Effect of ketorolac in pediatric sickle cell vaso-occlusive pain crisis. High-dose intravenous methylprednisolone therapy for pain in children and adolescents with sickle cell disease. A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain. A family-based randomized controlled trial of pain intervention for adolescents with sickle cell disease. Randomised trial of oral morphine for painful episodes of sickle-cell disease in children. Enhancement of pain control with ketorolac tromethamine in patients with sickle cell vaso-occlusive crisis. The evaluation of analgesic effects in cancer patients as exemplified by a double-blind, crossover study of immediate-release versus controlled-release morphine. Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Comparative efficacy and safety of controlled-release morphine suppositories and tablets in cancer pain.
Ketorolac is a parenteral, nonsteroidal analgesic that does not have a narcotic's risks of respiratory depression, hypotension, or dependence. Its usefulness in providing pain relief in pediatric patients with acute vaso-occlusive crisis of sickle cell disease has not been studied to date.
                Twenty-nine patients with sickle cell disease between the ages of 5 and 18 years who presented to The Children's Hospital of Alabama emergency department (ED) with 41 distinct episodes of acute vaso-occlusive pain crisis were enrolled prospectively and randomized to receive either 0.9 mg/kg intravenous (IV) ketorolac or placebo in a double-blind fashion. All patients also received IV fluids and an initial 0.1 mg/kg of IV morphine. Subsequent standardized doses of morphine were given every 2 hours over a 6-hour observation period based upon severity of pain as scored by a 10-cm linear visual analog scale (VAS). Vital signs and pain severity were recorded initially and assessed hourly. Disposition was made at the end of the observation period.
                Patients receiving ketorolac and those receiving placebo were of similar age, weight, gender, number of prior ED visits, number of prior hospital admissions, duration of pain prior to presentation, and initial pain score. The total dose of morphine received, reduction in severity of pain as measured by VAS, rate of hospital admission, and rate of return to the ED for discharged patients did not differ significantly between the two groups.
                We were unable to demonstrate a synergistic analgesic effect for ketorolac in the treatment of pain from acute vaso-occlusive crisis in pediatric sickle cell disease. Further investigations involving larger samples of sickle cell patients may be needed to further define a role for ketorolac in the acute management of sickle cell vaso-occlusive pain. The management of episodes of severe pain in patients with sickle cell disease is a difficult clinical problem. We studied 36 children and adolescents with sickle cell disease who had 56 acute episodes of severe pain (44 in 27 patients with sickle cell anemia, 8 in 7 patients with sickle cell-hemoglobin C disease, and 4 in 2 patients with sickle cell-beta (+)-thalassemia). The patients were randomly assigned in double-blind fashion to receive an intravenous infusion of either saline placebo or high-dose methylprednisolone (15 mg per kilogram of body weight, to a maximum of 1000 mg) on their admission to the hospital and again 24 hours later. All the patients received intravenous morphine sulfate until severe pain abated and were then given acetaminophen with codeine.
                For all episodes of pain, the duration of inpatient analgesic therapy (intravenous and oral) was significantly shorter for the patients who received methylprednisolone than for those given placebo (mean, 41.3 vs 71.3 hours; P = 0.030). The difference was still significant (31.0 vs. 62.5 hours; P = 0.010) when we excluded seven episodes that were complicated by the chest syndrome (three in the methylprednisolone group and four in the placebo group). The patients who received methylprednisolone had recurrent episodes of pain shortly after the discontinuation of therapy more often than did the patients receiving placebo. No adverse effects of methylprednisolone were observed.
                A short course of high-dose methylprednisolone decreased the duration of severe pain in children and adolescents with sickle cell disease, but patients who received methylprednisolone had more rebound attacks after therapy was discontinued. On balance, corticosteroids are promising as an adjunct to supportive therapy for painful episodes in children and adolescents with sickle cell disease. To examine in a prospective manner the long-term safety and efficacy of chronic intrathecal morphine in patients with severe, nonmalignant pain refractory to less invasive modalities.
                Forty patients with severe, chronic nonmalignant pain poorly managed by systemic medications were identified as candidates for intraspinal trial of morphine. Thirty participants reported successful pain relief during trial and were implanted with an intraspinal delivery system. Standardized measures of pain and functional status were assessed before treatment was begun and at defined intervals during the subsequent 24 months. Intrathecal opioid use and pharmacological and device-related complications were also monitored.
                The participants had a mean age of 58 +/- 13 years and a mean pain duration of 8 +/- 9 years. Fifty-three percent of the study participants were women. Pain type was characterized as mixed neuropathic-nociceptive (15 of 30 patients, 50%), peripheral neuropathic (10 of 30 patients, 33%), deafferentation (4 of 30 patients, 13%), or nociceptive (1 of 30 patients, 3%). Forty-seven percent of the patients were diagnosed with failed back surgery syndrome. Significant improvement over baseline levels of visual analog scale pain was measured at each follow-up examination after implant. Overall, 50% (11 of 22 patients) of the population reported at least a 25% reduction in visual analog scale pain after 24 months of treatment. In addition, the McGill Pain Questionnaire, visual analog scale measures of functional improvement and pain coping, and several subscales of the Chronic Illness Problem Inventory showed improvement throughout the follow-up period. Pharmacological side effects were managed medically by morphine dose reduction, addition of bupivacaine, or replacement of morphine with hydromorphone. Device-related complications requiring repeat operations were experienced by 20% of the patients.
                Continuous intrathecal morphine can be a safe, effective therapy for the management of severe, nonmalignant pain among a carefully selected patient population and can result in long-term improvement in several areas of daily function. The study had 2 aims---to determine the efficacy of a family-based cognitive-behavioral pain management intervention for adolescents with sickle cell disease (SCD) in (1) reducing pain and improving health-related variables and (2) improving psychosocial outcomes. Each adolescent and a family support person were randomly assigned to receive a brief pain intervention (PAIN) (n=27) or a disease education attention control intervention (DISEASE ED) (n=26) delivered at home. Assessment of primary pain and health-related variables (health service use, pain coping, pain-related hindrance of goals) and secondary psychosocial outcomes (disease knowledge, disease self-efficacy, and family communication) occurred at baseline (before randomization), postintervention, and 1-year follow-up. Change on outcomes did not differ significantly by group at either time point. When groups were combined in exploratory analyses, there was evidence of small to medium effects of intervention on health-related and psychosocial variables. Efforts to address barriers to participation and improve feasibility of psychosocial interventions for pediatric SCD are critical to advancing development of effective treatments for pain. Sample size was insufficient to adequately test efficacy, and analyses did not support this focused cognitive-behavioral pain management intervention in this sample of adolescents with SCD. Exploratory analyses suggest that comprehensive interventions, that address a broad range of skills related to disease management and adolescent health concerns, may be more effective in supporting teens during healthcare transition. Oral controlled-release morphine can provide effective analgesia through a non-invasive route and may facilitate outpatient management of severe episodes of sickle-cell pain. We compared the clinical efficacy and safety of oral morphine with continuous intravenous morphine in children with severe episodes of sickle-cell pain, by a double-blind, randomised, parallel-group design.
                56 children aged 5-17 years received loading doses of intravenous morphine of up to 0.15 mg/kg, followed by randomly assigned oral morphine 1.9 mg/kg every 12 h plus intravenous placebo (saline), or intravenous morphine 0.04 mg kg-1 h-1, plus placebo tablet. Breakthrough pain was treated with oral, immediate-release morphine 0.4 mg/kg every 2-3 h as required. Pain was assessed daily at 0900 h, 1300 h, 1700 h, and 2100 h with a picture face scale, a pictorial scale (Oucher), a behavioural-observational scale (CHEOPS), and by an investigator.
                50 children completed the study (28 boys, 22 girls; mean age 11.2 years [SD 3.5]; mean oral morphine dose 2.99 mg/kg daily [0.75]; mean intravenous morphine dose, 0.81 mg/kg daily [0.30]). Mean overall pain scores were similar for oral and intravenous morphine (CHEOPS, 6.3 [1.5] vs 6.4 [1.4], p = 0.8; Oucher, 31.5 [25.4] vs 39.2 [21.7], p = 0.3; Faces, 2.2 [1.4] vs 2.4 [1.3], p = 0.6; clinical rating, 1.7 [0.7] vs 1.9 [0.5], p = 0.3). Opioid analgesia was required for a mean of 4.2 days (1.7) and 5.4 days (2.6), respectively (p = 0.0591). Pain scores from all scales correlated significantly (r = 0.5865-0.8980, p = 0.0001). Frequency of rescue analgesia did not differ significantly between the oral and intravenous morphine groups (0.7 [0.8] vs 0.9 [0.7] doses daily, p = 0.2). Frequency and severity of adverse events did not differ significantly.
                Oral, controlled-release morphine is a reliable, non-invasive alternative to continuous intravenous morphine for the management of painful episodes of sickle-cell disease in children. Twenty one patients with sickle cell disease admitted to the hospital with the pain of vaso-occlusive crisis (VOC) were treated by continuous IV infusion of ketorolac or normal saline for up to 5 days. All patients received supplemental IM injections of meperidine, 100 mg, as necessary, but not more frequently than every 3 hr. Over the 5 days the ketorolac treated patients (KT) required 33% less meperidine than did the placebo treated patients (PL), P = 0.04, and had significantly better pain relief as assessed by categorical, visual analog, and pain relief scales. By the end of 5 days infusions had been discontinued in six KT and one PL. The time to discontinuation of the infusion was significantly shorter in KT, (P = 0.009). The median duration of hospital stay from the start of treatment was 3.3 days for KT and 7.2 days for PL, P = 0.027. Adverse events were mainly related to the digestive system. This study showed that continuous infusion of ketorolac significantly reduced total meperidine requirement and that the analgesia produced by this combination was superior to that produced by meperidine alone. Further evaluation of this drug in the management of sickle cell VOC is warranted. We compared the effects of controlled-release and immediate-release morphine preparations in adult patients with moderate-to-severe cancer pain and report methodologic approaches to pain evaluation. The study consisted of a two-phase randomized crossover trial preceded by a titration phase; all phases were conducted under double-blind conditions. To evaluate pain intensity, a visual analogue scale (VAS) and the Present Pain Intensity scale of the McGill Pain Questionnaire were used. Additional morphine solution for breakthrough pain was used as an outcome measure. Pain was evaluated nine times daily, which permitted correlation of pain scores with the pharmacokinetic patterns of the test drugs. Side effects were rated once daily, using a scale from 0 to 3. To assess the relative importance of side effects, a toxicity index was designed based on both the intensity and duration of each side effect. The overall VAS pain scores during treatment with controlled-release and immediate-release morphine were 1.3 (SD = 0.1) and 1.4 (SD = 0.2), respectively. Use of supplemental morphine solution for breakthrough pain expressed as the percentage of the daily dose of the test drug was 5.5% for the controlled-release drug and 10.9% for the immediate-release drug. Differences in pain scores, side effects, and supplemental morphine requirement between the two groups were not significant. We discuss methodologic issues in double-blind clinical trials of analgesics, in particular the validity of "Patient Preference" as an outcome measure and problems related to the titration phase. A randomized double-blind clinical trial was performed to test the safety and efficacy of a low-molecular-weight heparin, tinzaparin (Innohep), for the management of acute painful vasoocclusive crisis characteristic of sickle cell anemia (SCA). We studied 253 patients with acute painful crisis but with no other complications of SCA, randomized to treatment or control groups. In the treatment group, 127 patients received tinzaparin at 175 IU/kg, subcutaneous once daily, along with supportive care including morphine analgesia; in the control group, 126 patients received placebo and the same supportive care. The maximal experimental treatment period was seven days. Analysis revealed a statistically significant reduction in number of days with the severest pain score, overall duration of painful crisis, and duration of hospitalization (p < 0.05 for each comparison of tinzaparin vs. placebo). The decline in pain intensity was sharper for tinzaparin-treated patients, and complications consisted of two minor bleeding events that were reported and treated by cessation of tinzaparin. This investigation demonstrated that tinzaparin, administered at its approved treatment regimen, reduced the severity and duration of acute crisis of SCA. Although the oral route is the preferred method of opioid therapy in patients with cancer pain, many patients will require an alternate route of analgesic administration at some point during the trajectory of their illness. This study compared the efficacy and safety of a novel, controlled-release suppository of morphine (MSC-R) and controlled-release morphine tablets (MSC-T) in patients with cancer pain. In a double-blind crossover study, 27 patients with cancer pain were randomized to receive MSC-R or MSC-T every 12 hours for 7 days each, using a 1:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Pharmacodynamic assessments were made by the patient at 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM and rescue morphine use recorded in a daily diary. There were no significant differences between MSC-R and MSC-T in overall scores for pain intensity VAS, ordinal pain intensity, and sedation. There was a small but significant difference in overall nausea VAS score in favor of MSC-R. Mean daily rescue analgesic use did not differ significantly during between treatment with MSC-R and MSC-T. MSC-R provides pain control comparable to that provided by MSC-T when given every 12 hours at a 1:1 dose ratio, and represents a reliable alternative method of pain control for patients unable to take oral opioid agents.
There were no studies addressing chronic pain in sickle cell disease. There is limited evidence for analgesic interventions in acute pain crises. Studies have been under-powered. There is not enough data for inter-trial comparisons. In one trial, there was no difference in the efficacy of sustained-release oral versus parenteral morphine, which suggests that oral morphine should be considered for acute pain. Parenteral corticosteroids appear to shorten the period over which analgesics are required and hospital length-of-stay, without producing short-term major adverse effects.More research is needed to improve pain management in sickle cell disease.