1 Rocky Mountain Tobacco Treatment Specialist Certification (RMTTS-C) Program

2 Module 5: Pharmacotherapy Training Notes:In this module, we will discuss pharmacotherapy as it relates to tobacco use and cessation.

3 Module 5: Pharmacotherapy ObjectivesDescribe the biology of tobacco dependence Describe the symptoms and duration of nicotine withdrawal Provide information on: All approved tobacco dependence medications Second-line medications Combination therapy Alternative therapies Special considerations for specific groups Training Notes: This module provides information on: The biology of tobacco dependence; Cessation pharmacotherapy; Special considerations.

4 Evidence-Based Tobacco CessationThe U.S. Department of Health & Human Services - Public Health Service Clinical Guideline: Treating Tobacco Use and Dependence Update “Counseling and medication are effective when used by themselves for treating tobacco dependence. The combination of counseling and medication, however, is more effective than either alone.” Training Notes: The U.S. Department of Health & Human Services - Public Health Service (PHS) Clinical Guideline: Treating Tobacco Use and Dependence Update contains evidence-based strategies and recommendations to assist clinicians, tobacco dependence treatment specialists, healthcare administrators, insurers, & purchasers in delivering and supporting effective treatments for tobacco use and dependence. Counseling and medication are effective when used by themselves for treating tobacco dependence. The combination of counseling and medication, however, is more effective than either alone. Thus, clinicians should encourage all individuals making a quit attempt to use both counseling and medication. (Clinical Guideline, 2008) Tobacco cessation medications assist with tobacco cessation in numerous ways: Provides relief for nicotine cravings and withdrawal symptoms Allows the individual to continue to experience stress release and increased arousal without the harmful chemicals in tobacco products Allows individuals to focus on changing behaviors related to tobacco use Improves chances of a successful quit attempt.

5 Tobacco Cessation Treatment StrategiesTreatment Format Abstinence Rate Unaided 4-7% Self-help 11-14% Quitline 11-15% Individual counseling 15-19% Group counseling 12-16% Medication alone 22% Medication + counseling 25-30% Training Notes: Research shows that tobacco cessation treatment works (Fiore et al., 2008).

6 Tobacco dependence is a 2-part problemTobacco Dependence Has Two Parts Tobacco dependence is a 2-part problem Physical Behavior Treatment The addiction to nicotine Medications for cessation The habit of using tobacco Behavior change program Training Notes: Tobacco addiction is a chronic brain disease, and it is best treated using two different approaches at the same time. We need to treat the physical addiction as well as the behavior (the habit). Addiction can be treated by using medications approved by the Food and Drug Administration (FDA) for tobacco cessation. The behavior (habit) can be treated through programs focusing on changing behavior, such as individual counseling, group therapy, and other cessation programs. The Clinical Practice Guideline for treating tobacco use and dependence tells us that the best strategy for helping someone quit is a combination of counseling and FDA-approved cessation medications (Fiore et al., 2008). Treatment should address both the addiction and the habit. Courtesy of the University of California, San Francisco

7 The Biology of Tobacco DependenceTraining Notes: This section will provide information on the biological underpinnings of nicotine addiction.

8 What is Nicotine? Nicotine is:The major pharmacologically active alkaloid in tobacco A naturally occurring, colorless liquid Properties of nicotine allow it to cross blood brain barrier It is toxic at high doses but can be safe and effective at lower doses for cessation treatment Training Notes: Nicotine is a basic, water soluble compound known as an alkaloid. Alkaloids are a group of compounds that are typically produced by plants to discourage animals from eating them. There is little or no absorption of nicotine in acidic environments (Nicotine, n.d.). Nicotine commonly comes from the tobacco plant but there are 66 other plants from which nicotine can be obtained. These plants are a part of the nightshade family (including eggplant, tomato, potato, green pepper) (Nicotine, n.d.). It is toxic at high doses but can be safe and effective for cessation treatment (nicotine replacement) at lower doses (QuitSmoking, n.d.). Free-base nicotine is used as an insecticide since it is highly poisonous and reactive with oxygen and other chemicals, destroying cells and tissues (Nicotine, n.d.).

9 Nicotine differs from other drugs of abuse since a greater percentage of those who try it become daily users than those who try other drugs. Training Notes: Nicotine is an incredibly addictive drug. In fact, individuals with addictions to other substances such as alcohol, heroin, or cocaine very often report that tobacco was the most difficult addiction for them to overcome. While there are a variety of bio-psycho-social factors that lead to nicotine addiction, in this module we describe the biological action of nicotine. Reference for this slide: Tobacco Freedom.org & InfoImagination, n.d.

10 Arousal, Mood Modulation, PleasureTobacco Use Cycle Tobacco Product Used Nicotine Absorption Arousal, Mood Modulation, Pleasure Tolerance Withdrawal Symptoms Craving Training Notes: People use addictive substances because there are rewards. While rewards may be psychological, social, or biological, this module focuses on the biological rewards such as arousal and pleasure. An addiction is when individuals engage in compulsive behaviors that have negative consequences. Tobacco addiction is no different than any other addiction. Drug addictions involve physical dependence--tolerance, and withdrawal. As tobacco users become tolerant, they must increase nicotine use to realize the same biological benefits, which leads to greater addiction. When nicotine is withdrawn, users experience withdrawal symptoms and cravings. In the addiction cycle, tobacco is used to avoid withdrawal symptoms as much as it is used for initial rewards.

11 Tobacco Smoke Delivery and AbsorptionCigarettes can readily deliver approximately 1-2 mg of nicotine Reaches the brain within 10 seconds after inhalation 90% of nicotine is absorbed through inhaled or “mainstream” smoke directly from a cigarette rather than second-hand or “sidestream” smoke Training Notes: With the exception of oral tobacco products and electronic cigarettes, tobacco is typically consumed through combustion, in which tobacco leaves are burned at high temperatures and the resulting smoke is inhaled. The cigarette is the vehicle for moving nicotine to the brain. Tobacco companies have spent many decades perfecting how to get tobacco to the brain as rapidly as possible. A cigarette delivers about 1 to 2 milligrams of nicotine. After a person takes a puff, nicotine from that inhalation will reach the brain within 10 seconds, which is faster than if the nicotine had been administered intravenously. The majority of nicotine is absorbed through the act of inhaling – this is often termed “mainstream” smoke, which refers to inhaled and exhaled smoke. But nicotine also comes from other sources such as “sidestream” smoke, which refers to the smoke that goes into the air directly from burning tobacco. “Sidestream” smoke is the main component of second-hand smoke (Benowitz & Jacobs, 1984). The rapid absorption of nicotine from cigarette smoking, and the high arterial levels which reach the brain as a result, allow the smoker to titrate nicotine levels for rapid behavioral reinforcement from smoking. Cigarette smoking is the most reinforcing and dependence producing form of nicotine. Nicotine in other forms, such as patches and gum, doesn’t reach the brain nearly as fast as when using cigarettes, nor can they be titrated like nicotine from cigarettes. Thus, these other forms of nicotine have a much lower potential for abuse (Benowitz, 1999a). Reference for this slide: Henningfield, 1984.

12 Smoked Tobacco Products Delivery and AbsorptionNicotine is distilled from burning tobacco and is carried on “tar” droplets The lungs present an enormous surface area for the inhaled smoke Absorption into the pulmonary circulation results in rapid delivery Training Notes: Absorption is through the surface of alveolar capillaries deep in the lungs. Our lungs have tiny sacs called alveoli. The average adult's lungs contain about 600 million of these spongy, air-filled sacs that are surrounded by capillaries (The Franklin Institute, n.d.). Inhaled smoke passes into the alveoli and then diffuses through the capillaries into the arterial blood (Benowitz, 2009). Cigarette smoke is designed to be acidic (pH 5.5) – ideal for absorption in the lungs, which have a pH of 7.4. The acidity of cigarette smoke facilitates the transfer of nicotine across cell membranes.

13 Smokeless Tobacco Products Delivery and AbsorptionNicotine is readily absorbed through oral and nasal mucous membrane from products like chew or snuff Absorption is slower than for cigarettes The highest levels of nicotine occur after about 30 minutes Training Notes: Spit tobacco, pipe, and cigar smoke nicotine is alkaline (pH 9.5) — ideal for absorption in mouth. Nicotine absorption depends on the nicotine in the product, size of tobacco cuttings and acidity level of the product. For smokeless tobacco, plasma nicotine concentrations rise more slowly than with smoked tobacco (e.g., cigarettes). Nicotine levels plateau by about 30 minutes, declining slowly over approximately two hours. Nicotine is continually released throughout the time of exposure. Reference for this slide: Henningfield, London, & Pogun, 2009.

14 Dopamine Reward PathwayNicotine enters brain Stimulation of nicotine receptors Dopamine release Prefrontal cortex Nucleus accumbens Ventral tegmental area Training Notes: Drugs such as cocaine, heroin, amphetamine, and nicotine exert profound effects on the brain. These agents have in common the ability to stimulate the release of the neurotransmitter dopamine in the midbrain. Dopamine induces feelings of euphoria and pleasure and is responsible for activating the dopamine reward pathway (Leshner, 1997). Nicotine is unique in comparison to most drugs in that its profile changes from stimulant to sedative/pain killer as dose and use increases. The dopamine reward pathway, as depicted in this simplified diagram, is a network of nervous tissue in the middle of the brain that elicits feelings of pleasure in response to certain stimuli. The important interconnected structures of the reward pathway include the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex (area of the brain responsible for thinking and judgment). The neurons of the VTA contain the neurotransmitter dopamine, which is released in the nucleus accumbens and in the prefrontal cortex. Behaviors that naturally stimulate the reward pathway include eating to relieve hunger, drinking to alleviate thirst, or engaging in sexual activity. On a primitive, neurochemical level, stimulation of the reward pathway reinforces the behavior so that it will be repeated. Obviously these behaviors are necessary for continued survival of the organism. The reward pathway can also be stimulated by drugs of abuse such as cocaine, opiates, amphetamine, and nicotine. When these unnatural stimuli trigger the reward pathway, the same pleasurable feelings are elicited. Researchers believe that, with chronic drug use, the brain becomes chemically altered—transforming a drug user into a drug addict (Leshner, 1997). Consider cigarette smoking as an example. Immediately following inhalation, a bolus of nicotine enters the brain, stimulating the release of dopamine, which induces nearly immediate feelings of pleasure and relief of symptoms of nicotine withdrawal. This rapid dose-response reinforces and perpetuates the smoking behavior (Leshner, 1997).

15 Nicotine Reward PathwayTraining Notes: There are nicotinic receptors in muscles and the brain. This is a depiction of the action of nicotine on the brain’s neurons. Signaling pathways are made up of neurons which send electrical impulses throughout the brain. Nicotine binds to receptors located on nerve terminals or on axons on cell bodies.

16 Nicotine binds to receptors on the presynaptic neuronTraining Notes: Nicotine binds to receptors on the presynaptic neuron. Nicotine mimics acetylcholine and binds to acetylcholine receptors.

17 The increased APs cause additional dopamine to be released into the synapseTraining Notes: Nicotine interferes with the binding of acetylcholine, as it binds to the receptor which then opens the ion channel releasing sodium into the cell. Depolarization causes an action potential. The increased action potentials (or AP) cause additional dopamine to be released into the synapse. This creates an action potential in the presynaptic neuron that releases dopamine into the gap between presynaptic and postsynaptic neurons. Dopamine is one kind of neurotransmitter which acts as a messenger of neurologic information from one cell to another.

18 This additional dopamine then binds to receptors, producing a rewarding effectTraining Notes: The dopamine then locks into dopamine receptors on the postsynaptic neuron. The artificial increase in extracellular dopamine causes the body to compensate in two ways: Decreasing the functioning of presynaptic nicotine receptors (Downregulation) Increasing the number of postsynaptic dopamine receptors (Upregulation)

19 Nicotine Receptors Not all nicotine receptors are alikeNicotinic acetylcholine receptors Mimics acetylcholine (agonist) α4β2 subtype mediates nicotine dependence Training Notes: Nicotinic acetylcholine receptors are made up of alpha and beta subunits. Different combinations of these subunits have different effects in the body (Benowitz, 2009). The most abundant neuronal nicotinic cholinergic receptor subunits are 4, 5, β2 and 7 (Benowitz, 2009). There are different binding sites. Nicotine has a high affinity for 42 sites and low affinity for 7 sites. The 42 receptor subtype is predominant in the human brain and thought to be the main receptor mediating nicotine dependence in humans (Benowitz, 2009). Receptor binding capacity is increased in smokers compared to non-smokers (reviewed in Benowitz et al., 2009). Miller & Giddings

20 Neurochemical Effects of NicotineDopamine Norepinephrine Acetylcholine Glutamate -Endorphin GABA Serotonin  Pleasure, reward  Arousal, appetite suppression  Arousal, cognitive enhancement  Learning, memory enhancement  Reduction of anxiety and tension  Mood modulation, appetite suppressant Training Notes: Nicotine induces a constellation of effects that reinforce tobacco use behavior. While the primary neurotransmitter nicotine acts on is dopamine, nicotine stimulates the release of many neurotransmitters, which have been associated with these neurochemical effects (Benowitz, 1999a). Nicotine also may lead to improvement in short-term memory and attention, faster cognitive processing, relaxation, stress reduction, decreased pain, mood improvement, and appetite suppression. Some of these effects may actually be relief from nicotine withdrawal.

21 Other Effects of NicotineTraining Notes: Other effects of nicotine include increased heart rate, increased blood pressure, vasoconstriction (Benowitz, 2009), increased metabolic rate, lipolysis, skeletal muscle relaxation and EEG desynchronization. Reference for this slide: Häggström, 2009.

22 Initial Effects of NicotineInitial experience with smoking can cause nausea, dizziness, and/or coughing in some individuals It can also cause pleasurable experiences in others (e.g., head rush, buzz, dizziness) Aversive effects diminish quickly with repeated tobacco use Training Notes: The initial effects of tobacco vary across individuals. For some, there is initial nausea, dizziness, and coughing. While for others, even initially, tobacco use is pleasurable. Aversive effects diminish quickly with repeated tobacco use. Reference for this slide: Laviolette & van der Kooy, 2004.

23 Nicotine Withdrawal EffectsIrritability, frustration, anger Anxiety Difficulty concentrating Restlessness, impatience Depressed mood Insomnia Increased appetite Most symptoms: Appear within first 1–2 days Peak within the first week Decrease within 2–4 weeks Training Notes: When people stop using tobacco products, depending on their level of use, it is likely they will experience withdrawal symptoms like the ones noted on this slide (Hughes, 2007; USDHHS, 2010). Most of these symptoms are relieved within a few weeks after quitting (USDHHS, 2010). Cravings, urges, or thoughts about cigarettes are very common and sometimes take longer (even months or years) to go away after quitting (Hughes, 2007). Dopaminergic and serotonergic systems may become less active leading to symptoms of depression. Tobacco users usually experience a strong desire or craving for tobacco. In general, withdrawal symptoms manifest within the first 1–2 days, peak within the first week, and gradually dissipate over the next 2–4 weeks (Hughes, 2007).

24 Nicotine Addiction CycleTraining Notes: To alleviate the symptoms of withdrawal, smokers re-dose themselves throughout the day. This figure depicts the typical nicotine addiction cycle a cigarette smoker experiences on a daily basis. Explanation of elements in this figure: The jagged line represents venous plasma concentrations of nicotine as a cigarette is smoked every 40 minutes from 8 am to 9 pm. The upper solid line indicates the threshold concentration for nicotine to produce pleasure or arousal. The lower solid line indicates the concentrations at which symptoms of abstinence (i.e., withdrawal symptoms) from nicotine occur. The shaded area represents the zone of nicotine concentrations (neutral zone) in which the smoker is comfortable without experiencing either pleasure/arousal or abstinence symptoms. After smoking the first cigarette of the day, the smoker experiences marked pharmacologic effects, particularly arousal. No other cigarette throughout the day produces the same degree of pleasure/arousal. For this reason, many smokers describe the first cigarette as the most important one of the day. Shortly after the initial cigarette, tolerance begins to develop. Accordingly, the threshold levels for both pleasure/arousal and abstinence rise progressively throughout the day as the smoker becomes tolerant to the effects of nicotine (USDHHS, 2010). With continued smoking, nicotine accumulates, leading to an even greater degree of tolerance. As a result, the smoker experiences greater withdrawal symptoms between successive cigarettes. Late in the day, each individual cigarette produces only limited pleasure/arousal; instead, smoking primarily alleviates nicotine withdrawal symptoms (USDHHS, 2010). Cessation of smoking overnight allows resensitization of drug responses (i.e., loss of tolerance). Most dependent smokers tend to smoke a certain number of cigarettes per day (usually more than 10) and tend to consume 10–40 mg of nicotine per day to achieve the desired effects of cigarette smoking and minimize the symptoms of nicotine withdrawal (USDHHS, 2010).

25 Regulating Nicotine IntakeWide variability in the amount of nicotine absorbed The typical smoker will take 10 puffs per cigarette This equals 200 hits of nicotine to the brain each day for a pack-a-day habit Smokers consciously and unconsciously regulate nicotine intake Training Notes: For smokers, there is wide variability in the amount of nicotine absorbed. Smokers have different conscious and unconscious strategies for regulating their daily nicotine intake so that they do not experience withdrawal symptoms and also avoid nicotine toxicity (e.g., nausea, palpitations, tremors). To maintain desired nicotine blood levels, smokers may block the ventilation holes in filters, smoke more of the cigarette and/or change how they are inhaling. For this reason, the dose of nicotine to a smoker cannot be predicted from the nicotine content of the tobacco. Therefore, the idea that light cigarettes are less harmful than regular cigarettes is a myth. They do not lead to less nicotine absorption because smokers learn to use them differently to increase nicotine intake. Absorption depends on puff volume, depth of inhalation, rate of puffing and intensity of puffing. Ventilation holes in most brands are not visible. Most smokers are unaware of ventilation holes or that blocking then increases tar/nicotine yield. Many smokers, consciously or unconsciously, block the ventilation holes with their lips or fingers. References for this slide: Henningfield, 1984; Benowitz, 1999b; Benowitz, 1984.

26 Nicotine Metabolism Most nicotine (about 85-90%) is metabolized in the liver by cytochrome P450 enzymes, primarily CYP2A6 70% of nicotine is cleared from the blood during each pass through the liver 5-10% of nicotine is excreted via urine, unchanged The half-life of nicotine in the blood is ~120 minutes Training Notes: In humans, the major enzyme involved in the metabolism of nicotine to cotinine is hepatic (liver) enzyme cytochrome P450 2A6 (CYP2A6) (Benowitz, 2009; Messina, Tyndale, & Sellers, 1997). The elimination half-life of nicotine in the body is around two hours (Benowitz, Hukkanen, & Jacob, 2010). Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). The large individual variability in this cytochrome is the reason for differences in nicotine metabolism in humans (Messina, Tyndale, & Sellers, 1997).

27 How Nicotine is MetabolizedTraining Notes: This figure shows how nicotine is metabolized. Cotinine is nicotine’s major metabolite. Cotinine has a half-life of hours while nicotine’s half-life is about 2 hours. Therefore, cotinine tests are commonly used to detect if an individual has been using tobacco. CYP2A6 also catalyzes the further metabolism of cotinine to its major metabolite 3’-hydroxycotinine (3OH) (Nakajima et al., 1996).

28 Variations in Nicotine MetabolismSlow metabolizers (compared to fast metabolizers): Smoke fewer cigarettes per day Are less dependent on nicotine Are more likely to quit Training Notes: Individuals can have an impaired or enhanced ability to metabolize nicotine (Xu et al., 2002). Decreased metabolism leads to higher plasma levels and less need for increased nicotine. Slow metabolizers are protected against becoming a smoker Slow metabolizers smoke fewer cigarettes per day Slow metabolizers quit smoking more easily (Benowitz, 2009).

29 Factors Affecting MetabolismAge: Nicotine half-life is 3 to 4 times longer in newborns than adults Nicotine metabolism is decreased by 23% in adults over 65 compared to younger adults Diet: Nicotine metabolism increases about 40% 30 to 60 minutes after the end of a meal Training Notes: In newborns exposed to tobacco smoke, nicotine metabolism is much slower than in adults (especially in the first few weeks of life). Nicotine half-life is about 3 to 4 times longer than in adults. Compared to young adults, adults over 65 years of age in one study metabolized nicotine about 23% slower. This decline in metabolic rate is probably due to age-related blood flow reduction in the liver, which is associated with slower metabolism more generally. After meals, metabolism increases by about 40%, resulting in a decline of nicotine concentrations. The maximum effect is seen 30 to 60 minutes after the end of a meal. There is also some evidence that menthol (used in foods, mouthwash, toothpaste, and some cigarettes) slows down metabolism of nicotine. References for this slide: Benowitz, 2009; Benowitz et al., 2009.

30 Factors Affecting MetabolismGenetics and Ethnicity: A small percentage of individuals have defective CYP2A6 genes Genetic variants in the CYP2A6 genes are associated with race Asians and African-Americans metabolize nicotine more slowly than Caucasians Training Notes: A small percentage of individuals have a defective CYP2A6 gene leading to decreased metabolism. These individuals are less likely to be smokers, and if they are smokers, they smoke less (Rao et al., 2000). Genetic polymorphisms in CYP2A6 genes are associated with wide individual variability and racial/ethnic differences in the rate of nicotine metabolism. Asians and African Americans metabolize nicotine more slowly on average than do Caucasians or Hispanics (Benowitz, 2009).

31 Factors Affecting MetabolismSex Hormones: Women (not taking oral contraceptives) metabolize nicotine 13% faster than men Women taking oral contraceptives metabolize nicotine 28% faster than women not taking oral contraceptives Women who are pregnant metabolize nicotine 60% faster than postpartum women Training Notes: Sex hormones substantially influence CYP2A6 activity (Benowitz, 2009). A twin study in which individuals were infused with concentrations of nicotine and cotinine demonstrated increased nicotine and cotinine clearance (13% and 24%, respectively) in women who were not taking oral contraceptives compared to men (reviewed in Benowitz et al., 2009). The same twin study demonstrated increased nicotine and cotinine clearance (28% and 30%, respectively) in women who were taking oral contraceptives compared to those who were not (reviewed in Benowitz et al., 2009). Pregnancy has a marked inducing effect in nicotine and especially cotinine clearance. Clearance is increased by 60 and 140% for nicotine and cotinine, respectively, in pregnancy compared to postpartum (reviewed in Benowitz et al., 2009).

32 Explaining the Addiction ProcessGroup Exercise Explaining the Addiction Process Training Notes: Break up into pairs—one person is the TTS and the other is a client. The TTS will explain to the client what is happening to their brains when they use tobacco, as well as factors we discussed that may influence nicotine dependence (i.e. metabolism). Explain this as simply as possible and in lay terms (Tip: Metaphors can be helpful!). After five minutes, switch roles. This exercise will take 20 minutes. At the end of the practice, we debrief for 20 minutes.

33 Cessation PharmacotherapyTraining Notes: This section will provide information on all tobacco dependence medications approved by national regulatory agencies and will include the following topics: Correct use Efficacy Adverse events Contraindications Side effects Exclusions This section also discusses second line medications and alternative therapies.

34 Why Use a Medication for Quitting?Medications: Make people more comfortable while quitting by reducing withdrawal symptoms Allow people to focus on changing their behavior Improve chances of a successful quit attempt Training Notes: Cessation medications help to alleviate nicotine withdrawal, mimic the effects of nicotine, and block the effects of nicotine. When people stop using tobacco products, the amount of nicotine in their body decreases, and they experience withdrawal symptoms. Withdrawal symptoms can make people so uncomfortable that they often relapse and begin to use again. Cessation medications help make people more comfortable while they are working to change their smoking behavior or habit. The biggest benefit of the medications is that they improve chances of quitting (Fiore et al., 2008). There is also some evidence that use of bupropion mediates weight gain during a quit attempt (Hays et al., 2001). It is important for Tobacco Treatment Specialists to have a thorough understanding of cessation medications even when they are not prescribers. This knowledge allows TTSs to educate individuals and make appropriate referrals. Whenever TTSs become aware of side effects related to cessation medications, they need to immediately refer the individual back to their prescribing healthcare provider and, as appropriate, consult with peers regarding the best course of action.

35 Tobacco Cessation MedicationsThe only medications approved by the Food and Drug Administration (FDA) for tobacco cessation are: Nicotine gum Nicotine lozenge Nicotine patch Nicotine nasal spray Nicotine inhaler Bupropion SR tablets Varenicline tablets Training Notes: The seven medications approved by the Food and Drug Administration (FDA) for smoking cessation are listed on this slide. The next slides go into each medication in detail. These are considered first line therapies for treating tobacco addiction. Currently there are five types of medications which contain nicotine, called nicotine replacement therapy or NRT, and two medications that do not contain nicotine. They fall into three categories: Nicotine Replacement Therapy (NRT) (Nicotine gum, lozenge, patch, nasal spray, and inhaler); Psychotrophics (bupropion SR or Zyban); Partial Nicotinic Receptor Agnosist (varenicline or Chantix). It is important to note that nicotine replacement medications do not have cancer-causing chemicals in them, and, as we stated earlier, many provide relief of withdrawal symptoms so people can focus on changing their behavior. The best medication to use is based on the choice of the person who is attempting to quit. Consider a person’s health history, their experiences with past quit attempts, reasons for relapse, the amount of tobacco used, and level of dependence. Sometimes more than one product is used at the same time. Thus, the “best” product (or combination of products) depends on the person who will be using it. When you are working with someone who is attempting to quit, strongly encourage them to talk with their provider to determine what products and what amounts are best for them. Medications available without a prescription include the nicotine gum, lozenge, and patch. Medications available only with a prescription are the nasal spray, inhaler, bupropion, and varenicline.

36 Safety of NRT No interactions with most psychiatric medicationsSafe in presence of cardiovascular disease Effective for patients with chronic obstructive pulmonary disease (COPD) Safe while individual is still smoking General precautions: Within 2 weeks of a heart attack Serious arrhythmia Uncontrolled hypertension Peptic ulcers Insulin-dependent diabetes Severe or worsening angina Training Notes: NRT is a very safe medication with typically few side effects. There are no interactions with psychiatric medications. However, the concomitant use of bupropion and NRT for tobacco cessation may increase risk for hypertension. Nevertheless, FDA still approves combination therapy with bupropion and NRT. NRT can be used safely by individuals with stable cardiovascular disease, but should not be used within two weeks of a heart attack or if the individual has a serious arrhythmia (abnormal heart rhythm) or severe or worsening angina (chest pain due to an inadequate supply of oxygen to the heart muscle). References for this slide: Furguson, Shiffman, & Gitchell, 2011; Moore et al., 2009.

37 Plasma Nicotine ConcentrationsTraining Notes: Each of the 5 types of nicotine replacement therapy (NRT) that reach maximal plasma nicotine concentrations at different rates. NRT that is long-acting with a slow onset is provided by the patch. Characteristics of the patch include: Constant nicotine level to avoid withdrawal Simplest to use, best compliance User has no control over dose The other NRTs are short-acting cessation medications. Gum, lozenges, and inhalers are used orally and have an intermediate onset, while spray is used nasally and has a rapid onset. Characteristics of these NRTs include: Nicotine blood levels fluctuate more Requires more training to use properly User controls dosage Reference for this slide: Hukkanen, Jacob & Benowitz, 2005.

38 Nicotine Patch Nicotine is absorbed through the skinSold without a prescription Do not cut in half Apply a new patch every 24 hours Training Notes: The nicotine begins to be absorbed within 1 to 4 hours after the patch is put on. The highest level of nicotine in the body occurs 3 to 12 hours after the patch is put on (depending on the brand). The patch should be changed every 24 hours and should be worn throughout the night unless experiencing sleeping problems. The patch should not be cut in half. Once the patch has been cut, the nicotine seeps through the cut immediately instead of sustained release over the 24 hours. This can lead to an overdose of nicotine.

39 NRT Patch Dosages and ApplicationNicoDerm CQ (OTC) Patch strength Duration 21 mg/day 6-8 weeks 14 mg/day 2-4 weeks 7 mg/day 2-4 weeks Generic (OTC) Possible side effects: local skin reaction, insomnia Training Notes: The available strengths are 21mg, 14mg, and 7mg. The starting strength is based on the amount of tobacco the person used on a daily basis. An individual who smokes a pack of cigarettes per day should begin with the 21mg patch. If a person is smoking 2 packs per day, start with a 2 x 21 mg patch dose. The recommended doses are for individuals smoking ≤10 cigarettes/day (if less than 10 cigarettes per day consider other NRT or start with patch at 14mg/day or 7mg/day depending on number of cigarettes smoked). Possible skin reactions include redness, burning, and itching. Skin reactions are usually caused by the adhesive. Since adhesives vary by manufacturer, patients should be advised to try an alternative brand if irritation is bothersome. While up to 50% of patients experience this reaction, fewer than 5% discontinue use as a result. The patch should be avoided in patients with dermatologic conditions such as psorasis, eczema, atopic dermatitis, or have a known allergy to adhesives. The diagram on this slide shows the areas of skin best suited to patch application. These include the upper body or upper outer area of the arm. To minimize skin irritation, the patch should be applied to a different area each day. The patch should be changed daily and a single patch should not be left on the skin for more than 24 hours.

40 Patch Application: Tips for ClientsPeel off ½ of the adhesive backing Apply adhesive exposed side to skin Peel off remaining backing Press firmly with palm of hand for 10 seconds Make sure patch is firmly adhered to skin Do not cut the patch in half Carefully dispose of patch after removing Training Notes: It is helpful to provide clients with instructions for how to properly use the patch, as proper use will determine its effectiveness. When the patch is not properly applied, it has a tendency to fall off. Additionally, the patch does not withstand water well (this includes sweating with exercise), and clients should be aware of this.

41 Nicotine Gum Sugar-free chewing gum baseAvailable in different flavors Absorbed through the lining of the mouth Available in two strengths Sold without a prescription May not be a good choice for people with jaw problems, braces, retainers, or significant dental work Training Notes: Sold by brand name (e.g., Nicorette, Nicorelief, Thrive, and ZONNIC) and generic. Nicorette and generic are sold in large boxes containing 100 doses of gum and in smaller boxes of 20. ZONNIC is popping up in gas stations and is sold in quantities of 10 with a disclaimer that this dosage may not represent a full day’s supply. The available strengths are 2mg and 4mg. The starting strength is based on the amount of tobacco the person uses on a daily basis and the intensity of their withdrawal symptoms and cravings. Nicotine gum is available in several different flavors; cherry, mint, fruit, cinnamon, and original. The individual should chew until a peppery or flavored taste emerges and then park the gum along their gum line for 2 to 3 minutes. The nicotine from the gum is absorbed across the lining of the mouth. Acidic beverages will interfere with absorption, so individuals should be directed to have no food/juices/sodas 15 minutes prior to use and during use. Some people may find the gum difficult to chew, and it is not an ideal choice for people with jaw problems, braces, retainers, or significant dental work. Newer, softer to chew flavors of Nicorette are now available. The gum is available in brand name and generic.

42 Nicotine Gum Dosages Scheduled dosing increases success with this treatment <20 cigarettes per day 2 mg gum every 1-2 hours >20 cigarettes per day or smoke within 30 minutes of waking up 4 mg gum every 1-2 hours Slowly taper dosing as tolerated over 8 to 12 weeks No less than 9 doses and no more that 24 doses per day Training Notes: Most individuals should start using the 2-mg dose. However, individuals may want to start with the 4-mg gum if they: Smoke more than 20 cigarettes a day, Smoke as soon as they wake up in the morning, Have severe withdrawal symptoms when they don't smoke, or Have tried to quit on a lower dose and failed (American Academy of Family Physicians, 2001). Dosing recommendations vary, and a TTS will likely run into different recommendations. However, growing expert opinion is that NRT is often under-dosed, leading the user to believe that it doesn’t work. A TTS should work with the prescriber to assess individuals, particularly in the first few weeks of quitting, to ensure that individuals are using enough NRT to address withdrawal symptoms and cravings. The general manufacturer's recommendation for Nicotine gum dosing when it is used alone and not in combination with other treatments is no less than 9 doses and no more than 24 doses per day. Reference for this slide: American Academy of Family Physicians, 2001; U.S. National Library of Medicine, 2013.

43 Nicotine Gum: Directions for UseChew each piece slowly until the gum releases a peppery taste or a slight tingling occurs “Park” the gum between cheek and gum to allow for absorption across the buccal mucosa Resume chewing when taste or tingle fades When tingle returns, stop chewing and park gum in a different place in mouth Repeat process until the tingle is gone (about 30 minutes) Training Notes: It is important to have a discussion with clients about using the gum correctly. When the gum is used incorrectly, it can cause: Less effective absorption by buccal mucosa; More nicotine goes to stomach; Increased experience of side effects (e.g., mouth soreness, hiccups, dyspepsia (indigestion) and jaw ache). Note that effectiveness is decreased by some foods and drinks. Advise clients not to have acidic drinks like coffee, juice, wine, and soft drinks for fifteen minutes before using oral NRT.

44 Nicotine Lozenge Sugar-free lozenge Available in different flavorsAbsorbed through the lining of the mouth Available in two strengths Sold without a prescription Use 1 lozenge every 1 to 2 hours Possible side effects are mouth/ throat soreness or indigestion Training Notes: The available strengths are 2mg and 4mg. The starting strength is based on the amount of tobacco the person used on a daily basis. The lozenge comes in sugar-free mint, cappuccino and cherry flavors. The lozenge is not meant to be chewed or swallowed whole. Instead, the individual should place the lozenge in their mouth and allow it to slowly dissolve. They should occasionally move the lozenge from one side of their mouth to the other. Individuals should also try not to swallow very often while nicotine lozenges are dissolving. It may take 20 to 30 minutes for nicotine lozenges to completely dissolve. Acidic beverages will interfere with absorption, so individuals should be directed to have no food/juices/sodas 15 minutes prior to use and during use. The nicotine from the lozenge is absorbed across the lining of the mouth. Because the nicotine lozenge dissolves completely, it provides about 25% more nicotine than an equal dose of nicotine gum (Choi, Byron, Abrams, & Shields, 2003). The nicotine lozenge improves quit rates significantly compared to placebo (Choi, Byron, Abrams, & Shields, 2003).

45 Nicotine Nasal Spray About 100 doses per bottleQuickly absorbed through the lining of the nose Sold with a prescription as Nicotrol NS Training Notes: Nicotine nasal spray delivers nicotine through the nose. One dose is two sprays - one in each nostril. A dose is equal to 1 mg of nicotine. Each bottle contains about 100 doses (200 sprays), which is a 1-week supply for most people. Nicotine is absorbed more quickly through the spray (11–13 minutes) than through the use of the gum, patch, or inhaler (Fiore et al., 2008). Clients should start with 1-2 doses per hour. Increase to maximum dosage of 5 doses per hour, if needed. For best results, patients should use at least 8 doses daily for the first 6-8 weeks. Gradual tapering over an additional 4-6 weeks is recommended. To administer the nasal spray, instruct individuals to tilt their head slightly back and to not sniff, swallow or inhale through nose while administering the dose because this might cause irritation. Possible side effects are nasal irritation that decreases over time, nasal congestion, change in sense of smell/taste, and development of dependence. The nicotine nasal spray improves quit rates compared to placebo (Fiore et al., 2008).

46 Nicotine Inhaler Absorbed through the lining of the mouthAllows for similar hand- to-mouth ritual of smoking Sold with a prescription Possible side effects are throat/mouth irritation, coughing, and runny nose Training Notes: The Nicotrol Inhaler (nicotine inhalation system) has two parts: a mouthpiece and a plastic cartridge. Each kit comes with about 42 cartridges. Each cartridge delivers approximately 4mg of nicotine (Schneider, Olmstead, Franzon, & Lunell, 2001). Clients should start with at least 6 cartridges/day during the first 3-6 weeks of treatment (one cartridge every 1-2 hours with a maximum of 16 cartridges daily). Recommended duration of therapy is 3 months. Titrate dosage down slowly over the next 6-12 weeks. A person who smokes a pack a day repeats the motion of bringing a cigarette to their mouth up to 200 times a day or 73,000 times a year. Therefore, it is not surprising many people who smoke find they miss holding a cigarette and the act of putting a cigarette to their mouth. The nicotine inhaler was made to be used in a way that is similar to smoking and allows nicotine to be absorbed through the lining of the mouth. The highest nicotine levels occur after 30 minutes, compared to 5 minutes after cigarette smoking. The nicotine oral inhaler significantly improves quit rates compared to placebo. The downside to using the inhaler is that it reinforces the hand-to-mouth behavior of smoking (Schneider, Olmstead, Franzon, & Lunell, 2001).

47 Nicotine Inhaler DirectionsTraining Notes: Show the video instruction about how to use the nicotine inhaler. Link to video: https://www.youtube.com/watch?v=UIyInRGafqs

48 Label Update: Nicotine Replacement TherapyPrevious Label Drug Facts Labeling Warnings Do not use. If you continue to smoke, chew tobacco, use snuff, or use a different NRT product or other nicotine-containing products. Directions Stop smoking completely when you begin using the NRT product. It is important to complete treatment. Stop using the NRT product at the end of a specified number of weeks. If you still feel the need to use the NRT product, talk to you doctor. Current Label Drug Facts Labeling Warnings None. The “Do not use” statement has been removed. Directions Begin using the NRT product on your quit day. It is important to complete treatment. If you feel you need to use the NRT product for a longer period to keep from smoking, talk to you healthcare provider. Training Notes: There are no significant safety concerns associated with the concomitant use of nicotine replacement therapy (NRT) products with other nicotine-containing products, including cigarettes. There are no significant safety risks associated with the use of NRT products for longer than the labeled number of weeks of use. Current marketed NRT products do not appear to have significant potential for abuse or dependence.

49 Bupropion SR Tablets Does not contain nicotineThe tablet is swallowed whole, and the medication is released over time Sold with a prescription as Zyban or generic Training Notes: Bupropion sustained-release (SR) is a medication commonly used to treat depression (also known as Wellbutrin). The SR stands for sustained release, which means the medication is released over time. This medication does not contain nicotine. It is sold with a prescription as Zyban or as a generic. Using bupropion SR can double the chances of quitting compared to a placebo (Fiore et al., 2008). Effect is independent of depression history or symptoms. Bupropion has been found to be effective for treating smoking for people who do and do not have a history of depression (Cox, Patten, & Niaura, 2004; Piper et al., 2009). May reduce short-term cessation-associated weight gain. Initial dose of 150 mg/day for 3 days followed by 150 mg twice daily for approximately 6 to 12 weeks, although it can safely be used longer. Long-term treatment with bupropion SR may reduce or delay relapse to smoking. Bupropion SR can be stopped abruptly and does not require tapering. Initial dose of 150 mg/day for 3 days, followed by mg twice daily for 6-12 weeks

50 Bupropion Side Effects and PrecautionsSide effects include: Insomnia (35-40%) Dry mouth (<10%) Agitation, decreased appetite, dizziness, headache, nausea Avoid recommending to individuals: With eating disorders At increased risk for seizures Diagnosed with bipolar disorder With concomitant or recent use (past 2 weeks) of MAO inhibitors Take precautions for individuals with schizophrenia Training Notes: Insomnia is a common side effect of bupropion. Other possible side effects are insomnia, dry mouth, agitation, decreased appetite, dizziness, headache, and nausea. There are a number of contraindications (i.e., inadvisable treatments) for bupropion. Bupropion can lead to higher incidence of seizures, including among individuals with anorexia or bulimia. For those with bipolar disorder or at risk for bipolar disorder, bupropion can precipitate mania. Until December 2016, both bupropion and varenicline had a “black box” warning, which is used when a prescription drug is known to be effective for some patients, but may cause serious side effects in others based on adverse events that are reported. Some people who had taken Chantix or Zyban had reported experiencing unusual changes in behavior, becoming depressed, or had their depression worsen, and had thoughts of suicide or dying. Because of these findings, independent studies have examined the safety of varenicline specifically in people with serious mental illness, and these studies found no significant safety concerns. Additionally, a very large randomized, controlled study was conducted to more definitively address the issue. Over 8000 people from 16 countries were included, half of whom had been diagnosed with a psychiatric disorder. The study found that even in this high-risk group, neither varenicline nor bupropion resulted in more serious adverse events than did NRT or placebo. The conclusion of the study is that there is no neuropsychiatric safety risks of using these medications in people who have been diagnosed with psychiatric disorders. In light of these results, in December 2016 the FDA announced removal of the black box warning for both varenicline (Chantix) and bupropion (Zyban) (Anthenelli et al., 2016).  

51 Varenicline Does not contain nicotine The tablet is swallowed wholeSold with a prescription only as Chantix People who take Chantix should be in regular contact with their doctor Training Notes: Varenicline, marketed as “Chantix,” is available by prescription only. This medication does not contain nicotine. Varenicline is a selective alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist. It works in two ways: It acts like nicotine in the brain but does not have as strong of an effect. Facilitator use light bulb metaphor—when nicotine from a cigarette binds with the nicotinic acetylcholine receptor the connection is strong – like a 100 watt bulb. Varenicline binds with the receptor as well—but at a lower level—like a 50 Watt bulb. It blocks the places in the brain where nicotine would normally work. It is important to note that, like bupropion, some people using varenicline have reported changes in behavior, agitation, depressed mood, suicidal thoughts or actions when attempting to quit smoking. A person should talk to his or her doctor before taking this medication to determine if varenicline might be a right fit for them. Anyone taking varenicline who reports agitation, depressed mood, or changes in behavior that are not typical for that person, or if they develop suicidal thoughts or actions, should stop taking varenicline and see a doctor right away (Pfizer, 2008). Independent studies have been done on the safety of varenicline in persons with serious mental illnesses. Researchers did not find any significant safety concerns within this population and found varenicline to be more effective in cessation compared to patch or placebo (Grassi et al., 2011; Stapleton et al., 2007). Varenicline increases chances of quitting compared to placebo and compared to bupropion SR (Fiore et al., 2008). Dosing for the first week of treatment with varenicline is 0.5 mg once daily for 3 days and then twice daily for 4 days; the dosage is then “ramped up” to 1mg twice daily for 11 weeks. Initial dosing is 0.5 mg/day for 3 days and then twice daily for 4 days. For next 11 weeks, dosing is 1 mg twice daily

52 Varenicline Side Effects and PrecautionsSide effects include: Nausea Headache Insomnia and abnormal dreams Constipation and flatulence Precautions for individuals: Operating heavy machinery With kidney or cardiac problems Taking insulin, asthma medications, or blood thinners Training Notes: The most common side effect of varenicline is nausea, which is often transient, disappearing over continued use. Nausea may also be controlled by taking the medication with meals. Many individuals experience vivid dreams. While not nightmares, individuals may find these dreams disturbing. Other possible side effects are headache, constipation, and flatulence. There is a small increased risk of cardiovascular events. Until December 2016, both bupropion and varenicline had a “black box” warning, which is used when a prescription drug is known to be effective for some patients, but may cause serious side effects in others based on adverse events that are reported. Some people who had taken Chantix or Zyban had reported experiencing unusual changes in behavior, becoming depressed, or had their depression worsen, and had thoughts of suicide or dying. Because of these findings, independent studies have examined the safety of varenicline specifically in people with serious mental illness, and these studies found no significant safety concerns. Additionally, a very large randomized, controlled study was conducted to more definitively address the issue. Over 8000 people from 16 countries were included, half of whom had been diagnosed with a psychiatric disorder. The study found that even in this high-risk group, neither varenicline nor bupropion resulted in more serious adverse events than did NRT or placebo. The conclusion of the study is that there is no neuropsychiatric safety risks of using these medications in people who have been diagnosed with psychiatric disorders. In light of these results, in December 2016 the FDA announced removal of the black box warning for both varenicline (Chantix) and bupropion (Zyban) (Anthenelli et al., 2016).   TTSs and prescribers can watch for onset of new psychiatric symptoms (suicidal thinking, aggressive behavior, depression, psychosis) and refer back to the prescribing provider and instruct the individual to discontinue varenicline. In March 2015, the FDA approved additional label warnings concerning varenicline and people’s reaction to alcohol and the reports of seizures in patients treated with Chantix. The label warns that until patients know how Chantix affects their ability to tolerate alcohol, they should decrease the amount of alcohol they drink. Patients who have a seizure while taking Chantix should stop the medicine and seek medical attention immediately. There are a number of contraindications (i.e., inadvisable treatments) for varenicline. It may impair the ability to drive or operate machinery. Also those with kidney or cardiac problems, or taking insulin, asthma medications, or blood thinners need to consult their prescribing provider before use.

53 Cytisine Similar to varenicline Marketed as TabexBut found to have less side effects Marketed as Tabex Has demonstrated efficacy Very low cost Training Notes: Cytisine has been used as a smoking cessation medication in eastern Europe for several decades; however, it is not yet approved by regulatory authorities outside eastern and central Europe. It is available for sale in the U.S. Cytisine or Tabex has a molecular structure similar to nicotine and acts in much the same way as varenicline. Cytisine is an acetylcholine agonist and has strong binding affinity for the nicotinic acetylcholine receptor. Recent Phase III clinical trials using Tabex have shown similar efficacy to varenicline but at a fraction of the cost. A 2011 study found cytisine improved 12-month abstinence from nicotine from 2.4% with placebo to 8.4% with cytisine (West et al., 2011). A 2013 meta-analysis of eight studies demonstrated that cytisine has similar effectiveness to varenicline but with substantially lower side effects (Hajek, McRobbie, & Myers, 2013).

54 Other Medications Clonidine Nortriptyline Ineffective medicationsPrecautions for individuals with Cardiovascular disease Taking MAO inhibitor medications Operating heavy machines Ineffective medications SSRI antidepressants Naltrexone Training Notes: There are several medications that are referred to as “second line,” meaning they are not often preferred as the medication of choice. Clonidine and nortriptyline fall into this category. These would typically be used if other first line FDA-approved medications had failed or there were contraindications for these medications. Clonidine is primarily used for hypertension and migraines. It is also used for psychiatric disorders such as attention deficit disorder and anxiety. It has a number of potential side effects, commonly including dry mouth, drowsiness, dizziness, sedation, constipation, lower blood pressure and hypertension. Nortriptyline is an older generation antidepressant called a tricylcic antidepressant. It has multiple possible side effects including sedation, dry mouth, blurred vision, lightheadedness, shaky hands, urinary retention, cardiotoxicity, seizures and coma with overdose. Precautions should be taken for individuals with cardiovascular disease, taking MAO inhibitor medications, or operating heavy machines. Several other medications have been found to be ineffective for tobacco cessation. These include SSRI antidepressants and naltrexone (Fiore et al., 2008).

55 Pharmacotherapy EfficacyAbstinence rates compared to placebo at 6 months or greater post-quit Medication Number of Trials (People) Estimated Risk Ratio NRT 117 (51,265) 1.6 ( ) Bupropion 44 (13,728) 1.6 ( ) Varenicline 14 (6,166) 2.3 ( ) Training Notes: To assist the United States Preventative Services Task Force with updating its 2009 recommendations for tobacco cessation interventions, a large review of clinical trials looking at the efficacy of behavioral and pharmacological interventions was conducted. This chart reviews results from several meta-analyses, in which data from multiple studies are pooled together for analysis (Patnode et al., 2015). NRT, bupropion SR, and varenicline improve the chances of smoking cessation at 6 months follow up or longer, compared to a placebo (a sugar pill). Reviews of 117 trials of NRT suggest that NRT was effective in all forms and might increase smoking abstinence at >= 6 months by 53-68%, with an absolute cessation difference of 7% compared to placebo or no NRT (Stead et al., 2012). Reviews of 44 trials of bupropion SR suggest that bupropion might increase smoking abstinence at >=6 months by 49-76%, with an absolute cessation difference of 8% compared to placebo (Hughes et al., 2014). Reviews of 14 trials of varenicline found relatively larger effects and suggest that varenicline might increase smoking abstinence at >= 6 months by %, with an absolute cessation difference of 26% compared to placebo (Cahill et al., 2012).

56 Number of Studies (People)NRT Efficacy Abstinence rates compared to placebo at 6 months or greater post-quit Medication Number of Studies (People) Estimated Risk Ratio Patch 43 (19,586) 1.6 ( ) Gum 56 (22,581) 1.5 ( ) Lozenge 7 (3,405) 2.0 ( ) Inhaler 4 (976) 1.9 ( ) Nasal Spray 4 (887) 2.0 ( ) Training Notes: This table shows the effects for NRT broken down by the type of NRT. There were no significant differences among different NRT products. (Perera et al., 2012.)

57 Long-Term (36-month) Quit Rates for Cessation MedicationsPercent quit Training Notes: This slide provides a snapshot of quit rates maintained over a 36-month (3-year) period across all FDA-approved medications. Note the quit rates for individuals who use some form of cessation medication are higher than for those individuals who used a placebo (Silagy & Stead, 2004; Hughes, Stead, & Lancaster, 2004; Gonzales et al., 2006).

58 Combination Therapy Use of two or more forms of tobacco cessation medications can improve cessation rates PLUS OR Training Notes: There are a number of new strategies for using FDA-approved cessation medications which we will discuss in the following slides. We will first discuss combination pharmacotherapy. A common complaint from people who have made quit attempts using tobacco cessation medication is that the medications did not work. Given this complaint, many researchers began looking at how effective combination therapy was compared to using only one form of medication (Kozlowski et al., 2007; Bohadana, Nilsson, Rasmussen, & Martinet, 2000; Piper et al., 2009). Researchers found cessation rates were higher when they used combination therapy, compared to using only one of the therapies at a time (Kozlowski et al., 2007; Bohadana, Nilsson, Rasmussen, & Martinet, 2000; Piper et al., 2009). In 2008, the Public Health Service updated their medication recommendations in the Clinical Practice Guideline to include combination therapy (Fiore et al., 2008). Their recommendations are: nicotine patch along with the nicotine gum, nicotine lozenge, nicotine nasal spray or nicotine inhaler, or the nicotine patch and bupropion SR. PLUS OR PLUS

59 Number of Studies (People)Abstinence rates compared to single medication at 6 months or greater post-quit Medication Number of Studies (People) Estimated Risk Ratio Patch + Other NRT vs. Patch only 9 (4,664) 1.34 ( ) Patch + Bupropion Vs. Bupropion only 4 (1,991) 1.2 ( ) Training Notes: The same review of meta-analyses mentioned earlier also looked at abstinence rates at 6 months or longer after quitting using multiple forms of NRT compared to a single form of NRT. The previous table showed that a single form of NRT increases abstinence rates. This table is showing the additional benefit from using more than one form of NRT (Perera et al., 2012). Additionally, four studies showed that using the nicotine patch with bupropion increases abstinence rates. These effects are fairly modest, increasing the abstinence rates by 20% to 35%.

60 Pre-Cessation Nicotine ReplacementStudies show individuals who used NRT before their quit date: Did not experience any significant side effects Experienced an increase in their quit rates Were twice as likely to maintain their abstinence at 6 months Training Notes: It is unlikely that a person would overdose on nicotine through smoking alone. The FDA stated in 2013, "There are no significant safety concerns associated with using more than one over-the-counter (OTC) nicotine replacement therapy at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette" (FDA, 2013). Providers have also started using nicotine replacement therapies before the individual makes a quit attempt, and results in studies have shown: Individuals who used the patch prior to quitting did not experience any significant side effects, and side effects were not different or more significant compared to individuals who did not smoke while using the patch (Schiffman & Ferguson, 2008; Rose, Herskovic, Behm, & Westman, 2009). At six months, those who used the patch before their quit date were twice as likely to have maintained their abstinence as those who used the patch on their quit date (Schiffman & Ferguson, 2008; Rose, Herskovic, Behm, & Westman, 2009).

61 Considerations for Specific GroupsTraining Notes: This section will provide information on the special considerations when recommending pharmacotherapy to specific population groups.

62 Women and Pregnancy and Nursing MothersNRT is not as effective with women Women may need more intensive behavioral and pharmacological support Pregnant/nursing mothers Pharmacotherapy should only be considered when behavioral treatments fail Treatment must be monitored by a physician Although NRT exposes woman to nicotine, it does NOT expose her to the other harmful chemicals in tobacco Training Notes: Women may have less long term (>6 month) benefit from NRT if not combined with other medications and psychosocial treatments. Women may need more intensive behavioral and pharmacological support when quitting (Perkins & Scott, 2008; Steinberg, Akincigil, Delnevo, Crystal, & Carson, 2006). Women may benefit more from Zyban (bupropion) due to this medication helping to control short-term weight gain associated with tobacco cessation (Anczak & Nogler, 2003). Nicotine easily crosses the placenta with fetal concentrations that are generally 15% higher than maternal levels (Einarson & Riordan, 2009). After entering the fetal circulation and crossing the fetal blood-brain barrier, nicotine interacts with nicotinic acetylcholine receptors (nAChRs). Overproduction of these receptor proteins, particularly in lung and brain cells, leads to impaired lung function and nervous system development (Lindstrom, 1997; Boyd, 1997; Albuquerque et al., 2009). Importantly, under-development of brain stem centers which regulate breathing and other vital functions may exacerbate poor lung function and may explain the link between smoking and Sudden Infant Death Syndrome (SIDS) (Lavezzi et al., 2014). Pharmacotherapies such as NRT, bupropion, and varenicline have not been sufficiently tested for pregnant patients and should not be used as first line smoking cessation strategies for these patients (American College of Obstetrics and Gynecology, 2011). Because pregnancy results in faster metabolism of nicotine, it is possible that in the few small studies to examine the efficacy of NRT in pregnant population, NRT was under-dosed, leading to inconclusive results. If this is true, costs and benefits of administering relatively large doses of NRT to pregnant women would have to be carefully assessed, as prescribers would want to ensure pregnant women are not administered MORE nicotine than they would be getting through smoking alone (Wickstrom, 2007). Although the use of NRT exposes pregnant women to nicotine, smoking exposes them to nicotine plus numerous other harmful chemicals (Fiore et al., 2008). The American Congress of Obstetricians and Gynecologists recommends NRT only if behavioral therapy fails to achieve smoking cessation. It is also recommended that it only be administered under the supervision of a physician (USDHHS, 2014). If pharmacotherapy is considered for a pregnant smoker who is unable to quit smoking by other means, it is important that the woman demonstrates resolve to quit smoking and understands the benefits and risks of the medication to herself and her fetus (American College of Obstetrics and Gynecology, 2011).

63 Youth NRT is a consideration for youth who are clearly nicotine dependent Use is “off-label” Must present a clear desire to quit Evidence and recommendations are mixed Training Notes: NRT for tobacco users under 18 years is “off-label,” but it can be prescribed. It should be considered only when there is clear evidence of nicotine dependence and a meaningful desire to quit. The evidence and recommendations are mixed for youth. The 2008 Clinical Practice Guideline does not recommend use of NRT or bupropion SR for adolescents as there is little evidence of effectiveness (Fiore et al., 2008), while the Institute for Clinical Systems Improvement (ICSI) Health Care Guideline for Patients and Families: Tobacco Prevention Cessation for Children (2004) recommends aggressive treatment intervention for smoking cessation in adolescents age 16 years or older, including NRT and/or other pharmacotherapy (Wilkinson et al., 2013).

64 Smokeless Tobacco UsersThere is limited research on the effectiveness of tobacco cessation medications for smokeless tobacco cessation Use of bupropion and NRT in this population is inconclusive One study showed that varenicline appears to increase abstinence rates Behavioral interventions are effective in increasing short-term quit rates Training Notes: Given the limited research and findings on smokeless tobacco cessation (Ebbert, Montori, Erwin and Stead, 2011), there are no clear guidelines on the use of pharmacotherapies for smokeless tobacco cessation. In the research that has been performed, the expected effects of tobacco cessation medications have not been shown in this population. The reasons for this are still unknown. The evidence for the effectiveness of bupropion and NRT is at this point inconclusive. One study has shown that varenicline appears to increase abstinence rates. Behavioral interventions similar to those used for cigarette users are effective in increasing short-term quit rates. These behavioral interventions should be tailored to the individual. Many individuals who use smokeless tobacco do so for cultural reasons. Focusing on these in treatment is helpful for cessation (Ebbert, 2012).

65 Schizophrenia Decreased α-7 nicotinic receptorsNicotine activates nAChR Partially normalizes sensory processing deficits Smoking may improve negative symptoms and cognitive functioning, including attention and orientation Training Notes: Some individuals with psychiatric disorders such as schizophrenia are more biologically susceptible to nicotine addiction due to deficient nicotinic receptors. Nicotine activates acetylcholine and for short amounts of time may normalize attention and orientation. Because these individuals attempt to maintain short-lived gains provided by nicotine products, they often become very nicotine dependent and chain smoke. This leads to increased death and disability. If there was a medication that had the same action as nicotine in this respect, it could be extremely beneficial to individuals with these neurological deficits. Thus far, while some medications have held promise, none have demonstrated sufficient efficacy. Reference for this slide: Leonard & Adams, 2006.

66 Cessation Medications for Persons with Mental Illnesses and AddictionsHigher levels of nicotine dependence There is no medical reason not to use cessation medications First line treatments are recommended for all Comfortable detox for temporary abstinence Recent trials of varenicline for schizophrenia and depression Effective No greater side effects Training Notes: Persons with mental illnesses and addictions are often more nicotine dependent than tobacco users without these conditions. These levels of addiction warrant intensive pharmacotherapy and counseling. There is no known reason not to use FDA-approved medications with the precautions and contraindications mentioned in previous slides. First line FDA-approved medications are recommended for all tobacco users. If inpatient treatment settings and hospitals are tobacco-free, it is important to offer cessation medications to make temporary abstinence comfortable. Among psychiatric inpatients, those not provided NRT are two times as likely to discharge from hospitals against medical advice (Fiore et al., 2008; Prochaska, Gill & Hall, 2004). Clinical trials have found varenicline to be effective in individuals with past or current psychiatric disorders, including schizophrenia and depression. Additionally, recent clinical trials of varenicline and bupropion have found no increased risks of serious adverse events – even when used by people diagnosed with psychiatric disorders (Anthenelli et al., 2016; Anthenelli et al., 2013; Williams et al., 2012). It is important to be aware that smoking also decreases the effectiveness of certain psychiatric medications, so if a client plans to quit smoking, their healthcare provider needs to be made aware (Desai, Seabolt & Jann, 2001). Immediately refer the individual back to their prescribing healthcare provider and, as appropriate, consult with peers regarding the best course of action.

67 Medications Known or Suspected To Have Their Levels Affected by Smoking and Smoking Cessation ANTIPSYCHOTICS Chlorpromazine (Thorazine) Olanzapine (Zyprexa) Clozapine (Clozaril) Thiothixene (Navane) Fluphenazine (Permitil) Trifluoperazine (Stelazine) Haloperidol (Haldol) Ziprasidone (Geodon) Mesoridazine (Serentil) ANTIDEPRESSANTS Amitriptyline (Elavil) Fluvoxamine (Luvox) Clomipramine (Anafranil) Imipramine (Tofranil) Desipramine (Norpramin) Mirtazapine (Remeron) Doxepin (Sinequan) Nortriptyline (Pamelor) Duloxetine (Cymbalta) Trazodone (Desyrel) MOOD STABLIZERS Carbamazepine (Tegretol) ANXIOLYTICS Alprazolam (Xanax) Lorazepam (Ativan) Diazepam (Valium) Oxazepam (Serax) OTHERS Acetaminophen Riluzole (Rilutek) Caffeine Ropinirole (Requip) Heparin Tacrine Insulin Warfarin Rasagiline (Azilect) Training Notes: It is important to know that tobacco cessation can affect the blood level of many different types of medications including many psychiatric medications. As tobacco users metabolize and excrete nicotine and other chemicals in cigarettes, they also more quickly metabolize prescribed medications. So when an individual quits smoking, blood levels of many medications can significantly, and sometimes dangerously, increase. Sometimes side effects of higher dosages of prescribed medications are confused with nicotine withdrawal or psychiatric symptoms. It is important that prescribing providers are aware that their patients are quitting and that they need to monitor medication levels. Tobacco use and cessation have the same effect on caffeine. Individuals who use large amounts of caffeine may no longer be able to tolerate these levels when they quit smoking. Individuals may report increased anxiety for instance, but this could be due to the amounts of caffeine they are continuing to use.

68 Pharmacotherapy Practice – AliceWhat factors should be considered in identifying options for pharmacotherapy? Training Notes: Break up into small groups. Use the following vignette to discuss pharmacotherapy recommendations for this individual. Alice is a 50-year-old African American woman who has a 35-year smoking history. She began smoking at age 15. Alice smokes between 15 and 18 cigarettes per day and usually has her first cigarette an hour after waking. Alice has struggled with weight issues most of her life. Recently, she was diagnosed with obesity and pre-diabetes. She has a history of mild anxiety and depression and sees a counselor monthly. Alice has made multiple attempts to quit “cold turkey” and tried the nicotine patch on one recent quit attempt thought she relapsed because of strong urges to smoke and concerns about additional weight gain. She identifies smoking with her co-workers as a “pleasurable and social” benefit to smoking and that smoking “makes her feel better.” Her husband has asked her to quit smoking several times, and she is worried about the effects of smoking on her health. Alice is interested in discussing options to help her to quit smoking. Possible considerations: Alice has a history of anxiety and depression. She has been smoking over half a pack of cigarettes daily and has been smoking for 35 years. She is overweight which puts her at higher risk for hypertension, etc. Possible advice: I would advise for Alice to discuss bupropion as an option with her doctor since she has mild anxiety and depression. I would also advise for her to consider NRT of her choice (2 mg. nicotine lozenge) to use in combination with bupropion. I would also ask if she felt comfortable signing a release of information so her TTS, counselor, and doctor could discuss her plan/recommendations for her tobacco cessation treatment plan.

69 Pharmacotherapy Practice – JustinWhat factors should be considered in identifying options for pharmacotherapy? Training Notes: Justin is a 19-year-old full-time college student who began smoking when he was 13 years old. He currently smokes on average 6-7 cigarettes a day, more when he is out at clubs. When he is in situations where he cannot smoke, he vapes. He is a moderate to heavy drinker on the weekends but doesn’t usually drink during the week. He also vapes marijuana in the evenings to help him sleep. When Justin goes to “raves” with friends (maybe five or six times a year), he likes to take “Molly” (another name for ecstasy or MDMA). Recently, Justin began a new relationship with a young man, Mark, who does not smoke. Although they get along well, Mark has strongly urged Justin to stop smoking and even indicated that Justin’s continued smoking could be a “deal breaker” for any long-term relationship. Justin doesn’t see his smoking as a problem. He thinks of himself as a light smoker and doesn’t view vaping as tobacco use. However, he very much wants to continue his relationship with Mark. He saw a flyer on campus for a smoking cessation program and has come to the student health center for more information. Possible considerations: Justin has been smoking for 6-years and currently smokes just under a half a pack of cigarettes a day. However, he also vapes. He really cannot accurately assess how much nicotine he takes in when vaping. He also uses marijuana daily, alcohol on the weekends, and occasionally uses ecstasy. Possible advice: Because of his polysubstance use, I wouldn’t recommend bupropion or varenicline as the first line of defense to stop smoking (due to potential medication interactions with the methamphetamines, marijuana, and alcohol) unless Justin was willing to stop using those substances. The nicotine patch (14 mg) in combination with the nicotine lozenge or gum would be good options for him, in addition to attending a tobacco cessation group, calling the quitline, etc.

70 Pharmacotherapy Discussion Training Notes:Review pharmacotherapy recommendations as a group. Allow 15 minutes for discussion.