Managing delayed or missed pregabalin doses in patients with focal epilepsy: a Monte Carlo simulation study.

BACKGROUND: Delayed or missed doses are inevitable in epilepsy pharmacotherapy. The current remedial measures recommended by the United States Food and Drug Administration (FDA) for non-adherence are generic and lack clinical evidence. AIM: To assess remedial strategies for delayed or missed pregabalin doses in patients with epilepsy using Monte Carlo simulations. METHOD: Monte Carlo simulations were performed using a published population pharmacokinetic model for pregabalin. The applicability of five proposed remedial regimens as well as FDA recommendations was evaluated by simulating various poor adherence scenarios in eight populations, including those with renal dysfunction. RESULTS: All proposed remedial strategies were associated with delay duration and renal function. When delays are relatively short, an immediate regular dose is advised. The cut-off time points for taking the regular dose as a remedial regimen were 1, 2, 4, and 12 h for patients with mild renal impairment and normal renal function, moderate renal impairment, severe renal impairment, and end-stage renal disease, respectively. However, when delay aligns closely with a dosing interval, a regular dose combined with a partial dose proves effective. Generally, supplementing 1.3-fold the regular dose at the next scheduled time adequately compensates for the missed dose. CONCLUSION: Model-based simulations provided quantitative evidence for the effectiveness and feasibility of remedial strategies for missed or delayed pregabalin doses.

The investigation of antidepressant and anxiolytic effects of pregabalin and its mechanisms of action in rats.

OBJECTIVES: Pregabalin (PGB) is used in drug-resistant epilepsy. Also, it has analgesic effects in painful syndromes. Depression and anxiety are commonly seen in epilepsy and neuropathic pain patients. PGB is often combined with anxiolytics and antidepressants. We aimed to investigate the antidepressant and anxiolytic effects of PGB and compare its effects with those of antidepressant and anxiolytic drugs and their combined use. METHODS: Wistar Albino rats were used, and PGB (5, 10, 20, and 40 mg/kg), amitriptylin (AMT), fluoxetine (FLX), ketamine (KET), and diazepam (DZM), as well as combinations of PGB (20 mg/kg) with AMT, FLX, KET, and DZM, were administered. Elevated plus maze, forced swimming, and locomotor activity tests were performed. RESULTS: In the elevated plus maze, PGB10, 20, 40, AMT, FLX, and DZM increased open arm time. The PGB20+FLX combination increased compared to PGB20. In forced swimming, PGB doses increased immobility time. AMT, FLX, DZM, and KET decreased compared to control and PGB doses. Other combinations of PGB20 reversed immobility time, except FLX. In locomotor activity, PGB20, AMT, KET, and DZM decreased distance. CONCLUSION: PGB had a depressant effect in all doses and a dose-dependently anxiolytic effect. In combinations of PGB with AMT, KET, and DZM, it reversed their antidepressant effects. We assumed FLX could be preferred instead of AMT in patients using PGB. When PGB is used in combination, drug interactions should be considered. These results are also very remarkable in terms of pharmacoeconomics.

Ultrasound assisted membrane-assisted solvent extraction for the simultaneous assessment of some drugs involved in drug-facilitated sexual assaults by liquid chromatography-tandem mass spectrometry.

A simple and highly efficient ultrasound assisted membrane-assisted solvent extraction (MASE) pre-treatment method for urine has been developed and validated for the simultaneous determination of twenty-two drugs involved in drug-facilitated sexual assaults (DFSAs) by liquid chromatography-tandem mass spectrometry. MASE was performed with 4.0 mL of urine (pH adjusted at 12), 400 µL of hexane as an organic solvent inside the polypropylene membrane, and ultrasonication (45 kHz, 120 W) for 10 min. A pre-concentration factor of 40 was achieved after evaporation (N2 stream) and re-dissolution in 100 µL of methanol. Analytes were separated using a Zorbax Eclipse Plus C18 column under gradient elution with aqueous 10 mM NH4HCO3 (pH 8.0) and methanol as mobile phases. Matrix-matched calibrations allowed the assessment of DFSA drugs of quite different octanol-water partition coefficients (Ko/w), from 1.32 101 for pregabalin to 2.45 105 for clomipramine (Log P values from 1.12 (pregabalin) to 5.39 (clomipramine)). The limit of detection (LOD) was between 0.0075 to 0.37 µg L-1, with analytical recoveries ranging from 73 to 103%, and relative standard deviations (RSDs) within the 2-20% range. The applicability of the method was demonstrated after analysing urine samples under forensic investigation.

Systematic assessment of non-medical use of prescription drugs using doctor-shopping indicators: A nation-wide, repeated cross-sectional study.

AIMS: The aim of this study was to present the first nation-wide, systematic, repeated assessment of doctor-shopping (i.e. visiting multiple physicians to be prescribed the same drug) during 10 years for more than 200 psychoactive prescription drugs in the 67 million inhabitants in France. DESIGN: This was a nation-wide, repeated cross-sectional study. SETTING AND PARTICIPANTS: Data are from the French National Health Data System in 2010, 2015 and 2019 for 214 psychoactive prescription drugs (i.e. anaesthetics, analgesics, antiepileptics, anti-Parkinson drugs, psycholeptics, psychoanaleptics, other nervous system drugs and antihistamines for systemic use). MEASUREMENTS: The detection and quantification of doctor-shopping relied upon an algorithm that detects overlapping prescriptions from repeated visits to different physicians. We used two doctor-shopping indicators aggregated at population level for each drug dispensed to more than 5000 patients: (i) the quantity doctor-shopped, expressed in defined daily doses (DDD), which measures the total quantity doctor-shopped by the study population for a given drug; and (ii) the proportion doctor-shopped, expressed as a percentage, which standardizes the quantity doctor-shopped according to the use level of the drug. FINDINGS: The analyses included approximately 200 million dispensings to approximately 30 million patients each year. Opioids (e.g. buprenorphine, methadone, morphine, oxycodone and fentanyl), benzodiazepines and non-benzodiazepine hypnotics (Z-drugs) (e.g. diazepam, oxazepam, zolpidem and clonazepam) had the highest proportions doctor-shopped during the study period. In most cases, the proportion and the quantity doctor-shopped increased for opioids and decreased for benzodiazepines and Z-drugs. Pregabalin had the sharpest increase in the proportion doctor-shopped (from 0.28 to 1.40%), in parallel with a sharp increase in the quantity doctor-shopped (+843%, from 0.7 to 6.6 DDD/100 000 inhabitants/day). Oxycodone had the sharpest increase in the quantity doctor-shopped (+1000%, from 0.1 to 1.1 DDD/100 000 inhabitants/day), in parallel with a sharp increase in the proportion doctor-shopped (from 0.71 to 1.41%). Detailed results for all drugs during the study period can be explored interactively at: https://soeiro.gitlab.io/megadose/. CONCLUSIONS: In France, doctor-shopping occurs for many drugs from many pharmacological classes, and mainly involves opioid maintenance drugs, some opioids analgesics, some benzodiazepines and Z-drugs and pregabalin.

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Constructing the Gendered Risk of Illness in Lyrica Ads for Fibromyalgia: Fear of Isolation as a Motivating Narrative for Consumer Demand.

Direct-to-consumer television advertisements for Lyrica in the United States create narratives of gendered domestic normalcy to which women with fibromyalgia are encouraged to aspire through pharmaceutical intervention. This paper unpacks images and narratives within these advertisements to demonstrate that they rely on metaphors that represent gendered expectations in order to evoke guilt and provoke a desire for what Joseph Dumit calls "health as risk reduction," and what I argue is an attempt to show disability being erased. Following Stuart Hall's Encoding/Decoding model of communication, viewers play a role in constructing societal expectations for women with chronic pain and for themselves.

Discovery and Development of Pregabalin (Lyrica): The Role of Public Funding.

BACKGROUND AND OBJECTIVES: Pregabalin (Lyrica), a widely used drug that has generated billions in revenue as a treatment for diabetic neuropathy and other conditions, was originally discovered in an academic medical center, largely supported by public funding. We aimed to define the extent of direct federal public funding that contributed to various stages of pregabalin's development prior to US Food and Drug Administration (FDA) approval. METHODS: We identified key research, scientists, and organizations involved in the development of pregabalin from its discovery through FDA approval. Using key terms (e.g., its indications and mechanism of action), we searched PubMed for relevant publications and determined whether each publication was based on federal public funding using the NIH RePORTER. For each award prior to the drug's FDA approval, we scored its potential relatedness to pregabalin's development based on its title, investigator, and organization, and then examined descriptions of the most relevant awards to aid in defining these relationships. The budgets for all related awards were converted to 2020 dollars. RESULTS: Pregabalin was discovered largely on the basis of publicly funded research at Northwestern University; in 1990, it was licensed to Parke-Davis, which further developed it through its FDA approval in 2004. Most key terms were related to the drug and drug target (n = 5) and organizations involved (n = 5), followed by patent-listed inventors (n = 3). These key terms linked 6,438 core project awards and we identified 37 NIH awards related to pregabalin's development: 9 awards through 1990 ($3.3 million) and 28 from 1991 through 2004 ($10.5 million). CONCLUSION: Like that of many other widely sold medications, the development of pregabalin relied on public sector as well as industry contributions to its discovery, with relevant NIH awards totaling $13.8 million during its preapproval development.

Assessment of the Anti-Allodynic and Anti-Hyperalgesic Efficacy of a Glycine Transporter 2 Inhibitor Relative to Pregabalin, Duloxetine and Indomethacin in a Rat Model of Cisplatin-Induced Peripheral Neuropathy.

Cisplatin, which is a chemotherapy drug listed on the World Health Organisation's List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), indomethacin (1-10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose-response curve warrants further translational considerations.

Pregabalina para o tratamento de dor neuropática e fibromialgia / Pregabalin for pain management neuropathic and fibromyalgia

INTRODUÇÃO: A dor neuropática é causada por lesões ou doenças que afetam o sistema somatossensorial, caracterizada por dor espontânea ou anormal evocada por estímulo. Por outro lado, a fibromialgia é uma condição crônica caracterizada por dor musculoesquelética generalizada, fadiga, distúrbios do sono, comprometimento cognitivo e ansiedade, sem uma etiologia conhecida. No Brasil, no âmbito do Sistema Único de Saúde (SUS), o tratamento da dor crônica é direcionado, atualmente, pelo Protocolo Clínico e Diretrizes Terapêuticas da Dor Crônica. Dada a complexidade do tratamento da dor crônica neuropática e a ausência de tratamento medicamentoso para tratar a fibromialgia, o presente relatório foi elaborado com o objetivo de compreender a viabilidade do uso de pregabalina no manejo dessas condições clínicas, visando sua possível incorporação no SUS. TECNOLOGIA: Pregabalina (ALOND®, ÁPICE®, DORENE®, DORENE TABS®, GABALGIN®, GLYA®, INSIT®, KONDUZ®, LIMIAR®, LYRICA®, LYSUGI®, MOBALE®, NEUGABA®, PREBICTAL®, PREFISS®, PREGALPHA®, PRENEURIN®, PROLEPTO®, VOLVER®). PERGUNTA: Pregabalina é eficaz, segura e custo-efetiva para o tratamento de pacientes adultos com dor neuropática e fibromialgia, co

Pregabalina para o tratamento de dor neuropática e fibromialgia / Pregabalin for Pain Treatment neuropathic and fibromyalgia

INTRODUÇÃO: A dor neuropática é causada por lesões ou doenças que afetam o sistema somatossensorial, caracterizada por dor espontânea ou anormal evocada por estímulo. Por outro lado, a fibromialgia é uma condição crônica caracterizada por dor musculoesquelética generalizada, fadiga, distúrbios do sono, comprometimento cognitivo e ansiedade, sem uma etiologia conhecida. No Brasil, no âmbito do Sistema Único de Saúde (SUS), o tratamento da dor crônica é direcionado, atualmente, pelo Protocolo Clínico e Diretrizes Terapêuticas da Dor Crônica. Dada a complexidade do tratamento da dor crônica neuropática e a ausência de tratamento medicamentoso para tratar a fibromialgia, o presente relatório foi elaborado com o objetivo de compreender a viabilidade do uso de pregabalina no manejo dessas condições clínicas, visando sua possível incorporação no SUS. TECNOLOGIA: Pregabalina (ALOND®, ÁPICE®, DORENE®, DORENE TABS®, GABALGIN®, GLYA®, INSIT®, KONDUZ®, LIMIAR®, LYRICA®, LYSUGI®, MOBALE®, NEUGABA®, PREBICTAL®, PREFISS®, PREGALPHA®, PRENEURIN®, PROLEPTO®, VOLVER®). PERGUNTA: Pregabalina é eficaz, segura e custo-efetiva para o tratamento de pacientes adultos com dor neuropática e fibromialgia, comparada a gabapenti

Toxicity assessment of concurrent gabapentin/pregabalin administration with high-dose melphalan in autologous hematopoietic cell transplant recipients.

A theoretical pharmacokinetic interaction mediated through L-amino acid transporter 1 and 2 exists between gabapentin (GP) and pregabalin (PG) with melphalan. Peripheral neuropathy is a common toxicity of various multiple myeloma regimens commonly utilized prior to autologous hematopoietic cell transplant (auto-HCT) with high-dose melphalan (HD-Mel). Therefore, it is likely concurrent administration of either GP or PG will occur in patients receiving HD-Mel conditioning for auto-HCT, which could potentially increase cellular uptake and worsen the mucosal injury. A retrospective chart review of adult patients from January 2012 to July 2016 who received HD-Mel (140-200 mg/m2) at West Virginia University Medicine was performed to assess toxicity and outcomes in these patients. A total of 80 patients were included in the study, with 30 patients receiving GP or PG and 50 control patients. There were no significant differences in grade 2 or higher mucositis, admissions for nausea/vomiting/diarrhea, intravenous opioid requirements, oral topical therapies, antidiarrheal medication use, rescue anti-emetics, days of nausea or vomiting, pain scores, neutrophil or platelet engraftment, treatment-related mortality, progression-free survival, or overall survival. Our data suggest that it is safe to continue GP/PG therapy throughout HD-Mel therapy, with no negative transplant outcomes. Prospective studies or evaluations of larger databases are necessary to better characterize the clinical effect of concomitant therapy.

Cost-effectiveness analysis of 5% lidocaine-medicated plaster compared with pregabalin for the treatment of post-herpetic neuralgia in China.

BACKGROUND: Post-herpetic neuralgia (PHN) is the most common complication of herpes zoster and is defined as pain that lasts for one month or more after the outbreak itself heals. While the annual incidence of herpes zoster is approximately 3-5%, 9-34% of these patients will develop PHN. Approximately 30-50% of these cases last for more than a year but some cases can persist for 10 years or more. To date, the economic burden of PHN in China has not been studied. The first-line topical therapy for PHN is application of lidocaine-medicated plasters (LMPs) which have shown good efficacy and tolerability. Furthermore, LMPs were added to China's National Health Insurance List in 2019, thereby significantly relieving the financial burden on patients. A cost-effectiveness analysis was performed on LMPs compared with pregabalin in the treatment of PHN to provide a reference for the basis for clinical treatments and health decisions in patients with PHN. METHODS: A Markov model was built according to the PHN disease characteristics. The efficacy data were extracted from a randomized controlled trial conducted in China, and the transition probability, utility value, and medical cost of each state in the model were collected through a systematic review of the literature and public databases. The outcome measure was cost per quality-adjusted life year (QALY) gained. The incremental cost-effectiveness ratios (ICERs) were calculated. Sensitivity analysis was conducted to confirm the robustness of the model. RESULTS: In the base case analysis, treatment for a 6-month period with pregabalin and lidocaine plasters led to a mean QALY gain of 0.34012 and 0.42543, respectively, and mean incremental costs of 5,720 Chinese Yuan (CNY) and 3690 CNY, respectively. The ICER of treatment with 5% lidocaine plaster was negative, indicating that lidocaine plasters had absolute advantage. Monte Carlo simulation resulted in an estimate of 90% probability that the 5% lidocaine plaster treatment was cost-effective. CONCLUSIONS: Within the Chinese medical and health system, LMPs can reduce the economic burden of patients with PHN. LMPs are more cost-effective and more efficient in absolute terms compared to the first-line treatment systemic drug pregabalin in the treatment of PHN.

Prevalence of and Factors Associated with Gabapentinoid Use and Misuse Among Texas Medicaid Recipients.

BACKGROUND AND OBJECTIVES: Gabapentin and pregabalin have been considered relatively safe opioid-sparing adjuncts for pain management. However, rising prescribing trends, presence of gabapentinoids in opioid-related overdoses, and the growing body of evidence regarding gabapentinoid misuse and abuse, have caused gabapentinoids to emerge as a drug class of public health concern. This study aimed to assess the prevalence of, and factors associated with gabapentinoid use and misuse. METHODS: This retrospective study of Texas Medicaid data from 1/1/2012 to 30/8/2016 included patients aged 18-63 years at index date, with ≥ 1 gabapentinoid prescription, and continuously enrolled 6 months pre-index and 12 months post-index. Gabapentinoid misuse was defined as ≥ 3 claims exceeding daily doses of 3600 mg for gabapentin and 600 mg for pregabalin. Age, gender, concurrent opioid use, neuropathic pain diagnoses and gabapentinoid type were independent variables. Descriptive and inferential statistics were used. RESULTS: Of included subjects (N = 39,000), 0.2% (N = 81) met study criteria for gabapentinoid misuse. Overall, the majority (76.4%) of gabapentinoid users were aged 41-63 years with a mean ± SD age of 48.2 ± 10.7 years. Those patients meeting the study criteria for gabapentinoid misuse were significantly younger (45.1 ± 11.0 vs 48.2 ± 10.7, p = 0.0084). Majority of the study sample was female (68.1%). However, a significantly higher proportion of males met the study criteria for gabapentinoid misuse compared to females (0.3% vs 0.2%, p = 0.0079). Approximately one-half (51.9%) of the study sample had neuropathic pain, and gabapentinoid misuse was significantly higher in neuropathic pain patients compared to those without neuropathic pain (0.3% vs 0.1%, p = 0.0078). Over three-quarters (77.4%) of patients were using gabapentin; however, gabapentinoid misuse was significantly higher among pregabalin users (0.4% vs 0.2%, p = 0.0003). Approximately 20% (17.3%) of gabapentinoid users had ≥ 90 days of concurrent opioid use. However, there was no significant difference in gabapentinoid misuse among patients with concurrent opioid use compared to patients without (0.3% vs 0.2%, p = 0.1440). Factors significantly associated with misuse included: male sex (odds ratio [OR] 0.486; 95% confidence interval [CI] 0.313-0.756; p = 0.0013); neuropathic pain (OR 2.065; 95% CI 1.289-3.308; p = 0.0026); and pregabalin versus gabapentin use (OR 2.337, 95% CI 1.492-3.661; p = 0.0002). Concurrent opioid use was not significantly associated with gabapentinoid misuse (OR 1.542, 95% CI 0.920-2.586; p = 0.1006). CONCLUSION: Prevalence of gabapentinoid misuse was low (0.2%) among Texas Medicaid recipients. Younger age, male gender, neuropathic pain diagnosis and pregabalin use were significantly associated with higher levels of gabapentinoid misuse.

Healthcare expenditure and its predictors in a cohort of Australians living with sciatica.

PURPOSE: To estimate the healthcare resource utilisation of an Australian cohort of people with sciatica and explore individual-level factors associated with expenditure. METHODS: Healthcare utilisation (services and medication) data from a randomised, double-blind, placebo-controlled trial of pregabalin in patients with sciatica (n = 185) were analysed to estimate healthcare expenditure of participants over 12 months. Associations between key baseline socio-economic, pain and quality of life characteristics and healthcare expenditure were examined using generalised linear imputation models. RESULTS: On average, participants accessed AUD$1,134 of healthcare over the year, predominantly made up of $114 of medication and $914 of health services, which included $418 of physiotherapy services. Participants randomised to receive pregabalin incurred higher expenditure ($1,263 compared to $1,001 for placebo), which was largely driven by pregabalin ($158) and greater health services ($107). Healthcare expenditure was significantly higher for participants prescribed pregabalin, earning greater than $1,700 per week ($88,400 per year) and reporting poorer quality of life (physical and mental). CONCLUSION: Our results suggest inefficiency in the use of healthcare resources due to increased healthcare resource utilisation in people with sciatica treated with pregabalin, compared to placebo. Costs of treating sciatica varied based on individual quality of life and socio-economic characteristics.

Gabapentinoid and Opioid Utilization and Cost Trends Among Injured Workers.

OBJECTIVE: To characterize changes in opioid, gabapentin, and pregabalin utilization patterns and cost trends between 2008 and 2018 in a Louisiana workers' compensation claims population and explore the role of gabapentinoids as alternative analgesics during the opioid epidemic. METHOD: Filled prescriptions for gabapentinoids and opioids were studied for 11 years in a cohort of 18,737 claimants. RESULTS: The proportion of claimants prescribed gabapentin increased 2-fold (8.9% to 18.9%) and average drug cost per claimant decreased 22% ($612 to $480). The proportion of claimants prescribed pregabalin decreased approximately 80% (11.7% to 2.5%) and average drug cost per claim increased 224% ($911 to $2952). Proportion of claimants prescribed opioids decreased 20% (80% to 64.2%) and average drug cost per claim decreased 46% ($691 to $371). CONCLUSIONS: Utilization increased substantially for gabapentin and decreased for pregabalin and opioids.

Efficacy of pregabalin as a monotherapy versus combined pregabalin and milnacipran in the management of fibromyalgia.

AIM: To compare the efficacy and tolerability of combined pregabalin (PGB) and milnacipran (MLN) in female patients with fibromyalgia (FM) versus PGB as a monotherapy. METHODS: The present randomized open study included 58 female patients diagnosed with FM (registered on 4/2/19: NCT03905486). Patients were randomly divided into 2 groups (2:2); group 1 included 29 patients who received PGB monotherapy (150 mg twice daily) and group 2 included 29 patients who received combined PGB (150 mg twice daily) and MLN (50 mg twice daily) for 3 months. At the initial visit, patients were subjected to demographic data collection and assessed by the visual analog scale (VAS) for pain and the FM impact questionnaire (FIQ). Outcome measures after 3 months: FIQ, VAS and Leeds Sleep Evaluation Questionnaire. RESULTS: The median disease duration was 2 years in group 1 (6 months to 5 years) and 2 years in group 2 (6 months to 12 years). The dropout rate was 20.7% in group 1 (n = 6) and 10.3% in group 2 (n = 3). At the follow-up evaluation, a statistically significant improvement was observed in VAS and FIQ scores in both groups (P < 0.001). Although the percentage of patients demonstrating significant improvement in pain, disease impact and sleep pattern were higher in group 2, this did not reach statistical significance. CONCLUSION: Although PGB as a monotherapy and in combination with MLN have both shown adequate efficacy in the treatment of patients with FM, the combined therapy did not demonstrate superiority over the monotherapy.

Assessment of the anti-allodynic efficacy of a glycine transporter 2 inhibitor relative to pregabalin and duloxetine in a rat model of prostate cancer-induced bone pain.

BACKGROUND: The pathobiology of prostate cancer-induced bone pain (PCIBP) is underpinned by both inflammatory and neuropathic components. Here, we used a rat model of PCIBP to assess the analgesic efficacy of a glycine transporter 2 (GlyT2) inhibitor (N-(6-((1,3-dihydroxypropan-2-yl)amino)-2-(dimethylamino)pyridin-3-yl)-3,5-dimethoxy-4-(4-(trifluoromethyl)phenoxy) benzamide) relative to two clinically available adjuvant drugs that are recommended for the relief of neuropathic pain, viz, pregabalin and duloxetine. METHODS: PCIBP was induced in male Wistar Han rats following intra-tibial injection (ITI) of rat prostate cancer (AT3B) cells into the left tibia. Sham-rats received an ITI of heat-killed AT3B cells. PCIBP rats with fully developed mechanical allodynia in the ipsilateral hindpaws as assessed using von Frey filaments, received single oral (p.o.) bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), or vehicle. Baseline paw withdrawal thresholds (PWTs) were determined in the ipsilateral (injured side) and contralateral hindpaws immediately prior to dosing and at scheduled times for 3 h post dosing in individual animals. RESULTS: Single oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg) evoked partial pain relief at the doses tested in the ipsilateral hindpaws of PCIBP rats without any discernible behavioural side effects. By contrast, single oral bolus doses of pregabalin at 10-100 mg/kg evoked dose-dependent and complete alleviation of mechanical allodynia. By comparison, single oral bolus doses of duloxetine at doses up to 100 mg/kg lacked efficacy. CONCLUSION: Oral administration of this GlyT2 inhibitor evoked partial pain relief in PCIBP rats and did not evoke central nervous system side effects in contrast to GlyT2 inhibitors reported by others.

Capsaicin 8% dermal patch in clinical practice: an expert opinion.

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.