[Persistent olfactory impairment after COVID-19-recommendations of the Working Group on Olfactology and Gustology of the German Society of Oto-rhino-laryngology, Head and Neck Surgery]. / Persistierende Riechminderung nach COVID-19 ­ Empfehlungen der Arbeitsgemeinschaft Olfaktologie und Gustologie der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e. V.

This article does not intend to comprehensively review the existing literature on coronavirus disease 2019 (COVID-19)-associated smell disorders, but aims to summarize scientific evidence for otorhinolaryngological practice and provide recommendations for diagnosis and treatment of persistent smell disorders following COVID-19.

[Diagnosis and Therapy of Olfactory Dysfunction - State of the ArtThe neglected sense-new evidence highlights the significance of the human sense of smell]. / Riechstörungen evidenzbasiert diagnostizieren und behandeln. Der unterschätzte Sinn ­ neue Erkenntnisse belegen die Bedeutung und Leistungsfähigkeit des menschlichen Geruchssinns.

Recent research shows that the human sense of smell seems to be more efficient than previously believed and to have a major impact on our health condition and quality of life. During the COVID-19 pandemic, an increased clinical interest has become evident for the SARS-CoV-2 related impact on olfactory function. This article highlights important aspects in the diagnosis and therapy of the chemical senses.

Hypothalamic-Pituitary-Adrenocortical Axis Activity in Alcohol-Dependent Patients During Treatment with High-Dose Baclofen.

AIMS: Activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been reported to be affected in alcohol use disorder (AUD). It has been suggested that pharmacological relapse prevention in AUD might exert its effects partly by modulation of HPA axis activity. Here, we assessed the effects of high-dose treatment with baclofen on HPA axis activity in alcohol-dependent patients within a 24-week randomized, placebo-controlled trial (BACLAD study). METHODS: Plasma levels of copeptin, adrenocorticotropic hormone (ACTH), and cortisol were measured at 3 timepoints in alcohol-dependent patients during the study. Corresponding plasma levels in healthy controls were assessed once. RESULTS: ACTH blood levels were significantly higher in the group of alcohol-dependent patients compared to controls. In patients receiving individually titrated high-dose baclofen, plasma cortisol levels decreased significantly, whereas no significant alterations were found in the placebo group. CONCLUSIONS: Our study underlines again the role of HPA axis alterations in AUD. Furthermore, a decrease in hormonal stress levels during treatment with high-dose baclofen might contribute to the relapse preventive effects of this compound.

Changes in Nutrition-Related Behaviors in Alcohol-Dependent Patients After Outpatient Detoxification: The Role of Chocolate.

BACKGROUND: Previous studies have reported changes in nutrition-related behaviors in alcohol-dependent patients after alcohol detoxification, but prospective studies assessing the effects of these changes on maintaining abstinence are lacking. OBJECTIVES: To assess changes in craving and consumption of chocolate and other sweets over time up to six months after outpatient alcohol detoxification treatment and to detect differences in abstinent versus nonabstinent patients. METHODS: One hundred and fifty alcohol-dependent patients were included in this prospective observational study. Participants completed self-report questionnaires on nutrition-related behaviors and craving before detoxification treatment (baseline, t1), one week (t2), one month (t3), and six months later (t4). RESULTS: Significant changes in craving for and consumption of chocolate as well as in craving for other sweets were observed over time. Increases were most prominent within the first month. Patients who remained abstinent until t3 consumed three times more chocolate than nonabstainers. One quarter of the patients switched from being rare (t1) to frequent (t3) chocolate eaters, and 84% of these remained abstinent until t3. No significant correlations were found between craving for alcohol and craving for or consumption of chocolate or other sweets. CONCLUSIONS/IMPORTANCE: In the first month after outpatient alcohol detoxification treatment, significant changes in nutrition-related behaviors were observed. These changes were not associated with alcohol craving. For a subgroup, increasing the frequency of chocolate consumption might be a temporary protective factor with respect to alcohol relapse.

Neural activation during processing of aversive faces predicts treatment outcome in alcoholism.

Neuropsychological studies reported decoding deficits of emotional facial expressions in alcohol-dependent patients, and imaging studies revealed reduced prefrontal and limbic activation during emotional face processing. However, it remains unclear whether this reduced neural activation is mediated by alcohol-associated volume reductions and whether it interacts with treatment outcome. We combined analyses of neural activation during an aversive face-cue-comparison task and local gray matter volumes (GM) using Biological Parametric Mapping in 33 detoxified alcohol-dependent patients and 33 matched healthy controls. Alcoholics displayed reduced activation toward aversive faces-neutral shapes in bilateral fusiform gyrus [FG; Brodmann areas (BA) 18/19], right middle frontal gyrus (BA46/47), right inferior parietal gyrus (BA7) and left cerebellum compared with controls, which were explained by GM differences (except for cerebellum). Enhanced functional activation in patients versus controls was found in left rostral anterior cingulate cortex (ACC) and medial frontal gyrus (BA10/11), even after GM reduction control. Increased ACC activation correlated significantly with less (previous) lifetime alcohol intake [Lifetime Drinking History (LDH)], longer abstinence and less subsequent binge drinking in patients. High LDH appear to impair treatment outcome via its neurotoxicity on ACC integrity. Thus, high activation of the rostral ACC elicited by affective faces appears to be a resilience factor predicting better treatment outcome. Although no group differences were found, increased FG activation correlated with patients' higher LDH. Because high LDH correlated with worse task performance for facial stimuli in patients, elevated activation in the fusiform 'face' area may reflect inefficient compensatory activation. Therapeutic interventions (e.g. emotion evaluation training) may enable patients to cope with social stress and to decrease relapses after detoxification.

Olfactory Dysfunction: Etiology, Diagnosis, and Treatment.

BACKGROUND: Disorders of the sense of smell have received greater attention because of the frequency with which they occur as a symptom of SARS-CoV-2 infection. Olfactory dysfunction can lead to profound reduction in quality of life and may arise from many different causes. METHODS: A selective literature review was conducted with consideration of the current version of the guideline issued by the Association of the Scientific Medical Societies in Germany. RESULTS: The cornerstones of diagnosis are the relevant medical history and psychophysical testing of olfactory function using standardized validated tests. Modern treatment strategies are oriented on the cause of the dysfunction. While treatment of the underlying inflammation takes precedence in patients with sinunasal dysosmia, olfactory training is the primary treatment option for other forms of the disorder. The prognosis is determined not only by the cause of the olfactory dysfunction and the patient's age, but also by the olfactory performance as measured at the time of diagnosis. CONCLUSION: Options for the treatment of olfactory dysfunction are available but limited, depending on the cause. It is therefore important to carry out a detailed diagnostic work-up and keep the patient informed of the expected course and prognosis.

Effects of baclofen on insular gain anticipation in alcohol-dependent patients - a randomized, placebo-controlled, pharmaco-fMRI pilot trial.

RATIONALE: One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system. OBJECTIVES: Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg. METHODS: Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2). RESULTS: Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group. CONCLUSIONS: By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen. TRIAL REGISTRATION: Identifier of the main trial (the BACLAD study) at clinical.gov: NCT0126665.

[S1 guidelines for the management of postviral conditions using the example of post-COVID-19]. / Leitlinie S1 für das Management postviraler Zustände am Beispiel Post-COVID-19.

These S1 guidelines are an updated and expanded version of the S1 guidelines on long COVID differential diagnostic and management strategies. They summarize the state of knowledge on postviral conditions like long/post COVID at the time of writing. Due to the dynamic nature of knowledge development, they are intended to be "living guidelines". The focus is on practical applicability at the level of primary care, which is understood to be the appropriate place for initial access and for primary care and treatment. The guidelines provide recommendations on the course of treatment, differential diagnostics of the most common symptoms that can result from infections like with SARS-CoV-2, treatment options, patient management and care, reintegration and rehabilitation. The guidelines have been developed through an interdisciplinary and interprofessional process and provide recommendations on interfaces and possibilities for collaboration.

Efficacy and safety of pregabalin in the treatment of alcohol withdrawal syndrome: a randomized placebo-controlled trial.

AIMS: The objective of this study was to collect preliminary data on the efficacy and safety of pregabalin in attenuating the severity of alcohol withdrawal symptoms during detoxification treatment in alcohol dependence. METHODS: Forty-two alcohol-dependent patients with an alcohol withdrawal syndrome (AWS) were included in the prospective randomized double-blind placebo-controlled trial during inpatient alcohol detoxification. For 6 days, participants either received pregabalin or placebo according to a fixed dose schedule starting with 300 mg/day. Depending on the score of the AWS Scale (AWSS), diazepam was additionally administered as a rescue medication. The primary endpoint was the total amount of diazepam required from Day 2 to 6 of detoxification treatment in each of the two groups. Secondary outcome variables were the difference in AWSS and Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores between Day 2 and 6, tolerability and safety data, drop-out rates as well as changes in the neuropsychological scales. RESULTS: Pregabalin and placebo were equally safe and well tolerated. However, no statistically significant difference was found comparing the total amount of additional diazepam medication required in the two study groups. Pregabalin and placebo also showed similar efficacy according to alterations of scores of the AWSS, CIWA-Ar and neuropsychological scales. The frequency of adverse events and drop-outs did not differ between the both treatment groups. CONCLUSIONS: The study demonstrates the relative safety of pregabalin in the treatment of AWS. However, the results do not provide evidence in favor of pregabalin compared with placebo concerning its efficacy in the treatment of AWS.

Altered serum levels of brain-derived neurotrophic factor in patients with pathological gambling.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays important roles in neurotransmitter release and synaptic plasticity and has been hypothesized to be involved in the development and maintenance of addictive disorders. The objective of this study was to investigate alterations of BDNF expression in a non-substance-related addiction, i.e. pathological gambling (PG). METHODS: Serum levels of BDNF were assessed in male patients with PG (n = 14) and healthy control subjects (n = 13) carefully matched for sex, age, body mass index, smoking status and urbanicity. Symptoms and severity of PG were measured by the adapted form of the Yale-Brown Obsessive-Compulsive Scale. RESULTS: BDNF serum levels were significantly increased in patients with PG in comparison to healthy control subjects (p = 0.016). There were no significant correlations between BDNF serum levels and severity of PG or clinical and demographic variables. CONCLUSIONS: Our results show alterations of BDNF serum levels in patients suffering from a behavioural addiction and suggest that non-substance-related addictions like PG might be associated with neuroendocrinological changes similar to the changes observed in substance-related addictions.

[Guideline S1: Long COVID: Diagnostics and treatment strategies]. / Leitlinie S1: Long COVID: Differenzialdiagnostik und Behandlungsstrategien.

This guideline comprises the state of science at the time of the editorial deadline. In view of the high turnover of knowledge the guideline is designed as a living guideline. The main objective was to provide a tool for the use in primary care, being considered well suited as a first point of entry and for the provision of care. The guideline gives recommendations on the differential diagnosis of symptoms following SARS-CoV­2 infection, on their therapeutic options, as well as for guidance and care of the patients concerned. It also offers advice concerning return to daily life and rehabilitation. Long COVID being a very variable condition, we chose an interdisciplinary approach.

On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study.

BACKGROUND: The average treatment effect of antidepressants in major depression was found to be about 2 points on the 17-item Hamilton Depression Rating Scale, which lies below clinical relevance. Here, we searched for evidence of a relevant treatment effect heterogeneity that could justify the usage of antidepressants despite their low average treatment effect. METHODS: Bayesian meta-analysis of 169 randomized, controlled trials including 58,687 patients. We considered the effect sizes log variability ratio (lnVR) and log coefficient of variation ratio (lnCVR) to analyze the difference in variability of active and placebo response. We used Bayesian random-effects meta-analyses (REMA) for lnVR and lnCVR and fitted a random-effects meta-regression (REMR) model to estimate the treatment effect variability between antidepressants and placebo. RESULTS: The variability ratio was found to be very close to 1 in the best fitting models (REMR: 95% highest density interval (HDI) [0.98, 1.02], REMA: 95% HDI [1.00, 1.02]). The between-study standard deviation τ under the REMA with respect to lnVR was found to be low (95% HDI [0.00, 0.02]). Simulations showed that a large treatment effect heterogeneity is only compatible with the data if a strong correlation between placebo response and individual treatment effect is assumed. CONCLUSIONS: The published data from RCTs on antidepressants for the treatment of major depression is compatible with a near-constant treatment effect. Although it is impossible to rule out a substantial treatment effect heterogeneity, its existence seems rather unlikely. Since the average treatment effect of antidepressants falls short of clinical relevance, the current prescribing practice should be re-evaluated.

Total and acylated ghrelin plasma levels as potential long-term response markers in alcohol-dependent patients receiving high-dose of the GABA-B receptor agonist baclofen.

The orexigenic hormone ghrelin is involved in the regulation of food intake and energy balance. Previous findings suggest its involvement in the modulation of mesolimbic reward pathways, thus potentially being relevant in the pathophysiology of substance use disorders such as alcohol dependence. In the present study, we assessed plasma levels of total and acylated ghrelin within the BACLAD trial, where alcohol-dependent patients received individually titrated high-dose baclofen (30-270 mg/d) within a randomized, placebo-controlled design. Plasma levels of total ghrelin and acylated ghrelin were measured at baseline, during treatment with individually titrated high-dose baclofen and after termination of the study medication within a timeframe of up to 20 weeks. Multivariate longitudinal non-parametric analysis revealed that plasma levels of total ghrelin significantly decreased in the group of abstinent patients receiving high-dose baclofen. In addition, plasma levels of total ghrelin correlated negatively with days of abstinence during treatment with high-dose baclofen. Plasma levels of acylated ghrelin increased during the study in the group of relapsed patients under baclofen and placebo treatment. These findings suggest that the long-term response to baclofen treatment in alcohol use disorder (AUD) might be monitored by assessing total and acylated ghrelin plasma levels.

Plasma levels of leptin in patients with pathological gambling, internet gaming disorder and alcohol use disorder.

Leptin has been suggested to be involved in the pathophysiology of addictive disorders via modulation of mesolimbic reward pathways. Previous studies in patients with substance use disorders (alcohol, tobacco, cocaine) found positive correlations of leptin blood levels with craving. Here, we investigated leptin blood levels in patients with non-substance related addictive disorders such as pathological gambling (PG) and internet gaming disorder (IGD) in comparison to patients with alcohol use disorder (AUD) and healthy controls. Plasma levels of leptin were measured in male patients with PG (n = 14), male patients with IGD (n = 11), male patients with AUD (n = 39) and male healthy controls (n = 12). Additionally, correlation analyses with blood levels of HPA axis hormones were performed. Leptin plasma levels of patients with PG, IGD or AUD and healthy controls did not differ significantly across groups. In patients with PG, leptin plasma levels were correlated with copeptin, a surrogate for arginine vasopressin. Our findings do not suggest an involvement of leptin in abstinent patients with AUD or in patients with active IGD. In patients with active PG, leptin blood levels were not related to craving for gambling, but leptin might be involved in PG via an interaction with the HPA axis.

Effects of high-dose baclofen on cue reactivity in alcohol dependence: A randomized, placebo-controlled pharmaco-fMRI study.

Increased functional brain response towards alcohol-associated stimuli is a neural hallmark of alcohol dependence and a promising target for pharmacotherapy. For the first time, we assessed the effects of individually titrated high-dose baclofen on cue reactivity and functional connectivity in alcohol-dependent (AD) patients in a randomized controlled trial (RCT). We investigated 23 recently detoxified AD patients and 23 matched healthy controls (HC) with a cue reactivity functional magnetic resonance imaging task. Patients were further scanned at baseline without medication and during treatment with high-dose baclofen/placebo (30-270 mg/d). Analyses were conducted for alcohol cue-elicited brain response, alcohol cue-modulated and stimulus-independent functional connectivity with left ventral tegmental area (VTA) as seed region. At baseline, AD patients (N = 23) showed increased cue-elicited brain activation in the ventral striatum (VS) compared to HC (N = 23), which was decreased at the second scanning session compared to baseline. Patients receiving baclofen (N = 10) showed a significant stronger decrease in cue-elicited brain activation in left orbitofrontal cortex (OFC), bilateral amygdala and left VTA than patients receiving placebo (N = 13). Treatment with baclofen further led to a decrease in alcohol cue-modulated functional connectivity between left VTA and left anterior cingulate cortex (ACC) as well as left medial prefrontal cortex (MPFC). Regarding clinical outcome, significantly more patients of the baclofen group remained abstinent during the high-dose period. Baclofen specifically decreased cue-elicited brain responses in areas known to be involved in the processing of salient (appetitive and aversive) stimuli. Treatment with high-dose baclofen seems to provide a pharmacological relief of this neural "warning signal" evoked by alcohol-related cues, thereby possibly supporting patients in remaining abstinent. Trial Registration Identifier of the main trial [BACLAD study] at clinicaltrials.gov: NCT01266655.

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30-80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an "off-label" prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

Pharmacotherapy of alcoholism - an update on approved and off-label medications.

INTRODUCTION: Only a few medications are available for the treatment of alcohol use disorders (AUDs). Areas covered: This paper discusses approved AUD medications, including the opioid antagonists naltrexone and nalmefene (the latter is licensed for reduction of alcohol consumption only), the putative glutamate receptor antagonist acamprosate and the aldehyde dehydrogenase inhibitor disulfiram. It also covers off-label medications of interest, including topiramate, gabapentin, ondansetron, varenicline, baclofen, sodium oxybate and antidepressants. Clinical implications, benefits and risks of treatment are discussed. Expert opinion: Acamprosate, naltrexone, nalmefene and disulfiram are the only approved 'alcohol-specific' drugs. Acamprosate and naltrexone have been evaluated in numerous clinical trials and represent evidence-based treatments in AUDs. Nalmefene use, however, is controversial. Supervised disulfiram is a second-line treatment approach. Compounds developed and licensed for different neuropsychiatric disorders are potential alternatives. Encouraging results have been reported for topiramate, gabapentin and also varenicline, which might be useful in patients with comorbid nicotine dependence. The GABA (γ-aminobutyric acid)-B receptor agonist baclofen has shown mixed results; it is currently licensed for the treatment of AUDs in France only. Gabapentin may be close to approval in the USA. Further studies of these novel treatment approaches in AUDs are needed.

Alcohol Dependence and Harmful Use of Alcohol.

BACKGROUND: In Germany today, there are more than 1.8 million persons who are dependent on alcohol, and 1.6 million persons whose use of alcohol is harmful. The many complications of alcohol use are both mental and physical-in particular, gastrointestinal and neurological. Yet more than 80% of persons whose alcohol use is problematic still receive no treatment for their harmful use or dependence, despite contact with the health-care system. METHODS: This article is a selective review of the pertinent literature, including guidelines, meta-analyses, and Cochrane Reviews. RESULTS: The treatment is divided into an early interventional and motivational phase, qualified withdrawal, long-term cessation therapy, and a stabilization phase. Pharmacotherapy with acamprosate or naltrexone increases the rate of abstinence (number needed to treat: 12 and 20, respectively). If a patient lacks the motivation to abstain from alcohol entirely, reduced consumption can be agreed upon as a goal of treatment. 85% of patients relapse if no further treatment is given after initial detoxification. CONCLUSION: What is needed in routine medical practice is practical diagnostic evaluation followed by individually tailored treatment, based on the severity of the condition, the development of the patient's motivation to be treated, and the local treatment options (e.g., outpatient addiction clinics, counseling centers, or day clinics).