Table of Contents
- Overview and Perspective
- Asthma Stepwise Therapy as a Model for Tobacco-Dependence Treatment
- Efficacy and Effectiveness
- Practical Treatment Tips
- Combination Pharmacotherapy Safety
- Reliever (or Rescue) Medications-Efficacy and Effectiveness Detail
- Medication Safety
- Specific, Medication-Specific Side Effects
- Depression, Suicidality and Tobacco Dependence
- Second-Line Medications as Controller Medications
- Duration of Use and Medication Tapering
Overview and Perspective
Stopping smoking “is a struggle, but researchers have learned a lot about what works to help people [stop]. We need to make sure that effective [treatment] reaches the people who need them the most… To increase demand for treatments, we most motivate smokers to want them, expect them, and use them.”
David Ransohoff, MD
Professor of Medicine, University of North Carolina
Chair, NIH Consensus Conference
“Treating Tobacco Dependence”
Wednesday, July 14, 2006
Tobacco dependence is a fatal disease.158 Tobacco dependence kills half of its victims.176 But stopping smoking by age 50 cuts the risk of death by half and stopping smoking at age 30 eliminates nearly all excess mortality risk.176 In other words, tobacco dependence is a treatable disease, and, with the medications available today, a chronic disease that can be treated effectively. How to accomplish this is the topic of this section of the CHEST Tool Kit.
While it is true, in absolute numbers, that most cigarette smokers who have ever stopped smoking have done so without any treatment, this unfortunate approach – “cold turkey” – is the least effective available, causing most smokers who stop to relapse and resume smoking in less than 30 days. In fact over 50% resume smoking 14 days after stopping cold turkey; over 75% within in 30 days.103
For many people, the most effective treatments are pharmacologic and the tobacco user’s physician should proactively offer them to all people who smoke,1, 2 not merely those who ask for them. Then, the treating physician needs to regularly monitor treatment effectiveness and safety-just as we would do for asthma, a far less lethal medical disease.
Tobacco dependence is a chronic medical disease that may require pharmacological treatment for optimal treatment outcome.1, 2, 112, 113, 177 Maximal health benefit results when the patient has been able to stop smoking completely and for long-term. Unfortunately, most clinical trials of pharmacotherapeutic agents have been based on a treatment paradigm that originated in the 1960s, when there were no medications available and before the neurogenetics, neuropathology, and neurobiology of nicotine addiction had become understood. Since the clinical psychology treatment paradigm of the mid-1960s was based on 6 weeks of group therapy sessions, the initial pharmacological research in the late 1960s and early 1970s used this same 6-week treatment paradigm. But at that time, the worth of such short-term tobacco-dependence treatment was and, in many circles, continues to be based upon long-term nonsmoking status, meaning percent not smoking at 1 year, or 10½ months after treatment had ended.
The asthma counterpart to this type of trial design would be testing a new inhaled corticosteroid in a randomized, double-blind, placebo-controlled trial, in which the new inhaled corticosteroid is administered for 3 months, but the value of the new medication is to be based on the improvement in FEV1 9 months after treatment had been stopped. Studies of clinical efficacy of asthma medications are not designed that way. The lack of a carry-over therapeutic effect after its use has been stopped (e.g., Strunk RC, et al. 2009.178) does not negate the therapeutic value of the medication. Similar logic should have been applied in the design of pharmacologic tobacco-dependence clinical trials-not assuming a therapeutic carry-over effect.
We know now that tobacco dependence, like asthma, is a chronic medical disease.1, 2, 177 We also know that tobacco dependence, like asthma, has a defined and described genetic, sub-cellular, and cellular basis and pathobiology.112, 179-185Based on their mechanisms of action, we have no reason to think, a priori, that any of the medications available to treat tobacco dependence — bupropion, nicotine, or varenicline — can reverse any of the underlying neuropathology underpinning tobacco dependence. Indeed, the few published trials designed to provide treatment for 6-12 months or longer all show that longer treatment produces significantly better treatment results (i.e., stop-smoking rates).69, 73, 137,138, 186
Therefore, most published clinical trials, placing emphasis on nonsmoking status after treatment has ended are flawed. This is not to say that these thousands of published, peer-reviewed, tobacco-dependence clinical trials do not contain useful information. They do. The most salient outcome is the end-of-treatment results.
Randomized, double-blind, placebo-controlled, fixed treatment trials show that, at the end of a 3-month treatment period, between 40-50% of study participants will have been 100% tobacco-free since their Target Stop Date.54, 55, 149 Generally half relapse 9 months after treatment stops, most of those in the first several months after treatment ends.54, 55, 149 The few studies that have specifically studied those individuals who are highly nicotine dependent on the Fagerström Tolerance Questionnaire (FTQ)127 scale (≥7 points out of 11) or the Fagerström Test for Nicotine Dependence128 (≥5 points out of 10) show that nearly 100% of highly nicotine dependent individuals relapse within a few months after a 3 months’ treatment course has ended.149, 187 Moreover, data relevant to the chest physician show that 75% of patients presenting for tobacco-dependence treatment today are highly nicotine dependent.125 Thus, treatment for them will need to continue much longer than 3 months. How long has not been studied. Based on the fundamental neurobiology of nicotine addiction (see Tobacco-Dependence Treatment Process and Approach) and the clinical experience of Tool Kit Committee Members, most highly nicotine dependent patients need at least several years of treatment and many will need lifetime treatment. Thus, the gradual tapering approach based on level of disease control, as outlined in the previous section (§1.6) and this one, makes sense.
In addition, the U.S. Public Health Service Clinical Practice Guideline: Treating Tobacco Use and Dependence, 2008 Update recommends prescribing at least one medication, even for low-nicotine-dependent patients, those who score below 5 or 6 on the Fagerström Test for Nicotine Dependence (FTND) or smoke fewer than 10 cigarettes per day.1 The reason for this recommendation is that all studies that have defined low nicotine dependent subgroups have shown up to 10-fold better treatment results from active medication compared to placebo.149, 187 Moreover, for low FTND patients, unlike those with a high FTND, a short, 12-week treatment course can produce permanent cure for 75%-80%.149
The U.S. Public Health Service Clinical Practice Guideline: Treating Tobacco Use and Dependence (2008 Update) identifies seven first-line medications (bupropion, nicotine gum, nicotine inhaler, nicotine lozenge nicotine nasal spray, nicotine patch, and varenicline) and two second-line medications (clonidine and nortriptyline) for treating tobacco dependence.1First-line therapies have been found to be both safe and effective, with varenicline the most effective monotherapy (see Table 2).1 The U.S. Public Health Service Guideline also states that the use of combination therapy is particularly effective and more effective than monotherapy (see Table 1).1
Second-line medications have been shown to be effective for treating tobacco dependence but are not FDA-approved for the tobacco-dependence indication and should only be used after first-line treatments have been attempted and have either not been tolerated (rare) or not been effective (even rarer). (see Quick Reference Guide to Pharmacotherapy and the Stepwise Tobacco-Dependence Treatment Guide).
How Medications Will Be Presented in This Tool Kit
As is standard practice in journal articles, medication effectiveness will be discussed first, because if a medication is ineffective, there is little relevance to side effects. Second, we shall present a discussion of medication safety and side effects, starting with the most commonly occurring side effects. We shall conclude each section’s discussion of medication safety with a discussion of potentially serious side effects, such as seizure and suicidality, that have a low incidence of occurrence.
Please be advised that in certain instances, this Tool Kit includes treatment recommendations that are not approved in the US (so-called off-label uses of pharmaceutical products). For prescribing information, please see package inserts for all pharmacotherapeutics mentioned in this Tool Kit.
Asthma Stepwise Therapy as a Model for Tobacco-Dependence Treatment
As discussed in previous sections of this Tool Kit, in the Third Edition of the Tool Kit, the CHEST Tool Kit Committee sought a model that would provide guidance to the clinician while also being flexible to adapt to individual practice style and needs. We realized that the model used in the NHLBI’s Guidelines for the Diagnosis and Management of Asthma was also an appropriate model for determining tobacco-dependence disease severity and deciding on appropriate treatment (see Stepwise Tobacco-Dependence Treatment Guide).By applying the concept of using “reliever/rescue” and “controller” medications to improve asthma management to the treatment of tobacco dependence, CHEST Tool Kit Committee Members have found that we can substantially improve tobacco-dependence treatment outcome and make it nearly painless for the patient to be able to stop smoking. This requires applying rational pharmacotherapeutic principles to tobacco-dependence management.
Additionally, the use of nicotine medications, recommended in this CHEST Tool Kit, is fully consistent with the covered services by the United Kingdom’s National Health Service, as of 2002, and changes to the official prescribing indications of the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA), as of 2006.188, 189 These indications include extended use, combination medication use, and use of nicotine medications by cardiac patients, pregnant women, and pediatric patients.188, 189 (See also: New advice on use of nicotine replacement therapy and Smoking in England)
The foundation for tobacco-dependence treatment, as in asthma, is using at least one controller medication. There are three controllers: bupropion SR, nicotine patch, and varenicline. The three controller medications are discussed in detail below (see Combination Pharmacotherapy).
Tobacco dependence is characterized by acute episodes of reversible nicotine withdrawal symptoms superimposed upon CNS α4β2 nicotinic receptor up-regulation and desensitization. α4β2 nicotinic receptors are part of the family of CNS nicotinic acetylcholine receptors (nAChR). The controller medications control and stabilize the CNS α4β2 nicotinic receptor abnormalities, while the reliever medications relieve acute breakthrough nicotine withdrawal symptoms, such as increased irritability, short temperedness, or cigarette craving, literally rescuing the patient from relapsing to cigarette use.
This really is precisely the way we conceptualize and manage asthma. Asthma is characterized by acute episodes of reversible bronchoconstriction superimposed upon chronic airway inflammation, hyper-responsiveness, obstruction, and remodeling. The asthma controller medications control airway inflammation and remodeling, while the asthma reliever medications relieve bronchospasm and the hallmark asthma symptoms, such as shortness of breath, cough, chest tightness, or wheezing.
But do all tobacco-dependent patients need medications in order to be able to stop smoking and remain stopped? The overwhelming majority-about 90%-will. We all know individuals, however, who have successfully stopped smoking without using any medication. The large majority-65%-though, relapses within only 14 days after stopping smoking49, 103 and 75% within 30 days49, 103 because of nicotine withdrawal symptoms.104-106 Those who don’t relapse are generally low-nicotine-dependent smokers, with scores of 0, 1, or 2 on the FTND (see Fagerström Test for Nicotine Dependence), who have minimal nicotine withdrawal symptoms.
“Reliever” or “Rescue” Medications
Nicotine’s addictive potential is directly related to the speed and concentration with which nicotine is delivered to the brain. The cigarette is the most efficient drug-delivery system humanity has yet devised. It delivers nicotine more rapidly and in far higher concentration than any other device. Because of that, the cigarette is most efficient at creating impact and addiction. Conversely, because pharmaceutical nicotine sources achieve brain delivery rates that are considerably slower and with relatively low concentration, their addictive potential is quite low to nonexistent. Pharmaceutical nicotine has the additional advantage of being extremely safe. It is the 5,000 toxins contained in inhaled tar and gases, not nicotine, that cause tobacco’s dangerous and serious health consequences. These toxins are absent from therapeutic nicotine sources. Nicotine medications lessen withdrawal symptoms, give patients a sense of control over the withdrawal process, and increase the likelihood of long-term nonsmoking. Nicotine medications can be used as “reliever” or “rescue medications” (nicotine gum, lozenge, nasal spray, and oral inhaler) and as a “controller” medication (nicotine patch).
There are 4 reliever, or rescue, medications available: Nicotine nasal spray, nicotine [oral] inhaler, nicotine polacrilex gum, and nicotine polacrilex lozenge. (Nicotine sub-lingual tablet is available in some countries, but not the United States.) The patient should use reliever medications on an as-needed (prn) basis to control acute, breakthrough nicotine withdrawal symptoms, often occurring because of an acute, severe stressor. The four reliever medications are discussed in detail below (see Reliever Medications-Details, following the section on Combination Pharmacotherapy).
Efficacy and Effectiveness
Combination medication use is the currently recommended treatment standard for tobacco dependence, not only by the 2008 Update to the U.S. Public Health Service Clinical Treatment Guideline1 and the United Kingdom’s National Health Service,189 but also in the rapidly expanding body of scientific studies, including randomized, double-blind, placebo-controlled trials62, 68, 69, 141, 186, 190-194 and studies involving consecutive patients in tobacco-dependence treatment clinics.107, 109
Varenicline is the most effective monotherapy1 (see also Table 1″Efficacy of Controller and Reliever Medications, Used in Combination” in section below ; see also “Safety”, below in this section). A recently published Phase II, open-label study indicates that the combination of varenicline and bupropion may be the most effective.193 To get an idea of the combination effect, we can juxtapose the results from a 2009 study193 to results from one of the original randomized, double-blind, placebo-controlled trials of varenicline and bupropion SR from 2006.55 In the 2009 study, the varenicline + bupropion combination193 demonstrated 71% not smoking at the end of 12 weeks treatment,193 compared to 21% (placebo) or 51% (varenicline) from the earlier study55 (approximate odds ratio of stopping smoking at 12 weeks for the varenicline + bupropion combination against placebo is 9.2; 95% Confidence Interval = 2.2-16.2). At 6 months, 3 months after treatment end, the varenicline + bupropion combination showed 58% not smoking,193 compared to 17% (placebo) or 35% (varenicline) from the 2006 study.55 This would approximate a varenicline + bupropion odds ratio against placebo of 6.7 (95% CI = 1.9-11.5). If confirmed by larger-scale, double-blind, head-to-head trials, this is a far higher stop-smoking rate than any other combination, let alone monotherapy. Given varenicline’s and bupropion’s mechanisms of action, this result is not surprising, because these two medications have mechanisms of action that should be complementary and synergistic.113, 195, 196
Theoretically, based on varenicline’s mechanism of action as a nicotinic receptor partial agonist, we would think that adding any of the nicotine reliever medications (patch, gum, inhaler, lozenge, or nasal spray) to varenicline would not improve varenicline’s effectiveness and would likely substantially increase varenicline’s side effects, particularly nausea and vomiting. This turns out not to be the case. Both safety and efficacy of varenicline + nicotine medications (controller and relievers) used in combination have just been recently been shown in a series of 104 consecutive patients from the Mayo Clinic residential program.192 Also, members of the CHEST Tool Kit Committee have found use of varenicline + nicotine reliever medications an effective and safe combination, with varenicline + bupropion + nicotine reliever medications being especially effective.
A recent study utilizing a randomized, double-blind, double-dummy, placebo-controlled, head-to-head design and a sample size of 1,504 study participants, presented at an international scientific conference just as this Tool Kit was going to press, showed that the combination of nicotine patch (controller) + nicotine lozenge (reliever) was significantly more effective at the end of the 8 weeks of treatment than nicotine patch alone, nicotine lozenge alone, or bupropion SR alone (54%, 45%, 40%, and 40%, respectively).194 Also, the combination of bupropion SR (controller) + nicotine lozenge (reliever) showed 50% not smoking at 8 weeks, which was significantly more effective than the 3 monotherapies studied: nicotine patch, nicotine lozenge, and bupropion SR (45%, 40%, and 40%, respectively).194 This unique study extends previous work that had shown that using bupropion SR + nicotine patch-two controllers-was significantly more effective than either medication alone, as monotherapy,1, 62 to also show that bupropion SR + nicotine lozenge (controller + reliever) was significantly more effective than either medication alone.194 Both combinations studied and all 3 monotherapies studied in this head-to-head study were significantly more effective than placebo treatment (double-dummy) at the end of the 8-week treatment phase (30%).194 This single study, testing 2 novel combinations against 3 active monotherapies confirms what all, previous combination-studies have shown: combination therapy with at least 2 controllers or 1 controller + 1 reliever is significantly more effective than only one medication.
Essentially all studies included in the 2008 Update to the Public Health Service Clinical Practice Guideline have deliberately excluded patients with underlying medical and psychiatric disease. The first study to specifically test a triple-medication, tobacco-dependence treatment regimen in a randomized study design also did so in 127 patients with 1 or more pre-defined chronic medical or psychiatric diseases.186 The triple-medication intervention group could use any combination of the 3 medications (nicotine patch, nicotine inhaler, and bupropion [but at ½ standard dose]) for a flexible duration, up to 6 months, based on patient perception of nicotine withdrawal symptom control. The control group of similar, chronic disease patients received a fixed, standard-dose and fixed, standard-duration (10 weeks) nicotine patch treatment regimen, per package insert. The triple-medication regimen-2 controllers, nicotine patch + bupropion, + 1 reliever, nicotine oral inhaler-was significantly more effective than nicotine patch, only: 62% vs. 37% at the end of 8 weeks treatment and 35% vs. 19% at 6 months from Target Stop Date (OR=2.57 [95%CI=1.05-6.32]).186
Efficacy of Controller and Reliever Medications, Used in Combination
Estimated odds ratio and 95% Confidence Interval (CI) for continuous nonsmoking at 6 months using medication combinations, when compared to placebo or nicotine patch, are from Fiore MC, et al.1 and were based on studies using basically medically well, healthy study participants, unless otherwise noted:
|Medication||Odds Ratio & 95% CI (vs. Placebo)||Odds Ratio & 95% CI (vs. Nicotine Patch)|
|Nicotine patch (reference group)||—-||1.0|
|COMBINATION MEDICATION TREATMENT|
|Nicotine patch + Bupropion SR + Nicotine Inhaler*,230||No Placebo Condition||2.8 (1.1-6.3)|
|Varenicline + Bupropion SR192||6.7 (1.9-11.5)||2.6 (0.8-4.5)|
|Nicotine patch (Long-term: > 14 weeks + ad lib nicotine reliever medication (gum or nasal spray)||3.6 (2.5-5.2)||1.9 (1.3-2.7)|
|Individualized nicotine patch dose (up to 45-mg nicotine/16 hrs) to reach 100% nicotine replacement (from patch cf. smoking baseline)† 58||3.2 (0.9-11.7)||No Single-Patch Condition|
|Nicotine patch + Bupropion SR||2.5 (1.9-3.4)||1.3 (1.0-1.8)|
|Nicotine patch + Nicotine
|2.3 (1.4-3.3)||1.3 (0.8-1.7)|
|Nicotine patch + Nortriptyline||2.3 (1.3-4.2)||0.9 (0.6-1.4)|
|Nicotine patch + Nicotine inhaler||2.2 (1.3-3.6)||1.1 (0.7-1.9)|
|Nicotine patch + 2nd-generation anti-depressant (paroxetine or venlafaxine)||2.0 (1.2-3.4)||1.0 (0.6-1.7)|
|Bupropion SR + Nicotine lozenge194||1.8 (1.0-2.5)||1.0 (0.6-1.3)|
*All study participants had 1 or more pre-defined chronic medical or psychiatric illnesses (see text).
† 12-week, end-of-treatment, continuous nonsmoking percent (placebo patch [n=31] vs. 100% replacement [n=31]) was 26% vs. 65% (odds ratio 5.2; 95% CI 1.8-15.6; P=0.0029)58
Efficacy of Controller and Reliever Medications, Used as Monotherapy
Estimated odds ratio and 95% Confidence Interval (CI) for continuous nonsmoking at 6 months using first-line medications, when compared to placebo or nicotine patch, are from Fiore MC, et al.1 and were based on studies using basically medically well, healthy study participants, unless otherwise noted:
|Medication||Odds Ratio & 95% CI (vs. Placebo)||Odds Ratio & 95% CI (vs. Nicotine Patch)|
|Nicotine patch (reference group)||—-||1.0|
SINGLE MEDICATION TREATMENT
|Varenicline (2 mg/day)||3.1 (2.5-3.8)||1.6 (1.3-2.0)|
|Nicotine nasal spray||2.3 (1.7-3.0)||1.2 (0.9-1.6)|
|Nicotine patch (High-dose: > 25 mg)||2.3 (1.7-3.0)||1.2 (0.9-1.6)|
|Nicotine gum (Long-term: > 14 weeks)||2.2 (1.5-3.2)||1.2 (0.8-1.7)|
|Varenicline (1 mg/day)||2.1 (1.5-3.0)||1.1 (0.8-1.6)|
|Nicotine inhaler||2.1 (1.5-2.9)||1.1 (0.8-1.5)|
|Clonidine||2.1 (1.2-3.7)||1.1 (0.6-2.0)|
|Bupropion SR||2.0 (1.8-2.2)||1.0 (0.9-1.2)|
|Nicotine patch (6-14 weeks treatment duration)||1.9 (1.7-2.2)||1.0 (N/A)|
|Nicotine patch (Long-term: > 14 weeks)||1.9 (1.7-2.3)||1.0 (0.9-1.2)|
|Nortriptyline||1.8 (1.3-2.6)||0.9 (0.6-1.4)|
|Nicotine gum (6-14 weeks treatment duration)||1.5 (1.2-1.7)||0.8 (0.6-1.0)|
Practical Treatment Tips
Treating tobacco dependence using multiple drugs with different mechanisms of action or differing pharmacokinetic profiles, as discussed immediately above, is often necessary to achieve maximum treatment effectiveness, as is the case with many other chronic illnesses including asthma. The family of nicotine medications have identical mechanisms of action as nicotinic receptor agonists but all have quite different pharmacokinetic profiles. In fact, each type of nicotine patch has different pharmacokinetic delivery. The mechanisms of action for the nicotine medications, bupropion, and varenicline, at the cellular and sub-cellular levels, are different. Also, when treating tobacco dependence, as is the case with asthma, it is critical that you select the correct tools to monitor treatment efficacy and safety. To facilitate such measurement, this Tool Kit contains instruments that are standard in tobacco dependence treatment and that we on the Tool Kit Committee have used in clinical practice. These include a quantitative Nicotine Withdrawal Symptom (NWS) Scale, based on the validated University of Minnesota, Hughes-Hatsukami scale and a reliable, validated tool for simply and accurately screening for depression. These should be used at each visit, particularly including the pre-stop-date visit(s). In this Tool Kit, for depression, we shall illustrate using the PHQ-9. Other excellent, validated depression tools include the Beck Depression Inventory (BDI-II) scale and the Centers for Epidemiologic Studies-Depression Scale (CES-D).
The PHQ-9, developed in 2001 by Kroenke et al.,197 contains 9 easy-to-answer questions, one of which deals specifically with suicidality, rated on a 0-3 Likert scale, for a maximum score of 27. The BDI-II®, developed in 1996 by Beck, Steer, and Brown, is a validated improvement and second edition of their earlier, validated 1961 Beck Depression Inventory (BDI).198 The BDI-II® contains 21 easy-to-answer questions, one of which deals specifically with suicidal ideation, another of which deals with irritability and takes 5 minutes to complete. Each question is rated on a 0-3 Likert scale, for a maximum score of 63 points.
In general, you should treat all patients in your practice who smoke with pharmacotherapy and with more than one medication, but at a minimum with at least one agent.1, 2, 188, 189 Like stepwise therapy for asthma, the prevailing concept is to balance the use of controller medication(s) with reliever/rescue medication(s). (See Stepwise Tobacco-Dependence Treatment Guide. We have designed the Stepwise Tobacco-Dependence Treatment Guide to help you pick a starting medication regimen for your patient based, on pre-diagnostic factors that you can readily determine with the tools provided in this Tool Kit. Like the NHLBI Asthma Treatment grid, note that presence of any one factor indicating a higher level of disease severity places the patient at that more severe disease state and thus intensifies therapy. You need to see and re-assess the patient 3-5 days after the Target Stop Date and after the patient commences with the initial treatment plan so that you can evaluate treatment response to make certain that:
- The patient has been able to readily stop smoking.
- Nicotine withdrawal symptoms are suppressed.
- The patient is not feeling depressed or dysphoric (occurs in only 10%-15% of patients stopping smoking, if treated with adequate pharmacotherapy for tobacco dependence).
- In essence, the patient is feeling normal for himself or herself.
At each follow-up visit, if your patient is not already on a controller medication or your patient is using reliever/rescue medication(s) with high frequency (>10-15 times/day), then you should consider adding a controller to your patient’s treatment regimen. This will simplify the treatment plan and facilitate treatment adherence. If your patient is already on a controller, e.g., nicotine patch, then either you should increase the patient’s dose (say, go from applying 1, to 2, Step 1 patches each morning), or you should add a second controller, e.g., bupropion.
The combination of bupropion and 1, standard, Step 1 nicotine patch is the only combination approved by the FDA for treatment of tobacco dependence. However, as discussed in detail earlier in this section, every combination tested and published in the scientific literature shows benefit over and above each single medication, while still maintaining an excellent safety profile. This multimodality approach has yielded significantly higher treatment success rates than either medication alone. Each of these medications acts on a different site on the dopamine and norepinephrine neurons.112 As noted above,194 the combination of bupropion and nicotine lozenge has also recently been shown to be effective and safe. There is every reason to think that bupropion + any other nicotine reliever medication would be similarly effective.
Using a sustained-release controller, the nicotine patch, in combination with any near-immediate-delivery nicotine reliever medication is significantly more effective than any of the medications alone. Nicotine patch + gum,68, 190 or lozenge,194 or nasal spray,69 or oral inhaler141 is more effective than using a single form of nicotine medication. Only one study in the tobacco dependence literature has studied long-term follow-up for 5 years after 1 year of active-medication treatment. That study showed that even 6 years after the target stop date, patients who had received the combination of nicotine patch + nicotine nasal spray for the first year were 2 to 3 times more likely to remain nonsmokers.69 These same studies have also shown these combinations to be safe.1 Regulation of nicotine intake is controlled at the CNS level; the brain literally will not let a person “overdose” with nicotine reliever medications. Such combinations can be especially helpful in reducing, if not completely eliminating, breakthrough nicotine withdrawal symptoms and thereby preventing relapse.1, 113
Combination Pharmacotherapy Safety
Data regarding medication safety is discussed below for each individual medication.
Controller Medications-Efficacy and Effectiveness Detail
Bupropion SR (Sustained Release), first marketed as an antidepressant, received a second FDA indication for treatment of tobacco dependence in May 1997. Bupropion is only available by prescription and comes in three separate formulations: Immediate Acting, which should be dosed every 8 hours; Sustained Release (SR), which should be dosed approximately every 12 hours; and Extended Release (XL), which should only be dosed once per day, in the morning.* A common misconception is that bupropion works by elevating mood in tobacco-dependent patients. Instead, bupropion works by slowing re-uptake of dopamine at the distal dopaminergic neuron and for some patients, filling the α4β2 nicotine receptors, thereby increasing dopaminergic neurotransmitter tone. This reduces the intensity of the compulsion to smoke and nicotine withdrawal-symptom severity. Indeed, the bupropion SR registration trials for the tobacco-dependence indication specifically excluded any one who was depressed.54, 62, 137
Bupropion has been shown to be effective tobacco-dependence treatment for non-depressed study participants;54depressed study participants;204 low-income, poorly educated, African-American study participants;205 adolescent study participants;206 primary care patients (as distinct from study participants),207, 208 and re-treating tobacco-dependent patients who used bupropion successfully in the past but relapsed after stopping bupropion.209
When used as monotherapy for non-depressed patients, bupropion SR shows classic, highly significant, dose-response outcome at the end of 6-weeks treatment from Target Stop Date; 44% not smoking with 300 mg, daily; 39% with 150 mg daily; 29% with 100 mg daily; and 19% with placebo.54
Practical Treatment Tips
Treatment with bupropion should be initiated 1-2 weeks before the anticipated target stop date to allow for adequate CNS levels. Typically, start the patient with 150 mg of bupropion SR each morning for three days, and then increase to 150 mg b.i.d (or 300 mg, qAM, for the XL formulation).
Combination treatment with bupropion and nicotine medication is particularly effective1, 113 and is recommended to help reduce withdrawal symptoms and also reduce the likelihood of weight gain. (Also, see above.)
Nicotine transdermal system has been available by prescription in the United States since late December1991, and over-the-counter (OTC) since July 1996. The United States Food and Drug Administration (FDA) based its decision on moving the patch from prescription to OTC status primarily on the safety of the nicotine patch as a medication for treating tobacco dependence. The efficacy of the patch was definitive and unequivocal. The standard, over-the-counter nicotine patch dosing instructions, however, as printed on the box (only 1, Step 1 patch delivering 21-mg nicotine/24 hrs or 15-mg nicotine/16 hrs), inadequately treats about 80% of users, failing to suppress nicotine withdrawal symptoms and therefore causing the patient to relapse. Most tobacco-dependent individuals who smoke ≥1 pack per day or have a serum or saliva cotinine level ≥250-ng cotinine/mL blood will need at least 2, Step 1 patches57, 210 plus a second controller, i.e., bupropion SR (see “Combination Pharmacotherapy”, above), plus prn use of one or more nicotine reliever/rescue medications (see above) in order to adequately suppress nicotine withdrawal symptoms. As discussed in §1_6 of
this Tool Kit, this approach-providing effective pharmacotherapy-requires physician supervision and monitoring. (See also Stepwise Tobacco-Dependence Treatment Guide, in this Tool Kit.) Side effects such as sleep disturbance and bizarre dreams are reduced if the patient removes the prescribed nicotine patch dose at bedtime, approximately 16 hours after applying the patch(es) in the morning. Finally, remember that, despite similar amounts of available nicotine in a Step 1 patch compared to a pack of cigarettes, absorption differences between the routes of administration can profoundly affect blood levels achieved, making it necessary to adjust dose and frequency to effect rather than relying on a simple substitution calculation.
Varenicline tartrate was the first medication approved for treating tobacco dependence in almost a decade. In May 2006, the FDA approved varenicline, a sustained-release medication that is a selective α4β2 nicotinic receptor partial agonist and an α7 nicotinic receptor full agonist.211, 212 Varenicline blocks, but not completely, nicotine from binding to these receptors and prevents nicotine from producing the reinforcing and rewarding effects associated with tobacco use. On the agonist side, varenicline, binding into the α4β2 and α7 nicotinic receptors, stimulates the dopaminergic neuron to release some dopamine at the distal terminus of the neuron, attenuating-but only partially-nicotine withdrawal symptoms. Varenicline is clearly the most effective monotherapy for tobacco dependence (see Table 2).1 Three independent studies showed varenicline to be superior to bupropion SR in tobacco-dependence treatment efficacy.55, 170, 213
When used as monotherapy, varenicline shows classic, highly significant, dose-response outcome at the end of 6-weeks treatment from Target Stop Date; 41% not smoking with 1 mg, twice daily (2-mg total, daily dose); 31% with 1 mg, once daily; 25% with 0.3 mg, once daily; and 14% with placebo.213 (This same trial also had a fifth arm, bupropion SR, 150 mg, twice daily [300-mg total, daily dose]. Percent not smoking, at the same time-point, was 29%, which was significantly better than placebo but not significantly better than varenicline, 1 mg, twice daily.213) In a series of larger trials specifically designed to compare treatment efficacy of varenicline head-to-head with bupropion SR, tobacco-dependent patients treated with varenicline had a biochemically confirmed quit rate of 50% at the end of 12-weeks treatment, superior to and significantly better than those patients treated with bupropion SR (36%) or placebo (21%).55, 170 Thus, three independent trials show monotherapy with varenicline, 1 mg, twice daily, to be superior to monotherapy with bupropion SR, 150 mg, twice daily.55, 170, 213
Practical Treatment Tips
Treatment with varenicline should be initiated a minimum of 7 days before the anticipated Target Stop Date to allow for development of adequate therapeutic CNS varenicline levels. Many clinical experts, including those on the CHEST Tool Kit Committee, start varenicline 2 or more weeks before the Target Stop Date, depending on patient response. (Some patients, within days after starting varenicline and before their Target Stop Date, see the number of cigarettes they are smoking daily falling, without any particular effort on their part and without any nicotine withdrawal symptoms.) Typically, start the patient with 0.5 mg of varenicline each morning for three days; then, increase to 0.5 mg, b.i.d., for four days; and then on treatment-day 8, increase the dose to 1.0 mg, b.i.d.
Clinical Caveat: Although FDA package labeling states that the Target Stop Date should be the very day that the varenicline total daily dose is increased from 1 mg daily to 2 mg daily, this makes no pharmacokinetic sense, because it takes at least 4 days after a dose change for varenicline serum (and presumably brain) levels to reach new steady-state equilibrium.211 This is probably the reason why many clinical experts want their patients using varenicline for a total of 2 weeks before Target Stop Date.
Reliever (or Rescue) Medications-Efficacy and Effectiveness Detail
Nicotine polacrilex gum was approved by the FDA in 1984, and has been available without prescription-over-the-counter (OTC)-since 1996 in both 2- and 4-mg dosage formulations and comes in several flavors. Nicotine is released through the chewing action and absorbed into the bloodstream through the lining of the mouth. To maintain the even flow of nicotine, it must be chewed slowly until a slight tingling occurs or a peppery taste is experienced. Then it must be placed between the cheek and the gingiva and parked until the peppery taste or tingling is gone. This cycle is repeated for about 30 minutes per piece. Technique is important; if chewed improperly, the gum loses effectiveness because absorption is compromised while the likelihood of gastrointestinal side effects such as nausea and hiccups increases.
In general, patients should not exceed 20 pieces per day, but some will need more, particularly if this is the only medication they are using. The CHEST Tool Kit Committee members’ experience is that patients do better if they start with the 4-mg dose, even if this is being used with controller medications, such as nicotine patch or bupropion SR (see below). However, most people report that 9 to 12 pieces per day of the 4-mg dose controls their urge to smoke and suppresses nicotine withdrawal symptoms. Highly dependent users, for example those whose time to first cigarette after awakening is shorter than 30 minutes, should be encouraged to use the 4-mg rather than the 2-mg dose.
Nicotine polacrilex lozenge was approved by the FDA for OTC distribution in late 2002. It is available in 2- and 4-mg forms and comes in several flavors. The use strategy is much the same as with nicotine gum; at least 9 lozenges are required per day for initial, effective treatment (weeks 1-6), with 20 the probable maximum. The 4-mg dose is generally more effective at suppressing nicotine withdrawal symptoms, so patients should generally start with that strength, and particularly those patients who smoke their first cigarette of the day within 30 minutes of waking.214 The 2-mg strength is more useful for tapering. Elderly or edentulous patients, or those with difficulty chewing may better tolerate lozenges than the gum. The nicotine lozenge should be placed between the cheek and gum, and allowed to dissolve slowly over a 20-30 minute period while occasionally moving the lozenge to a different place in the mouth. The lozenge should never be placed under the tongue, since that will stimulate excessive saliva production, causing the patient to swallow the nicotine-laden saliva and suffer side effects, such as nausea, abdominal cramping, or heartburn.
Nicotine [oral] inhaler was approved by the FDA in 1997. Only available by prescription, the inhaler works by releasing nicotine into the mouth and throat through a mouthpiece containing a plastic cartridge. The name “inhaler” is a misnomer; the nicotine is not inhaled into the lungs. Nicotine is absorbed only across the oral mucosa,215 the same site as nicotine gum and lozenge. An important difference, though, is that the nicotine absorption from the oral inhaler is unaffected by oral pH. Release of nicotine from both the nicotine gum and lozenge is highly pH-dependent.216 Thus, for social settings, such as at a bar or party, the oral inhaler and nasal spray would be a better reliever medications than gum or lozenge. In fact, deep inhalation from the oral inhaler can increase side effects (cough and sore throat) without adding to its efficacy. Nicotine that enters the bloodstream through the mucous membranes of the mouth or throat does so more slowly than the nicotine in cigarettes. The “dose” of the inhaler is determined by the frequency and intensity of puffing. Patients can use the inhaler alone or as an adjunct to the nicotine patch or bupropion, and can use it at scheduled time intervals to control cravings, or as a PRN reliever in response to acute, cue-induced cravings.
Nicotine nasal spray, approved by the FDA in 1996 and available by prescription only, reaches the bloodstream faster than any other nicotine medication. As a result, it has an impact more similar to the cigarette than other forms of nicotine replacement. Nicotine is sprayed into the nose where it is absorbed through the nasal mucosal lining. Effectiveness is maximized when used in conjunction with the nicotine patch.69 Like the oral inhaler, nicotine absorption from in the nasal spray is not affected by pH, because the nicotine is not at all bound to a pH-dependent ion exchange molecule, as is the case with nicotine gum and lozenge.
Nicotine water and nicotine lollipops have no role in the treatment of tobacco use and are not currently recommended. In fact, many are concerned that they are being marketed not for their therapeutic efficacy but rather as early nicotine addiction systems for young children.
E-Cigarette. In 2009 an electronic device that vaporizes nicotine at high temperature and which contains no tobacco has been commercially marketed in the United States as the E-Cigarette. This device has not been approved by the FDA and no data of any kind are available.217 No information defining the contents of the volatilized nicotine is available. No toxicology data are available. No safety data are available. No efficacy data are available. Because this device does not claim to be a cigarette or tobacco product, but a nicotine delivery system, it falls under the FDA’s authority to regulate. As of this Tool Kit’s press time, the manufacturer had not submitted any data for review to the FDA, so the FDA is likely going to require the manufacturer to pull the E-Cigarette from the market.217 The CHEST Tool Kit Committee cannot recommend use of the E-Cigarette at this time.
- All FDA-approved tobacco-dependence medications-nicotine medications, bupropion, and varenicline-are generally safe and well tolerated. The safety record of nicotine medications and bupropion has been established over decades of use in tens of millions of tobacco-dependent patients. The most commonly occurring side effects (see Quick Reference Guide to Pharmacotherapy) are not of any significant medical consequence, are generally mild, and oftentimes either resolve within a few weeks, or can be readily treated so that the patient can continue to get the benefit of needed tobacco-dependence pharmacotherapy.
- For example, insomnia, specifically difficulty remaining asleep, occurs in 30% of all bupropion users and is mild in about three fourths of those. Insomnia usually resolves in several weeks. If a continuing problem, though, before the Target Stop Date, switching the patient to the same dose, but in the once-daily XL formulation, taken in the morning, will usually solve the problem. Alternatively, if the patient is taking bupropion SR, 150 mg, q12h, the second dose can be taken earlier, 8 hours after the first dose.
- Similarly, nausea is the most frequently occurring side effect from varenicline, occurring in 30%-40% of patients. For three-fourths of them nausea is mild and generally not a problem that warrants intervention. Such nausea usually resolves within 2-3 weeks. Once again, this is a good reason to delay the Target Stop Date so that the patient is feeling back to baseline before stopping smoking. Most patients find the benefits of varenicline far outweigh this side effect. If the nausea is more than mild and is not resolving before Target Stop Date, then you can lower the dose, because all of varenicline’s side effects are dose-related. Its therapeutic effectiveness is also dose-related, so reducing the dose to control nausea may provide the patient with a sub-therapeutic dose of varenicline. In that case you and your patient could consider adding an anti-emetic, so that the patient can continue using a therapeutically effective dose of varenicline. Alternatively, you could switch to a completely different medication treatment plan. For many reasons, including your patient’s sense of self-confidence and being in control of the situation, this is all best sorted out before the Target Stop Date.
- Medications with extensive cytochrome metabolism, such as theophylline and warfarin, or other medications, including insulin and thyroxin, may require dose adjustments after stopping smoking.
- Despite the well-established safety record of these medications and despite their effectiveness in treating the single leading cause of premature death and disability in the United States-tobacco dependence-physicians and patients underutilize them because of unfounded fears and concerns regarding their safety. We would never think of denying an asthmatic use of effective pharmacotherapy. We must approach treatment of tobacco dependence with same level of medical insight, sophistication, thoroughness, and urgency that we bring to the care of our asthmatic patients.
- Treatment-emergent depression, mood changes, and suicidality can occur whenever a person stops smoking, with or without medications, including bupropion, nicotine medications, and varenicline. If a tobacco-dependent patient is depressed, the physician should evaluate if the depression is due to nicotine withdrawal and therefore under-dosing of tobacco-dependence medication(s) or due to unmasked depression that requires a psychiatric evaluation. In rare cases, the changes in behavior or mood may be caused by the medication or inadequate dose of the medication. The physician should routinely monitor for the development of psychiatric problems at each office visit, using a tool such as the PHQ-9 discussed above, and, depending on the underlying cause, either increase nicotine medication dose, change controller medications, increase the doses of other controller medications, or add nicotine rescue medications. Also, the treating physician should consider psychiatric referral in such cases to determine whether these changes reflect an underlying psychiatric state, or are merely a manifestation of nicotine withdrawal. On July 1, 2009, the United States Food and Drug Administration (FDA) issued a Black Box warning for both the bupropion and varenicline prescribing labels, highlighting the apparent association of serious neuropsychiatric symptoms in patients using these medications.218 These symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide. The possible risks of serious adverse events occurring while using varenicline or bupropion should always be weighed against the “… health benefits of quitting smoking [which] are immediate and substantial.”218 Given our present state of knowledge, however, “it is impossible to know whether the psychiatric symptoms and suicidal behavior reported in patients taking varenicline or bupropion in order to stop smoking are due to the drugs, the smoke, the smoker, the cessation of smoking or simply the usual causes of such symptoms and behavior in the larger community.”
Specific, Medication-Specific Side Effects
All FDA-approved tobacco-dependence medications-nicotine medications, bupropion, and varenicline-are exceptionally safe and well tolerated. The most commonly occurring side effects (see Quick Reference Guide to Pharmacotherapy) are not of any significant medical consequence, are generally mild, and oftentimes either resolve within a few weeks, or can be readily treated so that the patient can continue to get the benefit of needed tobacco-dependence pharmacotherapy.
- The most common side effects when using bupropion are:
- Headache (30%)
- Insomnia, specifically difficulty remaining asleep (30%)
- Xerostomia, or dry mouth (15%)
These side effects are generally mild and resolve within 2-4 weeks of starting bupropion.
- Bupropion SR has a reported seizure incidence of 0.1%. This is less than the reported seizure incidence of SSRI-type anti-depressants. Seizure has not turned out to be a problem in tobacco-dependence over the past 12 years. Patients with any of the following pre-existing conditions should not routinely be prescribed bupropion. Doing so reduces the seizure probability to close to zero:
- History of grand mal or petit mal seizures
- History of brain surgery
- History of significant brain trauma
- History of anorexia nervosa
- History of bulimia
- Taking a medication known to lower seizure threshold
- Current alcoholic
- Hypertensive patients receiving combination bupropion and nicotine therapy should be monitored for treatment-induced blood pressure increase.
- Patients, especially those with a history of depression or suicidality, should be carefully monitored for nicotine withdrawal induced or bupropion-induced depression or suicidality (see below for details). That said, in 12 years of use in tobacco-dependence clinical practice, bupropion is a highly effective and safe medication, particularly for use in tobacco-dependent patients with psychiatric co-morbidities.
- The most common side effects of nicotine medications are generally related to the specific nicotine delivery system:
- Erythema, edema, or pruritis at the patch application site.
- Gum and Lozenge
- Nasal Spray
- Nasal mucosal irritation
- Oral Inhaler
Most of the side effects are secondary to incorrect usage of the delivery system and can be corrected by re-instruction in optimal use technique. In the case of cutaneous irritation at the nicotine patch application site, this is usually due to the adhesive of the specific patch brand. Switching brands frequently solves this problem. When it does not, treating the patch application with an appropriate topical steroid or prescribing a non-sedating anti-histamine or a leukotrine modulator will solve the problem.
- Nicotine medical products must be kept out of reach of children and pets. Don’t forget, this includes those that have been used and discarded, particularly nicotine patches.
- Contrary to widespread belief and product insert disclaimers, smoking while using nicotine medications is not in any way a deadly combination.139,218 While tobacco-dependent patients should be encouraged to stop smoking completely, the treating physician should emphasize that patients should continue their medications particularly in the face of a lapse. Patients should also realize that a lapse while using a given treatment combination means that their treatment plan is not completely adequate. Thus, they should call their treating physician promptly so that the treatment plan can be revised and effectiveness improved. (see Treatment Process and Approach, particularly the section describing the ARMR concept.)
- Overdose with nicotine medications is rare. It is more likely to occur with nicotine patch, since the patch has a fixed, pre-programmed amount of nicotine to deliver. Overdose is extraordinarily unlikely with the nicotine rescue medications, since the central nervous system self-regulates nicotine intake, just as it does when the person is smoking cigarettes. There is a large margin between achieving therapeutic effect, suppressing all nicotine withdrawal symptoms, and appearance of nicotine toxicity signs or symptoms. The first symptoms of nicotine overdose are abdominal queasiness, followed by nausea, then emesis. Serum nicotine level must get acutely much higher in order for tachycardia to occur, let alone tachyarrhythmias.
- Patients with heart disease or hypertension can safely use nicotine medications.218, 219 Surveillance of blood pressure control and cardiac status is prudent, especially for patients on high-dose nicotine therapy.
- The decision to use nicotine medications in pregnant or breast-feeding patients should be individualized based on the relative risk-benefit of continued smoking. Use of any tobacco-dependence medications during pregnancy should proceed only under physician guidance. (See U.S. Public Health Service, Clinical Practice Guideline: Treating Tobacco Use and Dependence (2008 Update),1 Hodgkin JE, Celli BR, and Connors GL (Eds), Pulmonary Rehabilitation: Guidelines for Success, 4th Edition, 2009, Chapter 16,113 and recent documents from the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA)188,220 for more detailed discussion of this point.)
- Nicotine medications, including the controller nicotine patch (see below) are among the safest medications used in a pulmonary medicine practice.139 It is important to remember that not one patient has died from therapeutic nicotine since nicotine gum was approved in 1984, while in that time over 8 million cigarette smokers have died from the myriad diseases caused by tobacco. Simply stated, these medications are woefully underutilized by physicians and by the patients who could benefit from them.
As is the case with the nicotine medications and bupropion, varenicline is also safe for the vast majority of patients and generally well tolerated. The most common side effect is nausea, which occurred in 30% of study subjects, was mild in 75%, and tended to resolve by the Target Stop Date.55, 73, 170 In those studies, nausea was also the most common cause of premature study withdrawal for an adverse event, with 3% withdrawing.
- The most common varenicline side effects, also generally mild, but occurring significantly more frequently than placebo, are:
- Nausea (30%)
- Abnormal Dreams (13%)
- Headache (13%)
- Constipation (9%)
- Flatulence (6%)
- Xerostomia (Dry Mouth) (6%)
- Emesis (5%)
- Patients, especially those with a history of depression or suicidality, should be carefully monitored for nicotine withdrawal induced or varenicline-induced depression or suicidality (see below for details)
- Varenicline does not produce drowsiness or seizure disorder.
Depression, Suicidality and Tobacco Dependence
Suicide is associated with cigarette use159, 160 and is unequivocally linked in a significant dose-response relation to number of cigarettes smoked per day.221-223 For example, cigarette smokers have an increased odds ratio of committing suicide that is 2.6 compared to the non-smoker (95%CI = 1.6-4.2).224 Moreover, the risk of committing suicide among cigarette smokers not trying to stop smoking increases significantly (P<0.001) with the number of cigarettes smoked/day,221 with those smoking >20 cigarettes/day more than 2-fold more likely to commit suicide than those who have never smoked.221Cigarette use may also be an independent, dose-response risk factor predicting suicide.221-223 In addition, suicide incidence is higher in cigarette users, independent of confounding factors, such as income, race, previous myocardial infarction, diabetes, alcohol use,224 and also previous depression history or substance abuse.159
Depression, Suicide, Cigarette Use and Pharmacotherapy
Major depressive disorder occurs in up to 31% of people without any prior history of depression if they attempt to stop cigarette use without the benefit of pharmacotherapy, and in up to 75% of those who have had a previous depressive episode even though not depressed when they tried to stop cigarettes.200 CHEST Tool Kit Committee Members have observed this in clinical practice and have also observed acute suicidality when patients have attempted to stop smoking without pharmacotherapy. They have also observed psychiatric problems and suicidal ideation when the medication doses were sub-therapeutic. In all cases major depressive disorder or suicidality have promptly resolved upon either increasing the dose of nicotine medication, adding a rescue medication, such as nicotine nasal spray, to controller, such as nicotine patch or bupropion, using nicotine patch in combination with bupropion or increasing the dose of either until the depression or suicidality has come under control. Additionally, CHEST Tool Kit Committee Members have consistently observed that such acute psychiatric states resolve within minutes after the patient takes as few as 1 or 2 cigarette inhalations. This holds true whether the patient is on no medications or sub-therapeutic doses of tobacco-dependence medication.
On July 1, 2009, the United States Food and Drug Administration (FDA) issued a Black Box warning for both the bupropion and varenicline prescribing labels. This was based on the reporting of 37 tobacco-dependent patients taking varenicline who either made a suicide attempt or actually committed suicide. Of the 37, 18 were attempted suicides.225 However, neither the prescribing information nor the FDA newsletter placed these 19 completed suicides into perspective, which could have been done by expressing them as the annualized number of suicides/100,000 varenicline users. For example, over approximately this same time period 5.5 million Americans used varenicline. This would then calculate as a completed suicide incidence rate of 0.49/100,000 varenicline users/year, which is far lower than the overall suicide incidence rate in the U.S. population of 11.01/100,000/year.226
Furthermore, in the largest published, peer-reviewed study to date, comparing 412 consecutive patients (64 of whom had diagnosed depressive disorder, 14 bipolar disorder, 24 psychosis and depression, 7 psychosis, only, and 2 eating disorders), 208 received varenicline and 204 nicotine medications, no patient in either treatment condition, with or without mental illness, committed suicide or experienced worsening or new onset of depression or other mental disorder.202
Clearly, the risk benefit analysis favors the use of tobacco cessation medications when compared to the fact that each year 443,394227 of the 43 million U.S. cigarette smokers40 die of tobacco-caused illnesses. Over their lifetime, 50% of all cigarette smokers, if not provided effective tobacco-dependence treatment, will die of tobacco-caused diseases.158, 176That is an annualized death rate of 1,031.1 deaths/100,000 cigarette smokers per year.
Second-Line Medications as Controller Medications
Second-line medications have variable efficacy in tobacco use treatment, and should be considered for use only after first-line treatments have failed. The primary reasons for this recommendation include: (1) they do not currently have FDA approval for treatment of tobacco dependence, and (2) there are more potential side effects than exist with the first-line treatments.
Clonidine is primarily used as an antihypertensive. Specific dosing regimens for use in cessation have not yet been determined. Its efficacy in cessation is limited by its rather significant side-effect profile. Abrupt discontinuation of clonidine can result in nervousness, agitation, headache, tremors, a rapid rise in blood pressure, and elevated catecholamine levels.
Nortriptyline is an antidepressant but published scientific studies show it to have comparable efficacy in tobacco dependence to bupropion SR.138, 228, 229 However its TID dosing schedule and expanded side-effect profile make it less well tolerated and harder to use. It has therefore not received the same endorsement that bupropion has secured. Nortriptyline should be considered in smokers who are likely to benefit from the addition of an antidepressant, but for whom bupropion is contraindicated (i.e. seizure disorder, eating disorder, prior adverse reaction to bupropion, etc.).
Duration of Use and Medication Tapering
Longer-duration pharmacotherapy improves stopping smoking.1, 2, 69, 73, 137, 138, 230 Six months or 1 year of treatment produces higher, continuous non-smoking rates than 6 weeks or 3 months of treatment. Most patients who want to stop smoking therefore should receive a minimum of 6 months of nicotine, bupropion, varenicline, or an appropriate combination. Most adverse events to any of the tobacco-dependence medications occur within the first few days or weeks of use. No evidence exists that extended medication use beyond 6 months or 1 year exposes the patient to any increased medical risk. In fact, the FDA specifically recommends a longer term (> 6 months) maintenance treatment for bupropion SR, in part because of the strong supporting clinical trial data showing improved effectiveness with longer treatment.137,231, 232
Unfortunately, in general the manufacturers’ recommendations for treatment duration with nicotine medications are not based on systematic research. Patients generally use nicotine medications for only 2 weeks5 — not long enough to derive any clinical benefit. To obtain the best result, patients should receive at least a 3- to 6-month treatment course with nicotine medications1, 2, 113, 233, 234
Patients who are especially likely to benefit from more intensive and longer-duration treatment, including more frequent office visits, and combination pharmacotherapy rather than monotherapy, include cigarette users who are highly nicotine dependent (as measured by the Fagerström Test for Nicotine Dependence (FTND)),52, 104, 149, 155, 235, 236 have a higher serum cotinine level while still smoking,152, 153 smoke more cigarettes per day,61,237,238 are alcoholic,239 depressed,200,240 unmarried (divorced, separated, never married, or widowed), female,58, 61, 69, 150, 241-243 have another cigarette smoker in the household,150, 244 previously tried to quit smoking,150, 244 experienced nicotine withdrawal symptoms with previous quit attempts,104-106 were <17 years old when they started smoking,153, 244 or are younger at the start of treatment.150, 231, 245
Generally, after 3-6 months the patient should attempt to gradually reduce dosage of nicotine medications, one at a time, under medical supervision. It is crucial for the treating physician to closely monitor nicotine withdrawal symptoms and mood state, including depression and suicidality, after reducing or stopping any tobacco-dependence medication and reinstating the previous doses if withdrawal symptoms or dysphoria increase. Increased nicotine withdrawal symptoms generally account for most cases of relapse,113 and must remain suppressed in order for the patient to remain tobacco free.
Long-term continuous use of pharmacotherapy may be appropriate in some patients. Although gradual reduction in doses and number of medications is the pharmacotherapeutic goal, protracted, indefinite use is obviously preferable to relapse. Occasionally, patients will express a concern that prolonged use of nicotine medications will delay abstinence; however this is a misconception. Unlike tobacco use, these medications do not contain toxins, the nicotine medications, specifically, do not produce nicotine surges in the bloodstream, or do not lead to dependence, and can be used for long periods without significant safety concerns.1, 2, 234, 246
Relapse is common following termination of medication, and is more likely to occur with higher FTND scores. This effect is seen irrespective of treatment approach. It is useful to think of the compulsion to smoke as the visible manifestation of a poorly controlled disturbance in nicotinic neurobiology, similar to the notion that wheeze is the audible manifestation of poorly controlled airway inflammation. As with asthma, there is no evidence that any of the pharmacotherapeutic agents reverse the underlying root cause of the abnormalities. Instead, medications should be intended to control the compulsion to smoke long enough to allow the patient to reverse the neuropathologic changes related to nicotine addiction. Nicotine dependence is a chronic condition, and some patients will require maintenance therapy of indefinite duration. Relapse should be anticipated and prevented but if it does occur, then it should be treated, as with any chronic condition.112, 113Patients may require lifetime treatment or repeated cycles of treatment. Therefore, the physician and patient should have a plan for regular follow-up visits, as would be done with asthma.
This Chapter presents a completely new concept in the pharmacologic management of tobacco dependence, based on rational, pharmacotherapeutic principles that the members of the CHEST Tool Kit Committee, as well as other physicians, have used in routine clinical practice for over 10 years. This approach is effective, it works, and it can be adopted and modified for any medical office or inpatient practice setting. The approach proffered by this Tool Kit changes the paradigm for tobacco-dependence treatment. As one of our Committee members accurately pointed out, “If we always do what we’ve always done, we’ll always get what we’ve always gotten.”