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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 . . .

Most women receiving systemic therapy for breast cancer experience hot flashes. We undertook a randomised, double-blind, placebo-controlled, multi-institutional trial to assess the efficacy of gabapentin in controlling hot flashes in women with breast cancer. 420 women with breast cancer who were having two or more hot flashes per day were randomly assigned placebo, gabapentin 300 mg/day, or gabapentin 900 mg/day by mouth in three divided doses for 8 weeks. Each patient kept a 1-week, self-report diary on the frequency, severity, and duration of hot flashes before the start of the study and during weeks 4 and 8 of treatment. Analyses were by intention to treat. Evaluable data were available on 371 participants at 4 weeks (119 placebo, 123 gabapentin 300 mg, and 129 gabapentin 900 mg) and 347 at 8 weeks (113 placebo, 114 gabapentin 300 mg, and 120 gabapentin 900 mg). The percentage decreases in hot-flash severity score between baseline and weeks 4 and 8, respectively were: 21% (95% CI 12 to 30) and 15% (1 to 29) in the placebo group; 33% (23 to 43) and 31% (16 to 46) in the group assigned gabapentin 300 mg; and 49% (42 to 56) and 46% (34 to 58) in the group assigned gabapentin 900 mg. The differences between the groups were significant (p=0·0001 at 4 weeks and p=0·007 at 8 weeks by ANCOVA for overall treatment effect, adjusted for baseline values); only the higher dose of gabapentin was associated with significant decreases in hot-flash frequency and severity. Gabapentin is effective in the control of hot flashes at a dose of 900 mg/day, but not at a dose of 300 mg/day. This drug should be considered for treatment of hot flashes in women with breast cancer.

Background A large number patients struggle with migraine which is classified as a chronic disorder. The relative efficacy, safety and tolerability of prophylactic medications for migraine play a key role in managing this disease. Methods We conducted an extensive literature search for popular prophylactic medications that are used for migraine patients. Pairwise meta-analysis and network meta-analysis (NMA) were carried out sequentially for determining the relative efficacy, safety and tolerability of prophylactic medications. Summary effect for migraine headache days, headache frequency, at least 50% reduction in headache attacks, all-adverse events, nausea, somnolence, dizziness, withdrawal and withdrawal due to adverse events were produced by synthesizing both direct and indirect evidence. Results Patients with three interventions exhibited significantly less average migraine headache days compared with those treated by placebo (topiramate, propranolol, divalproex). Moreover, topiramate and valproate exhibited a significantly increased likelihood of at least 50% reduction in migraine headache attacks compared to placebo. Patients with topiramate and propranolol also exhibited significantly reduced headache frequency compared to those with placebo. On the other hand, patients with divalproex exhibited significantly higher risk of nausea compared to those with placebo, topiramate, propranolol, gabapentin and amitriptyline. Finally, divalproex was associated with an increased risk of withdrawal compared to placebo and propranolol. Conclusions Topiramate, propranolol and divalproex may be more efficacious than other prophylactic medications. Besides, the safety and tolerability of divalproex should be further verified by future studies.

Epilepsy is a heterogeneous disorder, with outcomes ranging from immediate remission after taking a first antiepileptic drug to frequent unremitting seizures with multiple treatment failures. Few prognostic models enable prediction of outcome; we therefore aimed to use data from the SANAD study to predict outcome overall and for patients receiving specific treatments. The SANAD study was a randomised controlled trial in which standard antiepileptic drugs were compared with new treatments. Arm A included patients for whom carbamazepine was considered the first-line treatment, most of whom were newly diagnosed with focal epilepsy. Patients were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Outcomes were time to treatment failure overall, because of inadequate seizure control, and because of adverse events, and time to 12 months of remission from seizures. In this post-hoc study we used regression multivariable modelling to investigate how clinical factors affect the probability of treatment failure and the probability of achieving 12 months of remission. For time to treatment failure, we identified several significant risk factors: sex (male vs female, hazard ratio [HR] 0·86, 95% CI 0·75–0·99), treatment history (taking non-SANAD antiepileptic drugs [other than those listed above] vs treatment naive, 1·27, 1·05–1·53), age (eg, older than 71 years vs 10 years or younger, 0·68, 0·51–0·91), total number of seizures (eg, four to 11 seizures vs two or fewer, 1·08, 1·05–1·11), electroencephalogram results (epileptiform abnormality vs normal, 1·26, 1·07–1·50), seizure type (eg, secondary generalised vs simple or complex partial only, 0·78, 0·66–0·91), site of onset (not localised vs temporal lobe, 1·25, 1·06–1·47), and treatment (lamotrigine vs carbamazepine, 0·76, 0·61–0·95). Significant factors for time to 12 months of remission were sex (male vs female, 1·19, 1·05–1·35), treatment history (taking a non-SANAD antiepileptic drug vs treatment naive, 0·64, 0·52–0·78), age (eg, older than 71 years vs 10 years or younger, 1·60, 1·26–2·03), time from first seizure (60–239 months vs ≥2 months, 1·14, 1·01–1·29; >240 months vs ≤2 months, 1·39, 1·04–1·86), neurological insult (present vs absent, 0·75, 0·61–0·93), total number of seizures before randomisation (eg, four to 11 vs two or fewer, 0·87, 0·85–0·90), and treatment (gabapentin vs carbamazepine, 0·71, 0·59–0·86; topiramate vs carbamazepine, 0·81, 0·68–0·98). We present a thorough investigation of prognostic factors from a large randomised controlled trial in patients starting antiepileptic monotherapy. If validated, our models could aid in individual patient risk stratification and the design and analysis of epilepsy trials. National Institute for Health Research (UK).

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.

Summary Objective The safety and tolerability of three treatments for diabetic peripheral neuropathic pain (DPNP) were compared. Methods A 12‐week, randomized, open‐label study confirming the non‐inferiority of duloxetine (N = 138) vs. pregabalin (N = 134) and the combination of duloxetine plus gabapentin (N = 135) as the primary outcome was previously published. Patients had an inadequate pain response to a stable dose of gabapentin (≥ 900 mg/day) for ≥ 5 weeks prior to study enrolment. Data from that study were assessed in this current analysis for a detailed report of safety and tolerability. Results Completion rates did not differ significantly between the groups. Discontinuation because of adverse events was significantly greater in the duloxetine (19.6%) vs. pregabalin group (10.4%; p = 0.04); no differences emerged between the duloxetine vs. duloxetine plus gabapentin (13.3%) groups (p = 0.19) or pregabalin vs. duloxetine plus gabapentin groups (p = 0.57). Adverse event rates varied: nausea, insomnia, hyperhidrosis and decreased appetite were reported significantly more often in patients treated with duloxetine vs. patients treated with pregabalin (each p ≤ 0.01); insomnia significantly more in patients treated with duloxetine vs. duloxetine plus gabapentin (p = 0.01); peripheral oedema significantly more in patients treated with pregabalin vs. duloxetine and duloxetine plus gabapentin (p ≤ 0.001 each) and nausea, hyperhidrosis, decreased appetite and vomiting significantly more in patients treated with duloxetine plus gabapentin vs. pregabalin (each p ≤ 0.05). At end‐point, weight change differed significantly among treatment groups: patients in the pregabalin group on average gained weight (1.0 ± 0.04 kg); while, patients in the duloxetine and duloxetine plus gabapentin groups on average lost weight (−2.39 ± 0.04 and −1.06 ± 0.04 kg, respectively) (pregabalin vs. duloxetine, p ≤ 0.001; pregabalin vs. duloxetine plus gabapentin, p ≤ 0.001; duloxetine vs. duloxetine plus gabapentin, p = 0.01). Conclusion Duloxetine, pregabalin and duloxetine plus gabapentin were generally safe and tolerable for the treatment of DPNP.

Background Postherpetic neuralgia (PHN) is a chronic neuropathic pain that results from alterations of the peripheral nervous system in areas affected by the herpes zoster virus. The symptoms include pain, paresthesia, dysesthesia, hyperalgesia, and allodynia. Despite the availability of pharmacological treatments to control these symptoms, no treatments are available to control the underlying pathophysiology responsible for this disabling condition. Methods/design Patients with herpes zoster who are at least 50 years old and have a pain score of 4 or higher on a visual analogue scale (VAS) will be recruited. The aim is to recruit 134 patients from the practices of general physicians. Participants will be randomized to receive gabapentin to a maximum of 1800 mg/day for 5 weeks or placebo. Both arms will receive 1000-mg caplets of valacyclovir three times daily for 7 days (initiated within 72 h of the onset of symptoms) and analgesics as needed. The primary outcome measure is the percentage of patients with a VAS pain score of 0 at 12 weeks from rash onset. The secondary outcomes measures are changes in quality of life (measured by the SF-12 questionnaire), sleep disturbance (measured by the Medical Outcomes Study Sleep Scale), and percentage of patients with neuropathic pain (measured by the Douleur Neuropathique in 4 Questions). Discussion Gabapentin is an anticonvulsant type of analgesic that could prevent the onset of PHN by its antihypersensitivity action in dorsal horn neurons. Trial registration ISRCTN Registry identifier: ISRCTN79871784 . Registered on 2 May 2013.

Introduction. Painful diabetic neuropathy (PDN) is a prevalent and impairing disorder. The objective of this study was to show the efficacy and safety of gabapentin (GBP) plus complex B vitamins: thiamine (B1) and cyanocobalamine (B12) compared to pregabalin in patients with moderate to severe intensity PDN. Method. Multicenter, randomized, blind study. Two hundred and seventy patients were evaluated, 147 with GBP/B1/B12 and 123 with PGB, with a 7/10 pain intensity on the Visual Analog Scale (VAS). Five visits (12 weeks) were scheduled. The GBP/B1 (100 mg)/B12 (20 mg) group started with 300 mg at visit 1 to 3600 mg at visit 5. The PGB group started with 75 mg/d at visit 1 to 600 mg/d at visit 5. Different safety and efficacy scales were applied, as well as adverse event assessment. Results. Both drugs showed reduction of pain intensity, without significant statistical difference (P=0.900). In the GBP/B1/B12 group, an improvement of at least 30% on VAS correlated to a 900 mg/d dose, compared with PGB 300 mg/d. Likewise, occurrence of vertigo was lower in the GBP/B1-B12 group, with a significant statistical difference, P=0.014. Conclusions. Our study shows that GPB/B1-B12 combination is as effective as PGB. Nonetheless, pain intensity reduction is achieved with 50% of the minimum required gabapentin dose alone (800 to 1600 mg/d) in classic NDD trials. Less vertigo and dizziness occurrence was also observed in the GBP/B1/B12 group. This trial is registered with ClinicalTrials.gov NCT01364298.

Background Treatment of postherpetic neuralgia (PHN) is more complicated in elderly patients, and multiple daily dosing, complex titration, and high incidences of adverse events can be limiting for many pharmacological treatment options. Objective The aim of this study was to determine whether the efficacy and tolerability of once-daily gastroretentive gabapentin (G-GR) is similar between elderly patients (≥75 years) and younger patients (<75 years). Methods Data from two phase III, placebo-controlled studies of 1,800 mg G-GR once daily with dinner in patients with PHN were integrated and analyzed by age subgroups (<75 years, n  = 527; ≥75 years, n  = 192). Efficacy assessments at endpoint (week 10) included baseline-adjusted change in average daily pain (ADP) and average daily sleep interference (SIS) scores, the proportion of responders (≥30 % pain reduction), and the proportion of patients feeling “Much” or “Very Much” improved on the Patient Global Impression of Change (PGIC). Results Compared with placebo, patients in both age subgroups treated with G-GR (placebo/G-GR) had greater reductions in mean ADP (≥75: −21.9/−34.2 %, p  = 0.0348; <75: −29.9/−38.3 %, p  = 0.0079) and SIS (≥75: −1.3/−2.4, p  = 0.0017; <75: −1.8/−2.7, p  < 0.0001), more patients were responders (≥75: 30.4/52.0 %, p  = 0.0025; <75: 45.0/54.7 %, p  = 0.0265), and more felt “Much” or “Very Much” improved on the PGIC (≥75: 20.7/35.0 %, p  = 0.0272; <75: 33.6/44.9 %, p  = 0.0077). The most common (placebo/G-GR) adverse events (AEs) were dizziness (≥75: 3.3/12.0 %; <75: 1.8/10.4 %), nausea (≥75: 1.0/5.4 %; <75: 2.9/4.2 %), and somnolence (≥75: 0/5.0 %; <75: 3.7/4.2 %). For all patients, AEs rapidly decreased to low steady levels after 4–5 weeks of treatment. The incidence of serious AEs was low and they were reported more frequently in the placebo than in the G-GR group. Conclusions Therapy with once-daily G-GR was as effective for treating pain associated with PHN in elderly patients as it was in younger patients. G-GR was well tolerated, and the incidence of the most common AEs did not appear to be age related.

A prospective examiner-blind, cross-over study was conducted to compare the efficacy of memantine (40 or 60 mg/day) and gabapentin (1,200 mg/day) as therapy for acquired fixational pendular nystagmus (APN) in 11 patients with multiple sclerosis. APN was documented in 20 eyes by electrooculography (EOG). The primary objective of the study was an at least 50% reduction in amplitude and/or frequency of APN compared with baseline values in EOG. This aim was reached for 17 of 20 APN-affected eyes with memantine 40–60 mg and for 11 eyes with gabapentin up to 1,200 mg. A complete cessation of APN was achieved in eight eyes (four patients) with memantine 40 mg and in a further four eyes (two patients) with memantine 60 mg. One patient achieved the same benefit with memantine 40 mg and gabapentin. In two other eyes APN completely subsided with gabapentin 1,200 mg only, but not with memantine. Near visual acuity, a secondary outcome parameter, improved by at least 0.1 in 11 of 17 eyes treated with memantine and in 8 out of 16 eyes treated with gabapentin. In summary, memantine and gabapentin are safe and effective treatment options for APN.