Pharmacotherapy for Tobacco Dependence Pharmacotherapy for Tobacco Dependence

Richard D. Hurt, M.D.Richard D. Hurt, M.D.Professor of MedicineProfessor of Medicine

Director, Nicotine Dependence Center Director, Nicotine Dependence Center

Mayo Clinic Mayo Clinic

rhurt@mayo.edurhurt@mayo.edu

http://ndc.mayo.eduhttp://ndc.mayo.edu

Richard D Hurt MDRichard D Hurt MDFinancial Disclosure 2/12Financial Disclosure 2/12

• Current consulting (Scientific Advisory Current consulting (Scientific Advisory Boards) : NoneBoards) : None

• Current Industry Grants: Pfizer Medical Current Industry Grants: Pfizer Medical Education GrantEducation Grant

• HAVE NOT AND WILL NEVER HAVE NOT AND WILL NEVER ACCEPT ACCEPT ANYANY MONEY FROM THE MONEY FROM THE TOBACCO INDUSTRYTOBACCO INDUSTRY

Basic ConceptsBasic Concepts

• Treat tobacco dependence for the Treat tobacco dependence for the serious medical problem it isserious medical problem it is

• Motivational counseling plus Motivational counseling plus pharmacotherapypharmacotherapy

• Dose response to counselingDose response to counseling

• Higher nicotine patch doses are betterHigher nicotine patch doses are better

• Combinations are betterCombinations are better

• Longer treatment is better. This is not Longer treatment is better. This is not strep throat nor a UTIstrep throat nor a UTI

52 Y/O Married Man With Back Pain52 Y/O Married Man With Back Pain

• Smoker since age 14 smoked 40 cpd until Smoker since age 14 smoked 40 cpd until a 2 months ago, now smoking 20-30 cpd.a 2 months ago, now smoking 20-30 cpd.

• Wife is an ex-smoker but very supportive.Wife is an ex-smoker but very supportive.

• Smokes first cigarette within 5 minutes of Smokes first cigarette within 5 minutes of arising in the morning.arising in the morning.

• Longest period of smoking abstinence 1 Longest period of smoking abstinence 1 month- nicotine patch but had w/d.month- nicotine patch but had w/d.

• Nicotine gum and bupropion did not Nicotine gum and bupropion did not relieve cravings. Varenicline no help in relieve cravings. Varenicline no help in stopping smoking.stopping smoking.

52 Y/O Married Man With Back Pain52 Y/O Married Man With Back Pain What phramcotherapy?What phramcotherapy?

• A. Bupropion + nicotine gumA. Bupropion + nicotine gum

• B. 21 mg nicotine patch + nicotine B. 21 mg nicotine patch + nicotine inhalerinhaler

• C. 2- 21 mg nicotine patches + C. 2- 21 mg nicotine patches + nicotine inhaler.nicotine inhaler.

• D. VareniclineD. Varenicline

Treating Tobacco Dependence in a Treating Tobacco Dependence in a Medical SettingMedical Setting

Best PracticesBest Practices

• USPHS Guideline (USPHS Guideline (www.ahrq.govwww.ahrq.gov))

• Behavioral, addictions, pharmacologic Behavioral, addictions, pharmacologic treatment, and relapse preventiontreatment, and relapse prevention

• Neurobiology of tobacco dependenceNeurobiology of tobacco dependence

• ““Teachable moment”Teachable moment”

• Telephone quitlines and internet sitesTelephone quitlines and internet sites

• Public policy-Taxes and smoke-free Public policy-Taxes and smoke-free workplacesworkplacesHurt RD, et al CA Cancer J Clin 59:314, 2009Hurt RD, et al CA Cancer J Clin 59:314, 2009

Cigarettes and Tobacco DependenceCigarettes and Tobacco Dependence

• Cigarette smoke – complex mixture of 4,000 Cigarette smoke – complex mixture of 4,000 chemicals with over 60 known carcinogenschemicals with over 60 known carcinogens

• Most efficient delivery device for nicotine that Most efficient delivery device for nicotine that exists- better than intravenousexists- better than intravenous

• Cigarette manufacturers have modified cigarettes Cigarette manufacturers have modified cigarettes over the past decades to maximize nicotine over the past decades to maximize nicotine delivery to the braindelivery to the brain

• High doses of arterial nicotine cause upregulation High doses of arterial nicotine cause upregulation of the nicotinic acetylcholine receptorsof the nicotinic acetylcholine receptors

• Genetic factors influence tobacco dependenceGenetic factors influence tobacco dependence

• Left untreated 60% of smokers die from a Left untreated 60% of smokers die from a tobacco-caused diseasetobacco-caused disease

Hurt RD, Robertson CR JAMA 280:1173, 1998Hurt RD, Robertson CR JAMA 280:1173, 1998

• Why would anyone Why would anyone smoke with this smoke with this hanging over their hanging over their head?head?

• It is in the brain! It is in the brain!

Perry, DC, et al. J Pharmacol Exp Ther, 289:1545, 1999Perry, DC, et al. J Pharmacol Exp Ther, 289:1545, 1999

Smoking Saturates Nicotinic ReceptorsSmoking Saturates Nicotinic Receptors

Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006

0.0 Cigarette 0.1 Cigarette 0.3 Cigarette 1.0 Cigarette 3.0 Cigarette

kBq/mL

9

0

Nondisplaceable

MRI

2 A’s and an R2 A’s and an R• AAsk about tobacco usesk about tobacco use

• AAdvise to stopdvise to stop

• RRefer for counseling and efer for counseling and pharmacotherapypharmacotherapy

• Internal resources- NDC Tobacco Internal resources- NDC Tobacco Treatment SpecialistsTreatment Specialists

• External resources-Telephone External resources-Telephone quitlines, TTS Clinics, internet quitlines, TTS Clinics, internet resources(resources(www.becomeanEX.orgwww.becomeanEX.org))

Schroeder SA JAMA 294:482, 2005Schroeder SA JAMA 294:482, 2005

USPHS Clinical Practice Guideline- 2008USPHS Clinical Practice Guideline- 2008PharmacotherapyPharmacotherapy

• First lineFirst line• nicotine gumnicotine gum• nicotine patchnicotine patch• nicotine lozengenicotine lozenge• nicotine nasal spraynicotine nasal spray• nicotine inhalernicotine inhaler• bupropionbupropion• vareniclinevarenicline• combinationscombinations

• Second lineSecond line• clonidineclonidine• nortriptylinenortriptyline

Tailoring PharmacotherapyTailoring PharmacotherapyLong Acting + Short ActingLong Acting + Short Acting

Long actingLong acting

Pick 1 or 2 from herePick 1 or 2 from here

• Nicotine patchNicotine patch

• BupropionBupropion

• VareniclineVarenicline

Short actingShort acting

Plus 1 or 2 from herePlus 1 or 2 from here

• Nicotine gumNicotine gum

• Nicotine inhalerNicotine inhaler

• Nicotine lozengeNicotine lozenge

• Nicotine nasal sprayNicotine nasal spray

Treating Tobacco Dependence in a Treating Tobacco Dependence in a Medical SettingMedical SettingPharmacotherapyPharmacotherapy

• Clinical decision-making using clinician skills Clinical decision-making using clinician skills and knowledge of pharmacology to decide on and knowledge of pharmacology to decide on medication selection and dosesmedication selection and doses

• Patient involvement: past experience and/or Patient involvement: past experience and/or preferencepreference

• Nicotine patch, varenicline and/or bupropion Nicotine patch, varenicline and/or bupropion viewed as “floor” medicationsviewed as “floor” medications

• Short acting NRT products for withdrawal Short acting NRT products for withdrawal symptom controlsymptom control

• Combination pharmacotherapy frequently usedCombination pharmacotherapy frequently usedHurt RD, et al CA Cancer J Clin 59:314, 2009Hurt RD, et al CA Cancer J Clin 59:314, 2009

CotinineCotinine

• Major metabolite of nicotineMajor metabolite of nicotine

• Pharmacologically inactivePharmacologically inactive

• Quantitative marker of nicotine intakeQuantitative marker of nicotine intake

• Pre-abstinence levels correlate with Pre-abstinence levels correlate with withdrawal and treatment outcomewithdrawal and treatment outcome

• Half-life 18-20 hoursHalf-life 18-20 hours

Hurt RD, et al. Clin Pharmacol Ther 54:98-106, 1993Hurt RD, et al. Clin Pharmacol Ther 54:98-106, 1993

Nicotine Patch TherapyNicotine Patch TherapyBackgroundBackground

• Placebo-controlled trials show Placebo-controlled trials show doubling of stop ratesdoubling of stop rates

• Time to peak concentration 4-6 hrsTime to peak concentration 4-6 hrs

• Growing literature showing a dose Growing literature showing a dose responseresponse

• ~50% median replacement with ~50% median replacement with standard dosestandard dose

• Reduced smoking while using Reduced smoking while using nicotine patchnicotine patch

Lawson GM, et al. J Clin Pharmacol 38:502-509, 1998Lawson GM, et al. J Clin Pharmacol 38:502-509, 1998

High Dose Patch TherapyHigh Dose Patch TherapyConclusionsConclusions

• High dose patch therapy safe for heavy smokersHigh dose patch therapy safe for heavy smokers

• Smoking rate or blood cotinine to estimate Smoking rate or blood cotinine to estimate initial patch doseinitial patch dose

• Assess adequacy of nicotine replacement by Assess adequacy of nicotine replacement by patient response or percent replacementpatient response or percent replacement

• More complete nicotine replacement improves More complete nicotine replacement improves withdrawal symptom reliefwithdrawal symptom relief

• Higher percent replacement may increase Higher percent replacement may increase efficacy of nicotine patch therapyefficacy of nicotine patch therapy

Dale LC, et al. JAMA 274:1353, 1995Dale LC, et al. JAMA 274:1353, 1995

High Dose Patch TherapyHigh Dose Patch TherapyDosing Based on Smoking RateDosing Based on Smoking Rate

<10 cpd<10 cpd 7-14 mg/d7-14 mg/d

10-20 cpd10-20 cpd 14-21 mg/d14-21 mg/d

21-40 cpd21-40 cpd 21-42 mg/d21-42 mg/d

>40 cpd>40 cpd 42+ mg/d42+ mg/d

Dale LC, et al. Mayo Clin Proc 75:1311, 1316, 2000Dale LC, et al. Mayo Clin Proc 75:1311, 1316, 2000

Extended Nicotine Patch TherapyExtended Nicotine Patch Therapy

• 24 weeks (n= 287) vs 8 weeks (288) 21 24 weeks (n= 287) vs 8 weeks (288) 21 mg/d dosemg/d dose

• Similar smoking abstinence at week 8 Similar smoking abstinence at week 8

• At week 24 point prevalence smoking At week 24 point prevalence smoking abstinence 32% vs 20% (OR 1.81)abstinence 32% vs 20% (OR 1.81)

• At week 52 prolonged smoking abstinence At week 52 prolonged smoking abstinence > with extended patch therapy (P=0.0270> with extended patch therapy (P=0.0270

• Delayed relapse to smoking with extended Delayed relapse to smoking with extended patch therapypatch therapy

Schnoll RA, et al Ann Int Med 152:144, 2010Schnoll RA, et al Ann Int Med 152:144, 2010

Schnoll RA, et al. Annals of Intern Med 2010; (152)3:149

Nicotine Gum and Lozenges 2 & 4 mg SizesNicotine Gum and Lozenges 2 & 4 mg Sizes

BupropionBupropionBackgroundBackground

• Monocyclic antidepressantMonocyclic antidepressant

• Inhibits reuptake of norepinephrine and Inhibits reuptake of norepinephrine and dopaminedopamine

• May inhibit nicotinic ACH receptor May inhibit nicotinic ACH receptor functionfunction

• Mechanism in helping smokers stop is Mechanism in helping smokers stop is not clearnot clear

• May attenuate weight gain in abstinent May attenuate weight gain in abstinent smokerssmokers

BupropionBupropionSide EffectsSide Effects

• Relatively free of anticholinergic, Relatively free of anticholinergic, sedative, cardiovascular or sexual sedative, cardiovascular or sexual dysfunction side effectsdysfunction side effects

• Most common side effects: dry mouth Most common side effects: dry mouth and insomniaand insomnia

• Seizure incidence 0.1%Seizure incidence 0.1%

• HypertensionHypertension

BupropionBupropionSummarySummary

• Dose response efficacy in treating Dose response efficacy in treating smokerssmokers

• Attenuates weight gainAttenuates weight gain

• More effective than nicotine patch therapyMore effective than nicotine patch therapy

• Delays relapse to smokingDelays relapse to smoking

• Can be prescribed to diverse populations Can be prescribed to diverse populations of smokers with expected comparable of smokers with expected comparable resultsresults

Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003

VareniclineVareniclineMode of ActionMode of Action

• PPartial agonist with specificity for the artial agonist with specificity for the αα4B2 4B2 nicotine acetylcholine receptornicotine acetylcholine receptor

• Agonist action: stimulates the nACHr Agonist action: stimulates the nACHr to to ↓ nicotine withdrawal↓ nicotine withdrawal

• Antagonist action: blocks the nACHr Antagonist action: blocks the nACHr to to ↓ the reinforcing effect of smoking↓ the reinforcing effect of smoking

Varenicline Varenicline Mechanism of ActionMechanism of Action

Varenicline vs. Bupropion vs. PlaceboVarenicline vs. Bupropion vs. Placebo

Jorenby, D.E., et. al. JAMA; 296:56-63, 2006

Varenicline vs. Bupropion vs. PlaceboVarenicline vs. Bupropion vs. PlaceboSide EffectsSide Effects

VareniclineVarenicline

N=692N=692

BupropionBupropion

N=669N=669

PlaceboPlacebo

N=684N=684

NauseaNausea 28%28% 10%10% 9%9%

HeadacheHeadache 14%14% 11%11% 12%12%

InsomniaInsomnia 14%14% 22%22% 13%13%

Abnormal Abnormal DreamsDreams 12%12% 6%6% 5%5%

Dry MouthDry Mouth 6%6% 8%8% 4%4%

Discontinuation Discontinuation because of AE’sbecause of AE’s 10%10% 14%14% 8%8%

SubjectsSubjects• Male or female outpatient cigarette smokers Male or female outpatient cigarette smokers • 18-75 yr old, motivated to quit smoking18-75 yr old, motivated to quit smoking• Average of ≥10 cigarettes/day during past yearAverage of ≥10 cigarettes/day during past year

Secondary Endpoint:Secondary Endpoint:CO-confirmed continuous CO-confirmed continuous abstinence rate wk abstinence rate wk 13–5213–52

Wk12Wk12 2424 5252

NONTREATMENTNONTREATMENTFOLLOW-UPFOLLOW-UP

DOUBLE-BLIND DOUBLE-BLIND OPEN-LABELOPEN-LABEL

Primary Endpoint:Primary Endpoint:CO-confirmed continuous abstinence rate wk CO-confirmed continuous abstinence rate wk 13–2413–24

Varenicline 1mg bidVarenicline 1mg bid Varenicline 1mg bidVarenicline 1mg bid

PlaceboPlacebo

Quitters randomizedQuitters randomized

12 weeks

Maintenance of AbstinenceMaintenance of AbstinenceStudy DesignStudy Design

Varenicline Maintenance StudyVarenicline Maintenance Study

Tonstad, S., et. al. JAMA; 296:64-71, 2006

Varenicline for Smokers with Varenicline for Smokers with Cardiovascular DiseaseCardiovascular Disease

• For smokers with coronary heart disease For smokers with coronary heart disease stopping smoking stopping smoking decreases all cause decreases all cause mortality by 36%mortality by 36%

• Randomized double-blind placebo Randomized double-blind placebo controlled trial in 714 smokers with stable controlled trial in 714 smokers with stable cardiovascular diseasecardiovascular disease

• Mean age 56, 78% male, 22 CPD, 40 years Mean age 56, 78% male, 22 CPD, 40 years of smoking, FTND 5.7of smoking, FTND 5.7

• EOT continuous smoking abstinence- 47% EOT continuous smoking abstinence- 47% vs 14% (OR 6.11, CI 4.18-8.93)vs 14% (OR 6.11, CI 4.18-8.93)

Rigotti, NA et al Circ 121:221, 2010Rigotti, NA et al Circ 121:221, 2010

Rigotti NA et al. Circulation 121:221, 2010

Seven-day point prevalence tobacco abstinence rates

Varenicline: FDA WarningVarenicline: FDA Warning

““All patients being treated with Chantix All patients being treated with Chantix should be observed for should be observed for neuropsychiatric symptoms including neuropsychiatric symptoms including changes in behavior, agitation, changes in behavior, agitation, depressed mood, suicidal ideation, depressed mood, suicidal ideation, and suicidal behavior. These and suicidal behavior. These symptoms, as well as worsening of symptoms, as well as worsening of pre-existing psychiatric illness, have pre-existing psychiatric illness, have been reported in patients attempting been reported in patients attempting to quit smoking while taking to quit smoking while taking Chantix…Chantix…””

Varenicline and Neuropsychiatric SymptomsVarenicline and Neuropsychiatric Symptoms

• Advise patients and family members that Advise patients and family members that this has been observedthis has been observed

• Ask patients and/or family to report any Ask patients and/or family to report any symptoms like this to yousymptoms like this to you

• Patients with serious psychiatric Patients with serious psychiatric comorbidity were not included in clinical comorbidity were not included in clinical trialstrials

• No cause and effect relationship has been No cause and effect relationship has been establishedestablished

VareniclineVareniclineSummarySummary

• First selective First selective αα4B2 partial agonist4B2 partial agonist

• Effective in initiating smoking abstinence and Effective in initiating smoking abstinence and longer term use improves long term smoking longer term use improves long term smoking abstinenceabstinence

• Nausea is a frequent but mild side effectNausea is a frequent but mild side effect

• To date appears to be safe and effectiveTo date appears to be safe and effective

• First line pharmacotherapyFirst line pharmacotherapy

• Possible combination use- bupropion Possible combination use- bupropion

Varenicline plus BupropionVarenicline plus Bupropion• Open label pilot study in 38 smokersOpen label pilot study in 38 smokers

• Mean age 49 years, smoking 20 CPD Mean age 49 years, smoking 20 CPD for 30 yearsfor 30 years

• 12 weeks of varenicline and 12 weeks of varenicline and bupropion SRbupropion SR

• Smoking abstinence at EOT 71% and Smoking abstinence at EOT 71% and at 6 months 58%at 6 months 58%

• Sleep distrubance 26% and nausea Sleep distrubance 26% and nausea 24%24%

Ebbert, JO et al, Nic & Tob Res, 3:234, 2009Ebbert, JO et al, Nic & Tob Res, 3:234, 2009

Triple Pharmacotherapy In Medically Ill Triple Pharmacotherapy In Medically Ill Smokers Smokers

• RCT nicotine patch (10 wks) vs RCT nicotine patch (10 wks) vs nicotine patch + bupropion + nicotine nicotine patch + bupropion + nicotine inhaler (flexible duration)inhaler (flexible duration)

• Mean medication use: 35 d vs 89 dMean medication use: 35 d vs 89 d

• Time to relapse: 23 d vs 65 dTime to relapse: 23 d vs 65 d

• AE generated discontinuance same AE generated discontinuance same in both groupsin both groups

• Smoking Abstinence at 6 months: Smoking Abstinence at 6 months: 35% vs 19% 35% vs 19%

Steinberg MB et al, Ann Intern Med, 150: 447, 2009Steinberg MB et al, Ann Intern Med, 150: 447, 2009

Short-acting vs Long-acting vs CombinationShort-acting vs Long-acting vs CombinationN=1,504N=1,504

• RCT of lozenge, patch, patch + RCT of lozenge, patch, patch + lozenge, bupropion + lozenge vs lozenge, bupropion + lozenge vs placeboplacebo

• 8 week treatment 8 week treatment

• All pharmacotherapies more effective All pharmacotherapies more effective than placebothan placebo

• At 6 months nicotine patch + lozenge At 6 months nicotine patch + lozenge had best OR of 2.3, p<0.001 vs had best OR of 2.3, p<0.001 vs placeboplacebo

Piper, ME et al, Arch Gen Psychiatry 66:1253, 2009Piper, ME et al, Arch Gen Psychiatry 66:1253, 2009

Piper, M. E. et al. Arch Gen Psychiatry 66:1253-1262 2009

Treating Tobacco Dependence in a Treating Tobacco Dependence in a Medical SettingMedical SettingPharmacotherapyPharmacotherapy

• Clinical decision-making using clinician skills Clinical decision-making using clinician skills and knowledge of pharmacology to decide on and knowledge of pharmacology to decide on medication selection and dosesmedication selection and doses

• Patient involvement: past experience and/or Patient involvement: past experience and/or preferencepreference

• Nicotine patch, varenicline and/or bupropion Nicotine patch, varenicline and/or bupropion viewed as “floor” medicationsviewed as “floor” medications

• Short acting NRT products for withdrawal Short acting NRT products for withdrawal symptom controlsymptom control

• Combination pharmacotherapy frequently usedCombination pharmacotherapy frequently usedHurt RD, et al CA Cancer J Clin 59:314, 2009Hurt RD, et al CA Cancer J Clin 59:314, 2009

Center for Tobacco-Free Living

SummarySummary

• Treat tobacco dependence for the Treat tobacco dependence for the serious medical problem it isserious medical problem it is

• Ask, Advise and ReferAsk, Advise and Refer

• Supportive counseling plus Supportive counseling plus pharmacotherapypharmacotherapy

• Combination pharmacotherapy is the Combination pharmacotherapy is the rule (long acting plus short acting) rule (long acting plus short acting)

• Pharmacotherapy for “as long as it Pharmacotherapy for “as long as it takes”takes”

52 Y/O Married Man With Back Pain52 Y/O Married Man With Back Pain

• Smoker since age 14 smoked 40 cpd until Smoker since age 14 smoked 40 cpd until a 2 months ago, now smoking 20-30 cpd.a 2 months ago, now smoking 20-30 cpd.

• Wife is an ex-smoker but very supportive.Wife is an ex-smoker but very supportive.

• Smokes first cigarette within 5 minutes of Smokes first cigarette within 5 minutes of arising in the morning.arising in the morning.

• Longest period of smoking abstinence 1 Longest period of smoking abstinence 1 month 21mg nicotine patch but had w/d.month 21mg nicotine patch but had w/d.

• Nicotine gum and bupropion did not Nicotine gum and bupropion did not relieve cravings. Varenicline no help in relieve cravings. Varenicline no help in stopping smoking.stopping smoking.

52 Y/O Married Man With Back Pain52 Y/O Married Man With Back Pain What phramcotherapy?What phramcotherapy?

• A. Bupropion + nicotine gumA. Bupropion + nicotine gum

• B. 21 mg nicotine patch + nicotine B. 21 mg nicotine patch + nicotine inhalerinhaler

• C. 2- 21 mg nicotine patches + C. 2- 21 mg nicotine patches + nicotine inhaler.nicotine inhaler.

• D. VareniclineD. Varenicline

52 Y/O Married Man With Back Pain52 Y/O Married Man With Back PainTelephone call f/u at 2 weeksTelephone call f/u at 2 weeks

• Started 2-21 mg nicotine patches + Started 2-21 mg nicotine patches + nicotine inhaler for ad lib use.nicotine inhaler for ad lib use.

• Good initial response with w/d relief most Good initial response with w/d relief most of the day. Stopped smoking for 10 days.of the day. Stopped smoking for 10 days.

• Frequency of inhaler use increased toward Frequency of inhaler use increased toward early evening as cravings seemed to early evening as cravings seemed to increase and continue until he goes to increase and continue until he goes to bed.bed.

• Next steps?Next steps?

52 Y/O Married Man With Back Pain52 Y/O Married Man With Back PainNext StepsNext Steps

• A. Toughen up and tough it out.A. Toughen up and tough it out.

• B. Back off using the inhaler so much B. Back off using the inhaler so much concern about over use. concern about over use.

• C. Add nicotine lonzenges for ad lib C. Add nicotine lonzenges for ad lib useuse

• D. Add a 14 mg nicotine patch in the D. Add a 14 mg nicotine patch in the late afternoon.late afternoon.

52 Y/O Married Man With Back Pain52 Y/O Married Man With Back PainPhone call 2 weeks laterPhone call 2 weeks later

• 14 mg patch @ 4PM. Evening cravings 14 mg patch @ 4PM. Evening cravings resolvedresolved

• Less frequent inhaler useLess frequent inhaler use

• Continue on 2-21 mg patches in the AM Continue on 2-21 mg patches in the AM and a 14 mg patch at 4 PMand a 14 mg patch at 4 PM

• Continue ad lib nicotine inhalerContinue ad lib nicotine inhaler

• Phone back in 2 weeksPhone back in 2 weeks

• Encouraged to use the medications until Encouraged to use the medications until he is very comfortable in ability to abstain he is very comfortable in ability to abstain then then morning patch dose morning patch dose