Introduction:
Tobacco use continues to be the leading cause of preventable disease and death in the world. According to the World Health Organization (WHO) is a risk factor of six of the eight leading causes of mortality highlighting cardiovascular diseases as the most significant. It has been seen that smokers die on average 10 years earlier than nonsmokers and that the cessation of tobacco use at 60, 50, 40 or 30 years increases life expectancy in 3, 6, 9 or 10 years respectively 2 .
In Chile, it is estimated as a causal factor of 15,000 deaths per year, which constitute 17% of all deaths 3 . These figures are conditioned because in the country there is a high prevalence of consumption, both in adults and in young people, 4,5 having the sad record of being the country of the Americas with the highest consumption among young people 6 .
NicoDerm CQ Nicotine Patch, Clear, Step 1 to Quit Smoking, 21mg, 14 Count
Given the seriousness of the problem, the WHO prompted an international treaty on public health to control this epidemic in the world, culminating with the approval, in 2003, of the Framework Convention on Tobacco Control. In Chile, this treaty was approved in March 2005.
Under these guidelines, WHO, in 2008, launched the initiative MPOWER 7 , which summarizes the strategies that should be implemented for tobacco control at the international level. The six points this strategy consist of:
• Monitoring: Monitor tobacco consumption and preventive measures
• Protecting: Protecting the population from exposure to tobacco smoke
• Offering: Offer help for the abandonment of tobacco use
• Warning: Warn of the dangers of tobacco
• Enforcing: Enforcing the prohibitions on advertising, promotion and sponsorship
• Raising: Increasing tobacco taxes
In this context, smoking cessation aids appear as one of the pillars for the control of smoking, where the professionals of the health team have a great responsibility.
In this article we present the bases of tobacco addiction mechanisms, a general approach to their treatment and the psychosocial and pharmacological therapies available today.
Smoking, chronic addictive disease.
Since 1988, the year in which the Report of the US Surgeon General, entitled "Addiction to Nicotine," 8 was published , there is solid evidence of the addictive condition of tobacco use. The main conclusions of this report were that tobacco is addictive, that nicotine is the drug that causes addiction and that the psychopharmacological process involved in this addiction is similar to that of other drugs, such as heroin or cocaine.
At present, the addictive capacity of tobacco is beyond doubt and it is considered that smoking is a chronic systemic disease that belongs to the group of addictions, classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) of the American Psychiatric Association 9 . According to this classification, nicotine dependence is diagnosed by the presence of 3 or more of the seven proposed criteria ( Table 1 ), during a continuous period of 12 months. In turn, the criteria for the diagnosis of nicotine withdrawal are specified ( Table 2 ). The WHO International Classification of Diseases (ICD-10) also includes smoking within the "Mental and behavioral disorders due to tobacco use", in section F17, whose criteria are very similar to those of IVD IV: Once 7 criteria are condensed into 5 and a sixth is added in relation to the intense desire to consume the substance 10 .
The origin of the addiction is multifactorial, involving biological, genetic, psychological and social factors. The clinical manifestations depend on the individual personality characteristics of each individual, as well as the socio-cultural circumstances that surround them. The main symptom is the imperative or compulsive need to return to consume tobacco to experience the reward it produces and also avoid the withdrawal syndrome.
Although tobacco contains thousands of substances, it is nicotine that is most frequently associated with dependence. Nicotine is a psychoactive drug that generates dependence, with specific physical alterations and behaviors, producing in the smoker the search and compulsive use of the drug, despite the negative consequences for health.
Structurally, nicotine is a tertiary amine. Its absorption is mainly at the alveolar level, this being very fast, due to the large contact surface of the alveoli and the dissolution of nicotine in fluids with physiological pH. Minorly it is absorbed in the buccal mucosa, where it is dependent on pH, since the cigarette smoke is acidic (pH 5.5) and therefore nicotine is ionized, hindering its absorption.
After inhaling the smoke, nicotine reaches the brain in just 9 seconds. Then, their brain levels decline rapidly as it is distributed in other tissues (autonomic ganglia, adrenal medulla and neuromuscular junctions) and is metabolized in the liver by enzymes of the CYP2A6 family. Finally, its metabolites are excreted through the kidney, with an average life of 2 hrs. approximately 11 .
Nicotine acts through its binding to nicotinic acetylcholine receptors, whose structure corresponds to ion channels composed of 5 subunits. There are about 17 different subunits and the combination of these gives different properties to each receiver. It has been shown that, in nicotine addiction, α4β2 receptors play a determining role due to their high affinity and sensitivity to nicotine. They are formed by two subunits α4 and three β2 and are located mainly in the ventral tegmental area (within the reward circuit of the brain). The α4 subunit would be more important in the production of the pleasure sensation when smoking and the β2 subunit in the self-administration behavior associated with nicotine 12 .
Nicotine produces a series of alterations in the CNS that would explain its addictive power, in which the most relevant is the increase in dopamine release in the nucleus accumbens, producing a sensation of pleasure and good , which determines physical dependence. Although the dopaminergic system is the most studied for its importance in the reward, it is necessary to mention that nicotine also acts in other brain systems that help mediate its addictive effects (cholinergic, gabaergic, glutamaergic, serotoninergic, noradre -nérgico, opiate and endocannabinoid). The advances that are achieved in the subject, will be very useful in the future for the progress of the pharmacotherapy of this addiction.
Treatment of smoking.
At present, there is a consensus that smoking cessation interventions must have two components: psycho-social and pharmacological. Both should be included in the support of anyone requesting help to quit smoking.
Psycho-social strategies, which mostly have a cognitive-behavioral approach, are aimed at the smoker recognizing his addiction, his personal characteristics, modifying behavior patterns, developing strategies and skills to achieve and maintain abstinence, which usually means changing routines and lifestyles, that is to learn to "live without tobacco".
Clinical confrontation of smoking
Anyone who consults a health facility, public or private, should be asked whether or not they consume tobacco, according to the algorithm shown in Figure 1 . When the person is willing to try to stop smoking, the recommended general strategy is that of the 5 A, which can be adapted from the brief to the specialized intervention, depending on the time spent on the intervention and the therapist's training. When the smoker does not want to stop smoking at that time, the strategy of the 5 Rs is used. In the following paragraphs the two mentioned strategies are developed.
Figure 1: Algorithm to treat tobacco consumption. Modified from ref. 13
Brief counseling: 5 A methodology
In practice, most of the interventions are based on a methodology called 5 A 13 , by the initial of the 5 stages that constitute it: Find out, Advise, Agree, Help and Accompany. It basically consists in stimulating and promoting the intention to stop smoking and to help those already motivated in the cessation of smoking. The brief counseling should be carried out in the consultation of any health professional, regardless of the reason for consultation. A trained professional should not take more than two to three minutes in his application.
Find out: all patients should be asked about tobacco consumption, taking advantage of all instances through which they attend health facilities. He is asked about the number of cigarettes he smokes daily and the time of the first cigarette after getting up.
Advise: after asking, the patient should be advised to stop smoking. The advice should be clear and firm, personalizing the convincing arguments: in adolescents, the effect of smoking on their ability to exercise and poor school performance should be emphasized; the pregnant woman is concerned about her child and the risks of childbirth; the adult is more afraid of the diseases that could develop from tobacco and the possible damage that it can cause to his children and those around him.
Agree on the type of intervention: there are different types of interventions, depending on their availability to change. a) If the patient does not want to stop smoking now: explain the harmful effects of tobacco use and offer support for the future. b) If the patient is insecure: discuss their fears or fears and encourage motivation explaining the advantages of not smoking. Invite him to quit when he is ready. c) If the patient is determined: offer help and plan a strategy to stop smoking.
Help: if the patient is willing to try to stop smoking, he should be helped to develop a plan of action and eventual pharmacological support. A date to quit smoking is selected with the patient, within the next 2 to 4 weeks, which is called "Day D". It is not advisable to do it in periods of high stress, and on the other hand, it is necessary to consider that there is no ideal time to stop smoking, but before it is better than after. To consolidate the commitment, it is suggested that a contract-commitment be signed specifying the agreed date and where the therapist also commits to provide all patient support.
Accompany: patient follow-up should be scheduled. It is recommended to establish a follow-up visit one to two weeks after 'D-Day.' A second follow-up visit should be scheduled one month after the first, as a further control.
Strategy to use when patients do not want to stop smoking: 5 R
There are patients who are not willing to make an attempt to stop smoking at that time. In front of these smokers the strategy of the "5 R" 14 must be developed, named for the initial of the 5 points to be considered: Relevance, Risks, Rewards, Resistances and Repetition.
Relevance: Discuss with the patient the importance of quitting smoking for him, for his children and family.
Risks: Help the patient identify the risks of smoking. Emphasize that smoking low nicotine cigarettes or using other forms of tobacco will not eliminate these risks. Examples: worsening of their illnesses, sexual impotence, spouse with higher risk of lung cancer and coronary heart disease, etc.
Rewards: Encourage the patient to recognize the benefits of quitting. Examples: improvement of your health, saving money, better personal and household smell, healthier children, etc.
Resistances: Try that the patient identifies the barriers to stop smoking and offer help to deal with them. Examples: withdrawal symptoms, weight gain, etc.
Repetition: This strategy should be repeated every time you consult a non-motivated smoker.
If this is done systematically, many smokers are motivated and made concrete attempts to stop smoking.
Next we will refer to the pharmacological treatment, subject in which there have been important advances in the last years.
Pharmacotherapy of smoking
Up to now, the US Food and Drug Administration (FDA) has approved the use of 3 types of drugs in smoking cessation treatment: Nicotine Replacement Therapy (NRT), Bupropion and Varenicline. There are two other medications, although they are not approved by the FDA, they are used as second-line drugs, such as Clonidine and Nortriptyline.
I. Nicotine Replacement Therapy.
The drugs most studied and used for the management of tobacco dependence are those that contain nicotine. Several clinical studies have shown that they are safe and effective, increasing twice the success rate of behavioral therapy.
Its main mechanisms of action: reduction of withdrawal symptoms, reduction of reinforcing effects and the production of certain effects previously sought in cigarettes (relaxation, facilitation of the confrontation of stressful situations, etc.) 15 . The use of NRT should start on the day when smoking is stopped.
Some adverse effects are common to all NRT products, with the most frequent being dizziness, nausea and headache. The contraindications are serious cardiovascular diseases, severe cardiac arrhythmias, uncontrolled hypertension and recent AVE.
There are different nicotine replacement formulations, which can be used alone or in combination with other medications.
1. Nicotine gum
It corresponds to the most studied and widely used NRT method since the 80s 14 . Currently in the USA it is available in various flavors (mint, orange and fruit) and in formulations of 2 and 4 mg, this last recommended dose for smokers of more than 25 cigarettes / day. In Chile there is only the presentation with mint flavor of 2 mg.
There are two ways to indicate chewing gum: by schedule, in which the recommended initial dose is one chewing gum every 1 to 2 hours for 6 weeks, then one unit every 2 to 4 hours for three weeks, and then 1 chewing gum every 4 to 8 hours for three weeks. Another alternative use is ad-libitum, that is, how many gums are needed according to the urgency of smoking and especially in stimulating situations for smoking.
2. Nicotine patches
Nicotine patches deliver a stable dose of nicotine for 16 to 24 hours. They are placed once a day, which facilitates adherence to treatment. They are available in doses of 7, 14 and 21 mg. It is recommended that those patients who smoke more than 10 cigarettes a day start with the dose of 21 mg / 24 hours, this dose being titratable according to clinical response or serial measurements of cotinine (performed while the patient is still smoking). It has been recommended to use them for 10 to 12 weeks, decreasing the doses in the last 4, although sometimes longer periods of treatment are needed.
3. Nicotine nasal spray
The nasal spray releases nicotine directly into the nasal mucosa. Within the NRT, it is the method that most rapidly reduces withdrawal symptoms. A puff is used in each nostril, releasing a total of 1 mg of nicotine.
4. Nicotine inhaler
It is a product designed to meet the needs of the hand-mouth ritual. It consists of a device that contains a nicotine cartridge and a vaporizer system that is used in the mouth.
These last two forms of NRT, in addition to losenge (compressed to be dissolved in the mouth), are not available in Chile
5. New forms and uses of Nicotine Replacement Therapy 17
5.1 Quick release chewing gum
Quick release method of nicotine, via oral mucosa, of recent appearance. It differs from conventional chewing gum in achieving faster and more complete relief of withdrawal symptoms during the first 3 minutes of use. More efficacy studies are required for its use in bulk.
5.2 Combined forms of TRN
There are basically 2 forms of nicotine administration: passive and active. The passive form corresponds to the sustained release of nicotine during the day, without presenting a marked plasma peak, as they act, for example the nicotine patches. The rest of the TRN medications are called active forms, as they depend on the person's "active" decision to use them. They have short half-lives and produce a nicotine plasma peak that simulates the effect of the cigarette, but of less intensity.
The combination of a passive delivery drug, plus another active delivery product that allows self-administration in times of urgency due to smoking, has allowed to enhance the effect of each one separately. The most used combination of products is the most chewing gum patch administered ad-libitum.
5.3 Consumption reduction
One strategy for currently unmotivated smokers or those who feel incapable of complete cessation is the use of NRT as part of a "consumption reduction" strategy. This consists of encouraging the smoker to reduce consumption by half, using active delivery methods. If the consumption has not decreased after 3 months, the NRT is suspended. If this has decreased, it is continued for up to 1 year, with the goal of 6 months to abstain completely.
5.4 Electronic cigarette:
Until now, its usefulness as a pharmacological aid to stop smoking has not been demonstrated. It has been found that some brands contain, in addition to nicotine in various amounts, carcinogenic and toxic substances, which makes their use inadvisable, since it would not be effective or safe 18 .
II. Bupropion
Bupropion was the first non-nicotinic drug approved for the treatment of smoking. It is a monocyclic antidepressant that acts by inhibiting the reuptake of nora-drenaline (NA) and dopamine (DA) in certain areas of the brain. It is not yet known exactly how it acts for the cessation of smoking, but it is believed that it is partly due to its effect on the levels of DA and NA. Therapeutic efficacy:
The effectiveness of bupropion to stop smoking is clearly demonstrated. A meta-analysis, which included 12 randomized clinical trials, showed an odds ratio of 1.56 (95% CI 1.1-2.21) at 12 months compared to placebo 19 . It has also been shown that bupro-pion reduces the weight gain that occurs when smoking stops and that it alleviates withdrawal symptoms, such as moodiness, anxiety, difficulty concentrating, sadness and desire to smoke 20 . Despite the fact that bupropion is effective for the treatment of smoking in smokers with or without depression, it is believed that patients with depression or anxiety disorders could benefit more from bu-propion than with another medication. 21
Side effects:
The recommended dose of 300 mg / day is generally well tolerated. Approximately 10% of patients should suppress it due to side effects. The most frequent effects are insomnia (frequency of 30-45% of those who use 300 mg / day), dry mouth (5-15%) and nausea. Other more serious side effects that can be observed are seizures and hypersensitivity reactions, each with an incidence of 0.1%.
Recommendations for use:
Bupropion is recommended as a first-line drug in the treatment of smoking 20 . The maximum recommended dose is 150 mg twice a day, starting one or two weeks before the date set to quit smoking. The first 5-7 days a dose of 150 mg is administered in the morning and then the second dose of 150 mg is added at 8 hours of the first (to prevent insomnia). The recommended duration of treatment is 7-9 weeks. If side effects appear, the dose can be lowered to 150 mg / day.
It should be used with caution in patients at increased risk of seizures: alcohol or cocaine abuse, or use of other drugs such as antipsychotics, antidepressants, theophylline, tramadol, quinolones, systemic corticosteroids or sedative anti-histamines. In elderly patients and / or with liver or kidney failure or diabetes, caution should also be exercised, using lower doses than usual (150 mg / day). It has been seen that due to the concomitant use of bupropion and nicotine patches there is an increase in the incidence of hypertension, so care must be taken with this association in patients who tend to increase their pressure.
Its use is contraindicated in patients with a history of seizures, CNS tumors, bulimia, anorexia or bipolar disorder (in the latter a manic episode may be precipitated). It is also contraindicated to use it together with MAO inhibitors, since the acute toxicity of bupropion is potentiated with these drugs, producing agitation, psychotic changes and seizures 21 . It is not recommended to administer it during pregnancy or lactation, as it can cross the placental barrier and can be excreted in breast milk.
III. Varenicline
Varenicline is a partial agonist of the nico-tínicos acetylcholine α4β2 receptors, recently approved by the FDA for the treatment of smoking. It has been available in Chile since 2007 and has become an attractive alternative, not only for its novel mechanism of action, but also for its high efficacy and good tolerance reported in several studies.
Pharmacological properties:
Nicotine dependence is due in part to its agonist activity at nicotinic α4β2 receptors. When stimulated, dopamine release occurs in the nucleus accumbens, a neurotransmitter that produces the pleasant effects sought by the smoker. When he stops smoking, the absence of nicotine decreases dopamine levels, producing an urge to smoke ("craving"), an important contributor to relapse.
Several studies suggest that by stimulating these receptors with a partial agonist such as varenicline, dopamine levels would increase, alleviating the symptoms of deprivation. In addition, competitive binding to α4β2 receptors would at least partially block the dopaminergic activation caused by nicotine in case of relapse. This double mechanism would be responsible for the efficacy of varenicline as a treatment for smoking 22
It has also been observed that this new drug, not being metabolized in cytochrome P450, does not alter the pharmacokinetics of several drugs (NRT, bupropion, warfarin, digoxin, cimetidine, and metformin), making it a very safe medicine.
Therapeutic efficacy
The efficacy of 12-week therapy with varenicline 1 mg 2 times a day for the treatment of smoking was compared with bupropion 150 mg twice daily and placebo in 2 randomized, multicenter, phase III studies 24,25 . In both studies, at 12 weeks those participants in the varenicline group achieved significantly higher rates of abstinence than in the other groups. The results were similar in both studies with an OR of 1.9 for varenicline versus bupropion (p <0.001) and an OR of 3.9 for varenicline versus placebo (p <0.001).
In the long term (week 52), the abstinence rate was significantly higher with varenicline than with bupropion in one of the studies (OR 1.8, 95% CI 1.2-2.6, p = 0.004), but not in the other (OR 1.5; 95% CI 1.0-2.2, p = 0.05). In both studies varenicline was superior to placebo (OR 3.1 and OR 2.7, both with p <0.001).
Side effects:
The most frequent side effect is nausea, reaching 34.9% 39 ; however, in most cases, they are mild to moderate and decrease over time. The discontinuation of varenicline due to adverse effects is 10.5%, compared with 12.6% and 7.3% in the bupropion and placebo groups, respectively. 25
In addition, an increase in weight of 2.89 kg has been observed on average, versus 1.8 and 3.1 kg in the bupropion and placebo groups, respectively 23 . These results suggest that weight gain is a consequence of quitting smoking, rather than related to varenicline per se.
Psychiatric effects
In the post-marketing period of the use of varenicline, some reports emerged about the possible association between its use and the risk of suicide, which led the US and the British drug regulatory agencies (MHRA) to determine in the year 2009, the obligation to include a warning about the possible risk in the package insert of the medicine. However, the causal relationship has not been established, since it is necessary to separate the possible effects of varenicline from those related to cessation of smoking. In a recent publication 26 no neuropsychiatric effects were found that were superior to placebo, except for sleep disturbances. In another large study in England 27 of a retrospective cohort of more than 80,000 smokers, there was no clear evidence that the use of varenicline increased the risk of depression, suicide or suicidal thoughts, compared to the use of bupropion or nicotine replacement therapy. .
Cardiovascular effects
Very recently, in June 2011, a meta-analysis 28 was published on the risks of cardiovascular adverse effects, where it is concluded that the use of varenicline was associated with a significant increase in cardiovascular adverse effects (ischemia, arrhythmias, congestive heart failure, sudden death). ) compared with placebo: 1.06% vs. 0.82%. The FDA issued a communiqué29 in which it warns that there is a small increase in cardiovascular risks with varenicline, and that the absolute risk of adverse CV events in relation to its efficacy is small. It makes a call for caution with the use of varenicline, and requested the pharmaceutical company to place this warning on the written information that accompanies the product, which has already been done 30 .
Recommendations for use.
The recommended dose is 1 mg twice a day, after meals. The treatment should start one week before the scheduled date to quit smoking. Varenicline should be titrated for a week, using progressively higher doses until the target dose is achieved.
By way of summary, Table 3 presents the drugs approved by the FDA.
FDA: US Food and Drug Administration TRN: Nicotine Replacement Therapy. Modified from ref. 22
IV. Other drugs for the treatment of smoking
Clonidine
It is a noradrenergic α2 agonist. In a meta-analysis of 6 randomized clinical trials comparing clonidine and placebo, higher cessation rates were observed in the first group. Only one of the studies showed statistically significant values, whose OR is comparable with any NRT (OR 1.89, 95% CI: 1.3-2.7) 31 . The most observed adverse effects are dry mouth (25 ^ 40%), sedation (12-35%), hypotension (15%) and constipation (10%).
In general, clonidine is not as effective as NRT in the treatment of smoking and its high rate of adverse effects limits its use.
Nortriptyline
Tricyclic antidepressant that blocks the recapture of noradrenaline and serotonin, thus improving withdrawal symptoms and post-cessation depressive symptoms. Different studies have shown that it is 2 times more effective than placebo. However, a comparative study of nortriptyline and bupropion showed significant superiority of bupropion (42 versus 31% abstinence at 6 months) 32 . The most frequent side effects are dry mouth and constipation, which occur in a high number of patients.
Antinicotine vaccine
The idea behind the concept of antinicotine vaccine is to prevent nicotine from reaching the brain, through the production of antinicotine antibodies. By reducing the arrival of nicotine in the brain, the reward effect is blocked. Studies in animals have shown a 65% reduction in nicotine reaching the nicotinic receptors in the brain and a significant decrease in the amount of dopamine produced by nicotine stimulation. 33
There are several pharmaceutical companies that are developing vaccines, with different types of haptens that bind to nicotine to produce the immunogenic effect. It has been seen that there is a relationship between the antibody titer and the efficacy of the vaccine. The results of studies in phase 1 and 2 suggest that these vaccines are safe, well tolerated and immunogenic, and there are still no publications of phase 3 studies.
While these results are encouraging, especially in their use to prevent relapse, the current evidence is limited and conclusions about its effectiveness are still premature.
Acupuncture and Hypnosis.
They have not proven to be better than placebo, according to recent Cochrane reviews 35, 36 י, so their use is not recommended.
A long-term promising line of work is drug pharmacogenetic studies, which would allow predicting the effect of drugs in certain subgroups of smokers characterized according to specific genetic studies. Thus, medications that do not seem to be useful in the group of patients, could be beneficial in a subgroup of these 37 .
Final comments
At present, the greater understanding of the psychopathology of tobacco addiction and the motivations for behavioral change has allowed us to improve the psycho-social support that can be provided. These advances, together with better knowledge of the psychopharmacological mechanisms of nicotine and the development of new, more effective drugs, should encourage health team professionals and especially physicians to assume a more active role in offering support and treatment to Any smoker who shows intention to stop smoking. We have identified barriers 38 that in the past made this role difficult: fear of damaging the doctor-patient relationship, lack of knowledge on how to help patients and belief that it will be ineffective. But the evidence today is different and much can be done to help smokers. Any contact of the smoker with the health care system should be used to encourage and promote the cessation of tobacco use. It is also imperative to involve all health professionals so that in each consultation they make the brief intervention. If the patient can not quit smoking, they should be referred for a specialized intervention. On the other hand, the training for confronting smoking should be part of the undergraduate curriculum of all health careers, with greater extension and depth than is currently done. There should also be a more explicit and permanent concern of medical societies to train their members on this issue, especially those most related to the damages of tobacco consumption, contributing in a significant way to reduce the alarming rates of morbidity and mortality produced by the disease. smoking in the country and in the world.