Complex Regional Pain Syndrome in Cancer Cases: Current Knowledge and Perspectives.

Background: Complex regional pain syndrome (CRPS) is a disabling painful disorder caused by many different and poorly understood mechanisms. It often affects the distal limbs and usually happens as consequence of a trauma. Its severity can remarkably affect patients' quality of life. When this painful complication happens in a cancer patient, the impact may be exponential. To date, there is limited knowledge of the surrounding circumstances of CRPS cases in this population. Methods: We present two clinical cases of patients diagnosed with cancer-related pain presenting with symptoms and signs compatible with CRPS. In one case, CRPS was attributed to direct tumor nerve compression, and it responded successfully to an interventional pain procedure. The second case was associated with a Zoster infection in an immunocompromised cancer patient. Patient responded to multidisciplinary pain management strategies. Additionally, we conducted a literature review to investigate the coexistence of cancer pain and CRPS and suggest some pathophysiology mechanisms of action. Results and Discussion: Literature reviewed and potential pathophysiology mechanisms are simultaneously explored in terms of classification, etiopathology, evidence, challenges, and future scientific directions. Conclusion: Comorbid CRPS can impact negatively in cases of cancer pain by affecting their diagnosis and treatment. Further studies are necessary to elucidate how these two conditions present together and how they can be better addressed.

Pulsed radiofrequency to stellate ganglion for brachial plexus injury-induced complex regional pain syndrome: A case series.

Brachial plexus injury (BPI) occurs commonly in young adults following trauma. This may result in the development of complex regional pain syndrome (CRPS) following injury, which is difficult to treat. We present a group of patients with CRPS secondary to BPI. These patients were managed with neuromodulation of the stellate ganglion (SG) with pulsed radiofrequency (PRF) and followed up for a period of 3 months to assess for pain relief and a decrease in the intake of medications after the intervention. PRF to SG was found to have significant pain relief lasting around three months.

Causalgia: A Review of Nerve Resection, Amputation, Immunotherapy, and Amputated Limb CRPS II Pathology.

BACKGROUND: Causalgia and complex regional pain syndrome (CRPS) type II with nerve injury can be difficult to treat. Surgical peripheral nerve denervation for causalgia has been largely abandoned by pain clinicians because of a perception that this may aggravate a central component (anesthesia dolorosa). METHODS: We selectively searched Pubmed, Cochrane, MEDLINE, EMBASE, CINAHL Plus, and Scopus from 1947 for articles, books, and book chapters for evidence of surgical treatments (nerve resection and amputation) and treatment related to autoimmunity and immune deficiency with CRPS. RESULTS: Reviews were found for the treatment of causalgia or CRPS type II (n = 6), causalgia relieved by nerve resection (n = 6), and causalgia and CRPS II treated by amputation (n = 8). Twelve reports were found of autoimmunity with CRPS, one paper of these on associated immune deficiency and autoimmunity, and two were chosen for discussion regarding treatment with immunoglobulin and one by plasma exchange. We document a report of a detailed and unique pathological examination of a CRPS type II affected amputated limb and related successful treatment with immunoglobulin. CONCLUSIONS: Nerve resection, with grafting, and relocation may relieve uncomplicated causalgia and CRPS type II in some patients in the long term. However, an unrecognized and treatable immunological condition may underly some CRPS II cases and can lead to the ultimate failure of surgical treatments.

Ketamine for Complex Regional Pain Syndrome: A Narrative Review Highlighting Dosing Practices and Treatment Response.

This is a narrative review of intravenous ketamine infusions for the treatment of complex regional pain syndrome (CRPS). It briefly covers the definition of CRPS, its epidemiology, and other treatments before introducing ketamine as the article's focus. A summary of ketamine's evidence base and its mechanisms of action is provided. The authors then review ketamine dosages reported in peer-reviewed literature for the treatment of CRPS, and their associated duration of pain relief. The observed response rates to ketamine and predictors of treatment response are also discussed.

Clinical course of a complex regional pain syndrome type II in upper limb.

INTRODUCTION: the complex regional pain syndrome type II, also called causalgia, is a rare clinical condition that appears after a traumatic or surgical event with evidence of nervous system involvement. Its clinical presentation is the consequence of a multifactorial pathogenic process that involves peripheral and central mechanisms and has variable clinical manifestations. We present the photographic record of a patient with complex regional syndrome type II. CLINICAL CASE: 43-year-old patient who consulted for neuropathic pain during the last four years, of severe intensity, associated with sensory, vasomotor and trophic changes in the right upper limb, as a consequence of neurectomy of the palmar digital nerves of the third finger. CONCLUSION: achieving the photographic record of the clinical phases of complex regional pain syndrome type II in its entirety is difficult, because not all patients present all clinical phases, a fact that gives relevance to this case.

INTRODUCCIÓN: el síndrome doloroso regional complejo (SDRC) tipo II, también llamado causalgia, es una condición clínica poco frecuente que aparece después de un evento traumático o quirúrgico con evidencia de afectación del sistema nervioso. Su presentación clínica es consecuencia de un proceso patogénico multifactorial que involucra mecanismos periféricos y centrales y tiene manifestaciones clínicas variables. Presentamos el registro fotográfico de un paciente con síndrome regional complejo tipo II. CASO CLÍNICO: paciente de 43 años que consultó por dolor neuropático durante los últimos cuatro años, de intensidad severa, asociado a cambios sensoriales, vasomotores y tróficos en miembro superior derecho, como consecuencia de neurectomía de los nervios digitales palmares propios del tercer dedo. CONCLUSIÓN: lograr el registro fotográfico de las fases clínicas del SDRC tipo II en su totalidad resulta difícil, debido a que no todos los pacientes presentan todas las fases clínicas; hecho que otorga la relevancia a este caso.

Combining Stellate ganglion block and intravenous regional anesthesia to treat complex regional pain syndrome: A 19-years' experience in a tertiary center.

OBJECTIVES: To study reduction in pain score after treatment with intravenous regional anesthesia (IVRA) and Stellate ganglion block (SGB) combination on complex regional pain syndrome (CPRS) patients and to quantify patients' satisfaction with treatment and occurrence of complications. METHODS: This is a record-based retrospective review carried out in 2020, targeting patients treated in the University of Jordan Hospital, Amman, Jordan, over the years 2002-2020. RESULTS: Among 99 patients, a significant drop in pain scores occurred in 88% of the patients' sample. Gender, age, type of CRPS, and duration of symptoms didn't affect statistical results. An average of 8.6 sessions needed to achieve 50% drop in pain score, and 2-3 sessions for first clinical improvement. Patients with previous application of plaster of Paris had increased success rates. CONCLUSION: We find it practical, inexpensive, safe, and straightforward to combine SGB with IVRA for CRPS patients.

Clinical practice guidelines for the management of patients with complex regional pain syndrome: a systematic appraisal using the AGREE II instrument.

Aim: Complex regional pain syndrome (CRPS) is a debilitating, painful condition of limbs that often arises after an injury and is associated with significant morbidity. Materials & methods: The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument, used to assess the quality of clinical practice guidelines (CPGs), was used to evaluate seven CRPS management guideline. Results: Out of the seven CPGs evaluated using the AGREE II instrument, only one from Royal College of Physicians was found to have high-quality consensus guidelines for diagnosis and management of CRPS. Conclusion: Future CPGs should be backed by systematic literature searches, focus on guidelines clinical translation into clinical practice and applicability to the desired patient population.

Causalgia: a military pain syndrome.

Causalgia, officially known as complex regional pain syndrome type II, is a pain syndrome characterized by severe burning pain, motor and sensory dysfunction, and changes in skin color and temperature sensation distal to an injured peripheral nerve. The pain syndrome primarily tends to affect combat soldiers after they sustain wartime injuries from blasts and gunshots. Here, the authors provide a historical narrative that showcases the critical contributions of military physicians to our understanding of causalgia and to the field of peripheral nerve neurosurgery as a whole.

Impacto da dor orofacial na qualidade de vida de portadores de câncer de boca e orofaringe / Impact of orofacial pain on the quality of life of mouth and oropharynge cancer patients

RESUMO Objetivo investigar o impacto da dor orofacial na qualidade de vida de portadores de câncer de boca e orofaringe. Métodos trata-se de um estudo de corte transversal, observacional, descritivo, com amostra de conveniência. Participaram da pesquisa 30 pacientes de ambos os sexos, na faixa etária de 35 a 75 anos. Para a coleta de dados, foi utilizado questionário sociodemográfico elaborado pelos pesquisadores e o Questionário de Dor McGill. Resultados Os achados experimentais apresentaram resultados relevantes em diversos níveis classificatórios para dor orofacial. As maiores repercussões foram encontradas nos aspectos sociais, como em relação ao sono (40%), apetite/alimentação (78%), higiene pessoal (55%) e lazer (40%), que foram os subitens que tiveram maior impacto da dor na qualidade de vida dos portadores de câncer de boca e orofaringe. Conclusão Portadores de câncer de boca e orofaringe apresentam variados níveis de dor orofacial e sofrem impactos em suas vidas, principalmente nos quesitos relacionados a atividades simples do cotidiano.

ABSTRACT Purpose To investigate the impact of orofacial pain on the quality of life of patients with oral and oropharyngeal cancer. Methods This is a cross-sectional, observational, descriptive study with a convenience sample. Thirty patients of both sexes participated in the research, aged between 35 and 75 years. For data collection, a sociodemographic questionnaire prepared by the researchers, the McGuill pain protocol, was used. Results The experimental findings show us relevant results at different classification levels for orofacial pain. The greatest repercussions were found in social aspects, such as sleep (40%), appetite/food (78%), personal hygiene (55%) and leisure (40%), which were the sub-items that had the greatest impact on pain (or which were the sub-items mostly affected by pain), affecting the the quality of life of patients with oral and oropharyngeal cancer. Conclusion Under these experimental conditions, it is concluded that patients with oral and oropharyngeal cancer present different levels of orofacial pain, and suffer impacts on their lives, especially in matters related to simple daily activities.

Síndrome doloroso regional complejo, a propósito de un caso. La importancia del diagnóstico precoz / Complex regional pain syndrome. The importance of early diagnosis

El síndrome de dolor regional complejo es una enfermedad de etiopatogenia poco conocida que se desarrolla tras un fenómeno nocivo desencadenante y que se manifiesta por dolor espontáneo o alodinia/hiperalgesia no limitado a la distribución territorial de un nervio periférico y desproporcionado al episodio desencadenante. Se presenta un caso que evoluciona con dolor mantenido en el tiempo, cambios tróficos e impotencia funcional pese al uso de múltiples técnicas terapéuticas. El diagnóstico precoz y el tratamiento temprano son fundamentales para conseguir una evolución favorable y evitar complicaciones discapacitantes. (AU)

Complex regional pain syndrome is a disease of uncertain pathogenesis that develops after a harmful triggering phenomenon and manifests itself by spontaneous pain or allodynia / hyperalgesia, not limited to the territorial distribution of a peripheral nerve and disproportionate to the triggering episode. We present a case that evolves with pain maintained over time, trophic changes and functional impotence despite the use of multiple therapeutic techniques. Early diagnosis and early treatment are essential to achieve a favorable outcome and avoid disabling complications (AU)

Complex Regional Pain Syndrome: A Comprehensive Review.

Complex regional pain syndrome (CRPS) is a chronic pain condition often involving hyperalgesia and allodynia of the extremities. CRPS is divided into CRPS-I and CRPS-II. Type I occurs when there is no confirmed nerve injury. Type II is when there is known associated nerve injury. Female gender is a risk factor for developing CRPS. Other risk factors include fibromyalgia and rheumatoid arthritis. Unfortunately, the pathogenesis of CRPS is not yet clarified. Some studies have demonstrated different potential pathways. Neuropathic inflammation, specifically activation of peripheral nociceptors of C-fibers, has been shown to play a critical role in developing CRPS. The autonomic nervous system (ANS) is involved. Depending on whether it is acute or chronic CRPS, norepinephrine levels are either decreased or increased, respectively. Some studies have suggested the importance of genetics in developing CRPS. More consideration is being given to the role of psychological factors. Some association between a history of depression and/or post-traumatic stress disorder (PTSD) and the diagnosis of CRPS has been demonstrated. Treatment modalities available range from physical therapy, pharmacotherapy, and interventional techniques. Physical and occupational therapies include mirror therapy and graded motor imagery. Medical management with non-steroidal anti-inflammatory drugs (NSAIDs) has not shown significant improvement. There have been supporting findings in the use of short-course steroids, bisphosphonates, gabapentin, and ketamine. Antioxidant treatment has also shown some promise. Other pharmacotherapies include low-dose naltrexone and Botulinum toxin A (BTX-A). Sympathetic blocks are routinely used, even if their short- and long-term effects are not clear. Finally, spinal cord stimulation (SCS) has been used for decades. In conclusion, CRPS is a multifactorial condition that still requires further studying to better understand its pathogenesis, epidemiology, genetic involvement, psychological implications, and treatment options. Future studies are warranted to better understand this syndrome. This will provide an opportunity for better prevention, diagnosis, and treatment of CRPS.

Silas Weir Mitchell, MD, LLD, FRC: Neurological Evaluation and Rehabilitation of the Injured Upper Extremity.

Appreciating the history of Hand Surgery is part of what most of us enjoy about our profession. Most of us know that Silas Weir Mitchell, MD, coined the terms "Causalgia" and "Phantom Limb," yet few of us know that our present-day evaluation of the sensory and motor function of the hand and some of our rehabilitation methods for motor palsy were introduced by Mitchell as he worked, scholarly, in Turner's Lane Hospital, the first hospital devoted to nerve injuries, to understand Civil War gunshot wounds related to musket ball. Mitchell's contributions to neurosensory and motor evaluation were reviewed by reading his historical publications. Mitchell's described cervical sympathetic injury Horner's Syndrome), sensory recovery preceding motor recovery after proximal nerve injury, that more sensory information can be perceived by applying greater pressure, importance of passive joint movement to prevent contracture, value of electrical stimulation after motor palsy, value of rest to facilitate healing, ability of 1- and 2-point sensory testing to evaluate sensibility, value of testing temperature to understand neuropathology, importance of experimental peripheral nerve surgery to clinical care, recorded muscle strength by manual evaluation, staged degree of nerve injury, described Saturday night and crutch palsy, and first described Hoffmann-Tinel sign. Mitchell made signifiant and seminal observations, that have largely gone unrecognized and that we use today in care of the injured upper extremity.

The Tourniquet Ischemia Test in the Diagnosis of Complex Regional Pain Syndrome.

BACKGROUND: The tourniquet ischemia test (IT) is a hitherto rarely used tool for the diagnostic work-up of patients with suspected complex regional pain syndrome (CRPS). This analysis aims to determine the sensitivity and specificity of this test, and elucidate factors that can influence the test result. METHODS: Consecutive data on clinical presentation, results of the IT and other diagnostic tests, and clinical characteristics were analyzed from patients presenting at our autonomic laboratory between 2000 and 2011. IT results were compared with the final clinical diagnosis at discharge, and statistical analysis was performed to determine specificity, sensitivity, and positive and negative predictive values of the IT. RESULTS: A total of 78 patients were assessed. IT results were positive (≥50% reduction in pain during ischemia) in 26 cases and negative in 52 cases. CRPS was the final diagnosis in 45 cases, and in 33 cases, a different diagnosis was made. This results in a test sensitivity of 49% and a specificity of 88%, with a positive predictive value of 85% and a negative predictive value of 56%. Age, sex, the type and stage of CRPS, and the affected extremity did not influence the test result in a statistically significant manner. Specificity worsened to 76% if any pain reduction was rated as a positive test result. CONCLUSIONS: A positive tourniquet IT has a high positive predictive value for the diagnosis of CRPS. It is thus useful as a confirmatory assay in patients with suspected CRPS. Low sensitivity rules out its use as a screening test. SIGNIFICANCE: This study retrospectively analyzed the clinical significance of the tourniquet IT that was routinely used in patients with suspected CRPS. It showed that a positive IT result is useful as a confirmatory assay in patients fulfilling the clinical criteria.

Prevalência de dor odontogênica em um serviço de pronto-atendimento odontológico público do Sul do Brasil / Prevalence of odontogenic pain in a public dental urgency service in Southern Brazil

Objetivo: Identificar as principais causas de dor odontogênica que levam à busca pelo atendimento no Serviço de Pronto Atendimento Odontológico (SPAO) da Faculdade de Odontologia da Universidade de Passo Fundo (UPF), que funciona junto ao Hospital São Vicente de Paulo e está ligado ao Sistema Único de Saúde (SUS). Métodos: Realizou-se um estudo epidemiológico transversal e retrospectivo, baseado em dados de prontuários odontológicos de pacientes atendidos entre novembro de 2016 e outubro de 2017. Os dados foram analisados buscando-se a prevalência das diversas origens de dor odontogênica dos pacientes atendidos no período: pulpar (pulpite reversível, pulpite irreversível, necrose); periapical (pericementite, abscesso periapical); ou periodontal (periodontite, abscesso periodontal). Além disso, foi catalogada a conduta realizada durante os atendimentos de urgência. Resultados: Ao todo, foram analisados 1.275 prontuários. Desses, 868 pacientes (68,1%) apresentavam dor ao atendimento. Dos pacientes que relataram dor, 62,3% apresentavam dor odontogênica pulpar; 11,1%, dor periapical; e 12,2%, dor periodontal. A conduta mais adotada para tratamento da dor foi a terapia com analgésicos e/ou antibióticos (21,0% dos casos), seguida por acessos endodônticos (18,7%) e exodontias (17,9%). Conclusão: No serviço de pronto atendimento analisado, prevaleceram os casos de dor de origem pulpar. Os resultados obtidos contribuem para o desenvolvimento de estratégias de controle da dor odontogênica, bem como para a melhoria dos protocolos clínicos adotados na faculdade em questão (AU).

Objective: To identify the main causes of odontogenic pain that lead to people search for care in the Urgency Service of the School of Dentistry of University, Passo Fundo/RS/Brazil (SPAOH), localized in the Hospital São Vicente de Paulo. Methodology: A cross-sectional and retrospective study, carried out between the period from November 1, 2016 to October 31, 2017, when data from dental care records were collected and tabulated. The data were analyzed looking for the prevalence of several causes of odontogenic pain, with pulp origin (reversible, irreversible pulpitis, necrosis); periapical (pericementitis, abscess); periodontal (periodontitis); and others, in addition to the conduct performed in attendance. Results: A total of 1,275 dental records were analyzed, involving 868 patients, of which 68.1% reported the presence of pulp (62.3%), periapical (11.1%) and periodontal (12.2%) odontogenic pains. Analgesic or antibiotic therapies were the most common approaches, totaling 21.0% of cases, followed by endodontic accesses (18.7%) and extractions (17.9%). Conclusion: In the studied dental urgency service, cases of pulp pain prevail. The results obtained contribute to the development of strategies to control odontogenic pain, as well as to the improvement of clinical protocols (AU).

Complex Focal Pain Syndrome: An Unusual Variant of Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain condition that is often overlooked by clinicians and typically occurs within an entire limb. There is considerable clinical variability in presentation among patients with CRPS. We report a case of extremely focal CRPS localized to the left small finger (LSF) following crush injury. A 48-year-old right-handed male presented with LSF stiffness and severe pain of three months' duration following crush injury. He endorsed severe allodynia and minimal flexion at the proximal interphalangeal and distal interphalangeal joints of the LSF. Physical examination was significant for overt shininess and edema isolated to the LSF. X-ray performed at the time of injury and three months after were devoid of any fracture or dislocation. Chronic focal pain syndrome (CFPS) may be a subset of CRPS that has yet to be documented in the literature.

Peripheral Nerve Stimulation for the 21st Century: Sural, Superficial Peroneal, and Tibial Nerves.

OBJECTIVE: Peripheral nerve stimulation (PNS) of the lower extremity has progressed significantly over the last decade. From the proof of concept that ultrasound-guided, percutaneous implantation was possible to advances in waveforms, the field has been rapidly evolving. While most nerves in the lower extremity can be PNS targets, consideration must be given to the ergonomics of pulse generator placement, patient comfort, and avoidance of lead migration. For this paper, we examine some of the conditions amenable to lower extremity PNS, review the evidence and history behind PNS for these conditions, and describe approaches for the tibial, sural, and superficial peroneal nerves. METHODS: A literature search was conducted using PubMed. Search terms used were "peripheral nerve stimulation," "lower extremity entrapment neuropathies," "sural nerve," "superficial peroneal nerve," "tibial nerve," and "tarsal tunnel syndrome." Emphasis was placed on randomized controlled studies, anatomical dissections, and comprehensive review articles. Approaches to nerves and ultrasound images were based on anecdotal PNS cases from an experienced implanter (SP). CONCLUSIONS: The development of ultrasound as a viable method of image guidance for percutaneous peripheral nerve stimulation has led to an exponential growth in the field. Lower extremity percutaneous lead placement is both feasible and an appropriate treatment modality for certain pain conditions.

Complex regional pain syndrome secondary to sacrococcygeal dislocation following trauma to the lumbosacral region. case report

ABSTRACT Introduction: The complex regional pain syndrome (CRPS) is a rare condition characterized by inflammatory, vasomotor and central nervous system (CNS) involvement. Its clinical presentation can be subacute, acute or chronic, and may have severe effects on the patient's quality of life. Case description: 21-year-old female patient with trauma in the lumbosacral region associated with pain and functional limitation. Diagnostic imaging showed sacrococcygeal dislocation with subsequent inflammatory and acute and chronic autonomic symptoms that were treated medically and surgically. The patient responded to treatment with long-term improvement of the symptoms. Discussion: In this case, CRPS occurred after trauma and caused subacute symptoms that became even more acute until reaching a chronic presentation. Inflammation, vasomotor dysfunction and CNS involvement made this case a multidisciplinary diagnostic and therapeutic challenge. Conclusion: CRPS is a rare disease that is difficult to diagnose. However, diagnosis should be timely in order to initiate personalized treatment, since this disease considerably affects the patient's quality of life.

RESUMEN Introducción. El síndrome doloroso regional complejo (SDRC) es una patología poco frecuente que se caracteriza por causar compromiso a nivel inflamatorio, vasomotor y del sistema nervioso central (SNC). Su presentación clínica puede ser subaguda, aguda o crónica y puede afectar considerablemente la calidad de vida del paciente. Presentación del caso. Paciente femenina de 21 años con trauma en región lumbosacra asociado a dolor y limitación funcional, a quien se le practicaron imágenes diagnosticas que evidenciaron luxofractura sacrococcígea con posterior presencia de síntomas inflamatorios y autonómicos (agudos y crónicos) que se trataron con medicamentos y cirugía. La paciente respondió al tratamiento con mejoría de la sintomatología a largo plazo. Discusión. El SDRC se presentó posterior a un traumatismo y ocasionó sintomatología subaguda que se agudizó hasta llegar a la presentación crónica de la enfermedad. La inflamación, la disfunción vasomotora y el compromiso del SNC hacen de este caso un reto diagnóstico y terapéutico multidisciplinario. Conclusión. El SDRC es una patología poco frecuente y de difícil diagnóstico; sin embrago, es necesario diagnosticarlo de forma oportuna para poder iniciar un tratamiento personalizado, ya que es una enfermedad que compromete considerablemente la calidad de vida del paciente.

Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) has been described as pain a patient feels that is disproportionate to the inciting event. CRPS is also associated with autonomic dysfunction, swelling, dystrophic skin changes, stiffness, functional impairment, and eventual atrophy. This hyperalgesic disease affects musculoskeletal, neural, and vascular structures more commonly in the upper extremity than the lower extremity. Although the etiology behind the pathophysiology of CRPS is unknown, the pain pathway extending from peripheral nociception to central nervous system modulation of stimuli is highly sensitized and overactive, disrupting the surrounding autonomic response. The diagnosis and treatment of CRPS are reviewed.

Anesthetic Management of a Complex Regional Pain Syndrome (CRPS) Patient With Ketamine.

Complex regional pain syndrome (CRPS) is a potentially debilitating form of neuropathic pain that may manifest following a traumatic injury or surgery. CRPS is also known as algodystrophy, causalgia, or reflex sympathetic dystrophy (RSD). Patients describe unbearable burning pain from nonnociceptive stimuli, such as when taking a shower or brushing against another object. Regular tactile stimuli encountered during routine dental procedures may not be well-tolerated by a patient with CRPS. Ketamine infusions have been reported to help alleviate acute exacerbations or "flare-ups" of CRPS symptoms. This case report provides a brief overview of CRPS pathophysiology and treatment including data supporting the use of ketamine infusions and a discussion regarding the anesthetic management of a patient with CRPS presenting for dental care under deep sedation utilizing high-dose intravenous ketamine.