Does the Use of Botulinum Toxin in Treatment of Myofascial Pain Disorder of the Masseters and Temporalis Muscles Reduce Pain, Improve Function, or Enhance Quality of Life?

BACKGROUND: The efficacy of botulinum toxin for management of myofascial pain disorder (MPD) remains controversial. PURPOSE: The purpose was to determine if the use of onabotulinumtoxinA (onabotA) in patients with MPD reduces pain, improves function, or enhances quality of life (QoL). STUDY DESIGN, SETTING, AND SAMPLE: This is a multicenter, prospective, randomized, double-blinded, placebo-controlled clinical trial. Subjects with orofacial pain were screened for MPD as defined by the Diagnostic Criteria for Temporomandibular Disorders. PREDICTOR VARIABLE: The primary predictor variable was MPD treatment with random assignment to onabotA or placebo (saline). MAIN OUTCOME VARIABLE: The primary outcome variable was pain before treatment (T0) and at 1 month (T1) using a visual analog scale. Secondary outcome variables included pain at 2 months (T2) and 3 months (T3), maximal incisal opening (MIO), jaw function (jaw functional limitation scale), and QoL (Short Form 36) measured at T0, T1, T2, and T3. COVARIATES: Covariates included subject demographics, prior treatments, and temporomandibular joint signs/symptoms. ANALYSES: Descriptive and bivariate statistics included χ2 test, Fisher's exact test, or t-test. RESULTS: Seventy five subjects with a mean age of 37 (±11) and 35 (±12) years in the onabotA and placebo groups, respectively (P = .6). Females represented 32 (86%) and 29 (76%), respectively (P = .3). Mean visual analog scale pain score in the onabotA group was 58 (±15), 39 (±24), 38 (±23), and 38 (±20) at T0, T1, T2, and T3, respectively; and the placebo group was 54 (±14), 40 (±23), 34 (±20), and 36 (±22) at T0, T1, T2, and T3, respectively. There was no statistically significant difference in pain between groups at any time point (P = .36). There was no statistically significant difference between groups in MIO (P = .124), jaw function (P = .236), or QoL domains (P > .05) at any time point. Within-group improvement in pain was seen in both groups (P < .005). Within-group improvement in jaw function was seen in the onabotA (P = .007) and placebo (P = .005) groups. There was no within-group improvement in MIO or QoL with either group (P > .05). CONCLUSIONS: OnabotA and saline (placebo) injections both decrease pain and improve jaw function in subjects with MPD.

Clinical Approaches to Cannabis: A Narrative Review.

Cannabis use in the United States is growing at an unprecedented pace. Most states in the United States have legalized medical cannabis use, and many have legalized nonmedical cannabis use. In this setting, health care professionals will increasingly see more patients who have questions about cannabis use, its utility for medical conditions, and the risks of its use. This narrative review provides an overview of the background, pharmacology, therapeutic use, and potential complications of cannabis.

LVV-hemorphin-7 (LVV-H7) plays a role in antinociception in a rat model of alcohol-induced pain disorders.

Alcohol can increase the sensitivity to painful stimulation or convert insensibility to pain at different stages. We hypothesized that chronic alcohol consumption changes the level of LVV-hemorphin-7 (abbreviated as LVV-H7, an opioid-like peptide generated from hemoglobin ß-chain), thereby affecting pain sensation. We established a chronic alcohol-exposed rat model to investigate the effects of LVV-H7. Adult male Sprague-Dawley rats were subjected to daily intraperitoneal injection of 10 % ethanol (w/v) at 0.5 g/kg for 15 days and subsequent alcohol withdrawal for 5 days. Using different pharmacological strategies to affect the LVV-H7 level, we investigated the correlation between LVV-H7 and pain-related behavior. Tail-flick and hot plate tests were employed to investigate alcohol-induced pain-related behavioral changes. The serum level of LVV-H7 was determined by ELISA. Our results showed that alcohol first induced an analgesia followed by a hyperalgesia during alcohol withdrawal, which could be driven by the quantitative change of LVV-H7. A positive correlation between the level of LVV-H7 and Δtail-flick latency (measured latency minus basal latency) confirmed this finding. Moreover, we revealed that the LVV-H7 levels were determined by the activity of cathepsin D and red blood cell/hemoglobin counts, which could be affected by alcohol. These results suggest that the deterioration of anti-nociception induced by alcohol is correlated to the decreased level of LVV-H7, and this could be due to alcohol-induced anemia. This study may help to develop LVV-H7 structure-based novel analgesics for treating alcohol-induced pain disorders and thus ameliorate the complications in alcoholics.

Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine.

Fremanezumab is a fully humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), a key neuropeptide involved in the pathophysiology of migraine. Fremanezumab is approved for quarterly and monthly subcutaneous dosing for the preventive treatment of migraine in adults. The phase 3 clinical development program for fremanezumab aimed to evaluate the efficacy of this preventive treatment across different patient populations, including those with difficult-to-treat migraine. Two pivotal 12-week, phase 3, placebo-controlled studies investigated quarterly and monthly dosing of fremanezumab in participants with chronic migraine (HALO CM) and episodic migraine (HALO EM). The efficacy of fremanezumab was further explored in individuals with difficult-to-treat chronic or episodic migraine in the 12-week FOCUS study, which enrolled participants who had previously experienced an inadequate response to 2-4 pharmacological classes of migraine preventive medications. The long-term efficacy of fremanezumab was assessed in a 12-month long-term study (HALO LTS), which enrolled participants completing the 12-week HALO studies and new participants. Across these studies, treatment with fremanezumab dosed quarterly or monthly provided significant reductions in the frequency of migraine days, headache days of at least moderate severity, and migraine- and headache-related disability compared with placebo. Sustained improvements were seen with long-term fremanezumab treatment. Subgroup analyses of participants with difficult-to-treat migraine (those with comorbid depression, overuse of acute headache medications, and concomitant use of other migraine preventive medications) demonstrated the effectiveness of quarterly or monthly fremanezumab in these populations. Ongoing studies are further exploring the potential benefits of fremanezumab in difficult-to-treat migraine and other headache and pain disorders.

Life-Threatening Serotonin Syndrome Precipitated by Discontinuation of Serotonin-Dopamine Antagonist in the Presence of Serotonergic Agents: A Case Report.

INTRODUCTION: Serotonin syndrome is caused by excessive activation of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission. Although the discontinuation of antipsychotics with 5-HT2 receptor antagonistic characteristics could theoretically result in serotonin syndrome, there have been very few reports on the syndrome thus far. CASE PRESENTATION: A 75-year-old woman with somatoform disorder was transferred to our emergency room because of pyrexia, unconsciousness, and myoclonus with hyperreflexia. She had been taking milnacipran and perospirone for 10 years and had started taking duloxetine 2 months before the event. Thereafter, she suffered diaphoresis, gait disturbance, and tremor. Her psychiatrist advised her to stop taking perospirone, because of suspicion of extrapyramidal symptoms, a day before admission. The clinical diagnosis of serotonin syndrome was made based on her symptoms while using serotonergic agents. Her symptoms were so severe that she was transferred to the intensive care unit, where supportive care was successful. CONCLUSIONS: Discontinuation of antipsychotics that are 5-HT2 receptor antagonists may lead to serotonin syndrome in patients who take serotonergic agents. As extrapyramidal symptoms and serotonin toxicity share some clinical features, detailed drug history and physical examination are necessary for successful treatment.

Distinct psychopathology profiles in patients with epileptic seizures compared to non-epileptic psychogenic seizures.

OBJECTIVE: Similarities in clinical presentations between epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES) produces a risk of misdiagnosis. Video-EEG monitoring (VEM) is the diagnostic gold standard, but involves significant cost and time commitment, suggesting a need for efficient screening tools. METHODS: 628 patients were recruited from an inpatient VEM unit; 293 patients with ES, 158 with PNES, 31 both ES and PNES, and 146 non-diagnostic. Patients completed the SCL-90-R, a standardised 90-item psychopathology instrument. Bayesian linear models were computed to investigate whether SCL-90-R domain scores or the overall psychopathology factor p differed between groups. Receiver operating characteristic (ROC) curves were computed to investigate the PNES classification accuracy of each domain score and p. A machine learning algorithm was also used to determine which subset of SCL-90-R items produced the greatest classification accuracy. RESULTS: Evidence was found for elevated scores in PNES compared to ES groups in the symptom domains of anxiety (b = 0.47, 95%HDI = [0.10, 0.80]), phobic anxiety (b = 1.32, 95%HDI = [0.98, 1.69]), somatisation (b = 0.84, 95%HDI = [0.49, 1.20]), and the general psychopathology factor p (b = 1.35, 95%HDI = [0.86, 1.82]). Of the SCL-90-R domain scores, somatisation produced the highest classification accuracy (AUC = 0.74, 95%CI = [0.69, 0.79]). The genetic algorithm produced a 6-item subset from the SCL-90-R, which produced comparable classification accuracy to the somatisation scores (AUC = 0.73, 95%CI = [0.64, 0.82]). SIGNIFICANCE: Compared to patients with ES, patients with PNES report greater symptoms of somatisation, general anxiety, and phobic anxiety against a background of generally elevated psychopathology. While self-reported psychopathology scores are not accurate enough for diagnosis in isolation, elevated psychopathology in these domains should raise the suspicion of PNES in clinical settings.

[Impairments of cognitive control in patients with somatoform disorders and their treatment]. / Narusheniia kognitivnogo kontrolia u patsientov s somatoformnymi rasstroistvami i ikh lechenie.

AIM: To study impairments of cognitive control in patients with somatoform disorders (SD) and to evaluate the efficacy of recognan in the treatment of this pathology. MATERIAL AND METHODS: Forty-six patients with SD, aged from 18 to 45 years, were studied. A clinical history, neurological examination, and assessment of autonomic disorders were collected from all patients. For the objectification of the severity of asthenic and emotional disorders, the Subjective Scale of Asthenia (MFI-20), the Hamilton Anxiety Scale (HARS), the Cognitive Emotion Regulation Questionnaire (CERQ were used. A quantitative assessment of impaired attention and impulsivity was performed using the psychophysiological test TOVA. Patients were treated with recognan (citicoline). The control group consisted of 30 healthy people aged from 18 to 45 years. RESULTS AND CONCLUSION: Patients with SD had specific characteristics of the cognitive sphere, most pronounced in the form of attention disorders. The psychological study showed the higher level of anxiety. In addition, patients with SD were characterized by the low levels of emotional intelligence and cognitive control of emotions compared with the control group. The results of the follow-up study after treatment suggest the high efficacy of recognan in the treatment of SD (improvement was noted in 67.4% of patients). A significant decrease in the severity of autonomic disorders and in indicators characterizing asthenia was established after the treatment.

Medication prescriptions in 322 motor functional neurological disorder patients in a large UK mental health service: A case control study.

OBJECTIVE: This study describes medication prescribing patterns in patients with motor functional neurological disorder (mFND) treated in South London and Maudsley NHS Foundation Trust (SLaM), comparing outcomes to a control group of psychiatric patients from the same hospital trust. METHOD: This is a retrospective case-control study using a psychiatric case register. Cross-sectional data were obtained from 322 mFND patients and 644 psychiatry controls who had had contact with SLaM between 1st January 2006 and 31st December 2016. RESULTS: A slightly lower proportion of mFND patients received medication compared to controls (76.6% v. 83.4%, OR: 0.59, CI: 0.39-0.89, p < 0.05). Of medication recipients, mFND patients were prescribed a higher number of agents (mean: 4.7 v 2.9, p = 0.001) and had higher prescription rates of antidepressants, anti-epileptics, analgesics, and certain non-psychotropic medications. Higher numbers of prescriptions were associated with co-morbid physical conditions, and previous psychiatric admissions. CONCLUSIONS: This is the first study to describe medication prescriptions in a large cohort of mFND patients. Patients were prescribed a wide range of psychiatric and physical health medications, with higher rates of polypharmacy than controls. Psychotropic medication prescription is not necessarily the first line treatment for mFND, where physiotherapy and psychotherapy may be offered initially. There is limited, early-phase evidence for pharmacological therapies for mFND, and as such, the benefit-to-risk ratio of prescribing in this complex and poorly understood disorder should be carefully assessed.

Sodium Channels in Human Pain Disorders: Genetics and Pharmacogenomics.

Acute pain is adaptive, but chronic pain is a global challenge. Many chronic pain syndromes are peripheral in origin and reflect hyperactivity of peripheral pain-signaling neurons. Current treatments are ineffective or only partially effective and in some cases can be addictive, underscoring the need for better therapies. Molecular genetic studies have now linked multiple human pain disorders to voltage-gated sodium channels, including disorders characterized by insensitivity or reduced sensitivity to pain and others characterized by exaggerated pain in response to normally innocuous stimuli. Here, we review recent developments that have enhanced our understanding of pathophysiological mechanisms in human pain and advances in targeting sodium channels in peripheral neurons for the treatment of pain using novel and existing sodium channel blockers.

A novel frameshift variant in the CADASIL gene NOTCH3: pathogenic or not?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) represents the most common monogenic cause of adult-onset ischemic stroke and vascular dementia. It is caused by heterozygous missense mutations in the NOTCH3 gene, encoding a transmembrane receptor protein on vascular smooth muscle cells. Classical CADASIL mutations affect conserved cysteine residues of the Notch3 protein. By contrast, the role of non-canonical genetic variation in NOTCH3, in particular of variants causing a hypomorphic Notch3 protein, is subject to an ongoing scientific debate. In this context, we here report a novel NOTCH3 frameshift variant in exon 18 (NM_000435.2: c.2853_2857delTCCCG), causing a frameshift and introducing a premature stop codon, which was detected in a 43-year-old woman and her father. Both carriers of the variant were carefully evaluated, including serial follow-up in the index. Neither clinical nor imaging features provided convincing evidence for a classical CADASIL phenotype, thus reinforcing the concept of hypomorphic NOTCH3 variants most likely not being causative for CADASIL. Our finding, which is discussed in the light of the published literature, has practical implications for interpreting results of NOTCH3 molecular genetic testing as well as patient counseling.

The use of prescription medication in 239 patients with multiple functional somatic syndromes.

OBJECTIVE: To describe the use of prescription drugs and their association with patient characteristics in patients with multiple functional somatic syndromes (FSS) focusing on drugs generally recommended and not recommended in FSS treatment. METHOD: Using data from a national prescription registry, we describe the drug use during a two-year period for 239 trial participants. Using regression models, we analyse the associations of patient characteristics with the patterns of use of antidepressants, anticonvulsants, opioids and sedatives. RESULTS: The use of prescription drugs was highly heterogeneous. Antidepressants were used at least temporarily by 34% (88/239), anticonvulsants by 7% (16/239), opioids by 26% (61/239) and sedatives by 20% (47/239) of the patients. Severe impairment due to multiple FSS was associated with use of opioids or sedatives (OR 6.49 (95% CI 2.68-15.68; p < 0.001)) but also with use of antidepressants or anticonvulsants (OR 3.42 (95% CI 1.35-8.65; p = 0.009)). Poor self-reported physical health, additional physical comorbidities and low socioeconomic status were associated with use of opioids or sedatives only. CONCLUSION: Antidepressants and anticonvulsants were modestly used. Opioids and sedatives were especially used by the severely affected patients. Balancing treatment expectations and enhancing patients' understanding of FSS may direct treatments towards more generally recommended drugs.

Identifying psychogenic seizures through comorbidities and medication history.

OBJECTIVE: Low-cost evidence-based tools are needed to facilitate the early identification of patients with possible psychogenic nonepileptic seizures (PNES). Prior to accurate diagnosis, patients with PNES do not receive interventions that address the cause of their seizures and therefore incur high medical costs and disability due to an uncontrolled seizure disorder. Both seizures and comorbidities may contribute to this high cost. METHODS: Based on data from 1,365 adult patients with video-electroencephalography-confirmed diagnoses from a single center, we used logistic and Poisson regression to compare the total number of comorbidities, number of medications, and presence of specific comorbidities in five mutually exclusive groups of diagnoses: epileptic seizures (ES) only, PNES only, mixed PNES and ES, physiologic nonepileptic seizurelike events, and inconclusive monitoring. To determine the diagnostic utility of comorbid diagnoses and medication history to differentiate PNES only from ES only, we used multivariate logistic regression, controlling for sex and age, trained using a retrospective database and validated using a prospective database. RESULTS: Our model differentiated PNES only from ES only with a prospective accuracy of 78% (95% confidence interval =72-84%) and area under the curve of 79%. With a few exceptions, the number of comorbidities and medications was more predictive than a specific comorbidity. Comorbidities associated with PNES were asthma, chronic pain, and migraines (p < 0.01). Comorbidities associated with ES were diabetes mellitus and nonmetastatic neoplasm (p < 0.01). The population-level analysis suggested that patients with mixed PNES and ES may be a population distinct from patients with either condition alone. SIGNIFICANCE: An accurate patient-reported medical history and medication history can be useful when screening for possible PNES. Our prospectively validated and objective score may assist in the interpretation of the medication and medical history in the context of the seizure description and history.

Imipramine versus placebo for multiple functional somatic syndromes (STreSS-3): a double-blind, randomised study.

BACKGROUND: Functional somatic syndromes, including chronic fatigue syndrome or irritable bowel syndrome, often co-exist. Treatment guidelines supported by high quality evidence exist for most functional somatic syndromes, but are lacking for multiple comorbid functional somatic syndromes. We aimed to assess the effect of the tricyclic antidepressant, imipramine, in patients with multiple functional somatic syndromes defined by the criteria for multiorgan bodily distress syndrome, a unifying diagnosis that encompasses most functional somatic syndromes and somatoform disorders. METHODS: In this single-centre, double-blind, randomised trial done in a Danish university hospital setting, participants were patients consecutively referred (age 20-50 years) fulfilling criteria for multiorgan bodily distress syndrome with no concurrent comorbid depression or anxiety disorder. Participants were randomly assigned (1:1) to receive either 10 weeks of low-dose imipramine or placebo (oral daily doses of 25-75 mg). The hospital pharmacy handled randomisation (computer-generated) and masking, providing sequentially numbered packs of study drug that were given serially to the participants. All others involved were masked to allocation. Primary outcome was patient-rated overall health improvement on a 5-point clinical global improvement scale. Improvement was defined as patients responding "better" or "much better" as opposed to "unchanged" and "worse" or "much worse" when rating their overall health status after 10 weeks of minimum 25 mg study drug. Analyses included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01518634. FINDINGS: Between Jan 30, 2012, and Nov 24, 2014, 138 patients were randomly assigned; 70 to receive imipramine and 68 to receive placebo. The study was completed on May 1, 2015. 125 patients received at least one dose of study drug: 65 received imipramine and 60 received placebo. Treatment was terminated prematurely for eight (12%) patients receiving imipramine and seven (12%) patients receiving placebo. Data were missing for two (3%) patients receiving imipramine and three (5%) patients receiving placebo. Of the 120 patients (96%) who provided primary outcome data, 33 (53%) receiving imipramine reported their overall health status as "better" or "much better" compared with 14 patients (25%) receiving placebo. The improvement after imipramine was significantly greater than after placebo (odds ratio 3·3 [95% CI 1·6-6·8]; p=0·001). Number needed to treat was 3·6 (95% CI 2·3-8·9). Analysis of the worst-case scenario for patients with missing outcome did not change the interpretation of the results. 32 patients (49%) receiving imipramine and 10 patients (17%) receiving placebo had at least one adverse event of moderate intensity (p=0·0001); eight patients (12%) receiving imipramine and three patients (5%) receiving placebo had at least one adverse event of severe intensity (p=0·1496). One patient (1%) receiving placebo experienced a serious adverse event (a subdural haematoma sustained after an accident). Adverse events caused dropout in four patients (6%) receiving imipramine and three patients (5%) receiving placebo. INTERPRETATION: Imipramine treatment compared with placebo significantly improved overall health in patients with multiple functional somatic syndromes when both treatments were supported by regular contacts with clinicians. Adverse events were more common in the imipramine group, but only rarely led to discontinuation of treatment. FUNDING: The Danish Foundation, Trygfonden.

[Update Opipramol]. / Update Opipramol.

Opipramol was developed in the 1960s as an antidepressant and has chemical similarities with tricyclic antidepressants. Pharmacodynamic properties with absent reuptake inhibition of serotonin and noradrenaline and agonism at sigma receptors distinguish opipramol from tricyclics. Furthermore, antidepressive effects are smaller than the anxiolytic ones. The mechanism of action of opipramol is currently not sufficiently understood. Agonistic effects at sigma receptors have been linked with therapeutic effects. Excessive hepatic metabolism (primarily via CYP2D6) should be considered, particularly in patients with impaired hepatic function and polypharmacy. The available clinical data suggest good tolerability and safety within the approved dose range. Mild disturbances of vigilance and anticholinergic adverse events are the predominant side effects. In Germany, opipramol is approved for the treatment of somatoform disorders and generalized anxiety disorder, and there is sufficient evidence for the efficacy of opipramol in these disorders. The agent is still prescribed very often in Germany, yet plays a minor role in the clinical as well as scientific setting. In view of the limited availability of (pharmacologic) treatment options for generalized anxiety disorder and particularly somatoform disorders, opipramol should be considered in the treatment of these entities.

[Efficiency of cytoflavin in the treatment of somatoform disorders]. / Issledovanie éffektivnosti tsitoflavina v lechenii somatoformnykh rasstroistv.

AIM: To study the efficacy of cytoflavin in patients with somatoform disorders (SD). MATERIAL AND METHODS: The study included 60 patients with SD, aged from 27 to 43 years. The efficacy was assessed by the results of psychological and neurophysiological examinations. RESULTS AND CONCLUSION: The higher efficacy of cytoflavin (the improvement of patient's condition in 63,3% of cases) compared to that of ethylmethylhydroxypyridine succinate (56,7% of cases) was found. Patient's state was more stable after treatment with cytoflavin.

The effect of local injection of methylprednisolone acetate on the hypothalamic-pituitary-adrenal axis among patients with greater trochanteric pain syndrome.

Greater trochanteric pain syndrome (GTPS) is a common clinical entity for which the most effective treatment is local corticosteroid injection (LCI). There are no studies on the effect of LCI among patients with GTPS on the hypothalamic-pituitary-adrenal axis. The present study recruited nonselected patients diagnosed with GTPS. After consenting, participants received low dose (1 µg) of adrenocorticotropin hormone (ACTH) stimulation test at 09:00. Immediately following the test, participants received a LCI of 80 mg of methylprednisolone acetate at the greater trochanteric region. The ACTH stimulation test was repeated 1, 2, 4, and 6 weeks following the LCI. Cortisol samples were obtained at just prior to (basal) and 30 min (post-stimulation) following every ACTH stimulation test. Serum cortisol levels of <500 µmol/l obtained 30 min following the ACTH stimulation test were considered evidence of secondary adrenal insufficiency. The study enrolled 22 patients, 21 of whom completed participation. There were 19 female participants (~90%), and mean age of all the participants was 55.2 ± 8.6 years. Four participants showed evidence of secondary adrenal insufficiency, which was observed only at weeks 1 and 2 following the LCI. Mean serum cortisol level among these four participants 30 min following the ACTH stimulation test was 354 µmol/l, with a range of 268-430 µmol/l. LCI of 80 mg of methylprednisolone acetate in the greater trochanteric area among patients with GTPS was associated with transient secondary adrenal insufficiency in ~20% of the patients, mainly 1 week following the injection.