg group (median 3.5 mg/kg) (median differences 1.5, P < .00005, in both comparisons). CONCLUSION: The addition of fentanyl 1 mcg/kg to propofol for brief painful procedures reduces movement, propofol dose, and recovery time.

Opioid misuse and abuse: risk assessment and management in patients with cancer pain.

The FDA's 2012 risk evaluation and mitigation strategy is a major step toward systematically reducing the inherent risks of chronic opioid therapy for pain, but does not distinguish between risks related to sources of pain. This article discusses the effect of risk mitigation in the treatment of cancer pain, with a focus on pretreatment screening and ongoing monitoring in this patient population that often requires pain management at some time during cancer treatment. Experience with screening, risk stratification, and interventions at one cancer center is shared, along with some recommendations for practice. A new screening checklist is proposed that summarizes known risk factors. Patients with cancer are not protected from the problems of opioid abuse/misuse, and the multidisciplinary cancer treatment team should coordinate an evaluation of risk and the monitoring of aberrant behaviors as part of the comprehensive care plan.

Parent-controlled PCA for pain management in pediatric oncology: is it safe?

Patient-controlled analgesia offers safe and effective pain control for children who can self-administer medication. Some children may not be candidates for patient-controlled analgesia (PCA) unless a proxy can administer doses. The safety of proxy-administered PCA has been studied, but the safety of parent-administered PCA in children with cancer has not been reported. In this study, we compare the rate of complications in PCA by parent proxy versus PCA by clinician (nurse) proxy and self-administered PCA. Our pediatric institution's quality improvement database was reviewed for adverse events associated with PCA from 2004 through 2010. Each PCA day was categorized according to patient or proxy authorization. Data from 6151 PCA observation days were included; 61.3% of these days were standard PCA, 23.5% were parent-proxy PCA, and 15.2% were clinician-proxy PCA days. The mean duration of PCA use was 12.1 days, and the mean patient age was 12.3 years. The mean patient age was lower in the clinician-proxy (9.4 y) and parent-proxy (5.1 y) groups, respectively. The complication rate was lowest in the parent-proxy group (0.62%). We found that proxy administration of PCA by authorized parents is as safe as clinician administered and standard PCA at our pediatric institution.

Risk of catheter-associated infection in young hematology/oncology patients receiving long-term peripheral nerve blocks.

BACKGROUND: Continuous peripheral nerve blocks (CPNBs) are increasingly used to control postoperative and chronic pain. At our pediatric oncology institution, the duration of CPNBs is often prolonged. The risk of catheter-associated infection with prolonged CPNBs has not been previously investigated. AIM: We analyzed the incidence of CPNB-related infection and its relation to catheter duration, catheter site, intensive care stay, and antibiotic coverage. METHODS: All CPNBs placed at our institution between August 1, 2005 and October 31, 2010 were studied. Primary diagnosis and the site, indication, duration, and infectious adverse effects of CPNBs were obtained from our Pain Service QI database. Patients' age and sex, antibiotic administration, and number of days in intensive care were collected from patients' medical records. RESULTS: The use of 179 catheters in 116 patients was evaluated. Mean age at CPNB placement was 15.1 years (median, 14.7; range, 0.4-26.9). The most frequent indication for CPNB was surgery (89.4%), most commonly orthopedic (78.8%). Mean CPNB duration was 7.2 days (median, 5.0; range, 1-81 days). Two cases (1.12%) of CPNBs developed signs of infection, both associated with femoral catheters. The infections were mild and necessitated catheter removal at days 10 and 13, respectively. CONCLUSION: Nerve block catheter-associated infections are infrequent at our institution despite prolonged CPNB use. Both patients with infection had femoral catheters and prolonged catheter (≥ 10 days) use.

Neuropathic pain during treatment for childhood acute lymphoblastic leukemia.

BACKGROUND: Improved cure rates for childhood acute lymphoblastic leukemia (ALL) over the past 2 decades have allowed greater attention to patients' quality of life. Neuropathic pain (NP) is an unpleasant side effect of chemotherapeutic agents for leukemia, especially vincristine. PROCEDURE: We retrospectively reviewed the records of 498 patients treated on a single protocol for ALL to investigate the risk factors, the incidence, and the use of therapeutic and prophylactic gabapentin treatment for NP. RESULTS: White non-Hispanic race was the only patient variable predictive of NP. One hundred and seventy-four of 498 patients (34.9%) experienced 207 episodes of NP; 16% (28 of 174) patients experienced at least one recurrence of pain after the initial episode. No statistical significance was found in the relation between the severity (grade) of the NP episode and the cumulative dose of vincristine (P = 0.45) or the vincristine dose that immediately preceded the diagnosis (1.5 mg/m(2) versus 2.0 mg/m(2) [correction made here after initial online publication], P = 0.59). Of 180 episodes with treatment data, 62.2% (112) and 37.8% (68) were treated with gabapentin or opioids, respectively. The selection of treatment with gabapentin or opioids was not influenced by the pain intensity score at the time of diagnosis of NP (P = 0.91). The mean gabapentin dose used for 112 episodes was 15.5 mg/kg/day (SD 7.9). We found no evidence that gabapentin prevented recurrence of NP. CONCLUSIONS: Our results highlight the need for prospective randomized studies to elucidate the value of gabapentin regimen for prevention or treatment of vincristine-related pain during treatment of childhood leukemia.

Use of epidural and peripheral nerve blocks at the end of life in children and young adults with cancer: the collaboration between a pain service and a palliative care service.

BACKGROUND: Clinicians may avoid continuous pain blocks in pediatric cancer patients at the end of life for fear of complications or of interfering with the desired location of death. OBJECTIVES: To examine the impact of epidural or peripheral nerve catheters on pain control in children and young adults with cancer within the last 3 months of life. METHODS: We retrospectively reviewed the medical records to assess pain scores, systemic opioid requirements, and impact on death at the preferred location. RESULTS: Ten patients (4.4-21.3 years of age), nine with solid tumors, one with lymphoma, had 14 devices (11 epidural, 3 peripheral nerve catheters) for a range of 3-81 days. Twelve of 13 catheters provided improvement by at least one of three criteria: improved mean pain scores at 24 h (8 of 13) and decreased opioid requirement at 24 h in nine cases and at day 5 in nine cases. Eight patients died in their preferred setting. Six patients had catheters (five epidural, one peripheral) until death, including two who died at home. In some cases, typical contraindications for indwelling catheters (spinal metastasis, vertebral fracture, thrombocytopenia, fever) were superseded by palliative care needs. We found no bleeding, infectious, or neurological complications. CONCLUSIONS: Our findings suggest that continuous catheter-delivered pain blockade at the end of life contributes to analgesia, moderates opioid requirements, and usually does not preclude death at the preferred location.

Methadone prolongs cardiac conduction in young patients with cancer-related pain.

OBJECTIVE: Methadone prolongs cardiac conduction, from mild corrected QT (QTc) prolongation to torsades de pointes and ventricular fibrillation, in adults. However, methadone use for pain and its effects on cardiac conduction have not been investigated in pediatric populations. METHODS: A retrospective review of QTc intervals in patients receiving methadone analgesia was conducted. Medical records from a 4-year period (September 2006 to October 2010) at a pediatric oncology institution were reviewed, and correlations were tested between cardiac conduction and methadone dosage and duration of therapy, electrolyte levels, renal and hepatic dysfunction, and concurrent medications. RESULTS: Of the 61 patients who received methadone, 37 met our inclusion criteria and underwent 137 electrocardiograms (ECGs). During methadone treatment, the mean QTc was longer than that at baseline (446.5 vs 437.55 ms). The mean methadone dose was 27.0±24.3 mg/d (range, 5-125 mg/d; median, 20 mg/d) or 0.47±0.45 mg/kg per day (range, 0.05-2.25 mg/kg per day; median, 0.37 mg/kg per day), and the mean duration of therapy was 49 days. The authors identified a correlation between automated and manual ECG readings by two cardiologists (Pearson r=0.649; p<0.0001), but the authors found no correlations between methadone dose or duration and concurrent QTc-prolonging medications, sex, age, electrolyte abnormalities, or renal or hepatic dysfunction. CONCLUSION: At a clinically effective analgesic dose, methadone dosage and duration were not correlated with QTc prolongation, even in the presence of other risk factors, suggesting that methadone use may be safe in pediatric populations. The correlation between automated and manual ECG readings suggests that automated ECG readings are reliable for monitoring cardiac conductivity during the reported methadone-dosage regimens.

Pediatric palliative sedation therapy with propofol: recommendations based on experience in children with terminal cancer.

BACKGROUND: The use of propofol for palliative sedation of children is not well documented. OBJECTIVE: Here we describe our experience with the use of propofol palliative sedation therapy (PST) to alleviate intractable end-of-life suffering in three pediatric oncology patients, and propose an algorithm for the selection of such candidates for PST. PATIENTS AND METHODS: We identified inpatients who had received propofol PST within 20 days of death at our institution between 2003 and 2010. Their medical records were reviewed for indicators of pain, suffering, and sedation from 48 hours before PST to the time of death. We also tabulated consumption of opioids and other symptom management medications, pain scores, and adverse events of propofol, and reviewed clinical notes for descriptors of suffering and/or palliation. RESULTS: Three of 192 (1.6%) inpatients (aged 6-15 years) received propofol PST at the end of life. Consumption of opioids and other supportive medications decreased during PST in two cases. In the third case, pain scores remained high and sedation was the only effective comfort measure. Clinical notes suggested improved comfort and rest in all patients. Propofol infusions were continued until the time of death. CONCLUSIONS: Our experience demonstrates that propofol PST is a useful palliative option for pediatric patients experiencing intractable suffering at the end of life. We describe an algorithm that can be used to identify such children who are candidates for PST.

Methadone use in children and young adults at a cancer center: a retrospective study.

OBJECTIVE: To augment the literature on methadone applications in pediatric oncology, the authors reviewed the use of methadone at a pediatric cancer center over a 5-year period. DESIGN AND SETTING: Forty-one patients received methadone for inpatient or outpatient pain management. The authors retrospectively reviewed their demographic characteristics, diagnoses, type of pain (nociceptive, neuropathic, or mixed) and causes of pain, and the indications, dose regimens, adverse effects, and outcomes of methadone treatment. RESULTS: There were four types of clinical uses for methadone in 41 patients (10 patients had two): nociceptive pain unresponsive to other opioids (17 patients, 33.3 percent), neuropathic pain (20 patients, 39.2 percent), facilitation of weaning from opioids (11 patients, 21.6 percent), and end-of-life pain management (3 patients, 5.9 percent). The mean age of the 24 males (58.5 percent) and 17 females (41.5 percent) at the start of treatment was 15.7 years (range, 0.6-23 years). The most common diagnoses were leukemia (n = 10, 24.4 percent), osteosarcoma (n = 7, 17.0 percent), and rhabdomyosarcoma (n = 5, 12.2 percent). The causes of pain were bone marrow transplant (n = 13, 31.7 percent), amputation (n = 6, 14.6 percent), chemotherapy (n = 5, 12.2 percent), tumor (n = 5, 12.2 percent), limb-sparing surgery (n = 4, 9.8 percent), and other (n = 8, 19.5 percent). Efficacy was assessed at the end (or after 6 months) of methadone treatment. For many patients (43.1 percent), methadone showed efficacy in achieving the purpose for which it was prescribed, including reduction of nociceptive or neuropathic pain and prevention of opioid withdrawal. Sedation was the most common side effect (24.4 percent). CONCLUSIONS: Methadone was effective for pediatric patients with neuropathic pain or nociceptive pain unresponsive to other opioids, and it effectively prevented opioid withdrawal.