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Introduction: There is a great need to find alternative treatments for chronic pain which have become a healthcare problem. We discuss current therapeutic targeting Nav1.7. Areas Covered: Nav1.7 is a sodium ion channel protein that is associated with several human pain genetic syndromes. It has been found that mutations associated with Nav1.7 lead to the loss of the ability to perceive pain in individuals that are otherwise normal. Several therapeutic interventions are presently undergoing preclinical and research using the methodology of damping Nav1.7 expressions as a methodology to decrease the sensation of pain leading to analgesia. Expert Opinion: It is our strong belief that there is a viable future in the targeting of protein of Nav1.7 for the relief of chronic pain in humans. The review will look at the genomics associated with SCN1A and proteomic of Nav1.7 as a foundation to explain the mechanism of the therapeutic interventions targeting Nav1.7, the human disease that are associated with Nav1.7, and the current development of treatment for chronic pain whether in preclinical or clinical trials targeting Nav1.7 expressions. The development of therapeutic antagonists targeting Nav1.7 could be a viable alternative to the current treatments which have led to the opioid crisis. Therefore, Nav1.7 targeted treatment has a major clinical significance that will have positive consequences as it relates to chronic pain interventions.
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Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.
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PURPOSE: To report a case of neurotrophic keratopathy (NK) in a patient with complex regional pain syndrome (CRPS) with ipsilateral facial involvement. METHODS: Case report. RESULTS: An 18-year old woman with a 5-year history of CRPS type I, a systemic disorder with a neuropathic component with associated limb and right facial involvement, presented with an insidious onset of blurred vision and pain in the right eye. Ocular examination revealed decreased corneal sensation, as measured by Cochet-Bonnet testing, associated with recurrent epithelial defects and whorl-like superficial corneal epitheliopathy. NK was suspected and confirmed by in vivo confocal microscopy (IVCM), which revealed rarefaction of the subbasal nerve plexus in the affected eye. To enhance corneal nerve health, plasma rich in growth factors drops were used. Persistence of NK prompted a superficial keratectomy with placement of an amniotic membrane graft and a course of cenegermin 0.002% (Oxervate; Dompé Farmaceutici SpA, Italy) in the postoperative period. This combination therapy resulted in successful epithelial closure and vision improvement after 8 weeks of therapy with no recurrence of disease for 11 months. Importantly, at that final visit, IVCM demonstrated growth of corneal nerves for the first time in this patient. CONCLUSIONS: This is the first case report of NK occurring in the context of CRPS, a neuropathy with ipsilateral facial pain involvement. IVCM was important in the diagnosis of NK, which responded successfully to ocular surface treatments focused on nerve health stimulation that ultimately resulted in corneal nerve growth.
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Síndromes da Dor Regional Complexa/complicações , Córnea/inervação , Doenças da Córnea/etiologia , Doenças do Nervo Trigêmeo/complicações , Adolescente , Curativos Biológicos , Síndromes da Dor Regional Complexa/diagnóstico , Córnea/diagnóstico por imagem , Doenças da Córnea/diagnóstico , Doenças da Córnea/terapia , Feminino , Humanos , Ceratectomia/métodos , Microscopia Confocal , Fator de Crescimento Neural/administração & dosagem , Soluções Oftálmicas/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Doenças do Nervo Trigêmeo/diagnósticoRESUMO
There is no question that the opioid use problem in America has reached unacceptable proportions. What is in question, however, is the best way to address this problem. Unfortunately, this is a multidimensional problem that will not be solved with a simple unidimensional solution. This commentary examines the multidimensional nature of this problem and the resultant guidelines that have been proposed to address it. There is a cautionary tale of the historical dangers of applying an "obvious" solution to a problem, only to find that more investigation and an iterative approach can actually lead to the correct solution. In particular, the authors question the wisdom of implementing guidelines that have no provisions for re-examination, to assess both intended as well as unintended consequences that might occur. This is the standard for good evidence-based guideline development and implementation. To do less, even under such dire circumstances as these, is to provide less than optimum medical care.
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Patients experiencing a terminal drug related event reflect a sentinel event. If this pharmacotherapy is a widely used agent, it may be viewed as a catastrophic problem. If patients are dying from illegal drug use when the medical establishment fails them by withdrawing or minimizing their medically prescribed medication, then the burden rests with their health care providers, legislation, and insurance carriers to actively participate in a collegial fashion to achieve parity. Causing a decay in functionality in previously functional patients, may occur with appropriately prescribed opioid medications addressing non-cancer pain when withdrawing or diminishing either with or without patient consent. The members of the medical profession have diminished their prescribing of opioids for their patients out of apparent fear of reprisal, state or federal government sanctions, and other concerned groups. Diminishing former dosages or deleting the opioid medication, preferably in concert with the patient, often results in inequitable patient care. Enforcing sanctioned decreases or ceasing to prescribe from their former required/established opioid medications precipitate patient discord. In absence of opioid misuse, abuse, diversion or addiction based upon medical "guidelines" and with a poor foundation of Evidence Based Medicine the CDC guidelines, it may be masked as a true guideline reflecting a decrement of clinical judgment, wisdom, and compassion. This article also discusses the role of pharmacy chains, insurance carriers, and their pharmacy benefit managers (PBMs) contribution to this multidimensional problem. There may be a potential solution, identified in this paper, if all the associated political, medical and insurance groups work cohesively to improve patient care. This article and the CDC guidelines are not focused at hospice, palliative, end of life care pain management.
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Analgésicos Opioides/efeitos adversos , Analgésicos/efeitos adversos , Centers for Disease Control and Prevention, U.S./legislação & jurisprudência , Transtornos Relacionados ao Uso de Opioides/mortalidade , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Centers for Disease Control and Prevention, U.S./organização & administração , Indústria Farmacêutica/economia , Uso Indevido de Medicamentos/mortalidade , Uso Indevido de Medicamentos/estatística & dados numéricos , Overdose de Drogas/epidemiologia , Overdose de Drogas/mortalidade , Medicina Baseada em Evidências/legislação & jurisprudência , Feminino , Pessoal de Saúde/legislação & jurisprudência , Humanos , Seguro Saúde/economia , Seguro Saúde/legislação & jurisprudência , Seguro Saúde/estatística & dados numéricos , Masculino , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Guias de Prática Clínica como Assunto/normas , Estados Unidos/epidemiologiaRESUMO
Headache attributed to temporomandibular disorders (TMDH) is defined as a secondary headache by the International Classification of Headache Disorders 3rd edition (ICHD-3). OBJECTIVE: The objective of this case-control study is to investigate the phenotypic characteristics of chronic TMD with and without TMDH. We hypothesize that chronic TMD with TMDH is associated with increased number of bodily pain conditions, more painful sites in the head and neck region, and greater TMD pain intensity. METHODS: This is a retrospective cross-sectional review of the medical records of consecutive patients who sought treatment at the University of North Carolina Orofacial Pain Clinic between 2013 and 2014. The inclusion criterion was a diagnosis of myalgia or arthralgia according to the Research Diagnostic Criteria for Temporomandibular Disorders. In addition, cases had a diagnosis of TMDH according to the ICHD-3 criteria. Data on the presence and the number of self-reported bodily pain conditions (such as fibromyalgia and low back pain), pain intensity, number of painful sites in the head and neck upon palpation, and TMD pain onset were analyzed. RESULTS: A total of 295 records were reviewed. Thirty-four (29.3%) patients fulfilled inclusion criteria for cases (TMD+TMDH) and 82 (70.7%) for controls (TMD-TMDH). Cases reported greater number of bodily pain conditions than controls, with a mean of 1.97 ± 1.50 and 1.26 ± 1.28 of bodily pain conditions, respectively (P = .012, OR = 1.43 [95% CI 1.07-1.92]). In fact, 55.9% of cases reported at least 2 comorbid pain conditions compared to 37.8% controls (P = .044). Compared to controls (8.65 ± 5.32), cases (13.05 ± 4.46) exhibited greater number of painful sites upon palpation in the head and neck region (P < .0001, OR = 1.18 [95% CI 1.09-1.30]), and greater TMD pain intensity, with a mean of 6.00 ± 2.17 for cases and 5.09 ± 2.14 for controls (P = .041, OR = 1.22 [95% CI 1.01-1.47]). CONCLUSION: In a population of patients with chronic TMD seeking pain management, TMDH was significantly associated with an increased number of self-reported bodily pain conditions, a greater number of painful sites in the head and neck regions, and higher TMD pain intensity.
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Cefaleia/etiologia , Dor/epidemiologia , Transtornos da Articulação Temporomandibular/complicações , Adulto , Idoso , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Feminino , Cefaleia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/epidemiologia , Cervicalgia/epidemiologia , Especificidade de Órgãos , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
In Primary Headache Disorders, Part 1, we discuss three of the primary headache disorders using the headache definitions from ICHD-III (Beta): Migraine, with and without aura; its pathophysiology and treatment are discussed. We then discuss the Trigeminal Autonomic Cephalalgias (TACs), including Cluster Headache and Hemicrania Continua, two more primary headache disorders, as well as the other TAC Headaches. We discuss pathophysiology as well as diagnosis, treatment, and pharmacotherapeutic management of these headache diatheses.
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Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/fisiopatologia , Cefalalgias Autonômicas do Trigêmeo/diagnóstico , Cefalalgias Autonômicas do Trigêmeo/fisiopatologia , Feminino , Nível de Saúde , Humanos , Masculino , Transtornos de Enxaqueca/classificação , Medição de Risco/estatística & dados numéricos , Cefalalgias Autonômicas do Trigêmeo/classificaçãoRESUMO
In Part 2 of Primary Headache disorders, we discuss the fourth Primary Headache Disorder, Tension-Type Headache (TTHA). We are again using the ICHD-III (Beta) definitions of such headaches, taking into consideration episodic and chronic TTHA, as well as the presence or absence of pericranial muscle tenderness. We discuss the pathophysiology and pharmacotherapeutic treatment of TTHA, and the aspects of the Myofascial Pain Syndrome that enhance and help the development of TTHA. We then discuss Medication Overuse Headache (MOH), itself a Secondary headache disorder, but one that is extremely important as it assists with the chronification of both migraine and TTHA. Finally we discuss how to manage and treat those patients with MOH. Chronic migraine, which is TTHA, Migraine as well as, in many patients, MOH, is discussed along with the treatment of this multifaceted disorder.
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Transtornos da Cefaleia Secundários , Manejo da Dor/métodos , Cefaleia do Tipo Tensional , Tomada de Decisão Clínica , Diagnóstico Diferencial , Transtornos da Cefaleia Secundários/diagnóstico , Transtornos da Cefaleia Secundários/fisiopatologia , Transtornos da Cefaleia Secundários/terapia , Humanos , Medição da Dor/métodos , Assistência Centrada no Paciente , Fatores de Risco , Cefaleia do Tipo Tensional/diagnóstico , Cefaleia do Tipo Tensional/fisiopatologia , Cefaleia do Tipo Tensional/terapiaRESUMO
This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.
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Dor Aguda/dietoterapia , Analgésicos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Medição da Dor/normas , Projetos de Pesquisa , Ensaios Clínicos como Assunto/normas , Humanos , Projetos de Pesquisa/normasRESUMO
Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.
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Dor Crônica/terapia , Ensaios Clínicos como Assunto/normas , Manejo da Dor/normas , Guias de Prática Clínica como Assunto/normas , Projetos de Pesquisa/normas , Pesquisa Biomédica/métodos , Pesquisa Biomédica/normas , Dor Crônica/diagnóstico , Ensaios Clínicos como Assunto/métodos , Congressos como Assunto/normas , Humanos , Manejo da Dor/métodos , Fatores de TempoAssuntos
Analgésicos Opioides/administração & dosagem , Aprovação de Drogas/legislação & jurisprudência , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Dor/tratamento farmacológico , Comitês Consultivos/organização & administração , Analgésicos Opioides/efeitos adversos , Humanos , Estados Unidos , United States Food and Drug Administration/organização & administraçãoRESUMO
Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.
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Dor Crônica/terapia , Ensaios Clínicos como Assunto , Projetos de Pesquisa , Dor Crônica/tratamento farmacológico , Humanos , Tamanho da AmostraRESUMO
Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.
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Analgésicos , Dor/tratamento farmacológico , Dor/epidemiologia , Uso Indevido de Medicamentos sob Prescrição/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto , Determinação de Ponto Final , Humanos , Medição da Dor , População , Uso Indevido de Medicamentos sob Prescrição/psicologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Estudos Retrospectivos , Risco , Fatores de Risco , Fatores Socioeconômicos , Detecção do Abuso de Substâncias , Terminologia como AssuntoRESUMO
A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.
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Analgésicos Opioides/efeitos adversos , Ensaios Clínicos como Assunto/normas , Neurologia/normas , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/etiologia , Avaliação de Resultados em Cuidados de Saúde/normas , Guias de Prática Clínica como Assunto , Humanos , Internacionalidade , Medição de RiscoRESUMO
A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.
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Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Dor Crônica/epidemiologia , Dor Crônica/psicologia , Humanos , Manejo da Dor/métodos , Manejo da Dor/normasRESUMO
UNLABELLED: AIMS To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects. METHODS: Double-blind, randomized, placebo-controlled single and multiple rising dose studies and an open-label, randomized, food effect study were conducted. Plasma and urine PF-04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed. RESULTS: PF-04457845 was rapidly absorbed (median t(max) 0.5-1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady-state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5- to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated. CONCLUSIONS: PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.
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Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piridazinas/farmacologia , Ureia/análogos & derivados , Adulto , Amidoidrolases/metabolismo , Análise de Variância , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Ureia/efeitos adversos , Ureia/farmacocinética , Ureia/farmacologia , Adulto JovemRESUMO
"Animal Models of Neural Disease" was the focus of General Session 5 at a 2010 scientific symposium that was sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The objective was to consider issues that dictate the choice of animal models for neuropathology-based studies used to investigate neurological diseases and novel therapeutic agents to treat them. In some cases, no animal model exists that recapitulates the attributes of the human disease (e.g., fibromyalgia syndrome). Alternatively, numerous animal models are available for other conditions, so an essential consideration is selecting the most appropriate experimental system (e.g., Alzheimer's disease). New technologies (e.g., genetically engineered rodent models) promise the opportunity to generate suitable animal models for syndromes that currently lack any in vivo animal model, while in vitro models offer the opportunity to evaluate xenobiotic effects in specific neural cell populations. The complex nature of neurological disease requires regular reassessment of available and potential options to ensure that animal-derived data sets support translational medicine efforts to improve public health.