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β-Phenyl-γ-aminobutyric acid (phenibut) is an analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that was first synthesized in Russia in the early 1960s. It is marketed as a nootropic (smart drug) to improve cognitive performance, and to treat generalized and social anxiety, insomnia, and alcohol withdrawal. The use of phenibut is legal in the USA and it is widely available online without a prescription. Increased public awareness of phenibut has led to a growing number of reports of acute intoxication and withdrawal. In this review, we describe the pharmacology of phenibut, the presentation and management of acute intoxication, and regulatory issues, placing particular emphasis on the treatment of acute withdrawal, for which there are no comparative studies. Among 29 cases of phenibut withdrawal, patients were successfully treated with baclofen, benzodiazepines, and phenobarbital, as individual agents or in various combinations. Ancillary medications included antipsychotics, dexmedetomidine, gabapentin, and pregabalin. After stabilization, a number of patients did well on baclofen tapers, whereas others were weaned off benzodiazepines or phenobarbital. Phenobarbital may be preferred over baclofen, or used as an added agent, in patients at risk for seizures. As long as phenibut remains legal, cases of phenibut intoxication and withdrawal are likely to increase. As urine or plasma drug screening for phenibut is not widely available, it is vital that clinicians obtain a detailed medication history in patients presenting to the emergency department with nonspecific symptoms that may represent phenibut intoxication or withdrawal. Further, clinicians may wish to consult an addiction specialist or toxicologist in these situations., (© 2024, The American College of Clinical Pharmacology.)

There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues., (© 2021, The American College of Clinical Pharmacology.)

Background: Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense sedative properties and may exacerbate psychotic symptoms, have been used to treat TD., Objectives: 1. Primary objectiveThe primary objective was to determine whether using non-benzodiazepine GABA agonist drugs for at least six weeks was clinically effective for the treatment of antipsychotic-induced TD in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.2. Secondary objectivesThe secondary objectives were as follows.To examine whether any improvement occurred with short periods of intervention (less than six weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.To examine whether there was a differential effect between the various compounds.To test the hypothesis that GABA agonist drugs are most effective for a younger age group (less than 40 years old)., Search Methods: We searched the Cochrane Schizophrenia Group Trials Register (last searched April 2017), inspected references of all identified studies for further trials, and, when necessary, contacted authors of trials for additional information., Selection Criteria: We included randomised controlled trials of non-benzodiazepine GABA agonist drugs in people with antipsychotic-induced TD and schizophrenia or other chronic mental illness., Data Collection and Analysis: Two review authors independently selected and critically appraised studies, extracted and analysed data on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous data we calculated mean differences (MD). We assumed that people who left early had no improvement. We contacted investigators to obtain missing information. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE., Main Results: We included 11 studies that randomised 343 people. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, participants and outcome assessors were not clearly blinded. For some studies we were unsure if data were complete, and data were often poorly or selectively reported.Data from six trials showed that there may be a clinically important improvement in TD symptoms after GABA agonist treatment compared with placebo at six to eight weeks follow-up (6 RCTs, n = 258, RR 0.83, CI 0.74 to 0.92; low-quality evidence). Data from five studies showed no difference between GABA agonist treatment and placebo for deterioration of TD symptoms (5 RCTs, n = 136, RR 1.90, CI 0.70 to 5.16; very low-quality evidence). Studies reporting adverse events found a significant effect favouring placebo compared with baclofen, sodium valproate or progabide for dizziness/confusion (3 RCTs, n = 62 RR 4.54, CI 1.14 to 18.11; very low-quality evidence) and sedation/drowsiness (4 RCTS, n = 144, RR 2.29, CI 1.08 to 4.86; very low-quality evidence). Studies reporting on akathisia (RR 1.05, CI 0.32 to 3.49, 2 RCTs, 80 participants), ataxia (RR 3.25, CI 0.36 to 29.73, 2 RCTs, 95 participants), nausea/vomiting (RR 2.61, CI 0.79 to 8.67, 2 RCTs, 64 participants), loss of muscle tone (RR 3.00, CI 0.15 to 59.89, 1 RCT, 10 participants), seizures (RR 3.00, CI 0.24 to 37.67, 1 RCT, 2 participants), hypotension (RR 3.04, CI 0.33 to 28.31, 2 RCTs, 119 participants) found no significant difference between GABA drug and placebo (very low-quality evidence). Evidence on mental state also showed no effect between treatment groups (6 RCTS, n = 121, RR 2.65, CI 0.71 to 9.86; very low-quality evidence) as did data for leaving the study early (around 10% in both groups, 6 RCTS, n = 218, RR 1.47, CI 0.69 to 3.15; very low-quality evidence). No study reported on social confidence, social inclusion, social networks, or personalised quality of life, a group of outcomes selected as being of particular importance to patients., Authors' Conclusions: We are uncertain about the evidence of the effects of baclofen, progabide, sodium valproate or tetrahydroisoxazolopyridinol (THIP) for people with antipsychotic-induced TD. Evidence is inconclusive and unconvincing. The quality of data available for main outcomes ranges from very low to low. Any possible benefits are likely to be outweighed by the adverse effects associated with their use.

Background: Fibromyalgia (FM) is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Anticonvulsants (antiepileptic drugs) are drugs frequently used for the treatment of chronic pain syndromes., Objectives: To assess the benefits and harms of anticonvulsants for treating FM symptoms., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE (1966 to August 2013), PsycINFO (1966 to August 2013), SCOPUS (1980 to August 2013) and the reference lists of reviewed articles for published studies and www.clinicaltrials.gov (to August 2013) for unpublished trials., Selection Criteria: We selected randomised controlled trials of any formulation of anticonvulsants used for the treatment of people with FM of any age., Data Collection and Analysis: Two review authors independently extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion., Main Results: We included eight studies: five with pregabalin and one study each with gabapentin, lacosamide and levetiracetam. A total of 2480 people were included into anticonvulsants groups and 1099 people in placebo groups. The median therapy phase of the studies was 13 weeks. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM. The amount and quality of evidence was sufficient to draw definite conclusions on the efficacy and safety of pregabalin in FM. Therefore, we focused on our interpretation of the evidence for pregabalin due to our greater certainty about its effects and its greater relevance to clinical practice. All pregabalin studies had a low risk of bias. Reporting a 50% or greater reduction in pain was more frequent with pregabalin use than with a placebo (risk ratio (RR) 1.59; 95% confidence interval (CI) 1.33 to 1.90; number needed to treat for an additional beneficial outcome (NNTB) 12; 95% CI 9 to 21). The number of people who reported being 'much' or 'very much' improved was higher with pregabalin than with placebo (RR 1.38; 95% CI 1.23 to 1.55; NNTB 9; 95% CI 7 to 15). Pregabalin did not substantially reduce fatigue (SMD -0.17; 95% CI -0.25 to -0.09; 2.7% absolute improvement on a 1 to 50 scale) compared with placebo. Pregabalin had a small benefit over placebo in reducing sleep problems by 6.2% fewer points on a scale of 0 to 100 (standardised mean difference (SMD) -0.35; 95% CI -0.43 to -0.27). The dropout rate due to adverse events was higher with pregabalin use than with placebo use (RR 1.68; 95% CI 1.36 to 2.07; number needed to treat for an additional harmful outcome (NNTH) 13; 95% CI 9 to 23). There was no significant difference in serious adverse events between pregabalin and placebo use (RR 1.03; 95% CI 0.71 to 1.49). Dizziness was reported as an adverse event more frequently with pregabalin use than with placebo use (RR 3.77; 95% CI 3.06 to 4.63; NNTH 4; 95% CI 3 to 5)., Authors' Conclusions: The anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems. Pregabalin use was shown not to substantially reduce fatigue compared with placebo. Study dropout rates due to adverse events were higher with pregabalin use compared with placebo. Dizziness was a particularly frequent adverse event seen with pregabalin use. At the time of writing this review, pregabalin is the only anticonvulsant drug approved for treating FM in the US and in 25 other non-European countries. However, pregabalin has not been approved for treating FM in Europe. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM.

Generalized estimating equations (GEE) is a general statistical method to fit marginal models for longitudinal data in biomedical studies. The variance-covariance matrix of the regression parameter coefficients is usually estimated by a robust "sandwich" variance estimator, which does not perform satisfactorily when the sample size is small. To reduce the downward bias and improve the efficiency, several modified variance estimators have been proposed for bias-correction or efficiency improvement. In this paper, we provide a comprehensive review on recent developments of modified variance estimators and compare their small-sample performance theoretically and numerically through simulation and real data examples. In particular, Wald tests and t-tests based on different variance estimators are used for hypothesis testing, and the guideline on appropriate sample sizes for each estimator is provided for preserving type I error in general cases based on numerical results. Moreover, we develop a user-friendly R package "geesmv" incorporating all of these variance estimators for public usage in practice., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background and Purpose: The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia-reperfusion injury., Key Results: In this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC₅₀ 3 μM) and organic cation transporter 2 (OCTN2, IC₅₀ 3 μM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg(-1)) decreased the infarct size by 45-48%. In vivo pretreatment with Methyl-GBB (20 mg·kg(-1)) attenuated the infarct size by 45% and improved 24 h survival of rats by 20-30%., Conclusions and Implications: Reduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia-reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism., (© 2014 The British Pharmacological Society.)

Background: Pain is frequent and distressing in people with dementia, but no randomized controlled trials have evaluated the effect of analgesic treatment on pain intensity as a key outcome., Methods: Three hundred fifty-two people with dementia and significant agitation from 60 nursing home units were included in this study. These units, representing 18 nursing homes in western Norway, were randomized to a stepwise protocol of treating pain (SPTP) or usual care. The SPTP group received acetaminophen, morphine, buprenorphine transdermal patch and pregabalin for 8 weeks, with a 4-week washout period. Medications were governed by the SPTP and each participant's existing prescriptions. We obtained pain intensity scores from 327 patients (intervention n = 164, control n = 163) at five time points assessed by the primary outcome measure, Mobilization-Observation-Behaviour-Intensity-Dementia-2 (MOBID-2) Pain Scale. The secondary outcome was activities of daily living (ADL). We used a linear intercept mixed model in a two-way repeated measures configuration to assess change over time and between groups., Results: The SPTP conferred significant benefit in MOBID-2 scores compared with the control group [average treatment effect (ATE) -1.388; p < 0.001] at week 8, and MOBID-2 scores worsened during the washout period (ATE = -0.701; p = 0.022). Examining different analgesic treatments, benefit was conferred to patients receiving acetaminophen compared with the controls at week 2 (ATE = -0.663; p = 0.010), continuing to increase until week 8 (ATE = -1.297; p < 0.001). Although there were no overall improvements in ADL, an increase was seen in the group receiving acetaminophen (ATE = +1.0; p = 0.022)., Conclusion: Pain medication significantly improved pain in the intervention group, with indications that acetaminophen also improved ADL function., (© 2014 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

This paper presents a Bayesian model for meta-analysis of sparse discrete binomial data, which are out of the scope of the usual hierarchical normal random-effect models. Treatment effectiveness data are often of this type. The crucial linking distribution between the effectiveness conditional on the healthcare center and the unconditional effectiveness is constructed from specific bivariate classes of distributions with given marginals. This assures coherency between the marginal and conditional prior distributions utilized in the analysis. Further, we impose a bivariate class of priors that is able to accommodate a wide range of heterogeneity degrees between the multicenter clinical trials involved. Applications to real multicenter data are given and compared with previous meta-analysis., (Copyright © 2014 John Wiley & Sons, Ltd.)

We provide a template for finding target allocation proportions in optimal allocation designs where the target will be invariant for both shifts in location and scale of the response distributions. One possible application of such target allocation proportions is to carry out a response-adaptive allocation. While most of the existing designs are invariant for any change in scale of the underlying distributions, they are not location invariant in most of the cases. First, we indicate this serious flaw in the existing literature and illustrate how this lack of location invariance makes the performance of the designs very poor in terms of allocation for any drastic change in location, such as the changes from degrees centigrade to degrees Fahrenheit. We illustrate that unless a target allocation is location invariant, it might lead to a completely irrelevant and useless target for allocation. Then we discuss how such location invariance can be achieved for general continuous responses. We illustrate the proposed method using some real clinical trial data. We also indicate the possible extension of the procedure for more than two treatments at hand and in the presence of covariates., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Epilepsy is a common chronic neurological disease with an estimated prevalence of 1% in the UK. Approximately one third of these people continue to have seizures despite drug treatment. In order to try to improve outcomes a number of new antiepileptic drugs have been developed and pregabalin is one of these. This review is an update of a previous Cochrane review (Pulman 2008); no further studies have been added since the previous update in 2012 and only one study has been identified as an ongoing trial., Objectives: To summarise evidence from randomised controlled trials regarding the efficacy and tolerability of pregabalin when used as an add-on antiepileptic treatment in drug-resistant partial epilepsy. The definitions of drug resistance used were those employed by the authors of the included trials., Search Methods: We searched the Cochrane Epilepsy Group Specialized Register (Jan 2014), CENTRAL (the Cochrane Central Register of Controlled Trials, The Cochrane Library 2013, Issue 12), MEDLINE (Ovid, 1946 to 09/01/2014) and contacted Pfizer Ltd. (the manufacturers of pregabalin) to identify published, unpublished and ongoing trials., Selection Criteria: We included randomised controlled trials comparing pregabalin with placebo or an alternative antiepileptic drug for people with drug-resistant partial epilepsy. Outcomes included 50% or greater reduction in seizure frequency, seizure freedom, treatment withdrawal for any reason, treatment withdrawal for adverse events and nature of adverse events., Data Collection and Analysis: Two review authors (JP and AGM) independently selected and assessed suitable trials and extracted data. Primary analyses were by intention-to-treat (ITT). Results are presented as risk ratios (RR) with 95% confidence intervals (CI). Included studies were assessed for risk of bias by two authors using the Cochrane 'Risk of bias' tool., Main Results: Six suitable industry-sponsored trials (2009 participants) were identified and included in the analysis. Trials tested doses of pregabalin ranging from 50 mg/day to 600 mg/day. For the primary outcome, 50% or higher seizure reduction was significantly more likely in patients randomised to pregabalin than to placebo (RR 2.61; 95% CI 1.70 to 4.01). A dose-response analysis suggested increasing effect with increasing dose. Pregabalin was significantly associated with seizure freedom (RR 2.59; 95% CI 1.05 to 6.36). Patients were significantly more likely to have withdrawn from pregabalin treatment than placebo treatment for any reason (RR 1.39; 95% CI 1.13 to 1.72) or for adverse effects (RR 2.69; 95% CI 1.88 to 3.86). Ataxia, dizziness, somnolence and weight gain were significantly associated with pregabalin. The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 2.12; 95% CI 1.76 to 2.54). Overall, the evidence was rated as low/unclear risk of bias due to the possibility of publication bias. The quality of the evidence was rated as moderate using the GRADE approach., Authors' Conclusions: Pregabalin, when used as an add-on drug for treatment-resistant partial epilepsy, is significantly more effective than placebo at achieving a 50% or greater seizure reduction and significantly increasing seizure freedom. Results demonstrate efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses. The trials included in this review were of short duration and longer-term trials are needed to inform clinical decision making better.

A practical and efficient enantioselective synthesis of the anticonvulsant drug pregabalin is described for the first time using Jacobsen's hydrolytic kinetic resolution of a terminal epoxide as a key step and a source of chirality., (© 2013 Wiley Periodicals, Inc.)

Background: Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009., Objectives: To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use., Methods: We included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data.We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation., Main Results: No studies reported top tier results.For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more.For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias.Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine., Authors' Conclusions: Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin.There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.

Background: Fibromyalgia (FM) is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Anticonvulsants (antiepileptic drugs) are drugs frequently used for the treatment of chronic pain syndromes., Objectives: To assess the benefits and harms of anticonvulsants for treating FM symptoms., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE (1966 to August 2013), PsycINFO (1966 to August 2013), SCOPUS (1980 to August 2013) and the reference lists of reviewed articles for published studies and www.clinicaltrials.gov (to August 2013) for unpublished trials., Selection Criteria: We selected randomised controlled trials of any formulation of anticonvulsants used for the treatment of people with FM of any age., Data Collection and Analysis: Two review authors independently extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion., Main Results: We included eight studies: five with pregabalin and one study each with gabapentin, lacosamide and levetiracetam. A total of 2480 people were included into anticonvulsants groups and 1099 people in placebo groups. The median therapy phase of the studies was 13 weeks. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM. The amount and quality of evidence was sufficient to draw definite conclusions on the efficacy and safety of pregabalin in FM. Therefore, we focused on our interpretation of the evidence for pregabalin due to our greater certainty about its effects and its greater relevance to clinical practice. All pregabalin studies had a low risk of bias. Reporting a 50% or greater reduction in pain was more frequent with pregabalin use than with a placebo (risk ratio (RR) 1.59; 95% confidence interval (CI) 1.33 to 1.90; number needed to treat for an additional beneficial outcome (NNTB) 12; 95% CI 9 to 21). The number of people who reported being 'much' or 'very much' improved was higher with pregabalin than with placebo (RR 1.38; 95% CI 1.23 to 1.55; NNTB 9; 95% CI 7 to 15). Pregabalin did not substantially reduce fatigue (SMD -0.17; 95% CI -0.25 to -0.09; 2.7% absolute improvement on a 1 to 50 scale) compared with placebo. Pregabalin had a small benefit over placebo in reducing sleep problems by 6.2% fewer points on a scale of 0 to 100 (standardised mean difference (SMD) -0.35; 95% CI -0.43 to -0.27). The dropout rate due to adverse events was higher with pregabalin use than with placebo use (RR 1.68; 95% CI 1.36 to 2.07; number needed to treat for an additional harmful outcome (NNTH) 13; 95% CI 9 to 23). There was no significant difference in serious adverse events between pregabalin and placebo use (RR 1.03; 95% CI 0.71 to 1.49). Dizziness was reported as an adverse event more frequently with pregabalin use than with placebo use (RR 3.77; 95% CI 3.06 to 4.63; NNTH 4; 95% CI 3 to 5)., Authors' Conclusions: The anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems. Pregabalin use was shown not to substantially reduce fatigue compared with placebo. Study dropout rates due to adverse events were higher with pregabalin use compared with placebo. Dizziness was a particularly frequent adverse event seen with pregabalin use. At the time of writing this review, pregabalin is the only anticonvulsant drug approved for treating FM in the US and in 25 other non-European countries. However, pregabalin has not been approved for treating FM in Europe. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM.

Anorgasmia is the inability to reach orgasm during sexual intercourse, and, although it is believed that around 90% of anorgasmia problems are related to psychological issues, the use of serotoninergic drugs, including antidepressants and atypical antipsychotics, is a common cause of situational anorgasmia. Pregabalin is a new antiepileptic drug, structurally related to gabapentin, and commonly used as adjunctive therapy for partial epilepsy and treatment of neuropathic pain in adults. Herein, we describe three men with epilepsy, who experienced severe anorgasmia after pregabalin add-on treatment.

Background: Chronic pain can often occur after surgery, substantially impairing patients' health and quality of life. It is caused by complex mechanisms that are not yet well understood. The predictable nature of most surgical procedures has allowed for the conduct of randomized controlled trials of pharmacological interventions aimed at preventing chronic postsurgical pain., Objectives: The primary objective was to evaluate the efficacy of systemic drugs for the prevention of chronic pain after surgery by examining the proportion of patients reporting pain three months or more after surgery. The secondary objective was to evaluate the safety of drugs administered for the prevention of chronic pain after surgery., Search Methods: We identified randomized controlled trials (RCTs) of various systemically administered drugs for the prevention of chronic pain after surgery from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 17 July 2013.  , Selection Criteria: Included studies were double-blind, placebo-controlled, randomized trials involving adults and evaluating one or more drugs administered systemically before, during or after surgery, or both, which measured pain three months or more after surgery., Data Collection and Analysis: Data collected from each study included the study drug name, dose, route, timing and duration of dosing; surgical procedure; proportion of patients reporting any pain three months or more after surgery, reporting at least 4/10 or moderate to severe pain three months or more after surgery; and proportion of participants dropping out of the study due to treatment-emergent adverse effects., Main Results: We identified 40 RCTs of various pharmacological interventions including intravenous ketamine (14 RCTs), oral gabapentin (10 RCTs), oral pregabalin (5 RCTs), non-steroidal anti-inflammatories (3 RCTs), intravenous steroids (3 RCTs), oral N-methyl-D-aspartate (NMDA) blockers (3 RCTs), oral mexiletine (2 RCTs), intravenous fentanyl (1 RCT), intravenous lidocaine (1 RCT), oral venlafaxine (1 RCT) and inhaled nitrous oxide (1 RCT). Meta-analysis suggested a modest but statistically significant reduction in the incidence of chronic pain after surgery following treatment with ketamine but not gabapentin or pregabalin. Results with ketamine should be viewed with caution since most of the included trials were small (that is < 100 participants per treatment arm), which could lead to the overestimation of treatment effect., Authors' Conclusions: Additional evidence from better, well designed, large-scale trials is needed in order to more rigorously evaluate pharmacological interventions for the prevention of chronic pain after surgery. Furthermore, available evidence does not support the efficacy of gabapentin, pregabalin, non-steroidal anti-inflammatories, intravenous steroids, oral NMDA blockers, oral mexiletine, intravenous fentanyl, intravenous lidocaine, oral venlafaxine or inhaled nitrous oxide for the prevention of chronic postoperative pain.

Generalized estimating equations (GEEs) are routinely used for the marginal analysis of correlated data. The efficiency of GEE depends on how closely the working covariance structure resembles the true structure, and therefore accurate modeling of the working correlation of the data is important. A popular approach is the use of an unstructured working correlation matrix, as it is not as restrictive as simpler structures such as exchangeable and AR-1 and thus can theoretically improve efficiency. However, because of the potential for having to estimate a large number of correlation parameters, variances of regression parameter estimates can be larger than theoretically expected when utilizing the unstructured working correlation matrix. Therefore, standard error estimates can be negatively biased. To account for this additional finite-sample variability, we derive a bias correction that can be applied to typical estimators of the covariance matrix of parameter estimates. Via simulation and in application to a longitudinal study, we show that our proposed correction improves standard error estimation and statistical inference., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007., Objectives: To describe and assess the evidence from controlled trials on the efficacy and tolerability of gabapentin/gabapentin enacarbil or pregabalin for preventing migraine attacks in adult patients with episodic migraine., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013., Selection Criteria: Studies were required to be prospective, controlled trials of gabapentin/gabapentin enacarbil or pregabalin taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both., Data Collection and Analysis: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between gabapentin and comparator (placebo, active control, or gabapentin in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with ≥ 50% reduction in headache frequency), we calculated odds ratios (ORs) and numbers needed to treat (NNTs). We also summarised data on adverse events from all single dosage studies and calculated risk differences (RDs) and numbers needed to harm (NNHs)., Main Results: Five trials on gabapentin and one trial on its prodrug gabapentin enacarbil met the inclusion criteria; no reports on pregabalin were identified. In total, data from 1009 patients were considered. One trial each of gabapentin 900 mg (53 patients), and gabapentin titrated to 1200 mg (63 patients) and 1800 mg (122 patients) failed to show a statistically significant reduction in headache frequency in the active treatment group as compared to the placebo group, whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (MD -0.80; 95% confidence interval (CI) -1.55 to -0.05). The pooled results of these four studies (MD -0.44; 95% CI -1.43 to 0.56; 351 patients) do not demonstrate a significant difference between gabapentin and placebo. One trial of gabapentin titrated to 1800 mg (122 patients) failed to demonstrate a significant difference between active treatment and placebo in the proportion of responders (OR 0.97; 95% CI 0.45 to 2.11), whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (OR 2.79; 95% CI 1.09 to 7.17). The pooled results of these two studies (OR 1.59; 95% CI 0.57 to 4.46; 235 patients) do not demonstrate a significant difference between gabapentin and placebo. Comparisons from one study (135 patients) suggest that gabapentin 2000 mg is no more effective than gabapentin 1200 mg. One trial of gabapentin enacarbil (523 participants) failed to demonstrate a significant difference versus placebo or between doses for gabapentin enacarbil titrated to between 1200 mg and 3000 mg with regard to proportion of responders; there was also no evidence of a dose-response trend. Adverse events, most notably dizziness and somnolence, were common with gabapentin., Authors' Conclusions: The pooled evidence derived from trials of gabapentin suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. Since adverse events were common among the gabapentin-treated patients, it is advocated that gabapentin should not be used in routine clinical practice. Gabapentin enacarbil is not efficacious for the prophylaxis of episodic migraine in adults. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults.

Objective: The goal of this systematic review was to examine the evidence for the use of the neuromodulating agents, amitriptyline, gabapentin, pregabalin, and baclofen, in the management of chronic, idiopathic cough patients., Data Sources: Online databases, including PubMed, Embase, Cochrane Review, and Web of Science, and publications cited in bibliographies were used., Review Methods: Literature was searched by the 2 authors with a priori criteria for study selection., Results: Eight relevant articles were identified, including 2 randomized controlled trials, 2 prospective cohort or case-series designs with consecutive patients, 1 retrospective case series of consecutive patients, 1 retrospective case series whose consecutive status was not known, and 2 case reports of 6 and 2 patients, respectively. Improvements in cough-specific quality of life were noted in the randomized controlled trials. Cough severity was reduced in studies that measured this outcome measure. In the remaining studies, cough symptoms were less after neuromodulator treatment., Conclusion: Benefit from neuromodulator treatment with amitriptyline, gabapentin, pregabalin, and baclofen in chronic, idiopathic cough patients was demonstrated. Further investigations using objective and subjective outcome measures are needed as well as studies exploring optimal dose, length of treatment, and relapse rates posttreatment.

Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability. Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma gabapentin concentration data obtained after administration of GEn in 12 phase 1 to 3 GEn studies in healthy adults or patients with RLS (dose range, 300-2400 mg/d), a population pharmacokinetic (PK) model was developed by nonlinear mixed-effect modeling using NONMEM. Data were similar in subjects with and without RLS. Population PK-pharmacodynamic (PD) models were evaluated using gabapentin exposure and change from baseline in investigator- or patient-rated Clinical Global Impression of Improvement (CGI-I) or International Restless Legs Scale (IRLS) total score. Potential PK-PD models for sleep outcomes and safety parameters were also explored. The CGI-I response increased with increasing GEn dose, whereas the IRLS total score was similar at all exposures tested. Early adverse events of dizziness or somnolence/sedation were more frequent for GEn 600 mg than higher doses; however, this is confounded by the fact that all subjects received the 600-mg dose for 3 days prior to titration to higher dosages., (© 2012 The Author(s).)

Objective: An open pilot study to evaluate the effect of pregabalin (PGB) as add-on therapy on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy (BTRE)., Materials and Methods: We recruited 25 consecutive patients with BTRE and uncontrolled seizures. At baseline and during follow-up, patients underwent a complete physical and neurological examination and were evaluated using the QOLIE 31P (V2), EORTC QLQ C30, Adverse Events Profile, and Hamilton Anxiety Rating Scale (HAM-A). At baseline, a seizure diary was given., Results: During follow-up, 17 patients underwent chemotherapy, none underwent radiotherapy, 9 had disease progression, and 3 died. Mean duration of follow-up was 4.1 months. Mean PGB dosage was 279 mg/day. At baseline, mean weekly seizure frequency was 5.3 (±10) and at last available follow-up visit was 2.8±5. This difference was statistically significant (p=0.016). The responder rate was 76%. Ten patients dropped out; 4 as a result of seizure worsening, 1 as a result of unchanged seizure frequency, 3 as a result of a lack of compliance, and 2 as a result of side effects. Based on the QOLIE-31-P, a significant improvement of the subscale "seizure worry" (p=0.004) and a significant decrease in distress scores related to AEDs and social life (p=0.009 and p=0.008, respectively) were observed. A significant decrease in HAM-A score (p=0.002) was documented. CONCLUSIONS; These data indicate that PGB may represent a valid alternative as add-on treatment in this patient population, based on its efficacy on seizure control and anxiety.

The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (±14.3) months from diagnosis. At the end of the study, 36 dogs were still alive; five dogs died of an unrelated or unknown cause, and seven were euthanased due to severe clinical signs suggestive of NeP. During the follow-up period, the clinical signs of scratching, facial rubbing behaviour, vocalisation and exercise ability were evaluated. Nine out of 48 dogs stopped scratching (P<0.001), but there was no statistically significant change in the number of dogs exhibiting exercise intolerance, vocalisation or facial rubbing behaviour. The overall severity of clinical signs based on a visual analogue scale (VAS) (0 mm: no clinical signs 100 mm: severe clinical signs) increased (from median 75 mm (interquartile ranges (IQR) 68-84) to 84 mm (IQR 71.5-91), P<0.001). A quarter of the dogs were static or improved. In general, the majority of the owners felt that the quality of life of their dogs was acceptable. Medical treatments received were gabapentin or pregabalin and/or intermittently, carprofen. The owner's perception of their animal's progress, and progress based on VAS, had strong positive correlation (Spearman's rank correlation (s(r)) 0.74, P<0.001). Overall, this study suggests that clinical signs suggestive of NeP progress in three-quarters of CKCSs with CM and/or SM.

Background: Many people with epilepsy suffer from poorly controlled seizures, despite current antiepileptic treatments. Due to high rates of treatment resistance, there is interest in new pharmacological treatment options such as pregabalin. However, it remains unclear whether existing evidence of pregabalin is rigorous enough to support its monotherapy., Objectives: To determine the efficacy and tolerability of pregabalin in people with epilepsy., Search Methods: We searched the Cochrane Epilepsy Group's Specialized Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7 ), MEDLINE (1946 to August week 1, 2012), EMBASE (1974 to August 2012) and the Chinese Biomedical Literature Database (CBM) (1978 to August 2012). No language restrictions were imposed., Selection Criteria: Randomised controlled trials (RCTs) comparing pregabalin with placebo or another antiepileptic drug monotherapy for epilepsy., Data Collection and Analysis: Two review authors (QZ and LY) independently extracted trial data and assessed trial quality. We assessed the following outcomes: (1) time to withdrawal after randomisation; (2) time to achieve six-, 12- or 24-month remission; (3) the proportion of participants who remained seizure-free for six or more continuous months; (4) time to first seizure after randomisation; (5) validated quality of life measures; (6) health economic outcomes; (7) adverse effects. We expressed time-to-event outcomes as hazard ratios (HRs) with 95% confidence interval (CI), where an HR > 1 indicates an event is more likely to occur earlier on pregabalin than the comparator., Main Results: Two short-term studies involving 753 participants met the inclusion criteria. Only one study investigated the effects of pregabalin compared with lamotrigine in patients with newly diagnosed partial seizures, and the other study investigated the effects of pregabalin compared with gabapentin in hospitalised patients with refractory partial epilepsy. There were no studies on generalised-onset tonic-clonic seizures (with or without other generalised seizure types).We found that pregabalin was inferior in comparison to lamotrigine when measuring time to withdrawal due to inadequate seizure control after dose stabilisation from randomisation: hazard ratio (HR) 4.52; 95% confidence interval (CI) 1.93 to 10.60; time to achieve six-month remission after dose stabilisation from randomisation: HR 0.56; 95% CI 0.41 to 0.76; the proportion of participants who remained seizure-free for six or more continuous months: RR 0.76, 95% CI 0.67 to 0.87 (Europe: 0.83, 95% CI 0.69 to 0.99; Asia: RR 0.70, 95% CI 0.57 to 0.86; the Americas: RR 0.62, 95% CI 0.33 to 1.19); and time to first seizure after dose stabilisation from randomisation: HR 1.74; 95% CI 1.26 to 2.39. There was no significant difference in safety-related outcomes between pregabalin and lamotrigine, but more participants in the pregabalin group developed somnolence, weight increase and convulsion. Pregabalin was better than gabapentin when measuring time to withdrawal due to all reasons after randomisation: HR 0.25; 95% CI 0.11 to 0.57; and time to withdrawal due to inadequate seizure control after randomisation: HR 0.41; 95% CI 0.18 to 0.92. No significant difference was found in safety-related outcomes between pregabalin and gabapentin. But we found some limitations in the study design which may have had an influence on the results., Authors' Conclusions: Pregabalin seems to have similar tolerability but inferior efficacy in comparison to lamotrigine for newly diagnosed partial seizures. However, considering the limitations in the study design (such as the short-term follow-up and the low initial target dose selection), the results should be interpreted with caution. The available data were too limited to draw any conclusions between pregabalin and gabapentin. The result indicated that the treatment effects were influenced by the study regions. The clinical disadvantage of pregabalin was more prominent in Asia when compared with lamotrigine. We should determine whether pregabalin has ethnic differences in the treatment of epilepsy in the future. This review does not inform any treatment policy for patients with generalized onset tonic-clonic seizures. Further long-term trials are needed to investigate the genuine effectiveness of pregabalin as monotherapy.

Background and Purpose: Impulsivity is a core symptom in many neuropsychiatric disorders. The main objective of this study was to evaluate the effects of topiramate and pregabalin on the modulation of different impulsivity dimensions in DBA/2 mice., Experimental Approach: The effects of acute and chronic administration of pregabalin (10, 20 and 40 mg·kg(-1) ) and topiramate (12.5, 25 and 50 mg·kg(-1) ) were evaluated in the light-dark box (LDB), hole board test (HBT) and delayed reinforcement task (DRT). α(2A) -Adrenoceptor, D(2) -receptor and TH gene expression were evaluated by real-time PCR in the prefrontal cortex (PFC), accumbens (ACC) and ventral tegmental area (VTA), respectively., Key Results: Acute pregabalin administration showed a clear anxiolytic-like effect (LDB) but did not modify novelty-seeking behaviour (HBT). In contrast, topiramate produced an anxiolytic effect only at the highest dose, whereas it reduced novelty seeking at all doses tested. In the DRT, acute pregabalin had no effect, whereas topiramate only reduced motor impulsivity. Chronically, pregabalin significantly increased motor impulsivity and topiramate diminished cognitive impulsivity. Pregabalin decreased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and increased TH in the VTA. In contrast, chronic administration of topiramate increased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and also increased TH in the VTA., Conclusions and Implications: These results suggest that the usefulness of pregabalin in impulsivity-related disorders is related to its anxiolytic properties, whereas topiramate modulates impulsivity. These differences could be linked to their opposite effects on α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a condition that is detrimental to the quality of life of men. Evidence suggests that it may have a neuropathic origin and therefore medications such as pregabalin might have a role in the controlling of symptoms., Objectives: The primary objective was to compare pregabalin to other modalities of pain relief to alleviate men's symptoms of CP/CPPS.The secondary objective was to assess the safety and effectiveness of pregabalin to improve various individual symptoms consistent with CP/CPPS., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to May 2012), EMBASE (1980 to May 2012), CINAHL, clinicaltrials.gov, Google Scholar, and reference lists of articles and abstracts from conference proceedings, without language restriction for pregabalin treatment of Class III prostatitis and CP/CPPS., Selection Criteria: Randomized controlled trials (RCTs) comparing pregabalin to placebo or other types of analgesics for the management of patients with CP/CPPS were included. Patients with known causes of pain/discomfort were excluded., Data Collection and Analysis: Only one RCT was included. The trial compared pregabalin to placebo for patients who had CP/CPPS., Main Results: For men who responded clinically (≥ 6-point improvement), there was no difference between the pregabalin (103/218; 47.2%) and placebo (38/106; 35.8%) arms (risk ratio (RR) 1.32; 95% CI 0.99 to 1.76). There was less pain with a higher point improvement in the pregabalin group compared to the placebo group (4.2 points versus 1.7 points, respectively; mean difference (MD) -2.3 points; 95% CI -4.0 to -0.7 points).Though 59% (191/324) of the patients developed side effects, no serious effects were experienced. There were significantly more neurologic side effects in the pregabalin group compared to the placebo group (38.5% (84/218) versus 22.6% (24/106), respectively; RR 1.7; 95% CI 1.15 to 2.51), and less pain in the pregabalin group than in the placebo group (17.4% (38/218) versus 33.3% (35/106), respectively; RR 0.53; 95% CI 0.36 to 0.78). However, no significant differences were seen between the pregabalin and placebo groups with regards to gastrointestinal disturbances (18.3% (40/218) versus 18.9% (20/106), respectively; RR 0.97; 95% CI 0.60 to 1.58), ocular/visual symptoms (6.9% (15/218) versus 2.8% (3/106), respectively; RR 2.43; 95% CI 0.72 to 8.22), and renal/genitourinary symptoms (5.5% (12/218) versus 1.9% (2/106), respectively; RR 3.03; 95% CI 0.67 to 13.79)., Authors' Conclusions: There is evidence from one RCT that pregabalin does not improve CP/CPPS symptoms and causes adverse effects in a large percentage of men. However, research is required to assess further whether pregabalin has a role in patients with CP/CPPS for symptom control.

Lysophosphatidic acid (LPA), an initiator of neuropathic pain, causes allodynia. However, few studies have evaluated the pharmacological profile of LPA-induced pain. In this study, a LPA-induced pain model was developed and pharmacologically characterized with clinically relevant drugs used for neuropathic pain, including antiepileptics, non-steroidal anti-inflammatory agents, analgesics, local anaesthetics/antiarrhythmics and antidepressants. Gabapentin (1-30 mg/kg, p.o.) significantly reversed LPA-induced allodynia, but neither indomethacin (30 mg/kg, p.o.) nor morphine (0.3-3 mg/kg, s.c.) did, which indicates that LPA-induced pain consists mostly of neuropathic rather than inflammatory pain. Both pregabalin (0.3-10 mg/kg, p.o.) and ω-CgTX MVIIA (0.01-0.03 μg/mouse, i.t.) completely reversed LPA-induced allodynia in a dose-dependent manner. Lidocaine (1-30 mg/kg, s.c.), mexiletine (1-30 mg/kg, p.o.) and carbamazepine (10-100 mg/kg, p.o.) significantly ameliorated LPA-induced allodynia dose dependently. Milnacipran (30 mg/kg, i.p.) produced no significant analgesic effect in LPA-induced allodynia. In LPA-injected mice, expression of the α2δ1 subunit of the voltage-gated calcium channel (VGCC) was increased in the dorsal root ganglion (DRG) and spinal dorsal horn. Furthermore, the VGCC current was potentiated in both the DRG from LPA-injected mice and LPA (1 μM)-treated DRG from saline-injected mice, and the potentiated VGCC current was amended by treatment with gabapentin (100 μM). The LPA-induced pain model described here mimics aspects of the neuropathic pain state, including the sensitization of VGCC, and may be useful for the early assessment of drug candidates to treat neuropathic pain., (© 2011 European Federation of International Association for the Study of Pain Chapters.)

Background: Pharmacotherapy remains an important modality for the treatment of neuropathic pain. However, as monotherapy current drugs are associated with limited efficacy and dose-related side effects. Combining two or more different drugs may improve analgesic efficacy and, in some situations, reduce overall side effects (e.g. if synergistic interactions allow for dose reductions of combined drugs)., Objectives: This review evaluated the efficacy, tolerability and safety of various drug combinations for the treatment of neuropathic pain., Search Methods: We identified randomised controlled trials (RCTs) of various drug combinations for neuropathic pain from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 9 April 2012., Selection Criteria: Double-blind, randomised studies comparing combinations of two or more drugs (systemic or topical) to placebo and/or at least one other comparator for the treatment of neuropathic pain., Data Collection and Analysis: Data extracted from each study included: proportion of participants a) reporting ≥ 30% pain reduction from baseline OR ≥ moderate pain relief OR ≥ moderate global improvement; b) dropping out of the trial due to treatment-emergent adverse effects; c) reporting each specific adverse effect (e.g. sedation, dizziness) of ≥ moderate severity. The primary comparison of interest was between study drug(s) and one or both single-agent comparators. We combined studies if they evaluated the same drug class combination at roughly similar doses and durations of treatment. We used RevMan 5 to analyse data for binary outcomes., Main Results: We identified 21 eligible studies: four (578 participants) evaluated the combination of an opioid with gabapentin or pregabalin; two (77 participants) evaluated an opioid with a tricyclic antidepressant; one (56 participants) of gabapentin and nortriptyline; one (120 participants) of gabapentin and alpha-lipoic acid, three (90 participants) of fluphenazine with a tricyclic antidepressant; three (90 participants) of an N-methyl-D-aspartate (NMDA) blocker with an agent from a different drug class; five (604 participants) of various topical medications; one (313 participants) of tramadol with acetaminophen; and another one (44 participants) of a cholecystokinin blocker (L-365,260) with morphine. The majority of combinations evaluated to date involve drugs, each of which share some element of central nervous system (CNS) depression (e.g. sedation, cognitive dysfunction). This aspect of side effect overlap between the combined agents was often reflected in similar or higher dropout rates for the combination and may thus substantially limit the utility of such drug combinations. Meta-analysis was possible for only one comparison of only one combination, i.e. gabapentin + opioid versus gabapentin alone. This meta-analysis involving 386 participants from two studies demonstrated modest, yet statistically significant, superiority of a gabapentin + opioid combination over gabapentin alone. However, this combination also produced significantly more frequent side effect-related trial dropouts compared to gabapentin alone., Authors' Conclusions: Multiple, good-quality studies demonstrate superior efficacy of two-drug combinations. However, the number of available studies for any one specific combination, as well as other study factors (e.g. limited trial size and duration), preclude the recommendation of any one specific drug combination for neuropathic pain. Demonstration of combination benefits by several studies together with reports of widespread clinical polypharmacy for neuropathic pain surely provide a rationale for additional future rigorous evaluations. In order to properly identify specific drug combinations which provide superior efficacy and/or safety, we recommend that future neuropathic pain studies of two-drug combinations include comparisons with placebo and both single-agent components. Given the apparent adverse impact of combining agents with similar adverse effect profiles (e.g. CNS depression), the anticipated development and availability of non-sedating neuropathic pain agents could lead to the identification of more favourable analgesic drug combinations in which side effects are not compounded.

The purpose of this study was to describe longitudinal daily seizure count data with respect to the effects of time and pregabalin add-on therapy. Models were developed in a stepwise manner: base model, time effect model, and time and drug effect (final) model, using a negative binomial distribution with Markovian features. Mean daily seizure count (λ) was estimated to be 0.385 (relative standard error [RSE] 3.09%) and was further increased depending on the seizure count on the previous day. An overdispersion parameter (OVDP), representing extra-Poisson variation, was estimated to be 0.330 (RSE 11.7%). Interindividual variances on λ and OVDP were 84.7% and 210%, respectively. Over time, λ tended to increase exponentially with a rate constant of 0.272 year⁻¹ (RSE 26.8%). A mixture model was applied to classify responders/nonresponders to pregabalin treatment. Within the responders, λ decreased exponentially with respect to dose with a constant of 0.00108 mg⁻¹ (RSE 11.9%). The estimated responder rate was 66% (RSE 27.6%). Simulation-based diagnostics showed the model reasonably reproduced the characteristics of observed data. Highly variable daily seizure frequency was successfully characterized incorporating baseline characteristics, time effect, and the effect of pregabalin with classification of responders/nonresponders, all of which are necessary to adequately assess the efficacy of antiepileptic drugs.

We investigate methods for data-based selection of working covariance models in the analysis of correlated data with generalized estimating equations. We study two selection criteria: Gaussian pseudolikelihood and a geodesic distance based on discrepancy between model-sensitive and model-robust regression parameter covariance estimators. The Gaussian pseudolikelihood is found in simulation to be reasonably sensitive for several response distributions and noncanonical mean-variance relations for longitudinal data. Application is also made to a clinical dataset. Assessment of adequacy of both correlation and variance models for longitudinal data should be routine in applications, and we describe open-source software supporting this practice., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background and Purpose: An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied., Experimental Approach: The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed., Key Results: The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs., Conclusion and Implications: These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Purpose: Information about the time course of adverse drug reactions (ADRs) is often lacking. If this information would be available, it could help increase patient's adherence to drugs when experiencing an ADR. The aim of this study was to demonstrate how a web-based intensive monitoring system using the patient as a source of information can be used to gather longitudinal safety data of a drug. In this study, pregabalin was used as an example., Methods: First-time users of pregabalin were approached in Dutch pharmacies between 1 August 2006 and 31 January 2008. After online registration, patients received questionnaires by email 2 weeks, 6 weeks, 3 months and 6 months after the start of the drug use. Data on patient characteristics, drug use and ADRs were collected and analysed., Results: A total of 1373 patients registered for the pregabalin study. Of these patients, 1051 (76.5%) filled in at least one questionnaire. On an aggregated level, the ADR profile remained relatively stable over time. Incidence densities showed that the five most frequently reported reactions occurred early in the treatment. Initially, the majority of the patients did not undertake any action when experiencing an ADR. Recovery did not seem to be completely dependent of drug cessation., Conclusions: With web-based intensive monitoring, it is possible to study the time course of ADRs. This method can be a valuable addition to pharmacovigilance because it can generate other types of information as compared with spontaneous reporting and other intensive monitoring methodologies., (Copyright © 2011 John Wiley & Sons, Ltd.)

Dizziness represents a major determinant of dropout in the treatment of generalized anxiety disorder with pregabalin. Titration (dose escalation) regimens based on clinical judgment were implemented to mitigate this adverse event and reduce patient dropout across clinical trials. Dropout is an important treatment failure endpoint, which can be analyzed using time-to-event models that incorporate daily dosing or other time-varying information. A parametric discrete-time dropout model with daily dizziness severity score as a covariate afforded a systematic, model-based assessment of titration dosing strategies, with model predictions evaluated against corresponding nonparametric estimates. A Gompertz hazard function adequately described the decreasing dropout hazard over time for individuals with severe or moderate dizziness and a lower, constant hazard for individuals reporting no dizziness or mild dizziness. Predictive performance of the model was adequate based on external validation with an independent trial and other goodness-of-fit criteria. Prospective simulations highlight the utility of this approach in reducing dropout based on examination of untested titration scenarios for future generalized anxiety disorder or other trials.

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti-nociceptive drugs. The effect of oxycodone (0-10 mg/kg, i.p.), tramadol (0-10 mg/kg, i.p.), ibuprofen (0-300 mg/kg, i.p.) and pregabalin (0-31.6 mg/kg, i.p.) on negative affect and mechanical hypersensitivity accompanying carrageenan-induced (0.5% intraplantar) inflammatory nociception was assessed using conditioned place aversion (CPA) and Randall Selitto paw pressure test, respectively. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). All four anti-nociceptive drugs dose-dependently reduced carrageenan-induced CPA and mechanical hypersensitivity. Furthermore all drugs induced CPP, except for ibuprofen. Similar to morphine, oxycodone and tramadol showed a large dissociation of anti-aversive versus anti-nociceptive potency, i.e. 10 times more potent against the affective versus the sensory component of nociception. Oxycodone and tramadol were 30 and 10 times more potent to produce CPP in animals under normal versus painful conditions. Ibuprofen and pregabalin also showed a dissociation of anti-aversive and anti-nociceptive potency, but less pronounced (i.e. three times more potent against the affective component). However, pregabalin showed no dissociation between rewarding potency under normal versus painful conditions. Taken together, these data suggest that the dissociation of rewarding potency in animals under normal versus painful conditions is limited to drugs with an opioid mechanism of action, while the dissociation of anti-aversive and anti-nociceptive potency applies to anti-nociceptive drugs with different mechanisms of action., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

The neuropathic origin of a case of unilateral burning mouth syndrome, previously diagnosed as psychogenic, was ascertained by intra-oral mucosa biopsy, which showed a severe sensory fibers damage, probably caused by maxillary anesthetic block and dental surgery., (© 2010 American Headache Society.)

As statistical methods for testing the null hypothesis of no difference between two groups for the matched pairs design, the paired-t test, Wilcoxon signed rank sum test and McNemar test are well known. However, there is no simple test for the comparison of incidence rate of recurrent events. This paper proposes a simple statistical method and a sample size formula for the comparison of counts of recurrent events over a specified period of observation under the matched pairs design, where the subject-specific incidence of recurrent events is assumed to follow a time-homogeneous Poisson process. As a special case, the proposed method is found to be virtually equivalent in form to Mantel-Haenszel method for a common rate ratio among the set of stratified tables based on person-time data. The proposed methods are illustrated with the within-arm comparison of data from a clinical trial of 59 epileptics with baseline count data., (Copyright © 2010 John Wiley & Sons, Ltd.)

Background: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post-traumatic peripheral neuropathic pain (including post-surgical)., Methods: Patients with a pain score >or=4 (0-10 scale) were randomized and treated with either flexible-dose pregabalin 150-600 mg/day (n = 127) or placebo (n = 127) in an 8-week double-blind treatment period preceded by a 2-week placebo run-in., Results: Pregabalin was associated with a significantly greater improvement in the mean end-point pain score vs. placebo; mean treatment difference was -0.62 (95% CI -1.09 to -0.15) (P = 0.01). The average pregabalin dose at end-point was approximately 326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain-related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all-patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end-point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group., Conclusion: Flexible-dose pregabalin 150-600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post-traumatic peripheral neuropathic pain.

Pregabalin has shown clinical efficacy for treatment of neuropathic pain syndromes, partial seizures, and anxiety disorders. Five studies in healthy volunteers are performed to investigate single- and multiple-dose pharmacokinetics of pregabalin. Pregabalin is rapidly absorbed following oral administration, with peak plasma concentrations occurring between 0.7 and 1.3 hours. Pregabalin oral bioavailability is approximately 90% and is independent of dose and frequency of administration. Food reduces the rate of pregabalin absorption, resulting in lower and delayed maximum plasma concentrations, yet the extent of drug absorption is unaffected, suggesting that pregabalin may be administered without regard to meals. Pregabalin elimination half-life is approximately 6 hours and steady state is achieved within 1 to 2 days of repeated administration. Corrected for oral bioavailability, pregabalin plasma clearance is essentially equivalent to renal clearance, indicating that pregabalin undergoes negligible nonrenal elimination. Pregabalin demonstrates desirable, predictable pharmacokinetic properties that suggest ease of use. Because pregabalin is eliminated renally, renal function affects its pharmacokinetics.

Data from 4 phase 2/3 studies were pooled to characterize the exposure response of daily pregabalin (150-600 mg) in patients with fibromyalgia using self-assessed daily pain scores (PAIN) and end-of-treatment patient global impression of change (PGIC). The exposure responses of both endpoints were characterized by an Emax model using nonlinear mixed-effects modeling (NONMEM). Drug effect on PAIN relative to placebo was significant with additional maximum effect of 1.51 points on the logit scale and EC50 of 1.54 ng/mL (dose of 174 mg) and a rapid onset (half-life of 11 hours), consistent with the half-life of the drug. The decrease in PAIN with placebo occurred more slowly, reaching maximum response (1.52 points on the logit scale) after 1 month. Drug response in fibromyalgia was dependent on age and sex, with greater PAIN reduction in older patients, in addition to the effect of creatinine clearance, and in females. For PGIC, administration of pregabalin resulted in an increase in the proportion of patients reporting improvement with an ED50 of 228 mg. The analyses support the recommended dose of pregabalin in patients with fibromyalgia of 300 to 450 mg/d.

Background and Purpose: N-arachidonoyl glycine (NAGly) is an endogenous lipid that is structurally similar to the endocannabinoid, N-arachidonoyl ethanolamide (anandamide). While NAGly does not activate cannabinoid receptors, it exerts cannabimimetic effects in pain regulation. Here, we have determined if NAGly, like anandamide, modulates vascular tone., Experimental Approach: In rat isolated small mesenteric arteries, the relaxant responses to NAGly were characterized. Effects of N-arachidonoyl serine and N-arachidonoyl gamma-aminobutyric acid were also examined., Key Results: In endothelium-intact arteries, NAGly-induced relaxation (pEC(50%)= 5.7 +/- 0.2; relaxation at 30 microM = 98 +/- 1%) was attenuated by l-NAME (a nitric oxide synthase inhibitor) or iberiotoxin [selective blocker of large conductance Ca(2+)-activated K(+) channels (BK(Ca))], and abolished by high extracellular K(+) concentration. Endothelial removal reduced the potency of NAGly, and the resultant relaxation was inhibited by iberiotoxin, but not l-NAME. NAGly responses were sensitive to the novel cannabinoid receptor antagonist O-1918 independently of endothelial integrity, whereas pertussis toxin, which uncouples G(i/o) proteins, attenuated NAGly relaxation only in endothelium-intact arteries. Treatments with antagonists for CB(1), CB(2) and TRPV1 receptors, or inhibitors of fatty acid amide hydrolase and COX had no effect. The two other arachidonoyl amino acids also induced iberiotoxin- and L-NAME-sensitive relaxations., Conclusion and Implications: NAGly acts as a vasorelaxant predominantly via activation of BK(Ca) in rat small mesenteric arteries. We suggest that NAGly activates an unknown G(i/o)-coupled receptor, stimulating endothelial release of nitric oxide which in turn activates BK(Ca) in the smooth muscle. In addition, NAGly might also activate BK(Ca) through G(i/o)- and nitric oxide-independent mechanisms.

Background and Purpose: Pregabalin has demonstrated efficacy in controlled trials as adjunctive treatment in patients with refractory seizures., Methods: This open-label, 21-week study in adults with at least two partial seizures in the last 2 months, who were inadequately controlled with one to three antiepileptic drugs, evaluated pregabalin 150-600 mg/day (dosed twice daily). The study comprised a prospective or retrospective 8-week baseline phase, and 9-week dose optimization and 12-week maintenance periods. The primary assessment was the mean percentage change in 28-day seizure frequency between baseline and end-point (last 12 weeks of treatment, last observation carried forward, modified intention-to-treat population)., Results: Four hundred and seventy-six patients from Europe were included in this study (51% men; mean age/epilepsy duration 40.1/24.1 years). The median baseline seizure frequency was 5.5/28 days. Amongst the patient population, 78% completed the 21-week treatment period; 7% discontinued for lack of efficacy and 12% because of adverse events (AEs). The mean last pregabalin dose was 359 mg/day. The mean (95% CI) reduction in seizure frequency was 36% (31%; 41%). The median reduction was 33%, and 39% of patients had a >or=50% reduction in seizure frequency. There were 19% and 8% of patients free of seizures during their last 4 and 12 weeks of treatment, respectively. The three most common AEs were dizziness (17%), somnolence (13%) and weight increase (13%)., Conclusions: This open-label study of pregabalin demonstrated efficacy that was consistent with that observed in previous controlled epilepsy trials. Pregabalin was well tolerated. The AE profile was also consistent with that reported in previous trials.

The quadratic inference function (QIF) is a new statistical methodology developed for the estimation and inference in longitudinal data analysis using marginal models. This method is an alternative to the popular generalized estimating equations approach, and it has several useful properties such as robustness, a goodness-of-fit test and model selection. This paper presents an introductory review of the QIF, with a strong emphasis on its applications. In particular, a recently developed SAS MACRO QIF is illustrated in this paper to obtain numerical results.

Background: Antiepileptic drugs have been used in pain management since the 1960s. Pregabalin is a recently developed antiepileptic drug also used in management of chronic neuropathic pain conditions., Objectives: To assess analgesic efficacy and associated adverse events of pregabalin in acute and chronic pain., Search Strategy: We searched MEDLINE, EMBASE, and CENTRAL to May 2009 for randomised controlled trials (RCTs). Additional studies were identified from the reference lists of retrieved papers and on-line clinical trial databases., Selection Criteria: Randomised, double blind trials reporting on the analgesic effect of pregabalin, with subjective pain assessment by the patient as either the primary or a secondary outcome., Data Collection and Analysis: Two independent review authors extracted data and assessed trial quality. Numbers-needed-to-treat-to-benefit (NNTs) were calculated, where possible, from dichotomous data for effectiveness, adverse events and study withdrawals., Main Results: There was no clear evidence of beneficial effects of pregabalin in established acute postoperative pain. No studies evaluated pregabalin in chronic nociceptive pain, like arthritis.Pregabalin at doses of 300 mg, 450 mg, and 600 mg daily was effective in patients with postherpetic neuralgia, painful diabetic neuropathy, central neuropathic pain, and fibromyalgia (19 studies, 7003 participants). Pregabalin at 150 mg daily was generally ineffective. Efficacy was demonstrated for dichotomous outcomes equating to moderate or substantial pain relief, alongside lower rates for lack of efficacy discontinuations with increasing dose. The best (lowest) NNT for each condition for at least 50% pain relief over baseline (substantial benefit) for 600 mg pregabalin daily compared with placebo were 3.9 (95% confidence interval 3.1 to 5.1) for postherpetic neuralgia, 5.0 (4.0 to 6.6) for painful diabetic neuropathy, 5.6 (3.5 to 14) for central neuropathic pain, and 11 (7.1 to 21) for fibromyalgia.With 600 mg pregabalin daily somnolence typically occurred in 15% to 25% and dizziness occurred in 27% to 46%. Treatment was discontinued due to adverse events in 18 to 28%. The proportion of participants reporting at least one adverse event was not affected by dose, nor was the number with a serious adverse event, which was not more than with placebo.Higher rates of substantial benefit were found in postherpetic neuralgia and painful diabetic neuropathy than in central neuropathic pain and fibromyalgia. For moderate and substantial benefit on any outcome NNTs for the former were generally six and below for 300 mg and 600 mg daily; for fibromyalgia NNTs were much higher, and generally seven and above., Authors' Conclusions: Pregabalin has proven efficacy in neuropathic pain conditions and fibromyalgia. A minority of patients will have substantial benefit with pregabalin, and more will have moderate benefit. Many will have no or trivial benefit, or will discontinue because of adverse events. Individualisation of treatment is needed to maximise pain relief and minimise adverse events. There is no evidence to support the use of pregabalin in acute pain scenarios.

The purpose of this study is to analyze the effect of pregabalin (PGB) on pain alleviation, use of health care and non-health care resources, and associated costs in patients with trigeminal neuralgia under usual clinical practice in primary care settings. Sixty-five PGB-naïve patients receiving PGB as monotherapy (n = 36, 55%) or combined with other drugs (n = 29, 45%) fulfill criteria for inclusion in a secondary analysis from a 12-week, multicenter, observational prospective study aimed to ascertain the cost of illness in subjects with neuropathic pain. Pain is evaluated using the Short Form McGill Pain Questionnaire. Use of health care and non-health care resources and lost workdays equivalents (LWDEs) are also recorded. PGB significantly reduces pain scores, use of health care resources (ancillary tests and unscheduled medical visits), and number of LWDEs. Additional cost of PGB treatment (+euro 174 +/- 106) is broadly compensated for by a reduction in both health care costs (-euro 621 +/-1211, P < .001) and indirect costs (-euro 1210 +/- 1141, P < .001). It is concluded that PGB as monotherapy or combined with other drugs is effective in pain management in patients with trigeminal neuralgia and reduces the cost of illness.

Background and Purpose: To evaluate the effects of pregabalin (PGB) adjunctive therapy on sleepwake cycle and daytime somnolence in adult patients affected by partial epilepsy., Methods: Twelve patients affected by partial epilepsy underwent a 24-h ambulatory polysomnography and a subjective evaluation of daytime somnolence by means of the Epworth Sleepiness Scale (ESS), before and after 3 months treatment with PGB., Results: Pregabalin therapy reduced seizures by >50% in 8 out of 12 patients. It induced a significant increase of REM sleep and a decrease of stage 2 NREM sleep (S2). A significant increase of the ESS score was observed without reaching the pathological cut-off value (mean ESS score <10). No statistical correlation between REM sleep and seizure frequency was observed., Discussion: Pregabalin seems to be effective and safe in partial epilepsy. The increase of REM sleep may be indicative of an improvement of nocturnal sleep quality considering the involvement of REM sleep in learning and memory processes. REM sleep enhancement may be the result of both a direct effect of PGB on sleep generators and an indirect effect due to its clinical efficacy. The increase of ESS score within normal range suggests that daytime somnolence is a minor adverse effect of PGB.