Ilse Van Hove

Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study.

Objective: To evaluate the efficacy and safety of tapentadol extended release (ER) for the management of moderate to severe chronic low back pain. Research design: Patients (N = 981) were randomized 1:1:1 to receive tapentadol ER 100 – 250 mg b.i.d., oxycodone HCl controlled release (CR) 20 – 50 mg b.i.d., or placebo over 15 weeks (3-week titration period, 12-week maintenance period). Main outcome measures: Efficacy was assessed as change from baseline in average pain intensity (11-point NRS) at week 12 of the maintenance period and throughout the maintenance period; last observation carried forward was used to impute missing pain scores. Adverse events (AEs) were monitored throughout the study. Results: Tapentadol ER significantly reduced average pain intensity versus placebo at week 12 (least squares mean difference vs placebo [95% confidence interval], −0.8 [−1.22, −0.47]; p < 0.001) and throughout the maintenance period (−0.7 [−1.06,−0.35]; p < 0.001). Oxycodone CR significantly reduced average pain intensity versus placebo at week 12 (−0.9 [−1.24,−0.49]; p < 0.001) and throughout the maintenance period (−0.8 [−1.16,−0.46]; p < 0.001). Tapentadol ER was associated with a lower incidence of treatment-emergent AEs (TEAEs) than oxycodone CR. Gastrointestinal TEAEs, including constipation, nausea, and vomiting, were among the most commonly reported TEAEs (placebo, 26.3%; tapentadol ER, 43.7%; oxycodone CR, 61.9%). The odds of experiencing constipation or the composite of nausea and/or vomiting were significantly lower with tapentadol ER than with oxycodone CR (both p < 0.001). Conclusions: Tapentadol ER (100 – 250 mg b.i.d.) effectively relieved moderate to severe chronic low back pain over 15 weeks and had better gastrointestinal tolerability than oxycodone HCl CR (20 – 50 mg b.i.d.).

Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia

The pharmacokinetics and tolerability of long-acting risperidone (Risperdal Consta) were evaluated in a multicenter, prospective, open-label, 15-week study of 86 patients with schizophrenia. Subjects stabilized on 2, 4 or 6 mg of oral risperidone once daily for at least 4 weeks were assigned to receive i.m. injections of 25, 50 or 75 mg of risperidone, respectively, every 2 weeks for 10 weeks. The 90% confidence intervals for the i.m./oral ratios of the mean steady-state plasma-AUC, corrected for dosing interval, and of the average plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) were within the range of 80-125%, indicating bioequivalence of the i.m. and oral formulations. However, mean steady-state peak concentrations of the active moiety were 25-32% lower with i.m. than oral dosing (P < 0.05) and fluctuations in plasma active-moiety levels were 32-42% lower with the i.m. than oral regimen. Symptoms of schizophrenia continued to improve after switching from oral to i.m. dosing. Long-acting risperidone was well tolerated locally and systematically. Although overall bioequivalence of the two formulations was established, the differences in pharmacokinetic profiles between the two formulations indicate potential benefits for long-acting risperidone.

Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: A 10-day, phase III, randomized, double-blind, active- and placebo-controlled study

OBJECTIVES The primary objective of this study was to assess the efficacy and tolerability of tapentadol immediate release (IR) in patients who were candidates for joint replacement surgery due to end-stage joint disease. A secondary objective was to compare tapentadol IR with oxycodone HCl IR with respect to efficacy and prespecified tolerability end points. METHODS This 10-day, Phase III, randomized, double-blind, active- and placebo-controlled study compared the efficacy and tolerability of tapentadol IR, oxycodone HCl IR, and placebo in patients with uncontrolled osteoarthritis pain who were candidates for primary replacement of the hip or knee as a result of end-stage degenerative joint disease. Patients received tapentadol IR 50 mg, tapentadol IR 75 mg, oxycodone HCl IR 10 mg, or placebo every 4 to 6 hours during waking hours. The primary end point was the sum of pain intensity difference (SPID) over 5 days. Secondary efficacy end points included 2- and 10-day SPID; 2-, 5-, and 10-day total pain relief (TOTPAR); and the sum of total pain relief and pain intensity difference (SPRID). Prespecified noninferiority comparisons with oxycodone HCl IR were performed with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported adverse events (AEs) of nausea and/or vomiting and constipation). RESULTS Of 666 patients originally enrolled, 659 were included in the efficacy analysis (51% male; 91% white; mean age, 61.2 years; mean weight, 97 kg). Five-day SPID was significantly lower in those treated with tapentadol IR (tapentadol IR 50 mg: least squares mean difference [LSMD] = 101.2 [95% CI, 54.58- 147.89]; tapentadol IR 75 mg: LSMD = 97.5 [95% CI, 51.81-143.26]) or oxycodone HCl IR (LSMD = 111.9 [95% CI, 66.49-157.38]) (all, P < 0.001). Tapentadol IR 50 and 75 mg and oxycodone HCl IR 10 mg were associated with significant reductions in pain intensity compared with placebo, based on 2- and 10-day SPID and 2-, 5-, and 10-day TOTPAR and SPRID (all, P < 0.001). The efficacy of tapentadol IR 50 and 75 mg was noninferior to that of oxycodone HCl IR 10 mg; however, the incidence of selected gastrointestinal AEs (nausea, vomiting, and constipation) was significantly lower for both doses of tapentadol IR compared with oxycodone HCl IR 10 mg (nominal P < 0.001). The odds ratios for nausea and/or vomiting for tapentadol IR 50 and 75 mg relative to oxycodone HCl IR 10 mg were 0.21 (95% CI, 0.128-0.339) and 0.32 (95% CI, 0.204-0.501), respectively; for constipation, the corresponding odds ratios were 0.13 (95% CI, 0.057-0.302) and 0.20 (95% CI, 0.098-0.398). Rates of treatment discontinuation were 18% (28/157) in the tapentadol IR 50-mg group, 26% (43/168) in the tapentadol IR 75-mg group, 35% (60/172) in the oxycodone HCl IR 10-mg group, and 10% (17/169) in the placebo group. In a post hoc analysis, tapentadol IR 50 mg was associated with a significantly lower incidence of treatment discontinuation than was oxycodone HCl IR 10 mg (P < 0.001). CONCLUSIONS In these patients with uncontrolled osteoarthritis pain who were awaiting joint replacement surgery, tapentadol IR 50 and 75 mg were associated with analgesia that was noninferior to that provided by oxycodone HCl IR 10 mg. Tapentadol treatment was associated with improved gastrointestinal tolerability.

Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study

OBJECTIVES To evaluate the efficacy, safety, and tolerability of risperidone monotherapy for the treatment of an acute mixed or manic episode in children and adolescents with bipolar I disorder. METHODS This randomized, placebo-controlled, double-blind, 3-arm study (N = 169) included children and adolescents (ages 10-17 years) with a DSM-IV diagnosis of bipolar I disorder, experiencing a manic or mixed episode. Study participants were randomized to placebo (n = 58), risperidone 0.5-2.5 mg/day (n = 50), or risperidone 3-6 mg/day (n = 61) for 3 weeks. The primary efficacy measure was change in Young Mania Rating Scale (YMRS) total score from baseline to end point. Safety assessments included adverse event (AE) monitoring and scores on extrapyramidal symptom rating scales. RESULTS Improvement in mean YMRS total score was significantly greater in risperidone-treated subjects than in placebo-treated subjects [mean change (SD) -9.1 (11.0) for placebo; -18.5 (9.7) for risperidone 0.5-2.5 mg (p < 0.001); -16.5 (10.3) for risperidone 3-6 mg (p < 0.001)]. The most common risperidone-associated AEs were somnolence, headache, and fatigue. Mean (SD) weight gain was 0.7 (1.9) kg, 1.9 (1.7) kg, and 1.4 (2.4) kg in the placebo, risperidone 0.5-2.5 mg, and risperidone 3-6 mg groups, respectively, during this 3-week study. CONCLUSIONS At daily doses of 0.5-2.5 mg and 3-6 mg, risperidone was effective and well tolerated in children and adolescents experiencing acute manic or mixed episodes of bipolar I disorder. Results indicate that risperidone 0.5-2.5 mg has a better benefit-risk profile than risperidone 3-6 mg.

Short- and long-term efficacy and safety of risperidone in adults with disruptive behavior disorders

RationaleFunction in society can be severely affected by disruptive behaviors in adults.ObjectivesTo examine the efficacy and safety of risperidone in the treatment of disruptive behavior disorders in intellectually disabled adults.MethodsIntellectually disabled patients with disruptive behavior disorder were randomly assigned to receive risperidone (n=39) in a flexible dosage ranging from 1 to 4 mg/day (mean dosage, 1.45±0.08 mg/day) or placebo (n=38) for 4 weeks of double-blind treatment. Efficacy at endpoint was measured primarily by using the Aberrant Behavior Checklist (ABC); secondary efficacy measures included the Behavior Problems Inventory and Clinical Global Impressions scales. After this 4-week period, patients could enter open-label treatment with risperidone for 48 weeks.ResultsRisperidone was well tolerated, and patients treated with risperidone demonstrated significantly greater improvement at endpoint on the ABC than those who received placebo [−27.3 points (52.8% improvement) versus −14.9 points (31.3% improvement); P=0.036] and also improved on Behavior Problems Inventory and Clinical Global Impressions ratings. Over the 48-week, open-label follow-up period, there was a further decrease of 6.3 points (P≤0.05) on the ABC for patients who initially received risperidone and a decrease of 11.3 points (P≤0.05) for patients who initially received placebo and were switched to open-label risperidone. These results were achieved with a mean modal dosage of 1.8 mg/day.ConclusionRisperidone is efficacious and well tolerated in managing disruptive behavior disorders in adults with intellectual disability.

Poster 52: Health-related Outcomes of Tapentadol Extended Release Treatment for Chronic Low Back Pain

evaluations included 1,095. In the tapentadol ER and oxycodone CR groups, respectively, 85.7% and 90.6% of patients reported 1 treatment-emergent adverse event. Mean pain intensity scores at baseline were 7.58 and 7.61 for tapentadol ER and oxycodone CR, respectively, and decreased to 4.37 and 4.52 at endpoint. Mean improvements in SF-36 scores from baseline to study endpoint for tapentadol ER and oxycodone CR, respectively, were as follows: physical functioning, 12.9 and 9.6; role-physical, 20.1 and 10.7; bodily pain, 20.7 and 17.4; general health, 5.2 and 1.5; vitality, 8.5 and 5.8; social functioning, 11.6 and 4.8; role-emotional, 6.2 and 2.7; mental health, 3.5 and 3.5; mental component summary, 1.2 and 0.4; and physical component summary, 7.2 and 4.9. Tapentadol ER and oxycodone CR were evaluated as good, very good, or excellent at study endpoint by 75.1% and 72.3%, respectively, of patients, and 77.3% and 72.3%, respectively, of physicians. Conclusions: Long-term treatment with tapentadol ER for moderate to severe chronic pain was rated positively by both patients and physicians, with patients reporting numerically greater improvements in physical and social function with tapentadol ER (100-250mg bid) than with oxycodone CR (20-50 mg bid).

Poster 66: Tapentadol Extended Release for the Relief of Chronic Pain Associated With Osteoarthritis of the Knee: Assessment of Opioid Withdrawal From a Randomized, Active- and Placebo-controlled Study

Results: Our patient presented with pain and weakness in the C5-C6 myotome 3 months after cervical laminoplasty. Clinical presentation of herpes zoster (HZ) had an atypical activation period, with myotomal weakness occuring prior to the dermatomal rash. Diagnostic testing confirmed the diagnosis of segmental zoster paresis (SZP). The patient was treated appropriately for HZ infection. However, he recovered from the sensory/motor deficits more slowly than expected for an immunocompetent patient. Discussion: Paresis in an upper extremity is a notorious complication of surgery for cervical compression. Postsurgical paresis can affect multiple cervical nerve roots, with the C5 nerve most often affected. However, SZP can also present as pain and weakness after surgery and can complicate the diagnosis of postoperative paresis. SZP is a focal, asymmetric neurogenic weakness that may occur in a limb affected by HZ. While the pathogenesis of SZP is still uncertain, it appears that localized trauma and inflammation may lead to reactivation of HZ. SZP typically occurs 2-3 weeks after the herpetic rash and usually affects the myotome that corresponds to the dermatomal distribution. However, SZP may also initially present in an atypical pattern that resembles postsurgical paresis, with motor loss preceding the herpetic rash. Such atypical presentations can delay recognition and treatment of SZP following spinal surgery. Thus, physician awareness of the clinical diagnosis and treatment of SZP is important for proper management of this disease. Conclusions: Segmental zoster paresis can present following spinal surgery, causing pain and motor weakness with or without an associated herpetic rash. SZP can be confused with postsurgical paresis when presenting without a rash, thus complicating the diagnosis and treatment. Paresis in our patient was diagnosed as SZP and was not due to direct trauma to the C5-C6 nerve roots during surgery. SZP resulted from reactivation of HZ in the C5-C6 region with subsequent localized inflammation in the motor nerves following surgery.