Nicotine Replacement Therapy Formulations Research Articles

Injectable In Situ Gelling System for Sustained Nicotine Delivery as a Replacement Therapy for Smoking Cessation.

Nicotine replacement therapy (NRT) is widely used to limit the withdrawal symptoms associated with cigarette smoking cessation. However, the available NRT formulations are limited by their short release profiles, requiring frequent administrations along with local side effects. Thus, the objective of this study is to develop an NRT formulation that offers prolonged, sustained nicotine release. Thermoresponsive in situ gelling systems containing nicotine were prepared using poloxamer 407 (P407) and poloxamer 188 (P188). The system was optimized using a three-factor, two-level full factorial design (23). A formulation composed of P407 (20% w/w), P188 (5% w/w), and loaded with nicotine (0.5% w/w) exhibited sol-to-gel transition at a suitable temperature close to physiological temperature (30 °C). The rheological analysis demonstrated a Newtonian-like flow at room temperature, suggesting ease of administration via injection, and semisolid gel status at physiological temperature. The optimized formulation successfully sustained nicotine in vitro release over 5 days following single administration. The findings suggest that poloxamer based in situ gelling systems are promising platforms to sustain the release of nicotine.

A Time‐to‐Event Model Relating Integrated Craving to Risk of Smoking Relapse Across Different Nicotine Replacement Therapy Formulations

Smoking increases the risk of cancer and other diseases, causing an estimated 7 million deaths per year. Nicotine replacement therapy (NRT) reduces craving for smoking, therefore, increasing an individual's probability to remain abstinent. In this work, we for the first time quantitatively described the relationship between craving and smoking abstinence, using retrospectively collected data from 19 studies, including 3 NRT formulations (inhaler, mouth spray, and patch) and a combination of inhaler and patch. Smokers motivated to quit were included in the NRT or placebo arms. Integrated craving (i.e., craving over a period of time) was assessed with 4-category, 5-category, or 100-mm visual analogue scale. The bounded integer model was used to assess latent craving from all scales. A time-to-event model linked predicted integrated craving to the hazard of smoking relapse. Available data included 9,323 adult subjects, observed for 3weeks up to 2years. At the study end, 9% (11% for NRT and 5% for placebo), on average, remained abstinent according to the protocol definition. A Gompertz-Makeham hazard best described the data, with a hazard of smoking relapse decreasing over time. Latent integrated craving was positively related to the hazard of smoking relapse, through a sigmoidal maximum effect function. For the same craving, being on NRT was found to reduce the hazard of relapse by an additional 30% compared with placebo. This work confirmed that low craving is associated with a high probability of remaining smoking abstinent and that NRT, in addition to reducing craving, increases the probability of remaining smoking abstinent.

Electrospun α-Lactalbumin Nanofibers for Site-Specific and Fast-Onset Delivery of Nicotine in the Oral Cavity: An In Vitro, Ex Vivo, and Tissue Spatial Distribution Study.

Nicotine replacement therapy (NRT) formulations for oromucosal administration induce a delayed rise in nicotine blood levels as opposed to the immediate nicotine increase obtained from cigarette smoking, this being a shortcoming of the therapy. Here, we demonstrate that α-lactalbumin/polyethylene oxide (ALA/PEO) electrospun nanofibers constitute an efficient oromucosal delivery system for fast-onset nicotine delivery of high relevance for acute dosing NRT applications. In vitro, nicotine-loaded nanofibers showed fast disintegration in water, with a weight loss up to 40% within minutes, and a faster nicotine release (26.1 ± 4.6% after 1 min of incubation) of the loaded nicotine compared to two relevant marketed NRT formulations with a comparable nicotine dose (i.e., 7.9 ± 5.1 and 2.2 ± 0.3% nicotine was released from a lozenge and a sublingual tablet, respectively). Model-fitting of the release data indicated that the release mechanism of nicotine from the hydrophilic nanofibers was possibly governed by more than one type of release phenomena. Remarkably, ex vivo studies using porcine buccal mucosa demonstrated a more efficient permeation of the nicotine released from the nanofibers [flux of 1.06 ± 0.22 nmol/(cm2·min)] compared to when dosing even a ten-fold concentrated nicotine solution [flux of 0.17 ± 0.14 nmol/(cm2·min)]. Moreover, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MS) imaging of ex vivo porcine buccal mucosa exposed to nicotine-loaded nanofibers clearly revealed higher amounts of nicotine throughout the epithelium, as well as in the lamina propria and submucosa of the tissue. Our findings suggest that nicotine-loaded ALA/PEO nanofibers have potential as a mucosal, fast-releasing, and biocompatible delivery system for nicotine, which can overcome the limitations of the currently marketed NRTs.

Symptoms of nicotine toxicity in subjects achieving high cotinine levels during nicotine replacement therapy.

Nicotine replacement therapy (NRT) aids smoking reduction and cessation. Although NRT is effective and safe, some smokers may achieve high nicotine levels. The purpose of this study was to determine the incidence and severity of nicotine-related adverse events in subjects with levels of cotinine, a metabolite of nicotine, that increased by >50% compared with baseline smoking in controlled clinical trials of NRT. Data from participants in randomized, double-blind, controlled trials of various formulations of NRT (Nicorette®), including patch, gum, oral inhaler, sublingual tablet, nasal spray, mouth spray, and combinations, were extracted from a clinical database. Eligible studies were performed between 1989 and 2010. In addition to baseline, at least 1 subsequent plasma or salivary cotinine concentration was measured, and adverse events were recorded simultaneously. Of 28 eligible studies, 24 were smoking cessation studies and 4 were smoking reduction studies. Cotinine levels that increased by >50% above baseline were recorded during treatment in 746 of 7,120 subjects (10.5%). Nausea was reported in 16 subjects (0.2% of the total, upper 99% confidence limit [CL] 0.4%), vomiting in 2 subjects (0.0%, upper 99% CL 0.1%), palpitations in 5 subjects (0.1%, upper 99% CL 0.2%), dizziness in 11 subjects (0.2%; upper 99% CL 0.3%), and headache in 35 subjects (0.5%, upper 99% CL 0.7%). Typical symptoms indicating nicotine overdose together with high cotinine levels were rare during treatment with NRT. These findings support the safety of NRT for smoking cessation or reduction.

Smoking cessation post‐discharge following nicotine replacement therapy use during an inpatient admission

Cigarette smoking remains a health issue despite declining prevalence in Australia. The burden of tobacco-related morbidity affects hospitals, particularly those in lower socioeconomic areas where prevalence is highest. We have shown that nicotine replacement therapy (NRT) use during hospitalization increases motivation to quit post-discharge. We postulated that subjects using the nicotine patch post-discharge, in comparison to the inhaler, would have higher rates of abstinence at 12 months after discharge. The aim was to compare the efficacy of the nicotine patch or inhaler formulation for cessation post-discharge, following use during admission. Post-discharge, subjects chose their preferred formulation (patch or inhaler) based on their experience with NRT during admission. Tailored, medium-intensity support was provided with subsidized NRT during outpatient visits. Subjects were followed for 12 months. Exhaled breath CO confirmed non-smoking. Of 123 subjects enrolled, 37 elected to use the inhaler, 50 the patch and 36 no NRT. At 12 months continuous abstinence rates were 38%, 38% and 25% respectively. This study built upon the 'teachable moment' provided by hospitalization and the inpatient use of NRT, encouraging cessation post-discharge. Both NRT formulations provided similar 12 month cessation rates, and were superior to those achieved by subjects electing not to use NRT. Although the patch was the most popular formulation, the inhaler provided an equally efficacious alternative which addressed other facets of cigarette addiction. Subjects electing not to use NRT were less successful. Continuous abstinence rates were equivalent to community-based studies using NRT. We recommend a similar programme to other hospitals.

Treating heavy smokers in primary care with the nicotine nasal spray: randomized placebo‐controlled trial

Of six established nicotine replacement therapy (NRT) formulations, only the gum and patch have been tested without specialist clinic support in placebo-controlled trials. We aimed to broaden the evidence base by examining if the nicotine nasal spray (NNS) could be effective with only brief support in general practice. Randomized placebo-controlled trial. Twenty-seven English general practices. A total of 761 heavy smokers received brief support and 12 weeks of treatment with NNS (506) or placebo (255). The primary outcome was biochemically verified complete abstinence from smoking throughout weeks 3-12. NNS compared with placebo more than doubled the number who successfully stopped smoking [15.4% versus 6.7%, odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.5-4.4]. Many participants reported minor irritant adverse symptoms. NNS was particularly effective among those who were more highly dependent on nicotine (OR = 6.17, 95% CI = 2.13-17.9). Of those who failed to stop during the first week (417, 54.8%), only one (0.2%) achieved later success. NNS is effective when given in primary care. The benefit was lower than in a specialist clinic but similar to that with the nicotine patch in primary care. Unlike most other NRT formulations, bupropion or varenicline, NNS was especially helpful for more dependent smokers. Continuing treatment of those initially failing was not beneficial. An initial 1-week prescription to those more dependent on nicotine is likely to be the most cost-effective NNS treatment protocol. These results should offer support to the effectiveness of the other NRT formulations untested in this setting.

Smoking Cessation–Recent Advances

Smoking continues to be a major contributor to the burden of disease across the world although there has been a decrease in some developed countries such as USA and Australia. In countries of South-East Asia with a high prevalence of smoking, the incidence of tobacco-related diseases will continue to increase. We reviewed the literature in relation to the pharmacology of nicotine, the measures used to determine the efficacy of anti-smoking therapies, and the randomised controlled trials and systematic reviews of pharmacotherapies published between 2004 and 2010. We focused primarily on the three first line therapies that are currently available: nicotine replacement therapy (NRT), bupropion and varenicline. Randomised controlled trials and meta-analyses have demonstrated that single therapy with either NRT, bupropion or varenicline are all more effective than placebo for smoking cessation. Abstinence rates for monotherapies varies from 13.3% to 19% for NRT compared to 7.5% to 14% for placebo, 19% to 19.7% for bupropion versus 10.9% to 11% for placebo and 25.5% to 25.6% for varenicline versus 11.2% to 14.8% for placebo. Of current therapies varenicline appears to be more effective at achieving abstinence. Some combination therapies with one or two formulations of NRT or NRT plus bupropion have demonstrated superior results to monotherapy. To date there are no randomised controlled trials of varenicline in combination with NRT or bupropion. Further studies are required to address the uncertainty that exists on the most appropriate duration of therapy as well as the effectiveness and safety of combination pharmacotherapy. Post-marketing surveillance continues to play an important role in monitoring the adverse effects events associated with these therapies.

Current approaches to pharmacotherapy for smoking cessation

It is well established that smoking is the primary preventable cause of disease and death in the United States and that it is responsible for a wide range of negative health consequences, including but not limited to respiratory disease. According to the US Public Health Service, all patients attempting to quit smoking should be encouraged to use one or more effective pharmacotherapy agents for cessation except in the presence of special circumstances or in populations for which there is insufficient evidence of effectiveness (pregnant women, smokeless tobacco users, light smokers and adolescents). These medications are most effective when coupled with behavioral counseling interventions. This review article provides an overview of comprehensive (the 5 A's framework: Ask, Advise, Assess, Assist, Arrange) and brief (Ask, Advise, Refer) interventions for assisting patients with quitting, and a more detailed review of the seven first-line pharmacological agents for smoking cessation (nicotine replacement therapy formulations, bupropion SR and varenicline) and combination therapy regimens. This information will facilitate respiratory therapists in addressing the most important risk factor for pulmonary disease in the patient population that they serve.

Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals

BackgroundNicotine replacement therapy (NRT) is the most common form of smoking cessation pharmacotherapy and has proven efficacy for the treatment of tobacco dependence. Although expectations of mild adverse effects have been observed to be independent predictors of reduced motivation to use NRT, adverse effects associated with NRT have not been precisely quantified.ObjectiveA systematic review and meta-analysis aimed to identify all randomized clinical trials (RCTs) of NRT versus inert controls and all observational studies to determine the magnitude of reported adverse effects with NRT.MethodsSearches of 10 electronic databases from inception to November 2009 were conducted. Study selection and data extraction were carried out independently in duplicate. RCTs were pooled using a random effects method with Odds Ratio [OR] as the effect measure, while proportions were pooled from observational studies. A meta-regression analysis was applied to examine whether the nicotine patch is associated with different adverse effects from those common to orally administered NRT.ResultsNinety-two RCTs involving 32,185 participants and 28 observational studies involving 145, 205 participants were identified. Pooled RCT evidence of varying NRT formulations found an increased risk of heart palpitations and chest pains (OR 2.06, 95% Confidence Interval [CI] 1.51-2.82, P < 0.001); nausea and vomiting (OR 1.67, 95% CI 1.37-2.04, P < 0.001); gastrointestinal complaints (OR 1.54, 95% CI, 1.25-1.89, P < 0.001); and insomnia (OR 1.42, 95% CI, 1.21-1.66, P < 0.001). Pooled evidence specific to the NRT patch found an increase in skin irritations (OR 2.80, 95% CO, 2.28-3.24, P < 0.001). Orally administered NRT was associated with mouth and throat soreness (OR 1.87, 95% CI, 1.36-2.57, P < 0.001); mouth ulcers (OR 1.49, 95% CI, 1.05-2.20, P < 0.001); hiccoughs (OR 7.68, 95% CI, 4.59-12.85, P < 0.001) and coughing (OR 2.89, 95% CI, 1.92-4.33, P < 0.001). There was no statistically significant increase in anxiety or depressive symptoms associated with NRT use. Non-comparative observational studies demonstrated the prevalence of these events in a broad population.ConclusionThe use of NRT is associated with a variety of side effects. In addition to counseling and medical monitoring, clinicians should inform patients of potential side effects which are associated with the use of NRT for the treatment of tobacco dependence.

A Nicotine Mouth Spray for Smoking Cessation: A Pilot Study of Preference, Safety and Efficacy

Background: Various formulations of nicotine replacement therapy are commercially available. Objectives: It was the aim of this study to test preference, safety and efficacy of a new nicotine mouth spray (1 mg/actuation; NicoNovum). Methods: One hundred healthy smokers wanting to quit (mean age 43.1 ± 11.2 years) were included. They were given the mouth spray, as well as 2-mg nicotine gums and nicotine oral inhalers to try out for 1 week. Subsequently, all participants were randomized into 3 groups – mouth spray (n = 50), gum (n = 25) and inhaler (n = 25) – and treated for 3 months. Results: Fifty-four of the hundred smokers preferred the spray, compared with 28 and 18 who preferred the gum and inhaler, respectively (p < 0.01 for spray vs. both the gum and inhaler). At 6 months, the sustained abstinence rates were 8 (16%), 5 (20%) and 2 (8%) for the mouth spray, gum and inhaler, respectively (p values = n.s.). Adverse effects (AEs) were mostly drug-related local symptoms, most frequently reported at the end of the tryout period: out of 106 drug-related AEs, 90 were due to the spray, 11 and 5 to the inhaler and gum, respectively. The three most frequent AEs were almost exclusively caused by the spray: burning of the tongue/throat reported by 35, nausea by 18, and hiccup by 16 participants. Conclusions: Participants preferred the mouth spray over the gum and inhaler, but its use was coupled with a high rate of local AEs. The efficacy of the mouth spray seemed comparable with the one obtained by the gum and inhaler. Further studies are necessary to show whether a reduction in the dose per actuation to about 0.5 mg would result in less side effects, which in turn might yield higher long-term drug compliance and possibly higher success rates than the ones achieved with other forms of nicotine replacement therapy.

Nicotine Replacement Therapy for Tobacco Use Cessation

Tobacco use is the leading preventable cause of morbidity and mortality in the United States. Nicotine replacement therapy (NRT) remains a first-line pharmacotherapy for tobacco and smoking cessation. Five formulations of NRT for delivery of nicotine were approved by the US Food and Drug Administration between 1984 and 2002, including 3 available without prescription from pharmacies. A table was created as a tool for pharmacists to counsel patients about the NRT products. The table summarizes available doses, dosing regimen and schedules, administration technique, contraindications, and adverse effects.

Smoking Cessation Therapy in Pregnancy

Objective: To determine the safety and efficacy of pharmacologic therapy for smoking cessation in pregnancy by conducting a review of current literature, focusing on controlled clinical trials. Data Sources: A MEDLINE search (1966–May 2006) of English-language, human clinical trials was conducted. Key search terms included nicotine, nicotine replacement therapy, bupropion, smoking cessation, and pregnancy. In addition, relevant articles were cross-referenced to screen for additional information. Study Selection/Data Extraction: Studies were chosen for further review if they were randomized, controlled, long-term evaluations of the safety and/or efficacy of pharmacologic therapy for smoking cessation in pregnancy. A total of 5 trials met the criteria for review. Data Synthesis: Controlled clinical trials of smoking cessation therapy in pregnant women are limited. Three trials have examined the long-term use of nicotine replacement products. Neither of the 2 placebo-controlled trials found a statistically significant difference in abstinence rates between women receiving transdermal nicotine replacement therapy (NRT) and placebo. However, transdermal nicotine products appeared to be safe in this population. No long-term studies have evaluated use of other nicotine replacement products in pregnant women. Bupropion has demonstrated efficacy in smoking cessation in pregnancy, but the data are limited. Conclusions: Transdermal NRT appears to be safe in pregnant women, although its efficacy is unclear. Information on other NRT formulations in pregnancy is unavailable. Bupropion may be a nonnicotine alternative for smoking cessation in pregnancy, but data are currently incomplete. Further studies are needed to determine the ideal population for treatment, the timing of initiation, appropriate monitoring, and the optimal length of therapy.

What can we do in secondary prevention of cigarette smoking?

Cigarette smoking kills about six million smokers per year worldwide, and the cigarette has become a symbol of threat to mankind, particularly in industrialized countries. Tobacco smoking causes signs of addiction due to nicotine, but it is the inhaled and exhaled smoke that causes damage to health if cigarette smoking is continued for one or more decades. It is very difficult to attain a high efficacy of stopping smoking using methods of primary prevention in children and young adults. Secondary and tertiary prevention methods use medical and psychological support to the smoker (behavioural and aversion therapy) as well as medical advice in combination with drugs such as nicotine replacement or bupropion. Using a combination of these methods can increase effectiveness up to 45%. Use of nicotine replacement therapy (NRT) in combination with medical advice is the method of smoking cessation recommended by the World Health Organization. Bupropion causes several severe side effects which are not observed with NRT. This article reviews various NRT formulations, including chewing gum, patch, nasal spray, tablet and inhaler, and our experience of using NRT in medical practice, such as adverse events, withdrawal symptoms and the efficacy of NRT in patients with coronary heart disease (angina pectoris, cardiac arrhythmias, etc.), are briefly mentioned. Overall, we need greater efforts in practising primary and secondary prevention among current and future physicians to solve the health problems associated with tobacco use in many nations.

Risks and benefits of nicotine to aid smoking cessation in pregnancy.

Cigarette smoking during pregnancy is the single largest modifiable risk for pregnancy-related morbidity and mortality in the US. Addiction to nicotine prevents many pregnant women who wish to quit smoking from doing so. The safety and efficacy of nicotine replacement therapy (NRT) for smoking cessation during pregnancy have not been well studied. Nicotine is classified by the US Food and Drug Administration as a Pregnancy Category D drug. Animal studies indicate that nicotine adversely affects the developing fetal CNS, and nicotine effects on the brain may be involved in the pathophysiology of sudden infant death syndrome (SIDS). It has been assumed that the cardiovascular effects of nicotine resulting in reduced blood flow to the placenta (uteroplacental insufficiency) is the predominant mechanism of the reproductive toxicity of cigarette smoking during pregnancy. Short term high doses of nicotine in pregnant animals do adversely affect the maternal and fetal cardiovascular systems. However, studies of the acute effects of NRT in pregnant humans indicate that nicotine alone has minimal effects upon the maternal and fetal cardiovascular systems. Cigarette smoking delivers thousands of chemicals, some of which are well documented reproductive toxins (e.g. carbon monoxide and lead). A myriad of cellular and molecular biological abnormalities have been documented in placentas, fetuses, and newborns of pregnant women who smoke. The cumulative abnormalities produced by the various toxins in cigarette smoke are probably responsible for the numerous adverse reproductive outcomes associated with smoking. It is doubtful that the reproductive toxicity of cigarette smoking is primarily related to nicotine. We recommend the following. Efficacy trials of NRT as adjunctive therapy for smoking cessation during pregnancy should be conducted. The initial dose of nicotine in NRT should be similar to the dose of nicotine that the pregnant woman received from smoking. Intermittent-use formulations of NRT (gum, spray, inhaler) are preferred because the total dose of nicotine delivered to the fetus will be less than with continuous-use formulations (transdermal patch). A national registry for NRT use during pregnancy should be created to prospectively collect obstetrical outcome data from NRT efficacy trials and from individual use. The goal of this registry would be to determine the safety of NRT use during pregnancy, especially with respect to uncommon outcomes such as placental abruption. Finally, our review of the data indicate that minimal amounts of nicotine are excreted into breast milk and that NRT can be safely used by breast-feeding mothers.