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Refractory chronic cough causes substantial symptoms and quality-of-life impairment. Similarities between central reflex sensitisation in refractory chronic cough and neuropathic pain suggest that neuromodulators such as gabapentin might be effective for refractory chronic cough. We established the efficacy of gabapentin in patients with refractory chronic cough. This randomised, double-blind, placebo-controlled trial was undertaken at an outpatient clinic in Australia. Adults with refractory chronic cough (>8 weeks' duration) without active respiratory disease or infection were randomly assigned to receive gabapentin (maximum tolerable daily dose of 1800 mg) or matching placebo for 10 weeks. Block randomisation was done with randomisation generator software, stratified by sex. Patients and investigators were masked to assigned treatment. The primary endpoint was change in cough-specific quality of life (Leicester cough questionnaire [LCQ] score) from baseline to 8 weeks of treatment, analysed by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000248369. 62 patients were randomly assigned to gabepentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in LCQ score during treatment period 1·80, 95% CI 0·56–3·04; p=0·004; number needed to treat of 3·58). Side-effects occurred in ten patients (31%) given gabapentin (the most common being nausea and fatigue) and three (10%) given placebo. The treatment of refractory chronic cough with gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough. National Health and Medical Research Council of Australia and Hunter Medical Research Institute, Newcastle, Australia.

Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone. In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0–10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636. 45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0–10; numerical rating scale) was 5·4 (95% CI 5·0 to 5·8) at baseline, and at maximum tolerated dose, pain was 3·2 (2·5 to 3·8) for gabapentin, 2·9 (2·4 to 3·4) for nortriptyline, and 2·3 (1·8 to 2·8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (−0·9, 95% CI −1·4 to −0·3, p=0·001) or nortriptyline alone (−0·6, 95% CI −1·1 to −0·1, p=0·02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0·0001) or combination treatment (p<0·0001). No serious adverse events were recorded for any patients during the trial. Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain. Canadian Institutes of Health Research.

There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18-65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis-Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.

In a randomized trial, the combination of morphine and gabapentin led to better pain control than either agent alone in patients with diabetic neuropathy or postherpetic neuralgia. The dose of each agent was lower when used in combination than when used alone. Adverse effects were not more severe with the combined formulation. The combination of morphine and gabapentin led to better pain control than either agent alone in patients with diabetic neuropathy or postherpetic neuralgia. Neuropathic pain is a common complication of cancer, diabetes mellitus, degenerative spine disease, infection with the human immunodeficiency virus, the acquired immunodeficiency syndrome, and other infectious diseases, and it has a profound effect on quality of life and expenditures for health care. 1 Gabapentin and opioids have been proposed as two of several first-line treatments for neuropathic pain. 2 However, the maximal tolerated doses of these drugs, administered as single agents, reduce pain by only 26 to 38 percent, owing to incomplete efficacy, dose-limiting adverse effects, or both. 3 – 6 The combination of mechanistically distinct analgesic agents may result in additivity or synergism . . .

Sevoflurane causes emergence agitation (EA) in up to 80% of pediatric patients. Using midazolam, dexmedetomidine (DEX), and gabapentin, this work aimed to assess the prophylactic effect of oral premedication on EA incidence experienced by pediatric patients during recovery from sevoflurane anesthesia. Randomized controlled trial. Kafrelsheikh University, Kafrelsheikh, Egypt. This study was performed on 240 men and women aged 3 to 10 years who were scheduled for adenotonsillectomy. Patients were randomized into 4 equal-sized groups. Thirty minutes before general anesthesia, oral premedication was applied in the form an apple-flavored sugary fluid plus 0.5 mg/kg of midazolam in Group M, 4 µg/kg of DEX in Group D, 10 mg/kg of gabapentin in Group G, or no drugs whatsoever in Group P (placebo). The incidence of EA was reduced more greatly in the M, D, and G groups than in the P group, and the D group's incidence of EA was lower than that of the M or G groups. The severity of EA exhibited a more significant reduction in the M, D, and G groups than in Group P. Similarly, the time until extubation was more prolonged in the M, D, and G groups than it was in the P group. Hemodynamics measurements were significantly lower in Groups M, D, and G than in Group P, and the D group had a lower hemodynamics measurement than did the M or G groups. Sedation scores were greater in the D and G groups than in the P group, and the D group had a higher sedation score than did Group M. This study used a small sample, took place at a single center, and had a short follow-up period. Premedication using oral midazolam, DEX, or gabapentin reduced the incidence of EA, and DEX provided the best sedation and hemodynamics of all.

Background Pruritus is a common skin symptom manifesting with an unpleasant sensation and desire to itch and scratch. Pruritis can be a hallmark of many skin diseases as well as other non cuatneous diseases. Aim of the study To compare the efficacy of gabapentin versus narrow band UVB versus combination of both in treatment of uremic pruritus. Methods This study that included 60 patients diagnosed with uremic pruritus, randomly allocated into one of three groups. Group A received oral gabapentin 300 mg OD for six weeks, group B received NB-UVB phototherapy three times per week in nonconsecutive days for a total of 18 sessions (6 weeks) and group C received combination of both therapies for 6 weeks. Efficacy was assessed by visual analogue scale (VAS) and 5-D itch scale before and after the end of therapy. Results Significant difference of VAS score between groups A & C ( P  = 0.029) and between group B & C ( P  = 0.027) was demonstrated. Complete responders represented 55% of group C (combination treatment group), 20% of group A & only 15% of group B. The highest frequency of no response was detected for group A (30%) followed by group B (15%) and lowest for group C (5%). Conclusion Combination of both gabapentin and NB-UVB is a promising medication for the treatment of uremic pruritus. Further well-designed clinical and experimental studies are needed to clarify the relationship between the frequency of NB-UVB phototherapy sessions and gabapentin dosing for an optimal response.

Summary Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1–2 in 14–21 day cycles either alone (MT; Panel1/ n  = 18; 200 to 1800 mg) or in combination (CT; Panel2/ n  = 17; 100 to 225 mg) with IV docetaxel 60 mg/m 2 , determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC 0-12hr and C max increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t 1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

Chronic pelvic pain (CPP) affects 2.1-24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700 mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women's experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012-2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07-3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97-6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial.

Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters; however, the compounds differ in their pharmacokinetic and pharmacodynamic characteristics. Gabapentin is absorbed slowly after oral administration, with maximum plasma concentrations attained within 3–4 hours. Orally administered gabapentin exhibits saturable absorption — a nonlinear (zero-order) process — making its pharmacokinetics less predictable. Plasma concentrations of gabapentin do not increase proportionally with increasing dose. In contrast, orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 hour. Absorption is linear (first order), with plasma concentrations increasing proportionately with increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day, while the absolute bioavailability of pregabalin remains at <-90% irrespective ofthe dosage. Both drugs can be given without regard to meals. Neither drug binds to plasma proteins. Neither drug is metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs. Both drugs are excreted renally, with elimination half-lives of approximately 6 hours. Pregabalin and gabapentin both show dose-response relationships in the treatment of postherpetic neuralgia and partial seizures. For neuropathic pain, a pregabalin dosage of 450 mg/day appears to reduce pain comparably to the predicted maximum effect of gabapentin. As an antiepileptic, pregabalin may be more effective than gabapentin, on the basis of the magnitude of the reduction in the seizure frequency. In conclusion, pregabalin appearsto have some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect.

Hexamoll ® DINCH ® (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high molecular weight plasticizer and a non-aromatic phthalate substitute. In this follow-up study, we further investigated the extensive oxidative metabolism of Hexamoll ® DINCH ® after oral dosage of 50 mg to three male volunteers (0.552–0.606 mg/kg body weight). Urine samples were consecutively collected over 48 h post-dose. Chemical analysis was carried out by HPLC–MS/MS with labeled internal standards. New metabolites were tentatively identified and quantified via fragmentation analogies and new standard substances. In addition to the five urinary DINCH metabolites previously reported by us, we identified two groups of extensively oxidized metabolites characterized (a) by multiple side chain oxidation and breakdown and (b) by hydroxylation at the cyclohexane ring. The five newly identified carboxylated breakdown metabolites represented in sum 5.12 ± 0.49 % of the applied dose. MCHxCH (cyclohexane-1,2-dicarboxylic acid mono carboxyhexyl ester) was identified as a major metabolite (2.71 ± 0.34 %) and thus represents the second most important specific metabolite of DINCH after OH-MINCH (10.7 ± 2.1 %). Less than 1 % was excreted as ring-hydroxylated metabolites (four metabolites identified). Based upon a new reference standard, we can also update oxo-MINCH to 2.6 % of the applied dose. This follow-up study increases the total amount of the recovered dose from 39.2 to 45.7 % and describes a new major metabolite (MCHxCH) of DINCH that can be used as an additional valuable and specific biomarker to assess DINCH ® exposure in future human biomonitoring studies.