Roland van der Hoop - Academia.edu (original) (raw)

Papers by Roland van der Hoop

Clinical Neuropharmacology, 1990

Menopause, 1997

The objective of this study is to compare the frequency and duration of vaginal bleeding in postm... more The objective of this study is to compare the frequency and duration of vaginal bleeding in postmenopausal women randomized to receive unopposed esterified estrogens (ESE) in a dose of 0.3 mg, 0.625 mg, 1.25 mg, or placebo. A two-year randomized, double-blind, placebo-controlled, multicenter study was conducted in 269 non-hysterectomized postmenopausal women who recorded bleeding incidence and severity on diary cards. Amenorrhea occurred in 61% of women receiving placebo and 59%, 51%, and 24% of women treated with 0.3, 0.625, and 1.25 mg ESE, respectively. Combining spotting with amenorrhea, these numbers increased to 88%, 88%, 75%, and 61%, respectively. Onset of menopause greater than 1 year before study entry was associated with less bleeding than onset within 1 year (53% vs. 31%). Treatment with 0.3 mg ESE, a dose that is effective in preventing osteoporosis, did not result in a higher incidence of vaginal bleeding or endometrial hyperplasia than treatment with placebo over a 2-year period. Studies longer than 2 years will be needed to confirm that the beneficial effects on bone can occur without any detrimental endometrial effects.

New England Journal of Medicine, 2014

BACKGROUND Progesterone has been associated with robust positive effects in animal models of trau... more BACKGROUND Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial. METHODS We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury. RESULTS Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.

Toxicology and Applied Pharmacology, 1991

Toxicology and Applied Pharmacology, 1989

The in situ binding ofthe anticancer drug cis-diamminedichloroplatinum(I1) (cisDDP) to DNA was st... more The in situ binding ofthe anticancer drug cis-diamminedichloroplatinum(I1) (cisDDP) to DNA was studied in the rat dorsal root spinal ganglion (DRG), using an antiserum against cisDDP-modified calf thymus DNA in a quantitative immunocytochemical assay. Rats received a dose of cisDDP (I mg/kg), two times a week, up to a cumulative dose of I5 mg/kg (group I) or 34 mg/kg (group II). Rats of group III were given a single dose of 15 mg/kg. Rats were killed 48 hr (groups I and II) or 6 hr (group III) after the last injection. In groups I and II cisDDP-induced neurological damage was assessed by measuring both motor and sensory nerve conduction velocities (MNCV and SNCV). Whereas the MNCV was not influenced by the treatment with cisDDP, the SNCV decreased significantly. The level of cis-DDP-DNA binding in DRG satellite cells equalled that in liver cells, but binding could not be shown in DRG neuron nuclei. The level of cisDDP-DNA binding in spinal cord and brain was very low. The neuroprotecting peptide ORG.2766, an ACTH4.9 analog, was given SC (10 pg/rat) four times a week concomitantly with cisDDP to some rats of groups I and II. ORG.2766 prevented the decrease of the SNCV, but did not change the extent of cisDDP-DNA binding in satellite or liver cells. It is concluded that the amelioration of cisDDP toxicity by ORG.2766 is not directly related to the cisDDP-DNA binding in satellite cells. Q 1989 Academic PWS. ~nc.

Therapeutic Drug Monitoring, 2001

In two multicenter phase III efficacy studies, blood samples were obtained to evaluate the serum ... more In two multicenter phase III efficacy studies, blood samples were obtained to evaluate the serum concentrations of 17␤-estradiol (E2) and unconjugated estrone (E1) after administration of a percutaneous gel or transdermal patch containing estradiol. In postmenopausal women, normal laboratory E2 and E1 serum concentrations range from 10-30 pg/mL and 20-40 pg/mL, respectively. Study subjects were healthy postmenopausal women with moderate to severe hot flushes occurring at least seven times daily or 60 times per week. Study 1 was a randomized, double-blind, multicenter study of percutaneous E2 gel 1.25 or 2.5 g (0.75 and 1.5 mg E2, respectively) versus placebo gel. Study 2 was a double-blind (blinded to E2 gel dose), randomized, active-controlled, multicenter, 12-week phase 3 study of E2 gel 0.625, 1.25, or 2.5 g (0.375, 0.75, or 1.5 mg E2, respectively) versus a transdermal E2 patch delivering 0.05 mg E2 per day. Serum E2 and E1 concentrations were evaluated at baseline and at week 12 for study 1 and at baseline and weeks 4, 8, and 12 for study 2 using radioimmunoassay. Median serum concentrations of E2 after 1.25-and 2.5-g gel administration appeared to be dose-proportional throughout both studies. In study 1, the median serum concentrations of E2 at week 12 were 33.5 and 65.0 pg/mL for 1.25-and 2.5-g gel dose, respectively. The corresponding E1 values were 49.0 and 58.0 pg/mL. In study 2, both E2 and E1 concentrations were relatively stable at weeks 4, 8, and 12. E2 values at week 12 for 0.625-, 1.25-, and 2.5-g gel doses and E2 patch were 25.0, 32.0, 60.0, and 38.5 pg/mL, respectively. The corresponding E1 values were 39.0, 41.0, 62.5, and 40.0 pg/mL. Application of the 1.25-g gel dose and a transdermal patch delivering 50 g per day of E2 resulted in comparable median E2 and E1 concentrations. However, the 0.625-g gel dose did not produce E2 levels in a range expected to be consistently therapeutic in most postmenopausal women.

Journal of Clinical Psychopharmacology, 2004

Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Journal of Affective Disorders, 1995

Changes in depressed outpatients' experience of daily activities after 6 weeks of antidepressant ... more Changes in depressed outpatients' experience of daily activities after 6 weeks of antidepressant treatment were assessed with the experience sampling method (ESM). On the sickness impact profile, treatment responders (HAM-D I 7, n = 12) improved more than nonresponders (n = 9) in the domains of household chores, leisure and social activities. On ESM measures completed 10 X each day for 6 days pre-and posttreatment, responders showed greater increases in time spent in chores and greater decreases in passive leisure time than nonresponders. Responders showed greater increases in positive affect and greater decreases in negative affect during all activities. Thus, ESM provides quantitative evidence of changes in real life time use and subjective experience accompanying clinical improvement.

International Journal of Gynecology & Obstetrics, 1990

Fertility and Sterility, 2003

In some women, a decline in sexual interest accompanies a relative androgen insufficiency after m... more In some women, a decline in sexual interest accompanies a relative androgen insufficiency after menopause. We sought to characterize the hormonal effects of the combination of oral esterified estrogens and methyltestosterone and to investigate whether this regimen improves hypoactive sexual desire. Design: Double-blind randomized trial. Setting: Healthy volunteers in a multicenter research environment. Patient(s): Postmenopausal women taking estrogen therapy who were experiencing hypoactive sexual desire. Intervention(s): 4 months of treatment with 0.625 mg of esterified estrogens (n ϭ 111) or the combination of 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone (n ϭ 107). Main Outcome Measure(s): Baseline and end-of-study measurements of total and bioavailable testosterone and sex hormone-binding globulin (SHBG), and mean change in level of sexual interest or desire as rated on the Sexual Interest Questionnaire. Result(s): Treatment with the combination of esterified estrogens and methyltestosterone significantly increased the concentration of bioavailable testosterone and suppressed SHBG. Scores measuring sexual interest or desire and frequency of desire increased from baseline with combination treatment and were significantly greater than those achieved with esterified estrogens alone. Treatment with the combination was well tolerated. Conclusion(s): Increased circulating levels of unbound testosterone and suppression of SHBG provide a plausible hormonal explanation for the significantly improved sexual functioning in women receiving the combination of esterified estrogen and methyltestosterone.

European Journal of Pharmacology, 1990

Org 2766 is one of a series of melanocortins (ACTH and related peptides) that exert trophic influ... more Org 2766 is one of a series of melanocortins (ACTH and related peptides) that exert trophic influences on the central and peripheral nervous system of the rat. We used acrylamide neuropathy in rats as an experimental model of peripheral neuropathies of the dying-back type in order to assess the potential therapeutic efficacy of Org 2766 in this type of nerve damage. The peptide reversed the delayed persistent deficit in sensory conduction velocity without preventing the initial loss of motor coordination. The recovery of apparently normal coordination was unaffected by the peptide, but resistance to a second toxic challenge suggested that recovery was more complete in the peptide-treated rats. The finding that Org 2766 improved the quality of the repair following acrylamide neuropathy, together with previous studies showing beneficial effects in neuropathies caused by cisplatin or diabetes and after mechanical trauma, strongly suggests that Org 2766 may be beneficial in the treatment of various conditions in which the nervous system has sustained damage.

Diabetes, 1989

An injection of streptozocin (STZ) was used to study diabetes-induced peripheral neuropathy in ra... more An injection of streptozocin (STZ) was used to study diabetes-induced peripheral neuropathy in rats. In such rats the values of motor nerve conduction velocity and sensory nerve conduction velocity were decreased compared with the values obtained in nondiabetic controls from 3 wk after STZ injection onward. In recent years it has been extensively documented that peptides related to ACTH and MSH exert a neurotrophic effect on the nervous system that results in enhanced recovery of function after mechanical nerve damage. This article documents the beneficial effect of the peptide Org 2766, an ACTH-(4-9) analogue, in diabetic peripheral neuropathy. Chronic subcutaneous treatment of diabetic rats with Org 2766 results in a significant enhancement of both motor and sensory nerve conduction velocity compared with saline-treated diabetic rats. Histological analysis of cross sections of the sural nerve showed no difference in the total number of nerve fibers in saline-or peptide-treated diabetic rats. In contrast, a difference in fiber size distribution was demonstrated; i.e., the sural nerves of diabetic rats contained fewer thick myelinated fibers. Treatment with Org 2766 resulted in a normal distribution. Apparently, the peptide Org 2766 has a protective action on nerve fibers and nerve function during STZ-induced diabetes.

Current Medical Research and Opinion, 2006

Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naiv... more Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP). Patients > or = 18 years of age were titrated with oxymorphone ER (5- to 10-mg increments every 12 h, every 3-7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12 h for 12 weeks. Oxymorphone immediate release was available every 4-6 h, as needed, for the first 4 days and twice daily thereafter. Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4 mm at screening to 22.7 mm (p < 0.0001). After randomization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 +/- 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 +/- 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group. Stabilized doses of oxymorphone ER were generally safe and effective over a 12-week double-blind treatment period in opioid-naive patients with CLBP.

Clinical Neuropharmacology, 1990

Menopause, 1997

The objective of this study is to compare the frequency and duration of vaginal bleeding in postm... more The objective of this study is to compare the frequency and duration of vaginal bleeding in postmenopausal women randomized to receive unopposed esterified estrogens (ESE) in a dose of 0.3 mg, 0.625 mg, 1.25 mg, or placebo. A two-year randomized, double-blind, placebo-controlled, multicenter study was conducted in 269 non-hysterectomized postmenopausal women who recorded bleeding incidence and severity on diary cards. Amenorrhea occurred in 61% of women receiving placebo and 59%, 51%, and 24% of women treated with 0.3, 0.625, and 1.25 mg ESE, respectively. Combining spotting with amenorrhea, these numbers increased to 88%, 88%, 75%, and 61%, respectively. Onset of menopause greater than 1 year before study entry was associated with less bleeding than onset within 1 year (53% vs. 31%). Treatment with 0.3 mg ESE, a dose that is effective in preventing osteoporosis, did not result in a higher incidence of vaginal bleeding or endometrial hyperplasia than treatment with placebo over a 2-year period. Studies longer than 2 years will be needed to confirm that the beneficial effects on bone can occur without any detrimental endometrial effects.

New England Journal of Medicine, 2014

BACKGROUND Progesterone has been associated with robust positive effects in animal models of trau... more BACKGROUND Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial. METHODS We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury. RESULTS Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.

Toxicology and Applied Pharmacology, 1991

Toxicology and Applied Pharmacology, 1989

The in situ binding ofthe anticancer drug cis-diamminedichloroplatinum(I1) (cisDDP) to DNA was st... more The in situ binding ofthe anticancer drug cis-diamminedichloroplatinum(I1) (cisDDP) to DNA was studied in the rat dorsal root spinal ganglion (DRG), using an antiserum against cisDDP-modified calf thymus DNA in a quantitative immunocytochemical assay. Rats received a dose of cisDDP (I mg/kg), two times a week, up to a cumulative dose of I5 mg/kg (group I) or 34 mg/kg (group II). Rats of group III were given a single dose of 15 mg/kg. Rats were killed 48 hr (groups I and II) or 6 hr (group III) after the last injection. In groups I and II cisDDP-induced neurological damage was assessed by measuring both motor and sensory nerve conduction velocities (MNCV and SNCV). Whereas the MNCV was not influenced by the treatment with cisDDP, the SNCV decreased significantly. The level of cis-DDP-DNA binding in DRG satellite cells equalled that in liver cells, but binding could not be shown in DRG neuron nuclei. The level of cisDDP-DNA binding in spinal cord and brain was very low. The neuroprotecting peptide ORG.2766, an ACTH4.9 analog, was given SC (10 pg/rat) four times a week concomitantly with cisDDP to some rats of groups I and II. ORG.2766 prevented the decrease of the SNCV, but did not change the extent of cisDDP-DNA binding in satellite or liver cells. It is concluded that the amelioration of cisDDP toxicity by ORG.2766 is not directly related to the cisDDP-DNA binding in satellite cells. Q 1989 Academic PWS. ~nc.

Therapeutic Drug Monitoring, 2001

In two multicenter phase III efficacy studies, blood samples were obtained to evaluate the serum ... more In two multicenter phase III efficacy studies, blood samples were obtained to evaluate the serum concentrations of 17␤-estradiol (E2) and unconjugated estrone (E1) after administration of a percutaneous gel or transdermal patch containing estradiol. In postmenopausal women, normal laboratory E2 and E1 serum concentrations range from 10-30 pg/mL and 20-40 pg/mL, respectively. Study subjects were healthy postmenopausal women with moderate to severe hot flushes occurring at least seven times daily or 60 times per week. Study 1 was a randomized, double-blind, multicenter study of percutaneous E2 gel 1.25 or 2.5 g (0.75 and 1.5 mg E2, respectively) versus placebo gel. Study 2 was a double-blind (blinded to E2 gel dose), randomized, active-controlled, multicenter, 12-week phase 3 study of E2 gel 0.625, 1.25, or 2.5 g (0.375, 0.75, or 1.5 mg E2, respectively) versus a transdermal E2 patch delivering 0.05 mg E2 per day. Serum E2 and E1 concentrations were evaluated at baseline and at week 12 for study 1 and at baseline and weeks 4, 8, and 12 for study 2 using radioimmunoassay. Median serum concentrations of E2 after 1.25-and 2.5-g gel administration appeared to be dose-proportional throughout both studies. In study 1, the median serum concentrations of E2 at week 12 were 33.5 and 65.0 pg/mL for 1.25-and 2.5-g gel dose, respectively. The corresponding E1 values were 49.0 and 58.0 pg/mL. In study 2, both E2 and E1 concentrations were relatively stable at weeks 4, 8, and 12. E2 values at week 12 for 0.625-, 1.25-, and 2.5-g gel doses and E2 patch were 25.0, 32.0, 60.0, and 38.5 pg/mL, respectively. The corresponding E1 values were 39.0, 41.0, 62.5, and 40.0 pg/mL. Application of the 1.25-g gel dose and a transdermal patch delivering 50 g per day of E2 resulted in comparable median E2 and E1 concentrations. However, the 0.625-g gel dose did not produce E2 levels in a range expected to be consistently therapeutic in most postmenopausal women.

Journal of Clinical Psychopharmacology, 2004

Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Journal of Affective Disorders, 1995

Changes in depressed outpatients' experience of daily activities after 6 weeks of antidepressant ... more Changes in depressed outpatients' experience of daily activities after 6 weeks of antidepressant treatment were assessed with the experience sampling method (ESM). On the sickness impact profile, treatment responders (HAM-D I 7, n = 12) improved more than nonresponders (n = 9) in the domains of household chores, leisure and social activities. On ESM measures completed 10 X each day for 6 days pre-and posttreatment, responders showed greater increases in time spent in chores and greater decreases in passive leisure time than nonresponders. Responders showed greater increases in positive affect and greater decreases in negative affect during all activities. Thus, ESM provides quantitative evidence of changes in real life time use and subjective experience accompanying clinical improvement.

International Journal of Gynecology & Obstetrics, 1990

Fertility and Sterility, 2003

In some women, a decline in sexual interest accompanies a relative androgen insufficiency after m... more In some women, a decline in sexual interest accompanies a relative androgen insufficiency after menopause. We sought to characterize the hormonal effects of the combination of oral esterified estrogens and methyltestosterone and to investigate whether this regimen improves hypoactive sexual desire. Design: Double-blind randomized trial. Setting: Healthy volunteers in a multicenter research environment. Patient(s): Postmenopausal women taking estrogen therapy who were experiencing hypoactive sexual desire. Intervention(s): 4 months of treatment with 0.625 mg of esterified estrogens (n ϭ 111) or the combination of 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone (n ϭ 107). Main Outcome Measure(s): Baseline and end-of-study measurements of total and bioavailable testosterone and sex hormone-binding globulin (SHBG), and mean change in level of sexual interest or desire as rated on the Sexual Interest Questionnaire. Result(s): Treatment with the combination of esterified estrogens and methyltestosterone significantly increased the concentration of bioavailable testosterone and suppressed SHBG. Scores measuring sexual interest or desire and frequency of desire increased from baseline with combination treatment and were significantly greater than those achieved with esterified estrogens alone. Treatment with the combination was well tolerated. Conclusion(s): Increased circulating levels of unbound testosterone and suppression of SHBG provide a plausible hormonal explanation for the significantly improved sexual functioning in women receiving the combination of esterified estrogen and methyltestosterone.

European Journal of Pharmacology, 1990

Org 2766 is one of a series of melanocortins (ACTH and related peptides) that exert trophic influ... more Org 2766 is one of a series of melanocortins (ACTH and related peptides) that exert trophic influences on the central and peripheral nervous system of the rat. We used acrylamide neuropathy in rats as an experimental model of peripheral neuropathies of the dying-back type in order to assess the potential therapeutic efficacy of Org 2766 in this type of nerve damage. The peptide reversed the delayed persistent deficit in sensory conduction velocity without preventing the initial loss of motor coordination. The recovery of apparently normal coordination was unaffected by the peptide, but resistance to a second toxic challenge suggested that recovery was more complete in the peptide-treated rats. The finding that Org 2766 improved the quality of the repair following acrylamide neuropathy, together with previous studies showing beneficial effects in neuropathies caused by cisplatin or diabetes and after mechanical trauma, strongly suggests that Org 2766 may be beneficial in the treatment of various conditions in which the nervous system has sustained damage.

Diabetes, 1989

An injection of streptozocin (STZ) was used to study diabetes-induced peripheral neuropathy in ra... more An injection of streptozocin (STZ) was used to study diabetes-induced peripheral neuropathy in rats. In such rats the values of motor nerve conduction velocity and sensory nerve conduction velocity were decreased compared with the values obtained in nondiabetic controls from 3 wk after STZ injection onward. In recent years it has been extensively documented that peptides related to ACTH and MSH exert a neurotrophic effect on the nervous system that results in enhanced recovery of function after mechanical nerve damage. This article documents the beneficial effect of the peptide Org 2766, an ACTH-(4-9) analogue, in diabetic peripheral neuropathy. Chronic subcutaneous treatment of diabetic rats with Org 2766 results in a significant enhancement of both motor and sensory nerve conduction velocity compared with saline-treated diabetic rats. Histological analysis of cross sections of the sural nerve showed no difference in the total number of nerve fibers in saline-or peptide-treated diabetic rats. In contrast, a difference in fiber size distribution was demonstrated; i.e., the sural nerves of diabetic rats contained fewer thick myelinated fibers. Treatment with Org 2766 resulted in a normal distribution. Apparently, the peptide Org 2766 has a protective action on nerve fibers and nerve function during STZ-induced diabetes.

Current Medical Research and Opinion, 2006

Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naiv... more Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP). Patients > or = 18 years of age were titrated with oxymorphone ER (5- to 10-mg increments every 12 h, every 3-7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12 h for 12 weeks. Oxymorphone immediate release was available every 4-6 h, as needed, for the first 4 days and twice daily thereafter. Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4 mm at screening to 22.7 mm (p < 0.0001). After randomization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 +/- 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 +/- 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group. Stabilized doses of oxymorphone ER were generally safe and effective over a 12-week double-blind treatment period in opioid-naive patients with CLBP.