Nicotine replacement therapy (NRT) may be a helpful tool if you're trying to While some people may experience side effects, others may not. Although expectations of mild adverse effects have been observed to be independent predictors of reduced motivation to use NRT, adverse. Any side effects are usually mild. But if they're particularly troublesome, contact your GP as the dose or type of NRT may need to be changed.
Side Effects NRT
Available research suggests that smokers are less motivated to use NRT if they expect that it will cause mild adverse effects[ 7 ]. An understanding of the nature and likelihood of the most common side effects may help clinicians communicate to patients the benefits and risks associated with their use of NRT.
This information may also improve selection of specific delivery mechanisms based upon patient history, which may improve treatment adherence. While RCTs provide strong information on causation of adverse events, observational studies may report on associations or hypotheses about more rare events.
To determine the frequency and incidence of adverse events associated with NRT, we conducted a systematic review and meta-analysis of RCT's and observational studies of NRT in any delivery formulation. Our clinical question is, in patients receiving NRT for smoking cessation, compared to inert controls, what is the incidence of adverse events and what are those adverse events?
We included RCTs of any duration beyond 4 weeks. We chose 4 weeks to include the timeframe of maximum nicotine withdrawal symptoms so that adverse events may be differentiated from withdrawal symptoms[ 8 ]. We additionally sought out observational studies to examine the proportion of events occurring[ 9 ]. We evaluated adverse effects reported at any point in the duration of the studies.
We included any form of NRT delivery i. We did not examine efficacy in this analysis. We excluded post-hoc analyses, maintenance therapy, or relapse prevention studies. In consultation with a medical librarian, we established a search strategy. We searched independently, in duplicate, the following 10 databases from inception to November 20, Given that observational studies are poorly indexed in many databases, we also searched databases that include the full text of journals ScienceDirect , and Ingenta , including articles in full text from approximately journals since [ 10 ].
In addition, we searched the bibliographies of published systematic reviews and health technology assessments[ 4 - 6 , 11 - 16 ]. Searches were not limited by language, sex or age. Two investigators EM, PW working independently, in duplicate, scanned all abstracts and obtained the full text reports of records indicating that the study was either an RCT or observational study evaluating NRT on the outcomes of interest.
After obtaining full reports of the candidate studies either in full peer-reviewed publication or press article the same reviewers independently assessed eligibility via full text review. Two reviewers EM, PW conducted data extraction independently using a standardized pre-piloted form.
Reviewers collected information about the NRT intervention tested, the population studied age, sex, underlying conditions , treatment dosages and dosing schedules, the specific measurement of abstinence prolonged or point-prevalence , and the methods of biochemical confirmation.
The reviewers extracted data on adverse events characterized by the study authors as physical or mental adverse events. Recognizing that adverse events may include both physical and mental effects concomitantly, we defined physical adverse events as effects confined to physical parts of the body and mental adverse events as symptoms accompanied by psychological conditions.
We characterized serious adverse events as unexpected life-threatening events occurring during the trial period. A priori , we examined the follow life-threatening adverse events: Study quality evaluation included general methodological reporting features including allocation concealment, sequence generation, blinding status, intention-to-treat, and appropriate descriptions of loss to follow-up. In rating quality, failure to report a quality component of study design e.
We entered the data into an electronic database such that duplicate entries existed for each study. When the two entries did not match, we resolved differences through discussion and consensus.
In the absence of an inert control group, we considered randomized NRT dosing studies to be observational studies and collected data on proportion of combined events. For cohort studies, we additionally calculated events as proportions of events. Given that zero events in one treatment arm prevents a useful ratio from being developed, in circumstances of zero outcome events in one arm of a trial, we added 0. We first pooled studies of all NRT interventions versus all controls using the DerSimonian-Laird random effects method[ 19 ], which recognizes and anchors studies as a sample of all potential studies, and incorporates an additional between-study component to the estimate of variability[ 20 ].
We calculated the I 2 statistic for each analysis as a measure of the proportion of the overall variation that is attributable to between-study heterogeneity[ 21 ]. Given that we are examining adverse events, interpreting heterogeneity estimates can be challenging as even pooled analysis with large heterogeneity may provide important insights into the likelihood of events[ 9 ].
We then calculated the residual heterogeneity and present it as the residual I 2. While several methods of pooling proportions exist, the Freeman-Tukey method works well with both fixed and random effects meta-analysis and truncates at zero[ 22 ].
This is a variance-stabilizing transformation that removes the dependence of the variance on the mean of the transformed proportion ie.
Assessing heterogeneity in pooled proportions may be misleading[ 23 , 24 ], therefore we report the I 2 value, as this measure is less affected by the number of studies as the more commonly used I 2.
The square root of this number i. As with the RCT analysis, we applied a random-effects meta-analysis. Analyses were conducted using StatsDirect version 2. Ninety-two studies[ 26 - ] were RCTs involving 32, participants and 28[ 56 , 75 , 93 , , - ] were considered as observational studies involving , participants.
Duration of treatment ranged from 1 to 24 months, with varying levels of dosages for each form of NRT. Seventy-four RCTs[ 26 - 31 , 33 - 41 , 43 - 65 , 67 - 70 , 72 - 80 , 82 - 88 , 92 , 93 , 95 , 96 , 99 - , , - , - ] were conducted in healthy adult populations. An additional 6[ 36 , 66 , 89 , 97 , , ] were conducted among populations with medical and psychiatric co-morbidities.
Seventeen observational studies[ 75 , 93 , , - , - , - , ] used the nicotine patch; 2 [ , ]used a nasal spray, 1[ ] used the nicotine gum; and 8 used a combination of NRTs. Duration of treatment ranged from 4 to 26 weeks, with varying levels of dosages for each form of NRT.
Sixteen[ 56 , 75 , 93 , , , , , - , , , - , ] of the observational studies were conducted among healthy adult populations, 7 [ , , , , - ]among mixed healthy and unhealthy adult populations, 2[ , ] among adult populations with medical co-morbidities, 2[ , ] among adolescent populations, and 1[ ] among an older adult population.
Studies reported methodological issues variably. To confirm smoking abstinence, eighty four[ 26 - 28 , 30 - 46 , 48 , 66 , , - , 65 , 67 , 69 - 80 , 83 - 98 , - , , , - , ] studies used exhaled carbon monoxide CO ; 16[ 34 , 35 , 37 , 41 , 45 , 55 , 57 , 62 , 63 , 79 , 81 , 90 , 94 , , , ] used salivary cotinine; 5[ 29 , 36 , 47 , 60 , ] used serum cotinine; and 2[ 99 , ] used urinary cotinine.
No studies required participants to pay for the NRT. All observational studies are considered as non-comparative single-arm studies reporting prevalence of the adverse events in the community. We evaluated all forms of NRT for adverse events. Applying meta-regression, both the nicotine patch and orally administered NRT were associated with an increased risk OR 1.
There was a statistically significant increased risk of nausea or vomiting based on a pooled analysis of 31 RCTs OR 1. However, meta-regression showed that studies focusing on the nicotine patch were associated with a decreased risk OR, 0. A significantly heightened risk of oral adverse events including mouth and throat soreness was identified in a meta-analysis of 23 RCTs OR 1. Nicotine patch was associated with a statistically significant risk of skin irritation in an analysis of 32 RCTs OR 2.
However, nicotine patch was not associated with increased incidence of urticaria OR 1. An increased risk of insomnia was associated with the nicotine patch OR 1. Twenty five RCTs[ 47 , 54 , 71 , 73 - 77 , 79 , 80 , 82 , 84 , 85 , 91 - 93 , 97 , 98 , , , , , , , ] reported serious adverse events occurring, but none were statistically significant data not shown.
Eight studies[ 73 , 82 , 85 , 93 , 97 , , , ] reported on mortality by groups and did not find a significant association between NRT and controls.
One study[ ] of pregnant women found two cases of spontaneous abortions in the NRT group and one study[ 76 ] reported a case of spinal meningitis in the NRT group. We used meta-regression to explain heterogeneity. We were able to explain a large amount of heterogeneity examining the covariate of skin patch vs. We found that duration of study B coefficient 0. We also found heterogeneity in our analysis of insomnia that was explained by the duration of the trials. Longer duration trials had reduced rates of insomnia B coefficient Summary pooled estimates of adverse events reported in observational studies.
No studies compared NRT with an inert control group, thus we present the proportions of event occurrence, interpreted as prevalence. As our analysis uses pooled proportions, all analyses found an estimate of risk, but varied in magnitude. The prevalence of heart palpitations and chest pains were reported sporadically and amounted to 3. Coughing was reported as a prevalence of 8. In keeping with the RCT evidence indicating significant increases in specific events, the pooled observational evidence reported the nausea and vomiting prevalence to be 8.
The prevalence of indigestion and other gastrointestinal complaints was 3. Hiccoughs were a very common complaint in the RCT evidence, but poorly reported in the observational studies with a prevalence of just 2. With orally administered NRT, the prevalence of both mouth and throat soreness was 5.
For psychological complaints, the prevalence of insomnia was Anxiety and depression were more rarely reported 2. Dizziness was a more common complaint, with a prevalence of 7. Headaches were commonly reported 9. The prevalence of skin irritations associated with nicotine patch was reported as Serious adverse events were poorly reported in the observational studies. However, one study reported on a case of transient visual field impairment; one right-hemisphere stroke; one myocardial infraction; and one urticarial reaction from skin patch with symptoms of angiodema.
This review found that NRT is associated with an increased risk of gastrointestinal complaints and insomnia. There was also an observed increased risk of skin irritation with the nicotine patch and oropharyngeal complaints with orally administered NRT. Although NRT was associated with an increased risk of heart palpitations, the review did not observe an increased incident of heart attack or death. With the exception of insomnia, NRT does not appear to be associated with serious adverse psychiatric effects.
The reviewers actively sought serious adverse events. The most serious adverse event consistently reported in both RCTs and observational studies were heart palpitations and chest pains OR 2. NRT has been implicated in reports of atrial fibrillation and myocardial infarction among patients with risk factors[ - ].
Several possible explanations for this exist. First, among patients using NRT who continue to smoke, high serum concentrations may stimulate the sympathetic nervous system, so increasing blood pressure, stroke volume and cardiac output[ ].
Second, previous and current smokers may have established cardiovascular disease. Patients with unstable coronary syndrome, a common manifestation of coronary artery disease, may have unrecognized recent plaque ruptures including coronary vasoconstriction and increased strain placed on the heart due to tachycardia and hypertension[ ]. Unofficial guidelines[ ] caution the continued use of NRT in patients with known cardiovascular disease in the absence of a physician.
They recommend that patients be warned of these risks and counseled to desist smoking and arrange intensive behavioral support[ ]. In our analysis, we did not observe an increased risk for myocardial infarction or death from NRT.
Almost all studies demonstrated localized irritation related to NRT use, skin irritation with the use of NRT patch and mouth soreness and ulcerations with orally administered NRT. It has previously been understood that mouth lesions are associated with smoking cessation and not NRT[ ].
However, this review found a significantly increased risk of mouth ulcers with orally administered NRT users compared to inert controls who had ceased smoking. In order to prevent relapse due to treatment discontinuation, strategies should be developed to assist patients unable to continue oral administered NRT due to mouth ulcers such as increasing the nicotine patch dose, using the nicotine nasal spray, or switching to an alternative form of smoking cessation pharmacotherapy such as buproprion or varenicline.
Psychological adverse events, particularly suicidal ideation, are a major concern in patients initiating smoking cessation[ ]. We found only one large retrospective observational study that discussed this topic and reported no significant difference in fatal and non-fatal self-harm associated with NRT compared to other frequently used pharmacotherapies, bupropion HR 1.
A criticism of smoking cessation trials has been that they infrequently enroll participants with psychological difficulties, thus making generalizable statements about their safety difficult[ ].
The present review found that 56 RCTs specifically excluded participants with mental disorders. Only two RCTs targeting participants with concomitant psychological difficulties, specifically alcoholism and depression, were identified[ 89 , 92 ]. In these studies, the risk of insomnia was higher among those taking NRT, compared to controls, OR 1. Sleep disturbance can significantly worsen psychological distress and mental illness and impair quality of life[ ]. Therefore, clinicians should remain vigilant about NRT-related sleep disturbance among patients with a history of psychiatric illness.
An important issue to examine when describing adverse events from smoking cessation therapies is whether the adverse events are related to a pharmacotherapy or whether they are related to tobacco withdrawal[ ]. For example, insomnia and sleep disturbances could be related to tobacco abstinence. One way to assess this affect would be to compare side effects in those that have quit smoking in both groups. However, since individuals that quit smoking may differ from those that continue, this analysis would remove the benefits of randomization and introduce bias.
Our review has several limitations. These include limitations of the primary studies themselves as well as those associated with combining results across potentially heterogeneous studies or populations. The main limitation of the primary studies is the mechanism by which adverse events are recorded. In the majority of instances this would be through passive reporting and therefore be susceptible to the underreporting associated with such techniques.
The majority of our analyses had low or moderate heterogeneity, although a few had high levels of heterogeneity. Pooling proportions always results in large estimates of heterogeneity and statistical techniques do not yet exist to interpret the extent of real between-study heterogeneity[ ]. The review identified some discrepancies between observational studies and RCTs in terms of adverse event reporting.
Possible explanations of this include the use of a control group in the RCTs, which diminishes the impact of adverse events that are, in fact, unrelated to the intervention. Studies included in our review varied in the duration of treatment phase. While we would expect most adverse events to occur during the treatment phase receiving active NRT , it is possible that some adverse events occurred during follow-up and we cannot adequately explain their pathological processes.
There is emerging evidence that stopping smoking prior to any type of surgery decreases the potential for surgical complications[ ]. All pharmacotherapies used for smoking cessation demonstrate adverse events, albeit in differing conditions and severity[ 4 ]. However, given the cardiovascular concerns discussed above, and the fact that cardiovascular events are increased during the perioperative period[ ], it is reasonable to consider other behavioral or pharmacotherapies for at-risk patients undergoing major surgeries.
This review demonstrates that NRT is associated with adverse effects that may be discomforting for the patient but are not life-threatening. Given the long-term benefits of smoking cessation over continued smoking, concern about NRT related adverse events should be balanced against the benefits of cessation.
Clinicians should monitor for side effects that may worsen underlying conditions, such as insomnia in patients with depression, and consider additional or alternative treatments. Given the benefits of smoking cessation and the important role of NRT in achieving this goal, efforts should be made to counsel patients on the most common side effects and strategies should be developed to deal with them.
Edward Mills and Ping Wu were paid consultants to Pfizer in connection with the development of this manuscript. Kumanan Wilson and Job O. Ebbert received no compensation. Ian Lockhart is an employee of Pfizer. EM, PW carried out searches and data abstraction.
All authors read and approved the final draft. Characteristics of included RCTs. National Center for Biotechnology Information , U. Journal List Tob Induc Dis v. Published online Jul Author information Article notes Copyright and License information Disclaimer.
Received Jan 21; Accepted Jul This article has been cited by other articles in PMC. Abstract Background Nicotine replacement therapy NRT is the most common form of smoking cessation pharmacotherapy and has proven efficacy for the treatment of tobacco dependence.
Objective A 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.
Methods Searches of 10 electronic databases from inception to November were conducted. Results Ninety-two RCTs involving 32, participants and 28 observational studies involving , participants were identified.
Conclusion The use of NRT is associated with a variety of side effects. Introduction Smoking is the leading cause of preventable mortality world wide[ 1 ]. Search strategy In consultation with a medical librarian, we established a search strategy. Study selection Two investigators EM, PW working independently, in duplicate, scanned all abstracts and obtained the full text reports of records indicating that the study was either an RCT or observational study evaluating NRT on the outcomes of interest.
Data collection Two reviewers EM, PW conducted data extraction independently using a standardized pre-piloted form. Open in a separate window. Table 1 Characteristics of nicotine replacement therapy NRT observational studies. Table 2 Adverse events reported in RCTs. Cardiovascular and respiratory A pooled analysis of 12 RCTs found a statistically significant increased risk for heart palpitations and chest pains associated with NRT OR 2.
Gastrointestinal There was a statistically significant increased risk of nausea or vomiting based on a pooled analysis of 31 RCTs OR 1. Oral A significantly heightened risk of oral adverse events including mouth and throat soreness was identified in a meta-analysis of 23 RCTs OR 1.
Dermatological Nicotine patch was associated with a statistically significant risk of skin irritation in an analysis of 32 RCTs OR 2. Psychological An increased risk of insomnia was associated with the nicotine patch OR 1. Serious Adverse Events Twenty five RCTs[ 47 , 54 , 71 , 73 - 77 , 79 , 80 , 82 , 84 , 85 , 91 - 93 , 97 , 98 , , , , , , , ] reported serious adverse events occurring, but none were statistically significant data not shown.
Explanations of heterogeneity We used meta-regression to explain heterogeneity. Table 3 Adverse events reported in observational studies. Cardiovascular or respiratory The prevalence of heart palpitations and chest pains were reported sporadically and amounted to 3. Gastrointestinal In keeping with the RCT evidence indicating significant increases in specific events, the pooled observational evidence reported the nausea and vomiting prevalence to be 8.
Oral With orally administered NRT, the prevalence of both mouth and throat soreness was 5. Psychological and neurological For psychological complaints, the prevalence of insomnia was Dermatological The prevalence of skin irritations associated with nicotine patch was reported as Serious adverse events Serious adverse events were poorly reported in the observational studies.
Discussion Principal Findings This review found that NRT is associated with an increased risk of gastrointestinal complaints and insomnia. Limitations Our review has several limitations. Conclusions This review demonstrates that NRT is associated with adverse effects that may be discomforting for the patient but are not life-threatening. Competing interests Pfizer Ltd. Supplementary Material Additional file 1: Mortality from smoking worldwide.
Mortality in relation to smoking: Effectiveness of smoking cessation therapies: Smoking cessation services in primary care, pharmacies, local authorities and workplaces, particularly for manual working groups, pregnant women and hard to reach communities. Public Health Guidance PH Pharmacotherapies for smoking cessation: Understanding why smokers do not want to use nicotine dependence medications to stop smoking: Effects of abstinence from tobacco: Challenges in systematic reviews that assess treatment harms.
Searching for observational studies: A case study in depression and coronary heart disease. BMC medical research methodology. How compelling is the evidence? The use of nicotine replacement therapy in pregnancy is preferable to the continuation of smoking, but should be used only if smoking cessation without nicotine replacement fails. Intermittent therapy is preferable to patches but avoid liquorice-flavoured nicotine products.
Patches are useful, however, if the patient is experiencing pregnancy-related nausea and vomiting. If patches are used, they should be removed before bed. Nicotine is present in milk; however, the amount to which the infant is exposed is small and less hazardous than second-hand smoke. Intermittent therapy is preferred. Acidic beverages, such as coffee or fruit juice, may decrease the absorption of nicotine through the buccal mucosa and should be avoided for 15 minutes before the use of oral nicotine replacement therapy.
Patches should be applied on waking to dry, non-hairy skin on the hip, trunk, or upper arm and held in position for 10—20 seconds to ensure adhesion; place next patch on a different area and avoid using the same site for several days. Initially 1 spray should be used in both nostrils but when withdrawing from therapy, the dose can be gradually reduced to 1 spray in 1 nostril. The oral spray should be released into the mouth, holding the spray as close to the mouth as possible and avoiding the lips.
The patient should not inhale while spraying and avoid swallowing for a few seconds after use. If using the oral spray for the first time, or if unit not used for 2 or more days, prime the unit before administration. Slowly allow each lozenge to dissolve in the mouth; periodically move the lozenge from one side of the mouth to the other.
Lozenges last for 10—30 minutes, depending on their size. Insert the cartridge into the device and draw in air through the mouthpiece; each session can last for approximately 5 minutes. The amount of nicotine from 1 puff of the cartridge is less than that from a cigarette, therefore it is necessary to inhale more often than when smoking a cigarette. Chew the gum until the taste becomes strong, then rest it between the cheek and gum; when the taste starts to fade, repeat this process.
One piece of gum lasts for approximately 30 minutes. Flavours of chewing gum and lozenges may include mint, freshfruit, freshmint, icy white, or cherry. Patient or carers should be given advice on how to administer nicotine chewing gum, inhalators, lozenges, sublingual tablets, oral spray, nasal spray and patches.
Other drugs classified as nicotinic receptor agonists. By inhalation using inhalator For Adult As required, the cartridges can be used when the urge to smoke occurs or to prevent cravings, individuals should not exceed 12 cartridges of the mg strength daily, or 6 cartridges of the mg strength daily. By transdermal application using patches For Adult Individuals who smoke more than 10 cigarettes daily should apply a high-strength patch daily for 6—8 weeks, followed by the medium-strength patch for 2 weeks, and then the low-strength patch for the final 2 weeks; individuals who smoke fewer than 10 cigarettes daily can usually start with the medium-strength patch for 6—8 weeks, followed by the low-strength patch for 2—4 weeks; a slower titration schedule can be used in individuals who are not ready to quit but want to reduce cigarette consumption before a quit attempt; if abstinence is not achieved, or if withdrawal symptoms are experienced, the strength of the patch used should be maintained or increased until the patient is stabilised; individuals using the high-strength patch who experience excessive side-effects, that do not resolve within a few days, should change to a medium-strength patch for the remainder of the initial period and then use the low-strength patch for 2—4 weeks.
Nicotine replacement therapy
6 days ago Easy-to-read medicine information about nicotine replacement therapy (NRT) – what it is, how to use NRT safely and possible side effects. Nicotine Replacement Therapy (NRT) provides the nicotine without the other harmful Possible side effects of the nicotine patch include. Nicorette Patch: This medication belongs to a family of medications known as nicotine replacement therapies. It is used to help people over 18 years of age quit .