Efficacy of Oral and Sublingual Ketamine Formulations for Analgesia: A Systematic Review and Meta-Analysis

AimThe aim of this study was to undertake a systematic review and meta‐analysis to determine the effectiveness of oral and sublingual ketamine in pain management.Data SourcesA systematic search was conducted utilising four databases: MEDLINE, CINAHL, Embase, and Web of Science.Study SelectionThe study included randomised controlled trials investigating the use of oral or sublingual ketamine in the management of pain in inpatient or outpatient settings compared to any alternative oral or sublingual comparator, including placebo.ResultsTwenty‐one studies were included for systematic review, all assessing oral ketamine, including one comparing oral to sublingual ketamine. Of these, 12 studies evaluated oral ketamine in procedural pain, with 10 studies finding oral ketamine significantly better than the comparator at reducing procedural pain. Two studies focused on oral ketamine in postoperative pain, both finding oral ketamine reduced the requirement for additional analgesia compared to placebo. Five studies investigated oral ketamine in chronic pain with heterogenous results. Of the remaining two studies, one compared various doses of oral ketamine and the other compared oral to sublingual ketamine.Fifteen studies were included for meta‐analysis. Among them, seven studies compared oral ketamine to placebo and found oral ketamine was superior to placebo in reducing pain (p < 0.01). Eight studies compared oral ketamine to other oral medications such as methadone, codeine, midazolam, and dexmedetomidine and showed no significant benefit of oral ketamine in reducing pain (p = 0.18).ConclusionThe results suggest oral ketamine is an effective analgesic in the procedural setting.

Ketamine is the most common medication for procedural sedation and analgesia (PSA) of pediatric patients in the emergency department (ED). Since ketamine injection is painful, some studies have assessed the routes other than intravenous and intramuscular. Therefore, this systematic review aims to evaluate the details of noninjectable ketamine (NIK) administration. The review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis for Systematic Review (PRISMA) guidelines. MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science Core Collection (SCIE and ESCI), and Scopus were searched for relevant studies from inception to 3 July 2025. All English original clinical research on PSA with NIK administration in pediatric populations in the ED was included. Risk of bias and certainty of evidence (COE) were also assessed. From 5617 identified records, 12 studies (7 interventional and 5 observational) with a total number of 1484 patients were included. Most of the studies evaluated laceration repair among children 2-12 years of age. Seven single-center double-blinded randomized controlled trials showed that oral ketamine (5-10 mg/kg) alone or in combination with other medications (mainly midazolam) provided the desirable level of sedation (COE: very low) relative to the oral comparators. It also resulted in faster onset of action (OA) (15-35 min) and shorter duration of action (DA) (60-265 min) (COE: low). Oral and nasal ketamine studies did not report any serious adverse event (SAE) associated with invasive interventions (COE: moderate to low). Sedation with oral ketamine might have a desirable depth, faster OA, and shorter DA relative to the oral comparators. Furthermore, NIK probably showed no SAE during PSA. Nevertheless, the limited number of heterogeneous studies leaves uncertainty, highlighting the need for further research.

Nitrate delivery systems in perspective: A decade of progress

Ketamine Produced Quick Antidepressant Effect in Test

Isosorbide Dinitrate Plasma Concentrations and Bioavailability in Human Subjects after Administration of Standard Oral and Sublingual Formulations

The pharmacokinetic profiles of a sublingual and a conventional oral lorazepam tablet formulation were established following chronic administration to twelve healthy male volunteers. Fitting a multi-dose equation based on a one-compartment model to the observed data, the average elimination half-lives for the sublingual and oral doses are estimated to be 11 and 8 h, respectively, while the corresponding absorption half-lives are 15 and 55 min; this confirms earlier reports that the sublingual formulation is more rapidly absorbed. The observed time to steady-state for both formulations was approximately 3 days, which agrees well with that predicted from previous single dosing studies. Although the sublingual formulation yields a higher average steady-state minimum plasma concentration than the oral formulation (41.6 versus 38.1 ng ml-1), the maximum lorazepam concentration achieved during steady state was approximately 83 ng ml-1 for both formulations. The average steady-state plasma concentration is estimated to be 63 ng ml-1, independent of the formulation used.

BackgroundThe neuropathic pain management which is refractory to opioids treatments demands the development of new analgesics or new ways of using our classic medicines. Ketamine is scarcely used as an...

The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability. The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales. The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min–max) time of the peak plasma concentration was 0.75 h (0.25–1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability. Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.

Intravenous Ketamine has shown robust antidepressant efficacy although other routes of administration are currently needed. We conducted a systematic review and meta-analysis of studies evaluating the efficacy and tolerability of oral ketamine for depression. A comprehensive search of major electronic databases from inception to April 2020 was performed. Studies of oral ketamine for depression, from case series to randomized clinical trials, were eligible. Randomized controlled trials were included in a meta-analysis, focusing on response, remission, time to effect, and side effects. A total of 917 articles were identified with 890 studies screened, yielding a total of 10 studies included in our systematic review.Three randomized controlled trials (RCTs) (N = 161, mean age 37.9 ± 9.5 years, 58.6% females) were included in the meta-analysis. Pooled analysis suggested a significant antidepressant effect of oral ketamine (SMD: -0.75; 95% CI: -1.08, -0.43; p<0.0001; I2 = 0%) although remission rates (RR:2.77; 95% CI:0.96, 8.00; p = 0.06) and response rates (RR:2.58; 95% CI:0.94,7.08; p = 0.07) were marginal compared to placebo at the endpoint. Oral ketamine antidepressant effects seemed to take effect at the 2nd week (SMD: -0.71; 95% CI: -1.08, -0.35; p = 0.001; I2 = 0%). There were no significant differences in the overall side-effects between oral ketamine and the placebo group (RR 1.28, 95% CI: 0.89-1.83; p = 0.19). This focused meta-analysis of oral ketamine suggests a marginal efficacy for major depressive disorder without increased risk of adverse events. Further larger sample studies are needed to confirm these preliminary findings, analyzing differential response/remission rates by affective disorder, optimal dosing strategies, and its long-term effects.

Pediatric preoperative anxiety (PPA) is a prevalent condition that exhibits significant effects on the psychological and physiological status of children both preoperatively and postoperatively. We conducted systematic review and network meta-analysis. PubMed, Embase, Web of Science Core Collection, and The Cochrane Library were searched up to December 1, 2024. RCTs of pediatric patients (0-14 years) receiving preoperative sedatives were included. Primary outcome was Parental Separation Anxiety Scale (PSAS); secondary outcomes were Mask Acceptance Scale (MAS), postoperative nausea/vomiting (PONV), and delirium/agitation (PODA). Seventy studies (16,626 participants) were included. Five sedatives including midazolam, dexmedetomidine, ketamine (oral, intranasal, nebulized), clonidine (oral, intranasal), and melatonin (oral) were compared with placebo. Data from 20 interventions (5581 patients) assessed PPA. Intranasal dexmedetomidine (ID) showed highest single-drug efficacy (SUCRA: PSAS 68.1%, MAS 48.8%, PONV 65.7%, PODA 67.8%). Oral ketamine (OK) and midazolam (OM/IM) were effective alternatives. Combined regimens were promising but inconclusive. ID significantly alleviated PPA with minimal adverse effects in single-drug regimens (optimal dose: 1-2µg/kg). OK, OM or IM served as potential alternative options for clinical application. While combination regimens (notably OM+OK) demonstrated superior efficacy across outcomes, small sample sizes necessitate cautious interpretation, underscoring the need for future comparative studies.

Hypnotics in Insomnia: The Experience of Zolpidem

Ketamine and Esketamine for Late-Life Depression: A Systematic Review of Efficacy, Safety, and Tolerability.

Migraine is a complex neurological disease. Migraine headaches described as vascular headaches cause a throbbing and pulsating pain around the head. A migraine attack involves stimulating the sympathetic nerve system, and increased sympathetic activity leads to nausea, vomiting, and diarrhea. Therefore, treatment of migraine requires immediate onset of action of the drug to give fast relief from the pain. Absorption of drugs directly through the oral cavity is one of the efficient ways of treating various diseases. The oral cavity has low enzymatic activity, ease of access for patients to receive and administer medication, and high vascularization and permeability allowing pharmacological compounds to reach the bloodstream immediately. Oral Transmucosal formulations such as mouth-dissolving strips, buccal tablets, buccal patches, and bioadhesive films, sublingual formulations, soft palatable films provide better bioavailability and tackle the main drawbacks of oral therapy, including hepatic biotransformation, varying drug absorption across the gastrointestinal system, and enzymatic degradation. The effects of these formulations might be both systemic and localized. In this paper, a comprehensive review has been made to discuss the causes, types, and treatment of migraine. The role of Oral Transmucosal formulations in the prepared for the treatment of migraine.

Modulation of brain delivery and copulation by intranasal apomorphine hydrochloride

Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia. We conducted a systematic review and meta-analysis of randomized-controlled-trials (RCTs) comparing the second-generation long-acting injectable antipsychotics (SGA-LAIs) olanzapine, risperidone, paliperidone, and aripiprazole with placebo or their oral counterparts in acutely ill patients with schizophrenia. We analyzed 23 efficacy and tolerability outcomes, with the primary outcome being overall symptoms of schizophrenia. The results were obtained through random effects, pairwise meta-analyses, and subgroup tests. The study quality was assessed using the Cochrane-Risk-of-Bias-Tool version-1. Sixty-six studies with 16 457 participants were included in the analysis. Eleven studies compared second-generation long-acting injectable antipsychotics (SGA-LAIs) with a placebo, 54 compared second-generation oral antipsychotics (SGA-orals) with a placebo, and one compared an SGA-LAI (aripiprazole) with its oral formulation. All 4 SGA-LAIs reduced overall symptoms more than placebo, with mean standardized differences of -0.66 (95% CI: -0.90; -0.43) for olanzapine, -0.64 (-0.80; -0.48) for aripiprazole, -0.62 (-0.76; -0.48) for risperidone and -0.42 (-0.53; -0.31) for paliperidone. The side-effect profiles of the LAIs corresponded to the patterns known from the oral formulations. In subgroup tests compared to placebo, some side effects were less pronounced under LAIs than under their oral formulations. SGA-LAIs effectively treat acute schizophrenia. Some side effects may be less frequent than under oral drugs, but due to the indirect nature of the comparisons, this finding must be confirmed by RCTs comparing LAIs and orals head-to-head.