Assessment of pain relief after four botulinum toxin A injection cycles in patients with post-stroke lower limb spasticity: A prospective, observational study.

INTRODUCTION: Spasticity is common after a stroke and is an independent risk factor for developing pain. BotulinumtoxinA injection is the treatment of choice for focal spasticity. We examined the effect of intramuscular botulinumtoxinA on pain relief in patients in routine clinical practice who were experiencing pain as a primary complaint associated with post-stroke lower limb spasticity. METHODS: Prospective, multicentre, post-marketing observational study. The study period was 16 months. The primary effectiveness variable was the mean change from baseline on the pain 0-10 Numerical Rating Scale after four botulinumtoxinA injection cycles. Secondary endpoints included changes from baseline on the pain 0-100 Visual Analogue Scale, Goal Attainment Scale, modified Ashworth Scale, 10-Meter Walk Test, Penn Spasm Frequency Scale, and 36-item Short-Form Health Survey. RESULTS: Of 186 enrolled patients, 180 (96.8%) received botulinumtoxinA at least once. The mean (standard deviation) pain 0-10 Numerical Rating Scale score decreased significantly (p<0.0001) from 4.9 (2.2) at baseline to 2.5 (2.1) at study end, representing a 50% decrease in pain severity. Relief of pain due to spasticity was supported by improvement from baseline in all secondary variables except the 10-Meter Walk Test. Two adverse events (erysipelas and phlebitis) in one patient were considered likely to be related to botulinumtoxinA injection. CONCLUSION: BotulinumtoxinA appears to provide pain relief as an additional benefit of local treatment in patients with post-stroke lower limb spasticity for whom pain relief is a primary therapeutic goal (a Lay Abstract has been provided as Appendix A).

Healthcare resource utilization and costs among patients with post-stroke spasticity before and after spasticity management including onabotulinumtoxina.

BACKGROUND: Real-world data regarding the impact of onabotulinumtoxinA on healthcare resource utilization and costs for post-stroke spasticity are scarce. OBJECTIVE: To compare differences in 12-month healthcare resource utilization and costs before and after post-stroke spasticity management including onabotulinumtoxinA. METHODS: This retrospective claims analysis of IBM MarketScan Commercial and Medicare Supplemental databases included adults with ≥ 1 onabotulinumtoxinA claim for post-stroke spasticity (1 January 2010 to 30 June 2018) and continuous enrolment for ≥ 12 months pre- and post-index (first onabotulinumtoxinA claim date). All-cause and spasticity-related healthcare resource utilization and costs were compared 12 months pre- and post-index (McNemar's χ2 test or paired t-test). A subgroup analysis assessed effect of stroke-to-index interval on costs. RESULTS: Among 735 patients, mean (standard deviation) stroke-date-to-index-date interval was 284.5 (198.8) days. Decreases were observed post-index for mean all-cause outpatient (62.9 vs 60.5; p ≤ 0.05) and emergency department visits (1.1 vs 0.8; p ≤ 0.0001), and hospital admissions (1.5 vs 0.4; p ≤ 0.0001). Increase in prescription fills (43.0 vs 53.7) was seen post-index. Post-index decreases in all-cause (-66%) and spasticity-related (-51%) costs were driven by reduced inpatient care costs. Findings were consistent regardless of stroke-date-to-index-date interval. CONCLUSION: Significant reductions in healthcare resource utilization and costs were observed after 1 year of post-stroke spasticity management including onabotulinumtoxinA. Long-term studies are needed to establish causality.

A UK Single-Center, Retrospective, Noninterventional Study of Clinical Outcomes and Costs of Two BotulinumtoxinA Treatments for Limb Spasticity.

Service model changes at the North Staffordshire Rehabilitation Centre (UK) included switching spasticity treatment from onabotulinumtoxinA (onaBoNT-A) to abobotulinumtoxinA (aboBoNT-A). This noninterventional, retrospective, longitudinal study (NCT04396704) describes the clinical and economic outcomes in toxin-naive adults with spasticity who received onaBoNT-A (Cohort 1; 2015-2017) or aboBoNT-A (Cohort 2; 2017-2019). Outcomes included Goal Attainment Scale T (GAS-T) score, treatment satisfaction, quality of life (QoL; EQ-5D visual analog scale [VAS] score), and treatment costs. Adverse events were recorded for Cohort 2. Cohort 1 included 60 patients (mean [standard deviation] dose, 206.0 [98.8] U); Cohort 2 included 54 patients (753.7 [457.3] U). Mean (95% confidence interval) GAS-T scores for Cohorts 1 and 2 were 43.1 (39.3-46.9) and 47.8 (43.7-51.9) at Week 6, and 43.2 and 44.3 at Week 12, respectively. In both cohorts most patients were satisfied with treatment. At Week 12, QoL had not changed in Cohort 1 but had improved in Cohort 2 (EQ-5D VAS, -5). Mean estimated per-patient costs (in 2021) for Cohorts 1 and 2 were £315.56 and £249.25, respectively, at Week 6, and £343.20 and £273.21, respectively, at Week 12. Fifteen non-treatment-related serious adverse events and two deaths were recorded. These data may warrant a larger prospective study powered to compare outcomes of aboBoNT-A and onaBoNT-A.

Botulinum Toxin Utilization, Treatment Patterns, and Healthcare Costs Among Patients with Spasticity or Cervical Dystonia in the US.

INTRODUCTION: Spasticity and cervical dystonia (CD) are movement disorders with considerable direct and indirect healthcare cost implications. Although several studies have discussed their clinical impact, few have calculated the economic burden of these disorders. This study aimed to understand treatment/injection patterns of botulinum toxins type A (BoNT-As) and the characteristics, healthcare resource utilization (HCRU), and costs among patients with spasticity or CD. METHODS: Retrospective analyses were conducted using administrative healthcare claims from the IQVIA PharMetrics® Plus database, from October 1, 2015 to December 31, 2019. Eligible patients were selected based on Healthcare Common Procedure Coding System codes for BoNT-A (index date) and ICD-10 diagnosis codes for spasticity or CD with 6 months of continuous enrollment pre-index and 12 months post-index. Patients were stratified into adult spasticity, pediatric spasticity, and CD cohorts, and were evaluated for injection patterns, HCRU, and costs in the post-index period. RESULTS: Overall, 2452 adults with spasticity, 1364 pediatric patients with spasticity, and 1529 adults with CD were included. Total mean all-cause healthcare costs were US$42,562 (adult spasticity), $54,167 (pediatric spasticity), and $25,318 (CD). Differences were observed in the cost of BoNT-A injection visits between toxins, with abobotulinumtoxinA (aboBoNT-A) having the lowest injection cost across all indications. CONCLUSIONS: AboBoNT-A had the lowest injection visit costs across indications. These results are suggestive of real-world resource utilization patterns and costs, and, while helpful in informing insurers' BoNT-A management strategies, further research into cost differences is warranted.

Spasticity is an abnormal, involuntary muscle tightness due to extended muscle contraction. This resistance in movement can be caused by stroke, multiple sclerosis, or traumatic injuries to the brain or spinal cord. Cervical dystonia is a form of sustained involuntary muscle contractions that result in abnormal or repetitive muscle movements in the neck and upper shoulders. Spasticity and cervical dystonia are both associated with significant decrease in quality of life and work productivity as well as significant economic burden. It is therefore important to understand how disease management impacts these patients. Many studies have shown that botulinum toxins type A (BoNT-As) are safe and effective in reducing muscle tightness and improving normal range of motion. This study was conducted to better understand BoNT-A injection patterns, use of healthcare services, and the resulting costs in patients with spasticity or cervical dystonia.

Assessment of Health Care Costs and Total Baclofen Use Associated With Targeted Drug Delivery for Spasticity.

BACKGROUND: Chronic spasticity causes significant impairment and financial burden. Oral baclofen, the first-line therapy, can have intolerable, dose-dependent side effects. Targeted drug delivery (TDD) through intrathecal baclofen delivers smaller amounts of baclofen into the thecal sac via an implanted infusion system. However, the health care resource utilization of patients with spasticity receiving TDD has not been studied extensively. MATERIALS AND METHODS: Adult patients who received TDD for spasticity between 2009 and 2017 were identified using the IBM MarketScan® data bases. Patients' use of oral baclofen and health care costs were examined at baseline (one year before implantation) and three years after implantation. A multivariable regression model using the generalized estimating equations method and a log link function was used to compare postimplantation costs with those at baseline. RESULTS: The study identified 771 patients with TDD for medication analysis and 576 for cost analysis. At baseline, the median costs were $39,326 (interquartile range [IQR]: $19,526-$80,679), which increased to $75,728 (IQR: $44,199-$122,676) in year 1, decreased to $27,160 (IQR: $11,896-$62,427) in year 2, and increased slightly to $28,008 (IQR: $11,771-$61,885) in year 3. In multivariable analysis, the cost was 47% higher than at baseline (cost ratio [CR] 1.47, 95% CI: 1.32-1.63) in year 1 but was 25% lower (CR 0.75, 95% CI: 0.66-0.86) in year 2 and 32% lower (CR 0.68, 95% CI: 0.59-0.79) in year 3. Before implant, 58% of patients took oral baclofen, which decreased to 24% by year 3. The median daily baclofen dose decreased from 61.8 mg (IQR: 40-86.4) before TDD to 32.8 mg (IQR: 30-65.7) three years later. CONCLUSIONS: Our findings indicate that patients who undergo TDD use less oral baclofen, potentially reducing the risk of side effects. Although total health care costs increased immediately after TDD, most likely owing to device and implantation costs, they decreased below baseline after one year. The costs of TDD reach cost neutrality approximately three years after implant, indicating its potential for long-term cost savings.

The cost-effectiveness of abobotulinumtoxinA (Dysport) and onabotulinumtoxinA (Botox) for managing spasticity of the upper and lower limbs, and cervical dystonia.

OBJECTIVE: To evaluate the costs and benefits associated with the use of abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) for lower limb spasticity in children, upper and lower limb spasticity in adults, and cervical dystonia in adults. METHODS: This pharmacoeconomic analysis compared aboBoNT-A with onaBoNT-A. A decision tree model with a 1-year time horizon was conducted from a UK National Health Service (NHS) perspective using data from a variety of sources: randomized controlled trials (RCTs), network meta-analyses (NMAs), observational studies, and a physician survey investigating treatment patterns and resource utilization. Four patient populations were included: pediatric patients with lower limb spasticity (PLL), and adults with upper limb spasticity (AUL), lower limb spasticity (ALL), and cervical dystonia (CD). Outcomes included costs, quality-adjusted life years (QALYs) gained, cost per responder, and incremental cost per QALY gained. The effectiveness of each treatment was evaluated as a response to treatment. The base case assumption was that all patients in the model continued to receive botulinum toxin type A (BoNT-A) treatments at regular intervals regardless of treatment response status. Scenario analysis evaluated the impact of discontinuing BoNT-A for patients without a response to the first injection. RESULTS: The model found that aboBoNT-A resulted in greater quality-of-life and lower costs compared with onaBoNT-A for the management of spasticity and CD in all included indications. Across populations, cost savings ranged from £304 to £3,963 and QALYs gained ranged from 0.010 to 0.02 over a 1-year time horizon. Results were robust to scenario analyses and were driven by the impact of treatment response on health-related quality-of-life. CONCLUSIONS: AboBoNT-A was associated with higher treatment response, improved quality-of-life, and reduced costs in spasticity and CD versus onaBoNT-A. These findings could help deliver more effective and efficient healthcare in the NHS.

The objective of this study was to compare the costs and health outcomes associated with abobotulinumtoxinA (aboBoNT-A; Dysport) and onabotulinumtoxinA (onaBoNT-A; Botox) for treating children and adults with a variety of conditions related to limb spasticity and cervical dystonia. Therapies such as aboBoNT-A and onaBoNT-A have been shown to reduce spasticity, deformity, pain, and cervical dystonia symptoms. They can also improve function, movement, and self-care abilities. We estimated the treatment costs for patients with spasticity and patients with cervical dystonia receiving aboBoNT-A and onaBoNT-A in the UK. We also estimated other health-related costs that patients were expected to incur while receiving these treatments, as well as their quality of life.For each indication (spasticity in the upper and lower limbs in adults and children, cervical dystonia in adults), research studies were identified to estimate the likelihood of patient response for aboBoNT-A and onaBoNT-A. Survey studies were assessed to understand use of health services and costs for patients who respond to therapy vs. those who do not. We estimated total costs over one year and expected quality of life for patients. Costs included the costs of aboBoNT-A and onaBoNT-A treatments, as well as other health services.In all identified studies, the likelihood of response was higher for aboBoNT-A than for onaBoNT-A. This was associated with reduced need for other health services (and therefore lower costs), and better quality of life for patients receiving aboBoNT-A. In addition, the cost per year of aboBoNT-A treatment was lower than onaBoNT-A treatment for all indications. Therefore, treatment with aboBoNT-A was consistently associated with lower costs and better quality of life. This outcome is referred to as "economically dominant," meaning that from a health economic perspective, aboBoNT-A would be preferred to onaBoNT-A for treating patients with spasticity or cervical dystonia.

A systematic review of European regional and national guidelines: a focus on the recommended use of nabiximols in the management of spasticity in multiple sclerosis.

INTRODUCTION: Spasticity is a common, debilitating symptom of multiple sclerosis (MS) with several treatment options including the cannabinoid-based treatment, nabiximols. The purpose of this review was to examine the existing clinical practice guidelines that direct the management of multiple-sclerosis-associated spasticity (MSS), to identify areas of similarity and divergence, and suggest where standardization and improvement may be obtained. AREAS COVERED: Published literature (PubMed), websites of relevant European Medical Associations and Health Technology Assessment bodies were systematically searched to identify guidelines describing the pharmacological management of MSS, focussing on European countries where nabiximols (Sativex® oromucosal spray) is approved. Sixteen publicly available guidelines were identified. Analysis was focused on, but not restricted to, the use of nabiximols in the wider context of the pharmacological treatment of MSS. EXPERT OPINION/COMMENTARY: We believe that currently MSS is insufficiently treated and this would be improved if a clear and detailed set of guidelines were available and implemented in daily practice. We would welcome the update and amalgamation of the existing guidelines by an international panel, using an evidence-based approach, into a single guideline that is more detailed and standardized in its approach to the initiation, monitoring and optimization of anti-spasticity drugs.

People with multiple sclerosis often experience tight or stiff muscles and an inability to control those muscles. This is known as spasticity, which can have a devastating impact on a person's ability to carry out their daily activities. In addition to physiotherapy, doctors can prescribe various medicines to improve spasticity; these are known as anti-spasticity treatments. Often, prescription choices are steered by guideline documents, written by medical experts. These documents contain important information such as when to prescribe, what to prescribe, how much to prescribe and how to measure how well the treatment is working. The purpose of this study was to examine whether the guidelines that guide the prescription of anti-spasticity treatments in people with multiple sclerosis in Europe, are fit for purpose for day-to-day medical practice. In particular, this article examines how the guidelines represent the newer cannabis-based treatment known as nabiximols, sold under the name Sativex oromucosal spray, which has become more widely available in many European countries over the last 10 years.

Comprehensive Assessment of the Time Course of Biomechanical, Electrophysiological and Neuro-Motor Effects after Botulinum Toxin Injections in Elbow Flexors of Chronic Stroke Survivors with Spastic Hemiplegia: A Cross Sectional Observation Study.

Botulinum neurotoxin (BoNT) is commonly used to manage focal spasticity in stroke survivors. This study aimed to a perform comprehensive assessment of the effects of BoNT injection. Twelve stroke subjects with spastic hemiplegia (age: 52.0 ± 10.1 year; 5 females) received 100 units of BoNT to the spastic biceps brachii muscles. Clinical, biomechanical, electrophysiological, and neuro-motor assessments were performed one week (wk) before (pre-injection), 3 weeks (wks) after, and 3 months (mons) after BoNT injection. BoNT injection significantly reduced spasticity, muscle strength, reflex torque, and compound muscle action potential (CMAP) amplitude of spastic elbow flexors (all p < 0.05) during the 3-wks visit, and these values return to the pre-injection level during the 3-mons visit. Furthermore, the degree of reflex torque change was negatively correlated to the amount of non-reflex component of elbow flexor resistance torque. However, voluntary force control and non-reflex resistance torque remained unchanged throughout. Our results revealed parallel changes in clinical, neurophysiological and biomechanical assessment after BoNT injection; BoNT injection would be more effective if hypertonia was mainly mediated by underlying neural mechanisms. BoNT did not affect voluntary force control of spastic muscles.

Baclofeno para o tratamento da espasticidade / Baclofen for or treatment of spasticity

INTRODUÇÃO: A espasticidade é caracterizada por ser um distúrbio motor relacionado a reflexos de estiramento tônico (tônus muscular) com espasmos tendinosos exagerados. É sintoma frequente de outras condições que afetam o sistema nervoso central (SNC), então a incidência e a prevalência variam de acordo com elas, bem como gravidade, músculos afetados, tempo de acometimento pela doença e tratamento. No Brasil, no âmbito do Sistema Único de Saúde (SUS), o tratamento da espasticidade é direcionado pelo Protocolo Clínico e Diretrizes Terapêuticas de Espasticidade (2017), cuja principal terapia farmacológica abordada é a toxina botulínica do tipo A. Tendo isso em vista e o fato do baclofeno ser uma tecnologia utilizada na clínica para casos de espasticidade, o presente relatório foi elaborado com o objetivo de compreender a viabilidade do uso de baclofeno de administração oral no manejo da espasticidade para pacientes adultos, visando a incorporação do fármaco no SUS. TECNOLOGIA: Baclofeno oral. PERGUNTA: O uso de baclofeno de administração oral é eficaz, seguro e custo-efetivo para o tratamento de espasticidade em pacientes adultos? EVIDÊNCIAS CLÍNICAS: Foi realizada uma revisão sistemática da literatura com o objetivo de identificar todos os estudos clínicos randomizados (ECRs) que avaliassem a eficácia e segurança do baclofeno oral em comparação com as terapias atualmente disponíveis no SUS para pacientes adultos com espasticidade. No total, foram incluídos 09 ECRs, sendo sete comparando o baclofeno com placebo e dois comparando o medicamento com diazepam. Na avaliação, não foi possível a condução de uma metanálise ou qualquer outro tipo de análise estatística que sintetize as informações apresentadas pelos ECRs devido à heterogeneidade dos estudos em relação aos desfechos e a forma de medi-los/relatá-los. Quando comparado ao placebo, apesar dos resultados de parte dos ECRs indicarem tendência de melhora com o baclofeno, a diferença de efeito não era estatisticamente significativa para certos desfechos. Em relação ao diazepam, nenhum estudo demonstrou diferença estatisticamente significativa entre os dois medicamentos no que diz respeito à melhora da espasticidade. Para todos dos desfechos de interesse analisados, os ECRs apresentaram alto risco de viés, principalmente por problemas relacionados às etapas de randomização, sigilo de alocação e cegamento (ausência de descrição ou relato inadequado). AVALIAÇÃO ECONÔMICA: Foi elaborado um modelo de custo-minimização no qual se considerou a mesma probabilidade de melhora da espasticidade do baclofeno oral mais terapia padrão e da terapia padrão isolada. A análise econômica conduzida baseou-se em um modelo de árvore de decisão que projetou a relação entre custo da intervenção (baclofeno oral + terapia padrão) e do comparador (terapia padrão) durante um ano. O resultado da análise de custo-minimização foi de aumento de custo com o tratamento com o baclofeno, sendo R$ 85,72 por paciente. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A incorporação do baclofeno oral, no SUS, geraria um impacto incremental de R$ 955 mil no primeiro ano de incorporação, totalizando um incremento de R$ 4,7 milhões em 5 anos se a taxa de difusão for 30%. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: No horizonte considerado nesta análise, não foram detectadas tecnologias para o tratamento de espasticidade. CONSIDERAÇÕES FINAIS: Há limitação das evidências científicas que demonstram melhora da espasticidade com a utilização do baclofeno oral, o que pode ser, em parte, explicada pela data de condução dos estudos clínicos e do início da comercialização do medicamento na década de 1970. As limitações acabam por se estender para as análises econômicas, as quais foram baseadas em apenas um estudo clínico que não conseguiu demonstrar os benefícios clínicos do uso do medicamento. Por outro lado, o baclofeno apresentou um custo incremental relativamente baixo, de R$ 85,72 por paciente, em comparação à terapia padrão. Apesar das incertezas em relação à eficácia do baclofeno, ele é um medicamento de uso consolidado na prática clínica, para o qual não há evidência de eventos adversos graves, a sua dose tende a ser adaptada individualmente e, mesmo com a incerteza, diretrizes internacionais relatam que o seu uso é uma das alternativas terapêuticas para o tratamento da espasticidade. Além disso, entende-se que o impacto orçamentário incremental estimado da incorporação do baclofeno não afeta significativamente a sustentabilidade do SUS. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec, em sua 102ª Reunião Ordinária, realizada no dia 06 de outubro de 2021, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação do baclofeno oral para o tratamento da espasticidade. Para essa recomendação, a Conitec considerou que a evidência clínica é escassa, de baixa qualidade e não é demonstrada a superioridade do medicamento em relação ao placebo. Apesar da larga experiência de uso e diretrizes internacionais citando o baclofeno oral como alternativa, essas recomendações não são suportadas por evidências. A matéria foi disponibilizada em Consulta Pública. CONSULTA PÚBLICA: Foi realizada entre os dias 04/11/2021 e 23/11/2021. Foram recebidas 22 constribuições, sendo quatro pelo formulário para contribuições técnico-científicas e 18 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Após apreciação de todas elas, o Plenário da Conitec entendeu que não houve argumentação suficiente para mudança de entendimento acerca de sua recomendação preliminar, que foi desfavorável à incorporação da tecnologia no SUS. RECOMENDAÇÃO FINAL DA CONITEC: Pelo exposto, o Plenário da Conitec, em sua 105ª Reunião Ordinária, no dia 10 de fevereiro de 2022, deliberou por unanimidade recomendar a não incorporação de baclofeno para o tratamento de pacientes adultos com espasticidade no SUS. Os membros da Conitec consideraram escassas as evidências científicas disponíveis, além de antigas e de não mostrar efeito benéfico muito superior ao comparador analisado. Lembraram dos valores pouco expressivos das análises de custo-efetividade e de impacto-orçamentário, mas isso não mudou a posição sobre a não incorporação. Por fim, foi assinado o Registro de Deliberação nº 711/2022. DECISÃO: Não incorporar o baclofeno oral para o tratamento da espasticidade, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 25, publicada no Diário Oficial da União nº 52, seção 1, página 74, em 17 de março de 2022.

Cost Efficiency Analysis for Spasticity Management Based on Physician Botulinum Toxin Prescribing Habits.

OBJECTIVE: To estimate differences in botulinum toxin type A (BoNT-A) treatment costs per patient for spasticity-injecting physicians, with a focus on physicians' use of alternative BoNT-A agents other than onabotulinumtoxinA. DESIGN: Retrospective cohort study. SETTING: National Medicare data for fee-for-service beneficiaries in 2017. PARTICIPANTS: A total of 116 physicians, 6829 BoNT-A procedures, and 3051 patients were included in this analysis. Most physicians were physiatrists (84%) and used only onabotulinumtoxinA (82%). INTERVENTIONS: Type of BoNT-A selected by physicians was the independent variable of interest. Included physicians were separated into 2 groups: (1) onabotulinumtoxinA only injectors and (2) abobotulinumtoxinA and/or incobotulinumtoxinA injectors (may still use onabotulinumtoxinA). MAIN OUTCOME MEASURE: Average cost per patient per year. RESULTS: The total average BoNT-A cost per patient per year was significantly less for physicians who used abobotulinumtoxinA and/or incobotulinumtoxinA vs those who used only onabotulinumtoxinA ($3684 vs $4739; P=.01). Patients' average annual out-of-pocket costs also reflected a similar difference ($855 vs $1082; P=.02) between the groups. Doses used and numbers of injections per patient per year were not significantly different between groups. CONCLUSIONS: The present analysis demonstrated lower cost per patient for both the payer and patient when physicians used types of BoNT-A other than onabotulinumtoxinA for spasticity. Nevertheless, most physicians in this spasticity-focused study used exclusively onabotulinumtoxinA, the most expensive BoNT-A available. Reasons for this are complex and include history on the market and approved indications beyond those associated with spasticity. However, future research should continue to identify such issues with a goal of finding solutions to improve cost inefficiencies.

Assessment, goal setting, and botulinum neurotoxin a therapy in the management of post-stroke spastic movement disorder: updated perspectives on best practice.

INTRODUCTION: Post-stroke spastic movement disorder (PS-SMD) appears up to 20% in the first week following stroke and 40% in the chronic phase. It may create major hurdles to overcome in early stroke rehabilitation and as one relevant factor that reduces quality of life to a major degree in the chronic phase. AREAS COVERED: In this review, we discuss predictors,early identification, clinical assessments, goal setting, and management in multiprofessional team, including Botulinum neurotoxin A (BoNT-A) injection for early and chronic management of PS-SMD. EXPERT OPINION: The earlier PS-SMD is recognized and managed, the better the outcome will be. The comprehensive management in the subacute or chronic phase of PS-SMD with BoNT-A injections requires detailed assessment, patient-centered goal setting, technical-guided injection, effective dosing of BoNT-A per site, muscle, and session and timed adjunctive treatment, delivered in a multi-professional team approach in conjunction with physical treatment. Evidence-based data showed BoNT-A injections are safe and effective in managing focal, multifocal, segmental PS-SMD and its complications. If indicated, BoNT-A therapy should be accompanied with adjunctive treatment in adequate time slots. BoNT-A could be added to oral, intrathecal, and surgical treatment in severe multisegmental or generalized PS-SMD to reach patient/caregiver's goals, especially in chronic PS-SMD.

Descriptive analysis of the annual cost of treating spasticity with different types of botulinum toxin A.

INTRODUCTION: Botulinum toxin A is the first-line treatment for localised spasticity. However, the economic impact of this treatment is not fully known. This study aimed to describe the real costs of botulinum toxin A for the treatment of adult patients with spasticity at a spasticity clinic pertaining to a rehabilitation service, over a period of one year. METHODS: We retrospectively reviewed all medical procedures carried out during the year 2017. We collected data on the type of toxin used (incobotulinumtoxin A, onabotulinumtoxin A, or Abobotulinumtoxin A), the number of units injected, the anatomical region, and the time elapsed between infiltrations. The costs of medication and indirect costs, such as staff and consumables, were also calculated. RESULTS: This is the first study to describe the real costs of botulinum toxin treatment of spasticity in adult patients in Spain. In 2017, 510 infiltration procedures were performed in 164 patients. The total cost of treating spasticity in our service was 116 789.70. The mean annual cost per patient was 603.64 for onabotulinumtoxin A, 642.69 for abobotulinumtoxin A, and 707.59 for incobotulinumtoxin A. CONCLUSIONS: Our economic study of real clinical practice is consistent with the theoretical models published in the literature. The different characteristics of each toxin and the inability to establish an equivalence between the units of each drug prevents us from directly comparing these costs.

Comparative efficacy, safety, and cost-effectiveness of abobotulinumtoxinA and onabotulinumtoxinA in children with upper limb spasticity: a systematic literature review, indirect treatment comparison, and economic evaluation.

OBJECTIVE: The objective of this study was to compare clinical- and cost-effectiveness of type A botulinum toxin (BoNT-A) therapies for management of pediatric upper limb spasticity, including AbobotulinumtoxinA (aboBoNT-A) and Onabotulinumtoxin A (onaBoNT-A). METHODS: Systematic literature review and indirect treatment comparisons were conducted of randomized controlled trials reporting efficacy and safety outcomes. Efficacy was characterized by Modified Ashworth Scale (MAS) and Ashworth Scale (AS) up to 16-weeks post-injection. Results were used to inform a cost-effectiveness model with a 1-year time horizon, linking response rates with health-related quality-of-life (HRQoL) outcomes and costs from a UK perspective. Other data sources included in the cost-effectiveness model were drug unit costs, health care resource utilization based on UK physician survey, and HRQoL impacts of adverse events associated with oral anti-spasticity therapies. Results were characterized as cost per quality-adjusted life year and cost per responder. RESULTS: Six studies were included in evidence syntheses. There was a trend towards greater response rate for aboBoNT-A which resulted in improved HRQoL and lower annual costs compared with onaBoNT-A. Safety outcomes were similar across BoNT-A therapies. In cost-effectiveness analysis, aboBoNT-A was an economically dominant therapy with respect to cost per quality-adjusted life year. The cost per responder at 1 year was estimated to be £39,056 for aboBoNT-A vs. £54,831 for onaBoNT-A. LIMITATIONS AND CONCLUSIONS: Based on observed safety and efficacy data, aboBoNT-A is estimated to result in higher treatment response and consequently increased quality-of-life and reduced costs, vs. onaBoNT-A in children with upper limb spasticity. Limitations to the study include study heterogeneity limited details available for onaBoNT-A studies (e.g. use of physical therapy), and limited availability of responder data. Where assumptions were required, they were made to be conservative towards aboBoN-A.

Electrical Stimulation of Injected Muscles to Boost Botulinum Toxin Effect on Spasticity: Rationale, Systematic Review and State of the Art.

Botulinum toxin type A (BoNT-A) represents a first-line treatment for spasticity, a common disabling consequence of many neurological diseases. Electrical stimulation of motor nerve endings has been reported to boost the effect of BoNT-A. To date, a wide range of stimulation protocols has been proposed in the literature. We conducted a systematic review of current literature on the protocols of electrical stimulation to boost the effect of BoNT-A injection in patients with spasticity. A systematic search using the MeSH terms "electric stimulation", "muscle spasticity" and "botulinum toxins" and strings "electric stimulation [mh] OR electrical stimulation AND muscle spasticity [mh] OR spasticity AND botulinum toxins [mh] OR botulinum toxin type A" was conducted on PubMed, Scopus, PEDro and Cochrane library electronic databases. Full-text articles written in English and published from database inception to March 2021 were included. Data on patient characteristics, electrical stimulation protocols and outcome measures were collected. This systematic review provides a complete overview of current literature on the role of electrical stimulation to boost the effect of BoNT-A injection for spasticity, together with a critical discussion on its rationale based on the neurobiology of BoNT-A uptake.

Comparison of botulinum toxins for treatment of movement disorders: real-world utilization and cost analysis in a national Medicare population.

BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) is the single largest payer for health care in the United States and the largest payer by spending globally. Medicare Part B, with more than 50 million beneficiaries, currently has no broad mechanisms in place for promoting cost-effective care of injectable drugs. OBJECTIVE: To conduct a real-world utilization and cost analysis comparing botulinum toxins in movement disorders. METHODS: The 2017 Medicare Provider Utilization and Payment Data: Physician and Other Supplier dataset from CMS was used for this claims level analysis. Neurologists, ophthalmologists, or physiatrists who injected predominantly for movement disorders (defined as blepharospasm, cervical dystonia, sialorrhea, and/or spasticity) were included along with their patients. Botulinum toxins with FDA indications spanning these 3 specialties were included. RESULTS: A total of 891 physicians (406 ophthalmologists, 338 neurologists, and 147 physiatrists) along with their 29,954 botulinum toxin (27,441 onabotulinumtoxinA and 2,513 incobotulinumtoxinA) patients were included in the analysis. The average total drug cost per patient per year (PPPY) was significantly lower for incobotulinumtoxinA versus onabotulinumtoxinA ($2,099 vs. $3,115; P < 0.001), for an average savings of 32.6%. Annual average out-of-pocket costs were also significantly less expensive for incobotulinumtoxinA versus onabotulinumtoxinA ($486 vs. $719; P < 0.001), for an average savings of 32.4%. Across 74,346 total injection visits, there was no significant difference in dosing between the agents, with an average dosing ratio of 0.94 incobotulinumtoxinA to 1.0 onabotulinumtoxinA. Injections PPPY were 2.42 for onabotulinumtoxinA and 2.29 for incobotulinumtoxinA. Average reported wastage was 64% higher for onabotulinumtoxinA than it was for incobotulinumtoxinA. A budget impact analysis estimated that increasing incobotulinumtoxinA use in the movement disorder space to attain an overall 20% botulinum toxin market share would save Medicare $32.9 million over a 3-year period versus current use. CONCLUSIONS: IncobotulinumtoxinA was shown to be a less costly alternative than onabotulinumtoxinA with similar dosing in real-world practice in this large national Medicare population. Policies to increase use of agents that promote cost-effective evidence-based care should be further explored and implemented for this fundamental federal payer. DISCLOSURES: This research received no external funding. Kazerooni was an employee of Merz Pharmaceuticals at the time of the analysis. Watanabe received no compensation or funding for this research project. Watanabe is a member of the National Academies of Sciences, Engineering, and Medicine Forum on Drug, Discovery, Development, and Translation. This information, content, and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by the U.S. government or the National Academies of Sciences, Engineering.

Discontinuation of botulinum neurotoxin type-A treatment during COVID-19 pandemic: an Italian survey in post stroke and traumatic brain injury patients living with spasticity.

BACKGROUND: The COVID-19 pandemic has affected health-care systems worldwide, including the outpatient spasticity care with botulinum neurotoxin toxin type A (BoNT-A). AIM: The aim of this study was to investigate the impact of discontinuation of BoNT-A treatment on patients living with spasticity during the COVID-19 quarantine. DESIGN: A multicentric cross-sectional study. SETTING: Outpatients setting. POPULATION: Patients with spasticity after stroke and traumatic brain injury treated with BoNT-A. METHODS: A phone-based survey was conducted from March to May, 2020. Based on the International Classification of Functioning, Disability and Health (ICF), an ad hoc questionnaire CORTOX (CORonavirus TOXin survey) was developed to investigate patients' experiences following the discontinuation of their usual treatment for spasticity due to the lockdown and its implication on their health perception. It assessed patients' condition and explored different ICF domains related to spasticity: unpleasant sensations, mobility, self-care, facilitators and psychosocial factors. The sum of those represented the CORTOX score (Max 142). The questionnaire also collected data about the impact of COVID-19 on patients' wellbeing (mood, sleep, relationships, community life, motivation). RESULTS: A total of 151 participants completed the survey. Most participants (72.2%) experienced a worsening in perceived spasticity, 53% got worse in independence and 70.9% had a negative impact on quality of life. The mean CORTOX score was 52.85±27.25, reflecting a perceived worsening in all ICF domains investigated. Moderate to strong correlations were found between different sub-scores of the questionnaire and severity of spasticity (P<0.001). COVID-19 psychosocial related factors were associated with loss of independence (P<0.05) but only mood was associated with worsening of spasticity (P<0.001). The lack of rehabilitation therapy was significantly associated with the worsening of independence but not with the worsening of spasticity. Finally, respondents reported that BoNT-A was useful to their condition and should not be discontinued. CONCLUSIONS: The discontinuation of BoNT-A treatment was associated with worsening of activities and participation and perceived spasticity. COVID-19 related problems and rehabilitation showed an association with loss of independence. CLINICAL REHABILITATION IMPACT: This study will provide useful information in the field of spasticity management using a patient's centred approach, with consistent quantitative and qualitative information.

Tetraidrocanabinol 27 mg/ml + canabidiol 25 mg/ml para o tratamento sintomático da espasticidade moderada a grave relacionada à esclerose múltipla / Tetrahydrocannabinol 27 mg / ml + cannabidiol 25 mg / ml for the symptomatic treatment of moderate to severe spasticity related to multiple sclerosis

INTRODUÇÃO: Esclerose múltipla (EM) é uma doença neurológica crônica, inflamatória, que ocorre em pessoas geneticamente suscetíveis. A doença é caracterizada por infiltração de células imunes, perda de mielina e axônios e formação de placas multifocais no cérebro e medula espinhal. A prevalência média global da EM é de 33 por 100.000 pessoas, com variação entre os diferentes países. As taxas de prevalência no Brasil variaram de 1,36/100.000 a 27,2/100.000 habitantes dependendo da região. A espasticidade, percebida pelos pacientes como rigidez e espasmos musculares, é um sintoma comum na EM e está associado ao comprometimento funcional que pode exacerbar outros sintomas e reduzir a qualidade de vida. A espasticidade ocorre entre 60 a 84% dos pacientes, sendo os sintomas mais comuns associados: rigidez, espasmos e restrições de mobilidade, que ocorrem em cerca de três quartos dos pacientes, avaliados pelos médicos. Outros sintomas comuns incluem fadiga, dor e disfunção da bexiga. O tratamento não farmacológico geralmente inclui evitar fatores desencadeantes e fisioterapia regular. No Sistema Único de Saúde (SUS) está disponível para tratamento da espasticidade, de acordo com o Protocolo Clínico e Diretrizes Terapêuticas de Espasticidade, duas apresentações de toxina botulínica tipo A. A literatura descreve outros tratamentos como baclofeno, tizanidina e gabapentina. PERGUNTA: Tetraidrocanabinol + canabidiol (Mevatyl®) é eficaz e seguro para o tratamento da espasticidade moderada à grave associada à EM em pacientes adultos? EVIDÊNCIAS CLÍNICAS: Após a análise das evidências apresentadas pelo demandante foram incluídos sete ensaios clínicos, uma análise derivada de ensaio clínico e uma revisão sistemática. O demandante apresentou uma meta-análise, no entanto, como alguns estudos permitiram doses superiores a 12 sprays/dia, mesmo que a dose média dos estudos tenha sido menor que a estabelecida em bula, a Secretaria Executiva da Conitec optou por refazer as análises separando estes estudos. Em todas as avaliações, o THC:CBD foi associado a uma melhora média maior da espasticidade quando avaliada pela escala de Ashworth em comparação com o placebo, mão não foi estatisticamente significativo. Quando avaliada pela escala subjetiva foi associado a uma melhora significativa. Adicionalmente, o THC:CBD proporcionou uma redução significativa de ≥ 30% no escore de espasticidade avaliada pela escala NRS, considerada uma diferença clinicamente importante. A evidência foi considerada de baixa qualidade. AVALIAÇÃO ECONÔMICA: Com o preço proposto para incorporação de R$ 1.445,24, o custo mensal de THC:CBD como adjuvante a terapia padrão seria de R$ 1.597,36. Foi estimado um ganho de 0,55 anos de vida ajustados pela qualidade a mais com o tratamento com THC:CBD comparado ao tratamento padrão isolado, e 1,98 meses de controle da doença a mais que a terapia padrão. O custo incremental do tratamento com THC:CBD ao longo de 30 anos foi estimado em R$ 11.724,82 a mais que o custo do tratamento padrão, resultando em uma RCEI de R$21.271,79/QALY. O custo incremental por mês de controle da doença foi de R$ 5.438,76, resultando em uma RCEI de R$2.743,29/mês de espasticidade controlada. Há incertezas no desfecho por QALY pois a na estimativa da utilidade não incluiu população brasileira. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O demandante estimou que entre 823 a 859 pacientes seriam elegíveis e teriam acesso ao medicamento em cinco anos, com impacto orçamentário ao SUS estimado entre R$ 1,3 milhões, chegando a R$ 9,1 milhões no último ano dependendo da difusão de mercado adotada (Caso-base: 10% ao ano e Caso-alternativo: primeiro ano de 25%, com crescimento de 10% ao ano até 65% em 5 anos). Entretanto, foram identificadas algumas discrepâncias na população do modelo apresentado pelo demandante, com a população passando para 918 no primeiro ano a 958 no quinto ano. O impacto orçamentário utilizando a distribuição de mercado do caso-base, no primeiro ano seria de R$ 1,49 milhão, chegando a R$ 7,8 milhões em cinco anos. Já para o cenário do caso alternativo, no primeiro ano o impacto seria de 3,7 milhões e no quinto ano, com 65% dos pacientes recebendo o tratamento, 10,14 milhões. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Para a elaboração desta seção, realizaram-se buscas estruturadas nos campos de pesquisa das bases de dados ClinicalTrials.gov e Cortellis™, a fim de localizar medicamentos potenciais para tratamento sintomático da espasticidade moderada a grave relacionada à esclerose múltipla. Dessa forma, foram detectados dois medicamentos potenciais para a indicação terapêutica em questão, o arbaclofeno e o dronabinol. CONSIDERAÇÕES FINAIS: O THC:CBD proporciona uma diminuição da espasticidade subjetiva quando comparados com placebo, mas não apresentou nenhuma alteração na espasticidade medida objetivamente (escalas de Ashworth e Ashworth modificada). Embora o número total de eventos adversos seja maior que o placebo, o medicamento foi seguro no tratamento da espasticidade em pacientes com EM. As evidências foram consideradas de baixa qualidade. Não há evidências de estudos que avaliem a eficácia de canabinoides em comparação com outros tratamentos ativos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: No dia 06 de agosto de 2020, em sua 89ª reunião de plenário, os membros da Conitec recomendaram preliminarmente a não incorporação da associação tetraidrocanabinol + canabidiol como tratamento adjuvante para melhoria dos sintomas de pacientes adultos com espasticidade moderada a grave devido à esclerose múltipla que não responderam adequadamente a outra terapia. O plenário considerou que o medicamento só apresentou benefício quando avaliado por escala subjetiva e a ausência de eficácia do fitofármaco na redução da espasticidade por escala objetiva comparado ao placebo, além disso os estudos apresentaram médio a alto risco de viés, o que tornou a evidência de baixa qualidade. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: o Relatório de Recomendação da Conitec foi disponibilizado por meio da Consulta Pública nº 04/2020 entre os dias 15/09/2020 e 05/10/2020. Foram recebidas 306 contribuições, sendo 4 técnico-científicas e 302 contribuições de experiência ou opinião. Os principais temas presentes nas contribuições de experiência e opinião foram referentes a: eficácia; qualidade de vida; melhora da dor e segurança do tratamento. Foram recebidas referências estudos científicos, no entanto não foram consideradas no presente documento por não se enquadrarem na pergunta PICO. A Beaufour Ipsen Ltda - empresa fabricante da tecnologia avaliada reforçou os dados de eficácia do THC:CBD na redução da gravidade da espasticidade relacionada à EM e sintomas associados, como espasmos ou distúrbios do sono. Também abordaram a validade da escala NRS, por se tratar de muitas vezes ser desfecho primário dos estudos clínicos, incluindo ensaios controlados e de vida real e se tratar de um desfecho centrado no paciente com relevância clínica. Com relação a parte econômica, o demandante retrata que realizou vários cenários na avaliação de custo-efetividade: 1) inclusão de probabilidade e de custos relacionados a eventos adversos; 2) utilização do desfecho clínico NRS ≥ 30% (diferença clinicamente importante); 3) sub análise considerando o fornecimento gratuito de Mevatyl® no primeiro mês de tratamento; 5) comparador baclofeno, tizanidina e diazepam. No entanto, de modo geral, os resultados sofreram poucas alterações em relação àquelas apresentadas no documento de submissão. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 92ª reunião ordinária, no dia 03 de novembro de 2020, deliberaram por unanimidade recomendar a não incorporação tetraidrocanabinol (THC) 27 mg/ml + canabidiol (CBD) 25 mg/ml como tratamento adjuvante para melhoria dos sintomas de pacientes adultos com espasticidade moderada a grave devido à esclerose múltipla que não responderam adequadamente a outra terapia. Os membros presentes na reunião consideraram que não houve evidências adicionais para mudar a recomendação preliminar e que ainda há incertezas sobre a eficácia do fitofármaco. Também foi pontuado que existem outros tratamentos para espasticidade, assim há uma necessidade de avaliação ampla dessas tecnologias. Foi assinado o Registro de Deliberação nº 572/2020. DECISÃO: Não incorporar o tetraidrocanabinol 27mg/ml + canabidiol 25mg/ml para o tratamento sintomático da espasticidade moderada a grave relacionada à esclerose múltipla, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 59, publicada no Diário Oficial da União nº 228, seção 1, página 717, em 1º de dezembro de 2020.

Long-term assessment of the cognitive effects of nabiximols in patients with multiple sclerosis: A pilot study.

OBJECTIVE: Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods. The aim of this prospective pilot study was to assess the long-term effects of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex®) on cognition, mood and anxiety. PATIENTS AND METHODS: An extensive and specific battery of neuropsychological tests (Symbol Digit Modalities Test-SDMT, California Verbal Learning Test-CVLT, Brief Visuospatial Memory Test-BVMT; PASAT-3 and 2; Free and Cued Selective Remind Test-FCSRT, Index of Sensitivity of Cueing-ISC) was applied to longitudinally investigate different domains of cognition in 20 consecutive MS patients receiving Sativex for spasticity. The primary endpoint was to assess any variation in cognitive performance. Secondary outcomes regarding mood and anxiety were investigated by means of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Any change in patients' spasticity was evaluated using the 0-10 Numerical Rating Scale (NRS). RESULTS: Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p < 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p < 0.0001). CONCLUSIONS: These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility.

Cost-Effectiveness Analysis of Cannabinoid Oromucosal Spray Use for the Management of Spasticity in Subjects with Multiple Sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a highly symptomatic disease, with a wide range of disabilities affecting many bodily functions, even in younger persons with a short disease history. The availability of a cannabinoid oromucosal spray (Sativex) for the management of treatment-resistant MS spasticity has provided a new opportunity for many patients. OBJECTIVE: Our study aimed to assess the cost effectiveness of Sativex in Italian patients with treatment-resistant MS spasticity. The analysis was based on the real-world data of a large registry of Italian patients. METHODS: A cost-utility analysis was conducted using data collected prospectively from an electronic registry of all patients who began to use Sativex for MS-resistant spasticity between January 2014 and February 2015 in 30 specialized MS units across Italy and were followed up for ≤ 6 months. Data on drug consumption and spasticity/utility were used to estimate the incremental cost-effectiveness ratio (ICER) of Sativex, as compared with no intervention. No costs or spasticity/utility changes were assumed for no treatment intervention. The ICER was expressed as quality-adjusted life-years (QALYs) gained, using the Italian NHS perspective and a 6-month time horizon. RESULTS: Sativex effectiveness and consumption was estimated analyzing data of 1350 patients from the registry. These patients reported a mean (SD) utility increment of 0.087 (0.069) after 1 month of treatment, 0.118 (0.073) after 3 months' treatment and 0.127 (0.080) after 6 months' treatment. The 6-month cost of treating the entire population with Sativex was €1,361,266, with a €1008 cost and 0.0284 QALYs gained per patient. The estimated ICER was €35,516 per QALY gained, with little variability around the central estimate of cost-effectiveness, as shown by the cost-effectiveness acceptability curve. CONCLUSION: The use of Sativex could improve the quality of life of patients with a reasonable incremental cost resulting as a cost-effective option for patients with MS-resistant spasticity. These results could help clinicians and decision makers to develop improved management strategies for spasticity in patients with MS, optimizing the use of available resources.