Phosphodiesterase-4 inhibitors for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea, and a reduction in lung function, quality of life, and life expectancy. Apart from smoking cessation, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020. OBJECTIVES: To evaluate the efficacy and safety of oral PDE4 inhibitors for management of stable COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at web-based clinical trials registers. SELECTION CRITERIA: We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations). MAIN RESULTS: We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years. We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials. Lung function Treatment with a PDE4 inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV1) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence). Quality of life Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence). Incidence of exacerbations Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found. Adverse events More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE4 inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms. Participants treated with PDE4 inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups. Mortality No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials. AUTHORS' CONCLUSIONS: For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review. PDE4 inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg. The findings of this review provide cautious support for the use of PDE4 inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation, or mortality in COPD.

Bioavailability of phthalate and DINCH® plasticizers, after oral administration of dust to piglets.

For decades, phthalates have been widely used as plasticizers in a large number of consumer products, leading to a complex exposure to humans via ingestion, inhalation or dermal uptake. Children may have a higher unintended dust intake per day compared to adults. Therefore, dust intake of children could pose a relevant exposure and subsequently a potential health risk. The aim of this study was to determine the relative bioavailability of certain phthalates, such as di(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and the non-phthalate plasticizer diisononyl 1,2-cyclohexanedicarboxylic acid (DINCH®, Hexamoll®), after ingestion of dust. Seven 5-week-old male piglets were fed five different dust samples collected from daycare centers. Overall, 0.43 g to 0.83 g of dust sieved to 63 µm were administered orally. The piglets' urine was collected over a period of 38 h. The excreted metabolites were quantified using an LC-MS/MS method. The mean uptake rates of the applied doses for DEHP, DINP, and DINCH® were 43% ± 11%, 47% ± 26%, and 9% ± 3.5%, respectively. The metabolites of DEHP and DINP showed maximum concentrations in urine after three to five hours, whereas the metabolites of DINCH®, reached maximum concentrations 24 h post-dose. The oral bioavailability of the investigated plasticizers was higher compared to the bioaccessibility reported from in vitro digestion tests. Furthermore, the bioavailability of DEHP did not vary substantially between the dust samples, whereas a dose-dependent saturation process for DINP was observed. In addition to other intake pathways, dust could be a source of plasticizers in children using the recent intake rates for dust ingestion.

The efficacy of gabapentin in reducing pain intensity and morphine consumption after breast cancer surgery: A meta-analysis.

BACKGROUND: The purpose of this meta-analysis from randomized controlled trials (RCTs) was to determine the efficacy and safety of the preoperative use of gabapentin for the treatment of acute and chronic postoperative pain following breast cancer surgery. METHODS: In November 2017, a systematic computer-based search was conducted in PubMed, Embase, Web of Science, Cochrane Library, and Google databases. RCTs comparing gabapentin with placebo in patients undergoing breast cancer surgery were retrieved. The primary endpoint was the visual analog scale (VAS) after surgery and 24 hours after surgery and total morphine consumption. The secondary outcomes were incidence of chronic pain and complications (the incidence of nausea). Software Stata 12.0 was used for meta-analysis. RESULTS: Finally, 9 RCTs were included in the meta-analysis. Results indicated that gabapentin was associated with reduced pain scores after surgery and 24 hours after surgery. Meanwhile, oral gabapentin was associated with a reduction of the total morphine consumption after breast cancer surgery. Similarly, gabapentin was associated with a reduction in the incidence of chronic pain and the incidence of nausea. CONCLUSIONS: Preoperative use of gabapentin was able to reduce acute and chronic postoperative pain, total morphine consumption and the occurrence of nausea following breast cancer surgery. Further studies should determine the optimal dose of gabapentin for pain control after breast cancer surgery.

The Association of Gabapentin Use and Dose With Substance Use Disorders Prior to Inpatient Mental Health Treatment: A Cross-Sectional Study.

OBJECTIVE: To investigate the relationship between gabapentin use and dose with substance use disorders (SUDs) prior to inpatient mental health treatment. METHODS: A cross-sectional study was performed in current gabapentin users admitted to inpatient psychiatry services from December 2015 through January 2017 in a large urban teaching hospital. The primary analysis examined rates and doses of gabapentin use in relation to SUD. A multinomial logistic regression was performed to assess a predictive model for SUD in gabapentin users. The secondary analysis examined trends of off-label gabapentin use. RESULTS: Of 1,483 admissions to inpatient psychiatry services, 345 subjects (23.1%) were prescribed gabapentin as an outpatient prior to admission. Current SUD was identified in 88.1% of the sample, with 65.2% identified as polysubstance positive. Mean daily doses of gabapentin were higher in subjects with positive SUD than in those with no history of SUD. Gabapentin doses ≥ 1,800 mg/d were associated with opiate misuse (P < .001), need for detoxification (P = .004), and positive hepatitis C status (P = .001). Multinomial linear regression revealed that use of gabapentin doses ≥ 1,800 mg/d was predictive of opiate misuse and positive hepatitis C status, with 68.7% positive predictive value. CONCLUSION: High-dose gabapentin use can be predictive of opiate misuse disorder. Requests for high-dose gabapentin from patients may signal potential opioid misuse.

Does preemptive gabapentin modulate cytokine response in total knee arthroplasty? A placebo controlled study.

BACKGROUND: Gabapentin, as a structural analogue of γ-aminobutyric acid, has been investigated to provide pain relief in the early postoperative period following various surgical interventions. OBJECTIVES: The objective of this study was to investigate whether preemptive oral administration of gabapentin 800 mg can reduce postoperative pain and modulate the inflammatory cytokine response in comparison to placebo in patients undergoing total knee arthroplasty under general anesthesia. MATERIAL AND METHODS: Fifty-two patients were randomly divided into 2 groups before surgery, either to receive peroral gabapentin 800 mg or placebo drug, 1 h before surgery. All patients had general anesthesia with endotracheal intubation, in a standardized fashion, by the same anesthetist. Thirty min before completion of surgery, intramuscular diclofenac sodium 75 mg was administered. Following extubation, visual analogue pain scale (VAS) scores and additional analgesic requirements were recorded at 15 min at post-anesthesia care unit (PACU), and at 4th and 24th h postoperatively. Plasma levels of interleukin 6 (IL-6), and tumor necrosis factor R (TNF-R) were measured at predetermined time points (T0 1 h before administration of gabapentin, T1 at postoperative the 4th h mark, and T2 at postoperative at the 24th h mark). RESULTS: The VAS scores at postoperative 4th h were significantly higher in placebo and gabapentin groups compared with VAS scores at PACU and at 24th h. The groups did not differ in terms of additional analgesic requirements. In gabapentin group, IL-6 levels at T1 and T2 were significantly lower in comparison to values measured in placebo group at the same time points. This difference was not significant in TNF-R levels between the groups. CONCLUSIONS: Though preemptive oral gabapentin administration did not reduce postoperative pain and analgesic requirements in total knee arthroplasty surgery, it attenuated IL-6 production on the first postoperative day.

Effectiveness of gabapentin as a postoperative analgesic in children undergoing appendectomy.

PURPOSE: Though gabapentin is increasingly used as a perioperative analgesic, data regarding effectiveness in children are limited. The purpose of this study was to evaluate gabapentin as a postoperative analgesic in children undergoing appendectomy. METHODS: A 12-month retrospective review of children undergoing appendectomy was performed at a two-hospital children's institution. Patients receiving gabapentin (GP) were matched (1:2) with patients who did not receive gabapentin (NG) based on age, sex and appendicitis severity. Outcome measures included postoperative opioid use, pain scores, and revisits/readmissions. RESULTS: We matched 29 (33.3%) GP patients with 58 (66.6%) NG patients (n = 87). The GP group required significantly less postoperative opioids than the NG group (0.034 mg morphine equivalents/kg (ME/kg) vs. 0.106 ME/kg, p < 0.01). Groups had similar lengths of time from operation to pain scores ≤ 3 (GP 12.21 vs. NG 17.01 h, p = 0.23). GP and NG had similar rates of revisit to the emergency department (13.8 vs. 10.3%, p = 0.73), readmission (6.9 vs. 1.7%, p = 0.26), and revisits secondary to surgical pain (3.4 vs. 3.4%, p = 1.00). CONCLUSION: In this single-center, retrospective cohort study, gabapentin is associated with a reduction in total postoperative opioid use in children with appendicitis. While promising, further prospective validation of clinical effectiveness is needed.

Reverse Iontophoretic Extraction of Gabapentin: A Mechanistic Study.

BACKGROUND: For the narrow therapeutic index anti-epileptic drugs, monitoring of plasma concentration is a necessity for avoiding complications related to fluctuation of plasma level. OBJECTIVE: The work was aimed at extracting gabapentin by transdermal reverse iontophoresis to investigate its feasibility for noninvasive therapeutic drug monitoring. METHODS: Gabapentin was delivered in phosphate buffer (pH 7.4) at a therapeutic concentration range of 2-10 µg/ml. The same media was also used in receiver compartment. Extractions were carried out under an electric field of 5 V (current intensity range 0.3 -0.5 mA/cm2), provided by a custom-made power source for a period of 4 h. Samples were withdrawn at hourly intervals and drug content was analyzed by HPLC. RESULTS: Results indicated that gabapentin extraction occurred at both anode and cathode with cathodal extractions showing higher value at all concentrations. Extraction rates at both the chambers were affected by time, the first hour extraction was notably higher than the later hours. Highest extraction rate was noted at pH 5. Surprisingly, anodal extraction was found to show greater positive correlation with current intensity compared to cathodal extraction. CONCLUSIONS: As gabapentin carried no net charge at pH 7.4, orientation mediated electromigration was suggested to be the cause.

Pharmacokinetics of immediate release, extended release, and gastric retentive gabapentin formulations in healthy adults
.

OBJECTIVE: Gabapentin immediate release (GBP-IR), gabapentin gastric retentive (GBP-GR), and the prodrug gabapentin enacarbil extended release formulation (GEn) have been approved for management of postherpetic neuralgia (PHN) in adults. This is the first pharmacokinetic (PK) comparison of all three formulations using FDA-recommended doses for PHN. MATERIALS: This study compared the steady-state PK of GBP-IR 600 mg t.i.d., GBP-GR 1,800 mg q.d., and GEn 600 mg b.i.d. in healthy adults. METHODS: The open-label study consisted of a 3-day lead-in of escalating doses of GBP-IR, 5 days of treatment with each formulation (GPB-IR, GPB-GR, and GEn), and a 7-day taper period on 600 mg GEn q.d.. Plasma concentrations were collected on day 5 for each formulation. PK parameters were estimated from plasma concentration data. RESULTS: 14 healthy subjects (7 men, 7 women; mean (SD) age, 46.8 (7.60) years; mean (SD) body mass index, 26.7 (1.7) kg/m2) received all doses and completed the study. GBP-GR resulted in substantially (~ 4-fold) higher peak-to-trough ratio and percent fluctuation compared to GEn. GEn resulted in more sustained and less fluctuating daily exposure relative to GBP-IR, particularly at the end of 24 hours of dosing. In contrast, gabapentin fluctuation from GBP-IR consisted of 3 distinct peaks. After dose normalization, gabapentin exposure with GEn was ~ 2.2-fold and ~ 1.4-fold higher compared to GBP-GR and GBP-IR, respectively. All treatments were well tolerated. CONCLUSION: GEn requires less frequent dosing compared with GBP-IR and fluctuates less with sustained gabapentin exposure throughout the day. These PK differences may have clinically relevant implications.
.

Gabapentin dose and the 30-day risk of altered mental status in older adults: A retrospective population-based study.

Gabapentin is an effective treatment for chronic neuropathic pain but may cause dizziness, drowsiness, and confusion in some older adults. The goal of this study was to assess the association between gabapentin dosing and adverse outcomes by obtaining estimates of the 30-day risk of hospitalization with altered mental status and mortality in older adults (mean age 76 years) in Ontario, Canada initiated on high dose (>600 mg/day; n = 34,159) compared to low dose (≤600 mg/day; n = 76,025) oral gabapentin in routine outpatient care. A population-based, retrospective cohort study assessing new gabapentin use between 2002 to 2014 was conducted. The primary outcome was 30-day hospitalization with an urgent head computed tomography (CT) scan in the absence of evidence of stroke (a proxy for altered mental status). The secondary outcome was 30-day all-cause mortality. The baseline characteristics measured in the two dose groups were similar. Initiation of a high versus low dose of gabapentin was associated with a higher risk of hospitalization with head CT scan (1.27% vs. 1.06%, absolute risk difference 0.21%, adjusted relative risk 1.29 [95% CI 1.14 to 1.46], number needed to treat 477) but not a statistically significant higher risk of mortality (1.25% vs. 1.16%, absolute risk difference of 0.09%, adjusted relative risk of 1.01 [95% CI 0.89 to 1.14]). Overall, the risk of being hospitalized with altered mental status after initiating gabapentin remains low, but may be reduced through the judicious use of gabapentin, use of the lowest dose to control pain, and vigilance for early signs of altered mental status.

Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats.

Neuropathic pain is a worldwide health problem with no consensus regarding its optimal therapy. This study compared the analgesic effect and gastric, hepatic, and renal safety of combined low doses of diclofenac and celecoxib with gabapentin versus their individual high doses in the treatment of neuropathic pain in rats. Left sciatic nerve ligation was used as neuropathic pain model. Rats were allocated into 7 groups (7 rats for each): sham control; model group (received vehicle); Gaba-group (received gabapentin (100 mg/kg /day); Diclo 10-group (received diclofenac (10 mg/kg); Cele 10-group (received celecoxib (10 mg/kg/day); Gaba + Diclo 5 (receivedgabapentin(100 mg/kg /day) plus diclofenac (5 mg/kg); Gaba + Cele 5 (received gabapentin (100 mg/kg/day) plus celecoxib (5 mg/kg)). The analgesic effect was assessed using both hot plate and acetone tests. The impact of the used drugs on peptic ulcer index, liver enzymes, and serum urea and creatinine was evaluated, along with histopathological examination and oxidative stress parameters. Combination therapy of low dose of either diclofenac or celecoxib, with gabapentin showed higher analgesic effect compared with their individual high doses as indicated by prolonged response time in hot plate test and decreased frequency of paw withdrawal in acetone test. Their effect was associated with gentle effect on gastric mucosa, renal and hepatic integrity and oxidative stress parameters. In conclusion, the use of combined low doses of either diclofenac or celecoxib with gabapentin is better than high dose monotherapy regarding both the efficacy and safety.

Gabapentine 300 mg vs. 450 mg as anesthetic premedication for reactive hypertension, anxiety and analgesia / Gabapentina a dosis de 300 vs. 450 mg como premedicación anestésica para hipertensión reactiva, ansiedad y analgesia.

Objective: Observe the behavior of gabapentin to reduce reactive hypertension secondary to anxiety and pain in patients undergoing ophthalmic surgery as well as opioid consumption between groups. Method: Clinical randomized double blind controlled trial that analyzed 125 patients divided into three groups: Group A, gabapentin 300 mg; Group B, gabapentin 450 mg; and Group C, amaranth dragees as a control 2 h before the surgical procedure. Chi-squared test was used in sociodemographic variables and one-way ANOVA for continuous numeric variables. It was considered as significant a p < 0.05 for a study of two tails with a power of 80% beta. Results: Anxiety and analgesia intraoperative and postoperative had significant differences between groups. Lower consumption of opioid was found in the groups that used gabapentin. Conclusions: Gabapentin orally 300 or 450 mg h prior to surgery reduces pain, anxiety and postoperative opioid consumption in patients undergoing ophthalmic surgery.

Objetivo: Observar el comportamiento de la gabapentina para aminorar la hipertensión reactiva secundaria a ansiedad y dolor en pacientes sometidos a cirugía oftálmica, así como el consumo de opiáceos entre los grupos. Método: Ensayo clínico controlado aleatorizado y doble ciego que analizó a 125 pacientes divididos en tres grupos: grupo A, gabapentina 300 mg; grupo B, gabapentina 450 mg; grupo C, amaranto en grageas como control 2 horas antes del procedimiento quirúrgico. Se utilizó la prueba de ji al cuadrado para variables sociodemográficas y ANOVA de un factor para variables numéricas continuas. Se consideró como significativo un valor de p < 0.05 para un estudio de dos colas con un poder beta del 80%. Resultados: La ansiedad y la analgesia transoperatoria y posoperatoria tuvieron diferencias significativas entre los grupos. Se encontró menor consumo de opiáceos en los grupos que usaron gabapentina. Conclusiones: La gabapentina por vía oral, 300 o 450 mg, 2 horas antes de la cirugía, reduce el dolor, la ansiedad y el consumo de opiáceos durante el posoperatorio en pacientes sometidos a cirugía oftalmológica.

Optimizing the dose of local infiltration analgesia and gabapentin for total knee arthroplasty, a randomized single blind trial in 128 patients.

BACKGROUND AND PURPOSE: Effective analgesia is essential for postoperative recovery and rehabilitation in TKA. The challenge of analgesic regimes is to obtain adequate pain relief and maximum muscle control to mobilize and rehabilitate patients early. However, the optimal dose and best composition are not known. We hypothesized that there would be no differences in reported postoperative pain on the day of the TKA surgery as well as the first day after surgery when different combinations of ropivacain for LIA and gabapentin are given. METHODS: This prospective randomized trial examined 128 TKA patients treated with LIA and gabapentin in four groups. Group A: 300-mg ropivacain/600-300-300-mg gabapentin. Group B: 150-mg ropivacain/600-300-300-mg gabapentin. Group C: 300-mg ropivacain/300-100-100-mg gabapentin. Group D: 150-mg ropivacain/300-100-100-mg gabapentin. Primary endpoint was pain (NRS) at multiple moments. Secondary endpoints were number of adverse effects, length of hospital stay (LOS), the amount of consumption of pain medication, and wound leakage. Generalized estimating equation (GEE) was used to detect differences between the four groups regarding the course of pain. RESULTS: No differences regarding adverse effects, LOS, and wound leakage were found. GEE revealed a significant difference in course of pain between group A and B, with group B experiencing higher NRS scores postoperatively than group A (p=0.021). No differences between the other groups were found. INTERPRETATION: The results of the current study suggest that LIA with 300-mg (150ml) ropivacain might be more effective than 150-mg (75ml) ropivacain. Alteration in dose of gabapentin appears not to have influence on the course of pain.

All-Cause and Drug-Related Medical Events Associated with Overuse of Gabapentin and/or Opioid Medications: A Retrospective Cohort Analysis of a Commercially Insured US Population.

INTRODUCTION: Overuse of gabapentin and/or opioids occurs in a small percentage of patients at > 3-fold labeled dosages. Gabapentin may potentiate opioid effects. OBJECTIVE: The aim was to assess patient harm, defined as use of inpatient hospital (IPH) or emergency department (ED) services, associated with overuse of gabapentin with or without concomitant overuse of opioids. DATA SOURCE: Data were sourced from the Truven Health MarketScan® Commercial Claims and Encounters database, for the years 2013-2015. ELIGIBILITY CRITERIA: The eligibility criteria were two or more claims (billed encounters) and ≥120 days of treatment with gabapentin and/or opioids. METHODS: Cohort identification was based on daily-dosage thresholds of 50 morphine-milligram equivalents and 3600 mg of gabapentin in a 12-month follow-up: (1) no overuse; (2) mild overuse (two or more claims or two or fewer calendar quarters over threshold); and (3) sustained overuse (three or more over-threshold calendar quarters). IPH and ED use were measured for 6 months after the first overuse date (cohorts 2 and 3) or a randomly assigned date (cohort 1). Logistic regression analyses controlled for pre-treatment IPH/ED utilization, indication, addiction diagnosis, concomitant sedative/hypnotic use, and demographics. RESULTS: All-cause and drug-related IPH/ED utilization increased monotonically with degree of overuse, particularly of more than one medication. Sustained overuse of gabapentin multiplied odds of all-cause IPH by 1.366 [95% confidence interval (CI) 1.055-1.769], drug-related IPH by 1.440 (95% CI 1.010-2.053), and IPH/ED for altered mental status (e.g., euphoria, anxiety) by 1.864 (95% CI 1.324-2.624). Sustained overuse of both medications quadrupled odds of all-cause IPH, drug-related IPH, and IPH/ED for altered mental status or respiratory depression. CONCLUSION: Despite modest effects of gabapentin overuse alone, overuse of gabapentin with opioids may increase risk of harm and health-service utilization, supporting calls to make gabapentin a controlled substance in the USA.

Efficacy and Safety of Gabapentin in Comparison to Solifenacin Succinate in Adult Overactive Bladder Treatment.

OBJECTIVE: To evaluate the efficacy and safety of gabapentin in comparison to solifenacin succinate and placebo for the treatment of adult patients with overactive bladder (OAB). METHOD: A 12-week, randomized, double-blind, double dummy placebo-controlled, clinical trial was conducted between October 2010 and August 2014 at a tertiary medical center. Eligible and consenting patients included were randomized into three treatment groups (placebo, gabapentin and solifenacin). After a 12-week treatment period, an intention to treat analysis was applied to assess between group differences on the micturitions and urgency episodes per 24 h; which were evaluated by 3-day micturition diary mean change from baseline to post treatment. Health related quality of life (HRQOL) domains were likewise assessed by OAB questionnaire (OAB-q). Adverse event were monitored and summarized. Study results were analyzed at statistical significance of 0.05. (ClinicalTrials.gov ID NCT01486706) RESULT: A total of 94 participants were included for end-study efficacy and safety analysis. Compared to placebo, gabapentin and solifenacin have statistically significant improvement in mean number of micturitions per 24 h (adjusted mean difference [AMD] -1.179, 95%CI -1.98, -0.38; P < 0.001; -1.706, 95%CI -2.52, -0.09; P < 0.001; respectively), and in mean number of urgency episodes per 24 h (AMD -0.903, 95%CI -1.44, -0.37; P < 0.001; -0.896, 95%CI -1.44, -0.35; P < 0.001). Gabapentin also demonstrated significant improvement over the solifenacin in the mean number of nocturia episodes/24 h (AMD -0.607, 95%CI -1.04, -0.18; P < 0.001). Adverse event related to gabapentin treatment was lesser than solifenacin, and comparable to placebo. CONCLUSION: Gabapentin treatment with acceptable safety profile, improves OAB symptoms and HRQOL domains.

Policies to mitigate nonmedical use of prescription medications: how should emerging evidence of gabapentin misuse be addressed?

INTRODUCTION: Over the past decade, increased prescription supply has facilitated an epidemic of nonmedical use of controlled substances, including predominantly opioids, as well as benzodiazepines, z-hypnotics, and stimulants. Areas covered: More recently, misuse of noncontrolled prescriptions, such as gabapentin, has been detected. Gabapentin misuse has been associated with drug-related harm and increased healthcare service utilization in a few studies, including a recent large-sample analysis of commercially insured enrollees in the United States (U.S.) Responding to this emerging base of evidence, a small number of U.S. states have acted to prevent or detect gabapentin misuse by requiring the inclusion of gabapentin utilization in reporting to local Prescription Drug Monitoring Programs (PDMPs) and/or imposing other restrictions on gabapentin prescribing (e.g., classification as a controlled substance, quantity limits). These efforts may result in unintentional harm by (1) encouraging 'doctor shopping' across state lines to seek lenient regulatory policies and (2) placing the burden for mitigating misuse on individual practitioners. Expert opinion: We call for a unified national approach, comprising federal regulation and enhanced PDMP reporting to address gabapentin misuse, while laying the groundwork for management of new medications of abuse that the healthcare industry may encounter in the future.

Use of single-dose oral gabapentin to attenuate fear responses in cage-trap confined community cats: a double-blind, placebo-controlled field trial.

Objectives This double-blind, placebo-controlled study evaluated the safety and efficacy of single-dose oral gabapentin administered for the attenuation of fear responses in cage-trap confined community cats. Methods Community cats presented in cage traps for trap-neuter-return (TNR) were recruited and screened for inclusion. Each enrolled cat was randomly assigned and administered one of three equal-volume, single-dose treatments: placebo, low-dose gabapentin (50 mg) or high-dose gabapentin (100 mg). At baseline, 1, 2, 3 and 12 h post-administration, a single, blinded observer scored each cat for signs of fear and sedation using published paradigms, calculated the respiratory rate and documented any observable facial injuries. Results Fifty-three cats met the inclusion criteria and completed the study. Cat stress score (a measure of fear) was lower in cats that received gabapentin (50 or 100 mg) than in cats that received placebo (50 mg: P = 0.027; 100 mg: P = 0.029), with the greatest reduction at 2 h post-treatment ( P = 0.0007). Respiratory rates did not differ between treatment groups. There was no difference in sedation scores between the groups ( P = 0.86) at any time point ( P = 0.09). Cat facial injuries did not vary by treatment group or over time. No adverse effects were detected specific to gabapentin administration. At 1 h, hypersalivation was observed in four cats across all treatment groups. All cats recovered from surgery and anesthesia uneventfully. Conclusions and relevance This study supports the hypothesis that 50 mg or 100 mg gabapentin (9.2-47.6 mg/kg per cat) reduces fear responses in confined community cats without measurable sedation over 3 h post-administration vs placebo. Gabapentin treatment was well tolerated in this population of cats. Further studies are recommended to investigate the use of oral gabapentin earlier in the TNR process, such as immediately after trapping or prior to transport for the prevention of confinement-related injuries.

Evaluating the Implementation of a Preemptive, Multimodal Analgesia Protocol in a Plastic Surgery Office.

Many patients undergoing plastic surgery experience significant pain postoperatively. The use of preemptive, multimodal analgesia techniques to reduce postoperative pain has been widely described in the literature. This quality improvement project evaluated the implementation of a preemptive, multimodal analgesia protocol in an office-based plastic surgery facility to decrease postoperative pain, decrease postoperative opioid consumption, decrease postanesthesia care time, and increase patient satisfaction. The project included adult patients undergoing surgical procedures at an outpatient plastic and cosmetic surgery office, and the protocol consisted of oral acetaminophen 1,000 mg and gabapentin 1,200 mg. Using a pre-/postintervention design, data were collected from patient medical records and telephone interviews of patients receiving the standard preoperative analgesia regimen (preintervention group: n = 24) and the evidence-based preemptive, multimodal analgesia protocol (postintervention group: n = 23). Results indicated no significant differences between the pre- and postintervention groups for any of the outcomes measured. However, results showed that patients in both groups experienced moderate to severe pain postoperatively. In addition, adverse side effects such as dizziness and drowsiness were higher in the postintervention group than in the preintervention group. Although this quality improvement project did not meet the goals it set out to achieve for patients undergoing plastic surgery, it did illustrate the substantial presence of pain after surgical procedures. Thus, clinicians need to continue to focus on identifying targeted treatment plans that use multimodal, non-opioid-based strategies to manage and prevent postoperative pain.

Pharmacotherapy for Neuropathic Pain in Japan.

Neuropathic pain (NeP) results from injury to, or disease of, the peripheral or central components of the neural systems involved in pain. In contrast to inflammatory pain, NeP can persist after healing from the initial injury has resolved. Antipyretic agents, such as non-steroidal anti-inflammatory drugs, steroids, and acetaminophen are ineffective, while specific agents such as gabapentinoids, antidepressants, antiepileptics, and opioids are effective in treating NeP. In this review, we address the definition of NeP, pharmacotherapy for NeP in Japan, pain classification, setting goals for successful NeP medication, and the Japanese algorithm for the pharmacotherapy of NeP with specific prescription guidance.

Effects of a single preappointment dose of gabapentin on signs of stress in cats during transportation and veterinary examination.

OBJECTIVE To determine the effects of oral gabapentin administration prior to veterinary examination on signs of stress in cats. DESIGN Randomized, blinded, crossover clinical trial. ANIMALS 20 healthy pet cats with a history of fractious behavior or signs of stress during veterinary examination. PROCEDURES Cats were scheduled for 2 veterinary visits 1 week apart and randomly assigned to receive a capsule containing 100 mg of gabapentin (13.0 to 29.4 mg/kg [5.9 to 13.4 mg/lb]) or placebo (lactose powder) prior to the first visit and the opposite treatment prior to the second visit. Owners were instructed to administer the assigned capsule orally 90 minutes prior to placing the cat into a carrier and transporting it to the veterinary hospital. Standardized physical examinations and blood pressure readings were performed. Owners assigned a cat stress score during transportation and examination, and the veterinarian assigned a compliance score at the visit. Scores were compared between treatments, controlling for various factors. RESULTS Owner-assessed cat stress scores during transportation and veterinary examination and veterinarian-assessed compliance scores were significantly lower when cats received gabapentin than when they received the placebo. Sedation was a common effect of gabapentin administration, and ataxia, hypersalivation, and vomiting were also reported. All effects resolved within 8 hours after gabapentin administration. CONCLUSIONS AND CLINICAL RELEVANCE Owners' perception of stress in their cats is a primary reason for failing to seek veterinary care. Results of this study suggested that gabapentin is a safe and effective treatment for cats to help reduce stress and aggression and increase compliance for transportation and veterinary examination.