Outcome Inference in the Sensory Preconditioning Task in Opioid-Use Disorder

Background. People with substance-use disorders may have difficulty guiding their behavior on
the basis of not-yet-experienced outcomes such as long-term effects of substance use. Use of
mental inferences about future outcomes can be tested in a relatively simple laboratory task
called sensory preconditioning.

Objective. To test whether sensory-preconditioning performance is worse in people with
opioiduse disorder (OUD) than in healthy, demographically matched controls. To increase
generalizability, we will examine OUD participants who are in agonist treatment (abstinent or
not) and OUD participants who are abstinent but not in treatment. We do not have a hypothesis
about differences between those two groups, but we hypothesize that among agonist-treated OUD
participants, performance will correlate with degree of abstinence.

Participant population. We will enroll 3 groups of men and women: (1) history of OUD, but
abstinent for at least 3 weeks and not in agonist treatment, (2) OUD being treated with an
agonist (buprenorphine or methadone), (3) no history of a substance-use disorder (except
nicotine, for matching purposes) and not using any drug for nonmedical purposes.

Experimental design. Between-groups cross-sectional single-session laboratory study, with
telephone follow-up at 30 and 60 days.

Methods. Each participant will participate in a sensory preconditioning task conducted in a
single session. The task uses food odors delivered via nasal cannula and paired with visual
cues on a computer screen. There are three phases: (1) Preconditioning, in which 2 pairs of
visual cues (A+B, C+D) are shown on the computer screen; participants should acquire
automatic associations between A+B and between C+D. (2) Conditioning, in which participants
learn associations between the second cue of each pair (B and D) and either a sweet odor
(B1), a savory odor (B2), or no odor (D); and (3) Probe Test, in which participants predict
whether a visual cue will be paired with the sweet odor, the savory odor, or no odor, by
pressing a left, middle, or right button. No odors are actually delivered in the probe test.
The test of inferenceguided behavior is the ability to associate visual cues A and C with an
odor despite their never having been directly paired with an odor. In telephone follow-up at
30 and 60 days, participants will be asked to report drug use and associated problems since
the session or follow-up call.

Primary outcome measures. (1) Value-based outcome inference as measured using responding to
cues A minus C in the probe test. It is defined as the percentage of trials in which
behavioral responses indicate a prediction of any odorant (sweet or savory), independent of
whether this prediction is correct. Responding to cues B minus D will be used as a covariate
to control for differences in olfactory acuity and non-inference-based task performance.

Secondary outcome measures. (1) The percentage of trials in which the odor prediction is
correct. (2) Response latency per cue type. (3) Amplitude and (4) latency of respiratory
(sniff) responses per cue type. (5) Acquisition (% responding to B minus D in the last run of
conditioning) during the training portion of the inferencing task. (6) Drug use and
associated problems at follow-up.

- INCLUSION CRITERIA:

The enrollment target for the protocol is 120 (40 healthy controls, 40 patients on agonist
maintenance, and 40 participants who have met DSM 5 criteria for OUD, but are now abstinent
(for at least 3 weeks) and not on agonist maintenance.

All Participants

- Control Group

- Age between 21 and 50 years inclusive. Rationale: objective olfactory impairment
grows more prevalent with age; after age 53, the prevalence is 24.5%, increasing
to 62.5 % in people aged 80-97 years.

- Willing to fast for at least 6 hours prior to the study session and be exposed to
food odors.

- Abstinent OUD group

- Age between 21 and 50 years inclusive. Rationale: objective olfactory impairment
grows more prevalent with age; after age 53, the prevalence is 24.5%, increasing
to 62.5 % in people aged 80-97 years.

- Willing to fast for at least 6 hours prior to the study session and be exposed to
food odors.

- History of opioid-use disorder (DSM-5), to be assessed via the Mini International
Neuropsychiatric Interview (MINI). History of SUDs can include substances in
addition to opioids (e.g., cocaine).

- Abstinent > 3 weeks from all illicit substances (tobacco smoking and nondependent
drinking permissible), to be assessed via 90-day timeline follow-back calendar.
(Current abstinence will be confirmed via urine screen: see exclusion criteria.)
Rationale: Although heterogeneity will be considerable, what all enrollees will
have in common is having become abstinent from opioids long enough to be past
withdrawal symptoms. Their heterogeneity in duration of abstinence and other
drughistory measures will enable us to examine relationships between those things
and

inferencing performance.

- In-treatment OUD group

- Age between 21 and 50 years inclusive. Rationale: objective olfactory impairment grows
more prevalent with age; after age 53, the prevalence is 24.5%, increasing to 62.5 %
in people aged 80-97 years.

- Willing to fast for at least 6 hours prior to the study session and be exposed to food
odors.

- Current enrollment in treatment for OUD with buprenorphine or methadone. Current use
of illicit substances during treatment is permissible but not required. Rationale:
Again, heterogeneity will be considerable, but what all enrollees will have in common
is having sought treatment for their OUD and being currently maintained on an agonist
that permits adaptive everyday functioning. Their heterogeneity in ongoing use of
illicit substances will enable us to examine relationships between inferencing
performance and treatment response.

EXCLUSION CRITERIA:

- Control Group only

-- History of a substance-use disorder (except nicotine, for matching purposes), or
current use of any drug for nonmedical purposes

- Control Group and Abstinent Group

- Anosmia, dysosmia, or hyposmia (poor olfactory function), to be assessed via
Sniffin

Sticks threshold test <4; or presence of a known smell, taste or ear-nose-throat disorder,
to be assessed by history and physical.

-- History of degenerative processes of the CNS (Parkinson disease, Alzheimer disease);
other neurologic diseases (Huntington disease, multiple sclerosis, other

motor-neuron diseases); inflammatory conditions (sarcoidosis, Wegener granulomatosis); or
significant cerebrovascular disease including (but not limited to) epilepsy, stroke, or
meningitis. To be assessed by history and physical. Rationale: any of these could impair
task performance.

- History of traumatic brain injury (TBI) or major head trauma with sustained loss of
consciousness (>30 min). To be assessed by history and physical. Rationale: could
impair task performance.

- History of neurosurgery, ear/nose/throat (ENT) surgery (including laryngectomies,
tracheotomies), or cardiac surgery (including pacemaker or neurostimulator placement).
To be assessed by history and physical. Rationale: could impair task performance.

- Current use of medications that may impact olfaction including macrolides,
antimycotics, fluoroquinolones, ACE inhibitors, protein kinase inhibitors, proton pump
inhibitors, and intranasal zinc products. To be assessed by history and physical.
Rationale: could impair task performance.

- History of endocrine disorders, including hypothyroidism, hypoadrenalism, and diabetes
mellitus; significant medical illness including cardiovascular disease, cancer,
chronic obstructive pulmonary disease, asthma, renal insufficiency requiring dialysis,
etc. To be assessed by history and physical. Rationale: could impair task performance.

- History of DSM-5 major psychiatric disorder including uncontrolled major affective
disorder, obsessive-compulsive disorder, schizophrenia, and PTSD. To be assessed by
MINI interview. Rationale: could impair task performance.

- History of significant food or non-food allergy, including latex, detergents, soaps.
To be assessed by history and physical. Rationale: could make odorant exposure risky.

- Current sinusitis or allergic, acute, or toxic rhinitis or current nasal polyps or
tumors. To be assessed by history and physical. Rationale: could impair task
performance

- History of alcohol-use disorder. To be assessed by MINI interview, timeline
followback, and history and physical. Rationale: could impair task performance.

- Current use of medications that affect alertness (e.g. barbiturates, benzodiazepines,
cannabinoids, chloral hydrate, haloperidol, lithium, carbamazepine, phenytoin, etc.)To
be assessed by history and physical. Rationale: could impair task performance.

- For women: pregnancy. To be assessed by history and physical and by urine testing.
Rationale: Could affect task performance-physiological and hormonal changes during
pregnancy influence rhinological function.

- Any other medical illness or condition that in the judgment of the investigators is
incompatible with study participation.

- Cognitive impairment severe enough to preclude informed consent or valid self-report
(per History & Physical and Evaluation to Sign Consent).

- Urine positive for any illicit drug. Rationale: Controls should have no drug use;
abstinent OUD group should have no drug use in the last 3 weeks which would include
the several-day time frame to which urine screens are sensitive. In-treatment OUD
participants may test positive during screening because they may have ongoing use.
However, they will be asked to test negative on the day of their experimental session,
so that the three groups will be more comparable in terms of acute drug exposure.

- Current signs or symptoms of opioid withdrawal, to be assessed in the Abstinent group
via the Clinical Opioid Withdrawal Scale (COWS) and the Subjective Opioid Withdrawal
Scale (SOWS).

- Unwillingness to smell one of more of the task odors (pot roast; cooked onions; fried
potato; sauteed garlic; gingerbread; strawberry; cake; dulce de leche).

- In-treatment OUD group

- Anosmia, dysosmia, or hyposmia (poor olfactory function), to be assessed via Sniffin
Sticks threshold test <4; or presence of a known smell, taste or ear-nose-throat
disorder, to be assessed by history and physical.

- History of degenerative processes of the CNS (Parkinson disease, Alzheimer disease);
other neurologic diseases (Huntington disease, multiple sclerosis, other motor-neuron
diseases); inflammatory conditions (sarcoidosis, Wegener granulomatosis); or
significant cerebrovascular disease including (but not limited to) epilepsy, stroke,
or meningitis. To be assessed by history and physical. Rationale: any of these could
impair task performance.

- History of traumatic brain injury (TBI) or major head trauma with sustained loss of
consciousness (>30 min). To be assessed by history and physical. Rationale: could
impair task performance.

- History of neurosurgery, ear/nose/throat (ENT) surgery (including laryngectomies,
tracheotomies), or cardiac surgery (including pacemaker or neurostimulator placement).
To be assessed by history and physical. Rationale: could impair task performance.

- Current use of medications that may impact olfaction including macrolides,
antimycotics, fluoroquinolones, ACE inhibitors, protein kinase inhibitors, proton pump
inhibitors, and intranasal zinc products. To be assessed by history and physical.
Rationale: could impair task performance.

- History of endocrine disorders, including hypothyroidism, hypoadrenalism, and diabetes
mellitus; significant medical illness including cardiovascular disease, cancer,
chronic obstructive pulmonary disease, asthma, renal insufficiency requiring dialysis,
etc. To be assessed by history and physical. Rationale: could impair task performance.

- History of DSM-5 major psychiatric disorder including uncontrolled major affective
disorder, obsessive-compulsive disorder, schizophrenia, and PTSD. To be assessed by
MINI interview. Rationale: could impair task performance.

- History of significant food or non-food allergy, including latex, detergents, soaps.
To be assessed by history and physical. Rationale: could make odorant exposure risky.

- Current sinusitis or allergic, acute, or toxic rhinitis or current nasal polyps or
tumors. To be assessed by history and physical. Rationale: could impair task
performance.

- History of alcohol-use disorder. To be assessed by MINI interview, timeline
followback, and history and physical. Rationale: could impair task performance.

- Current use of medications that affect alertness (e.g. barbiturates, benzodiazepines,
cannabinoids, chloral hydrate, haloperidol, lithium, carbamazepine, phenytoin, etc.)
To be assessed by history and physical. Rationale: could impair task performance.

- For women: pregnancy. To be assessed by history and physical and by urine testing.
Rationale: Could affect task performance-physiological and hormonal changes during
pregnancy influence rhinological function.

- Any other medical illness or condition that in the judgment of the investigators is
incompatible with study participation.

- Cognitive impairment severe enough to preclude informed consent or valid self-report
(per History & Physical and Evaluation to Sign Consent).