Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT03857139 |
| Other study ID # |
STUDY00001467 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
December 2020 |
| Est. completion date |
January 2023 |
Study information
| Verified date |
May 2022 |
| Source |
University of Houston |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The selection hypothesis of smoking prevalence posits that smokers who are not able to quit
successfully are "burdened" by specific characteristics that make it more challenging to
quit1. For example, those less successful in quitting smoking may be more nicotine dependent
or more likely to suffer from substance use, psychiatric, or medical conditions. In line with
this perspective, smoking prevalence has stabilized in the US, presumably because the
remaining population has become increasingly representative of those "at-risk smokers" who
are unable to quit2. Emerging evidence suggests that persons who suffer from opioid misuse,
defined as opioid use without a prescription, at a dose or frequency higher than prescribed,
or for a non-medical purpose (e.g., getting high),3 may constitute such a high-risk group.
Opioid misuse affects greater than 16% adults who use opioids4 and up to 29% of those with
chronic pain.5 The prevalence of tobacco smoking in this group may exceed twice that observed
in the general population, and smokers misusing opioids are almost twice as likely to be
dependent on nicotine6,7. Yet, the role of opioid misuse in periods of early abstinence and
smoking cessation has yet to be explored. The main objective of the present proposal is to
fill existing gaps in knowledge by examining the extent to which opioid misuse is associated
with decreased success during early smoking abstinence and over the course of an attempt to
quit smoking, and to identify mediators and moderators of opioid-smoking relations in this
context. This contribution is clinically-significant from a public health standpoint because
it will directly guide the development of novel psychosocial/behavioral smoking cessation
interventions to help this high-risk population of smokers quit by targeting unique
vulnerability processes that result in poor cessation outcomes.
Description:
B. BACKGROUND/SIGNIFICANCE B.1. Tobacco Smoking. Smoking is responsible for over 40% of
premature deaths and disability in the US1, and has been estimated to cost $96 billion in
direct medical expenses and $97 billion in lost productivity each year12. Although over 40%
of the 48 million Americans that still smoke make a serious quit attempt each year, either on
their own (i.e., self-guided quit) or with assistance from formal treatment, less than 5% are
able to abstain from smoking for greater than 3 months9. The selection hypothesis of smoking
prevalence posits that smokers who are not able to quit successfully are "burdened" by
specific characteristics that make it more challenging to quit13. For example, those less
successful in quitting smoking may be more nicotine dependent or more likely to suffer from
substance use, psychiatric, or medical conditions. According to this perspective, smoking
prevalence should begin to stabilize as the remaining population becomes increasingly
representative of those "at-risk smokers" who are unable to quit1. There is consensus that
significant populations of at-risk adult smokers are present in the general population2. Yet,
there remains little understanding of the subgroups of "at-risk smokers" and the processes
governing relapse among them14. Emerging evidence suggests that smokers who suffer from
opioid misuse may constitute such a "high-risk group"15,16.
B.2. Prevalence of Comorbid Opioid Misuse and Tobacco Smoking. Like smoking, opioid misuse,
defined as opioid use without a prescription, at a dose or frequency higher than prescribed,
or for a non-medical purpose (e.g., getting high)3, is a critical national health problem
that burdens over 11.5 million American adults17, with annual direct medical treatment and
lost productivity costs in excess of $504 billion17. Opioid misuse often leads to
hypervigilance for somatic perturbation, significant emotional distress, physical
deconditioning, and functional disability18-20. According to NIH, the deleterious effects of
opioid misuse have been demonstrated in morbidity, immune function, sleep, cognition, eating,
mobility, and affective distress11. Clinical and epidemiological population estimates
indicate that the prevalence of smoking among persons misusing opioids (upwards of 48%21) may
be greater than twice the rate (19%) observed in the general population22-24. Daily smokers
are 5 times more likely than non-smokers to meet criteria for past year opioid misuse16.
B.3. Complex Interrelations between Opioid Misuse and Tobacco Smoking. Although
interrelations between opioid misuse and smoking have been of clinical interest for
decades25, research in this area has only begun to develop. Studies provide evidence of
covariation between tobacco smoking and the development and maintenance of opioid misuse16.
Chronic nicotine exposure may result in dysregulation of the endogenous opioid system,
leading to greater somatic perturbation (e.g., pain) and cross-tolerance to prescription
opioids26. There is also evidence that nicotine may sensitize the neural system to enhance
the rewarding properties of opioid medications27, which is consistent with
incentive-sensitization theories of addiction28,29. Although limited, available work has
begun to model the interrelations between opioid misuse and tobacco smoking. One recent study
using a representative sample, for example, found that smokers were more likely than
non-smokers to report past year opioid misuse, as well as meet criteria for opioid use
disorder, and these results were evident over and above depression and alcohol use16.
Further, initiating tobacco use prior to the age of 14 and reporting greater tobacco
dependence were robustly associated with past-year opioid misuse16.
B.4. Limitations of Opioid Misuse-Tobacco Research. Despite the public health importance of
the comorbidity between opioid misuse and smoking, there are substantive gaps in extant
research and knowledge. Without such knowledge, it is difficult to develop or adapt smoking
cessation treatments to meet the needs of this neglected population. First, despite the
established association between opioid misuse and smoking16,24, there are no data addressing
the impact of opioid misuse on smoking cessation. There is a clear need to develop research
to understanding the extent to which opioid misuse may impair successful smoking cessation.
To address this gap, the present proposal seeks to test the extent to which opioid misuse
interferes with smoking cessation and theoretically and empirically established factors of
negative affect states and nicotine withdrawal/craving that occur over the course of a
cessation attempt. This limitation impedes the ability to begin to understand the possible
linkages between opioid misuse and key affective and drug-state processes. It is unfortunate
theoretically and clinically because numerous studies have documented that smokers,
especially those with greater degrees of nicotine dependence or higher smoking rates, report
negative affect and problematic physical and affective nicotine withdrawal symptoms during
quitting30-32.
Second, it is yet unknown what specific processes account for poor smoking cessation outcomes
among smokers with opioid misuse. Identifying these processes is important for at least two
reasons: (a) understanding of the pathway(s) through which opioid misuse affects smoking
cessation outcomes so that we can develop a process-based theoretical model of opioid
misuse-smoking cessation relations; and (b) explicating such explanatory mechanisms is
essential to translating basic research knowledge about opioid misuse and smoking to advances
in specialized behavioral and pharmacologic smoking cessation interventions for smokers
misusing opioid33. The present proposal is therefore innovative in exploring mechanisms that
affect opioid-smoking linkages.
Third, there is a need to identify possible moderators of smoking-opioid relations. Although
many possible moderators exist, comorbid pain is one leading candidate. Symptoms of (current)
moderate to severe pain are more prevalent among both smokers and persons misusing
opioids16,34, often doubling rates observed in the general population. Among persons with
chronic pain, such comorbidity has been associated with overall greater pain intensity and
chronicity, increased functional impairment, and reduced pain-treatment efficacy35,36.
Theoretically, chronic pain is therefore apt to increase the severity of nicotine withdrawal
and craving and decrease quit success, especially among smokers with opioid misuse.
Additionally, sex is another potential candidate as a moderator of smoking-opioid
relations37. Specifically, females relative to males often report more difficulty quitting
smoking,38,39 due in part to holding more positive expectancies for smoking effects on mood
and appetite40-42. In terms of opioid misuse, although less is known, females compared to
males receive less treatment for opioid misuse43,44 and report more mood disturbances45-47.
Theoretically, these data may suggest that sex differences could exist among tobacco smokers
with opioid misuse, such that females may have greater difficulty reducing their tobacco use
in the context of opioid misuse.
B.5. Integrative Model. Although presently no integrative model of smoking-opioid co-use has
been offered, several mechanisms may be involved. Such mechanisms could include genes central
to regulating certain brain chemical systems48-50, neurobiological mechanisms involved in the
cross-tolerance and cross-sensitization to both drugs51,52; conditioning mechanisms (e.g.,
craving for opioids or nicotine elicited by certain environmental cues)53, or individual
differences in psychosocial factors (e.g., personality characteristics)54. There is highly
limited research addressing these mechanisms. Drawing from past work (see B.3.), I have
theorized that smokers with opioid misuse, compared to those without, may be more
cognitively, affectively, and behaviorally reactive to aversive internal cues (e.g., nicotine
withdrawal, negative emotional states) during periods of smoking deprivation. For example,
individuals who misuse opioids may be more apt to engage in catastrophic thinking toward
these aversive internal cues (e.g., "I cannot tolerate this distress!")55,56 and experience
greater change in the intensity of negative affect, nicotine withdrawal symptoms (e.g., more
intense restlessness ), and craving (e.g., "I need to smoke now"). As a result, opioid misuse
may drive the affective and drug-state experiences (negative affect and withdrawal symptoms)
experienced during a quit attempt. Consequently, individuals with misuse opioids may tend to
rely on smoking to cope with such aversive internal distress. From this perspective, aversive
internal states (negative affect and nicotine withdrawal symptom)57, may mediate the relation
between misuse and lapse/relapse to smoking. Further, individual differences factors, such as
severity of pain and sex, could moderate opioid-smoking relations.
