Nicotine Replacement Therapy

Mechanism of Action

Nicotine, classified as an alkaloid, is exclusively synthesized within tobacco plants. Structurally, nicotine is a tertiary amine featuring pyrrolidine and pyridine rings. Notably, the molecule exhibits selective binding to nicotinic-cholinergic receptors located in multiple regions of the body, including the brain, neuromuscular junctions, adrenal medulla, and ganglia. Nicotine inhalation through smoking cigarettes prompts its diffusion across lung tissue and subsequently into the systemic circulation and eventual passage into the brain. 

Nicotine influences the reward center located within the limbic system and exerts a stimulating impact on the cortex. This stimulation triggers dopamine release in key regions such as the frontal cortex, mesolimbic area, and corpus striatum. This surge of dopamine contributes to creating a pleasurable and rewarding experience in the brain. A recent study proposed that nicotine can modulate the activity of monoamine oxidase enzymes, namely MAO-A and MAO-B. These enzymes are involved in the degradation of dopamine, a neurotransmitter that mainly contributes to addiction.[6] NRTs are designed to replicate the nicotine response typically experienced through smoking, thereby helping individuals manage cravings and withdrawal symptoms. Elevated doses of NRTs tend to elicit a greater sense of reward, whereas lower nicotine doses produce more of a stimulating effect.[7][8]

Administration

Available Dosage Forms

The majority of NRT formulations are readily accessible without requiring a doctor's prescription and can even be obtained over the counter. Patients are advised to adhere to the specific instructions provided for each form of NRT to ensure effective usage and maximize the benefits of the therapy. Despite the availability of numerous brands and formulations of NRT, research indicates no significant variation in effectiveness among different types of NRT.

Although specific studies suggest that there may not be an advantage to using NRT for more than 8 weeks, other research has indicated that extending the treatment duration with nicotine patches could lead to a higher rate of successful smoking cessation. The initial dosing of NRT usually depends on the individual's daily cigarette consumption, with heavier smokers often requiring a higher strength or dose of nicotine therapy. Clinicians can prescribe different forms of NRT to individuals to aid in smoking cessation.[9]

Adult Dosage

The dosing information of various forms of NRT encompasses a wide range and should be viewed as a general guideline rather than a definitive recommendation. To accurately determine the appropriate nicotine dosing and titration for a patient, it is essential to consider multiple factors. These factors include the time elapsed between waking up and the first cigarette intake by a patient, as well as the number of cigarettes consumed per day by the patient.

For precise dosage information on various forms of NRTs listed below, it is recommended to adhere to the dosing instructions provided on the NRT packaging for accurate and appropriate usage of the therapy.

Nicotine transdermal patches: These patches are available in various brands, offering a range of dosages. Some patches are formulated with 5 to 52.5 mg dosages for once-daily application. The selection of higher doses is typically recommended for individuals who are heavier smokers. Certain patches are specifically designed to be worn for 16 hours daily and are available in dosages ranging from 5 to 25 mg. For optimal results, it is essential to apply the patches to a clean, hairless, and dry area of the upper body or arm. The patches should be firmly pressed onto the skin for 10 seconds to ensure proper adhesion, and they must be applied to a new location each time they are used. The recommended treatment duration for the patch is typically 8 to 10 weeks.

The highest dose of NRT is initiated for patients weighing over 45 kg and who smoke more than 10 cigarettes daily. Nicotine transdermal patches are regarded as the simplest NRT options, often leading to better patient compliance. This form of NRT offers continuous nicotine delivery, distinguishing it from other NRT products. The commonly used nicotine patch strengths include 21 mg, 14 mg, and 7 mg. For patients who smoke more than 10 cigarettes daily, a recommended approach is to initiate NRT with a 21 mg nicotine patch daily and gradually tapering down to a 14 mg patch and eventually to a 7 mg patch. For patients who smoke fewer than 10 cigarettes daily, a typical prescription involves using an initial 14 mg nicotine patch daily and gradually tapering down to a 7 mg patch.

Nicotine gum: This type of NRT is offered in varying doses, including 2 mg and 4 mg strengths. Nicotine gum is frequently utilized as a short-acting NRT. To use it effectively, a patient should chew the gum slowly until a tingling sensation emerges in their mouth and continue chewing it until the tingling sensation diminishes. Individuals are advised to chew the nicotine gum when their urge to smoke arises. For optimal results, the recommended dosage is 8 to 12 pieces of nicotine gum daily. Individuals should refrain from consuming acidic beverages, such as coffee or carbonated drinks, while using nicotine gums to improve absorption.

Nicotine lozenges: These lozenges are offered in doses of 1 mg, 1.5 mg, 2 mg, and 4 mg. To experience the full benefits of these lozenges, it is recommended to allow them to dissolve slowly in the mouth for approximately 20 to 30 minutes rather than chewing or swallowing them. The recommended usage is 8 to 12 lozenges daily to help manage cravings and withdrawal symptoms.

Nicotine inhalation cartridge: The inhalation cartridge is available in 10 mg strength. To use the inhaler effectively, the cartridge should be inserted into the inhaler and then securely popped into place. The individual using the cartridge should either inhale deeply or take consecutive short puffs through the mouthpiece. This approach addresses both the physical and behavioral components of nicotine dependence. The recommended usage is 6 to 16 cartridges daily.

Nicotine nasal spray: The spray is available at a strength of 0.5 mg per spray. Before using the nicotine nasal spray, patients should clear their nasal passages by blowing their nose. Then, with the head tilted back, the patient can insert the tip of the nasal spray bottle into each nostril and administer 1 spray in each nostril.

Nicotine sublingual tablets: This tablet is provided in a 2 mg dose and is unavailable in the United States. Patients taking nicotine sublingual tablets are advised not to use 2 doses consecutively. In case of a missed dose, they should administer it immediately for proper treatment functioning. Nevertheless, if the time for the next scheduled dose is nearing, patients can opt to skip the missed dose.

Specific Patient Populations

Hepatic impairment: For smokers with moderate liver function impairment, as indicated by a Child-Pugh score of 7, the total clearance of nicotine is reduced by approximately 40% to 50%. Currently, no available data exist regarding the pharmacokinetics of nicotine in smokers with a Child-Pugh score greater than 7. However, it is anticipated that patients with more severe liver impairment would experience even more pronounced effects on nicotine clearance than those with moderately impaired liver function. As a result, clinicians should be cautious and contemplate dose reduction when considering NRT for individuals with advanced liver impairment.

Renal impairment: Nicotine clearance is decreased by approximately 30% in patients with moderate renal impairment and approximately 50% in subjects with severe renal impairment. Given these alterations in clearance rates, clinicians should carefully assess and contemplate dose reduction when considering NRT for patients with renal impairment.

Pregnancy considerations: Nicotine, hydrogen cyanide, and carbon monoxide are the harmful substances in tobacco smoke, which pose severe risks to the developing fetus. Therefore, pregnant individuals should be particularly cautious about exposure to these toxic compounds. Although NRT products do not introduce hydrogen cyanide and carbon monoxide into the body, certain preclinical studies have indicated that nicotine can potentially cause fetal harm. Therefore, healthcare providers strongly recommend discontinuing smoking for pregnant patients through comprehensive behavioral interventions. Furthermore, if NRT is utilized during pregnancy or if a patient becomes pregnant while using NRT, healthcare providers should offer counseling to the patient regarding the potential risks to the fetus, as indicated in the manufacturer's labeling.

The available evidence regarding pharmacotherapy interventions during pregnancy, including NRT, is currently limited and insufficient to provide clear and specific recommendations. According to the United States Preventive Services Task Force (USPSTF), comprehensive behavioral interventions have demonstrated efficacy. Therefore, they are recommended as a preferred approach for supporting pregnant individuals in their efforts to quit smoking.[10]

Breastfeeding considerations: The professional consensus suggests abstaining from smoking and utilizing short-acting NRT right after breastfeeding to minimize nicotine exposure to the infant.[11] When using a 21 mg transdermal nicotine patch, it is observed that the nicotine concentration in breast milk is equivalent to that of smoking around 17 cigarettes daily. When using nicotine spray, maternal plasma nicotine concentrations are only about one-third of what smokers experience. This means that the nicotine levels in maternal milk are also significantly reduced. Certain researchers propose using nicotine replacement products in breastfeeding mothers to mitigate the potential risk to breastfed infants stemming from the inhalation of smoke and toxins present in maternal cigarette smoke. Nicotine can disrupt infant lung development and heighten the risk of sudden infant death syndrome. Given these concerns, experts often advise against using NRT in nursing mothers.[12]

Pediatric patients: The safety and efficacy of nicotine replacement products have not been established for individuals aged 18 or younger. In the case of older adolescents, it is recommended to consider the utilization of NRT only if the potential benefits outweigh the potential risks in this population.

Older patients: When prescribing NRT for older patients, initiating NRT at the lower end of the recommended dose range is prudent. This approach considers the increased likelihood of impaired hepatic, renal, or cardiac function, as well as the presence of comorbid medical conditions often observed in this age group. The limited evidence suggests that NRT can effectively promote smoking cessation among older adults.[13]

Adverse Effects

The known adverse effects of NRT include:

• Gastrointestinal (GI) symptoms such as abdominal pain, dyspepsia, hiccups, diarrhea, nausea, and vomiting.

• Central nervous system symptoms such as headache.

• Cardiovascular system symptoms such as palpitations and hypertension.[14]

• Neuropsychiatric symptoms such as depression, back pain, dizziness, nervousness, drooling, shakiness, cold sweats, hypertension, increased heart rate, and vivid dreams.

• Nose and mouth ulcers and irritation due to the absorption of NRTs through the oral or nasal mucosa. Excess salivation and swelling of the lips, throat, and tongue are the additional adverse effects of nicotine.

• Skin rash or irritation in some individuals due to transdermal patches of NRT. For patients experiencing skin irritation, the application of topical hydrocortisone 1% cream or ointment can provide relief.

• Hiccoughs, GI disturbances, and jaw pain associated with nicotine gum.

• Sore throat, coughing, dry lips, and mouth ulcers due to administering nicotine sublingual tablets. The nicotine nasal spray has adverse drug reactions such as a runny nose and nasal irritation.[15]

• Throat irritation, oral soreness, gastric reflux, and vomiting due to administering oral NRT products, as concluded in a recent meta-analysis.[16]

Patients are advised to promptly notify their healthcare providers if they experience any of the aforementioned adverse effects to ensure the safety and well-being of individuals undergoing NRT. Furthermore, healthcare providers should provide counseling to patients, emphasizing that all forms of nicotine have addictive potential, and there exists a possibility of developing a psychological and physical dependence on NRT, although significantly less than smoking tobacco. Hence, patients should adhere strictly to the regimen prescribed by their healthcare provider. 

Drug-Drug Interactions

Nicotine interactions are observed with adenosine, cimetidine, and varenicline. Adenosine might amplify the chronotropic effects of nicotine. Conversely, cimetidine can lead to elevated serum nicotine concentrations, potentially resulting in toxicity. When varenicline is coadministered with NRT, there is an increased risk of experiencing sleep disturbances, nausea, and cutaneous adverse drug reactions. These reactions may include localized erythema, itching, and worsening preexisting acne.[17]

Contraindications

The contraindications associated with NRT underscore the importance of careful consideration and consultation with healthcare providers before initiating NRT for individuals who wish to quit smoking.

• Individuals with hypersensitivity or allergies to nicotine should refrain from using NRT products.

• Individuals with a known allergy to soy should avoid using nicotine lozenges.

• Lactating women are advised by their healthcare providers to refrain from using NRT to mitigate the potential risk of exposing breastfed infants to nicotine through breast milk.[12]

Monitoring

Clinicians can enhance the effectiveness of NRT by maintaining regular follow-ups with patients on the therapy. This ongoing monitoring is essential for detecting adverse drug reactions, ensuring adherence to the NRT regimen, and offering comprehensive behavioral support.[4] 

Patients with cardiovascular or peripheral vascular disease should consider the potential risks and benefits before initiating NRT. This cautious approach is warranted due to the potential adverse effects of NRT, such as increased heart rate and hypertension, which could exacerbate preexisting cardiovascular conditions. Healthcare providers are advised to exercise caution when initiating NRT in patients with a history of angina or recent myocardial infarction. If palpitations or irregular heartbeats develop, NRT should be promptly discontinued.[18][19]

Toxicity

Nicotine metabolism primarily takes place in the liver. Therefore, when nicotine is administered through the GI system, it undergoes first-pass metabolism by the liver, leading to a bioavailability of only about 20%. This process inherently decreases the bioavailability of nicotine within the system and may cause adverse GI effects. Therefore, physicians recommend using non-pill forms of nicotine, including lozenges, sublingual tablets, transdermal patches, gum, inhalers, and sprays, to bypass the first-pass metabolism. These dosage forms facilitate nicotine absorption through the oral or nasal mucosa or skin, effectively bypassing the GI system and extending the duration of bioavailability.[20]

The absorption route of nicotine is contingent on pH levels. Consumption of acidic foods and beverages can decrease the absorption of nicotine. Moreover, the skin patch releases nicotine gradually, contributing to a controlled and sustained delivery of the substance. This controlled delivery approach significantly reduces the likelihood of nicotine toxicity and mitigates GI adverse effects. In the rare instance of a nicotine overdose, symptoms may include nausea, vomiting, diarrhea, dizziness, breathing difficulties, tachycardia, weakness, or rash.[20]

In situations involving nicotine cartridge poisoning, a recommended approach is administering repeated doses of activated charcoal until the nicotine cartridge has been entirely expelled through the GI tract. This step is crucial due to the prolonged release of nicotine from the cartridge, which mandates continuous treatment to prevent continued absorption of nicotine. Healthcare professionals must promptly cease nicotine exposure and prioritize securing and maintaining airways in patients. In cases of nicotine poisoning, clinicians should offer hemodynamic support to address hypotension and cardiovascular collapse. To manage seizures, benzodiazepines can be administered, whereas atropine can be used to counteract bronchial secretions and diarrhea.

Enhancing Healthcare Team Outcomes

Educating patients about the risks of smoking is a shared responsibility among all interprofessional healthcare team members, including physicians (MDs and DOs), advanced practice providers (NPs and PAs), nurses, pharmacists, and mental health professionals. Healthcare providers should provide their patients with comprehensive information about the available NRT options. Moreover, the interprofessional clinical team should counsel the patient to ensure optimal utilization of these options and enhance the likelihood of a successful treatment outcome. Research indicates that utilizing NRT substantially enhances the probability of successfully quitting smoking by approximately 50% to 70%. The common withdrawal symptoms experienced during smoking cessation include restlessness, heightened hunger, depression or irritability, and intense cravings for another cigarette.

Bupropion, an antidepressant with smoking cessation properties, can be used by clinicians in conjunction with nicotine patches to enhance the likelihood of successful smoking cessation. Patients undergoing this combined therapy require continual support and consistent positive reinforcement. The interprofessional team members should be responsible for actively supporting patients and promptly communicating with other team members regarding any shifts in the patient's condition, such as relapses, adverse events, or lack of compliance. Unfortunately, relapse rates remain substantial across all therapies. However, employing an interprofessional team approach along with the Ottawa Model for Smoking Cessation (OMSC) has been linked to higher smoking cessation rates in primary care settings.[21]