Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Multicenter, Randomized, Placebo-controlled Crossover Trial Evaluating Topical Lidocaine for Mechanical Cervical Pain.

BACKGROUND: There are few efficacious treatments for mechanical neck pain, with controlled trials suggesting efficacy for muscle relaxants and topical nonsteroidal anti-inflammatory drugs. Although studies evaluating topical lidocaine for back pain have been disappointing, the more superficial location of the cervical musculature suggests a possible role for topical local anesthetics. METHODS: This study was a randomized, double-blind, placebo-controlled crossover trial performed at four U.S. military, Veterans Administration, academic, and private practice sites, in which 76 patients were randomized to receive either placebo followed by lidocaine patch for 4-week intervals (group 1) or a lidocaine-then-placebo patch sequence. The primary outcome measure was mean reduction in average neck pain, with a positive categorical outcome designated as a reduction of at least 2 points in average neck pain coupled with at least a 5-point score of 7 points on the Patient Global Impression of Change scale at the 4-week endpoint. RESULTS: For the primary outcome, the median reduction in average neck pain score was -1.0 (interquartile range, -2.0, 0.0) for the lidocaine phase versus -0.5 (interquartile range, -2.0, 0.0) for placebo treatment (P = 0.17). During lidocaine treatment, 27.7% of patients experienced a positive outcome versus 14.9% during the placebo phase (P = 0.073). There were no significant differences between treatments for secondary outcomes, although a carryover effect on pain pressure threshold was observed for the lidocaine phase (P = 0.015). A total of 27.5% of patients in the lidocaine group and 20.5% in the placebo group experienced minor reactions, the most common of which was pruritis (P = 0.36). CONCLUSIONS: The differences favoring lidocaine were small and nonsignificant, but the trend toward superiority of lidocaine suggests more aggressive phenotyping and applying formulations with greater penetrance may provide clinically meaningful benefit.

Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study.

BACKGROUND: OnabotulinumtoxinA is approved for the prevention of headache in those with chronic migraine (CM); however, more clinical data on the risk-benefit profile for treatment beyond one year is desirable. METHODS: The Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) Study ( ClinicalTrials.gov , NCT01516892) is an international, multicenter, open-label long-term prospective study. Adults with CM received 155 U of onabotulinumtoxinA (31 sites in a fixed-site, fixed-dose paradigm across 7 head/neck muscles) every 12 weeks (±7 days) for 9 treatment cycles (108 weeks). The primary outcome was headache day reductions at 108 weeks; secondary outcomes were headache day reductions at 60 weeks and change in the 6-item Headache Impact Test (HIT-6) score. Safety and tolerability were assessed by reviewing the frequency and nature of adverse events (AEs). AEs were determined at each visit through patient self-report, general non-directed and, for specific AEs, directed questioning, and physical examination. Subgroup analyses for safety and efficacy included, but were not limited to, patients with/without concomitant oral preventive treatment and acute medication overuse at baseline. RESULTS: Enrolled patients (N = 716) were 18-73 years old and most were female (n = 607, 84.8%). At baseline, patients reported an average 22.0 (SD = 4.8) headache days per month. 52.1% of patients (n = 373) completed the study. By 60 and 108 weeks, a significant reduction in headache days (- 9.2 days and - 10.7 days, respectively, P < 0.0001) was observed. Significant improvements (P < 0.0001) in HIT-6 scores (- 7.1 point change at week 108) were also demonstrated. 131 patients (18.3%) reported ≥1 treatment-emergent adverse events; most frequently reported was neck pain (n = 29, 4.1%). One patient reported a serious treatment-related adverse event (rash). No deaths were reported. CONCLUSIONS: The COMPEL Study provides additional clinical evidence for the consistency of the efficacy and for the long-term safety and tolerability of onabotulinumtoxinA for the prevention of headache in those with CM who have been treated with onabotulinumtoxinA every 12 weeks over 2 years (9 treatments) with the fixed-site, fixed-dose injection paradigm. TRIAL REGISTRATION: Trial registration number: NCT01516892 . Name of registry: clinicaltrials.gov . Date of registration: January 20 2012. Date of enrollment of first patient: December 2011.

Utilization and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine from an observational study in Europe.

Objective To examine treatment utilization patterns and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine in routine clinical practice. Background Clinical trials support onabotulinumtoxinA for the prophylaxis of headache in patients with chronic migraine, but real-world data are limited. Design/methods A prospective, observational, post-authorization study in adult patients with chronic migraine treated with onabotulinumtoxinA. Data were collected at the first study injection and approximately every three months for ≤52 weeks for utilization and ≤64 weeks for safety data, and summarized using descriptive statistics. Results Eighty-five physicians (81% neurologists) at 58 practices in the United Kingdom, Germany, Spain, and Sweden participated and recruited 1160 patients (84.2% female, median age 46.6 years). At baseline, 85.8% of patients had physician diagnoses of chronic migraine/transformed migraine and reported an average of 11.3 (SD = 6.9) severe headache days per 28 days; 50.6% had previously used onabotulinumtoxinA for chronic migraine. A total of 4017 study treatments were observed. The median number of injection sites (n = 31) and total dose (155 U) were consistent across all treatment sessions, with a median 13.7 weeks observed between sessions. At least one treatment-related adverse event was reported by 291 patients (25.1%); the most frequently reported treatment-related adverse event was neck pain (4.4%). Most patients (74.4%) were satisfied/extremely satisfied with onabotulinumtoxinA treatment. Conclusions Patient demographics/characteristics are consistent with published data on the chronic migraine population. Utilization of onabotulinumtoxinA treatment for chronic migraine appears to be consistent with the Summary of Product Characteristics and published PREEMPT injection paradigm. No new safety signals were identified.

Cervical extravasation of bevacizumab.

Monoclonal antibodies such as bevacizumab are widely used in medical oncology, either alone or in combination with chemotherapy. No specific recommendations on the management of monoclonal antibodies extravasation exist. Incidence rates vary considerably. Estimates of 0.5-6% have been reported in the literature. Also, patient-associated and procedure-associated risk factors of extravasation are multiple, such as bolus injections or poorly implanted central venous access. We report on an 86-year-old woman with colon cancer with liver metastasis who was treated with 5-fluorouracil, folinic acid, and bevacizumab. Extravasation occurred during chemotherapy infusion because of a catheter migration of the port outside of the superior vena cava, causing cervical pain without skin modifications. Diagnosis was confirmed with the appearance of clinical right cervical tumefaction and cervicothoracic computed tomography scan indicated a perijugular hypodense collection, corresponding to the extravasation. Conservative management was proposed. The patient recovered within 3 weeks from all symptoms. Physicians should be aware that in cases of bevacizumab extravasation, a nonsurgical approach might be effective.

Treatment of cervical dystonia with Botox (onabotulinumtoxinA): Development, insights, and impact.

Cervical dystonia (CD), the most common focal dystonia encountered in neurologic practice, is a chronic disorder in which the muscles of the neck involuntarily contract and cause abnormal postures and movements of the head, neck, and shoulders. Treatment of CD prior to botulinum toxin was unsatisfactory, as existing therapies often did not improve symptoms. The use of botulinum toxin for CD grew out of its success in treating blepharospasm, another type of focal dystonia. On the basis of results from a double-blind, placebo-controlled trial, onabotulinumtoxinA was approved in 2000 in the US for the treatment of CD in adults in order to alleviate abnormal head position and neck pain. A subsequent large observational trial further demonstrated the effectiveness of onabotulinumtoxinA for CD, showing improvements in various rating scales, physician-reported measures, and profound positive effects on patient quality of life, including in amelioration of pain and improvements in work productivity. In addition, onabotulinumtoxinA treatment also reduced the complications of CD, as patients no longer develop contractures (permanent muscle and tendon shortening from prolonged untreated dystonia), which markedly limited the range of neck motion. The onset of onabotulinumtoxinA treatment also accompanied advances in understanding the functional anatomy of neck muscles, basal ganglia physiology, and video and other recording technology. Following the success of onabotulinumtoxinA in the treatment of CD, its use has been expanded into numerous other therapeutic indications, and these advances stimulated educational and training programs by various neurologic and other medical societies.

Inhibition of nitric oxide synthases prevents and reverses alpha,beta-meATP-induced neck muscle nociception in mice.

INTRODUCTION: Tension-type headache (TTH) is associated with noxious input from neck muscles. Intravenous administration of the unspecific nitric oxide synthase inhibitor L-NMMA in chronic TTH patients caused analgesia and reduction of neck muscle tenderness. METHODS: The unspecific nitric oxide synthase inhibitor L-NMMA was applied in an experimental model for neck muscle nociception in anesthetized mice (N = 25). RESULTS: Local injection of α,ß-meATP into semispinal neck muscles induced sustained facilitation of brainstem nociception as monitored by the jaw-opening reflex. Preceding intraperitoneal administration of L-NMMA (0.05, 0.1, 1 mg/kg) prevented reflex facilitation evoked by α,ß-meATP in a dose-dependent manner. Intraperitoneal injection of L-NMMA subsequent to intramuscular α,ß-meATP application reversed established brainstem reflex facilitation back to baseline values. DISCUSSION: Both experiments with preceding and subsequent L-NMMA indicate the involvement of nitric oxide synthases in the induction and maintenance of facilitation. However, future experiments will have to address the involvement of various isoenzymes in order to provide for new therapeutic concepts in TTH.

Acute dystonic reaction induced by a single dose of clebopride: A case report.

RATIONALE: Clebopride is known as a dopamine antagonist used for alleviating emetic symptoms with minimal side effects. Herein, we report a case of acute dystonic reaction possibly caused by administration of clebopride in a young male. PATIENT CONCERNS: A 19-year-old with no special medical conditions, visited a local clinic complaining of abdominal discomfort, associated with nausea and vomiting. The patient was prescribed with tiropramide, clebopride, simethicone, and mosapride citrate, only to visit the emergency department for abrupt neck pain followed with dystonic reactions upon oral administration of the drugs. The patient suffered involuntary movements of the neck to the right, while maintaining voluntary motor controls of the neck to the left. DIAGNOSIS: Vital signs and neurological exams showed no obscurity and the preliminary blood workup (a complete blood count and measurement of electrolytes, inflammatory marker levels, copper concentration, etc) were all within normal ranges. Additional imagery tests including brain computed tomography (CT), neck contrast-enhanced CT, and magnetic resonance imaging failed to prove any focal lesion pertinent to the condition. Drug screening was done and then clebopride was suspected to be the cause of the dystonic reactions. INTERVENTIONS: Benztropine (1 mg) was administered orally. OUTCOMES: The patient's symptoms improved after 1 hour, and he was observed for 6 more hours for possible recurrences before he was discharged. The patient was referred to an outpatient neurology department for 1 month, during which he had no recurrence or other extrapyramidal symptoms. LESSONS: Although it is uncommon to experience extrapyramidal symptoms by clebopride, its chemical closeness to metoclopramide may induce such symptoms under certain clinical situations. Therefore, physicians should take in consideration of this effect and dwell in caution upon prescribing the drug.

Head repositioning accuracy is influenced by experimental neck pain in those most accurate but not when adding a cognitive task.

Background and aims Neck pain can impair perception of cervical movement, but how this is affected by attention is unknown. In this study, the effects of experimental neck pain on head repositioning accuracy during standardized head movements were investigated. Methods Experimental neck pain was induced by injecting hypertonic saline into the right splenius capitis muscle in 28 healthy participants (12 women). Isotonic saline was used as control. Participants were blindfolded while performing standardized head movements from neutral (start) to either right-rotation, left-rotation, flexion or extension, then back to neutral (end). Movements were triplicated for each direction, separated by 5-s, and performed with or without a cognitive task at baseline, immediately after the injection, and 5-min after pain disappeared. Repositioning accuracy was assessed by 3-dimensional recordings of head movement and defined as the difference between start and end position. Participants were grouped into most/least accurate based on a median split of head repositioning accuracy for each movement direction at baseline without the cognitive task. Results The most accurate group got less accurate following hypertonic injection during right-rotation without a cognitive task, compared with the least accurate group and the isotonic condition (p < 0.01). No group difference was found when testing head repositioning accuracy while the participants where distracted by the cognitive task. Conclusions Experimental neck pain alters head repositioning accuracy in healthy participants, but only in those who are most accurate at baseline. Interestingly, this impairment was no longer present when a cognitive task was added to the head repositioning accuracy test. Implications The results adds to our understanding of what factor may influence the head repositioning accuracy test when used in clinical practice and thereby how the results should be interpreted.

Immobility response elicited by clamping the neck induces antinociception in a "tonic pain" test in mice.

Clamping the neck followed by body inversion to a supine position in mice elicits an immobility response called immobility by clamping the neck (ICN). The noxious pinch to the scruff of the neck produces antinociception in "phasic pain" models (e.g. tail-flick test). Here, a "tonic pain" model was used to test the antinociception associated with the ICN, and naloxone was used to determine the role of opioids in such antinociception. Mice were injected intraperitoneally with 0.3 mL of 0.4% acetic acid to produce writhing responses that were measured for one hour. ICN was induced every five minutes for one hour. Naloxone (5 mg/kg ip) was injected 10 min before acetic acid administration. There was a control group, sham clamping (SCLA). These mice were handled and restricted every five minutes as in the ICN but without real clamping. The repetitive inductions of ICN were able to reduce the writhing behavior; this antinociception was blocked by the naloxone pretreatment. In the SCLA group antinociception was not observed. These findings indicate that as in the "phasic pain" model, ICN also was able to elicit antinociception in this "tonic pain" model, and such antinociception seems to be mediated by opioids.

Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product.

Progesterone products are available in prescription form as well as over-the-counter (OTC) topical preparations sold for "cosmetic" uses. In a randomized study design, the authors compared the drug exposure from an OTC progesterone cream to a Food and Drug Administration-approved oral preparation at the labeled daily doses recommended for each product. Twelve healthy postmenopausal women received 200-mg oral progesterone capsules once daily for 12 days or progesterone cream 40 mg twice daily for 12 days. At steady state (day 12 of each phase), whole-blood samples were collected over 24 hours (oral progesterone) or 12 hours (topical progesterone) and assayed for total progesterone concentration. No significant differences were found in dose-normalized 24-hour progesterone exposure comparing the cream to oral capsules (median AUC(0-24) 12.5 ng x h/mL vs 10.5 ng x h/mL, respectively; P = .81). In light of the potential risks associated with long-term progesterone use, the authors question whether topical progesterone products should be available OTC.

Pain patterns and mandibular dysfunction following experimental trapezius muscle pain.

AIMS: To clarify the effects of experimental trapezius muscle pain on the spread of pain and on jaw motor function. METHODS: In 12 male subjects aged 25 to 35 years, experimental pain was induced in the superior border of the trapezius muscle by injecting 0.5 mL of hypertonic (6%) saline. The control infusion consisted of a 0.5-mL isotonic (0.9%) saline solution. Pain intensity was evaluated on a visual analog scale (VAS). An experimental (EX) and a control (CT) injection were administered to the subjects in a randomized sequence. RESULTS: Pain intensity as scored on the VAS increased immediately after the EX injection and decreased gradually after reaching a peak of 68.0 +/- 16.1 mm at 60 seconds after injection. The VAS scores in the EX condition were significantly higher than after the CT condition from 30 to 330 seconds after injection (P < .05, analysis of variance [ANOVA]). Mean (+/- SD) maximal unassisted mouth opening before injection in the EX condition was 54 +/- 5.7 mm and decreased immediately after the injection, reaching a low of 47.8 +/- 5.1 mm. A gradual recovery to normal was then observed. This reduction of mouth opening in the EX condition was significant compared with the CT condition from immediately after the injection to 60 seconds after the injection (P < .05, ANOVA). According to the subjects, pain spread most often to the infra-auricular zone (n = 6), and the posterolateral part of the neck (n = 10). CONCLUSION: The present results suggest that experimental trapezius muscle pain can spread over a wide area and is also accompanied by a temporary reduction of mouth opening.

Associations between pain and neuromuscular activity in the human jaw and neck muscles.

The aim of this study was to test the effects of glutamate-evoked jaw or neck muscle pain on electromyographic (EMG) activity of jaw and neck muscles in humans. EMG recordings were made from left (MAL) and right (MAR) masseter muscles, and right sternocleidomastoid (SCM) and splenius (SP) muscles in three different head positions (head rest, head back, head right) or during maximal jaw clenching in 19 men. Glutamate (1 M) or isotonic saline was injected into MAR or SP, and induced pain was recorded on visual analogue scales. EMG activity in MAL and MAR was increased in the head back position compared to head rest and head right positions, whereas EMG activity in SCM and SP was progressively increased as the head was moved from rest position to head back to head right positions. Glutamate-evoked MAR pain was associated with increases in EMG activity in MAR, SCM and SP at rest but not in the head back or head right positions. Glutamate-evoked SP pain was associated with an increase in SP EMG activity at rest and a decrease in SCM EMG activity in the head right position. Decreases in jaw clench-related EMG activity were observed in MAL, MAR and SCM muscles only during glutamate-evoked MAR pain. Isotonic saline injections induced no pain or EMG changes. In conclusion, experimental neck pain is not associated with tonic increases in jaw EMG activity although jaw muscle pain can be linked to increases in neck EMG activity with the head and jaw at rest.

Adverse reaction characterized by chest pain, shortness of breath, and syncope associated with verteporfin (visudyne).

PURPOSE: To report a serious adverse reaction associated with verteporfin infusion. DESIGN: Observational case report. METHODS: Case report of a single individual undergoing photodynamic therapy (PDT) with verteporfin. RESULTS: A 77-year-old man with long-standing asymptomatic atrial fibrillation, but no known coronary artery disease experienced severe chest and neck pain, shortness of breath, and syncope while undergoing a fourth photodynamic therapy (PDT) treatment with verteporfin. This infusion had been preceded by three prior infusions; the first two were uneventful, and the third was associated with milder, but similar symptoms. Evaluation demonstrated that the chest pain was noncardiac in origin. CONCLUSION: As verteporfin continues to be used around the world, physicians must be alert to the possibility of serious adverse side effects associated with its use.

Lamotrigine and aseptic meningitis.

OBJECTIVE: The purpose of this case series is to characterize a recently identified association of the antiepileptic drug (AED) lamotrigine with aseptic meningitis based on cases reported to the Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) database. METHODS: We performed a data mining analysis of 9 AEDs from the FDA's AERS database. We applied the multi-item gamma Poisson shrinker (MGPS) algorithm to the entire AERS database through November 2, 2009, to generate empirical Bayes geometric mean (EBGM) values with corresponding confidence intervals for 9 AEDs and the adverse event code "meningitis aseptic." The AERS database was also searched for postmarketing reports of aseptic meningitis associated with lamotrigine and a detailed review of each case was performed. RESULTS: Forty AERS cases were identified in this review. Findings from the AERS reports revealed CSF profiles with features of both bacterial as well as viral meningitis. Fifteen cases documented a positive rechallenge; the median time to onset of symptoms upon rechallenge was only 60 minutes. Data mining analysis of several anticonvulsants resulted in disproportionate reporting solely for lamotrigine. CONCLUSION: There appears to be an association between lamotrigine use and aseptic meningitis. It is notable that nearly 40% of cases in this case series reported a positive rechallenge. Lamotrigine-associated aseptic meningitis should be considered in the differential diagnosis of culture-negative meningitis. This case series highlights the need for continued pharmacovigilance and the importance of systematic monitoring of patients treated with antiepileptic medications.