Pharmacoresponsiveness of spontaneous recurrent seizures and the comorbid sleep disorder of epileptic Kcna1-null mice.

Drug resistant epilepsy affects ∼30% of people with epilepsy and is associated with epilepsy syndromes with frequent and multiple types of seizures, lesions or cytoarchitectural abnormalities, increased risk of mortality and comorbidities such as cognitive impairment and sleep disorders. A limitation of current preclinical models is that spontaneous seizures with comorbidities take time to induce and test, thus making them low-throughput. Kcna1-null mice exhibit all the characteristics of drug resistant epilepsy with spontaneous seizures and comorbidities occurring naturally; thus, we aimed to determine whether they also demonstrate pharmacoresistanct seizures and the impact of medications on their sleep disorder comorbidity. In this exploratory study, Kcna1-null mice were treated with one of four conventional antiseizure medications, carbamazepine, levetiracetam, phenytoin, and phenobarbital using a moderate throughput protocol (vehicle for 2 days followed by 2 days of treatment with high therapeutic doses selected based on published data in the 6 Hz model of pharmacoresistant seizures). Spontaneous recurrent seizures and vigilance states were recorded with video-EEG/EMG. Carbamazepine, levetiracetam and phenytoin had partial efficacy (67%, 75% and 33% were seizure free, respectively), whereas phenobarbital was fully efficacious and conferred seizure freedom to all mice. Thus, seizures of Kcna1-null mice appear to be resistant to three of the drugs tested. Levetiracetam failed to affect sleep architecture, carbamazepine and phenytoin had moderate effects, and phenobarbital, as predicted, restored sleep architecture. Data suggest Kcna1-null mice may be a moderate throughput model of drug resistant epilepsy useful in determining mechanisms of pharmacoresistance and testing novel therapeutic strategies.

A Comprehensive Review of the Diagnosis, Treatment, and Management of Urologic Chronic Pelvic Pain Syndrome.

PURPOSE OF REVIEW: Urologic chronic pelvic pain syndrome (UCPPS) is a chronic, noncyclic pain condition which can lead to significant patient morbidity and disability. It is defined by pain in the pelvic region, lasting for greater than 3 to 6 months, with no readily identifiable disease process. The aim of this review is to provide a comprehensive update of diagnosis and treatment of UCPPS. RECENT FINDINGS: UCPPS encompasses chronic pelvic pain syndrome or chronic prostatitis (CP/CPPS) in men and interstitial cystitis or painful bladder syndrome (IC/PBS) in women. Underlying inflammatory, immunologic, and neuropathic components have been implicated in the pathogenesis of UCPPS. For optimal patient management, an individualized and multimodal approach is recommended. Medical management and physical therapy are the mainstays of treatment. Injection therapy may offer additional relief in medically refractory patients. Further minimally invasive management may include spinal cord and peripheral nerve stimulation, though evidence supporting efficacy is limited.

Postoperative Nausea and Vomiting in Paediatric Anaesthesia.

Postoperative nausea and vomiting (PONV) is a common complication in paediatric anaesthesia and is a source of significant morbidity. Various independent risk factors have been implicated in the development of paediatric PONV, including higher pain scores postoperatively, the use of opioids for pain management and the use of volatile anaesthetics for the maintenance of anaesthesia. This review of the current literature regarding the prevention and treatment of paediatric PONV is based on a search of the PubMed database, which identified published clinical trials, systematic reviews and meta-analyses. While the occurrence of PONV in many cases is difficult to avoid entirely, the risk can be mitigated by the use of multimodal nonopioid analgesic regimens, total intravenous drugs in favour of volatile anaesthetics and an appropriate regimen of prophylactic pharmacotherapy. Frequently administered drug classes for the prevention of PONV include corticosteroids, 5HT3 antagonists and anticholinergics. The clinical use of the findings in the literature may help to reduce the occurrence of PONV in children. In this review, we provide comprehensive and updated information on the risk factors contributing the occurrence of PONV in children, outline the current opinion on the drugs that are commonly used for management and provide an overview of the guidelines that are used to help establish the prophylaxis and treatment of paediatric PONV.

An Evidence-Based Review of Elagolix for the Treatment of Pain Secondary to Endometriosis.

Purpose of Review: This is a review of elagolix use for pain related to endometriosis. It summarizes the background and recent data available about the pathogenesis of endometriosis and pain that is secondary to this syndrome. It then reviews the evidence to support the use of elagolix and the indications for use. Recent Findings: Endometriosis occurs in 10% of reproductive-age women and is a common source of chronic pelvic pain, infertility, and co-morbid disorders. It usually presents with some combination of dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Treatment options may be surgical or hormonal. Traditional treatment is divided into medical and surgical. The latter, though effective, is reserved for surgical emergencies and patients failing medical management. Medical management with NSAIDs is usually limited in efficacy. It is generally based on hormonal suppression leading to atrophy of endometrial lesions. Elagolix (Orlissa) is a GnRH antagonist that suppressed the entire hypophysis-gonadal axis. Reduced levels of estrogen and progesterone lead to involution of the endometrial lesions and improvement in symptoms. Clinical trials showed that elagolix is effective in treating dysmenorrhea and non-menstrual pain that is secondary to endometriosis. It is well tolerated and has a relatively safe usage profile. Studies up to 12 months long showed continued efficacy and reduction in dysmenorrhea of up to 75%, with 50%-60% reduction in non-menstrual pain. Elagolix was found effective when compared to both placebo and alternative treatments. Summary: Endometriosis is a common syndrome that causes significant pain, morbidity, and disability, as well as financial loss. Elagolix is an effective drug in treating the symptoms of endometriosis and is a relatively safe option. Phase 4 studies will be required to evaluate the safety and efficacy of long term chronic use.

Advances in the Understanding and Management of Chronic Pain in Multiple Sclerosis: a Comprehensive Review.

PURPOSE OF REVIEW: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that can lead to severe physical, cognitive, and neurological deficits that often manifest in young adults. Central neuropathic pain is a common presenting symptom, often prompting patients to seek treatment with opioids, NSAIDS, antiepileptics, and antidepressants despite minimal effectiveness and alarming side-effect profiles. Additionally, spasticity occurs in more than 80% of MS patients and is an important consideration for further study in treatment. RECENT FINDINGS: Related to inconsistencies in pain presentation and clinical reporting, current studies continue to investigate clinical patient presentation to define chronic pain characteristics to optimize treatment plans. Although often neuropathic in origin, the complex nature of such pain necessitates a multimodal approach for adequate treatment. While psychiatric comorbidities typically remain unchanged in their severity over time, physical conditions may lead to worsening chronic pain long-term, often due to decreased quality of life. The prevalence of neuropathic pain is ~ 86% in patients with multiple sclerosis and most commonly presents as extremity pain, trigeminal neuralgia, back pain, or headaches. As MS symptoms are frequently unremitting and poorly responsive to conventional medical management, recent attention has been given to novel interventions for management of pain. Among these, medicinal cannabis therapy, targeted physical therapy, and neuromodulation offer promising results. In this review, we provide a comprehensive update of the current perspective of MS pathophysiology, symptomatology, and treatment.

Minimally Invasive Interventional Management of Osteoarthritic Chronic Knee Pain.

Chronic knee pain is a widely prevalent issue that can have a significant impact on a patient's quality of life. One of the leading causes of chronic knee pain is osteoarthritis. Total knee replacement is often the last and definitive resort for patients with severe symptomatic osteoarthritis after trial of less invasive interventions with failure to achieve symptomatic relief. Intra-articular injections are a mainstay of adjunctive conservative management and have demonstrated efficacy in reducing pain. Radiofrequency treatment is a viable option for poor surgical candidates, or for patients having persistent, chronic pain following knee surgery. Extracorporeal shockwave therapy is another modality growing in use that may offer short-term symptomatic relief. In this review, we will discuss widely used minimally invasive interventional options for the symptomatic management of osteoarthritic chronic knee pain.