Vol. 19 No. 1(Suppl.) January 2000 Journal of Pain and Symptom Management S37 Proceedings Supplement NMDA-Receptor Antagonists: Evolving Role in Analgesia MorphiDex (MS:DM) Double-Blind, Multiple-Dose Studies In Chronic Pain Patients Nathaniel P. Katz, MD Brigham & Women s Hospital, Pain and Management Center, Boston, MA, USA Abstract Preclinical and double-blind single-dose placebo-controlled studies demonstrated that MorphiDex (MS:DM), a 1:1 ratio of morphine sulfate (MS) to dextromethorphan hydrobromide (DM), provides significantly greater analgesia than an equal dose of immediate release MS, with a faster onset, and a duration of 8 h. The analgesic effect of MS:DM compared to MS was evaluated in 2 double-blind, multiple-dose studies in 321 patients with cancer and other chronic pain: a crossover study that consisted of two 2-wk periods and a 4-wk parallel study. As specified in the study protocols, patients took sufficient MS or MS:DM to achieve satisfactory pain control. In the crossover study, the MS:DM group required half as much morphine as the MS group to achieve satisfactory pain control (80 mg and 162 mg, respectively). The interval between doses and the time from the last dose of the day to the first dose of the next day were significantly longer for MS:DM compared to MS. In the parallel study, MS:DM also provided pain control at a significantly lower dose. After four weeks of treatment, the mean daily dose of MS increased, while there was little change in the MS:DM mean daily dose (P 0.025) to maintain satisfactory pain control. More patients preferred MS:DM to run-in MS than preferred MS to run-in MS (P 0.026). The addition of DM to MS did not increase the incidence of adverse events, which were those commonly associated with opioid use. These studies confirm that MS:DM provides satisfactory pain relief but at a significantly lower morphine daily dose. J Pain Symptom Manage 2000;19:S37 S41. U.S. Cancer Pain Relief Committee, 2000. Key Words Morphine sulfate, dextromethorphan hydrobromide, MorphiDex, opioids, chronic pain, analgesia, allodynia, pain relief Address reprint requests to: Nathaniel P. Katz, MD, Brigham & Women s Hospital, Pain and Management Center, 75 Francis Street, Boston, MA 02115, USA. Accepted for publication: September 17, 1999. Introduction In preclinical and clinical single-dose studies, MorphiDex (MS:DM), a 1:1 ratio of morphine sulfate (MS) to dextromethorphan hydrobromide (DM), enhanced the analgesic properties of immediate-release MS. The enhancement of analgesia with MS:DM is due to a pharmacodynamic interaction between the two components rather than a pharmacokinetic interaction between MS and DM or their metabolites. Single-dose, placebo-controlled studies in postsurgical oral surgery and postsurgical orthopedic pain patients clearly demonstrate the significant enhancement of the anal- U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(99)00129-3
S38 Katz Vol. 19 No. 1(Suppl.) January 2000 Fig. 1. Mean percentage of days patients experienced satisfactory pain relief during the crossover study. The shaded bar represents the MS:DM group; the open bar represents the MS group. Overall, there was no statistical difference in pain relief between the MS:DM group and MS group at any time point. gesic properties of MS by DM versus an equal dose of MS. 1 Two multiple-dose clinical studies evaluated whether DM enhances the analgesic properties of MS in patients with chronic pain due to cancer or other conditions including muscoskeletal pain, back pain, and neuropathic pain. Mean daily doses and the interval between doses required to achieve satisfactory pain control with MS and MS:DM were compared. Patients were enrolled in one of two doubleblind, randomized, multicenter studies: a crossover study that consisted of two 2-wk periods and a 4-wk parallel study. In both studies, patients were instructed to take sufficient study medication to maintain satisfactory pain control. These studies confirm results of singledose studies that demonstrate that MS:DM provides satisfactory pain relief at a significantly lower morphine daily dose. Crossover Study A double-blind, crossover study compared the analgesic effect of MS:DM and MS by determining the dose of morphine required on a daily basis to achieve satisfactory pain control. Key efficacy parameters were the milligram amounts of morphine used daily, the average time interval between doses, the time from the last dose of the day to first dose of the next day, and patient satisfaction with pain control. This study consisted of two 2-wk double-blind periods. Prior to the double-blind study, the patient received open-label immediate-release MS (30-mg tablets) during a 3- to 7-day run-in period to establish their morphine daily dose needed to maintain satisfactory pain control. Following the open-label morphine run-in period, patients were randomized to one of two double-blind groups that received either MS:DM 15:15-mg or MS 30-mg capsules, identical in appearance. Patients were instructed to titrate the dose of study medication up or down to achieve satisfactory pain control. At the end of 2 weeks, patients rated their pain control, and then crossed over to receive the other study medication, with no washout period. At the end of the second 2-wk period, patients again assessed their pain control. The study population consisted of 89 patients (46 men and 43 women) with moderate to severe chronic pain. Approximately 17% of these patients had pain due to cancer; the remaining 83% had pain due to other causes. The mean age of the patients was 49 yr (range 24 79 yr). During both 2-wk treatment periods, mean pain scores at dosing and the percent of days that patients were satisfied with their pain control were similar between treatments as shown in Fig. 1. The mean number of capsules taken Table 1 Daily Dose and Average Time Interval Between Doses During the Double-Blind Crossover Study MS:DM MS P-value Daily dose of MS (mg) 80.3 30.9 161.5 53.3 0.0001 Number of doses per day 3.58 1.08 3.73 1.06 0.04 Number of capsules per day 5.35 2.06 5.38 1.78 NS Range 1.29 10.33 1.85 8.70 Mean time (h) between doses 6.99 3.6 6.42 2.2 0.05 Mean Time (h) since last dose of day to first dose of next day 9.83 4.6 8.90 3.2 0.01 The above values reflect the mean the standard error of the mean. The range is included for the average number of capsules per day.
Vol. 19 No. 1(Suppl.) January 2000 MorphiDex in Chronic Pain Patients S39 Fig. 2. Average increase or decrease in morphine daily dose used to achieve satisfactory pain control over the initial 2 wk of the crossover study. The decrease from baseline in the MS:DM group was significant (P 0.001). The increase from baseline in the MS group was significant (P 0.007). The MS:DM group and the MS group were significantly different from each other (P 0.001). per day also was similar between groups. A clinically and statistically significant finding was the difference in average daily MS dose: 80 mg in the MS:DM group compared to 162 mg in the MS group (P 0.0001). The range in number of capsules per day was large, suggesting that patients titrated the amount of study drug to achieve satisfactory pain control. Also, the mean number of doses per day was 3.58 for the MS:DM group versus 3.73 for the MS group, a small but statistically significant difference (P 0.04). MS:DM provided a longer duration of effect as indicated by the mean time interval between doses for the two groups (P 0.05). The time of the last dose of the day to the time of the first dose of the next day also was longer (P 0.01) for patients taking MS:DM (9.83 h compared with 8.90 h for MS), suggesting that MS:DM patients may have had the opportunity for longer periods of sleep. These data are presented in Table 1. A post-hoc analysis compared the two groups during the first parallel study period. This intent-to-treat analysis, which included all 89 patients enrolled, compared the change from baseline (run-in morphine dose) to the mean daily dose during the first 2-wk period. In the MS:DM group, the dose decreased significantly (approximately 50 mg, P 0.001) over the 2 wk. In the MS group, the dose increased significantly (approximately 20 mg, P 0.007). These changes from baseline, as well as the difference between groups, were statistically significant (P 0.001), as shown in Fig. 2. In summary, MS:DM provided the analgesic equivalent of twice the amount of morphine given alone. MS:DM provided a longer duration of effect compared to MS, as indicated by a longer interval between doses and a longer Fig. 3. Mean percentage of days patients experienced satisfactory pain relief during the run-in phase and during week 1, week 2, week 3, and week 4 of the parallel study. Shaded bars represent the MS:DM group; open bars represent the MS group. Overall, there was no statistical difference between the MS:DM group and the MS group at any time point.
S40 Katz Vol. 19 No. 1(Suppl.) January 2000 interval between the last dose of the day and the first dose of the next day. Parallel Study A double-blind, parallel study compared the analgesic effect of MS:DM and MS by determining the dose of morphine required daily to achieve satisfactory pain control. Key efficacy parameters were milligrams of daily morphine (for MS:DM and MS) required to maintain satisfactory pain control, and the global comparison of the double-blind medication to run-in morphine. The safety of MS:DM compared to MS alone was also evaluated. This study consisted of a 4-wk double-blind treatment period. Eligible patients required 90 mg of morphine daily. This requirement was confirmed in a 3- to 7-day run-in period with immediate-release MS (30-mg tablets). During this period, patients were titrated to satisfactory pain control (i.e., one or two capsules every 4 to 8 h as required) to determine their morphine daily dose. Following the morphine run-in period, patients were randomized to one of two treatment groups: MS or MS:DM. Study drugs were either MS 30 mg or MS:DM 30:30 mg provided as identically appearing capsules. Subjects were instructed to titrate their dose up or down as required each day to achieve satisfactory pain control. Safety parameters assessed during the study were adverse events, vital signs, physical examinations, clinical laboratory evaluations, and electrocardiographic recordings. The study population consisted of 232 patients (122 men and 110 women). Of these patients, 185 fulfilled all criteria for efficacy evaluation. Approximately 25% of these patients had pain due to cancer and the remaining 75% had pain due to other causes. The mean age of the patients was 52 yr, ranging between 24 and 94 yr. During the run-in period and throughout the 4-wk study period, both the MS:DM and MS treatment groups achieved satisfactory pain control (78% and 80% of days with satisfactory pain relief for MS:DM and MS, respectively), as shown in Fig. 3. To maintain satisfactory pain control over the 4-wk study period, the mean daily dose of morphine in the MS:DM group was significantly lower than that of the MS group at week 4 (193 vs. 217 mg, respectively, P 0.044). At Week 4, the change in the morphine daily dose from the run-in period increased by 16 mg in the MS group and 1.6 mg in the MS:DM group as shown in Fig. 4. After Week 4, patients rated their doubleblind medication as better, no different, or worse than their run-in medication (MS). These data are presented in Table 2. More patients preferred MS:DM to run-in MS than preferred MS to run-in MS (P 0.026). In conclusion, MS:DM patients achieved equivalent pain control at a significantly lower morphine dose compared to MS patients. MS patients increased their mean daily dose from run-in significantly more than MS:DM patients to maintain satisfactory pain control. More patients preferred treatment with MS:DM com- Table 2 Global Rating of Double-Blind Medication Versus Run-In Medication (MS 30 mg) During the Parallel Study Comparative Rating MS:DM (N 83) MS (N 91) Double-blind better than run-in MS 46 (55.4%) 39 (42.9%)* Double-blind no different than run-in MS 23 (27.7%) 39 (42.9%)* Double-blind worse than run-in MS 14 (16.9%) 13 (14.3%)* *P 0.026, calculated using Fisher s exact test, for the distribution of scores across the three categories. Fig. 4. Mean daily morphine dose (mg) during the run-in period (open bars) and after 4 wk (shaded bars) in patients randomized to receive MS or MS: DM. The change from the run-in period to the end of the 4-wk period measured at 16 mg in the MS group versus 1.6 mg in the MS:DM group, and was significantly different (P 0.025).
Vol. 19 No. 1(Suppl.) January 2000 MorphiDex in Chronic Pain Patients S41 Table 3 Pooled Adverse Event Incidence for MS:DM and MS from Double-Blind Studies* Treatment MS:DM (N 161) MS (N 160) Adverse Event n % n % Constipation 12 7.5 29 18.1 Nausea 28 17.4 20 12.5 Headache 9 5.6 16 10 Vomiting 19 11.8 14 8.8 Somnolence 18 11.2 14 8.8 Asthenia 10 6.2 13 8.1 Pruritus 7 4.3 11 6.9 Dizziness 19 11.8 7 4.4 Confusion 10 6.2 5 3.1 * From the parallel group (N 232 patients) and from the first period of the crossover study (N 89 patients). Of the 321 patients, 70% of the patients came from the parallel study. The symbols n and % reflect the number and percent of patients reporting one or more incidents. There were no statistically significant differences between treatments. The addition of DM to MS did not increase the incidence of adverse events. pared to run-in MS than preferred treatment with MS compared to run-in MS. Safety A potential safety issue was whether or not the addition of DM to MS would increase the incidence of adverse events. To answer this question, safety data from the first two weeks of the crossover study and from the 4-week parallel study were pooled. These data are presented in Table 3. There were no statistically significant differences between treatments. Hence, the addition of DM did not increase the incidence of adverse effects of MS:DM over MS alone. There were no clinically important differences in vital signs, physical examinations, laboratory values, or electrocardiographic measurements between the MS:DM and MS treatment groups. Summary In two double-blind, multiple-dose studies, patients achieved satisfactory pain control with significantly less daily morphine during treatment with MS:DM compared to MS. To maintain satisfactory pain control over 4 weeks, patients in the MS group increased their daily dose while patients in the MS:DM group did not increase their dose. This suggests that MS:DM may have reduced tolerance compared to MS alone. Finally, more patients preferred MS:DM than preferred MS over their run-in treatment with MS. Reference 1. Caruso FS. MorphiDex pharmacokinetic studies and single-dose efficacy analgesic studies in patients with postoperative pain. J Pain Symptom Manage 2000; 17 (suppl): S31 S36.