Sart 7-2013-085

Sart 7-2013-085

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  Substance Abuse: Researchand Treatment 2013:7 85–105 doi: 10.4137/SART.S8108 This article is available from http://www.la-press.com. © the author(s), publisher and licensee Libertas Academica Ltd. This is an open access article published under the Creative Commons CC-BY-NC 3.0 license. Open Access Full open access to this and thousands of other papers at http://www.la-press.com. Substance Abuse: Research and Treatment R e v i e w Substance Abuse: Research and Treatment 2013:7 85 Current and Emerging Pharmacotherapeutic Options for Smoking Cessation Kristin V. Carson1–3 , Malcolm P. Brinn1,3 , Thomas A. Robertson4 , Rachada To-A-Nan4 , Adrian J. Esterman5 , Matthew Peters6 and Brian J. Smith1,3 1 The Clinical Practice Unit, The Basil Hetzel Institute for Translational Health Research, Adelaide, Australia. 2 School of Medicine, The University of Adelaide, Adelaide, Australia. 3 Respiratory Medicine, The Queen Elizabeth Hospital, Adelaide, Australia. 4 Therapeutics Research Centre, School of Pharmacy and Medical Sciences, University of South Australia and The Basil Hetzel Institute for Translational Health Research, Adelaide, Australia. 5 School of Nursing and Midwifery, The University of South Australia, Adelaide, Australia. 6 Thoracic Medicine, The Concord Hospital, Sydney, Australia. Corresponding author email: [email protected] Abstract: Tobacco smoking remains the single most preventable cause of morbidity and mortality in developed countries and poses a significant threat across developing countries where tobacco use prevalence is increasing. Nicotine dependence is a chronic disease often requiring multiple attempts to quit; repeated interventions with pharmacotherapeutic aids have become more popular as part of cessation therapies. First-line medications of known efficacy in the general population include varenicline tartrate, bupropion hydro- chloride, nicotine replacement therapy products, or a combination thereof. However, less is known about the use of these products in marginalized groups such as the indigenous, those with mental illnesses, youth, and pregnant or breastfeeding women. Despite the effi- cacy and safety of these first line pharmacotherapies, many smokers continue to relapse and alternative pharmacotherapies and cessation options are required. Thus, the aim of this review is to summarize the existing and developing pharmacotherapeutic and other options for smoking cessation, to identify gaps in current clinical practice, and to provide recommendations for future evaluations and research. Keywords: smoking, smoking cessation, pharmacotherapy, pharmacotherapeutic, nicotine, varenicline tartrate, Champix, nicotine patches, bupropion, zyban
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  Carson et al 86 Substance Abuse: Research and Treatment 2013:7 Tobacco Use Since the 1950s, we have observed significant reductions in tobacco use prevalence across many countries.1–4 Despite these reductions, tobacco smok- ing remains the single most preventable cause of morbidity and mortality, contributing to more drug- related hospitalizations and deaths than alcohol and illicit drug use combined.1 Every year, approxi- mately 5.4 million people die from tobacco-related diseases, translating to 1 in every 10 deaths among adults ­worldwide.5 Tobacco use is known to cause up to 90% of all lung cancers and is a major risk factor of coronary heart disease, stroke, peripheral vascular disease,chronicobstructivepulmonarydisease,repro- ductive and fetal developmental diseases, and many other conditions.1,6 Tobacco cessation, even after a short period of time, is known to produce significant health benefits within as little as 20 minutes. Within 12 weeks of smoking cessation, improvements in oxy- gen transportation, smell, taste, breathing, energy, and immune responses are observed. Within 12 months, the risk of coronary heart disease will return to half that of a current smoker and is reduced to that of a non-smoker by 15 years.7 ­Moreover, smoking cessa- tion treatments have greater cost effectiveness and clinical efficacy in comparison to other preventative health measures such as treatment of hypertension and hypercholesterolemia,8–10 and research has shown that the cost per life year saved by smoking cessation interventions makes it one of the most cost-effective health care interventions.10,11 For these reasons, assisting individuals to stop smoking is a key health improvement objective in many countries12–14 and pharmacotherapeutic options areincreasinglybeingconsidered,particularlyforindi- viduals with high levels of nicotine addiction. Current first-line pharmacotherapies include nicotine replace- ment therapy, bupropion hydrochloride, and vareni- cline tartrate, with research suggesting that combining these with behavioral counseling increases efficacy and helps smokers achieve long term ­abstinence.15 Yet, these medications show some limitations and sig- nificant resources are invested into the development of designer smoking cessation pharmacotherapies, which target specific pathophysiological mechanisms in nicotine addiction in an attempt to improve the effectiveness and safety of ­pharmacotherapeutic ces- sation aids. In addition, adaptation of medications used primarily to treat other conditions which have the potential to act as smoking cessation aids are also being evaluated,16 as are novel adaptations to exist- ing smoking cessation treatments.17–19 As such, this ­article is intended to provide the reader with an over- view of current and emerging pharmacotherapeutic options for smoking cessation and provides recom- mendations for clinical practice, future evaluations, and research. Current Pharmacotherapeutic Options for Smoking Cessation The choice of any pharmacotherapy for smoking cessation should be guided by an individual’s pref- erence, contraindications, and precautions for use.13 ­Consideration should be given to specific factors such as the potential for adverse events, possible drug interactions, the individual’s experience with pharma- cotherapy, convenience, availability, and cost before prescribing any pharmacological interventions to aid smoking cessation.10 The level of nicotine addiction the individual is reported to have should also be taken into account based on a validated scale such as the Fagerström test for nicotine dependence.20 Smoking cessation guidelines and treatment algorithms recom- mend the use of pharmacotherapy only in the pres- ence of nicotine addiction to increase chances of a successful quit attempt, while non-pharmacological support is recommended for smokers who are not nicotine-dependent and those unwilling or unable to use pharmacotherapy.10,13,14,21 A systematic search of the Cochrane Database of Systematic Reviews’ Tobacco Addiction Group register was conducted to identify current and emerging pharmacotherapeutic options for smoking cessation. In addition, a search of Medline, EMBASE, and online clinical trial regis- tries were also conducted with the key words smoking OR tobacco OR nicotine OR tobacco cessation OR smoking cessation AND pharmacotherap*. First-line pharmacotherapies have been listed in ranked order of efficacy. First-line therapies Varenicline tartrate (Chantix or Champix) is a nico- tinic receptor partial agonist designed to selectively activate the α4β2 nicotinic acetylcholine ­receptor. It blocks the effect of subsequent nicotine challenge on mesolimbic neuronal dopamine release, while
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 87 ­mimicking the action of nicotine, causing the release ofmesolimbicdopamine.22 Clinicalpracticeguidelines report that varenicline is the most effective form of sin- gle pharmacotherapy for smoking cessation based on available evidence.10 A Cochrane meta-analysis of 14 trials comparing varenicline to placebo with respect to quit rate produced a risk ratio of 2.27 (95% CI 2.02 to 2.55), and compared to pharmacologically unassessed quit attempts varenicline improved the chances of long-term abstinence by two- to ­three-fold.23 Statisti- cally significant improvements have also been shown with varenicline for patients admitted to the hospital with smoking-related illnesses at 12 months follow- up.24 Varenicline is reported to be a superior smoking cessation aid to date for long-term abstinence in the general population, with direct and indirect compari- sons with bupropion,100 nicotine replacement therapy products,86 and cytisine.101 The most common adverse event is nausea, which is reported to be mild, self- limiting, and resolving over time (RR 3.28; 95% CI 2.89 to 3.73). Further details pertaining to dosing and prescription, efficacy, and adverse events are reported in Table 1. Bupropion hydrochloride (Zyban SR or Wellbutrin SR) is a norepinephrine and dopamine re-­uptake inhibitor that decreases nicotine cravings and symp- tomsofwithdrawal26 whilealsointeractingwithneural pathways underlying nicotine addiction.25 It can also be used as an antidepressant and is thought to reduce the depressive symptoms of nicotine withdrawal, as nicotine itself may cause antidepressant effects that bupropion helps maintain.26 Evidence from clinical trials report that bupropion aids long-term smoking abstinence when compared to placebo and nicotine replacement therapy products; however, when com- pared to varenicline, it showed reduced quitting suc- cess.23,25,27 The most common adverse events include insomnia, dry mouth, and nausea.25 Further details pertaining to dosing and prescription, efficacy, and adverse events are reported in Table 2. Nicotine replacement therapy (NRT) products are designed to control cravings by replacing nicotine through various delivery systems. Nicotine patches differ from other NRT products (eg, lozenges and gum) in that they deliver nicotine slowly and pas- sively over time.28 Transdermal patches are available in doses varying from 5 mg to 22 mg over a 16- to 24-hour period. Lozenges and chewing gum are available in strengths of 2 mg or 4 mg; however, no available NRT products deliver nicotine as quickly as a cigarette, being between 1 mg and 3 mg of nicotine per cigarette with the typical pack-per-day smoker absorbing 20 to 40 mg of nicotine per day.28,29 The most recent product on the market is the nicotine quick mist, which is a 1-mg oral mouth spray that produces levels of plasma nicotine similar to nicotine gums and lozenges.30 Areview of 132 trials found that NRT patches improved the likelihood of successful smoking cessation by 50% to 70% regardless of the setting.28 NRT products are available over the counter and the major side effects vary depending on the type of product, but typically include skin irritation from patches and irritation to the inside of the mouth from gum and tablets.28 Further details pertaining to dos- ing and prescription, efficacy, and adverse events are reported in Table 1. Other pharmacotherapeutic treatment options for smoking cessation Nicotine receptor antagonists Nicotine receptor antagonists include varenicline tartrate (as reported above), cytisine, dianicline, and mecamylamine, all of which moderate levels of dopamine to counteract withdrawal symptoms (ago- nist) and reduce smoking satisfaction (antagonist).23 A detailed summary of varenicline is described above and cytisine shows the highest efficacy of the remain- ing nicotine receptor agonists. A review of nicotine agonists identified one trial examining dianicline as a smoking cessation therapy, which was found to be ineffective.23 A separate Cochrane review examining mecamylamine identified two studies for inclusion, the results off which suggested that a combination of nicotine replacement therapy and mecamylam- ine may be superior to nicotine replacement therapy alone.31 However, these results were based on two studies with small sample sizes, and confirmation in larger studies is required before the treatment can be recommended clinically.31 Cytisine (Tabex) is derived from the plant Cytisus laburnum and acts as a low-efficacy partial nicotine agonist binding to subtypes of neuronal nicotine receptors, particularly the α4β2  subunits. Recent ­studies have highlighted the potential for this drug to be used in low- to medium-income countries27,33 where tobacco cessation is not supported by ­insurance plans
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  Carson et al 88 Substance Abuse: Research and Treatment 2013:7 Table1.Comprehensivesummaryoffirstlinetherapyoptionsforsmokingcessationavailableatpresent. StructuralformulaMolecularformulaSubstanceand(tradename/s)Chemicalname 1. Varenicline N N HN HO2C CO2H OH OH R R C13 H13 N3 C4 H6 O6 Vareniclinetartrate (ChampixorChantix) 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino [2,3-h][3]benzazepine DosingandprescriptionDosage:0.5 mgdailyfor3 days,0.5 mgtwicedailyforfourdays,1 mgtwicedailyforremainingtreatmentduration Prescription:Oral,tab.;recommendcommencement1weekbeforeestimatedquitdate;repeatscriptsareavailable withina1yearperioddependingoncountry;totalcoursedurationisbetween3and6 months;takewithfood; prescriptiononlymedicine;authorityrequired EfficacyAmeta-analysisof14RCTsproducedastatisticallysignificantbenefitinfavorofvareniclineforsustained CA(24weeks;RR2.27;95%CI2.02to2.55;totaln = 6,166;P , 0.00001).44 Ithasshownsuperiorityover bupropion,100 cytisine101 andNRT.86 Astudyusingvareniclineinitiatedintheinpatientsettingincludingpatientswith acutecardiovascular,respiratory,neurological,andvascularillnesses,showednoexacerbationofcardiovascular eventsorpsychologicalconditions.24,44 Limitations,adverseevents, andprecautions Limitations:Theefficacyofvareniclinehasyettobeadequatelyevaluatedinpatientswithpsychiatricdisorders, pregnantandbreastfeedingwomen,youth,andindigenouspopulations. Adverseeffects:Nausea(29%),insomnia(14%),headache(10%),constipation(6%),anddrymouth(6%);thereis anincreasedriskofseriousneuropsychiatricsymptomsincludingdepressedmood,agitation,suicidalbehavior,and suicidalideation;74,102,103 Post-marketingreportsincludehypersensitivityreactions(includingangioedema,whichcan belife-threateningduetorespiratorycompromise)andseverecutaneousreactionsincludingErythemaMultiformeand Stevens-JohnsonsSyndrome(alsopotentiallylife-threatening). Precautions:Recentevidencesuggestapossibleassociationwithincreasedcardiovascularevents104–107 and psychiatricconditions;102,108,109 Thoughonesmallstudyfoundimprovedmoodinoutpatientsmokerswithpersistent depressivesymptoms;110 Reduceddosingfrequencyof1 mgdailyisrecommendedforpatientswithsevererenal impairment. 2. Buproprion H N O Cl HCl C13 H18 ClNO HCl Bupropionhydrochloride (ZybanSRorWellburtin SR)(SRbeingsustained release) (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]- 1-propanonehydrochloride DosingandprescriptionDosage:150 mgtab.takendailyfor3 days,increasingto150 mgtwicedaily. Prescription:Oral,tab.;commencewhilstsmokingwithestimatedquitdatewithinthefirst2weeks;shouldbean intervalofatleast8 hoursbetweensuccessivedoses;prescriptiononlymedicine;authorityrequired;courseminimum 7weeks.
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 89 EfficacyAmeta-analysisof36RCTsfoundsustainedCAcomparedtoplacebo(RR1.69;95%CI1.53to1.85;totaln = 11,140; P , 0.00001);sixRCTswereunabletoproducesufficientevidencethataddingbupropiontoNRTprovidesadditional long-termCA(RR1.23;95%CI0.67to2.26;totaln = 1,106;P = 0.51);threeRCTsshowedlowerquittingwith bupropioncomparedtovarenicline(RR0.66;95%CI0.53to0.82;totaln = 1,622;P = 0.0002).25 Limitations,adverseevents, andprecautions Limitations:Theefficacyofvareniclinehasyettobeadequatelyevaluatedinpregnantandbreastfeedingwomen, youth,andinmostindigenouspopulations. Adverseeffects:Insomnia(40%),rhinitis(12%),dizziness(10%),nausea(9%),disturbedconcentration(9%), constipation(8%),andanxiety(8%).111 Precautions:Prescriptiontopatientswithanincreasedriskofseizuresshouldbeavoidedwithariskof1 in1,000;25 Thereisapossibilityofmetabolismandage-relatedreductionsindrugclearancerequiringmodificationofthestandard dosingprotocolto150 mgperday(firstweek)increasedto300 mgintheabsenceofadverseevents;112 Reports ofseizuresintheearlyformulationresultinginthedevelopmentoftheslowrelease(BupropionSR)preparation;25 ContraindicatedinpatientswithknownCNS.111 3. Nicotine NN H C10 H14 N2 Nicotine(includingNicotinell, QuitX,Nicobate,Nicoderm, NicotrolandNicorette) 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine 3.1. Nicotinepatch DosingandprescriptionDosage:Varyfrom5 mg,10 mgand15 mg16 hourpatchor7 mg,14 mg,21 mg,and22 mg24 hourpatch. Prescription:Transdermal,patch;availableoverthecounter;12-weekcourserecommended,step-downtitration recommended. EfficacyAreviewof41trialscomparingNRTpatchestono-treatmentorplaceboproducedastatisticallysignificantbenefit infavorofpatches(RR1.66;95%CI1.53to1.81;totaln = 18,237;P , 0.00001).28 OnestudycomparedNRTto bupropionwithsubjectsusingthenicotinepatchproducingalowerquitrate.113 VareniclinewassuperiortoNRTfor long-termCAthroughindirectcomparisonswhencomparedtoplacebo(OR1.6695%CI1.17to2.36;P = 0.004) andtoallcontrolsat1-yearfollow-up(OR1.73;95%CI1.22to2.45;P = 0.001),114 andinadirectcomparisonof 746participantsacrossfivecountries(OR1.40;95%CI0.99to1.99;P = 0.056).86 Limitations,adverseevents, andprecautions Limitations:Notappropriateforuseinpregnantorbreastfeedingwomen;smokingcessationefficacylessthanthatof vareniclinetartrateandbupropionhydrochloride. Adverseeffects:Applicationsitereaction(35%),headache(30%),coldandflu-likesymptoms(12%),dysmenorrhea (7%),insomnia(6%),nausea(6%),myalgia(6%),anddizziness(6%).115 Precautions:Contraindicatedinpeoplewithdiseasesoftheskinthatmaycomplicatepatchapplication;precautions areadvisedforpatientswithunderlyingcardiovasculardisease,diabetesmellitus,moderatetoseverehepatic impairment,pepticulcers,pheochromocytoma,anduncontrolledhyperthyroidism;smokingwhileonpatchesmay increasetheriskofcardiovascularevents(eg,angina);115 contraindicationstonicotineoranycomponentofthepatch. 3.2. Nicotinegum DosingandprescriptionDosage:2 mggumrecommendedforsmokersof,25cigarettesperday,4 mgforsmokers25cigarettesperday. Prescription:Donotexceed24piecesinaday;coursemax.12weeks;avoideatingordrinkinganythingexceptwater for15 minbeforeorduringchewing;variousflavors:classic,mintandcitrus;14 availableoverthecounter. EfficacyAreviewof53trialscomparingnicotinegumtono-treatmentorplaceboproducedastatisticallysignificantbenefitin favorofgum(RR1.43;95%CI1.33to1.53;totaln = 19,090;P , 0.00001).28 (Continued)
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  Carson et al 90 Substance Abuse: Research and Treatment 2013:7 Table1(Continued) StructuralformulaMolecularformulaSubstanceand(tradename/s)Chemicalname Limitations,adverseevents, andprecautions Limitations:Notrecommendedbeyond12weeks;smokingcessationefficacylessthanthatofvareniclinetartrateand bupropionhydrochloride. Adverseeffects:Hiccoughs,gastrointestinaldisturbances,jawpain,orodentalproblems,28 headache,indigestionand nausea;30 Somesymptomsmayberelievedbychewingmoreslowlyandrestingthegum.30,116,117 Precautions:Itispossiblethatpeopleusingthegummaytransfertheirnicotineaddictionfromcigarettestothegum;116 Contraindicationstonicotineoranycomponentofthechewingproduct. 3.3. Nicotineinhaler DosingandprescribingDosage:Use6to12cartridgesperday. Prescription:Drawbreaththroughthemouthpiecetakingshallowsuckingbreathsevery2 secondsor4 strongdeep breathsperminutes;20 minutesofcontinuoususewilldepleteonecartridge;avoideatingordrinkinganythingexcept waterfor15 minutesbeforeuseofinhaler;courseminimum12weeks,thenreducenumberofcartridgesandusefor extra6–8weeks;prescriptiononlymedicine.118 EfficacyAreviewof4trialscomparingnicotinegumtono-treatmentorplaceboproducedastatisticallysignificantbenefitin favorofinhaler(RR1.90;95%CI1.36to2.67;totaln = 976;P = 0.0002).28 Limitations,adverseevents andprecautions Limitations:Smokingcessationefficacylessthanthatofvareniclinetartrateandbupropionhydrochloride. Adverseeffects:localirritationaroundmouth,increasedsymptomsofthroatirritation,coughing,oralburning,28 sneezing,runnynose,headache,nausea,heartburn,andhiccoughs;mostusersratethesereactionsasmild,ifthe sideeffectsdonotsubsidewithin1–2weeksseekingmedicaladviceisrecommended;ifseveresymptomsoccur,do notsmokeandseekmedicaladvice.118 Precautions:Contraindicationstonicotineoranycomponentoftheinhalers. 3.4. Nicotinenasalandmouthspray DosingandprescriptionDosage:10 mg/mLnicotineconcentration;onespraydelivers0.5 mgnicotine.119 Prescription:Useonesprayineachnostril1–2timesperhour;recommended8–40dosesperday;courseminimum 3 months,max.6 months;prescriptiononlymedicine.101 EfficacyAreviewof4trialscomparingnicotinegumtono-treatmentorplaceboproducedastatisticallysignificantbenefitin favorofnasalspray(RR2.02;95%CI1.49to2.73;totaln = 887;P , 0.00001).28 Limitations,adverseevents, andprecautions Limitations:Smokingcessationefficacylessthanthatofvareniclinetartrateandbupropionhydrochloride. Adverseeffects:Localirritationinandaroundnose,runnynose,28 headache(18%),backpain(6%),dyspnea(5%), nausea(5%),arthralgia(5%).119 Mostusersratethesereactionsasmild,ifthesideeffectsdonotsubsidewithin 1–2weeksseekingmedicaladviceisrecommended.119 Formouthsprayadverseeffectsincludedincreasedhiccups,burningsensationonthelips,andlocalirritationofthe mouth,thoughnoneoftheseweresevere.120 Precautions:Contraindicationstonicotineoranycomponentofthesprays. 3.5. Nicotinelozenge DosingandprescriptionDosage:4 mglozengeiffirstcigarettewithin30 minutesofwakingupotherwise2 mg. Prescription:Weeks1–6 × 1lozengeevery1–2 hours,weeks7–9 × 1every2–4 hours,weeks9–12 × 1every 4–8 hours;max.5 in6 hours;allowlozengetodissolveinmouth,donotcheworswallowwhole;variousflavors includingmintorcherry;usualpacksizesare24,36,48,72,and100;availableoverthecounter;fortablet,swallow wholewithwater.101
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 91 EfficacyAreviewof6trialscomparingnicotinelozenges/tab.tono-treatmentorplaceboproducedastatisticallysignificant benefitinfavoroflozenge(RR2.00;95%CI2.63to2.45;totaln = 3,109;P , 0.00001).28 Limitations,adverseevents, andprecautions Limitations:Smokingcessationefficacylessthanthatofvareniclinetartrateandbupropionhydrochloride. Adverseeffects:Hiccoughs,burningandsmartingsensationinthemouth,sorethroat,cough,dry-lips,mouthulcers,28 indigestion,gas,andnausea;121,122 mostusersratethesereactionsasmild,ifthesideeffectsdonotsubsidewithin 1–2weeksseekingmedicaladviceisrecommended.121–124 Precautions:Contraindicationstonicotineoranycomponentofthelozenge/micro-tab. or the national health service23 as well as in the indig- enous setting.34 Efficacy trials show modest improve- ments in quit rates with outcomes similar to studies using nicotine replacement therapy,23 though twice as effective as placebo.34 Further details pertaining to dosing and prescription, efficacy, and adverse events are reported in Table 2. Pharmacological therapies that are used primarily to treat other medical conditions may also be used for treatingnicotineaddiction.Asresearchaimedatexplor- ing and understanding the biological mechanisms of nicotine addiction develop, new opportunities are aris- ing for existing pharmacological agents to be translated into the tobacco arena. The following section provides a summary of such medications, which have potential applications in treating nicotine addiction. Anxiolytics Anxiolytics are proposed as a smoking cessation treatment because of their ability to abate anxiety, one of the common symptoms of smoking ­cessation.35 There are many types of anxiolytics that may have a role as smoking cessation treatments including clo- nidine, buspirone, diazepam, doxepin, meprobam- ate, ondansetron, and the beta-blockers metoprolol, oxprenolol, and propanolol.35 The anxiolytic cloni- dine has the most evidence evaluating efficacy for smoking cessation out of the nine anxiolytics, and as such are a more detailed description of clonidine is reported below and in Table 2. Clonidine is marketed as an antihypertensive but also has applications for drug and alcohol withdrawal symptoms,36,37 as a treatment for chronic pain,38 menopausal flushes39,40 and Tourette’s syndrome. In a systematic review of tobacco withdrawal symptom studies, clonidine has been reported to ameliorate cravings, anxiety, restlessness, tension, and hunger, but also caused some side effects such as sedation, dry mouth, and dizziness, with twice as many patients taking clonidine discontinuing medication compared to placebo.42 For these reasons, clonidine is not con- sidered a first-line treatment; however it may be ben- eficial for targeted populations such as smokers who are likely to experience high levels of anxiety and agitation when stopping smoking and subsequently may benefit from the sedative effects.42 Further details pertaining to dosing and prescription, efficacy, and adverse events are reported in Table 2.
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  Carson et al 92 Substance Abuse: Research and Treatment 2013:7 Table2.Comprehensivesummaryofotherpharmacotherapeuticoptionsforsmokingcessationavailableatpresent. StructuralformulaMolecularformulaSubstanceand(tradename/s)Chemicalname 1. Cytisine NH N O C11 H14 N2 OCytisine(Tabex,Baptitoxine, Sophorine) (1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2a] [1,5]diazocin-8-one DosingandprescriptionDosage:Oral,tab.;increasingdosagesfromevery2hoursto1–2tabsperday. Prescription:Commence1tab.every2hoursfor3dayswhilereducingnumberofcigarettes;days4–12×5tab. perday;days13–16×4tab.perday;days17–20×3tab.perday;days21–25×1to2tab.perday;totalcourse approximately22days. EfficacyAmeta-analysisoftwoRCTscomparingcytisinetoplaceboatlongestfollow-upforCAproducedstatisticallysignificant benefitsinfavorofcytisine(RR3.98;95%CI2.01to7.87;totaln=937;P,0.0001);23 Quitrateswerearound9%in thetreatmentgroups.23 Limitations,adverseevents, andprecautions Limitations:Limitedresearchdataavailabletodeterminefullefficacy. Adverseeffects:Nausea,restlessness,insomnia,andirritability(23%ofonestudypopulationcomparedto20%in placebo)andgastrointestinaldisorders(13%vs.8%inplacebo);23 notcurrentlylicensedforuseintheEuropeanUnion mainlyduetoinsufficientCAdata.32 Precautions:Contraindicationstocytisineoranycomponentofthetablet. 2. Clonidine Cl H N H N N Cl C9 H9 Cl2 N3 Clonidine(Catapres)N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine DosingandprescriptionDosage:Oral,tab.;0.1mgtwicedaily;transdermalpatchonce/weekor0.2μgpatchperday. Prescription:Onetablettwicedailyforbetween4and12weeks;transdermalnicotinepatchfor12weeks. EfficacyAreviewofsixstudiesfoundthatalltrialfavoredclonidine,yetonlyoneproducedastatisticallysignificantresults infavoroftheinterventionarm,withpooledanalysissuggestingthatclonidineiseffectiveasasmokingcessation treatment(RR1.63;95%CI1.22to2.18).42 Thereissomeevidenceofclonidinebeingmoreeffectiveforwomen howevertheseresultsareonlybasedonsub-groupanalysesandshouldbeinterpretedwithcautionasonlyonestudy stratifiedbygenderpriortorandomisation.125 Limitations,adverseevents, andprecautions Limitations:Efficacyandsafetyhasnotbeenestablishedinthepediatricsetting. Adverseevents:Adverseeventswithclonidinearecommonwithtwiceasmanypatientsdiscontinuinguseprematurely incomparisontotheplacebopopulationinonereviewofstudies126 with23%to92%(median71%)ofclonidine subjectsand4%to61%(median28%)forsubjectstakingplaceboreportingadverseeffects.Symptomatichypotension wasreportedin10%ofsubjectstakingthe0.3mgdose. Precautions:Contraindicationstoclonidineoranycomponentofthetabletorpatch.
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 93 3. Nortriptyline N H C19 H21 NNortriptyline(Aventyl)3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)- N-methyl-1-propanamine DosingandprescriptionDosage:Oral,tab.;25to100mgperdayortitrateddosagestoserumlevelsrecommendedfordepression. Prescription:Titrationrecommendedforoneweektoonemonthpriortoestimatedquitdate;firstdosesuggested at25mg,increasingto75–100mgafterquitdate,continuingfor12weeks. EfficacyACochranereviewofantidepressantsidentifiedninestudiesexaminingtheeffectsofnortriptylineforsmokingcessation, producingastatisticallysignificantincreaseinlong-termsmokingcessationasevidenceinthesixstudiesthatwereable tobepooled(RR2.03;95%CI1.48to2.78).25 Thethreeremainingstudiesthatusednortriptylineinconjunctionwith nicotinereplacementtherapyshowednoevidenceofanyadditionalbenefitoverthatofnicotinepatchtherapy.25 Limitations,adverseevents, andprecautions Limitations:Notevaluatedinthepediatricsettingorforusebypregnantorbreastfeedingwomen. Adverseevents:Drowsiness,drymouth,light-headedness,blurredvision,urineretention,constipation,andtremor;the mostsignificantadverseeventinthereportedefficacystudieswascollapse/palpitations,whichwasthoughttopossibly becausedbytreatment. Precautions:Nortriptylinehasthepotentialforserioussideeffectsbutnonehavebeenobservedinthe methodologicallyrigoroussmokingcessationstudiesreportedtodate;25 contraindicationstonortriptylineorany componentofthetablet;nortriptylinecanbelethalinhighdoses. 4. Naltrexone HO O OH N O C20 H23 NO4 Naltrexone(NarpanTM, ReviaTM(injectable formulationunderVivitrol)) 17-(cyclopropylmethyl)-4,5α-epoxy-3, 14-dihydroxymorphinan-6-one DosingandprescriptionDosage:Oral,tab.;testdoseof25mgfirst;dosagebetween25mgto200mg. Prescription:Followingtestdosemultipletreatmentplanscanbeadministeredincluding:50mgdailyMon-Friwith 100mgSat;100mgeveryotherday,150mgeverythirdday,100mgMonandWedand150mgFri;150mgMon, 200mgTue.Durationvariesbutrecommendeddosageuptosixmonths. EfficacyFourstudieswereidentifiedfromaCochranereviewofopioidantagonistsreportinglong-termsmokingabstinence (sixmonthsormore).Allfourstudieswereunabletoidentifysignificantdifferencesinquitratesbetweennaltrexone andplacebowhenpooledinameta-analysis(OR1.26;95%CI0.80to2.01).43 Limitations,adverseevents, andprecautions Limitations:Treatmentwithopiatederivativesforcough,diarrheaandpainmaynolongerbeeffectiveifundergoing treatmentwithnaltrexoneforsmokingcessation. Adverseevents:Moodswings,light-headedness,dizziness,head-rushfollowingcigarette,nausea,vomiting,diarrhea, cramps,headache,insomnia,anxiety,irritability,anddepression.43 Precautions:Canbetoxicifhighdosesareadministeredoverprolongedperiodsoftime. (Continued)
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  Carson et al 94 Substance Abuse: Research and Treatment 2013:7 Table2.(Continued) StructuralformulaMolecularformulaSubstanceand(tradename/s)Chemicalname 5. Rimonabant N H N NN O Cl Cl ClC22 H21 Cl3 N4 ORimonabant(Acomplia, Bethin,Monaslim, Remonabent,Riobant, Slimona,Rimoslim, Zimulti,andRiomont) 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide DosingandprescriptionDosage:Oral,tab.;5mgto20mgdaily. Prescription:10weeksoftreatmentwitheitherthe5mgor20mgdoserecommended,followedbyamaintenance doseofanadditional40weeks. EfficacyACochranereviewofcannabinoidtype1receptorantagonistsidentifiedthreestudiesofrimonabantforinclusionwith a20mgdoseincreasingthechancesofquittingbyoneandahalffold(OR1.50;95%CI1.10to2.05),thoughno evidencewasdetectedtosupportlong-termabstinence.44 Limitations,adverseevents andprecautions Limitations:Post-marketingsurveillanceofrimonabantin2008ledtoSanofiAventiswithdrawingtheproductdueto linkswithmentaldisorders.44 Adverseevents:Nausea,upperrespiratorytractinfections,fatigue,depressedmood,anxiety,suicidalthoughtsand nasopharyngitis.44 Precautions:Withdrawnfromthemarketin2008duetolinkswithmentaldisorders. 6. Lobeline N OOH C22 H27 NO2 Lobeline(Lobelin,lobeline)2-((2R,6S)-6-((S)-2-hydroxy-2-phenylethyl)-1- methylpiperidin-2-yl)-1-phenylethanone DosingandprescriptionDosage:Oral,tab.;5mgwithsomestudiesexamining8mgdoses;lozenges0.5mg. Prescription:Oraltablettwicedaily;lozengeusedinadditionwhenthereisanurgetosmoke. EfficacyArecentCochranereviewidentifiednostudiesthatmettheinclusioncriteriatoexaminetheefficacyoflobeline.46 Other reviewshaveidentifiedstudiesexamininglobeline,thoughfewincludedstudieshadcontrolpopulationsandmostwere ofpoormethodologicaldesignresultinginaninabilitytodrawreliableconclusionsaboutefficacy.127,128 Limitations,adverseevents, andprecautions Limitations:LobelinehasbeenbannedbytheFDAasasmokingcessationaidasof1993duetoalackofefficacydata toascertainsafetyandeffectiveness.49 Adverseevents:Gastricsideeffects,dizziness,nausea,vomitingandthroatirritation.47,48 Precautions:Contraindicationstolobeliainflate;uterinetonelossobservedwithuseduringpregnancy/lactation.129 7. Silveracetate O− Ag+ OAgC2 H3 O2 Silveracetate(Healthbreak, Tabmit) Aceticacid,silver(1+)salt Silverethanoate
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 95 DosingandprescriptionDosage:Oral,2.5mglozenge,1.6mgchewinggum,andspraystonomorethanatotalof756mg. Prescription:Uselozenge,gumorsprayssixtimesperdayforthreetosixweeksprovidingthetotaldosedoesnot exceed756mg. EfficacyACochranereviewoftwostudiesfoundnoevidenceofeffectforsilveracetateforsmokingcessation,thoughtheupper limitoftheconfidenceintervalequatestoanabsoluteincreaseinthesmokingcessationrateofapproximately4%.129 Thereforeanyeffectofsilveracetateislikelytobelessthanthatobservedwithnicotinereplacementtherapyuse.129 Limitations,adverseevents, andprecautions Limitations:Littleevidencetosupporttheuseofsilveracetate. Adverseevents:Mainadverseeventsarethoseexperiencedaspartofaversivestimulusbeingunpleasanttaste, sensationsinthemouth,andgastrointestinaldisturbances;ifthedoseofsilveracetateexceeds756mg,itcanleadto argyrism,whichissilverdepositioninbodytissue.130 Precautions:Excessiveingestionofsilveracetatecanleadtoargyrism;130 contraindicationstosilveracetateorany componentsofthelozenge,gum,orspray. 8. Nicobrevin N H H N O H HO C20 H24 N2 O2,3 H2 OCombinationofquinine, menthylvalerate,camphor andeucalyptusoil (Nicobrevin,Qualaquin) (8α,9R)-6′-Methoxycinchonan–9–oltrihydrate DosingandprescriptionDosage:Oral,tab.;1–3capsulesperday. Prescription:Fourweekstothreemonthsduration;week1:1capsuleinthemorningand2capsulesatnight;week2: 1capsuleinthemorningand2capsulesatnight;weeks3to12:1capsuleatnight. EfficacyA2009Cochranereviewofnicobrevinforsmokingcessationwasunabletoidentifyanystudiesmeetingtheinclusion criteriaforthereview.52 Efficacyfornicobrevinisunknown. Limitations,adverseevents, andprecautions Limitations:WithdrawaloftheproductfromtheUKandothermarketsin2011.51 Adverseevents:Primarilygastrointestinalrelatedandincludingnausea,stomachpains,constipation,lossofappetite, vertigo,heartburn,burningtongueordrymouth,diarrhea,visionproblems(lightsensitivity),headaches,insomnia, sweating,biliarycolic,andpimples.51 Precautions:WithdrawaloftheproductfromtheUKandothermarketsin2011.51 Notrecommendedforuseduring pregnancy.
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  Carson et al 96 Substance Abuse: Research and Treatment 2013:7 Other antidepressants Other antidepressants, including tricyclics (doxepin, imipramine, and nortriptyline), monoamine oxidase inhibitors (moclobemide and selegiline), selective serotonin reuptake inhibitors (fluoxetine, paroxetine, and sertraline), atypical antidepressants (bupropion— mentioned above, tryptophan, and venlafaxine), and extracts (St. John’s Wort—Hypericum perforatum L.) have also been examined as smoking cessation aids.25 A Cochrane review of antidepressants for smoking cessation identified 66 trials, 49 or which were inves- tigating bupropion and 9 nortriptyline.25 Pooling of bupropion and nortriptyline studies indicated long- term smoking cessation efficacy similar to that of nicotine replacement therapies, while selective sero- tonin reuptake inhibitors did not.25 As bupropion is discussed above as a first-line smoking cessation aid, a detailed summary of nortriptyline is reported below and in Table 2 as it shows the most evidence of the remaining antidepressants for use as a smoking ces- sation medication. Opioid antagonists Opioid antagonists including naltrexone, buprenor- phine, and naloxone are thought to be potentially effective smoking cessation medications as they have the potential to attenuate the rewarding effects of cigarette smoking.43 Smokers report both positive and negative effects associated with smoking with the reinforcing properties of nicotine theorized to be mediated through the release of various neurotrans- mitters in the brain. There is evidence to suggest that the endogenous opioid system may have a reinforcing role in smoking, while other studies report that the system may also have a mediating role with nicotine withdrawal.43 Naltrexone is a long-acting opioid agonist mar- keted as a drug that blunts certain effects of narcotics such as heroin, meperidine, morphine, and ocycodone and is also used in the treatment of alcoholism.43 ­Naltrexone is thought to reduce nicotine cravings by diminishing the activation of mesolimbic dopamine receptors; thus, combination therapy with NRT is thought to offer an additive effect for achieving smoking abstinence due to its different mechanisms of action.43 Further details pertaining to dosing and prescription, efficacy, and adverse events are reported in Table 2. Cannabinoid type 1 receptor antagonists Cannabinoid type 1 receptor antagonists such as rimonabant and taranabant are thought to assist smok- ing cessation by restoring the balance of the endo- cannabinoid system, which can be disrupted with prolonged exposure to nicotine. Central cannabinoid receptors have been implicated in brain reward func- tion and are thought to play a role in dependence and habituation.44 It is thought that rimonabant may work by blocking the central cannabinoid receptors thus restoring the balance and inhibiting nicotine and food cravings.44 Rimonabant was originally manufactured to treat obesity and was later proposed as a smoking cessa- tion aid due to its potential for protecting successful quitters from significant post-cessation weight gain. Smoking cessation itself is associated with weight gain, which deters some smokers from making quit attempts; it was hoped that rimonabant would act as a cessation aid for these smokers. Reports of increased levels of suicidal thoughts and depression resulted in withdrawal of rimonabant as a prescription drug in European Countries in 2008.44 Further details pertain- ing to dosing and prescription, efficacy, and adverse events are reported in Table 2. Lobelia Lobelia (lobeline) is derived from the Indian tobacco plant Lobelia inflate and was first synthesized in the early 1900s when it was classified as a partial nico- tinic agonist.45 The first documented use of lobeline as a smoking cessation treatment was in the 1930s with a variety of dosages and delivery mechanisms tested since then, including tablet (8  mg as lobeline sul- phate), parenteral injection, buffered tablets, and fla- vored pastilles.46 All of these formulations produced varying degrees of adverse effects including gastric side effects, dizziness, nausea, vomiting, and throat irritation.47,48 In 1993, the FDA announced a ban on all over the counter smoking cessation products in the United States due to a lack of efficacy data.49 Further details pertaining to dosing and prescription, efficacy, and adverse events are reported in Table 2. Silver acetate Silver acetate is designed to act as an aversive stimulus to inspire smoking cessation by producing an unpleas- ant metallic taste when combined with ­cigarettes.50
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 97 Smokers are encouraged to use silver acetate prod- ucts such as lozenges, gums, and sprays so that the act of smoking becomes unpleasant to diminish or stop the urge to smoke.50 Efficacy studies have shown a possible small effect of silver acetate, though any benefit observed is less than that produced by nico- tine replacement therapy (NRT) and therefore silver acetate is not widely used to promote smoking ces- sation in the clinical setting with the exception of a possible combination use with NRT.50 Further details pertaining to dosing and prescription, efficacy, and adverse events are reported in Table 2. Nicobrevin Nicobrevin has been marketed as a smoking cessation aid in 11 countries including the United Kingdom (UK), New Zealand, and Germany, though in 2011 a governmental review found Nicobrevin to be ineffec- tive as a smoking cessation aid and identified several side effects. Thus, the risks of the product outweighed the benefits.51 This resulted in withdrawal of the prod- uct from the UK and other markets. Nicobrevin is a proprietary product containing four active ingredi- ents, including quinine (15  mg, thought to reduce cravings), menthyl valerate (100 mg, acts as a seda- tive), camphor (10 mg, relieves respiratory congestion and gastrointestinal disturbances), and eucalyptus oil (10 mg, relieves respiratory congestion and gastro- intestinal disturbances).52 Further details regarding to dosing and prescription, efficacy, and adverse events are reported in Table 2. Adaptive and novel approaches New formulations and innovative delivery systems for existing products are in development53,54 such as a straw containing nicotine beads, which allows the smoker to place drops of nicotine directly into a beverage,19 though safety and efficacy data remains unknown. Galenic formulations of varenicline are also being developed, including a controlled release formulation (ClinicalTrials.gov Identifier: NCT00741884 and NCT005227150), a free base solution (NCT00774605), and a free base patch (NCT01234142, NCT01013454, NCT00774605). ­Tailoring dosages of existing medications such as varenicline and nicotine patches are also being evalu- ated with administration of up to 5 mg dosages per day of varenicline for smokers not experiencing any adverse events during the standard first week of titra- tion(NCT01206010)and42 mgpatchesforfastmetab- olizers of nicotine (NCT00956943). ­Combinations of existing products are also being explored as options for enhancing abstinence rates, with some evidence of success for combining varenicline with nicotine replacement therapy55 (NCT01184664) and bupro- pion56 (NCT00935818). Electronic nicotine delivery systems or ‘E-­cigarettes’ are becoming increasingly ­popular, ­particularly among the youth and adolescents as ­flavored varieties are now being introduced.18 These small cigarette-shaped electronic devices use a battery-powered heating element, across which a solution of nicotine and propylene glycol (though other solutions are also used) is drawn. This causes the humectant to vaporize and subsequently be inhaled via a small tube as a mist.17 Despite marketing of the product as a safe alternative to cigarette smoking as it does not contain the harmful ingredients normally found in cigarettes, there are concerns regarding the wide-spread use of these devices, with FDA reports of some tested samples containing toxic substances including nitrosamines and even diethylene glycol.18 Moreover, many manufacturers still evade govern- ment regulation, raising issues around safety and harm reduction.17,18 E-cigarettes are currently being trialed for smoking cessation and reduction in smok- ers who are unwilling to quit (NCT01195597). Immunotherapy, also referred to as nicotine vac- cines, are currently being developed and evaluated through pharmaceutical studies some of which are phase III trials, with the most advanced vaccines expected to be launched in the first years of the 2010 decade.54,57 Nicotine is a small molecule that is unable to induce antibodies directed against it.58 ­Immunotherapy is designed to chemically link nic- otine to a carrier so that it acts as a hapten.59 This allows antibodies to bind to nicotine molecules in the plasma, resulting in a nicotine-antibody complex too large to cross the blood-brain barrier.60 Thus, anti- nicotine antibodies change the kinetics of nicotine accumulation in the brain as well as the distribution of nicotine between the brain and other body ­tissues. A review of four pharmaceutical trials found no long-term smoking cessation success to date,61 with none of these studies reporting any major side effects (NCT01178346, NCT001102114, NCT01280968).
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  Carson et al 98 Substance Abuse: Research and Treatment 2013:7 Alternative medical interventions and the role of pharmacogenomics To date, alternative therapies such as acupuncture,62 hypnotherapy,63 quit and win contests,64 and exercise interventions65 have, for the most part, been unsuc- cessful as a smoking cessation aid. There is evidence to support the use of behavior modification and cogni- tive interventions (including counseling and support programs), and these should be considered in com- bination with all pharmacological interventions24,66 and alternatives for people with contraindications to pharmacotherapies.50 Studies are currently underway to test genetic factors that may predict the effectiveness of ­smoking ­cessation therapies, including varenicline (NCT01228175) and nicotine replacement therapy (NCT00326781). Additionally, examinations into potential genetic moderators of nicotine, such as the mu opioid receptor gene (OPRM1) A118G polymor- phism, are being investigated with the hypothesis that AG/GG genotype smokers will have attenuated subjective-rewarding from intravenous ­administered nicotine compared to those with AA genotypes (NCT00969137). Specific nicotine biomarkers are also being evaluated to understand how these may influenceasmoker’s decisiontoquit(NCT01314001). Using biological indicators as a motivator for smoking cessation is not a new concept, with spirometric ‘lung age’used as a persuader in the early to mid-1980s.67 It is theorized that providing a smoker with an estimate of their individualized and personalized damage as a result of their tobacco use will motivate them into a quit attempt, though the exact mechanisms by which improvements are obtained remains unclear.68 Specific Populations Young people Some evidence-based guidelines recommend nico- tine replacement therapy as a means of cessation for youth aged 12 to 18 years who are dependent on nico- tine (ie, it is not recommended for use by occasional smokers).13 Other pharmacological interventions such as varenicline tartrate, however, have not yet specifi- cally been evaluated for safety or efficacy in youth and should be considered with caution. ­Considering that tobacco use typically begins in childhood or early adolescence69 with only 10% of new smokers initiating the habit after the age of 18 years,70 more investigation is needed in this area, particularly to prevent youth from experimenting with tobacco use in the first place. Gender differences Research suggests that gender differences exist in relation to nicotine dependence with females tending to smoke less and commence tobacco use at a later age than their male counterparts.71 Females are also less likely to be tobacco-dependent and subsequently less responsive to nicotine replacement therapy and more responsive to the sensory and behavioral aspects of smoking, which should be considered when consider- ing smoking cessation initiatives.71 Moreover, clini- cal research trials suggest that females may be more susceptible to the effects of tobacco use with greater deterioration of lung function, and more severe dis- ease in subjects with chronic obstructive pulmonary disease.72 Hospitalized individuals, those awaiting surgery, and cancer patients Each medical institution should have their own system for assisting individuals with craving control during times of enforced abstinence such as hospitalization, where smokers may not be able to access outdoor areas to smoke.13 This period of enforced abstinence also yields an opportunistic time to offer assistance to achieve long term abstinence. Varenicline tartrate has been trialed in hospitalized patients with tobac- co-related illnesses, producing successful results at 12 months follow-up.24 However, if craving control during hospitalization is the primary objective, then nicotine replacement therapy products offer the fastest delivery of nicotine to control cravings.13 Additional cessation support should be offered to patients with multi-session treatments and medications continu- ing for at least one month post-discharge.13 Smoking cessation pharmacotherapies for cancer patients are also recommended to assist with craving control dur- ing hospitalization or for obtaining long-term absti- nence as described above. However, it is important to consider timing of quit attempts for these individuals due to physiological changes following cessation that may affect the metabolism of some drugs and target- ing precision and accuracy of dose-volume histogram analyses for radiation therapy.73
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 99 Individuals with mental health issues Pharmacotherapies for smoking cessation have been specifically evaluated in individuals with mental health issues. There are contraindications for some products such as varenicline tartrate and bupropion hydrochloride, which carry boxed warnings from the FDA for people with suicidal ideation, self-injurious behavior, and severe depression.74 People with mental health issues who stop smoking while taking medica- tions for their illness should be monitored closely to determine if dosage reductions in their medications are necessary.13 Pregnant and breastfeeding women It is well-known that smoking during pregnancy can have devastating health consequences not only on the mother, but also the unborn child including growth restriction, preterm delivery, and stillbirth.75–77 ­However, there are reports of up to 13% of women in the US78 and 18% in France79 continuing to smoke up until delivery, with higher prevalence estimates reported amongst indigenous women (45% during pregnancy increasing to 63% post-partum in one Australian population).80 Nicotine replacement thera- pies can be considered for use by pregnant women; however, oral products are preferable to transdermal patches (for example gum, inhalers, micro tabs, and lozenges).13 Potential adverse effects are associated with all smoking cessation pharmacotherapies; thus, psychological interventions should be considered as the first line of treatment during pregnancy. There is a lack of evidence regarding safety for the use of other forms of pharmacological smoking cessation thera- pies during pregnancy or while breastfeeding, though the risks of continued smoking must be weighed against the detrimental health consequences of con- tinuing smoking. Indigenous populations A 2012 Cochrane systematic analysis identified four studies evaluating pharmacological interventions for smoking cessation in indigenous populations globally. This review highlighted the paucity of data in this cohort, despite indigenous populations being over-represented in the burden of smoking related morbidity and mortality.81 The authors were able to conclude that there was some evidence of effective- ness for combined pharmacological and cognitive initiatives that were culturally-tailored to the popu- lation; however, the evidence base is not strong and highlights the need for methodologically rigorous tri- als to bridge the gap between tobacco-related health disparities between the indigenous and non-indige- nous populations. To date, FDA-approved nicotine transdermal patches and bupropion have been evalu- ated in the indigenous setting, producing some suc- cess in smoking abstinence, though studies are still needed to evaluate the safety and efficacy of vareni- cline tartrate. Challenges to Consider Although many believe that the tobacco epidemic is under control, the latest epidemiological evaluations in developing countries suggest otherwise, with an increase in youth tobacco use, particularly amongst girls aged 13–15 years; aggressive tobacco industry marketing campaigns are mostly to blame.82 Moreover, the 2012 US Surgeon General’s Report states that rates of decline for tobacco smoking amongst youth have now stalled with smokeless tobacco use once again on the rise (Centers for Disease Control and Prevention and US Department of Health and Human Services, 2012). For each person that dies because of a smoking related illness (more than 1,200 per day), at least two youths or young adults are becoming regular ­smokers.2 This increase in youth tobacco use today means an increase in adult daily tobacco users tomorrow. As an example, had the success that was made between 1997 and 2003 been maintained in reducing youth tobacco use, there could potentially be three million fewer smokers in the United States of America today.2 On a worldwide scale, tobacco use currently costs governments and consumers hundreds of billions of dollars each year in lost productivity and health care expenditures.4 Data on the global impact of tobacco is incomplete; however, it is known to be high, with annual tobacco-related health care costs US$81 billion in the US, US$7 billion in Germany, and US$1 bil- lion in Australia.83 The cost in both human lives and economic resources will continue unless immediate action is taken to assist current tobacco users to quit, particularly those in high-risk populations, such as low- to medium-income countries, indigenous popu- lations, and youth. A major challenge for all tobacco researchers are smokers that are unwilling to quit. Most research to
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  Carson et al 100 Substance Abuse: Research and Treatment 2013:7 date has focused on highly motivated individuals who are eager to attempt cessation. However, recalcitrant smokers who continue to smoke despite the known consequences pose the greatest problems, yet attract the least amount of attention. This may partly explain why smoking cessation pharmacotherapies that suc- ceed within a randomized controlled trial fail to com- pletely translate into the real world setting.15 Some research projects are underway to examine pharma- cotherapeutic options for smokers unwilling to quit (NCT01195597); however, more research is needed. Similarly, insufficient research and clinical attention are given to maintaining abstinence once a person has made a quit attempt. Supporting long-term absti- nence can be considered a costly endeavor over the short-term, requiring regular follow-up, prescription of ongoing pharmacological support, and alterations to existing cessation strategies that may require in- depth consultations and discussions with the indi- vidual regarding their quitting status. However, the long-term benefits such as improved health, reduced health care costs, lower governmental expenditure, and quality of life should outweigh the short-term output, but more research is needed in this area to encourage policy makers and governments to con- sider such initiatives.84 Implications for Tobacco Cessation in Clinical Practice and Public Policy Although many people will quit tobacco use unaided, for some, particularly those with greater nicotine addiction, pharmacotherapies may offer the extra support needed to produce a successful long-term quit attempt. Many comprehensive, evidence-based clinical practice guidelines for smoking cessation have been developed. These are regularly updated by local governments and health institutions10,12–14,85 and provide recommendations for clinical practice based on the latest available evidence. All of these guidelines recommend smoking cessation pharmaco- therapies for smokers addicted to nicotine in addition to some form of regular counseling, as the chances of long-term abstinence are cumulative when used in combination.12 Efficacy data to date suggest that varenicline tartrate offers the best chance of long-term successful quit attempts,44,86 while nicotine replace- ment therapy is ideally situated for short-term craving control and for individuals with contraindications to ­varenicline or bupropion. Advice from health profes- sionals trained in smoking cessation strategies have been shown to increase the number and success of quit attempts among their patients.87 Providing brief advice to most smokers (as little as 3 minutes) is more effec- tive than spending longer time with a few patients.10 Moreover, a Cochrane systematic review evaluating the training of health professionals in smoking cessa- tion techniques found no evidence of additional ben- efits for interventions of greater duration over brief interventions.87 It is important to remember that most patients will relapse multiple times before achiev- ing successful long-term abstinence (known as the transtheoretical model of behavioral change theory), and guidelines for consultations are available to help individuals move from pre-contemplation to contem- plation, preparation, action, and maintenance, which will eventually result in a successful quit attempt.88 Recalcitrant and continued smoking fails to be classified in many medical circles as an illness, with too many health professionals considering tobacco use as an individual’s right and freedom of expression foremost and as an illness second. Thus, implemen- tation of tobacco cessation interventions is hindered. In reality, smokers become biologically dependent on nicotine, and until perceptions and attitudes within the health professions change, tobacco cessation pro- grams will continue to be hampered. Development of successful pharmacotherapies will do little if translation from research into public policy does not effectively occur. A multi-faceted approach is needed to increase the likelihood of success, which includes public policies such as smoking bans in pub- lic places, restrictions on the purchase of tobacco products, increased governmental legislations, and mass media awareness campaigns. Increased taxa- tion of tobacco products has been shown to prompt smoking cessation attempts and reduce existing pur- chases of tobacco products, with research indicat- ing that regular increases in tobacco tax may further encourage quitting activity.89 Governmental policies including tobacco product content regulation with extreme de-nicotinization and smoke pH regulation of cigarettes by tobacco companies have the potential to significantly impact tobacco use by reducing the addictive properties within cigarettes. Such legisla- tion is necessary and overdue in many countries, as absorption of nicotine across biological ­membranes
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  Pharmacotherapies for smokingcessation Substance Abuse: Research and Treatment 2013:7 101 largely depends on pH.90 Thus, controlling the manufacture of cigarettes will reduce the addictive properties, allowing tobacco users to truly make an informed decision about wanting to smoke. As part of this multifaceted approach, smoking cessation training programs including motivational interview- ing techniques for health professionals should be a mandatory component of medical training. Evidence confirms that a lack of training is a barrier to offering advice, as untrained health professionals report that they do not feel they have the skills, ability, or confi- dence to implement tobacco cessation programs,91,92 and yet the patients of health professionals trained in smoking cessation initiatives show statistically and clinically significant improvements in long-term abstinence.87 Future Evaluations and Research (Gaps in Current Practice) Nicotine addiction is a complex psychosocial, behav- ioral, and biological process that is not well-under- stood. For global reductions in tobacco use to occur, future researchers need to consider the biological and psychological aspects of nicotine addiction, as well as environmental factors contributing to existing lev- els of tobacco use prevalence. Particularly, a key area lacking investigation concerns the transportation of smokers from pre-contemplation through to action. Research is needed to identify motivational triggers among these individuals and determine existing bar- riers to smoking cessation. As technology advances, medical disciplines are moving toward the goal of personalized medicine, with individualized pharma- cotherapies based on specific genetic and environ- mentalfactorsassociatedwitheachindividualsmoker, which may increase the number of quit attempts. ­Researchers are consistently identifying new genetic properties that influence the pharmacokinetics and pharmacodynamics of nicotine, such as the poly- morphism of the CYP2A6 isoenzyme, resulting in a developing field of research that requires attention. The inability of preliminary immunotherapy studies to produce efficacy in long-term smoking abstinence also requires investigation, with potential limitations of existing animal models under the spotlight.57 Research into gender variances are needed to understand the impact that biological and cognitive differences have in smoking cessation ­strategies between the sexes,71 particularly with evidence sug- gesting that females may be more susceptible to the lung-damaging effects of cigarette smoking than males.72 Additionally, the steady increase in female tobacco use and reduction in male tobacco use over recent decades needs to be considered in relation to observed gender differences in addiction and health effects resulting from tobacco use.93 Efficacy research examining existing pharmacotherapeutic aids for smoking cessation is also lacking in other specific populations such as youth, individuals with mental health issues, and indigenous populations. There is a paucity of research to determine the efficacy of pharmacological interventions for smok- ing cessation in the indigenous setting, while most indigenous populations are overrepresented in the burden of substance-related morbidity and mortality. Current evidence suggests that significant amounts of resources are being invested, particularly by government bodies, yet methodologically rigorous evaluation procedures are significantly lacking.81 This carries substantial dangers with funding being invested into ineffective programs (which is possi- ble without effective evaluations to determine true treatment efficacy), resulting in an opportunity cost for potentially effective initiatives.94 Moreover, the few previous studies report significant shortcomings relating to the effective implementation of research methodology as intended, particularly related to the uptake of pharmacotherapies and behavioral change interventions.81,94,95 This indicates that the next phase of tobacco-related research for the indigenous set- ting should be qualitative in nature to examine where and why difficulties in existing research projects have occurred and to determine how they can be overcome. Qualitative research has been underutilized in the tobacco arena mostly due to concerns regard- ing methodological rigor and ambiguity in analyses resulting in qualitative analyses that lack strength.96 However, because the nature of nicotine abuse is two-fold and includes physiological addiction to nicotine and behavioral components including habit, a mixed method approach (combination of qualita- tive and quantitative research) should be consid- ered. This will facilitate more thorough evaluation of areas where existing evidence is lacking, par- ticularly for the specific populations as listed above
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  Carson et al 102 Substance Abuse: Research and Treatment 2013:7 in which existing smoking cessation approaches ­produce little effect.81,97–99 Such process evaluations, ­particularly for key components such as context and fidelity, can provide essential information to interven- tion studies across all settings. Conclusions The most common pharmacological aids for smok- ing cessation include nicotine replacement therapy, varenicline tartrate, and bupropion hydrochloride, with varenicline producing the greatest chance of long-term abstinence. Clinical practice guidelines recommend the use of counseling programs in con- junction with pharmacological interventions, with regular follow-up and continued support to improve chances of success. Emerging pharmacotherapies include adaptations to existing treatments, evaluation of medications used to treat other conditions, and the use of genetic and biological factors that have the potential to influence the mechanisms of nicotine addiction. A primary objective of future research should be to develop initiatives, which may include high efficacy pharmacotherapies, to assist smokers who are not willing or report being unable to quit. Moreover, for smoking cessation pharmacotherapies to be successful, effective implementation strate- gies must be clearly established with a multi-faceted approach that includes instigation of public policies, tobacco taxes, adequate support structures, and easy access to low-cost medications with high treatment efficacy. Author Contributions Conceived and designed the manuscript: KC, MB, TR, RT. Analysed the data: KC, MB, TR, RT, AE. Wrote the first draft of the manuscript: KC. Contrib- uted to the writing of the manuscript: KC, MB, TR, RT, AE, MP, BS. Agree with the manuscript results and conclusions: KC, MB, TR, RT, AE, MP, BS. Jointly developed the arguments and structure for the paper: KC, MB, TR, RT, AE, MP, BS. Made critical revisions and approved final version: KC, MB, TR, RT, AE, MP, BS. All authors reviewed and approved of the final manuscript. Funding Author(s) disclose no funding sources. Competing Interests Author(s) disclose no potential conflicts of interest. Disclosures and Ethics As a requirement of publication the authors have provided signed confirmation of their compliance with ethical and legal obligations including but not limited to compliance with ICMJE authorship and competing interests guidelines, that the article is neither under consideration for publication nor published elsewhere, of their compliance with legal and ethical guidelines concerning human and ani- mal research participants (if applicable), and that permission has been obtained for reproduction of any copyrighted material. This article was subject to blind, independent, expert peer review. The review- ers reported no competing interests. ­Provenance: the authors were invited to submit this paper. 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