A comparison of the efficacy and safety of olanzapine versus haloperidol during transition from intramuscular to oral therapy

Background: Acutely agitated patients with schizophrenia who receive intramuscular (IM) medications typically are switched to oral (PO) antipsychotic maintenance therapy Objective: The goal of this study was to assess the efficacy and safety of olanzapine versus those of haloperidol during transition from IM to PO therapy We used additional data from a previously reported trial to test the hypothesis that the reduction in agitation achieved by IM olanzapine 10 mg or IM haloperidol 7.5 mg would be maintained following transition to 4 days of PO olanzapine or PO haloperidol (5-20 mg/d for both). We also hypothesized that olanzapine would maintain its more favorable extrapyramidal symptom (EPS) safety profile. Methods: This was a multinational (hospitals in 13 countries), double-blind, randomized, controlled trial. Acutely agitated inpatients with schizophrenia were treated with 1 to 3 IM injections of olanzapine 10 mg or haloperidol 7.5 mg over 24 hours and were entered into a 4-day PO treatment period with the same medication (5-20 mg/d for both). The primary efficacy measurement was reduction in agitation, as measured by the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score. Adverse events and scores on EPS rating scales were assessed. Results: A total of 311 patients (204 men, 107 women; mean [SD] age, 38.2 [11.6] years) were enrolled (131, 126, and 54 patients in the olanzapine, haloperidol, and placebo groups, respectively). In all, 93.1% (122/131) of olanzapine-treated patients and 92.1% (116/126) of haloperidol-treated patients completed the IM period and entered the PO period; 85.5% (112/131) of olanzapine-treated patients and 84.1% (106/126) of haloperidol-treated patients completed the PO period. IM olanzapine and IM haloperidol effectively reduced agitation over 24 hours (mean [SD] PANSS-EC change, -7.1 [4.8] vs -6.7 [4.3], respectively). Reductions in agitation were sustained throughout the PO period with both study drugs (mean [SD] change from PO period baseline, -0.6 [4.8] vs -1.3 [4.4], respectively). During PO treatment, haloperidol-treated patients spontaneously reported significantly more acute dystonia than olanzapine-treated patients (4.3% [5/116] vs 0% [0/122], respectively; P = 0.026) and akathisia (5.2% [6/116] vs 0% [0/122], respectively; P = 0.013). Significantly more haloperidol-treated patients than olanzapine-treated patients met categorical criteria for treatment-emergent akathisia (18.5% [17/92] vs 6.5% [7/107], respectively; P = 0.015). Conclusions: In the acutely agitated patients with schizophrenia in this study, both IM olanzapine 10 mg and IM haloperidol 7.5 mg effectively reduced agitation over 24 hours. This alleviation of agitation was sustained following transition from IM therapy to 4 days of PO treatment (5-20 mg/d for both). During the 4 days of PO treatment, olanzapine-treated patients did not spontaneously report any incidences of acute dystonia, and olanzapine had a superior EPS safety profile to that of haloperidol. The combination of IM and PO olanzapine may help improve the treatment of acutely agitated patients with schizophrenia. Copyright (C) 2003 Excerpta Medica, Inc.

Intramuscular Olanzapine and Intramuscular Haloperidol in Acute Schizophrenia: Antipsychotic Efficacy and Extrapyramidal Safety During the First 24 Hours of Treatment

To determine the antipsychotic efficacy and extrapyramidal safety of intramuscular (IM) olanzapine and IM haloperidol during the first 24 hours of treatment of acute schizophrenia. Method: Patients (n = 311) with acute schizophrenia were randomly allocated (2:2: 1) to receive IM olanzapine (10.0 mg, n = 131), IM haloperidol (7.5 mg, n = 126), or IM placebo (n = 54). Results: After the first injection, IM olanzapine was comparable to IM haloperidol and superior to IM placebo for reducing mean change scores from baseline on the Brief Psychiatric Rating Scale (BRPS) Positive at 2 hours (-2.9 olanzapine, -2.7 haloperidol, and -1.5 placebo) and 24 hours (-2.8 olanzapine, -3.2 haloperidol, and -1.3 placebo); the BPRS Total at 2 hours (-14.2 olanzapine,-13.1 haloperidol, and -7.1 placebo) and 24 hours (-12.8 olanzapine, -12.9 haloperidol, and -6.2 placebo); and the Clinical Global Impressions (CGI) scale at 24 hours (-0.5 olanzapine, -0.5 haloperidol, and -0.1 placebo). Patients treated with IM olanzapine had significantly fewer incidences of treatment-emergent parkinsonism (4.3% olanzapine vs 13.3% haloperidol, P = 0.036), but not akathisia (1.1% olanzapine vs 6.5% haloperidol, P = 0.065), than did patients treated with IM haloperidol; they also required significantly less anticholinergic treatment (4.6% olanzapine vs 20.6% haloperidol, P < 0.001). Mean extrapyramidal symptoms (EPS) safety scores improved significantly from baseline during IM olanzapine treatment, compared with a general worsening during IM haloperidol treatment (Simpson-Angus Scale total score mean change: -0.61 olanzapine vs 0.70 haloperidol; P < 0.001; Barnes Akathisia Scale global score mean change: -0.27 olanzapine vs 0.01 haloperidol; P < 0.05). Conclusion: IM olanzapine was comparable to IM haloperidol for reducing the symptoms of acute schizophrenia during the first 24 hours of treatment, the efficacy of both being evident within 2 hours after the first injection. In general, more EPS were observed during treatment with IM haloperidol than with IM olanzapine.

Prolotherapy injections for chronic low back pain - A systematic review

Study Design. A systematic review of randomized and quasi-randomized controlled trials. Objectives. To determine the efficacy of prolotherapy injections in adults with chronic low back pain. Summary of Background Data. Prolotherapy is an injection-based treatment for chronic low back pain. Proponents of prolotherapy suggest that some back pain stems from weakened or damaged ligaments. Repeatedly injecting them with irritant solutions is thought to strengthen the ligaments and reduce pain and disability. Prolotherapy protocols usually include co-interventions to enhance the effectiveness of the injections. Methods. The authors searched MEDLINE, EMBASE, CINAHL, and Science Citation Index up to January 2004, and the Cochrane Controlled Trials Register 2004, issue 1, and consulted content experts. Both randomized and quasi-randomized controlled trials comparing prolotherapy injections to control injections, either alone or in combination with other treatments, were included. Studies had to include measures of pain and disability before and after the intervention. Two reviewers independently selected the trials and assessed them for methodologic quality. Treatment and control group protocols varied from study to study, making meta-analysis impossible. Results. Four studies, all of high quality and with a total of 344 participants, were included. All trials measured pain and disability levels at 6 months, three measured the proportion of participants reporting a greater than 50% reduction in pain or disability scores from baseline to 6 months. Two studies showed significant differences between the treatment and control groups for those reporting more than 50% reduction in pain or disability. Their results could not be pooled. In one, cointerventions confounded interpretation of results; in the other, there was no significant difference in mean pain and disability scores between the groups. In the third study, there was little or no difference between groups in the number of individuals who reported more than 50% improvement in pain and disability. The fourth study reporting only mean pain and disability scores showed no differences between groups. Conclusions. There is conflicting evidence regarding the efficacy of prolotherapy injections in reducing pain and disability in patients with chronic low back pain. Conclusions are confounded by clinical heterogeneity among studies and by the presence of co-interventions. There was no evidence that prolotherapy injections alone were more effective than control injections alone. However, in the presence of co-interventions, prolotherapy injections were more effective than control injections, more so when both injections and co-interventions were controlled concurrently.

Prolotherapy injections, saline injections, and exercises for chronic low-back pain: A randomized trial

Objectives. To assess the efficacy of a prolotherapy injection and exercise protocol in the treatment of chronic nonspecific low back pain. Design. Randomized controlled trial with two- by- two factorial design, triple- blinded for injection status, and single- blinded for exercise status. Setting. General practice. Participants. One hundred ten participants with nonspecific low- back pain of average 14 years duration were randomized to have repeated prolotherapy ( 20% glucose/ 0.2% lignocaine) or normal saline injections into tender lumbo- pelvic ligaments and randomized to perform either flexion/ extension exercises or normal activity over 6 months. Main outcome measures: Pain intensity ( VAS) and disability scores ( Roland- Morris) at 2.5, 4, 6, 12, and 24 months. Results. Follow- up was achieved in 96% at 12 months and 80% at 2 years. Ligament injections, with exercises and with normal activity, resulted in significant and sustained reductions in pain and disability throughout the trial, but no attributable effect was found for prolotherapy injections over saline injections or for exercises over normal activity. At 12 months, the proportions achieving more than 50% reduction in pain from baseline by injection group were glucose- lignocaine: 0.46 versus saline: 0.36. By activity group these proportions were exercise: 0.41 versus normal activity: 0.39. Corresponding proportions for > 50% reduction in disability were glucose- lignocaine: 0.42 versus saline 0.36 and exercise: 0.36 versus normal activity: 0.38. There were no between group differences in any of the above measures. Conclusions. In chronic nonspecific low- back pain, significant and sustained reductions in pain and disability occur with ligament injections, irrespective of the solution injected or the concurrent use of exercises.

Restriction of intramuscular neurite branching and extension is lost in agrin and rapsyn-deficient mice

The phrenic nerve enters the diaphragm at approximately embryonic day 12.5 (E12.5) in the mouse. The secondary nerve trunk advances along the centre of the diaphragm muscle and extends tertiary branches primarily towards the lateral side during normal embryonic development. In the present study we quantified the intramuscular neurite branching in the most ventral region of the diaphragm at E15.5 and E18.5 in wild-type mice, agrin knock-out mice (KOAG) and rapsyn knock-out mice (KORAP). KOAG and KORAP have decreased muscle contraction due to their inability to maintain/form acetylcholine receptor (AChR) clusters during embryonic development. Heterozygote mothers were anaesthetised via an overdose of Nembutal (30 mg; Boeringer Ingelheim, Ridgefield, CT, USA) and killed via cervical dislocation. There were increases in the number of branches exiting the medial side of the phrenic nerve trunk in KOAG and KORAP compared to wild-type mice, but not on the lateral side at E15.5 and E18.5. However, the number of bifurcations in the periphery significantly increased on both the medial and lateral sides of the diaphragm at E15.5 and E18.5 in KOAG and KORAP compared to control mice. Furthermore, neurites extended further on both the medial and lateral sides of the diaphragm at E15.5 and E18.5 in KOAG and KORAP compared to wild-type mice. Together these results show that the restriction of neurite extension and bifurcations from the secondary nerve trunk is lost in both KOAG and KORAP allowing us the opportunity to investigate the factors that restrict motoneuron behaviour in mammalian muscles.