Analyzing Milestones in Smoking Cessation: Illustration in a NicotinePatch Trial in Adult Smokers

Saul Shiffman, Deborah M. Scharf, andWilliam G. ShadelUniversity of Pittsburgh

Chad J. GwaltneyBrown University

Qianyu DangUniversity of Pittsburgh

Stephanie M. PatonBrown University

Duncan B. ClarkUniversity of Pittsburgh

Tests of addiction treatments seldom reveal where treatment exercises its effect (i.e., promoting initialabstinence, preventing lapses, and/or impeding progression from lapse to relapse). The authors illustrateanalyses distinguishing effects on these milestones in a randomized trial of high-dose nicotine patch (35mg; n � 188) versus placebo (n � 136) in adult smokers, who used electronic diaries to monitor smokingin real time during 5 weeks of treatment. High-dose patch promoted initial abstinence (hazard ratio [HR]� 1.3) and decreased the risk of lapsing among those who achieved abstinence (HR � 1.6). The biggesteffect of treatment was to prevent progression to relapse among those who had lapsed (HR � 7.1).Analysis of effects by milestones may enhance understanding of cessation treatments and their mecha-nisms of action.

Keywords: nicotine replacement, heavy smokers, nicotine cessation treatments, nicotine patch, nicotineaddiction

Addictions represent some of the most common and devastatingbehavioral disorders. Addictive disorders are estimated to accountfor 440,000 deaths (Mokdad, Marks, Stroup, & Gerberding, 2004)and to cost U.S. society $250 billion (Swan, 1998) per year.Cigarette smoking is considered the greatest preventable cause ofmorbidity and mortality in the Western world (Fiore et al., 2000).Although addictive behavior is very difficult to change (O’Brien,1996), both behavioral and pharmacological (Fiore et al., 2000)

treatments have demonstrated efficacy in helping persons withaddictive disorders achieve abstinence. Even when treatments areshown to be effective, however, the mechanism underlying effi-cacy is often not clearly understood. One impediment to under-standing treatment effects is that clinical trials often analyze finalend points (e.g., abstinence, heavy drinking), and thus do not shedlight on where in the process of establishing change the treatmenthas its effect.

This is nowhere more evident than in smoking cessation trials,in which continuous long-term abstinence is the sole treatmentoutcome (Silagy, Lancaster, Stead, Mant, & Fowler, 2004). Al-though analysis of final abstinence rates as an end point providesa common metric for outcome comparisons and is relevant tohealth outcomes, it may obscure information about the process bywhich the outcomes are achieved. Specifically, end-point analysesdo not distinguish among effects of treatment on intermediateoutcomes that cumulatively shape the eventual end point: achiev-ing initial abstinence (e.g., an initial period without drug use, suchas 24 hr without smoking), avoiding a lapse (an initial occasion offirst use after abstinence), and avoiding relapse (progression fromfirst use to significant use).

Theorists have sometimes posited processes that would specif-ically affect the occurrence of initial lapses (e.g., cue reactivity, seeNiaura et al., 1988; failure of immediate coping, see Shiffman,Paty, Kassel, & Hickcox, 1996) or progression from lapses torelapse (e.g., abstinence violation effects, see Curry, Marlatt, &Gordon, 1987; priming effects, see Sutton, 1989). However, these

Saul Shiffman, Deborah M. Scharf, William G. Shadel, and Duncan B.Clark, Department of Psychology, University of Pittsburgh; Chad J. Gwalt-ney and Stephanie M. Paton, Department of Psychology, Brown Univer-sity; Qianyu Dang, Center for Research on Health Care, University ofPittsburgh.

Saul Shiffman serves as consultant to GlaxoSmithKline ConsumerHealthcare on an exclusive basis regarding matters relating to smokingcessation and also is a partner in a company that is developing a newnicotine medication. He is a co-founder of invivodata, inc., which provideselectronic diary services for clinical research.

This study was supported by Grant DA06084 to Saul Shiffman from theNational Institute on Drug Abuse. Nicotine and placebo patches weregenerously provided by GlaxoSmithKline Consumer Healthcare, whichplayed no other role in the study.

Correspondence concerning this article should be addressed to SaulShiffman, Department of Psychology, University of Pittsburgh, SmokingResearch Group, 130 North Bellefield Avenue, Suite 510, Pittsburgh, PA15213. E-mail: shiffman@pitt.edu

Journal of Consulting and Clinical Psychology Copyright 2006 by the American Psychological Association2006, Vol. 74, No. 2, 276–285 0022-006X/06/$12.00 DOI: 10.1037/0022-006X.74.2.276

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differential process hypotheses have seldom been evaluated. Somesupportive data have been reported. For example, stable (enduringover time) and global (pervasive across situations) attributions(e.g., “This just shows how weak my character is”) predict relapsebut not lapse in smokers, cocaine, and methamphetamine users(Curry, Marlatt, & Gordon, 1987; Walton, Castro, & Barrington,1994). Similarly, day-to-day changes in self-efficacy did not pre-dict smoking lapses but did predict progression to relapse (Shiff-man et al., 2000), suggesting that different processes might operateat different phases or milestones in the quit process.

Outcome trials have not systematically analyzed these outcome“milestones.” However, analyses of naltrexone for treatment ofalcoholism suggests that naltrexone may not prevent lapses butspecifically prevents progression from lapse to relapse (e.g., Vol-picelli, Clay, Watson, & O’Brien, 1995). More recently, analysisof acamprosate effects has suggested that acamprosate may nothelp drinkers achieve initial abstinence but helps maintain absti-nence (Food and Drug Administration, 2004) and prevent progres-sion from lapse to relapse (Chick, Lehert, & Landron, 2003).

Our aim in this study was to introduce and illustrate a systematicapproach to analyzing outcome data in phases based on the mile-stones of initial abstinence, lapse, and relapse. We illustrate thisapproach in an analysis of smoking cessation therapy by using ahigh-dose nicotine patch (NP). Treatment with NP significantlyand reliably improves long-term abstinence rates compared withplacebo (Silagy et al., 2004). We tested a high-dose NP because“normal” NP doses in current use have been criticized as notproviding enough nicotine to replace smokers’ accustomed nico-tine intake (Johnstone et al., 2004). Current NP doses yield bloodlevels only 50% as high as those achieved during smoking, whichhas been seen as accounting for limited efficacy of NP treatment(Johnstone et al., 2004). Higher dose NP regimens have shownincremental efficacy for smoking cessation (see Fiore et al., 2000).

The mode of action of NP is not completely settled (Hughes,1993; Lerman, Patterson, & Berrettini, 2005), and the degree towhich NP helps smokers achieve initial abstinence, avoid lapses,or avoid relapse once they have lapsed has not been examined. NPmight be expected to have limited impact on initial abstinencebecause patches are typically first applied in the morning on theday the smoker is actually quitting. Yet, NP infuses nicotineslowly, typically taking 4–10 hours to reach peak levels (Fant,Henningfield, Shiffman, Strahs, & Reitberg, 2000), which couldlimit how much benefit NP might impart during those crucial firsthours. The effect of NP on initial abstinence has never beenevaluated.

Different hypotheses have divergent implications for the effectsof NP on lapse risk. Lapses typically are directly precipitated byexposure to provocative cues (e.g., Shiffman, Paty, et al., 1996),and NP treatment does not buffer smokers against the surge incraving that follows such cue exposures (Tiffany, Cox, & Elash,2000; Waters et al., 2004), suggesting that NP might have limitedeffects on lapse incidence. However, NP reliably relieves cravingand withdrawal (Niaura, Goldstein, & Abrams, 1994), which areassociated with initial lapses (Shiffman et al., 1997). Also, NPimproves continuous abstinence, which counts lapses as failures(Fiore et al., 2000).

Once a smoker lapses, the risk of progression to relapse is veryhigh (Kenford et al., 1994). NP could prevent progression fromlapse to relapse by maintaining tolerance and reducing the effect of

a priming dose (Shaham, Adamson, Grocki, & Corrigall, 1997) orreducing the reinforcing value of smoking in a lapse (Henningfield& Heishman, 1995; Hughes, 1993). However, NP-facilitated tol-erance might conceivably facilitate escalation of smoking towardrelapse. The effect of NP on progression to relapse has never beenexamined.

In this article, we analyze the outcomes of a placebo-controlledtrial of high-dose NP treatment by using analyses focusing sepa-rately on initial abstinence, first lapse, and progression to relapse.We analyzed progression to each milestone with survival analysis,which accounts for the fact that our observations of smokers intreatment are inevitably limited by censoring—for example, par-ticipants are only observed for a limited time, so we cannot say thatcertain persons never lapsed, only that they did not do so whileunder observation. Survival analysis uses time to an event (in ourcase, initial abstinence, lapse, and relapse) to estimate the risk overtime for the end points of interest. Our aim was not to establish theefficacy of high-dose NP but to illustrate an analytic approachfocused on outcome milestones and to provide insight as to themechanism by which NP treatment (and other nicotine replace-ment therapies) may help smokers achieve long-term abstinence.

Method

Design and Overview

This was a randomized, double-blind, placebo-controlled clinical trial ofhigh-dose NP to help smokers quit smoking. Smokers were randomized toreceive either a 35-mg patch (n � 188) or placebo (n � 136), starting ontheir target quit date (TQD). For 6 weeks following TQD, participants useda handheld electronic diary (ED) to record instances of smoking. Weanalyzed three outcomes: achievement of initial abstinence for 24 hr,occurrence of lapses (any smoking after abstinence), and progression torelapse (smoking for 7 consecutive days or 5 cigarettes/day for 3 consec-utive days). We used survival analysis, which analyzes the risk of the targetevent over time and uses data from incomplete (“censored”) participants.Participants were recruited between October 1997 and October 1999, anddata were collected between December 1997 and February 2000. The studywas run in cohorts of approximately 15 smokers each. This study wasapproved by the University of Pittsburgh’s Institutional Review Board.

Participants

Participants (N � 324) were cigarette smokers recruited via TV, radio,print advertising, and posted fliers. A brief telephone screening question-naire was used to determine their initial eligibility for the trial. To beincluded in the study, participants had to be between the ages of 21 and 65,have a smoking rate �15 more cigarettes per day for �5 years, be in goodhealth (self-reported), and have high motivation and confidence to quitsmoking (defined as a total of �150 on the sum of two 100-point scales).Exclusion criteria were regular use of noncigarette forms of tobacco,weight � 110 lbs, specific medical counterindications to NP use (e.g.,uncontrolled hypertension, allergy to adhesives), other serious medicalillness, history of recent alcohol and/or drug abuse or mental illness,current participation in a smoking cessation clinic or study, recent (in thelast 30 days) participation in a clinical trial for smoking cessation, or useof bupropion hydrochloride within the past 2 months. Women who were orwho were planning to become pregnant or who were breast-feeding werealso excluded. Smokers who were eligible, who passed a medical screen-ing, and who signed an informed consent form were enrolled.

Table 1 presents baseline demographic and smoking history variables forparticipants by treatment condition. For almost all variables, randomization

277CESSATION MILESTONES

was successful in equating the groups. Participants in the active NPcondition reported a significantly greater number of past quit attemptscompared with participants in the placebo condition, but our analysisshowed that this did not affect the results.

Procedure

Participants used EDs to monitor their smoking, affect, craving, andactivities in real time and their natural environments for 2 weeks prior tosmoking cessation (see Shiffman, Paty, et al., 1996; Stone & Shiffman,1994). Participants were enrolled in cognitive–behavioral smoking cessa-tion treatment and were given a designated TQD. On TQD, participantswere randomized (double-blind) to receive either active NP or placebopatches, to be applied starting the morning of TQD. Assessments via EDscontinued for 6 weeks after TQD, including recording of all smoking.Participants were seen at least weekly to verify their smoking status viacarbon monoxide (CO) testing and to report on adverse events.

NP treatment. Participants were randomized on the TQD to initiatetreatment with 35-mg transdermal nicotine patch or matched placebo.Patches were first applied upon waking the morning of TQD and every

morning thereafter. EDs prompted participants to apply patches uponwaking (EDs were programmed with an alarm clock) and asked forconfirmation that they had been applied. By design, 30% more participantswere randomized to active treatment than to placebo (to allow for equalnumbers of lapse events in the two groups). Randomization was stratifiedon the basis of reported smoking rate at entry (split at 20 cigarettes/day)and ED-monitored baseline craving intensity (split at 5.84 on a 10-pointscale). Assignments were made on the basis of a computer-generatedrandomization sequence by a staffer who had no participant contact.Blinding of participants was not directly assessed. All participants woretwo patches daily, 22 cm2 and 15 cm2, corresponding to marketed Nico-Derm CQ 21-mg and 14-mg patches, respectively. Individuals randomizedto active NP treatment received 35 mg for 3 weeks (both 21-mg and 14-mgpatch active), 21 mg for the next 2 weeks (only 21-mg patch active), andonly placebo patches for 1 final week (both patches inactive; excludedfrom analyses). Individuals randomized to placebo patch treatment alsowore two patches (also 22 cm2 and 15 cm2, both inactive) daily. Thehigh-dose NP did achieve complete replacement of baseline nicotine levels,with saliva cotinine levels on TQD averaging 125% (SD � 44%) ofbaseline. We tested a shorter than approved regimen in order to observe the

Table 1Baseline Variables Across Treatment Groups

VariableActive patch(n � 188)

Placebo patch(n � 136) p

AgeM 40.02 38.90 .28SE 0.68 0.78

Gender (n, %)Male 87, 47.00 71, 52.20 .64Female 101, 53.00 65, 47.80

Ethnicity (n, %)Caucasian 153, 84.50 117, 86.70 .89African American 20, 11.10 15, 11.10Hispanic 1, 0.60 0Native American 3, 1.70 2, 1.50Other 4, 2.20 1, 0.70

Average cigarettesM 24.65 23.79 .39SE 0.65 0.76

Years smokedM 22.77 21.04 .10SE 0.71 0.78

NDSSM 0.02 �0.08 .35SE 0.07 0.077

FTNDM 6.10 5.73 .12SE 0.16 0.18

Saliva cotinine (baseline)M 366.18 345.59 0.27SE 11.90 14.20

Expired carbon monoxide (baseline)M 37.53 38.57 .54SE 1.11 1.30

Ever quit (n, %)Yes 155, 82.45 116, 85.29 .53

Longest quit (days)M 233.78 342.49 .24SE 59.20 70.70

No. of quitsM 4.51 3.36 .03*SE 0.35 2.56

Note. NDSS � Nicotine Dependence Syndrome Scale; FTND � Fagerstrom Test for Nicotine Dependence.* p � .05.

278 SHIFFMAN ET AL.

possible effects of step down and withdrawal of medication and accom-modated the expected limits of intensive monitoring. This brief treatmentperiod was not expected to greatly affect the incidence of cessation orfailure events because the majority of initial abstinences, lapses, andrelapses tend to occur within 30 days of the TQD (e.g., Garvey et al.,1992).

Cognitive–behavioral treatment. Participants met in groups of 8–16smokers for six sessions of group cognitive–behavioral treatment forsmoking cessation, with two sessions occurring prior to the TQD, one onthe TQD, and three sessions occurring during treatment. The sessionsprovided psychoeducation and support (e.g., Brown, 2003) and were run bydoctoral students in clinical psychology who were blind to patchassignment.

ED system. ED system hardware consisted of a PalmPilot Professionalpalmtop computer with a touch screen used to present questions and solicitresponses. Software for the study was developed specifically for thispurpose (invivodata, Inc., Pittsburgh, PA) and resembled software used inpreviously published studies (Shiffman, Paty, et al., 1996).

Outcome measures. Outcomes analyses focused on outcomes in thefirst 35 days of treatment, when the active NP group was receivingnicotine. The outcomes were based on participants’ reports of smoking onED. Participants were to initiate entries any time they smoked. Addition-ally, at the end of each day, ED asked whether they had smoked withoutmaking an entry. Finally, participants were debriefed about smoking ateach clinic visit.

Three different outcome milestones were used in the analysis. Initialabstinence was defined as 24 hr without smoking. Participants were torecord all cigarettes smoked. ED determined achievement of 24 hr ofabstinence on the basis of a 24-hr period without any cigarette entries.Initial lapse was the first episode of any smoking after initial cessation,whether a single puff or multiple cigarettes (14% of lapsers smoked �1cigarette), and was recorded by participants on ED. Relapse was a resump-tion of regular smoking. Relapse was operationalized in the following twoways: The Ossip-Klein et al. (1986) definition required 7 consecutive daysof smoking (7-day relapse). We have previously used (Shiffman, Hickox,et al., 1996; Ockene et al., 2000) a more stringent definition, requiringsmoking at least five cigarettes a day for 3 consecutive days (5–3 relapse).This was computed by ED from entries of smoking episodes. (ED trackedthis latter milestone in real time and stopped soliciting reports of “lapses”when it was reached; thus, this definition was built into the ED protocol.)

We also report two traditional outcome measures (Hughes et al., 2003):7-day point prevalence, defined as reported abstinence for the preceding 7days (see Table 2), and continuous abstinence—no smoking since TQD.For these analyses, participants lost to follow-up were considered to besmokers.

Self-reported abstinence was confirmed by using weekly CO tests. Anyparticipant who reported abstinence but who had CO �10 ppm wasconsidered to have smoked on the first day after the last clean CO. On thebasis of this criterion, 2 participants (in the placebo group) were classifiedas having failed to achieve abstinence, and 4 participants (2 active, 2placebo) were counted as lapsed.

Analyses

We used survival analysis (Hughes et al., 2003; Niaura et al., 2001) toassess progression to each milestone (in days). Survival analysis estimatesthe risk of an event (e.g., a lapse) by analyzing the rate of event occurrenceover time in relation to independent variables such as treatment assign-ment. Because an event becomes more likely the longer one is at risk, theanalyses focused on the event risk (“hazard”) per unit time. Participantswho dropped out (“censored”) were included and contribute to the estima-tion because the absence of a lapse, despite a certain time at risk, isinformative. Similarly, participants who reached the predesignated end ofthe observation period without lapsing were informative because they wereat risk but did not lapse. Finally, for those who did lapse, the amount oftime they spent at risk before lapsing is also informative about the risk-per-unit time. Thus, in these analyses, no outcome was imputed forparticipants who dropped out; rather, the observation was treated as cen-sored (Hughes et al., 2003; Niaura et al., 2001). All analyses were con-ducted on the full sample eligible for each milestone (i.e., those participantswho had passed the previous milestone and were thus eligible for thesucceeding milestone).

The analysis focused on the period of ED monitoring and active patchwear, which was 5 weeks in duration; data were censored thereafter.Analysis indicated that the data fit a Weibull distribution, and we used aparametric Weibull model for statistical testing of treatment effects onsurvival. We also report hazard ratio (HR), derived from a Cox propor-tional hazards analysis. The HR expresses the ratio of risk (per unit time)in the active treatment group to the risk in the placebo group. We expressedthe HR so that a higher HR always indicates a favorable effect of treatment.We also report analyses of traditional outcome end points. These outcomeswere compared by using chi-square tests of association between outcomestatus and treatment.

Results

Disposition

Figure 1 shows the participants’ flow and disposition. Manypotential participants failed to report for medical screening, somewere disqualified for medical reasons, and others declined toparticipate after being medically qualified. A sample of 412 smok-ers initiated the study, but 88 (21%) dropped out during baselinemonitoring, before the TQD and random assignment to treatmentcondition. Of the 324 smokers who were randomized, 46 (14%)who were assigned to placebo patch withdrew from the studybefore the end of the treatment phase compared with 45 (14%)who were assigned to active patch, �2(1, N � 324) � 3.82, p �.06. This was partly a function of differential outcomes, as de-scribed below. Participants who withdrew from the study weresignificantly younger than those who were retained through Week5 (withdrew: M � 37.4, SD � 8.36 years; completed: M � 40.3,SD � 9.45 years), t(233) � 2.67, p � .008; no other significantdifferences were found. These withdrawals did not result in un-balanced treatment groups: There were no significant demographicor smoking history differences between treatment groups amongcompleters (n � 217).

Table 2Intent-to-Treat 7-Day Point Prevalence (Reported Abstinence forPreceding 7 Days) by Treatment Group

Weekpost-TQD

Placebopatch

(n � 136)

Activepatch

(n � 188)

�2 p �n % n %

1 62 46 99 53 1.582 53 39 92 49 3.173 35 26 112 60 36.46 .0014 40 29 104 55 21.45 .0015 35 26 98 52 22.72 .0016 46 34 92 49 7.37 .01

Note. N � 324. Participants who withdrew from the study were counted assmoking. TQD � target quit date.

279CESSATION MILESTONES

Patch Compliance, Safety, and Tolerability

Patch compliance was computed from real-time reports of patchapplication made each morning on ED and confirmed by counts ofreturned patches. Patches were applied on 99.3% of days. Therewere no differences in compliance between participants on activeand placebo patch.

Participants on active patch were more likely to report adverseevents (42% vs. 27%; p � .01). The most common adverse eventswere nausea (11.6%), insomnia (7.1%), dizziness (6.5%), abnor-mal dreams (6.2%), pruritus (6.2%), headache (5.8%), and rash(5.4%); these are typical effects of patch use (Zevin, Jacob, &Benowitz, 1998). There were no serious adverse events. Tenparticipants (4 on active patch, 6 on placebo) withdrew because ofside effects; their data were treated as censored observations insurvival analysis. An additional 17 participants on active patch and2 on placebo patch, �2(1, N � 324) � 7.54, p � .006, had theirdosage reduced because of side effects; these participants wereincluded in all analyses. (Excluding them made no difference.)

Treatment Outcome

Table 2 presents 7-day point prevalence rates by condition foreach week during active patch treatment. In this analysis, activepatch separated significantly from placebo by Week 3 and re-mained significantly higher thereafter. Note that people in the

active NP condition demonstrated a striking upturn in point prev-alence at Week 3 caused by a substantial number of participants onactive treatment who had smoked but recovered abstinence be-tween Weeks 2 and 3. Most participants in both groups smokedwithin the observation period; this occurred for 64% of those inactive treatment and 77% of those on placebo.

Table 3 presents the proportion of participants who reached eachsuccessive milestone and were therefore eligible for analysis ofprogress toward succeeding milestones. Figure 2 presents thesurvival curves for each milestone. For each milestone, we com-pared NP and placebo by survival analysis and analyzed theproportion of participants in each group who reached the mile-stone. As survival analysis uses information about how long par-ticipants were under observation without having reached a mile-stone, we also describe how long participants remained underobservation and distinguish censoring because of participant dropout and biochemical verification failure versus censoring as aresult of the end of the observation period.

Initial abstinence. Treatment with active patch was associatedwith initial abstinence: A significantly greater proportion of thoseon active patch achieved the initial abstinence milestone comparedwith those on placebo. Nineteen participants (5.9%) did notachieve abstinence and dropped out after an average of 5 days(SD � 6) of further observation. Survival analysis (Figure 2A)showed that participants on active patch had a greater likelihood of

Figure 1. Disposition of candidates and participants.

280 SHIFFMAN ET AL.

achieving 24-hr abstinence, �2(1, N � 324) � 24.3, p � .0001(HR � 1.26), though smokers in both conditions took a median of1.0 days to achieve initial abstinence. Figure 2 shows that whereasalmost all smokers who quit on active patch did so as scheduled onthe TQD (97%), only 80% of the smokers on placebo whoachieved abstinence did so on TQD; the remaining 20% achievedabstinence later. Failing to achieve abstinence on TQD impliessmoking on that day, even though participants were supposed toabstain starting when they woke up. We considered how longparticipants abstained before smoking on TQD. Participants whodid not remain abstinent all day on TQD did abstain for an averageof 14.54 hr (7.79 hr after waking on TQD). There were nodifferences between active patch (M � 14.2) and placebo patch(M � 14.3) in the number of hours to the first cigarette, W(1) �232, p � .77, on TQD.

Lapsing. Among the 305 participants who achieved initialabstinence, 67.2% lapsed. Similar proportions of active and pla-cebo participants lapsed (see Table 3). The 99 abstinent partici-pants who did not lapse were censored after an average of 28 days(SD � 9.10) after quitting; 21.4% of these dropped out after anaverage of 14.1 days, and 78.6% remained under observation untilthe end of the interval (average 32.0 days). Survival analysisshowed that active patch significantly decreased the risk of lapsing(Figure 2B), �2(1) � 13.18, p � .0003 (HR � 1.6). The medianduration of abstinence was 6 days for active patch and 2 days forplacebo.

Relapse. For the 206 participants who lapsed, we separatelyconsidered two definitions of relapse: 7 consecutive days of smok-ing and 3 consecutive days of smoking at least five cigarettes.Compared with active patch participants, more than three times as

Table 3Proportion of Participant by Treatment Group Reaching Each Milestone

Participant progress

Placebo patch Active patch

ORa HRb 95% CIn % n %

Reached TQD (eligible to quit, ITT denominator) 136 100 188 100Initial quit (24-hr abstinence) 122 89.70 183 97.30 4.20* 1.30* 1.00–1.60Lapse (smoked after abstinence) 92 75.40 114 62.30 1.89 1.60*** 1.20–2.107-day relapse (smoked for 7 consecutive days) 34 36.90 11 9.70 5.56**** 4.80**** 2.30–9.103–5 relapse (smoked �5 cigarettes for 3 consecutive days) 20 21.70 4 3.50 5.26**** 7.10*** 2.40–20.90

Note. TQD � target quit date; ITT � intent-to-treat; OR � odds ratio; HR � hazard ratio; CI � confidence interval.a The OR for achievement of the milestone during the study period is expressed such that higher ORs indicate a favorable effect of nicotine patch (NP).Statistical tests were based on chi-squares. b The HR was derived from proportional hazards analysis and represents the change in daily risk attributableto NP. The ratio is expressed such that higher ratios indicate a favorable effect of NP. Statistical tests were based on Weibull survival analysis.* p � .05. ***p � .0005. ****p � .0001.

Figure 2. Kaplan–Meyer survival curves for the four end points examined by survival analysis. (A) Target quitdate to initial abstinence; (B) initial abstinence to lapse; (C) lapse to relapse (7-day definition); and (D) lapse torelapse (3-day definition).

281CESSATION MILESTONES

many participants on placebo patch had a 7-day relapse (22.7% vs.77.3%), �2(1) � 25.32, p � .0001. The 161 lapsed participants forwhom a 7-day relapse was not recorded were observed for anaverage of 20.8 days after lapsing. Most (73.8%) remained underobservation until the end of the treatment period (M � 24.5 days,SD � 8.70), whereas 27.9% dropped out after an average of 11.05days (SD � 7.7) and were censored. In survival analysis, activepatch decreased the risk of relapse (Figure 2C), �2(1) � 16.67, p �.0001 (HR � 4.8); after their lapse, participants on active patchtook a median of 13 days to relapse compared with a median of 4.5days for those on placebo patches. The relapse curve in Figure 2Csuggests that many participants on placebo (18%) began relapsingimmediately after their first lapse; that is, the first lapse initiateddaily smoking. This was not so for those on active patch: Less than10% of participants progressed to relapse even after an average of20.8 days of observation following TQD.

Active patch treatment also reduced progression to relapse whenwe used a more stringent definition requiring smoking at least fivecigarettes per day for 3 consecutive days. Smokers on placebopatch were more than five times as likely as those on active patchto reach this relapse milestone, �2(1) � 16.83, p � .001. Of the182 lapsers who did not reach this 5–3 relapse, most (73.7%)remained in the study until the end (M � 25.1 days, SD � 8.3),whereas 26.3% dropped out after an average of 11.2 days (SD �7.50). By survival analysis, active patch significantly reduced therisk of progression from lapse to 5–3 relapse, �2(1) � 12.84, p �.0003 (HR � 7.1). After a lapse, participants on active patchrelapsed after a median of 25 days, compared with 16 days forthose on placebo patches. Notably, the pattern of progression tothis relapse criterion was quite different from that for the earlierrelapse definition: The initial lapse almost never initiated daily fivecigarettes/day smoking. In fact, relapse only began to occur in theplacebo group approximately 10 days after the initial lapse. Almostno one in the active group (3%) progressed to relapse by thisdefinition.

Discussion

We illustrated an approach to analyzing smoking cessationoutcome data by separate analysis of three outcome milestones.Although the efficacy of NP and high-dose NP has been previouslyestablished (Fiore et al., 2000), previous studies have not ad-dressed where NP might be exerting its influence. The resultsdemonstrate an unexpected pattern of NP efficacy across all threemilestones in treatment—initial quitting, first lapse, and lapse torelapse. Smokers who used active patches were more likely toachieve initial cessation and tended to achieve it earlier. Activepatch reduced the risk of lapsing among abstinent smokers, thoughthis was demonstrated more by delaying lapses than by avertingthem entirely. Finally, and surprisingly, by far the biggest treat-ment effects were observed among those who had already lapsed:Treatment with active patch significantly reduced the risk ofprogression toward relapse.

The observation that active patch treatment increased initialquitting—and did so about as well as it prevented lapses—wassomewhat surprising because smokers who apply patches on themorning of their quit day must make their initial transition fromsmoking to abstinence before nicotine from the patch has reachedsignificant levels. Smokers wake up in nicotine deprivation, and

levels from the patch peak about 4 hr later (Fant et al., 2000). Itmay be that many smokers are able to achieve a few hours ofabstinence on their own and are then able to benefit from active NP“kicking in” after a few hours. Indeed, even those who failed tostay abstinent on TQD did manage to avoid smoking for over 7 hr,on average, giving enough time for nicotine from the patch toreach peak or clinically useful levels. The patch we tested achievespeak blood levels faster than any other patch (Fant et al., 2000),which could have contributed to this effect; other patches shouldbe tested as well.

The effects of active patch on prevention of lapses were mixed.The protective effect of NP was evident in longer periods ofabstinence, suggesting lower risk, but after 35 days, smokers onNP were as likely to have lapsed as those on placebo. Activetreatment seemed to prevent lapsing early on, but the curves inFigure 2B later converge. Although it has been previously ob-served that nicotine patches have their biggest effects early intreatment (Killen & Fortmann, 1997), our results are at odds withthe bulk of the literature, which finds fewer lapses in smokerstreated with active NP even over longer periods (Fiore et al.,1994). However, patch treatment is not effective at preventing thesort of cue-triggered surges in craving that are associated withinitial lapses (Tiffany et al., 2000; Waters et al., 2004; Shiffman etal., 1996), which could weaken its effect against initial lapses.(Nicotine gum, in contrast, appears to work acutely to combatthese intense episodic cravings, Shiffman et al., 2003.) The down-titration of smokers to a lower dose patch at Week 3, which ismuch sooner than is typically done, may have undermined NPeffects on lapses.

The biggest treatment effect we observed was that NP impededprogression from lapse to relapse during the first 5 weeks of activetreatment. It is notable that this was by far the biggest effect oftreatment, at least threefold the size of the effects at earlier mile-stones. Effects on progression to relapse have not been previouslyreported and are notable for several reasons: First, this effect of NPis not assessed at all in traditional clinical trials that use continuousabstinence measures, which often count a lapse as complete treat-ment failure (Ockene et al., 2000). Second, because progressionfrom lapse to relapse is so common (Kenford et al., 1994) and nointerventions have been identified as effective in preventing theprogression, this effect could be clinically important if it persistsbeyond 35 days. Third, the current instructions for nicotine patchuse may systematically subvert this potential clinical benefit:Smokers are instructed to stop using the patch if they smoke (seeFiore et al., 2000; SmithKline Beecham, 1996), and many smokersalso falsely fear that smoking while on the patch may cause heartattacks (cf. Joseph et al., 1996). Our findings suggest that smokersshould be advised to stay on nicotine treatment following a lapsein order to prevent relapse and perhaps to reestablish abstinence.Finally, almost no research has examined the effect of NP (or anyother treatment) on the progression from lapse to relapse or themechanisms underlying it.

The mechanism by which nicotine patches impede progressionfrom lapse to relapse is not known, but there are several interestingpossibilities. Patches could exert their influence following lapsesin the same manner as they do before lapses, for example, byreducing craving and withdrawal and thus reducing the likelihoodof further relapsing. Alternatively, having steady-state nicotinelevels on board may reduce the reinforcing effects of nicotine

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self-administration in lapses (Hughes, 1993; Henningfield & He-ishman, 1995). There is some evidence that such nicotine “pre-loads” do reduce the subjective satisfaction of smoking, but theevidence is inconsistent (Rose, Behm, & Westman, 2001). Havingsignificant nicotine levels may also reduce the priming effects ofreexposure to nicotine (Sutton, 1991). Another possibility is thatnicotine replacement reduces cravings that may be elicited by alapse so that treatment participants can focus on reestablishingabstinence. Further studies are needed to explore these mecha-nisms. In any case, the fact that NP can impede progression fromlapse to relapse is consistent with analyses showing that variablesrelated to nicotine dependence influence this progression (Shiff-man, Hickcox, et al., 1996).

In this study, high-dose NP treatment affected all three outcomemilestones, though the effects varied in size. The fact that NPaffects different steps in the process of quitting smoking suggeststhat it works by multiple mechanisms, which could help explainwhy the mechanism has not been fully elucidated (Hughes, 1993;Lerman & Niaura, 2002). Other treatments may have more differ-entiated actions and may affect some milestones but not others. Forexample, nicotine vaccines, which are under investigation (Kosten& Biegel, 2002), are expected to work by preventing nicotine fromreaching the brain and delivering reinforcement during a lapse.This mechanism would work only to prevent lapses from progress-ing to relapse and would not be expected to promote initialabstinence or to prevent initial lapses. Similarly, education on theabstinence violation effect (Marlatt & Gordon, 1985) would beexpected to reduce progression from lapse to relapse but to have noeffect on quitting in the first place. Research to identify treatmentsand variables that differentially affect different milestones wouldhelp to validate the milestones and help to develop our conceptu-alization of the processes important at each step.

Limitations of this study need to be considered in any interpre-tation of the results. First, the NP treatment administered to par-ticipants was not typical of current clinical practice: It was higherin dosage and shorter in duration, so the substantive conclusionsabout NP might not be generalizable to standard regimens. We alsoused a particular nicotine patch formulation, with higher levels andfaster onset, so results may not generalize to other patches or toother nicotine replacement forms like gum or lozenge. Also, ouranalyses focused on the first 5 weeks following a quit attempt;thus, we cannot draw any conclusions about longer term smokingcessation outcomes or other milestones that occur after relapse(e.g., recycling to abstinence). It is possible that continuing activetreatment for the typical 10 weeks or longer would maintain andextend the treatment effects, but this was not tested here. We alsoonly looked at the period when smokers were on active therapy, soour analyses do not address what happens after treatment. (On theother hand, NP treatment has most of its effects in the first fewweeks [Hughes et al., 2003], and treatment effects should beexpected primarily while on treatment.) Further, the smokers inthis study may not be representative because they were thoroughlyscreened for health and motivation, were engaged in substantialself-selection, and were enrolled in an intensive research andtreatment program. Although assignment to patches was randomand blind, it is possible that smokers may have been “unblinded”by detecting what treatment they were getting, and, in turn, thismay have affected their behavior. Finally, although we obtainedbiochemical verification of participants’ smoking status at key

points, we could not verify every step of the milestones consideredin the analysis.

A conceptual and statistical issue in our analysis of milestonesarose because the milestones were sequential and cascading: Onlythose participants who passed a prior milestone (e.g., initial quit-ting) were even eligible for or at risk for the following one (e.g.,lapsing). Thus, each step of the analysis focused on a progressivelysmaller subset of the sample, and each step “filtered” the sampleand made it less representative of the original base of smokers whoentered the trial. Thus, each step in the analysis was potentiallyaffected by the prior selection process. For example, if the mostdependent smokers were least able to achieve abstinence, then theanalysis of lapses would be limited to the less dependent partici-pants (those who could achieve abstinence), which could limit theapparent effects of dependence on lapses. In this study, the factthat we observed significant effects for later milestones and thatthe strongest effects were seen at the last milestone (relapse)suggests that our analyses were not unduly affected by progressivefiltering of the sample, but this dynamic needs to be recognized inanalyses of these milestones. Also, the progressive filtering thatmight occur is not a bias introduced by the analytic methods or bymethodological artifact: The need for smokers to jump successivehurdles is part of the real-world process of quitting. Smokerscannot lapse without first quitting, and they cannot relapse withoutfirst lapsing. Thus, the analysis and flow of participants mirrors thereal-world process. The statistical challenges of modeling suchsequential outcomes has been recognized in other literatures(Meyer, 1990; Dekimpe, Van de Gucht, Hanssens, & Powers,1998); there is no accepted alternative approach.

The strengths of the present study include analysis based onintensive and detailed monitoring of participants’ smoking throughthe use of EDs, likely making timing of key events more accurate(Shiffman, Hufford, & Paty, 2001). The study used a stratified,randomized, double-blind, placebo-controlled design to evaluatetreatment effects in a moderately sized sample of smokers. The useof higher dose nicotine patches, though it does not mirror clinicalpractice, is also a strength in that it may allow one to better studythe treatment process as underdosing is reduced (Zevin et al.,1998). In any case, this is the first analysis of addiction treatmentthat explicitly examines the effects of treatment on initial absti-nence, lapsing, and relapsing. The strengths and weaknesses of thisparticular clinical trial notwithstanding, the conceptual and ana-lytic framework illustrated here may be useful in analysis of otherabstinence-oriented treatments for smoking and for other addic-tions. Some of the concepts embedded in this framework arealready implicit in some analyses of two treatments for alcoholism.Analyses of the effects of naltrexone (Volpicelli et al., 1995) haveimplied that its effects are primarily to impede progress from alapse to relapse. Similarly, analyses of acamprosate indicate that itlimits drinking once patients have lapsed (Chick et al., 2003) andthat it helps maintain abstinence only in drinkers who have alreadyachieved abstinence and undergone detoxification (Food and DrugAdministration, 2004; the concept of detoxification itself recog-nizes the achievement of abstinence as an important stage). Webelieve that systematic application of an analytic model that dis-tinguishes initial abstinence, lapsing, and relapsing as distinctmilestones in treatment would be fruitful in illuminating the pro-cesses and mechanisms involved not only in smoking cessationtreatment but also in abstinence-oriented treatment for other ad-

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dictions. Clinical outcome trials in addiction treatment should beanalyzed by milestones to shed light on treatment process.

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Received September 10, 2004Revision received June 29, 2005

Accepted July 11, 2005 �

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