This study enrolled adult patients (≥ 20 years of old) with cancer pain (numeric rating scale [NRS] ≥ 4) and sleep disturbance (NRS ≥ 4). Subjects have been administered with strong oral opioid analgesic for the purpose of cancer pain management. Exclusion criteria included evidence of cardiovascular, renal, hepatic, psychiatric, gastrointestinal disease or structural abnormalities, intolerance or hypersensitivity to hydromorphone, pregnancy, breastfeeding, and administration of monoamine oxidase inhibitor. The institutional review boards of the participating institutions approved this protocol, and written informed consents were obtained from all participants before entry into the study.

This study was conducted at 6 university hospitals in Korea, from September 2008 to February 2010. All hospitals had approval from their respective institutional review board. The primary objective is to evaluate the efficacy of HM-OROS in the treatment of sleep disturbance associated with cancer pain. This study consisted of 3 phases. The first phase was the screening phase (1 week) to evaluate the eligibility of potential subjects. The second phase (2 weeks) was to evaluate the efficacy and safety, and the third phase (12 weeks) involved extended follow-up for safety. Starting the first day of the second phase, participants took an equianalgesic dose of HM-OROS for two weeks. The dose of HM-OROS was determined based on the total dose of previous opioids that were administered on the last day of the screening phase [20]. If the dose of the previously administered opioids was appropriate (the number of short-acting opioid analgesic administrations for breakthrough pain treatment ≤ 3), the initial dose of the study drug was determined by an equivalent conversion ratio. If the dose of the previously administered long-acting oral opioids was not appropriate (the number of short-acting opioid analgesic administration for breakthrough pain treatment > 4), the higher dose of the study drug was set at the initial dose. When the dose of HM-OROS was ≤ 32 mg, we increased the first dose of HM-OROS by 8 mg, and if the dose was > 32 mg, we increased by 16 mg. We continuously adjusted the dose of the study drug every two days from day 3 of the second phase. We surveyed each subject’s pain intensity and short-acting opioid use for breakthrough pain. Sleep disturbance was evaluated at day 1 of the second phase and on the last day of the second phase. Pain was measured with the K-BPI, which consists of six parts: 1) presence of pain; 2) site of pain; 3) four-item pain score for the worst, least, and average pain during the previous 24 hours and at last evaluation; 4) type of pain medication; 5) percentage of pain relieved during the previous 24 hours; and 6) sevenitem associated symptom score, composed of interference with general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life [19]. To evaluate the preference to HM-OROS over that of the previous opioids, we conducted a preference questionnaire, including the reason for preference after the second phase. We also performed a clinical global impression-improvement survey of patients and physicians. Patients who completed phase 2 and suffered from continuing cancer pain were enrolled in the extension phase. Before the performance of any extension phase activity, the subjects were fully informed regarding this extension study and signed the written consent. During this extension phase, safety information, including adverse events, was collected.

The minimum sample size was 107, and the number of subjects in consideration of 20% of expected withdrawal rate was 134. This sample size provided approximately 80% power to detect a difference between HM-OROS and previous opioid for the primary efficacy analysis and a 2.5% type 1 error rate. Demographic information was collected from 190 patients who provided informed consent at the initial visit (Fig. 1). Safety assessment was evaluated from 120 patients who received the study drug at least once. Efficacy was assessed from 74 patients who completed the second phase (per protocol [PP] set), and 82 other patients (intentto-treat [ITT] set). In the ITT set, we included patients who took the study drug at least once, but excluded 38 patients who did not have major required variables or who committed serious protocol violations. Change from the baseline in pain score and sleep disturbance was tested using a paired t-test. The same analyses were also conducted for the subgroup of patients who maintained the same dose of the study drug during the study period. The proportion of sleep disturbance improvement and 95% confidence interval (CI) was calculated. To analyze the data for the secondary objectives of the study, Pearson’s chi-square test and multiple comparisons were conducted. The SAS program ver. 9.1 (SAS Institute Inc., Cary, NC) was used for all statistical analyses and the level of significance was 5%.

The baseline characteristics of the patient population are shown in Table 1. A total of 190 patients were enrolled in the study. However, only 120 patients received at least one dose of HM-OROS; of these 120, 74 completed the final assessment. Fig. 1 is a flow diagram of patient entry and completion, including the reasons of dropouts. The mean age was 56 years (standard deviation [SD], 11.2) and 129 (67.9%) of the patients were male (Table 1). All patients were diagnosed with cancer. The common primary diagnoses were colorectal (11%), lung (9.5%), pancreas (9%), stomach (8%), and breast (7%). The majority of these patients were stage IV (81.1%). The most common Eastern Cooperative Oncology Group performance statuses were 1 (68.9%) and 2 (24.3%). Seventyfive percent of patients had a history of previous treatment, including 121 cases of chemotherapy (63.7%), 30 cases of radiotherapy (15.8%), and 29 cases of surgical treatment (15.3%).

The ITT set was used as a primary population. At the second visit, we rotated previous opioids to HM-OROS at an equianalgesic dose (Fig. 1). The initial mean dose of HM-OROS was 22.6 mg (SD, 18.9; range 8 to 80 mg). At the third visit (endpoint of phase 2), the mean dose of HM-OROS was 30.2 mg (SD, 27; range, 8 to 112 mg). Forty patients (54.1%) maintained the same dose, while 19 patients (25.7%) needed dose escalation and 15 (20.3%) needed dose reduction. HM-OROS reduced the average pain score from 5.3 to 4.1 (p < 0.01), worst pain score from 6.7 to 5.4 (p < 0.01), sleep disturbance score from 5.9 to 4.1 (p < 0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p < 0.001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p=0.001). Table 2 shows the results for three questions regarding sleep disturbance. All three items improved during HM-OROS treatment. The mean proportion of improvement of sleep disturbance was 34.9% (95% CI, 27.4% to 41.9%), and 58.5% of the 82 (ITT) patients responded with greater than 30% improvement (Table 3). The result of K-BPI showed that pain, mood, walking ability, normal work, and sleep improved during the HM-OROS treatment (Table 4). In total, 57% of patients and 54% of physicians reported that HM-OROS was effective in global assessment (Table 5). The results from PP set were similar.

A total of 120 patients receiving HM-OROS were included in the safety analysis. Most of the adverse events were classified as either mild or moderate in intensity and were transitory. The most common adverse events were somnolence, asthenia, constipation, dizziness, and nausea (Table 6).

Only 2 cases (1 constipation, 1 dizziness) were severe, but were manageable. The constipation case was associated with the underlying disease (colon cancer) and the dizziness case was considered to be related to the study drug. None of the deaths was considered related to the study medication.

Of the patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous opioid. The reasons for this preference were as follows: decrease in medication frequency (53%), decrease in sleep disturbance (32%), and decrease in immediate release opioid use (13%).