SciCombinator

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Concept: Ketamine

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To describe the incidence of recorded mental illness and challenging behaviour in people with intellectual disability in UK primary care and to explore the prescription of psychotropic drugs in this group.

Concepts: Epidemiology, Ketamine, Opioid, Recreational drug use, Psychoactive drug, Drug

171

There is growing evidence that impaired sensory-processing significantly contributes to the cognitive deficits found in schizophrenia. For example, the mismatch negativity (MMN) and P3a event-related potentials (ERPs), neurophysiological indices of sensory and cognitive function, are reduced in schizophrenia patients and may be used as biomarkers of the disease. In agreement with glutamatergic theories of schizophrenia, NMDA antagonists, such as ketamine, elicit many symptoms of schizophrenia when administered to normal subjects, including reductions in the MMN and the P3a. We sought to develop a nonhuman primate (NHP) model of schizophrenia based on NMDA-receptor blockade using subanesthetic administration of ketamine. This provided neurophysiological measures of sensory and cognitive function that were directly comparable to those recorded from humans. We first developed methods that allowed recording of ERPs from humans and rhesus macaques and found homologous MMN and P3a ERPs during an auditory oddball paradigm. We then investigated the effect of ketamine on these ERPs in macaques. As found in humans with schizophrenia, as well as in normal subjects given ketamine, we observed a significant decrease in amplitude of both ERPs. Our findings suggest the potential of a pharmacologically induced model of schizophrenia in NHPs that can pave the way for EEG-guided investigations into cellular mechanisms and therapies. Furthermore, given the established link between these ERPs, the glutamatergic system, and deficits in other neuropsychiatric disorders, our model can be used to investigate a wide range of pathologies.

Concepts: Ketamine, Phencyclidine, Electroencephalography, Excitotoxicity, Macaque, Rhesus Macaque, Primate, NMDA receptor

160

Opioid analgesic overdose mortality continues to rise in the United States, driven by increases in prescribing for chronic pain. Because chronic pain is a major indication for medical cannabis, laws that establish access to medical cannabis may change overdose mortality related to opioid analgesics in states that have enacted them.

Concepts: Hydrocodone, Morphine, Ketamine, Tetrahydrocannabinol, Analgesic, Pain, Cannabis, Opioid

103

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response and non-adherence. Here we provide new support for the antidepressant effect of an anesthetic drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System. The results of the examination of population scale data revealed that patients who received ketamine had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain. The analysis also revealed that patients who took ketamine had significantly lower frequency of reports of pain and opioid induced side effects, implying ketamine’s potential to act as a beneficial adjunct agent in pain management pharmacotherapy. Further, the Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant action of other currently approved therapeutics including diclofenac and minocycline.

Concepts: Therapeutic effect, Classification of Pharmaco-Therapeutic Referrals, Therapy, Recreational drug use, Morphine, Pharmacology, Opioid, Ketamine

45

The intranasal route for medication administration is increasingly popular in the emergency department and out-of-hospital setting because such administration is simple and fast, and can be used for patients without intravenous access and in situations in which obtaining an intravenous line is difficult or time intensive (eg, for patients who are seizing or combative). Several small studies (mostly pediatric) have shown midazolam to be effective for procedural sedation, anxiolysis, and seizures. Intranasal fentanyl demonstrates both safety and efficacy for the management of acute pain. The intranasal route appears to be an effective alternative for naloxone in opioid overdose. The literature is less clear on roles for intranasal ketamine and dexmedetomidine.

Concepts: Ketamine, Naloxone, Intravenous therapy, Medicine, Morphine, Heroin, Opioid, Midazolam

35

Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent “two-hit hypothesis” of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.

Concepts: Recreational drug use, Protein, Receptor, Ketamine, Morphine, Opioid receptor, Pain, Opioid

31

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.Molecular Psychiatry advance online publication, 15 October 2013; doi:10.1038/mp.2013.130.

Concepts: Nitrous oxide, Ketamine, Pharmacology, Phencyclidine, Dextromethorphan, NMDA receptor

31

Ear tattooing is a routine procedure performed on laboratory, commercial and companion rabbits for the purpose of identification. Although this procedure is potentially painful, it is usually performed without the provision of analgesia, so compromising animal welfare. Furthermore, current means to assess pain in rabbits are poor and more reliable methods are required. The objectives of this study were to assess the physiological and behavioural effects of ear tattooing on rabbits, evaluate the analgesic efficacy of topical local anaesthetic cream application prior to this procedure, and to develop a scale to assess pain in rabbits based on changes in facial expression.

Concepts: Local anesthetics, Ketamine, Suffering, Prilocaine, Morphine, Pain, Opioid, Lidocaine

29

Self-mutilation (SM) not only occurs among patients with schizophrenia, personality disorders or transsexuality but also as a phenomenon induced by psychotropic substances (PS). We intended to find characteristics of patients at risk to perform SM induced by PS (SMIPS), frequent PS within this phenomenon and typical presentations of SMIPS. A systematic review of the literature (including Medline, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and Scopus) was conducted. On October 2011 we identified 26 cases (23 publications) of SM related to PS. Majority of patients (85%) was male, mean age was 30 years (median 41 years). Seventy-three percent of patients developed SM subsequent to the use of one PS, 27% presented SM after the use of more than one PS. Alcohol (25%), hallucinogens (25%) and amphetamines (22%) were found most frequently among the reported substances. Major impairment was present in 80%. Our findings suggest male sex, young age, a previous history of abuse of PS and the current use of alcohol, hallucinogens or amphetamines to favour SMIPS.

Concepts: Ketamine, Randomized controlled trial, Systematic review, Convention on Psychotropic Substances, Evidence-based medicine

28

AIMS: To review the recreational use of ketamine (“Special K”; KET) and explore the recent diffusion of its new derivative methoxetamine (“Special M”; MXE). METHODS: The literature search on the nonclinical/recreational use of KET and MXE was carried out in a range of medical databases. Considering the limitations of peer-reviewed information, data were integrated with a qualitative assessment of a range of websites, drug fora, and other online resources including e-newsgroups, chat rooms, mailing lists, e-newsletters, and bulletin boards. RESULTS: The recreational use of KET has started since its discovery in 1962. This was due to its rapid onset, short duration of action, and peculiar psychotropic effects (“K-hole”). The latter effect ranges from confusion to dissociation and depersonalization (near-death experience). However, KET abuse is often associated with physical and psychological side effects, of which the worst is urological/bladder toxicity. Recently, MXE has emerged as a legal and “bladder-friendly” KET alternative. MXE presents with the same dissociative effect of KET, but with slower onset and longer duration of action. However, MXE seems to be associated with worse side effects than KET, ranging from mood disturbances/suicidal attempts to acute cerebellar toxicity. CONCLUSIONS: After 50 years of its discovery, KET has led to the emergence of MXE. However, this latter derivative does not appear to be a safer alternative to KET itself.

Concepts: K-hole, Opioid, Psychoactive drug, Dextromethorphan, Dissociation, Near death experience, Recreational drug use, Ketamine