Efficacy and safety of lavender essential oil (Silexan) capsules among patients suffering from anxiety disorders: A network meta-analysis.

A systematic review and network-meta analysis (NMA) were performed to estimate significance of the anxiolytic effect of lavender essential oil taken as silexan capsules versus other comparators (i.e., placebo/paroxetine/lorazepam). The outcome of interest was Hamilton Anxiety Scale (HAMA). Weighted mean differences (WMD) were calculated to estimate the treatment effect at the confidence interval of 95%. League tables were generated using treatment effect, for all pairwise comparisons, where WMD < 0 favors the column-defining treatment. Five studies were identified with a total of 524 participants receiving treatment with silexan 80 mg and 121 participants taking silexan 160 mg. The NMA results indicated that consumption of silexan 160 mg resulted in higher decline of HAMA score [WMD -1.14 (-1.10, 3.39)] in comparison to silexan 80 mg, placebo [-2.20 (-4.64, 0.24)] and paroxetine [-1.24 (-5.34, 2.85)]. The effect of silexan 80 mg was observed to be same as that of paroxetine. Overall, silexan 160 mg was noticed to be a more efficient treatment giving significant decline in HAMA score across other comparators. However, no improvements in HAMA score was observed for the group receiving lorazepam 0.5 mg when compared to silexan 160 mg, silexan 80 mg, paroxetine 20 mg, and placebo.

Complicated Withdrawal Phenomena During Benzodiazepine Cessation in Older Adults.

The cause of prolonged or recurrent symptoms following the cessation of long-term benzodiazepine use is proposed to be related to downregulation and allosteric decoupling of the γ-aminobutyric acid/benzodiazepine receptor complex. This case series describes 2 patients with prolonged (>2 weeks) recurrent complications during attempted tapering of benzodiazepine doses after long-term treatment. Excited catatonia developed in a 90-year-old woman, and prolonged delirium developed in a 69-year-old woman. Both patients showed improvement of symptoms after resumption of higher doses of benzodiazepine treatment and recurrence of symptoms when the dose was again lowered. Caution should be exercised regarding the long-term use of benzodiazepines in older adults (aged ≥65 years). Tapering of benzodiazepines in older patients after long-term treatment may require slow decreases in dose over long periods. Psychotherapeutic interventions, such as brief cognitive therapy with psychoeducation and motivational enhancement, and osteopathic manipulative treatment to decrease paravertebral muscle tension may be beneficial during the tapering process.

Population Pharmacokinetic/ Pharmacodynamic Modelling of Auditory-Evoked Event-Related Potentials with Lorazepam.

Event-related potentials (ERPs) are commonly used in Neuroscience research, particularly the P3 waveform because it is associated with cognitive brain functions and is easily elicited by auditory or sensory inputs. ERPs are affected by drugs such as lorazepam, which increase the latency and decrease the amplitude of the P3 wave. In this study, auditory-evoked ERPs were generated in 13 older healthy volunteers using an oddball tone paradigm, after administration of single 0.5 and 2 mg doses of lorazepam. Population pharmacokinetics (PK)/pharmacodynamics (PD) models were developed using nonlinear mixed-effects methods in order to assess the effect of lorazepam on the latency and amplitude of the P3 waveforms. The PK/PD models showed that doses of 0.3 mg of lorazepam achieved approximately half of the maximum effect on the latency of the P3 waveform. For P3 amplitude, half the maximum effect was achieved with a dose of 1.2 mg of lorazepam. The PK/PD models also predicted an efficacious dose range of lorazepam, which was close to the recommended therapeutic range. The use of longitudinal P3 latency data allowed better predictions of the lorazepam efficacious dose range than P3 amplitude or aggregate exposure-response data, suggesting that latency could be a more sensitive parameter for drugs with similar mechanisms of action as lorazepam and that time course rather than single time-point ERP data should be collected. Overall, the results suggest that P3 ERP waveforms could be used as potential non-specific biomarkers for functional target engagement for drugs with brain activity, and PK/PD models can aid trial design and choice of doses for development of new drugs with ERP activity.

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations.

OBJECTIVE: Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b(+)/Ly6C(hi)) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and social avoidance behavior in mice subjected to RSD. METHODS: C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. RESULTS: Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b(+)/CD45(high)) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. CONCLUSION: These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.

Catatonia in resource-limited settings: a case series and treatment protocol.

OBJECTIVE: The catatonic syndrome ("catatonia") is characterized by motor and motivation dysregulation and is associated with a number of neuropsychiatric and medical disorders. It is recognizable in a variety of clinical settings. We present observations from the treatment of four individuals with catatonia in Haiti and Rwanda and introduce a treatment protocol for use in resource-limited settings. METHODS: Four patients from rural Haiti and Rwanda with clinical signs of catatonia and a positive screen using the Bush-Francis Catatonia Rating Scale were treated collaboratively by general physicians and mental health clinicians with either lorazepam or diazepam. Success in treatment was clinically assessed by complete remittance of catatonia symptoms. RESULTS: The four patients in this report exhibited a range of characteristic and recognizable signs of catatonia, including immobility/stupor, stereotypic movements, echophenomena, posturing, odd mannerisms, mutism and refusal to eat or drink. All four cases presented initially to rural outpatient general health services in resource-limited settings. In some cases, diagnostic uncertainty initially led to treatment with typical antipsychotics. In each case, proper identification and treatment of catatonia with benzodiazepines led to significant clinical improvement. CONCLUSION: Catatonia can be effectively and inexpensively treated in resource-limited settings. Identification and management of catatonia are critical for the health and safety of patients with this syndrome. Familiarity with the clinical features of catatonia is essential for health professionals working in any setting. To facilitate early recognition of this treatable disorder, catatonia should feature more prominently in global mental health discourse.

Pharmacokinetic evaluation of intranasally administered vinyl polymer-coated lorazepam microparticles in rabbits.

The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1 µm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5 mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5 µm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1 µm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T (max) 14.2 ± 4.9 min; MP2, T (max) 9.3 ± 3.8 min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.

Oral administration of analgesia and anxiolysis for pain associated with bone marrow biopsy.

AIMS: Medical literature provides only scarce data about the degree of pain experienced by patients undergoing a bone marrow aspiration and biopsy (BMAB), and little is known about the factors that can modify the perception of pain. In this study, we evaluated the effectiveness of a combination of analgesia and anxiolysis in reducing the pain score of patients undergoing BMAB. MATERIALS AND METHODS: Eighty-four consecutive adult patients underwent BMAB after local anesthesia with 5 mL of lidocaine hydrochloride 1% aqueous solution in the left posterior superior iliac crest. Analgesia was obtained with acetaminophen 650 mg and oxycodone 10 mg, and anxiolysis was obtained with lorazepam 2 mg, all drugs given once orally 30 min before the procedure. We assessed the pain level with the Wong-Baker Faces Pain Rating Scale, which distinguishes six levels of pain, from 0 to 5. RESULTS: The 34 patients who received an oral administration of analgesia and anxiolysis reported pain at lower levels, i.e., in the range of 0-2, more frequently than the 50 patients who underwent BMAB without analgesia/anxiolysis (78% vs 64%, respectively). Among several predictors analyzed using a multivariate regression model, three were found to be associated with decreased pain level: the use of analgesia/anxiolysis, male sex, and increase in age (all with p values <0.05). Length of the extracted bone specimen, body mass index, and need of a spinal needle for anesthesia in obese patients did not predict for pain level. CONCLUSIONS: An oral administration of prophylactic regimen of analgesia and anxiolysis, at the above-mentioned doses, produced a statistically significant reduction of the perception of pain in patients undergoing BMAB, but its effect did not seem to provide a major and clinically significant reduction of pain level.

Development and evaluation of lorazepam microemulsions for parenteral delivery.

The objective of this investigation was to develop lorazepam (LZM) microemulsions as an alternative to the conventional cosolvent based formulation. Solubility of LZM in various oils and Tween 80 was determined. The ternary diagram was plotted to identify area of microemulsion existence and a suitable composition was identified to achieve desired LZM concentration. The LZM microemulsions were evaluated for compatibility with parenteral fluids, globule size, in vitro hemolysis and stability of LZM. Capmul MCM demonstrated highest solubilizing potential for LZM and was used as an oily phase. LZM microemulsions were compatible with parenteral dilution fluids and exhibited mean globule size less than 200 nm. The in vitro hemolysis studies indicated that microemulsions were well tolerated by erythrocytes. The LZM microemulsions containing amino acids exhibited good physical and chemical stability when subjected to refrigeration for 6 months.

Case of acute psychosis from herbal supplements.

A recent study estimates that 15.2 percent of American adults use nonprescription dietary supplements for weight loss. Sale of ephedrine- and ephedrine-alkaloid-containing products was prohibited by the Food and Drug Administration in February 2004 after research demonstrated an increased risk of arrhythmia, mortality and hypertension following use of products containing these sympathomimetics. Subsequently, nutritional supplement manufacturers have turned to other products to promote weight loss. The following paper reports a case study of a 28-year-old woman with no prior psychiatric history who was hospitalized secondary to an acute psychotic episode. The patient reported starting several weight-loss and nutritional sports supplements approximately one week prior to admission. The relationship between the onset of psychosis and the initiation of the dietary supplements strongly suggests a correlation exists. Heightened consumer education regarding the contents of dietary supplements, along with their potential for causing adverse effects when used alone or in combination with other medications, is warranted. Patients who choose to take dietary supplements should be encouraged to inform their health care providers about the supplements they are taking.

Orbitozygomatic complex fracture reduction under local anesthesia and light oral sedation.

PURPOSE: Closed hook reduction is a well-accepted approach in reducing selected cases of isolated orbitozygomatic complex fractures. The potential of achieving such reductions under light sedation and local anesthesia has many potential benefits over general anesthesia and should therefore not be overlooked. The goal of this study was to verify if closed reduction under local anesthesia is a feasible alternative to reduction under general anesthesia for selected cases of orbitozygomatic complex fractures. Furthermore, an attempt was made at identifying those who would benefit from such an option without compromising end results as opposed to those who would require open reduction with the use of internal fixation devices (ORIF) to ensure favorable outcomes. MATERIALS AND METHODS: Over the period of July to October 2005, we attempted to reduce 8 consecutive orbitozygomatic complex fractures on an outpatient basis with the use of local anesthesia. RESULTS: We have successfully reduced 6 of 8 such fractures. CONCLUSION: Closed hook reduction under light sedation and local anesthesia is a feasible and safe procedure in selected cases of noncomminuted zygomatic fractures. Coupling both physical examination and immediate postoperative radiographic evaluation ensures substantiation of accurate reduction and permits immediate final corrections if considered necessary.

Efficacy and tolerability of a standardized herbal product from Galphimia glauca on generalized anxiety disorder. A randomized, double-blind clinical trial controlled with lorazepam.

Galphimia glauca Cav. is a plant used in Mexican traditional medicine as a "nerve tranquilizer". Previous studies have demonstrated that the methanolic extract from this plant species possess an anxiolytic effect. Galphimine B (GB, a nor-seco-triterpene), is the active principle, with an innovative action mechanism. Against this background, a standardized herbal medicinal product was developed from the aqueous extract of G. glauca (GgHP). The present work compared the therapeutic effectiveness, safety, and tolerability of the new GgHP with lorazepam on patients with generalized anxiety disorder (GAD). By means of a controlled, randomized, double-blind clinical trial, outpatients of either sex who matched the DSM-IV diagnostic criteria with a score of > or = 19 points on the Hamilton Anxiety Scale (HAM-A) were included. The experimental group was treated orally with GgHP in capsules twice a day for 4 weeks. The control group received lorazepam (1 mg) under the same conditions and presentation. A total of 152 patients were included in the trial (72 in the experimental group). From the first week of treatment, GgHP showed important anxiolytic effectiveness, very similar to that produced with lorazepam. Both treatments showed therapeutic safety (no alterations on biochemical analysis of hepatic and renal function). Nevertheless, concerning side effects, GgHP evidenced a considerably higher tolerability than lorazepam.

Safety of cataract surgery under topical anesthesia with oral sedation without anesthetic monitoring.

PURPOSE: The current study was conducted to determine whether topical anesthesia with oral sedation and without an anesthetist present in the operating room is a safe and cost-effective strategy for low-risk patients undergoing cataract surgery. METHODS: This retrospective interventional case series included cases conducted between 2001 and 2003 at the Brandon Regional Health Centre in Brandon, Manitoba. Patients with visually significant cataracts were screened for study inclusion by using the following criteria: good general health, good dilation, moderate cataracts, cooperation with in-office tests and procedures, and understanding of cataract surgery. Oral sedation was provided by lorazepam, and an anesthetist was available to manage any medical adverse events. Topical anesthesia was achieved by means of tetracaine drops, lidocaine hydrochloride jelly, and intracameral lidocaine hydrochloride, as necessary. Main outcome measures were heart rate, systolic and diastolic blood pressure, oxygen saturation, intraoperative complications, and medical adverse events necessitating anesthetist intervention. RESULTS: A total of 538 eyes of 373 patients were included in the cataract surgery case series. No medical adverse events were reported in 454 cases (84.4%); 84 patients (15.6%) experienced adverse events, classified as mild in 13.5%, moderate in 1.1%, and severe in 0.9% (5 cases). The most common adverse event was mild pain, experienced in 69 procedures (12.8%). Moderate pain, necessitating use of intracameral 1% lidocaine, occurred in 3 procedures (0.6%). INTERPRETATION: Topical anesthesia appears to be a safe alternative to injection anesthesia without many of the disadvantages of the latter and may be preferable in carefully selected patients.

The Misericordia Health Centre cataract comfort study.

BACKGROUND: All surgery provokes various degrees of anxiety for patients. The environment leading up to surgery can affect anxiety levels. We performed a prospective randomized study to compare environmental factors around the time of cataract surgery in order to identify interventions that would minimize stress for patients. METHODS: Patients scheduled to undergo cataract surgery at a university-affiliated hospital in Winnipeg were randomly assigned to 1) receive orally administered lorazepam or a placebo before surgery; 2) listen to relaxing music through headphones or routine background noise before surgery; 3) walk (or go by wheelchair if unable to walk) to the operating room or go by stretcher; and 4) listen to relaxing music through headphones or routine background noise during surgery. Randomization for part 1 was double blind; for parts 2 and 3 the surgeon and anesthetist were blinded, but the patient was not. Patients were asked to rate their anxiety, sedation, nausea and pain on arrival at the preoperative area, about 30 minutes after arrival, on arrival in the operating room and on arrival in the postoperative area, on a visual analogue scale graded from 0 ("None" [or "Wide awake" in the case of sedation]) to 10 ("Worst possible" [or "Asleep" in the case of sedation]). Patient satisfaction and willingness to repeat the exact same form of treatment were also rated. RESULTS: Of the 19 surgeons in the department 18 agreed to participate; I withdrew during the study. Data were collected for 144 patients aged 26 to 93 years. Anxiety was highest on arrival at the institution and decreased progressively thereafter. Oral sedation and listening to music before surgery were associated with decreased anxiety and increased levels of sedation (p = 0.002). Walking to the operating room provided no benefit over going by stretcher. Listening to music through headphones during surgery was not accepted by many patients and, when used, negatively affected the surgeon's assessment of the patient's ability to cooperate. Surgeons reported movement more often among patients who received oral sedation than among those who did not (chi2 = 0.01). Levels of pain and nausea were extremely low in all patients, and satisfaction was very high. Patients who received regional local anesthesia had less pain and higher satisfaction than those who received topical anesthesia. Willingness to repeat the same treatment was extremely high. INTERPRETATION: For patients undergoing cataract surgery, efforts should be directed toward reducing anxiety on arrival at the institution, when it is highest, and not just during surgery. Oral sedation and listening to music before surgery appear to be beneficial. Listening to music through headphones during surgery was not found to be advantageous.

Modulation of practice-dependent plasticity in human motor cortex.

Motor practice may lead to expansion of trained representations in the motor cortex, but it is unknown whether this practice-dependent plasticity can be purposefully enhanced or depressed. Evidence, mainly based on animal experiments, indicates that the activity of GABA-related cortical inhibition is important in controlling the extent to which plasticity may occur. We tested the role of GABA in modulating practice-dependent plasticity in the human motor cortex. A decrease in GABA-related cortical inhibition was achieved by ischaemic nerve block (INB) in the hand by deafferentation/deefferentation and an increase was achieved by administration of the GABA(A) receptor agonist lorazepam. In Experiment 1, healthy subjects performed motor practice (MP), consisting of repeated ballistic contractions of the biceps muscle in the absence (MP alone) or presence of INB (MP+INB). Changes in the biceps motor cortex representation were assessed by transcranial magnetic stimulation (TMS). MP+INB resulted in a dramatic increase in the size of the motor evoked potential (MEP) and in paired-pulse excitability compared with mild or no changes in the MP-alone and INB-alone conditions. In Experiment 2, this dramatic increase in biceps representation induced by MP+INB was replicated when subjects were pretreated with placebo, but this increase was prevented or even switched to a decrease when subjects were pretreated with lorazepam. These findings indicate that a decrease in GABA-related inhibition facilitates practice-dependent plasticity in the human motor cortex, whereas an increase depresses it. In Experiment 3, practice-dependent plasticity (assessed by TMS, as in the first two experiments) was also tested at the behavioural level. The dramatic increase in biceps MEP size induced by MP+INB was paralleled by an increase in peak acceleration of the fastest elbow flexion movements. Similarly, the lack of change in MEP size in the MP-alone condition was paralleled by a lack of change in peak acceleration. We propose that changes in GABA activity may be instrumented to modulate plasticity purposefully; for instance, to enhance plastic change and recovery of function after a lesion in neurological patients.

Combined sedation and topical anesthesia for cataract surgery.

PURPOSE: To determine whether lidocaine jelly is as efficacious as tetracaine drops for obtaining ocular anesthesia and to evaluate sublingual lorazepam as premedication for sedation in cataract surgery. SETTING: An ambulatory surgical center dedicated to ophthalmic surgery. METHODS: The study was divided into 2 phases. In the first, 100 patients were divided into 2 groups of 50 each. The first group received tetracaine 0.5% drops for anesthesia. The second group received lidocaine 2% jelly for topical anesthesia. In the second stage, 100 patients were divided into 2 groups of 50 each. The first 50 patients were given 1 mg of sublingual lorazepam before surgery. The second group had cataract surgery without sublingual lorazepam. All patients were operated on by the same surgeon in an ambulatory surgical center. The technique was temporal clear corneal cataract surgery with foldable intraocular lens implantation. Exclusions from the study were the need to convert to peribulbar or retrobulbar anesthesia, intraocular complications, and altered mental status. RESULTS: In the first phase of the study, lidocaine 2% jelly was as efficacious as tetracaine 0.5% drops for topical anesthesia in cataract surgery. In the second phase of the study, overall, patients in the lorazepam group had less anxiety, greater amnesia, and lower blood pressure than those not receiving lorazepam as sedation for topical anesthesia. CONCLUSIONS: Lidocaine 2% jelly combined with sublingual lorazepam provided excellent cost-effective anesthesia and sedation for topical anesthesia in cataract surgery and enhanced patient satisfaction with the procedure.

Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study.

A novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5 ms. The size of these MEP peaks was transiently suppressed by drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily controlled by GABA related neuronal circuits. The potential relevance of this non-invasive paired TMS protocol for the investigation of I-waves in patients with neurological disease will be discussed.