Title: Does Improvement in Symptoms of Attention Deficit Hyperactivity Disorder (ADHD) Mediate an Effect of Long-Acting OROS-Methylphenidate on Cigarette Smoking? A Secondary Analysis of CTN-0029
1Does Improvement in Symptoms of Attention Deficit
Hyperactivity Disorder (ADHD) Mediate an Effect
of Long-Acting OROS-Methylphenidate on Cigarette
Smoking?A Secondary Analysis of CTN-0029
- Edward V Nunes1, Lirio Covey1, Mei-Chen Hu1,
Martina Pavlicova1, Eugene Somoza2, Theresa
Winhusen,2 -
- 1Columbia University Medical Center (CTN Long
Island Node), - 2University of Cincinnati (CTN Ohio Valley
Node), - Funded by U10 DA13035 (NIDA-CTN) and K24 DA022412
(Nunes) -
2ABSTRACT CTN-0029 was a multisite,
randomized, double-blind, placebo-controlled
trial of long-acting OROS-methylphenidate
(OROS-MPH) for treatment of patients with both
nicotine dependence and attention deficit
hyperactivity disorder (ADHD). The principal
outcome analysis found, as expected, a robust
beneficial effect of OROS-MPH in improving
symptoms of ADHD, but no clear effect of OROS-MPH
on cigarette smoking outcomes. Since OROS-MPH is
primarily a treatment for ADHD, it is reasonable
to hypothesize that a beneficial effect on
smoking outcome might occur only among those
patients who experience a substantial improvement
in their ADHD during treatment. We therefore fit
a linear model in which prolonged abstinence at
week 10 (end of the acute treatment phase) was
modeled as a function of medication treatment
(OROS-MPH versus Placebo), the change in the ADHD
symptom severity score between baseline and end
of study, and the interaction between ADHD
improvement and treatment. The interaction was
significant, suggesting that among those patients
with the greatest improvement in ADHD symptoms
during treatment, OROS-MPH was superior to
Placebo in promoting prolonged abstinence from
nicotine. This secondary analysis suggests that
OROS-MPH may be effective in promoting smoking
cessation among the subset of patients whose ADHD
responds well to methylphenidate treatment.
3- Specific Aim
- To explore, among smokers with Attention Deficit
Hyperactivity Disorder (ADHD), whether a
beneficial effect of OROS-Methylphenidate
(OROS-MPH) on smoking cessation is mediated by
improvement in symptoms of ADHD - Rationale
- Stimulant treatment, such as with
OROS-Methylphenidate (OROS-MPH), is effective for
symptoms of ADHD. - A multisite, placebo-controlled CTN trial of
OROS-MPH among ADHD adults with cigarette smoking
found the expected effect of OROS-MPH to improve
ADHD symptoms, but no main effect of OROS-MPH on
cigarette smoking - However, a beneficial effect of stimulant
treatment on smoking outcome may occur only among
those patients whose ADHD symptoms improve - This would be consistent with the self-medication
hypothesis - If among patients with ADHD, nicotine is used
for its stimulant properties to improve attention - Then stimulant treatment should increase
nicotine abstinence only among those patients
whose ADHD gets much better in response to the
stimulant
4- Background
-
- ADHD is a neuropsychiatric condition that begins
in childhood and, in many cases, persists to
adolescence and adulthood. - In the U.S., ADHD is estimated to affect 2 to
18 of children and adolescents, and about 4.4
of adults. - ADHD has been linked with nicotine dependence.
- Persons with ADHD are more likely to become
regular smokers, begin smoking earlier, smoke
more heavily, and experience greater difficulty
to stop smoking, compared to persons without
ADHD. - Evidence that nicotine ameliorates
inattentiveness and performance deficits and that
nicotine can reduce deficits in dopaminergic
function related to inattentiveness suggests a
self-medication rationale for greater tobacco
use among persons with ADHD.
5- Methods
- A randomized, double-blind, placebo-controlled
trial comparing OROS-MPH vs. placebo as
adjunctive smoking cessation treatment (nicotine
patch and counseling). - Whites 202 Non-whites 51 (African-American1
5, Hispanic 16, Other20). - Males56.5, mean age37.8 years (s.d. 10.0),
mean years school 14.4 years (s.d. 2.4). - Six study sites, located in Cambridge
Massachusetts, Columbus Ohio, New York City New
York (2 sites), Portland Oregon, and Rochester
Minnesota, recruited participants. Study approved
by Institutional Review Board at each study site. -
- The trial included an 11- week treatment phase
(OROS-MPH vs. placebo) consisting of a four-week
pre-quit phase and seven weeks of a planned
abstinence period. All participants received
brief counseling(11 weeks) and nicotine patch
(during Weeks 4-11). - Conducted in CTN between December 2005 and
January 2008
6- Outcome and Data Analysis
- Abstinence outcome Prolonged abstinence for four
weeks at end of medication treatment (weeks 7 to
10) - Standard categorical measure of treatment success
recommended by Society for Research on Nicotine
and Tobacco - Mediator Change from baseline to end of study in
the ADHD symptom severity score (ADHD Rating
Scale (DuPaul, Power, et al., 1998)) - A continuous score, where higher change scores
indicate greater improvement in ADHD during
treatment. - Analysis A mixed effect model was fit, modeling
prolonged abstinence as a function of - Treatment (OROS-MPH vs Placebo)
- Mediator (change in ADHD symptom severity during
treatment) - Cigarettes per day at baseline as covariate
- Graph of the model Although the mediator was a
continuous covariate, for the purposes of
graphical presentation the score was divided into
four quartiles, from low to high change.
7Table 1 Baseline characteristics
8Model A Effect of Medication Treatment without
Accounting for Improvement in ADHD
Term in the model D.F Chi-Square P Comment
Site 5 18.79 .003
Treatment 1 0.05 .824 No Treatment Effect
Cigarettes per day at baseline 1 6.66 .010 Abstinence is less likely for heavier nicotine use
9Model B Effect of Medication Treatment
Improvement in ADHD included in the Model
Term in the Model D.F. Chi-Square P Comment
Site 5 11.04 .051
Treatment 1 3.53 .061
Cigarettes per day at baseline 1 6.06 .014 Abstinence is less likely for heavier nicotine use
Change in ADHD 1 6.26 .013 More improvement in ADHD associated with more abstinence
Interaction Treatment by ADHD change 1 6.83 .009 Effect of treatment on abstinence differs by level of ADHD change
10Percent of patients achieving prolonged
abstinence, as a function of medication
treatment, and improvement in ADHD during
treatment --When ADHD improvement is high,
medication is superior to placebo in promoting
abstinence --When ADHD improvement is lower,
medication trends to being worse than placebo in
abstinence
11Summary of Findings
- There was a significant interaction of treatment
with change in ADHD score during treatment - This suggests that ADHD change during treatment
mediates the impact of OROS-MPH on outcome - When OROS-MPH produces a large improvement in
ADHD symptoms, it improves smoking outcome
compared to placebo - When OROS-MPH produces little improvement in ADHD
symptoms, the trend is that smoking may get worse
12Implications
- Stimulant treatment, such as with OROS-MPH, may
be an effective intervention for smoking
cessation among smokers with ADHD--if the
stimulant produces a large improvement in ADHD
symptoms. - This is consistent with the self-medication
hypothesis, which would predict that unless ADHD
symptoms get very much better, patients will
continue to smoke to get the attention-improving
effects of the nicotine
13Clinical Implications
- ADHD responds quickly to stimulant
treatment--within a few weeks, depending on how
long it takes to adjust the dose - Several different stimulants, and stimulant
formulations, as well as non-stimulant
medications may be effective for ADHD, and
individuals differ in their response - Therefore, an effective strategy for cigarette
smokers with ADHD may be to treat the ADHD
aggressively, and change medications if needed
until a robust improvement in ADHD is achieved - More research is needed to test algorithmic
approaches such as this for the treatment of
patients with ADHD and nicotine dependence, and
perhaps for patients with co-occurring
psychiatric disorders and addictions in general
14Implications for Research on Treatment of
Co-Occurring Disorders
- Addictions are associated with increased rates of
many psychiatric disorders, and the co-occurrence
carries a poor prognosis - Depression, bipolar disorder, PTSD, other anxiety
disorders, ADHD - Many research studies have sought to improve
addiction treatment outcome by treating
co-occurring disorders - These studies may be inherently underpowered if
the effect of treatment on addiction outcome
resides only in the subgroup of patients whose
co-occurring disorder responds well. - For most co-occurring psychiatric disorders
different patients respond to different
treatments, and only a minority of patients will
respond to any one treatment. - Clinically, it may be that treatment of the
co-occurring disorder needs to be adjusted
aggressively until a good response is achieved - In designing studies of treatment of co-occuring
psychiatric and addictive disorders, we should
consider studying algorithms that seek to
maximize response of the co-occurring disorder,
by adjusting doses and changing treatments,
rather than testing single treatment strategies.