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Non-Nicotine Pharmacotherapies for Smoking Cessation$

Non-Nicotine Pharmacotherapies for Smoking Cessation$

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EVIDENCE-BASED REVIEW Non- pharmacotherapies for $

H. McRobbiea,b,Ã, M. Leea, Z. Junipera

aTobacco Dependence Research and Treatment Centre, Barts and The London, Queen Mary’s School of Medicine and Dentistry, Turner Street, London E1 2AD, UK bClinical Trials Research Unit, The University of Auckland, New Zealand

Received 6 January 2005; accepted 15 May 2005

KEYWORDS Summary International chronic obstructive pulmonary disease guidelines recom- Smoking cessation; mend that smokers be strongly advised to quit, and should be offered help in doing Non-nicotine; so. The most effective smoking-cessation interventions combine behavioural support ; with pharmacotherapies. For smokers who do not wish to use nicotine replacement ; treatments, bupropion is a safe and effective non-nicotine alternative first-line treatment. Nortriptyline and clonidine have demonstrated efficacy in aiding smoking cessation, but are regarded as second-line therapies. A number of other non-nicotine treatments show promise, but more data are required before these can be recommended in assisting smokers to stop. & 2005 Elsevier Ltd. All rights reserved.

Introduction deaths worldwide were a direct consequence of smoking.1 Chronic obstructive pulmonary disease Interventions to aid smoking cessation are among (COPD) accounted for one-fifth of these deaths. the most important treatments that can be offered Smokers who are susceptible to developing COPD to smokers to improve their current and future suffer a progressive decline in lung function, health and reduce the risk of premature death. In resulting in significant disability. For these people, the year 2000, an estimated 4.83 million premature smoking cessation is the only intervention that has

$The following Cochrane reviews have been cited in this evidence-based review: Silagy C, et al. Nicotine replacement therapy for smoking cessation, Issue 3, 2004; Hughes JR, et al. Antidepressants for smoking cessation, Issue 4, 2004; Hughes JR, et al. Anxiolytics and antidepressants for smoking cessationm Issue 4, 2004; Lancaster T, et al. Silver acetate for smoking cessation, Issue 3, 1997; Gourlay SG, et al. Clonidine for smoking cessation, Issue 3, 2000; Stead LF, et al. Lobeline for smoking cessation, Issue 3, 1997; Lancaster T, et al. (a nicotine antagonist) for smoking cessation, Issue 2, 1998; David S, et al. antagonists for smoking cessation, Issue 3, 2001. Copyright Cochrane Library, reproduced with permission. ÃCorresponding author. Clinical Trials Research Unit, The University of Auckland, Private Bag 92019, Auckland, New Zealand Tel.: +64 9 373 7599x84726; fax: +64 9 373 1710. E-mail address: [email protected] (H. McRobbie).

0954-6111/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2005.05.016 ARTICLE IN PRESS

1204 H. McRobbie et al. been proven to modify the course of airways smokers who try to quit using NRT relapse within a obstruction, and can result in improving pulmonary year.9 A large number of studies examining the function, decreasing respiratory symptoms, and efficacy of various non-nicotine pharmacotherapies decreasing acute respiratory tract infections.2 for smoking cessation have been published. This International COPD guidelines recommend that paper attempts to summarise the findings of smokers be strongly advised to quit, and should systematic reviews of these treatments. be offered help in doing so.3 Most smokers say they want to stop, and about two-thirds will make an attempt each year. How- Method ever, many will choose to make an unaided quit attempt; a method that has only a small chance of We searched the Cochrane Library, PubMed, and long-term success.4 The primary reason why many PsychLit databases for systematic reviews of non- smokers find it difficult to quit is because of their nicotine pharmacotherapies for smoking cessation. dependence on nicotine. smoke provides We have relied mainly on systematic reviews rapid delivery of nicotine to the central nervous contained in the Cochrane Library, as these have system, where it facilitates the release of a number clear and strict criteria for entry into the reviews of neurotransmitters, such as and nora- (Table 1). Seven reviews of non-nicotine treat- drenaline.5 In dependent smokers, nicotine depri- ments for smoking cessation have been published in vation precipitates a withdrawal syndrome, the Cochrane Library: antidepressants, anxiolytics, consisting of symptoms such as irritability, low clonidine, lobeline, mecamylamine, opioid antago- mood, poor concentration, and urges to smoke that nists, and silver acetate.10–16 On the basis of can undermine a smokers’ attempt to quit.6 conclusions from these reviews, and smoking- Two smoking-cessation medications are in com- cessation guidelines,17,18 we allocated treatments mon use: nicotine replacement therapy (NRT), of to one of three categories: (1) first-line medica- which there are six different products, and bupro- tions for smoking cessation; (2) second-line medi- pion (Zyban). NRT acts by replacing some of the cations for smoking cessation; and (3) medications nicotine smokers would have received from their not currently recommended for smoking cessation. cigarettes, and in doing so reduces the severity of withdrawal symptoms. NRT approximately doubles the chance of long-term abstinence (odds ratio First-line medications for smoking [OR] ¼ 1.74; 95% CI: 1.64–1.86),7 although the cessation absolute success rate depends upon the intensity of the additional support provided and the type of Bupropion, an atypical antidepressant, is the first, smoker being treated.8 Although effective, this and, so far, the only non-nicotine treatment medication is no magic cure, and at least 70% of licensed for smoking cessation.

Table 1 Summary of criteria for entry into Cochrane reviews of non-nicotine pharmacotherapies for smoking cessation.

Study types Randomised trials with adequate control group. Participants Current smokers and recent quitters. Intervention Use of a non-nicotine pharmacotherapy to aid smoking cessation or to prevent relapse. Most interventions combined pharmacotherapy with behavioural support and compared the treatment with placebo or an alternative smoking-cessation aid. Outcome measures Abstinence from smoking measured for at least 6 months after starting treatment.* Wherever possible the strictest criteria for abstinence outcome were used. Preference was given to continuous, or sustained, abstinence rates and biochemical verification of self-reported abstinence. Some reviews required studies to report biochemically validated abstinence to be included.12,15,16 Where biochemical verification of abstinence was undertaken, only those participants whose self-reports were validated were included as abstainers. One review included studies that measured cigarette reduction by 50% or less of baseline.10 Intention-to-treat analysis was used wherever possible. Participants lost to follow-up were counted as smokers.

*Clonidine review required at least 12 weeks of follow-up.13*Opioid antagonists review included short-term follow-ups that looked at withdrawal symptoms.16 ARTICLE IN PRESS

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There is good rationale for testing antidepres- placebo, achieved higher 1-year continuous absti- sants for smoking cessation, as a strong association nence rates (22% vs. 9%).29 When used in smokers exists between smoking and depression. A higher with mild to moderate COPD, bupropion was prevalence of smoking exists among people who associated with significantly higher abstinence have, or have had a history of, depression.19 rates at 6 months (16% vs. 9%)28 but not at 1 year Smokers who are depressed find it more difficult (10% vs. 9%).10 to quit, some smokers become depressed when Its use in preventing smoking relapse has also they stop smoking, and post-cessation depression is been examined.25,30 The results of one study related to relapse.20,21 However, not all antide- investigating the use of bupropion, compared with pressants have been shown to be helpful for placebo, for a year showed no difference in smoking cessation.4,10 continuous abstinence rates between groups at 1 Bupropion is presumed to help smokers quit or 2 years after quitting.25 Another study showed no through its ability to inhibit the neuronal advantage of using bupropion over placebo for of dopamine and noradrenaline, both important in preventing relapse in patients successfully quitting and withdrawal. It may also smoking using a nicotine patch.30 Therefore, help through its action as a non-competitive evidence currently available suggests there is little inhibitor of the nicotinic receptor, benefit for using bupropion long-term to prevent and perhaps by way of its effect on relapse.10 reuptake.22 Although the precise mechanism by Few studies have compared bupropion with other which this medication aids smoking cessation smoking-cessation medications. In one of the remains uncertain, bupropion has been proven to pivotal studies mentioned earlier, bupropion was increase abstinence rates10,18,22,23 and reduce the more effective than the nicotine patch.26 Combin- severity of withdrawal symptoms experienced by ing NRT and bupropion significantly increased 1- smokers when they abstain.24–28 year outcome compared with patch alone (23% vs. Two pivotal outcome studies were published in 10%). However, more recent studies have not the late 1990s. The first compared the effect of confirmed these results.10 Further data are needed three different daily doses (100, 150, and 300 mg) on this issue. with placebo.24 Results showed a linear effect of an Bupropion is a safe treatment when used increasing dose on point-prevalence cessation, correctly. Contraindications should be checked although no significant difference was found be- when prescribing this medication (Table 2). In tween 150 and 300 mg per day at 12 months follow- addition, some precautions need to be considered. up. The second major study randomised smokers to Smokers with a predisposition to seizures should receive either bupropion (300 mg/day), 21 mg/24 h not take bupropion unless the benefit of smoking nicotine patch, both bupropion and patch, or cessation outweighs any risks associated with using placebo.26 The 1-year continuous abstinence rates the medication.31 Bupropion, however, has been were 18%, 10%, 23%, and 6%, respectively. All active found safe to use in smokers with stable cardiovas- treatments were significantly better than placebo, cular disease, without adverse effects on blood and bupropion was better than patch alone. There pressure or heart rate.29 was no added advantage of using a combination Bupropion undergoes hepatic metabolism, pri- regimen compared with bupropion alone. marily by isoenzyme CYP2B6. Therefore, other Since these studies, a number of other studies drugs that affect this enzyme (e.g. cimetidine, examining the efficacy of bupropion have been sodium valproate and cyclophosphamide) may published. One Cochrane review10 identified a total affect bupropion metabolism. Bupropion inhibits of 24 that met their inclusion criteria. Nineteen the activity of CYP2D6, and so there may be a studies, which included more than 4000 smokers, reduced rate of metabolism of drugs such as beta- looked exclusively at the efficacy of bupropion blockers and Type 1C antiarrhythmics. A dose compared with placebo. All studies used adjunctive reduction in these medications may be required.32 behavioural support. The meta-analysis showed Bupropion is marketed for smoking cessation that, compared with placebo, bupropion approxi- under its trade name Zyban, and is available in mately doubled long-term abstinence rates 150 mg sustained-release tablets. The recom- (OR ¼ 2.06; 95% CI: 1.77–2.40). mended treatment regimen is described in Table The efficacy of bupropion has also been exam- 2. A reduced dose may be required in elderly ined in smokers with smoking-related disease, a people, people with diabetes, and smokers with population typically more dependent and therefore renal or hepatic impairment.32 Understandably, harder to treat. People with stable cardiovascular some smokers may be concerned that they are disease treated with bupropion, compared with receiving a less effective treatment if they are ARTICLE IN PRESS

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Table 2 Prescribing information for bupropion HCL SR 150 mg tablets (Zyban).

Contraindications10,32 Smokers under 18 years of age Pregnant women Hypersensitivity to bupropion A current or previous seizure disorder Tumour of the central nervous system A current or previous diagnosis of bulimia or anorexia nervosa Severe hepatic cirrhosis Concomitant use of bupropion and monoamine oxidase inhibitors A history of bipolar disorder Withdrawal from or

Precautions10,32 It is recommended that a risk–benefit assessment be undertaken before prescribing bupropion to patients with other risk factors for seizures.36 Risk factors for seizures include the following: Medications that lower seizure threshold (e.g. antidepressants, , antimalarials, quinolones, sedating , systemic corticosteroids, , ) Current use of and anorectics Alcohol abuse History of head injury

Dosage32 Days 1–6: one tablet daily; from day 7: one tablet twice a day, keeping at least 8 h between each dose. The quit date should be set between 8 and 14 days after. The smoker continues to smoke as normal up to their quit date and then stop completely, aiming not to have a single puff after this. A total course of 120 tablets should be prescribed, but it is sensible to give a smaller quantity initially so there is no wastage if the smoker experiences adverse events, or does not manage to achieve abstinence.

Dosage adjustments Elderly: 150 mg once daily is recommended. Hepatic/renal insufficiency: 150 mg once daily is recommended. Diabetes: If diet controlled, the standard dose can be prescribed. If well controlled with insulin or oral hypoglycaemics, prescribe 150 mg once daily. If poorly controlled use NRT

Adverse effects22,32 Common (occurrence41:100): dry mouth, insomnia, nausea, headache. Rare (occurrence41:10,000 ando1:1000): seizure, severe hypersensitivity reaction.

taking a reduced dose. Presently, only two studies smokers had received bupropion within the first 2 have investigated the efficacy of different years.35 Over this period, there were 60 fatal doses.24,33 When results were pooled, there was adverse events; however, bupropion was not no added advantage in 1-year abstinence rates implicated as a causative factor, and, in many between 300 and 150 mg per day.10 cases, an underlying smoking-related disease was Insomnia and dry mouth are common side- identified as the cause of death. One hundred and effects, experienced by more than one-third of eighty-four cases of seizure were reported, with users of bupropion.22 A rash may also occur, and, 50% of these having risk factors for or past history as with many other medications, there is also a of seizures. small risk of a severe allergic reaction.32 Another Overall, the benefit of bupropion-aided smoking adverse effect to note is an approximate 1:1000 cessation outweighs the risks of drug-related risk of seizure.32 This is similar to some other adverse events. Smoking cessation guidelines in antidepressants, including fluoxetine.34 Following the UK and USA recommend bupropion as a safe and its launch in the UK in 2000, the media reported a effective medication for those who are able to take number of deaths and serious adverse events in it and wish to use it.17,18,23 For the best chance of people using bupropion. Post-marketing surveil- success, it should be used in combination with lance in the UK estimated that about 540,000 intensive behavioural support. ARTICLE IN PRESS

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Second-line medications for smoking Given that other effective medications for cessation smoking cessation are readily available, nortripty- line is currently regarded as a second-line therapy. Furthermore, it is not FDA approved for smoking Nortriptyline cessation.18

As previously discussed, there is a good rationale for using antidepressants in aiding smoking cessa- tion. Nortriptyline is a that Clonidine inhibits the reuptake of noradrenaline and seroto- nin.4,5,36 It is presumed to act through its nora- Clonidine is an alpha-2 adrenoceptor that drenergic mechanism, reducing the severity of reduces sympathetic activity by decreasing nora- withdrawal symptoms. Other hypotheses for its drenaline release. It is generally used as an smoking-cessation properties include its anxiolytic antihypertensive and for prevention of recurrent effects and side-effects, such as dry migraine, but has also been used to treat opioid and mouth, which may make cigarettes less desirable.37 .5,36 Clonidine has been shown The Cochrane review identified six randomised- to ameliorate the symptoms of tobacco with- controlled trials that met their inclusion criteria.10 drawal, and, in some studies, increase abstinence These included trials that compared nortriptyline rates.13 with placebo as well as combining nortriptyline and The Cochrane review identified a total of 21 comparing it with nicotine patch. Altogether, when studies investigating its use for smoking cessation. pooled, the OR was 2.14 (95% CI: 1.49–3.06). However, these were of variable quality, many with Pooling the results from the four studies that only short-term follow-up. Only six studies met the compared nortriptyline with placebo only, nortrip- inclusion criteria, and the pooled results showed an tyline is found to at least double the chance of OR of 1.89 (95% CI: 1.30–2.74). This is comparable long-term abstinence (OR ¼ 2.79; 95% CI: with the efficacy of NRT and bupropion.7,10 Un- 1.70–4.59).10 An added advantage of nortri- fortunately, the adverse effects associated with ptyline is that it is a generic medication and this medication, such as postural hypotension, inexpensive. dizziness and dry mouth, makes its use less The treatment regimen involves a starting dose desirable. In addition, clonidine causes sedation, of 25 mg/day, increasing gradually over a period although this might be of some benefit to those who of some 3 weeks to a target dose of 75–100 mg/day, experience more intense symptoms of tobacco which is generally needed to reach a thera- withdrawal.13 Depression, sleep disturbance and peutic level of 50–50 ng/ml.37,38 The quit date is constipation are also reported, yet these are also usually set once therapeutic levels of the drug classic symptoms of nicotine withdrawal,6,40 and have been reached; this may take 10–28 days.18 therefore it is difficult to ascertain which of the The treatment period is typically 12 weeks, with two is the causal agent. Patients with a history of the dose tapered after this. There is limited depression or occlusive peripheral vascular disease evidence of benefit for extending treatment past should avoid using clonidine. 3 months.10 If clonidine is to be used for smoking cessation, The primary concern with using nortriptyline, then treatment should be started 2–3 days before like other tricyclic antidepressants, is its adverse quitting, allowing time to reach steady state cardiovascular effects. It is contraindicated in concentration. It has also been used in combi- those who have experienced a recent myocardial nation with NRT to help manage withdrawal. infarction or arrhythmias.36 Severe liver disease is Clonidine can be taken orally or through a another contraindication. In addition, there are a transdermal patch. Oral doses typically start with number of precautions to note, such as use in 0.1 mg/day, and then are gradually increased, up to people with cardiac disease, a history of epilepsy or 0.4 mg/day. The transdermal doses that have been psychosis, and women who are pregnant or breast- given are between 0.1 and 0.3 mg/day. The treat- feeding. ment period is usually short, given over the first Nortriptyline has a number of common side- 3–4 weeks after quitting when withdrawal sym- effects (e.g. dry mouth, light-headedness, shaki- ptoms are most intense. After this, the dose is ness, and blurred vision).39 Urinary retention, reduced over several days, which is particularly constipation, sexual difficulties, and seizure risk important to avoid hypertensive crisis and hypo- are also reported.36 In addition to these, an glycaemia in people with hypertension and diabetes, overdose of nortriptyline is commonly fatal. respectively.13,18 ARTICLE IN PRESS

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Medications not currently recommended rates compared with placebo. Pooling the results for smoking cessation of these studies, the estimated OR is 0.90 (95% CI: 0.68–1.18), concluding that the current Other tricyclic antidepressants research does not support using SSRIs for smoking cessation.10 As well as nortriptyline, other tricyclic antidepres- sants, such as and , have been Other antidepressants investigated for aiding smoking cessation. The Cochrane review identified only one small short- As well as bupropion, two other atypical antide- term study for doxepin.10 Although it suggested pressants have been reviewed. Tryptophan in- that doxepin might reduce urges to smoke, the creases serotonin, which leads to an expectation study failed to show a significant effect on that it might reduce withdrawal symptoms. How- abstinence. Further research is needed with larger ever, the only published study showed no effect of samples and longer-term follow-up before ruling this medication. , a serotonin and out this antidepressant. A small, short-term, noradrenaline reuptake inhibitor, has been exam- follow-up study of imipramine failed to find an ined in two studies, neither finding any beneficial 10 effect.10 effect.

Monoamine oxidase inhibitors Mecamylamine

Smoking is known to inhibit monoamine oxidase A Mecamylamine is a nicotine antagonist originally and B.41 Monoamine oxidase inhibitors (MAOIs), used to lower blood pressure through its ability to such as selegiline, and moclobemide, reduce activity. It was hypothesised may aid smoking cessation through their ability to that it may reduce urges to smoke by blocking the inhibit dopamine metabolism. rewarding effect of nicotine, and be most effective 15 Selegiline is a selective MAO-B inhibitor com- when combined with NRT. One Cochrane review monly used to treat Parkinson’s disease. A number identified two studies that met the inclusion of small randomised-controlled trials have sug- criteria. Although the results were promising, they gested that this medication might alleviate with- need to be replicated in larger long-term follow-up drawal symptoms and improve outcome.42–44 randomised-controlled trials. Until further evi- However, no systematic reviews have been under- dence is available, mecamylamine is not recom- 15 taken. mended for use. Moclobemide has been examined in one long- term trial, which found a significant effect on Lobeline smoking cessation at 6 months, but not at 1 year, compared with placebo.45 More recently, the same Lobeline, a partial nicotine agonist, has been investigator conducted an exploratory trial of promoted as a smoking-cessation aid since the lazabemide, finding that it increased short-term 1930s, and was readily available over the counter in abstinence compared with placebo.46 However, the the USA. However, early studies had poor metho- study had to be terminated prematurely, as there dology and, because of the lack of good efficacy were reports of liver toxicity from studies investi- data, it was banned by the FDA in 1993.14 A gating this drug for other purposes. Cochrane review has been undertaken but, owing to the lack of good quality trials, it concluded that Selective serotonin reuptake inhibitors there is currently no evidence to suggest that lobeline is effective in helping smokers stop.14 Five long-term follow-up studies of three different selective serotonin reuptake inhibitors (SSRIs) Anxiolytic medications were identified by the Cochrane review. Three examined the efficacy of fluoxetine, and, although Medications used for treating anxiety have been one showed a significant short-term effect, examined as possible smoking-cessation aids. The none demonstrated any long-term benefit. Only rationale for their use is two-fold: firstly, they may one trial was conducted for , which be able to moderate any anxiety experienced as a included a follow-up at 6 months, and again withdrawal symptom, and, secondly, these medica- showed short-term benefit only. Finally, a study tions increase dopamine, serotonin and noradrena- of found no effect on 6-month abstinence line, which play important roles in nicotine ARTICLE IN PRESS

Non-nicotine pharmacotherapies for smoking cessation 1209 dependence and withdrawal.11 Findings from a the results of each were pooled, the OR was 1.34 number of short-term trials are inconsistent, and, (95% CI: 0.49–3.63). The conclusion made by the in general, suggest that anxiolytics may have little authors was that an effect of could not effect on smoking cessation. One Cochrane sys- be ruled out, but, on the basis of results seen in tematic review of anxiolytics11 identified just one these two studies, no clear recommendations could trial each for , meprobamate, metoprolol be made on the clinical use of this medication for and oxprenolol, and two for buspirone that met the smoking cessation.16 inclusion criteria. Buspirone is an atypical anxiolytic, and is the most researched of the group. It is believed to act Silver acetate through its serotonergic and dopaminergic activity, and is non-sedating and non-addicting. However, Silver acetate has been used as a form of aversion there seems to be no clear effect on withdrawal therapy for smoking cessation. Smokers are in- symptoms, and pooled results from two long-term structed to use the product, which comes in the studies comparing buspirone with placebo showed form of chewing gum, spray or lozenges, on a no benefit of using buspirone for smoking cessation regular basis. When used in combination with (OR ¼ 0.71; 95% CI: 0.34–1.48).11 smoking, an unpleasant metallic taste is produced, Diazepam and meprobamate have not been thus making smoking less desirable. found to aid smoking cessation. Three beta-block- A small number of studies have investigated the ers have been examined (propanolol, metoprolol, effect of this substance with mixed results. How- and oxprenolol), but overall there is little evidence ever, one Cochrane review12 shows no advantage of for their effectiveness. There are no good long- silver acetate on abstinence rates compared with term studies of ondansetron, a 5-HT3 antagonist placebo (OR ¼ 1.05; 95% CI: 0.63–1.73). In addi- thought to affect the reinforcing properties of tion, argyrism (silver deposition) is an adverse nicotine. However, two short-term trials found no effect that needs to be avoided. It is recommended effect on abstinence or withdrawal symptoms.11 that the user should not exceed a total dose of The Cochrane review11 proposes that the ratio- 756 mg. This limits the length of time silver acetate nale for using anxiolytics might be an out-of-date can be used.12 assumption. The role of anxiety in cessation may have been overplayed, as anxiety seems to de- crease rather than increase after cessation.47 Other non-nicotine pharmacotherapies Therefore, the rationale for the use of anxiolytics is questionable. A number of other non-nicotine pharmacotherapies are being investigated for use in smoking cessation, but the relevant literature has not been included in Opioid antagonists systematic reviews. Glucose has been shown to reduce withdrawal and increase short-term absti- Opioid antagonists, such as and its longer- nence rates.50 Drugs that may reduce the reward- acting formulation naltrexone, are used in the ing effects of nicotine may be useful; for example, treatment of other chemical dependencies (e.g. , a selective cannabinoid receptor (CB1) , and alcohol). The rationale for antagonist,52 and , a GABA receptor using opioid antagonists in treating tobacco depen- agonist.52 A nicotine vaccine has been developed, dence comes from the principle that endogenous based on the hypothesis that if nicotine can be opioids might play a part in the reinforcing effects stopped from reaching the brain it will not be able of nicotine.48 to exert its central effects.53 Medications acting via In the 1980s, several studies were published the dopaminergic pathways have also been exam- reporting the effect of naloxone on smoking ined. Bromocriptine, a dopamine agonist, has been behaviour. Although some showed that it resulted shown to reduce cigarette smoking.54 The dopa- in a reduction of cigarette consumption compared mine precursor, levodopa, had no effect on with- with placebo, others did not demonstrate any drawal or abstinence in one study.55 Finally, effect.16 Conflicting results also exist for the effect , a partial agonist of the nicotinic of naltrexone on smoking behaviour.49 receptor, is said to reduce withdrawal and increase The Cochrane review identified only two studies abstinence compared with placebo.51 Some of that provided long-term abstinence data. The these medications look promising, but more require results of both studies failed to demonstrate a evidence before becoming generally recognised significant effect of naltrexone at 6 months. When effective treatments for smokers. ARTICLE IN PRESS

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Discussion and conclusion available, smokers should be referred to local smoking-cessation services. These provide good Nicotine has various actions within the central value for money, and offer the best chance of nervous system, and several neurochemical path- success.17 These services are especially important ways mediate nicotine withdrawal. A number of for those smokers with smoking-related disease non-nicotine medications acting at different points who are typically more dependent. in these pathways have been examined for their potential in aiding smoking cessation. Antidepressants have generally received the Practice points most attention. Two medications of this cate- gory are proven to help smokers quit. Bupropion  Bupropion is a non-nicotine pharmacother- is backed by the greatest amount of evidence apy currently recommended as a first-line for its effectiveness. Nortriptyline, although re- treatment that approximately doubles the garded as effective, is seen as a treatment chances of quitting smoking. It is currently second to bupropion and NRT. It has side-effects the only licensed alternative to NRT typical for tricyclic antidepressants, such as  The benefit of bupropion outweighs the risk dry mouth and blurred vision, and also has a of drug-related adverse events, and it less safe cardiovascular profile compared with should be available to all that are eligible. bupropion. For the best chance of success, it should be The only other medication known to significantly used in combination with intensive beha- increase long-term cessation rates is clonidine. Like vioural support nortriptyline, it has some unpleasant side-effects,  Nortriptyline and clonidine are not routinely and its efficacy is no greater than those of used in smoking-cessation services, but bupropion and NRT. It is not approved by the FDA could be considered in smokers who have as a smoking-cessation treatment, and is currently not responded to conventional treatments recommended as second-line treatment. However,  Protocols should be put in place to effec- further study of the effect of this medication is tively help smokers to stop. This should warranted. include referral to specialist smoking-cessa- The remainder of medications subjected to tion services systematic review failed to show any long-term benefit from their use. Anxiolytics are not helpful for smoking cessation or for reducing tobacco withdrawal symptoms, and therefore are not Research directions currently recommended. Substances such as silver acetate and lobeline are of little to no  Studies of bupropion have mostly used benefit, and smokers would be best advised to adjunctive intensive behavioural support. use one of the recognised first-line treat- Trials using bupropion with minimal, or no, ments. Although there may be some underlying support are warranted beneficial effect of drugs such as naltrexone and  Potential future non-nicotine medical mecamylamine, there is currently not enough therapies, such as glucose, rimonabant, evidence that demonstrates this beyond reasonable baclofen, nicotine vaccine, bromocriptine, doubt. and varenicline require further study and The field of smoking cessation is rapidly evolving, incorporation into systematic reviews and there is a need to find medications that will  Given the burden associated with COPD, help increase the number of long-term ex-smokers. and relative lack of effective smoking- It remains to be seen if drugs such as baclofen and cessation interventions in smokers with this bromocriptine will significantly influence cessation disease, further research is urgent and rates. Exciting new developments include vareni- should be prioritised cline, rimonabant and the nicotine vaccine. More  There is good rationale for using pharma- data on these medications are likely to appear in cotherapies such as mecamylamine, nal- the near future. trexone, SSRIs and MAOIs, and, although Medication to help in stopping smoking should be there is little current evidence for their accompanied, where possible, by behavioural sup- effectiveness, they might deserve further port. This has been shown to increase the likelihood investigation before being discarded as of successful outcomes, with the more intensive potential smoking-cessation aids the support the greater the abstinence rates.8 If ARTICLE IN PRESS

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