20 - ar - métodos para abandono do tabagismo-e.indd

Rev Bras Otorrinolaringol. V.71, n.6, 820-6, nov./dec. 2005 REVIEW ARTICLE
Methods for smoking cessation and treatment of nicotine dependence Aracy Pereira Silveira Balbani1,
Jair Cortez Montovani2
Key words: smoking, nicotine, tobacco use disorder, Smoking is related to 30% of cancer deaths. It is a risk factor for respiratory tract, esophagus, stomach, pancreas, uterine cervix, kidney and bladder carcinomas. Nicotine induces tolerance and addiction by acting on the central dopaminergic pathways, thus leading to pleasure and reward sensations within the limbic system. It stimulates the central nervous system (CNS), enhances alertness and reduces the appetite. A 50% reduction of nicotine consumption may trigger withdrawal symptoms in addicted individuals: anxiety, anger, sleep disorders, hunger, cognitive dysfunction and cigarette craving. Medical advice is the cornerstone of smoking cessation. Pharmacotherapy of nicotine addiction comprises first-line (bupropion and nicotine replacement therapy) and second-line (clonidine and nortriptyline) drugs. Bupropion is a non-tricyclic antidepressant that inhibits dopamine uptake, whose contraindications are: epilepsy, eating disorders, uncontrolled hypertension, recent alcohol abstinence and current therapy with MAO inhibitors. Nicotine replacement therapy can be done with patches or gums. Counseling groups and behavioral interventions are efficacious. The effects of acupuncture on smoking cessation are not fully elucidated. Prompt smoking cessation or gradual reduction strategies have similar success rates.
1 Ph.D. in Medicine, Volunteer Professor, Discipline of Otorhinolaryngology and Head and Neck Surgery, Medical School, Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP).
2 Full Professor, Discipline of Otorhinolaryngology and Head and Neck Surgery, Medical School, Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” Address correspondence to: Aracy P. S. Balbani - Rua Capitão Lisboa 715 cj. 33 18270-070 Tatuí SP.
This article was submitted through SGP on May 11, 2005 and approved on June 20, 2005.
BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 71 (6) PART 1 NOVEMBER/DECEMBER 2005 http://www.rborl.org.br / e-mail: [email protected] INTRODUCTION
ways. It is fundamental to diagnose and treat the chemical dependence in these patients, promoting smoking cessa- Tobacco is produced by two plant species - Nico- tion in order to prevent or cure these affections.
tiana tabacum and Nicotiana rustica, which come from The authors present a pharmacology outlook, ad- the Peruvian and equatorial Andes. These plants were dressing actions and nicotine dependence, as well as found out approximately 18,000 years ago, when Asiatic treatment modalities available for smoking cessation which may be prescribed by otorhinolaryngologists.
When Christopher Columbus arrived in the New World, the cultivation and use of tobacco had already Literature Review
been disseminated among Indians over the continent. It Indexed studies were reviewed through Lilacs and had several applications, including religious rituals and as Medline databases under the keywords in Portuguese, insecticide in agriculture. Tobacco was smoked in pipes, such as “tabagismo”, “nicotina”, “transtorno por uso do inhaled, chewed, eaten, and drunk as tea. Important tabaco”, “abandono do uso do tabaco”, “bupropiona” or medicinal plant, it was used for intestinal wash-ups, skin its related links in English: “smoking”, “nicotine”, “tobacco smear to kill louses, instilled as eye-wash and used in use disorder”, “tobacco use cessation”, “bupropion”.
ointments, analgesic and antiseptic formulations1.
Aware of smoking habits and the tobacco medicinal Nicotine Pharmacology
properties, explorers decided to take the plant seeds to Cigarette smoke consists of volatile chemical sub- Europe. In Portugal and in Spain, tobacco was cultivated stances (92%) and particulate material (8%) resultant of in royal palace gardens, while nobles used it to fight can- tobacco combustion5. Nicotine, a tertiary volatile amine, cer. Rapidly, tobacco became much valuable in Europe, is the most important active tobacco component4,6. When while English pirates invaded and plundered Spanish ships tobacco coal’s temperature reaches 800°C, racemic shapes coming from America, till the British government decided of nicotine emerge, which form four nitrosamines with to cultivate the plant in several colonies1.
cancer potential7. However, nearly 35% of nicotine is de- In 1850, the first manufactured cigarettes were sold stroyed during cigarette combustion; more than 35% is lost in England, whose consumption became popular during in non-inhaled smoke and 8% is not smoked6. Therefore, the First World War. Smoking habits summit took place in each cigarette contains 7-9 mg of nicotine, of which a the 50 and 60’s, declining in certain countries from 1970 little more than 1 mg is absorbed by the smoker4. Cured and on1. Today, there are more than a billion tobacco us- tobacco’s nicotine for pipes and cigars is alkaline and it ers around the world, among which 90% started smoking is more easily absorbed through the mouth. On the other hand, cigarette’s nicotine is acid, therefore it is practically From 1920’s, the increase of lung cancer incidence not absorbed by the mouth mucosa, and has to be inhaled was observed, which was confirmed in several studies thirty years later. In 1971, a formal report was published Nicotine is rapidly absorbed by the lung alveolus in the United States confirming that “smoking negatively and reaches the brain within 10 seconds. Its half-life is affects human health and contributes for the onset of of approximately 2 hours, and metabolization is mostly hepatic, through P450 cytochrome. The main enzyme in- Currently, the World Health Organization accounts volved is CYP2A6. Molecular biology studies demonstrate for more than four millions fatal victims caused by ciga- that capacity in metabolizing nicotine varies according rette each year2. It is known that smoking is related to at to each individual7. CYP2A6*2 and CYP2A6*3-allele in- least 30% of cancer deaths. It is a risk factor for the onset dividuals are less prone to be smokers, and if they do, of lung, mouth, pharynx, larynx, esophagus, stomach, they tend to consume less tobacco than CYP2A6*1-allele pancreas, uterine cervix, kidney and bladder carcinomas3. Moreover, morbidity by cardiovascular and cerebrovascular Vasconcelos et al. (2005)9 analyzed the genetic diseases, chronic obstructive pulmonary diseases (COPD) profile of CYP2A6 in a sample of an adult Brazilian and peptic diseases, as well as other affections, is higher population, composed by 147 Caucasian individuals, 142 Mulattos and 123 Blacks, among which 205 were smokers In 1988, a new North-American report concluded or ex-smokers, and 207 were non-smokers. The alleles that nicotine found in cigarettes and in other tobacco mostly found in this sample were: CYP2A6*1B (29.9%), products is a drug that causes dependence. It is estimated CYP2A6*2 (1.7%), CYP2A6*4 (0.5%) and CYP2A6*9 (5.7%). that 24% of the adult population in several countries, Brazil Contrary to expectations, frequency of CYP2A6*1B-allel individuals among non-smokers was higher. Distribution Frequently, otorhinolaryngologists receive smokers of CYP2A6*1B alleles also presented racial differences, with inflammatory or tumoral diseases of the upper air- with decreasing frequency among Caucasians, Mulattos BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 71 (6) PART 1 NOVEMBER/DECEMBER 2005 http://www.rborl.org.br / e-mail: [email protected] and Blacks. Presence of this allele was associated with a higher probability of nicotine dependency among Cauca- Nicotine Chemical Dependency
sians (a 14-fold higher risk) and Mulatto (a 3-fold higher Nicotine induces tolerance (need of progressively higher doses to obtain the same effect) and dependence The most important nicotine metabolite is cotinine, (desire of consumption) as it acts in the dopaminergic which can be detected in urine, saliva and blood7. Only pathways of the mesolimbic system, reducing the tha- 5% of nicotine is excreted without alterations by the lamus activity4. Similarly to other psychoactive drugs, it releases dopamine in the nucleus accumbens, located in the mesencephalus, stimulating a pleasant and “rewarding” Nicotine actions
sensation8,12. After the discomfort caused by the first drafts The systemic actions of nicotine are mediated by of tobacco (sickness, dizziness, nausea), the smoker expe- nicotinic receptors found in the central nervous system rience a pleasant sensation with the use of nicotine7.
(CNS), peripheral autonomic nodes, supra-renal glands, According to Marques et al. (2001)4, a 50% decrease sensitive nerves and the skeletal striated muscle4.
in nicotine consumption is enough to trigger withdrawal Nicotine’s main acute effects over the cardiovascular symptoms in dependent individuals. Nicotine abstinence system are10: peripheral vasoconstriction, increase of the syndrome is mediated by noradrenalin and starts 8 hours blood pressure and heart rate. Nicotine also interferes in after the last cigarette, reaching a peak on the third day. the endocrine system, yielding the release of antidiuretic Main symptoms include: anxiety, irritability, sleep disorders hormone and water retention. In the gastrointestinal sys- (insomnia and daytime sleepiness), appetite increase, cog- tem, nicotine acts parasympathetically, stimulating tonus nitive disorders (decrease of concentration and attention) increase and intestinal motor activity10.
and craving. That is why nicotine-dependent individuals In nervous endings, nicotine stimulates release of present abstinence relief when they smoke their first the following neurotransmitters: acetylcholine, dopamine (DA), glutamate, serotonin and gamma aminobutyric acid Irritability during nicotine withdrawal is a common smokers’ complaint4. Our experience includes a 34-year- Nicotine is CNS stimulant, leading to increased alert- old patient that used to smoke about 12 cigarettes per ness and to reduced appetite. After a draft, the sensation day and had quit smoking for two months. The patient may be compared to that described by amphetamine, says she had physically improved during withdrawal, but heroine, cocaine and crack users4. The main sensations started smoking again due to her husband’s insistence: may include dizziness, nauseas and vomiting10.
“He could no longer stand my bad mood”.
Rose et al. (2003)11 studied nicotine’s acute effects Unwanted weight gain is one of the symptoms that over the brain blood flow in adults through tomography mostly upset patients under nicotine abstinence. Mostly, by positrons emission (PET). Nicotine interferes in the re- weight gain gets around 4 to 6 Kg13, and in some people ticular formation blood flow, including areas of the pons, mesencephalus and thalamus, and plays a role in aware- Women and smokers that smoke over 25 cigarettes ness and awakening mechanisms. Low doses of nicotine per day tend to gain weight after smoking cessation, prob- have a central stimulating effect, while higher doses have ably due to food ingestion and metabolic adjustments4.
a depressing effect. Nicotine also leads to dose-dependent Epidemiologic studies show that more than 70% of increase of blood flow in the left hemisphere amygdala, smokers want to quit smoking8. However, less than 10% which may explain the anxiolytic effect of smoking.
reach their goal by their own, as discomfort caused by Experimental studies show that nicotine acts as en- nicotine abstinence and craving leads most ex-smokers to zymatic inductor in the liver. This way it reduces half-life relapse8,13. Relapses usually occur between two days and of several medicines such as: local anesthetics, morphine, codeine, teophyline, heparin, warfarin, amitriptyline, Cox et al. (2003)3 alert that 58% of cancer patients imipramine, propranolol, chlorpromazine, diazepam, continue smoking after diagnosis, usually due to behavioral chlordiazepoxide and indometacin. Thus, smokers may require larger doses of these medicines to have the ex-pected therapeutic effects10.
Treatment of Nicotine Dependency
Ingestion of nicotine-based insecticides may cause Medical support may enhance the success rate in acute intoxication, with the following symptoms: salivation, vomiting, muscle weakness, prostration, cold sudoresis, mental confusion and hypotension. In severe cases (inges- Patient and Family Counseling
tion of over 60 mg of nicotine), chronic convulsions and Talking with the patient is the first step for smok- ing cessation. It is important to evaluate if the patient is BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 71 (6) PART 1 NOVEMBER/DECEMBER 2005 http://www.rborl.org.br / e-mail: [email protected] nicotine-dependent or not, the quantity smoked, desire to First-line Therapy
quit, presence of associated diseases and feasible treat-ment modalities4,6.
There are many ways to assess nicotine depend- Bupropion is a non-tricyclic antidepressive that ency: through the International Classification of Diseases inhibits pre-synaptic dopaminergic and noradrenalin (ICD-10), Diagnosis and Statistics Manual of the Ameri- mechanisms8,14,15. Its action in the central dopaminergic can Psychiatric Association (DSM-IV), and others4. The pathways is believed to be the same mechanism respon- Fagerström Scale for nicotine tolerance and dependency sible for craving reduction in patients under nicotine assessment (Table 1) has English and Swedish originals and has been adapted to several languages. It includes In the United States, bupropion is indicated for six questions. Total score ranges from zero to 11, where addicts smoking 15 or more cigarettes/day or presenting low nicotine dependency (mild) is detected when total is below three. A score higher or equal to seven indicates Bupropion therapy should start 7 to 10 days before high nicotine dependency (severe)6. Patient should be patient stops smoking, since this interval is necessary for encouraged to quit smoking at each medical consultation. the balance of pharmacotherapeutic levels2,8. The rec- Other smokers in the family must also be counseled not ommended dosage is 150mg/day up to the third day of to smoke3. According to Jain (2003)13, gradual reduction treatment, increasing to 300mg/day at the fourth day, and or quit attempts to smoking cessation show the same maintaining this dosage from 7 up to 12 weeks4.
Clinical studies with bupropion have satisfactory results, presenting twice the period of abstinence when Pharmacotherapy
compared with placebo, plus reduced weight gain4.
Pharmacotherapy is indicated for nicotine depend- Bupropion’s adverse effects occur in 6-8% of ents and is divided into: first-line therapy (bupropion and patients16. The most common symptoms are: insomnia, nicotine-replacement therapy) and second-line therapy restlessness and xerostomia 8. Kolber et al. (2003)16 empha- size that incidence of adverse effects was observed in clini-cal studies sponsored by a pharmaceutical manufacturer, in which 35% of patients had not completed treatment.
Table 1. Portuguese version of Fagerström scale for nicotine-dependence evaluation (adapted by Do Carmo; Pueyo, 2002).
1. Quanto tempo você demora para fumar o primeiro cigarro da manhã? 2. É difícil abster-se e não fumar nos lugares onde é proibido (p. ex., hospital, biblioteca, igreja, ônibus, etc.)? 3. Se tivesse de escolher, que cigarro lhe custaria mais deixar de fumar? 5. Habitualmente você fuma mais nas primeiras horas do dia do que NOTE: score from zero to three: low nicotine-dependency (mild); score higher or equal to seven indicates high nicotine-dependency (severe).
BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 71 (6) PART 1 NOVEMBER/DECEMBER 2005 http://www.rborl.org.br / e-mail: [email protected] The authors carried out an independent study to gum between the cheeks and gingival region until numb- evaluate 39 patients, out of which 15 (38%) discontinued ness disappears, and restart chewing for 30 minutes to the use of bupropion due to adverse neuropsychiatric throw out the gum. Patient should not ingest any type of effects (trembling, restlessness, and confusion), insomnia and skin eruptions. Seven patients (18%) had to reduce The patient must stop smoking as soon as he starts bupropion dosage to 150 mg/day, so side effects could NRT. The most common systemic effects in nicotine replacement are: nausea, hiccups and headache18,20. Risk of convulsions in bupropion users is 1:1.000. Main adverse effect of nicotine gums is rash of mouth For this reason, this drug is contraindicated for epileptics4. Other contraindications include: nutrient disorders (nerv- NRT is contraindicated for individuals younger ous anorexia or bulimia), uncontrolled arterial hyperten- than 18 years and those with severe cardiovascular dis- sion, recent alcohol abstinence and use of monoaminoxi- eases (acute myocardial infarction occurred within the dase inhibitors (tranylcypromine or selegiline)2,4,8.
previous two weeks and instable angina)4. Use of NRT Bupropion is a B-category drug according to Food is possible in nicotine-dependent pregnant women and and Drug Administration, which means that there are not during breastfeeding, should treatment risks and benefits sufficient studies on secure use of this medicine during Second-Line Therapy
Nicotine Replacement Therapy (NRT)
Clonidine may be used at a 0.1 to 0.75 mg dosage Combined use of NRT and bupropion almost dou- per day to relieve nicotine-abstinence syndrome’s symp- bles the success rate of smoking cessation14.
toms. Its main adverse effects are sedation and orthostatic In Brazil, nicotine patches and chewing gum are hypotension. Sudden discontinuation of clonidine may available in the market. In the United States, there is also the nasal spray and nicotine mouthwash14.
Nortriptyline inhibits noradrenalin and dopamine Patches may be found in the Brazilian market in mechanisms in the CNS, producing antidepressive and dosages of 7, 14 and 21mg/unit and each pack contains anxiolytic effects. At short-term, its efficacy in smoking seven units. They maintain blood levels of nicotine for 16 cessation seems to be similar to that of bupropion4.
to 24 hours17, therefore they should be replaced on a daily basis. Their effects are observed in two to three days of Other therapies
use18. Mean period for treatment is eight weeks4.
Chewing gums contain 2mg of nicotine/unit and Acupuncture
The Acupuncture Consensus Panel of the United The following dosage is recommended18,19: States National Institutes of Health (NIH) (1998)21 confirms a) For patients who smoke ≤25 cigarettes per that acupuncture “may be useful as a supportive treatment, or acceptable alternative, or part of a comprehensive 1 gum (2mg) at 1-2 hour intervals in the first 4 weeks program” in drug-addiction therapy, including nicotine dependency. According to Approach Consensus and Treat- 1 gum (2mg) at 2-4 hour intervals from the 5th to ment of Smokers of the Health Ministry (2001)19, “so far, there are not sufficient scientific evidences to corroborate 1 gum (2mg) at 4-8 hour intervals from the 9th to the efficacy of acupuncture and of other methods, such as aromatherapy and hypnosis. Thus, acupuncture “is not recommended as a method of choice for smoking cessa- b) For patients who smoke >25 cigarettes per tion”, although it may be used “if this is the patient’s option and if there are no usage contraindications”.
2 gums (4mg) at 1-2 hour intervals in the first 4 He et al. (2001)22 followed 46 adults who smoked 10 or more cigarettes per day and divided them into two 1 gum (2mg) at 2-4 hour intervals from the 5th to groups. The study group was submitted to electroacu- puncture, auriculoacupuncture and auriculoacupressure 1 gum (2mg) at 4-8 hour intervals from the 9th to (manual technique, without needles) for three weeks. The activated spots corresponded to the lungs, airways and mouth. Individuals of the control group were submitted Gums should be strongly chewed until numbness of to acupuncture with stimulation of spots related to the the mouth mucosa occurs or a tobacco taste is perceived. muscle-skeletal system, presumably without influence in Then the patient should stop chewing and maintain the the organs affected by tobacco. Among the study group BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 71 (6) PART 1 NOVEMBER/DECEMBER 2005 http://www.rborl.org.br / e-mail: [email protected] patients, 32% abandoned smoking, against 23% of the functional recovery. Exhaled CO concentration of non- control group. The desire to smoke was reduced in both smokers is below 10 ppm (parts per million)24.
groups, although tobacco taste significantly worsened Some researchers use portable devices to quantify among those submitted to acupuncture. According to the exhaled CO, not only for focused clinical evaluation, but authors, acupuncture action mechanisms in smoking treat- also to encourage the patient during smoking cessation ment remain unknown, although it is possible that tobacco taste is reduced by this technique, with consequent fall of smoking desire.
A National Study
So far, there are not sufficient evidences that acu- Haggsträm et al. (2001)20 assessed 169 smokers puncture is effective in treating nicotine dependency13,23, which voluntarily enrolled in a university smoking ces- even though several patients feel better during smoking sation service. Most people who searched for assistance were women (67%), median age (mean 46 years), high educational level and motivated to quit smoking due to Cognitive-behavioral Therapy and Self-support groups
respiratory disorders (85%). Nicotine dependency was Marques (2001)4 emphasizes that self-support moderate in 50% of the cases, mild in 27% and severe in groups and psychotherapy – individual or group – with 22%. Proposed treatment was cognitive-behavioral psy- counseling sessions are effective adjuvant factors in treat- chotherapy for mild cases, psychotherapy associated with ing nicotine dependency. This is especially significant pharmacotherapy (or bupropion 300mg/day or NRT) for when dependency is followed by other affections, such moderate cases, and psychotherapy associated with phar- macotherapy (bupropion 300mg/day plus NRT) for severe Counseling helps to identify situations in which cases. About 30% of smokers abandoned the program in the tobacco-addicted chases a cigarette due to behavioral the first week. At the end of the study, 124 individuals (after the meals, a cup of coffee, when meeting friends) remained in the program; 49% had quit smoking and 13% or emotional reasons (anxiety, upsetting). Based on that, significantly reduced cigarette consumption. Success rate the tobacco-addicted learns several strategies to break in smoking cessation was: 23% in psychotherapy, 50% in the link between these factors and the act of automatic NRT, 59% in bupropion use and 59% in combined use of bupropion and NRT. Only one patient had to interrupt the Behavioral intervention and counseling is the base use of bupropion due to adverse effects.
of treatment against tobacco-use among teenagers2.
The National Cancer Institute (INCA) has a toll-free DISCUSSION
phone number 0800-703-7033, where information on smoking cessation methods is provided. In the call center Ironically, after five centuries, tobacco has gone menu options, INCA informs the phone numbers of state from a medicinal plant –used even to prevent cancer – to coordination centers for smoking treatment under the one of the worst world public health issues.
Central Healthcare System (SUS). Smokers that participate Nicotine dependency is currently one of the most in smoking cessation groups have the right to receive common chronic diseases in the population24. Differently from alcohol and illicit drugs, nicotine does not cause acute conditions due to overdose in addicted individuals. Assessment of Response to Treatment
Also, it does not lead to aggressive behavior or worsens Routinely, the main information for the physician to the psychomotor performance in car driving and ma- evaluate smoking reduction or cessation is self-reported chine operation. Therefore, nicotine dependency is less smoking cessation. However, in clinical studies, it is fun- shocking to society than alcohol dependency and other damental to adopt an objective and secure measurement psychoactive drugs. Exceptionally, tobacco addicts are to make sure that the patient has really quit smoking.
seen as inconvenient or dangerous – although, there is The most effective method in clinical research risk to accidentally burn furniture, clothes, tablecloths or studies for smoking cessation is blood, saliva or urine mattresses and causing disastrous fire.
On the other hand, an increasing number of people Another methodology is measurement of carbon show their disgust to tobacco and to passive smoking. In monoxide (CO) in exhaled air. In the respiratory tract public places, where smoking is still not prohibited by law, CO synthesis occurs through hemoxygenase enzymes, in smokers’ segregation is commonly seen. These measures proportional quantity as to local inflammatory process. protect non-smokers, although they are not effective to Tobacco-addicted usually presents high levels of CO in exhaled air. Approximately 24 hours after smoking cessa- Governmental campaigns against smoking have tion, CO exhaled levels start to fall, indicating pulmonary been intensified in the last decade, especially through the media and the warnings printed on cigarette packs. BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 71 (6) PART 1 NOVEMBER/DECEMBER 2005 http://www.rborl.org.br / e-mail: [email protected] However, around ¼ of the Brazilian population is nicotine- REFERENCES
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Laryngectomized patients due to cancer treatment have 10. Furtado RD. Implicações anestésicas do tabagismo. Rev Bras Anes- a two-fold probability of smoking abstinence than those 11. Rose JE, Behm FM, Westman EC, Mathew RJ, London ED, Hawk TC According to the literature, bupropion is effective et al. PET studies of the influences of nicotine on neural systems in cigarette smokers. Am J Psychiatry 2003; 160: 232-33.
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dosage reduction or drug discontinuation in about 38% 14. Grable JC, Ternullo S. Smoking cessation from office to bedside. 15. Tonnesen P, Tonstad S, Hjalmarson A, Lebargy F, Van Spiegel PI, Nicotine replacement therapy presents good out- Hider A et al. A multicentre, randomized, double-blind, placebo- comes when associated with bupropion, although it also controlled, 1-year study of bupropion SR for smoking cessation. J has limitations, besides not being considered for patients 16. Kolber M, Spooner GR, Szafran O. Adverse events with Zyban (bu- with severe cardiovascular diseases4.
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21. NIH Consensus Development Panel on Acupuncture. Acupuncture. CLOSING REMARKS
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BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 71 (6) PART 1 NOVEMBER/DECEMBER 2005 http://www.rborl.org.br / e-mail: [email protected]

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