A preliminary comparison of the efficacy and tolerability of botulinum toxin serotypes A and B in the treatment of myofascial pain syndrome: a retrospective, open-label chart review

BACKGROUND: Myofascial pain syndrome (MPS) is characterized by acute or chronic regional muscle pain associated with single or multiple trigger points within taut bands of muscle. Botulinum toxins have clinical utility when sustained focal muscle relaxation is required and may be a useful addition to the treatment armamentarium for MPS. OBJECTIVE: The purpose of the present article was to compare the efficacy and tolerability of botulinum toxin serotypes A and B (BTX-A and BTX-B) in the treatment of MPS. METHODS: This was a retrospective, open-label, single-center chart review. Charts of all patients who received either BTX-A or BTX-B for MPS between January and November 2001 were included in the review. Patients rated the intensity of their pain on a visual analog scale (VAS) from 0 = no pain to 10 = worst pain imaginable before and after receiving BTX-A or BTX-B. RESULTS: The charts of 91 patients (74.7% female, 25.3% male; mean [SD] age, 47 [10.2] years) who received BTX-A (n = 56; mean dose, 256.9 U; range, 100-600 U) or BTX-B (n = 35; mean dose, 9000 U; range, 2500-20,000 U) were included in this retrospective review. Patients who received BTX-A had significantly greater mean reductions in VAS pain scores compared with those who received BTX-B (mean reduction, 2.7 vs 1.8, respectively; P < 0.001). Patients who received BTX-A also reported significantly longer durations of pain relief compared with those who received BTX-B (4.5 vs 2.7) months; P < 0.001). Eight of 56 patients (14.3%) in the group that received BTX-A reported mild adverse events that included flulike symptoms, injection-site pain, and weakness of the neck muscles. Seven of 35 patients (20.0%) in the group that received BTX-B reported adverse events that included mild flulike symptoms, dry eyes, severe visual disturbances, and severe dry mouth. CONCLUSION: Patients with MPS who received BTX-A reported significantly greater reductions in pain for longer durations compared with those who received BTX-B. No patients who received BTX-A experienced severe systemic adverse events, compared with 4 patients who received BTX-B. The results of this comparison are consistent with the US Food and Drug Administration-approved labeling indicating that BTX-A is not interchangeable with any other botulinum toxin in terms of biological activity.     

Efficacy and safety of oxymorphone immediate release for the treatment of mild to moderate pain after ambulatory orthopedic surgery: results of a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To assess the analgesic efficacy and safety of 5 mg of oxymorphone immediate release (IR) for mild to moderate pain. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Ambulatory surgical centers. PARTICIPANTS: Outpatients (age, > or = 18 y) undergoing knee arthroscopy. INTERVENTION: Randomization to 5 mg of oxymorphone IR or placebo hourly as needed for up to 8 hours. MAIN OUTCOME MEASURE: Sum of pain intensity difference (SPID) from baseline to 8 hours. RESULTS: Among 122 patients randomized, 70.5% and 28.7% had moderate or mild postsurgical pain at baseline, respectively. The mean SPID score was significantly greater in the oxymorphone IR group, showing greater pain relief, compared with the placebo group (least squares mean difference +/- standard error, 76.9+/-28.09; 95% confidence interval, 21.26-132.59; P=.007). More placebo patients (48.4%) required rescue medication than oxymorphone IR patients (16.7%), with median times to use of rescue medication of 6 hours 54 minutes and more than 8 hours, respectively (P<.001). More patients (47.4%) rated oxymorphone IR "very good" or "excellent" for pain relief versus placebo (25.0%). No oxymorphone IR-treated patients discontinued because of adverse events (AEs) or experienced serious AEs. CONCLUSIONS: Five milligrams of oxymorphone IR was well tolerated and effective at relieving mild or moderate postsurgical pain after outpatient knee surgery.     

Rizatriptan 5 mg for the acute treatment of migraine in adolescents: a randomized,double-blind,placebo-controlled study

OBJECTIVE: To investigate the tolerability and efficacy of rizatriptan 5 mg in adolescent migraineurs. METHODS: Randomized, double-blind, placebo-controlled study. Patients aged 12 to 17 years received rizatriptan 5 mg (n = 149) or placebo (n = 147) for a moderate or severe headache and for up to two recurrences. Headache severity, presence or absence of associated symptoms, and functional disability were assessed over a 4-hour postdose period, and any adverse events were recorded. The primary efficacy measure was pain-free status at 2 hours postdose. RESULTS: Rizatriptan 5 mg was well tolerated. The most commonly reported adverse events (all with incidence of 5% or less) among patients receiving rizatriptan were dry mouth, dizziness, asthenia/fatigue, nausea, and somnolence. The percentage of patients pain-free at 2 hours was 32% for rizatriptan 5 mg versus 28% for placebo (P=.474). The percentage of patients with pain relief (reduction of predose pain intensity to mild or none) at 2 hours was 66% for rizatriptan versus 56% for placebo (P=.079). Placebo response rates were higher than those typically observed in previous studies of rizatriptan in adults. Compared with placebo, rizatriptan significantly improved functional disability at 1.5 and 2 hours, and nausea at 1 and 1.5 hours. Post hoc analysis showed a significant benefit of rizatriptan versus placebo in the percentage of patients who had pain relief when their migraine attacks were treated on weekends (65% versus 36%, P=.046) compared with weekdays (66% versus 61%, P=.365), and the weekend placebo response rate was similar to that seen in adults. CONCLUSIONS: Rizatriptan 5 mg was well tolerated and effective on some measures when used in adolescents for the treatment of a migraine attack.     

Effectiveness of Botulinum Toxin A in Treatment of Hemiplegic Shoulder Pain: A Systematic Review and Meta-analysis

ObjectiveTo evaluate the effectiveness of botulinum toxin A (BTX-A) in the treatment of hemiplegic shoulder pain.Data SourcesPubMed, EMBASE, Elsevier, Springer, Cochrane Library, Physiotherapy Evidence Database, CNKI, and VIP were researched from the earliest records to September 1, 2020.Study SelectionRandomized controlled trials that compared shoulder BTX-A injections vs a control intervention in patients with a history of hemiplegic shoulder pain after stroke were selected. Among the 620 records screened, 9 trials with 301 eligible patients were included.Data ExtractionOutcome data were pooled according to follow-up intervals (1, 2, 4, and 12 wk). The primary evaluation indices were pain reduction (visual analog scale [VAS] score) and range of motion (ROM) improvement. The second evaluation indices were upper limb functional improvement, spasticity improvement, and incidence of adverse events. Cochrane risk-of-bias was used to assess the methodological quality of studies independently by 2 evaluators.Data SynthesisMeta-analysis revealed a statistically significant decrease in the VAS score in the BTX group vs the control group at 1, 4, and 12 weeks postinjection (wk 1: standardized mean difference [SMD], 0.91; 95% confidence interval [CI], 0.27 to 1.54; wk 4: SMD, 1.63; 95% CI, 0.76 to 2.51; wk 12: SMD, 1.96; 95% CI, 1.44 to 2.47). Furthermore, the meta-analysis demonstrated a statistically significant increase in abduction at 1, 4, and 12 weeks postinjection (wk 1: SMD, 3.71; 95% CI, 0 to 7.41; wk 4: SMD, 8.8; 95% CI, 2.22 to 15.37; wk 12: SMD, 19.59; 95% CI, 9.05 to 30.13) and external rotation at 1, 2, 4 weeks postinjection (wk 1: SMD, 5.67; 95% CI, 0.88 to 10.47; wk 2: SMD, 9.62; 95% CI, 5.57 to 13; wk 4: SMD, 6.89; 95% CI, 2.45 to 11.33) in the BTX group.ConclusionsBTX-A injection provided greater analgesic effects and increased shoulder abduction and external rotation ROM compared with steroid or placebo injection for the treatment of HSP.     

Treatment of mild headache in disabled migraine sufferers: results of the Spectrum Study

OBJECTIVE: To evaluate the effectiveness of sumatriptan, 50-mg tablets, versus placebo for early intervention while head pain was mild in patients with disabling migraine. METHODS: A post hoc analysis was performed in a subgroup of patients from a large, randomized, placebo-controlled study of patients with disabling headache who treated while pain was mild. Pain-free response 2 and 4 hours postdose, headache recurrence, and safety were examined. Significance tests were performed only for the first-treated attacks. RESULTS: Twenty-six patients with disabling headache treated 46 mild and 166 moderate or severe headaches. For the first-treated headaches while pain was mild, pain-free rates were significantly higher for sumatriptan than placebo 4 hours postdose (78% versus 0%, P =.02), but not 2 hours postdose (52% versus 0%, P =.22). Across all headaches treated while pain was mild, pain-free responses were higher for sumatriptan than placebo 4 hours (85% versus 17%) and 2 hours (50% versus 0%) postdose compared with placebo. When the same patients treated headaches while pain was moderate or severe, pain-free rates were lower than that reported for treatment during mild pain. There was a trend toward lower headache recurrence in headaches treated while pain was mild compared with moderate or severe pain (13% versus 18%). No drug-related adverse events were reported in the headaches treated while pain was mild. CONCLUSIONS: Patients with disabling migraine may benefit from early intervention with sumatriptan, 50 mg, while pain is mild.     

Gait improvement by low-dose botulinum toxin A injection treatment of the lower limbs in subacute stroke patients

[Purpose] Lower-limb spasticity after stroke may be associated with worse functional outcome. Our study aim was to establish whether a low-dose botulinum toxin A (BTX-A) injection in subacute stroke patients can improve spasticity, gait, and daily living abilities. [Subjects] Twenty-three subacute stroke patients were randomly allocated to BTX-A treatment group (11 patients) and control group (12 patients). [Methods] In the BTX-A treatment group patients, 200 units BTX-A was injected into the triceps surae (150 iu) and posterior tibial (50 iu) by electrical stimulation-guided. The patients in the control group received the same volume of placebo solution into the same injection locations. Gait analysis (step length, cadence, speed), the 6-min walking test, Fugl-Meyer Assessment (FMA) of the lower limbs, modified Ashworth scale assess (MAS) assessment of the lower limbs, surface electromyography (sEMG), and modified Barthel index (MBI) assessment were performed before and at 4,8 weeks after treatment. [Results] We found that the FMA of the low limbs and MBI were significantly improved in both groups. The gait analysis, FMA, and MBI results in the BTX-A treatment group were better than those in the control group. MAS and surface electromyography (sEMG) showed better improvement of spasticity in the treatment group. [Conclusion] Early low-dose botulinum toxin A (BTX-A) injection in subacute stroke patients into the lower-limb may improve gait, spasticity, and daily living abilities.Key words: Botulinum toxin A, Stroke, Spasticity     

Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study

BACKGROUND: Opioid analgesics may be a useful alternative in patients with osteoarthritis who have not responded to first-line treatment with acetaminophen and in whom nonsteroidal anti-inflammatory drugs are contraindicated, ineffective, or poorly tolerated. OBJECTIVE: This study compared the efficacy and tolerability of tramadol LP 200 mg, a new once-daily,sustained-release formulation, with those of placebo in patients with osteoarthritis of the hip or knee. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-group study, patients with osteoarthritis of the hip or knee (European League Against Rheumatism criteria) were randomized to receive either tramadol LP 200 mg once daily or placebo for 14 days. The primary efficacy end point was the change from baseline to the end of the study in scores on the Huskisson visual analog scale for pain. Secondary end points were change in the Lequesne functional discomfort index, global efficacy assessed by the patient and the investigator, time to improvement, and use of acetaminophen as rescue analgesic medication. Global tolerability was assessed by both patients and investigators at the end of the study The number and severity of adverse events occurring during the study and for 2 weeks thereafter were also recorded. RESULTS: Two hundred thirty patients (167 women, 63 men) were evaluable for efficacy and safety Demographic data for the tramadol and placebo groups were as follows: mean (SD) age, 67.1 (7.1) and 66.4 (92) years, respectively; female sex, 72.1% and 73.1%; and mean body weight, 74.7 (13.6) and 74.6 (14.8) kg. All patients were white. The completer analysis included 197 patients (85 tramadol, 112 placebo). Pain was significantly reduced in the tramadol LP group compared with the placebo group on day 7 (P = 0.002) and day 14 (P = 0.010). In the patient's assessment of global efficacy, 77.6% (66) of the tramadol LP group reported improvement by day 14, compared with 59.8% (67) of the placebo group; in the investigator's assessment, the efficacy of tramadol LP was rated very good or good for 612% (52) of patients, compared with 30.4% (34) for placebo. Improvement was reported before day 7 in 882% (75) of patients in the tramadol LP group, compared with 65.2% (73) in the placebo group (P = 0.021); the mean time from the initiation of treatment to reported improvement was 3 days for tramadol LP and 6 days for placebo (P < 0.001). Rates of response (defined as > or =30% pain reduction between days 0 and 14) were 64.7% (55) for tramadol LP and 50.0% (56) for placebo (P = 0.039); no rescue medication was used by 60.0% (51) of the tramadol LP group and 36.6% (41) of the placebo group (P - 0.001). One or more adverse event was reported by 45.0% (50) of the tramadol LP group, compared with 193% (23) of the placebo group (P < 0.001). As would be expected with an opiate agonist such as tramadol, the most common adverse events with this agent involved the gastrointestinal system (nausea, 22.5% [25] of patients; vomiting, 17.1% [19]) and the central nervous system (somnolence, 11.7% [13]). CONCLUSIONS: In this study, tramadol LP 200 mg was significantly more effective than placebo in alleviating pain in patients with osteoarthritis of the hip or knee. It appeared to be relatively well tolerated for an opioid compound.     

Two doses of botulinum toxin type A for the treatment of trigeminal neuralgia: observation of therapeutic effect from a randomized,double-blind,placebo-controlled trial

Background

In the majority of cases, trigeminal neuralgia (TN) is a unilateral condition with ultra-short stabbing pain located along one or more branches of the trigeminal nerve. Although prophylactic pharmacological treatment is first choise, considering of insufficient effect or unacceptable side effects, neurosurgical treatment or lesion treatment should be considered. In addition to all these procedures mentioned above, one approach has been based on local intradermal and/or submucosal injections of Botulinum Toxin Type A (BTX-A).

Methods

We conducted a randomized, double-blind, placebo-controlled since November 2012, and adopted local multi-point injection in 84 cases of classical TN with different doses of BTX-A. Eighty four patients were randomized into following groups: placebo (n = 28); BTX-A 25U (n = 27); BTX-A 75U (n = 29). Follow-up visits were conducted every week after the injection, and the overall duration of the study for each patient were 8 weeks to observe the pain severity, efficacy and adverse reactions at endpoint.

Results

The visual analogue scale (VAS) scores of 25U and 75U groups reduced significantly compared to placebo as early as week 1, and sustained until week 8 throughout the study. There was no significant difference in VAS between 25U and 75U groups throughout the study. The response rates of 25U group (70.4%) and 75U group (86.2%) were significantly higher than placebo group (32.1%) at week 8, and there was no significant difference between 25U and 75U groups. Evaluation of the Patient Global Impression of Change (PGIC) demonstrated that 66.7% (25U group) and 75.9% (75U group) of the patients reported that their pain symptoms were ‘much improved’ or ‘very much improved’ versus 32.1% of the placebo group, and there was also no significant difference between 25U and 75U groups. All adverse reactions were graded as mild or moderate.

Conclusions

BTX-A injection in TN is safe and efficient. It is a useful treatment for refractory TN. Lower dose (25U) and high dose (75U) were similar in efficacy in short-term.     

Botulinum Toxin Type A for Painful Temporomandibular Disorders: Systematic Review and Meta-Analysis

This systematic review investigated the effectiveness and safety of botulinum toxin type A (BTX-A) for painful temporomandibular disorders. We searched for randomized controlled trials (RCTs) in 10 databases, from inception to February 12, 2019 (MEDLINE, EMBASE, CENTRAL, LILACS, BBO, Web of Science, Scopus, ClinicalTrials.gov, WHO and OpenGrey). We included 12 RCTs that compared BTX-A versus inactive or active interventions. BTX-A was slightly more effective than placebo for pain reduction at 1 month: mean difference −1.74 points (0–10 scale), 95% confidence interval −2.94 to −.54, 3 RCTs, 60 participants, I-square (I²) = 0%. However, there were no significant differences at 3 and 6 months. BTX-A was similar to no treatment for pain reduction at 3 and 6 months. BTX-A was more effective than conventional treatment and low-level laser therapy for pain reduction at 1, 6, and 12 months, but less effective than facial manipulation for pain reduction at 3 months. BTX-A was not associated with a significant increase in the risk of adverse events. The quality of the evidence was low, and results are insufficient to support the use of BTX-A for painful temporomandibular disorders. High-quality RCTs are needed to increase confidence in effect estimates.PerspectiveBTX-A for painful temporomandibular disorders appears to be well tolerated. For pain reduction, BTX-A is slightly more effective than placebo only at 1 month; conventional treatment and low-level laser at 1, 6, and 12 months. Low-quality evidence limits the applicability of these findings and precludes recommendations for practice.     

Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, placebo-controlled trial

BACKGROUND: Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs in reducing inflammatory pain while sparing the gastrointestinal and platelet toxicity associated with nonspecific COX-1 inhibition. OBJECTIVE: The aim of this study was to assess the analgesic efficacy and tolerability of valdecoxib 40 mg/d compared with placebo in the treatment of chronic low back pain. METHODS: This 4-week, prospective, randomized, double-blind placebo-controlled, parallel-group study was conducted at 37 centers across the United States and 5 centers in Canada. Patients aged > or =18 years with chronic low back pain in flare were enrolled. Patients were randomized to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated low back pain intensity on a visual analog scale and completed the Roland-Morris Disability Questionnaire and the modified Brief Pain Inventory-Short Form (mBPI-SF) at each visit. RESULTS: Two hundred ninety-three patients were enrolled. The valdecoxib group comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the placebo group included 145 patients (85 women, 60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients (91%) who received valdecoxib and 115 patients (79%) who received placebo. No statistically significant differences in patient baseline characteristics were noted between treatment groups, except in response to 1 mBPI-SF question; patients in the valdecoxib group reported significantly greater interference in relations with other people due to pain than did those in the placebo group (P = 0.048). Changes from baseline in low back pain intensity were significantly greater in valdecoxib-treated patients at each assessment (all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly greater pain relief with valdecoxib at each assessment (all, P < or = 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire score with valdecoxib were significantly greater than with placebo at each assessment (all, P < or = 0.003). Although the overall incidence of adverse events (AEs) was significantly higher among patients receiving valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042), no significant differences were found between groups for the incidence of any individual AE. Most AEs (89% [77/87 total events]) were mild or moderate in severity. CONCLUSIONS: In this study of patients with chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within 1 week) and consistent relief (over 4 weeks). In addition, significant improvement in function and decreased disability were found with valdecoxib compared with placebo.     

Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials

Risedronate sodium is a pyridinyl bisphosphonate effective for treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis. Some bisphosphonates have been associated with upper gastrointestinal (GI) tract adverse effects. The objective of this study was to determine the frequency of upper GI tract adverse events associated with risedronate, especially among high-risk patients. The GI tract adverse events reported during 9 multicenter, randomized, double-blind, placebo-controlled studies of risedronate conducted from November 1993 to April 1998 were pooled and evaluated. The evaluation included 10,068 men and women who received placebo (n=5048) or 5 mg of risedronate sodium (n=5020) for up to 3 years (intent-to-treat population). Studies incorporated a comprehensive, prospective evaluation of GI tract adverse events. Adverse event information was collected every 3 months. The treatment groups were similar with respect to baseline GI tract disease and use of concomitant treatments during the studies. At study entry, 61.0% of patients had a history of GI tract disease and 38.7% had active GI tract disease; 20.5% used antisecretory drugs during the studies. Sixty-three percent used aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the studies. Upper GI tract adverse events were reported by 29.6% of patients in the placebo group compared with 29.8% in the risedronate group. The risk of experiencing such an event in the risedronate group was 1.01 (95% confidence interval, 0.94-1.09) relative to the placebo group (P=.77). The rate of upper GI tract adverse events per 100 patient-years was 19.2 in the placebo group compared with 20.0 in the risedronate group (P=.30). Risedronate-treated patients with active heartburn, esophagitis, other esophageal disorders, or peptic ulcer disease at study entry did not experience worsening of their underlying conditions or an increased frequency of upper GI tract adverse events overall. Concomitant use of NSAIDs, requirement for gastric antisecretory drugs, or the presence of active GI tract disease did not result in a higher frequency of upper GI tract adverse events in the risedronate-treated patients compared with controls. Endoscopy, performed in 349 patients, demonstrated no statistically significant differences across treatment groups. The results of this extensive evaluation indicate that daily treatment with 5 mg of risedronate sodium is not associated with an increased frequency of adverse GI tract effects, even among patients at high risk for these events.     

Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study

BACKGROUND: Buprenorphine, a potent opioid analgesic, has been available in parenteral and oral or sublingual(SL) formulations for >25 years. In 2001, the buprenorphine transdermal delivery system (TES) was introduced at 3 release rates (35, 52.5, and 70 microg/h) for the treatment of chronic cancer and noncancer pain. OBJECTIVE: This study compared the analgesic efficacy and tolerability of buprenorphine TES at a release rate of 35 microg/h with those of buprenorphine SL and placebo in patients with severe or very severe chronic cancer or noncancer pain. METHODS: This multicenter, double-blind, placebo-controlled, parallel-group trial was 1 of 3 Phase III studies involved in the clinical development of buprenorphine TDS. It comprised a 6-day open-label run-in phase in which patients received buprenorphine SL 0.8 to 1.6 mg/d as needed and a double-blind phase in which patients were randomized to receive 3 sequential patches containing buprenorphine TES 35 microg/h or placebo, each lasting 72 hours. Rescue analgesia consisting of buprenorphine SL 02-mg tablets was available as needed throughout the double-blind phase. The main outcome measures were (1) the number of buprenorphine SL tablets required in addition to buprenorphine TES during the double-blind phase compared with the placebo group and compared with the buprenorphine SL requirement during the run-in phase, and (2) patients' assessments of pain intensity, pain relief, and duration of sleep uninterrupted by pain in the double-blind phase compared with the run-in phase. Adverse events were documented throughout the study. RESULTS: One hundred thirty-seven patients were included in the double-blind phase (90 buprenorphine TES, 47 placebo). The buprenorphine TES group included 47 men and 43 women (mean [SD] age, 56.0 [12.1] years), and the placebo group included 23 men and 24 women (mean age, 55.7 [12.9] years). Forty-five patients had cancer-related pain and 92 had noncancer-related pain. The 2 treatment groups were comparable with respect to sex distribution, age, height, and body weight Patients receiving buprenorphine TES significantly reduced their consumption of buprenorphine SL tablets in the double-blind phase compared with patients receiving placebo (reduction of 0.6 [0.4] mg vs 0.4 [0.4] mg; P = 0.03). The relationship between the buprenorphine SL dose in the run-in phase and the number of buprenorphine SL tablets required in the double-blind phase was dose dependent in the active-treatment group only. Patients' assessments of pain intensity and pain relief suggested better analgesia with buprenorphine TES than with placebo, although the differences did not reach statistical significance. The proportion of patients who reported sleeping for >6 hours uninterrupted by pain in the double-blind phase compared with the run-in phase increased by 6.4% in the buprenorphine TDS group (35.6% vs 292%, respectively), compared with a decrease of 5.9% in the placebo group (40.4% vs 463%); no statistical analysis of sleep duration data was performed. Buprenorphine TDS was well tolerated, with adverse events generally similar to those associated with other opioids. The incidence of systemic adverse events in the double-blind phase was similar in the 2 treatment groups (28.9% buprenorphine TDS, 27.6% placebo), with the most common adverse events being nausea, dizziness, and vomiting. After patch removal, skin reactions (mainly mild or moderate pruritus and erythema) were seen in 35.6% of the buprenorphine TDS group and 25.5% of the placebo group. CONCLUSIONS: In the population studied, buprenorphine TDS provided adequate pain relief, as well as improvements in pain intensity and duration of pain-free sleep. It may be considered a therapeutic option for the treatment of moderate to severe chronic pain.     

A clinical study of intrathecal baclofen using a programmable pump for intractable spasticity

OBJECTIVE: To determine the impact of intrathecal baclofen (ITB) therapy on outcomes of functional independence, pain, subjective improvement, performance, and standard measures of spasticity. DESIGN: A noncomparative, multicenter, prospective cohort trial of patients with implanted pumps followed up over a 12-month period for the assessment of spasticity, pain, and function. SETTING: Twenty-four European centers of neurology or rehabilitation familiar with implantable pump technique participated. PARTICIPANTS: Patients with intractable spasticity (N=138) who responded positively to a trial dose of baclofen (n=133) and who began ITB therapy (n=129) were enrolled. INTERVENTION: Implantation of a Medtronic SynchroMed Infusion System with the administration of ITB therapy. MAIN OUTCOME MEASURES: Ashworth Scale assessment, Penn Spasm Frequency Scale scores, pain assessment, FIM instrument scores or WeeFIM scores for children, Canadian Occupational Performance Measure (COPM), and subjective ratings of overall relief were the tools administered. RESULTS: Muscle tone, spasm scores, and pain intensity reductions were observed. Overall FIM scores increased significantly in cognitive and motor function. COPM scores for both performance and satisfaction also improved significantly. Patients reported increased relief from pain and spasticity, supported by physician reports. Forty-three percent of patients reported adverse events, mostly related to patients' underlying conditions (20%), the device implant surgery (10%), or complications with the catheter (9%). CONCLUSIONS: ITB therapy using a programmable pump is clinically effective and well tolerated, despite a seemingly high level of adverse events, in patients with intractable spasticity of spinal or cerebral origin and may offer improvements in pain relief and function.     

Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study

OBJECTIVE: To assess the efficacy and safety of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc., Irvine, CA) for the prophylaxis of headaches in patients with chronic daily headache (CDH) without the confounding factor of concurrent prophylactic medications. BACKGROUND: Several open-label studies and an 11-month, randomized, double-blind, placebo-controlled study suggest that BoNT-A may be an effective therapy for the prophylaxis of headaches in patients with CDH. DESIGN AND METHODS: This was a subgroup analysis of an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of adult patients with 16 or more headache days per 30-day periods conducted at 13 North American study centers. All patients had a history of migraine or probable migraine. This analysis involved data for patients who were not receiving concomitant prophylactic headache medication and who constituted 64% of the full study population. Following a 30-day screening period and a 30-day single-blind, placebo injection, eligible patients were injected with BoNT-A or placebo and assessed every 30 days for 9 months The following efficacy measures were analyzed per 30-day periods: change from baseline in number of headache-free days; change from baseline in headache frequency; proportion of patients with at least 30% or at least 50% decrease from baseline in headache frequency; and change from baseline in mean headache severity. Acute medication use was assessed, and adverse events were recorded at each study visit. RESULTS: Of the 355 patients randomized in the study, 228 (64%) were not taking prophylactic medication and were included in this analysis (117 received BoNT-A, 111 received placebo injections). Mean age was 42.4+/-10.90 years; the mean frequency of headaches per 30 days at baseline was 14.1 for the BoNT-A group and 12.9 for the placebo group (P=.205). After two injection sessions, the maximum change in the mean frequency of headaches per 30 days was -7.8 in the BoNT-A group compared with only -4.5 in the placebo group (P=.032), a statistically significant between-group difference of 3.3 headaches. The between-group difference favoring BoNT-A treatment continued to improve to 4.2 headaches after a third injection session (P=.023). In addition, BoNT-A treatment at least halved the frequency of baseline headaches in over 50% of patients after three injection sessions compared to baseline. Statistically significant differences between BoNT-A and placebo were evident for the change from baseline in headache frequency and headache severity for most time points from day 180 through day 270. Only 5 patients (4 patients receiving BoNT-A treatment; 1 patient receiving placebo) discontinued the study due to adverse events and most treatment-related events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A is an effective and well-tolerated prophylactic treatment in migraine patients with CDH who are not using other prophylactic medications.     

Tolerability profile of tasosartan, a long-acting angiotensin II AT1 receptor blocker, in the treatment of patients with essential hypertension

This paper summarizes tolerability data for 1420 patients with essential hypertension who were enrolled in eight double-masked, controlled clinical trials and who received tasosartan, a long-acting, nonpeptidic angiotensin II AT₁ receptor blocker. A total of 2084 patients were included in all treatment groups in these studies. Patients were treated with tasosartan at doses ranging from 10 to 600 mg, over periods of 3 to 16 weeks, except for one study with a 6-day treatment period. Tasosartan was administered once daily (seven studies) or twice daily (one study). No adverse events occurred at a significantly greater frequency in tasosartan-treated patients than in patients who received placebo. Headache, the most frequently reported adverse event, occurred significantly less frequently among tasosartan-treated patients than among those taking placebo (19% and 28%, respectively). The following adverse events (tasosartan and placebo groups) were reported by at least 3% of tasosartan-treated patients: asthenia (7% in each group), pharyngitis (7% in each group), dizziness (7% and 5%, respectively), infection (6% and 7%, respectively), rhinitis (4% and 6%, respectively), pain (4% in each group), diarrhea (4% in each group), nausea (3% in each group), and dyspepsia (3% and 2%, respectively). Cough occurred with a similar frequency in the tasosartan group and in the placebo group (2% and 3%, respectively). Peripheral edema occurred in 2.7% of tasosartan-treated patients and 3.4% of the patients who received placebo. Hyperglycemia occurred in <1% of patients in both groups. Potentially clinically significant laboratory values occurred with comparable frequency in the tasosartan and placebo groups. Discontinuation rates because of adverse events were similar in the tasosartan and placebo groups (2.8% and 2.6%, respectively). Discontinuations because of other medical events occurred less frequently in the tasosartan group than in the placebo group (2.5% vs 4.6%, respectively). Tasosartan had a smooth onset of action without clinical evidence of first-dose hypotension. Blood pressure gradually returned to baseline after tasosartan withdrawal. No safety concerns were identified in these studies. The excellent tolerability profile of tasosartan administered once daily makes it an attractive choice for the clinical management of essential hypertension.     

Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rheumatoid arthritis pain: a 1-week, randomized, double-blind, placebo-controlled trial

OBJECTIVE: This study evaluated the efficacy and tolerability of tramadol 37.5-mg/acetaminophen 325-mg combination tablets (tramadoUAPAP) as add-on therapy in subjects with rheumatoid arthritis (RA) pain that was inadequately controlled by NSAIDs and disease-modifying antirheumatic drugs alone. METHODS: Subjects in this multicenter, double-blind trial were randomized in a 3:1 ratio to receive 1 tramadol/ APAP tablet TID or a matching placebo for 1 week. Stable doses of previous medications were continued during the study. The primary efficacy variable was the mean daily pain relief score over 1 week, measured on a 6-point scale (4 = complete; ' = a lot; 2 = some; 1 = a little; 0 = none; -1 = worse). Secondary outcomes included the mean daily pain intensity score, measured on a 100-mm visual analog scale (VAS) (from 0 mm = no pain to 100 mm = extreme pain); pain intensity and pain relief at day 7; subjects' and investigators' mean overall assessments of study drug, measured on a Likert scale (from 2 = very good to -2 = very poor); and subjects' assessments of 8 aspects of physical function (measured on the Health Assessment Questionnaire). RESULTS: Of 277 subjects randomized to treatment, 267 (201 tramadol/APAP, 66 placebo) were included in the intent-to-treat population. Mean (SD) daily pain relief scores at the end of 1 week were significantly greater in the tramadol/APAP group compared with the placebo group (1.04 [0.89] vs 0.78 [0.80], respectively; P = 0.037), and mean daily pain intensity scores at the end of 1 week were significantly lower (47.23 [19.96] vs 53.81 [16.59]; P = 0.018). Physical function at the end of 1 week did not differ significantly between tramadol/APAP and placebo. Two hundred seventy-two subjects (205 tramadol/APAP, 67 placebo) were evaluable for tolerability. One hundred thirty-three of these subjects had at least 1 adverse event. The incidence of adverse events was significantly higher in the tramadol/APAP group than in the placebo group (57.6% vs 22.4%; P < 0.001). Discontinuations due to adverse events occurred in 19.0% of the tramadol/APAP group and 3.0% of the placebo group (P = 0.001). Of 213 treatment-related adverse events in tramadol/APAP subjects, nausea (34.1%) was the most frequent, followed by dizziness (20.0%) and vomiting (15.6%). One serious adverse event--chest discomfort, nausea, and vomiting after taking study medication-occurred in a subject receiving tramadol/APAP The symptoms resolved 1 day after discontinuing tramadol/APAP. CONCLUSIONS: In this study, tramadol/APAP used as add-on therapy in subjects with symptomatic RA was associated with a significant improvement in pain relief and a significant reduction in pain intensity compared with placebo, with no improvement in physical function. Use of tramadol/APAP may be considered when analgesics are needed in addition to conventional NSAIDs and disease-modifying antirheumatic drugs in subjects with RA.     

Chronic daily headache prophylaxis with tizanidine: a double-blind,placebo-controlled,multicenter outcome study

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.     

Efficacy of phenazone in the treatment of acute migraine attacks: a double-blind, placebo-controlled, randomized study

In this study we compared the efficacy of 1000 mg phenazone with that of placebo in the treatment of acute migraine attacks in a randomized double-blind, placebo-controlled study of 208 patients. The main target criterion was the number of patients with a pain reduction from severe or moderate to slight or no pain 2 h after taking the pain medication. The percentage of patients satisfying the main target criterion was 48.6% for phenazone and 27.2% (P < 0.05) for placebo. Freedom from pain after 2 h was reported by 27.6% with phenazone treatment and 13.6% (P < 0.05) with placebo. Compared with placebo, the phenazone treatment also resulted in a significant improvement in the associated migraine symptoms of nausea, phonophobia and photophobia. Of patients treated with phenazone 11.4%, and 5.8% of those treated with placebo reported adverse events. There was no significant difference between the groups with regard to numbers of patients with adverse events. No serious adverse events occurred. The results show that phenazone at a dosage of 1000 mg is effective and well tolerated in the treatment of acute migraine attacks.     

Botulinum Toxin Dilution and Endplate Targeting in Spasticity: A Double-Blind Controlled Study

Gracies J-M, Lugassy M, Weisz DJ, Vecchio M, Flanagan S, Simpson DM. Botulinum toxin dilution and endplate targeting in spasticity: a double-blind controlled study.

Objective

To determine the effects of botulinum neurotoxin type A (BTX-A) dilution and endplate-targeting in spastic elbow flexors.

Design

Double blind randomized controlled trial; 4-month follow-up after a 160-unit injection of BTX-A into spastic biceps brachii (4 sites). Randomization into: group 1: 100 mouse units (MU)/mL dilution, 0.4cc/site, 4-quadrant injection; group 2: 100MU/mL dilution, 0.4cc/site, 4 sites along endplate band; group 3: 20MU/mL dilution, 2cc/site, 4-quadrant injection (n=7 per group).

Setting

Institutional tertiary care ambulatory clinic.

Participants

Referred sample of 21 adults with spastic hemiparesis. No participant withdrew due to adverse effects.

Intervention

A 160-unit injection of BTX-A of different dilutions and locations into biceps brachii.

Main Outcome Measures

Primary: agonist and antagonist (cocontraction) mean rectified voltage (MRV) of elbow flexors/extensors during maximal isometric flexion/extension; secondary: maximal voluntary power of elbow flexion/extension; spasticity angle and grade in elbow flexors/extensors (Tardieu Scale); active range of elbow extension/flexion.

Results

BTX-A injection overall reduced agonist flexor MRV (-47.5%, P<0.0001), antagonist flexor MRV (-12%, P=.037), antagonist extensor MRV (-19%, P<.01), flexion maximal voluntary power (-33%, P<.001), elbow flexor spasticity angle (-30%, P<.001) and grade (-17%, P=.03), and increased extension maximal voluntary power (24%, P=.037) and active range of elbow extension (5.5%, 8°, P=.002). Agonist and antagonist flexor MRV reductions in group 3 (-81% and -31%) were greater than in groups 1 and 2, whereas increase in active range of elbow extension was greater in group 2 (10%) than in groups 1 and 3 (P<.05, analysis of covariance [ANCOVA]). Elbow flexor spasticity was significantly reduced in groups 2 and 3 only (P<.05, ANCOVA).

Conclusions

In spastic biceps, high-volume or endplate-targeted BTX-A injections achieve greater neuromuscular blockade, cocontraction and spasticity reduction, and active range of elbow extension improvement, than low volume, nontargeted injections.     

A型肉毒素局部注射对脑卒中后痉挛性上肢功能障碍的影响

目的评估A型肉毒毒素(BTX-A)局部注射对脑卒中后痉挛性腕及手功能障碍的影响。方法 36例患者于治疗前及治疗后1周、4周、8周和12周应用改良Ashworth量表(MAS)、Carroll上肢功能试验(UEFT)、肢体静息位置、疼痛视觉模拟评分(VAS)、改良Barthel指数(MBI)、上肢3个运动任务(清洗偏瘫侧的手掌、剪患侧手指甲、将患侧的手臂伸进袖子)中遇到的困难进行评估。结果治疗后,MAS、VAS、UEFT评分和3个上肢任务完成情况均有改善(P<0.05),改善于注射后1周出现,并至少维持12周。MBI与治疗前比较无显著性差异(P>0.05)。结论 BTX-A局部注射可以改善脑卒中后痉挛性上肢功能障碍,减轻疼痛。