Clinical trial NCT02932579
Conditions: Pain
Sponsor: University of Rochester
Start date: 2017-07-01; Completion date: 2021-01-13
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Opioid analgesics are the most common postoperative pain medications used among dentists in the United States.Although these medications are highly effective in the postoperative dental pain management, not all patients optimally benefit from this therapy. Many suffer adverse consequences such as nausea, emesis, and psychomotor impairment, and there is a high prevalence of opioid prescription misuse among substance abusers within the dental patient population.

The use of non-opioid analgesics including ibuprofen and acetaminophen in the management of postoperative dental pain has demonstrated equivalent or superior analgesic effects compared to opioid analgesic therapies, typically with significantly less adverse effects.However, despite these results, dentists have encountered a high variability in the success of non-opioid analgesic responses among the postoperative dental pain population.Thus, new strategies for earlier recognition of analgesic responses for pain medications is fundamental in the field of dentistry. Therefore, this study will evaluate the clinical utility of pharmacogenomic testing in acute postoperative dental pain management among healthy adults who undergo extraction of impacted mandibular third molar.

Detailed description:
To date, the use of pharmacogenomic methods in medicine has broadened our understanding of the important role of genes and different phenotypes/genotypes that make each individual unique in pain responses, including drug biotransformation, transportation, and drug-related side effects to name a few.Thus, recognizing the genetic profile of each individual prior to the prescription of pain medication for postoperative dental pain management will be essential to provide a more effective and safer pain therapy.Additionally, we suggest that 80% of the individuals in the general population exhibit a genetic profile that influence a normal pain response to non-opioid pain therapies. Hence we postulate that the integration of a pharmacogenomic testing to guide the prescription of ibuprofen and acetaminophen, not only, could lead to improved clinical postoperative dental pain outcomes, but also, significantly reduce opioid analgesics prescriptions by dentists.

Arms: arm 1: Individuals within this group will receive standard of care for postoperative dental pain secondary to extraction of impacted mandibular third molar(s) arm 2: Individuals within this group will receive pharmacogenomic testing guided prescription of pain medication for postoperative dental pain secondary to extraction of impacted mandibular third molar(s)
Interventions: intervention 1: Pharmacogenomic Testing intervention 2: Ibuprofen intervention 3: hydroxycontin/acetominophen intervention 4: acetominophen intervention 5: Oxycontin/acetominophen
Intervention descriptions: intervention 1: Saliva collection (5mL) intervention 2: 400 mg intervention 3: hydroxycontin 2.5 mg, acetominophen 325 mg intervention 4: 650 mg intervention 5: 5mg Oxycontin, 325 mg acetominophen. This will be a rescue medication is the other three pain medications do not work.

Protocol documents:
Prot_SAP_000.pdf: 
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Utility of Pharmacogenomic Testing and Postoperative Dental Pain Outcomes
Principal Investigator – Yanfang, Ren, D.D.S., MPH., PhD. Urgent Care/General Dentistry 
Department, Eastman Institute for Oral Health
Co-Principal Investigator/Monitor: Malmström, Hans, D.D.S. General Dentistry Department, 
Eastman Institute for Oral Health.
Sub- Investigator: Uribe Rivera, Armando, D.D.S. (OMS) General Dentistry Department, Eastman 
Institute for Oral Health
1.
PURPOSE OF THE STUDY AND BACKGROUND
1.1.
Background
Opioid analgesics are the most common postoperative pain medications used among dentists in the 
United States.1, 2 Although these medications are highly effective in the postoperative dental pain 
management, not all patients optimally benefit from this therapy.  Many suffer adverse consequences such 
as nausea, emesis, and psychomotor impairment, and there is a high prevalence of opioid prescription 
misuse among substance abusers within the dental patient population.3 Furthermore, the increase in annual 
opioid-related deaths continues to rise, impacting public health and leading clinicians and dentists to 
develop new strategies to reduce opioid prescription, while at the same time maintaining pain control 
outcomes. 4, 5 The use of non-opioid analgesics including ibuprofen and acetaminophen in the management 
of postoperative dental pain has demonstrated equivalent or superior analgesic effects compared to opioid 
analgesic therapies, typically with significantly less adverse effects. 6, 7 However, despite these results, 
dentists have encountered a high variability in the success of non-opioid analgesic responses among the 
postoperative dental pain population.  This has led many to continue use of opioid analgesics as first-
analgesic-line therapy in order to assure adequate analgesia and a positive postoperative recovery.8 As such, 
the combined formulation with hydrocodone and acetaminophen (i.e. Vicodin®) remains the analgesic most 
prescribed by dentists 
for 
controlling 
postoperative 
dental 
pain in the U.S.  9 
To date, the use of 
pharmacogenomic 
methods in medicine 
has 
broadened 
our 
understanding of the 
important role of genes 
and 
different 
phenotypes/genotypes 
that 
make 
each 
individual unique in 
pain 
responses, 
including 
drug 
biotransformation, 
transportation, 
and 
drug-related side effects 
to name a few.10, 11 For 
example, 
ibuprofen 
(IBU) is a racemic 


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mixture of two enantiomers, the pharmacologically active S-IBU and the virtually inactive form, R-IBU.  
However, an estimated 50-65% of R-IBU undergoes inversion to the active S-enantiomer.15 Inversion of 
R-IBU to S-IBU occurs via an acyl-CoA thio-ester by the enzyme Alpha-methylacyl-coenzyme A racemase 
(AMACR) (Figure 1; dashed arrow). 16  This can occur pre-systemically in the gut 15 as well as in the liver. 
17, 18 The primary metabolism (deactivation/facilitated excretion in this case) of racemic ibuprofen is an 
oxidative process and involves primarily membrane-associated cytochrome P450 (CYP) enzymes CYP2C9 
(S-IBU and R-IBU) and CYP2C8 (R-IBU) (Figure 1).12,13,14  The major primary metabolites found in the 
urine including one carboxy-IBU and three hydroxyl metabolites; 2-OH IBU; 3-OH IBU and 1-OH IBU (a 
minor product). These metabolites do not have apparent pharmacological activity in the system. 15 
Secondary metabolism of IBU also occurs by glucuronidation via the UGTs pathway 19 (not shown in figure 
1).  Previous studies have shown that individuals with variant alleles producing inactive forms of these CYP 
have very low clearance rates compared with non-carriers of mutations (Garcia et al., 2004).  While this 
may help prolong the analgesic effect of IBU, it also has been shown to result in increased risk for 
gastrointestinal bleeding and other adverse effects (Blanco et al., 2008; Pilotto et al., 2007; Carbonell et al., 
2010).  The frequency of distribution among the population for CYP2C9 (the major gene-pathway studied 
in this clinical trial) phenotype/genotypes is 80% Extensive Metabolizers [(EM) normal medication 
response], 12% Intermediate Metabolizers [(IM) abnormal medication response] and 8% PM Poor 
Metabolizers 
[(PM) 
abnormal 
medication 
response](Figure 
1; 
green 
color). 
 
Given 
the 
equivalence/superiority of IBU over standard opioid therapies, we posit that individuals with normal CYP 
2C9 (no genomic variation; approximately 80% of the population) will respond favorably to the 
administration of IBU for management of postoperative dental pain, while those with abnormality of 
CYP2C9 (approximately 20% of the population) will be more appropriately treated using alternative agents 
(i.e. opioids; acetaminophen).  
The second cytochrome P450 of relevance to this proposal is CYP2D6, which is an enzyme critical for 
the metabolism of numerous opioids.  Unlike inactivation/elimination functions described above for 
CYP2C9, the efficacy of certain opioid compounds (such as hydrocodone) is dependent upon successful 
metabolic conversion by CYP2D6 from the inactive pro-drug form to an active metabolite.  The frequency 
of distribution among the population for CYP2D6 phenotype/genotypes is (Figure 1; blue color): 70% 
[Extensive Metabolizers (EM); normal medication response], 20% [Intermediate Metabolizers (IM); 
abnormal medication response], 8% [Poor Metabolizers (PM); abnormal medication response] and 2% 
Ultrarapid Metabolizers [(UM) abnormal medication response].  Studies have demonstrated that ultrarapid 
CYP2D6 metabolizers experience increased analgesic effects from oxycodone (due to rapid conversion 
prodrug to an active form), but have increased side effects such as nausea and vomiting (Samer et al., 2010).  
Conversely, poor metabolizers experienced a significant reduction in analgesic efficacy due to the slow 
conversion to the active drug.  We posit that individuals with abnormal CYP2C9 function (ibuprofen 
inappropriate), but normal CYP2D6 function (normal response to opioid prodrugs), will benefit from the 
administration of hydrocodone for the management of postoperative dental pain.   
We further posit that individuals with both abnormal CYP2C9 and CYP2D6 function, will benefit from 
the administration of acetaminophen for the management of postoperative dental pain.  Acetaminophen is 
biotransformed by CYP2E pathway (not shown in Figure 1), and its use does not overlap with any of the 
other drugs’ metabolic enzyme pathways.  Determination of CYP2E status is currently unavailable, so 
assignment to this medication is by default.
Summarizing the discussion above, we suggest that we can minimize the prescription of opioid 
analgesics by at least 80% in the acute postoperative dental pain population. Therefore, we postulate that 
the integration of a pharmacogenomic testing to guide the prescription of ibuprofen and acetaminophen 
could lead to improved clinical postoperative dental pain outcomes and significantly reduce prescribing of 
opioid analgesics by dentists. 


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This hypothesis will be addressed with the following Specific Aims:
Specific aim 1: To compare the pain control outcomes between a single-dose of pharmacogenomics- 
testing-driven-prescription of ibuprofen (400mg) or acetaminophen (650mg) with those of single-
dose (standard of care) of combined formulation of hydrocodone and acetaminophen (Norco®; 
5/650mg).
Specific aim 2:  To determine the number of patients who did not require prescribed opioid 
analgesic ‘rescue’ after pharmacogenomic-guided acute postoperative dental pain management 
versus those taking the non-guided combined formulation of hydrocodone and acetaminophen.  
We will achieve these aims through a double-blind-randomized clinical trial of healthy adults, who have 
undergone extraction of at least three impacted mandibular third molars (wisdom teeth). Subjects will be 
randomly assigned to one of two groups: 1) Experimental – will receive a single dose of pharmacogenomics 
testing-driven-prescription of ibuprofen (400mg) (for those, whose genetic testing suggests they will 
respond normally to ibuprofen); or acetaminophen (650mg) (for those, whose genetic testing suggests they 
will respond abnormally to ibuprofen);  and 2) Control - will receive a single dose of standard of care 
medication for pain associated with the  extraction of impacted third molars, Norco® 
(hydrocodone/acetaminophen; 5/650mg). All subjects will receive preoperative pharmacogenomics testing 
through saliva sample collection (for phenotype recognition and  genotype analysis) by pharmacogenomics 
test kit (PGxOne®;Admera HealthTM; N.J). We will focus on assessment of the short-term pain outcome 
using a single dose of medication that potentially impacts the long-term use and prescription of opioids in 
the management of postoperative dental pain following the extraction of impacted third molars.
1.2     Purpose. 
To determine whether 
pharmacogenomic testing can 
help dental practitioners select 
appropriate non-opioid pain 
medications including ibuprofen 
and acetaminophen in the 
management of postoperative 
dental pain and whether data from 
this testing has an effect on both 
increased pain outcomes and 
reducing opioid prescription 
pattern by dentists.
2.
STUDY DESIGN 
2.1.
Overview (figure 2)
A randomized and double-blind 
clinical trial will be fashioned to 
determine the clinical utility of 
pharmacogenomics 
testing 
to 
guide the prescription of non-
opioid analgesics including; 1) 
ibuprofen (400mg). We will use 
postoperative dental pain related 


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to impacted third molar extraction, as study model. Both screening for eligibility and informed consent will 
occur at the preoperative appointment. All study participants will receive a preoperative pharmacogenomic 
testing through saliva collection (>5mL). Following impacted third molar surgical removal, those who meet 
final eligibility criteria will be assigned (by computer-generator-randomization) to 1 of 2 treatment groups 
include experimental (A) and control (B) groups. Pain medications and pharmacogenomic results will be 
blinded for both the investigators and participants (see section 7.4). Pain medication tablets will be provided 
into blister cards, envelops or containers to a non-blinded research collaborator by the investigational drug 
department at URMC. Of note, the the investigational drug department will identify the subject’s genetic 
profile related to the response to pain medication based on the results sent by genetics laboratory. . 
Individuals in the experimental group will receive the pharmacogenomics test driven-prescription of 
ibuprofen (400mg; 2 tablets of 200mg), or acetaminophen (650mg; 2 tablets of 325mg), based on (genetic 
profile) phenotypic (normal or abnormal metabolic enzyme rate biotransformation) results delivered by the 
pharmacogenomic testing. Subjects in the control group (B) will receive the standard of care for extraction 
of impacted third molar postoperative pain with hydrocodone/acetaminophen (Norco®5/650mg; 2 tablets 
of 2.5/325mg). All medications in this clinical trial will be administered as a single dose PO Final evaluation 
of eligibility will be based on achieving a minimum level of postoperative pain of at least 50mm out of a 
possible 100mm by the visual analog-Dental Pain Intensity Scale (DPIS) within 6 hours after surgery. If 
applicable, patients who fall asleep post-intervention during the final determination of eligibility, will be 
awakened as necessary to complete the DPIS.
All study data including pharmacogenomic test results, study times, pain control measurements, type of 
pain medication used among others will be recorded on the case report forms (CRFs).. 
2.2.
Rationale for Study Design
This study design follows the standard for clinical pain trials. The use of pharmacogenomics testing in this 
study is intended to effectively guide the prescription of ibuprofen and acetaminophen, reducing the need 
for opioid analgesics in the management of impacted third molar postoperative pain.
2.3.
Rationale for Dosage
Pain management therapies using ibuprofen, acetaminophen and narcotics in this study follow current 
standard-of-care recommendations and guidelines for postoperative dental pain (Hersh et al., 2011).   These 
drug/dose recommendations, based on severity of pain, are illustrated in Figure 3, and include updated 
recommendations for the use of acetaminophen for moderate pain (Qi et al., 2012). 


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CHARACTERISTICS OF THE RESEARCH POPULATION
2.4.
Subject Characteristics
a)
Number of Subjects:
 A total sample size of 238 individuals will be enrolled. 119 subjects will be assigned in each of the 
treatment groups. 
b)
Gender and Age of Subjects:  Equitable inclusion of both men and women will be undertaken in 
this study. The participation of healthy adult subjects will be encouraged in this study. Those 
individuals aged 18 to 35 years will be invited to participate in this clinical trial.  
c)
Racial and Ethnic Origin:  Ethnic distribution will be equitable in this research study. 
Furthermore, this study does not have any enrollment restriction based upon race or ethnic origin. 
d)
Vulnerable Subjects:  Not applicable for this study.
2.5.
Inclusion and Exclusion Criteria 
a)
Inclusion Criteria:
1)
ASA I or II


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2)
Age 18-35 years
3)
Patients scheduled to undergo surgical removal of 1 or more impacted third molars, at least 1 of 
which must be a bony mandibular impaction. 
4)
Patients who are able to read, comprehend, and sign the consent form, and willing to stay in the 
study unit for up to 12 hours.
5)
Patients who are reliable, cooperative, and of adequate intelligence to record the requested 
information on the questionnaire form(s). 
6)
Women of childbearing potential who are not pregnant, as assessed by a urine pregnancy quick 
test on the day of the procedure, prior to surgery. Women must be using a method of birth 
control deemed acceptable by the investigator and continue to use this method during the 
duration of dosing with study medication
7)
Patient who develop sufficient levels of pain (rated at 50mm or more out of a 100 mm) on the 
DPIS within 6 hours post-surgical extraction.
8)
Patients who agree not to take analgesics other than protocol-defined rescue analgesics during the 
post-operative treatment period of 6 hours.
9)
Patients who agree to refrain from alcohol and sedative consumption during the post-operative 
period of 6 hours.  
b)
Exclusion Criteria: 
Subjects with: 
1)Known opioids and NSAIDs allergies (or induced asthmatic attacks) 
2)Known history of opioid abuse 
3)Recent history of gastrointestinal ulceration
4)History of aspirin intolerance/cross-sensitivity
5)Recent myocardial disease 
6)Uncontrolled hypertension
7)Patients receiving anticoagulation therapy
8)Uncontrolled diabetes
9) Pregnant women
10)Immunosuppression
11)Recent history of opioid or NSAID therapies
12)Subjects who do not achieve a qualifying baseline pain threshold of 50mm out of 100mm on the visual 
analog DIPS within 6 hours of completion of surgery
2.6.
Discussion of Subject Population
The above inclusion/exclusion criterion for this study is selected based on minimizing the risks and 
enhancing subject’s safety. This study is designed to determine the clinical use of a pharmacogenomics test 
to guide the prescription of non-opioid analgesics in the management of impacted third molar postoperative 
pain. Those subjects with the above medical conditions within the exclusion criteria may be compromised 
by the use of any of the pain medications, thus they are excluded for safety issues.


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3.
SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
3.1.
Method of Subject Identification And Recruitment
Recruitment process.
Patients will be approached by a research assistant (see also section 7.3) at the time of their preoperative 
evaluation and will be invited to enroll in the study. Those who are interested in participating in our 
research, after informed consent, will be screened to determine eligibility prior to enrollment based on 
inclusion/exclusion criteria. Patients scheduled to undergo surgical removal of 1 or more impacted third 
molars, at least 1 of which must be a bony mandibular impaction.
Final screening determination.
Final screening evaluation will be completed following surgery (baseline), those patients who achieve a 
minimum level at least 50mm out of a possible 100mm of postoperative pain utilizing the visual analog-
Dental Pain Intensity Scale (DPIS) will be enrolled. DPIS is a standard of practice dental pain assessment 
used in clinical trials in dentistry. This measurement is based on a scale of 0-100mm.  Patients who fall 
asleep while in the clinic during final determination of the eligibility stage will be awakened by study 
personnel as necessary (i.e. hourly) to administer the DPIS.
Subject’s Privacy statement 
The identification of subjects will be protected. The investigators and research personnel will make every 
effort to protect the subject’s privacy in addition to avoiding undue influence.  Only investigators with 
routine access to prospective subjects (or subject records) will approach and recruit those individuals 
directly (“routine access” meaning the investigator already has a clinical/academic reason to know/review 
a patient’s record or is known to the prospective subject). Investigators who will not have routine access to 
prospective subjects will not contact subjects directly (i.e., no “cold calls”); they will work through the 
individual(s) with routine access. Subject’s Private information including medical records in this study will 
not be made public.
3.2.
Process of Consent
Written informed consent, in accordance with local clinical investigation regulations at the University of 
Rochester will be obtained prior to participation in the study. The study investigator or research coordinator 
will provide a description of study protocol (including any potential and possible hazards) and procedures. 
Information will be given in oral and written form. The patient information provided will be in a language 
understandable to the patient, and will not include any language that appears to waive any of the patient’s 
legal rights, or appears to release the Investigator or Institution from liability or negligence. In addition, the 
consent form includes HIPPA language, which explains to the patient how personal information will be 
managed and protected. Investigators will inform all subjects taking part of this study that potential 
treatments for postoperative dental pain management include; 1) Tylenol, Ibuprofen or a narcotic such as 
hydrocodone/acetaminophen or oxycodone/acetaminophen (rescue medication).
The investigator will provide the prospective patient sufficient time to consider whether or not to 
participate, minimizing the possibility of coercion or undue influence, and will discuss any questions the 
patients may have. The Investigator will explain to the patient that withdrawal from the study is possible at 
any time without detriment to care. The Investigator will then ask the patient to give consent in writing.
The consent will include acknowledgement that medical records and medical data derived from study may 
be forwarded to the responsible authorities or federal authorities.  


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4.
METHODS AND STUDY PROCEDURES 
Standard of care procedures.  
Impacted third molar surgical removal. 
Patients will report to the clinic on the morning of their surgery and will have fasted after midnight, except 
for clear liquids up to 2 hours prior to surgery. At the surgeon’s discretion, oral fluids prior to surgery will 
be allowed. The third molar surgical removal will be performed under standard of care protocols. Once 
local anesthesia is achieved, impacted third molar removal will be undertaken through full-thickness 
mucoperiosteal elevation flap, surgical bone removal [to uncover dental structure (if applicable)] with or 
without dental section (at surgeon’s discretion). Simple stiches or continuous stiches with resorbable suture 
materials will be utilized to close surgical incisions. Patient’s vital signs will be monitored all the time 
during surgery. 
Ice Pack use for postoperative pain management adjuvant treatment.
 The use of ice packs to the affected surgical site of the face and jaw will be permitted in this study. However 
the use of ice packs will be allowed 2 hours after dosing with pain medication. (See details in section 5). 
Research  procedures
DNA  collection 
DNA from all subjects who participate in the clinical trial will be collected by saliva samples. Saliva 
specimens will be stored into de-identified Eppendorf tubes and will be sent to Admera Health laboratories 
(S. Plainfield, N.J.), under standardized protocols to handle DNA sampling, for DNA sequencing. The 
analysis of these samples will provide the phenotype and genotype data (CYP2C9; CYP2D6) to categorize 
patients accordingly to normal or abnormal genetic profile related to the response of pain medications 
involving hydrocodone and ibuprofen. Laboratory analysis will include PCR with amplified methods in 
addition to next generation DNA sequencing technology.
Baseline 
For the purpose of this study baseline is defined as the time following the procedure when the subjects are 
asked to rest quietly in the dental chair before pain medication is administered. At baseline the patients will 
not be allowed to wear a watch and the room will not have a clock. Patients will be supplied with 2 
stopwatches that will have the time display covered when in use. The patients will complete the Baseline 
pain threshold (at least 50mm out of possible 100mm-VAS). Those subjects who do not achieve a qualifying 
baseline pain threshold at 6 hours of completion of surgery will not continue in the study.  
 
Extended postoperative stay at clinic facilities
Subjects who meet inclusion criteria will be informed by written consent and by word (from Investigator 
or research coordinator) that he/she will stay for up to 12 hours after intervention. We will measure pain 
after local anesthesia effect wears off the individual in around 4-6h after procedure. We will start the pain 
therapy described in figure 2 and the patient will stay at the dental clinic until a meaningful pain relief is 
achieved. This may take from 2-6 hours after administration of pain medication, depending on each 
individual. During this time we will monitor the subject’s vital signs and pain symptoms.  During the stay 
in the dental clinic for pain assessment, subjects will be provided with dietary supplements appropriate for 
the immediate postoperative stage that include, cold foods (water, clear fruit juices, ice-cream, , etc.) 
Pharmacogenomics test. (PGxOne®, Admera Health, N.J.  U.S.A)


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The pharmacogenomics test includes a kit with two laboratory tubes or containers. 1 special laboratory tube 
is used for saliva collection and the second laboratory tube contain the buffer solution to stabilize the cells 
and DNA from the body fluid.  (PGxone™ [Admera Health, N.J, U.S.A])Results will be delivered 7-10days 
after sending the saliva samples to the genetic laboratory at Admera Health. Pharmacogenomic results will 
be sent directly to the research coordinator or a non-blinded research personnel in order to be sent to the 
investigational drug department at URMC.. Pharmacogenomic results will include a pharmacogenomic  
algorithm with color codes of genetic profiles and medication recommendation. Recommendations are 
broken down into 5 categories including: 1) consider alternative; 2) proceed with caution; 3) normal 
response expected; 4) increase dose and 5) decrease dose. For purposes of this clinical trial we will ignore 
the last two options. Additionally, these results will include other relevant information including: a) 
subject’s 
phenotype 
(metabolic 
enzyme rate); b) genotype (allele 
function 
including 
decreased, 
increased, deletion, among others) 
and c) a clinical description of 
phenotype and genotype.
4.1.
Treatment Dosage and 
Administration
 
Eligible patients will be randomized 
into 1 of the following 2 treatment 
groups: 
•
Group A: Experimental group. 
Based on immediate phenotypic 
results 
these 
subjects 
will 
receive 
pharmacogenomics 
guided 
prescription 
of 
ibuprofen 
(400mg) 
or 
acetaminophen (650mg) single 
dose for impacted third molar 
postoperative 
pain 
management. (figure 3)
•
Group B. 
This group will receive the 
standard of care for impacted 
third molar postoperative pain 
with 
hydrocodone/acetaminophen 
(Norco®5mg/650mg) single dose.
Rescue medication. (figure 3) Oxycodone/acetaminophen (Percocet® 5mg/325mg) single dose will be 
administered if the first-line-analgesic prescription does not provide adequate analgesia. It is important 
to note that acetaminophen doses will be in the range of 650-975mg (i.e. below the recommended 
maximum of a 1000mg ‘single’ dose) if rescue medication is used on those subjects who will receive 
either acetaminophen (650mg) or Norco® (hydrocodone/acetaminophen; 5/650mg). The use of 
Percocet as rescue medication will assure that patients are not in risk of suffering postoperative pain 
(please see guidelines in figure 3. 


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4.2.
Efficacy Assessments
Primary outcome. Comparison between pain control outcomes over the 6-hour period following receipt of 
pharmacogenomic testing guided prescription of non-opioid medication and those of standard of care with 
opioid analgesics.
Primary endpoint: Subject’s success in pain relief over the 6-hour period post-intervention.
Secondary outcome. Examine the occurrence of meaningful change of drug regimen  
Secondary endpoints. 1) Subject’s metabolic enzyme rate (phenotype) known to affect a non-opioid 
medication identified by pharmacogenomic testing; 2) subject’s success in responding to pain relief without 
drug substitution or discontinuation over a 6-hour period post-dosing.
4.3.
Safety Assessments
Number of drug related adverse events over the 6-hour post-dosification period for pain control.
Adverse events (AEs) (if present)
AEs will be tabulated by treatment group, body system, and preferred term, AEs will be tabulated and 
analyzed by Fisher’s Exact test to determine if the is an overall treatment effect. AEs will be summarized 
separately for all drug-related AEs, severity, and severe adverse events.
Definition of drug-related AEs in this study is an AE that follows a reasonable temporal sequence from 
administration of the used drug ; follows a known response pattern to the specific drug ; and, when 
appropriate to the protocol, is confirmed by improvement after stopping the used drug (positive 
dechallenge) and by reappearance  of the reaction after repeat exposure (positive rechallenge); and cannot 
be reasonably explained by known characteristics of the patient’s clinical state or by other  therapies. 
Severity of AE is defined in this study as the intensity of an AE, which is measured as follows: 1) mild; 
does not interfere with routine activities, 2) moderate; interferes with routine activities, 3) severe; patient is 
unable to perform routine activities. 
For the purpose of this study AEs are defined as any sign, symptom, syndrome, or illness that occurs or 
worsens during the use of any analgesic or narcotic regardless of causality. A medical condition that is 
present when the patient enters the study is not defined as an AE unless this medical condition worsens 
after patient received the medication during the study. All AEs occurring during the 6 hours after dosing 
with medications used in this study will be recorded on the CRFs . All AEs must be followed by the 
Investigator(s) until resolved or until a stable status is achieved. AEs that occur after the patient is 
discharged from the study will not be recorded, unless they are determined to be serious adverse events 
(SAEs). SAEs will be recorded for 6 hours post dosing. SAEs include: 1) death, 2) a life threatening AE, 
3) inpatient hospitalization or prolongation of existing hospitalization, and 4) a persistent 
disability/incapacity. In addition, relevant medical events that may not result in death, be life threatening, 
or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the outcomes 
listed in this definition. 
In the event of a SAEs or death associated with the study that relates to the rights, safety, or welfare of the 
research participant the Investigator(s) must contact the RSRB immediately by telephone/telefax and follow 
up with a written description of the circumstances surrounding the event within 24 hours. Any SAEs 
occurring in a patient receiving any medication in the study or during the 6 hours following discontinuation 
of the medication must be reported to the Monitor and RSRB within 24 hours. Initial SAEs reports may be 
made by telephone, the originals copy of the completed SAEs Report Form (provided in the patients CRFs) 
must be sent to the RSRB by telefax.
 All additional follow-up evaluations must be reported to the Monitor and RSRB. Such data should be sent 
to the RSRB by telefax within 10 working days after occurrence of the SAE or as soon as available. If 


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required, the Investigator will file the Safety Report with the appropriate regulatory authorities.   
4.4.
Assessment of Subject Compliance
The investigators or study coordinator will instruct all study patients in completion of these scales prior to 
surgery or following surgery but prior to dosing. All efficacy scores will be marked on the source document 
by study subjects and under the supervision of study personnel. The study coordinator or designee will only 
transcribe the patient’s Baseline and Post-baseline period scores onto the CRFs.
4.5.
Data & Specimen Banking for Future Research Use
Data and specimens will be banked for future research use for the purpose of future analysis in other genes 
related to variability of analgesic responses associated with acute surgical pain. These specimens will be 
stored in de-identified Eppendorf tubes at Admera Health laboratories under standard of care protocols to 
store DNA samples. Only study personnel related to this clinical trial will have access to these 
data/specimens. The time to keep this data is not estimated because new genes related to acute surgical pain 
in the human genome are still pending to be identified. 
4.6.
Genetic/Genomic Research Activities
Genotyping Procedures. 
CYP2D6 and CYP2C9 will be genotyped using the Luminex xTAG system. Relevant regions will be 
amplified using PCR (polymerase chain reaction) and clarified using Exonuclease I and Shrimp Alkaline 
Phosphatase. Individual mutations will be identified using allele-specific primer extension primers tagged 
for hybridization to Luminex xTAG beads. The following CYP2D6 and CYP2C9 alleles will be identified: 
*1,*2, *2A, *3, *4, *5, *6, *7, *8, *9, *10, *11, *12, *14, *15, *17, *41 and duplication. 
      Single nucleotide polymorphisms identification and frequency.
      This test is performed by next generation DNA sequencing. It is a primary measure of gene-drug 
interaction and genomic status. This test has shown increase clarity of the implications of genotyping for 
both clinicians and patients.   
Target genotypes identification and frequency
This next generation of DNA sequencing test evaluates relevant regions to identified individual mutations 
in the three different cytochrome P40 alleles, studied in this proposal including allele 1, allele 2, and allele 
3. 
4.7.
Costs to the Subject
The subject or the subject’s insurance will be billed as a result of standard of care procedures associated 
with impacted third molar surgical removal. No additional costs will be incurred in regards to the 
pharmacogenomic or genomic test for the research participants. This pharmacogenomic test and analysis 
are covered by departmental funds at general dentistry and by Admera Health laboratory’s research funds. 
4.8.
Payment for Participation
Subjects will receive one payment of fifty dollars ($50.00,) after completion of the study, in the form of a 
check.
4.9.
Return of Individual Research Results
Genetic results will not be provided to the subjects at any time. However, incidental findings to adverse 
events will be managed according to the protocol guidance. 


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5.
CONCOMITANT AND DISALLOWED MEDICATIONS
Antibiotics. 
Prophylactic administration of penicillin V potassium (500mgs PO bid during 10 days) or clindamycin 
(300mg q6h PO during 10 days ) antibiotics will be allowed in subjects undergoing surgery at the surgeon’s 
discretion.
Antiemetics. 
In the event that the investigator estimates postoperative nausea and vomiting require management with an 
antiemetic, the non-phenothiazine compound Tigan® (trimethobenzamide hydrochloride) will be permitted 
(250mg PO 3 times daily). Emesis will be recorded as an AE.
 Ice Packs. 
Ice packs to the affected area of the face and jaw will be allowed 2 hours after dosing with medication(s), 
however, will not be used prior to that time. Ice packs will be removed at least 15 minutes prior to any 
scheduled pain assessments. The use of ice will be recorded in the individual’s source record and transcribed 
onto case report form by the study coordinator of any other designee. 
Anesthetics. 
Surgery will be performed under local anesthesia block(s) (for instance, 2% lidocaine, etc.). Light sedation 
under Nitrous Oxide may be used as required according to standard of care clinical practice. Precluded 
agents are all other sedatives or hypnotic agents, and all other local anesthetics. 
Rescue medication. 
Individuals in all groups will be administered Percocet® (oxycodone/acetaminophen, 5/325 mg single dose) 
as rescue medication. Rescue medication will be prohibited within the first hour after dosing with first line 
analgesic therapy. 
6.
SUBJECT WITHDRAWALS
Subjects will be advised in the written informed consent forms and verbally that they have the right to 
withdraw from the study at any time without prejudice. Subjects could be withdrawn by the investigator, in 
circumstances including non-compliance, termination of funding, worsening of the disease under study, 
inter-current illness, pregnancy, lost follow up, etc..  No additional study activities will be completed after 
subject withdrawal from the study.  Subjects withdrawn from the study will not be replaced.
7.
STUDY DRUG/DEVICE/BIOLOGIC ADMINISTRATION/ASSIGNMENT
7.1.
Study Drug/Device/Biologic
Admera Health has developed an innovative pharmacogenomics test that addresses major healthcare issues 
resulting from individual genetic variability and subject’s medication responses. PGxOne™, Admera 
Health’s pharmacogenomic test, analyzes 13 well-established genes involved in drug absorption, 
metabolism, and activity. The test utilizes next generation sequencing technology and provides information 
for individual patient responses to 76 FDA approved drugs.10* All drugs covered by PGxOne™ have been 
endorsed by the FDA (Food and Drug Administration), EMA (European Marketing Authority), and/or the 
CPIC (Clinical Pharmacogenetics Implementation Consortium), an organization that provides clinical 
guidelines and recommendations on pharmacogenomics. See product white paper for additional 
information on the pharmacogenomic test/algorithm utilized in this study.
7.2.
Dosage of Study Drug/Biologic
Not applicable for this study


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7.3.
Subject Enrollment/Randomization
Enrollment. 
Subjects will be recruited by collaborating with our large referral base at Eastman Institute for Oral Health, 
University of Rochester, N.Y. Both the General Dentistry and Dental Urgent Care departments have more 
than 300 local patients with diagnosis of partial or full bone third molar impaction. Healthy men and non-
pregnant women 18 to 35 years of age, scheduled to undergo surgical removal of 1 or more impacted third 
molars, at least 1 of which must be a bony mandibular impaction, who have received only specified 
preoperative medications/anesthetics, who develop sufficient levels of pain (50 of 100mm on dental pain 
100mm-visual analog scale) up to 6 hours after surgical removal, and who sign an informed consent form, 
will be enrolled in the study.
Randomization. 
Following impacted third molar surgical removal, each individual will be assigned a unique, number in 
chronological order of admission into the study. Subject numbers are determined by a computer-generator-
randomization-list generated by the research coordinator and correspond to the drug label number. A block-
wise randomization will be used. See table below. The sequential number will be verified by a blinded 
person at Eastman Dental Center and from entries in the screening logs. 
Treatment 
group
Participant 
Code
Treatment Description
A
participant 
initials and #1
Pharmacogenomic test guided pain medication prescription 
B
participant 
initials and #2
Standard of care medication
A
participant 
initials and #3
Pharmacogenomic test guided pain medication prescription
A
participant 
initials and #4
Pharmacogenomic test guided pain medication prescription
B
participant 
initials and # 5
Standard of care medication
A
participant 
initials and #6
Pharmacogenomic test guided pain medication prescription
B
participant 
initials and #7
Standard of care medication
This table is an example of the block-wise randomization method will be utilized in this study. Participant codes are fictitious. 
7.4.
Accountability of Investigational Supplies
  
Masking (over-encapsulation methodology)
Not applicable for this study due to the variable in size and other dimensions of the tablets for the drugs 
used in the study
7.4.1 Blinding Methodology for Subjects


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Unblinded 
investigators 
will administer the study 
medication to subjects who 
are blinded by way of 
wearing a mask over their 
eyes. 
Research pharmacy and 
dental clinic procedures
The study investigators or 
sub-investigator 
will 
schedule 
intervention 
day/time. At that time, the investigator(s) will be responsible to send two medication prescriptions 
including both opioid formulation (hydrocodone/APAP) and (oxycodone/APAP) into the inestigational 
drug department at URMC to secure medication dispensing and stock. For over-the-counter 
medications a prescription is not needed. Pharmacogenomic testing will be carried out at the 
preoperative appointment. However, the results will be blinded to investigators.. The investigational 
drug department personnel assigned to this study will review pharmacogenomic testing results and 
choose study group and type of medication to be administered, according to randomization scheduled 
list. (Figure 4, below). On the day of surgery, the non-blinded research staff will pick up two different 
blister cards or medication containers (if applicable) that include; the first-line-analgesic medication 
and the rescue medication, from the investigational drug department. The medications will be packaged 
into envelopes or blister cards with appropriate information (if applicable) and study codes. Once the 
intervention is completed, and after the local anesthesia effect wears off, the subjects will be given their 
first dose of pain medication, by the non-blinded research staff. Subjects will remain in the dental chair 
and will be asked to complete two additional pain questionnaires (Pain Severity Rating and a Dental 
Pain Relief Rating). These questionnaires are to be completed at 15minutes (baseline), 30 minutes, 1 
hour, 1.5 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours post-administration of pain medication. 
Subjects’ vital signs will be monitored all the time during dental clinic stay, there is the possibility that 
subjects will feel drowsy or sleepy (medication effect). Investigators will measure vital signs and awake 
the patient to accurately assess pain. In addition, 3-4 minutes after taking the study drug the subjects 
will be given two stopwatches and asked to stop one when they feel the first sign of pain relief. They 
will also be asked to stop the 2nd stopwatch when they feel meaningful (feels much better) pain relief. 
At the end of the 6-hour-period, they will be asked to provide an overall evaluation of the study 
medication. They will then be dismissed from the study.    
Subject Withdrawal of Study Drug
Subjects may stop the treatment in this study. However, they will not continue to be followed in this 
clinical trial. 
7.5.
Emergency Drug Disclosure
Identity of products used for this study
Because pain medication tablets will be packaged in blister cards (envelopes) consisting of 2 tablets (as 
appropriately indicated by Investigators) dosage units. The contents will be labeled with the, study 
code, protocol number, Principal Investigator number (if applicable), and directions for use. The 
information on these clinical supplies will be received and maintained by the research coordinator. 
Disclosure of the subject’s medication information will be accessed only in the case that first –line-
therapy is not effective or in a medical emergency. See section 4.3, adverse events, for appropriate 


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actions taken by the investigator in medical emergencies. In the case of a medical emergency the 
subjects will be withdrawn from the drug only. 
8.
SAFETY AND REPORTABLE EVENTS
8.1.
Adverse Event Definition
An adverse event is any symptom, sign, illness, or experience which develops or worsens during the 
course of the study, whether or not the event is considered related to study drug. See section 4.3 for 
further definitions.
8.2.
Serious Adverse Event
A serious adverse event is defined as any adverse medical experience that results in any of the following 
outcomes:
•
death;
•
is life-threatening;
•
requires inpatient hospitalization or prolongation of existing hospitalization;
•
results in persistent or significant disability/incapacity;
•
is a congenital anomaly/birth defect; or
•
requires medical or surgical intervention to prevent permanent impairment or damage.
8.3.
Recording Adverse Events
At each subject visit the site study staff will assess adverse events by recording all voluntary complaints 
of the subject and by assessment of clinical and laboratory features.  At each study visit, the subject 
should be questioned directly regarding the occurrence of any adverse experience since his/her last 
visit.  
All adverse events, whether observed by the Investigator, elicited from or volunteered by the subject, 
should be documented.  Each adverse event will include a brief description of the experience, the date 
of onset, the date of resolution, the duration and type of experience, the severity, the relationship to 
investigational product (i.e., drug or device), contributing factors, and any action taken with respect to 
the study drug/device.
Timeframe for recording AEs will occur 6 hours after dosing. Follow up of adverse experiences will 
be done until the event is resolved or stabilized including those that are ongoing/unresolved at the time 
of subject concluding study participation.
8.4.
Responsibilities for Reporting Serious Adverse Events
The Investigator/coordinator will make every effort to record all serious adverse experiences that occur 
during the study period in the appropriate source documents and/or AE log as applicable.  The study 
period for reporting serious adverse events will be indicated. AEs forms will be completed. The 
Investigator/ coordinator will comply with regulations and RSRB policy regarding the reporting of 
adverse events.  
9.
RISK/BENEFIT ASSESSMENT
9.1.
Potential Risks
1) The subject may/will experience additional discomfort by delaying pain medication until the DPIS 
reaches 50mm out of 100mm; 2) The proposed algorithm method may result in less than optimal pain 
control; 3) there is a risk for inadequate pain control and 4) there is a risk for loss of 


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privacy/confidentiality.
9.2.
Protection Against Risks
All subjects will be monitored for adverse events associated with the administration of opioids and 
saliva collection for genotyping. Subjects and legal representative(s) will be informed prior to each 
research intervention (saliva collection for genotyping and clinical data collection) during the study 
period. This may decrease the anxiety related to any inconvenience the subject may experience from 
these procedures in those subjects cognitively able to comprehend the provided information. Subjects 
will also be monitored for analgesia efficacy.  
All saliva samples will be collected using standard of care procedures to minimize the risk of infection. 
Appropriate medical supervision will be available on a 24-hour basis to ensure that subjects are 
appropriately cared for and monitored throughout their participation in the study. Prior to discharge, 
patients will be given standard postoperative home care instructions about third molar extraction 
including how to contact general dentistry and dental urgent care nurses or physicians for any concerns 
regarding the patient’s recovery at home.  An investigator will also be available 24 hours a day, 7 days 
a week via a hospital operator.
Adverse events, serious adverse events (SAE’s) and unanticipated events will be recorded in 
accordance with the IRB guidelines and documented in source materials and case report forms. For 
each occurrence, causality and relationship to drug will be documented and the information reported to 
the IRB as per standard operating procedures.
9.3.
Potential Benefits to Subjects
Individual study subjects will not derive any direct benefit from participation in the study.  We will 
make the genotype information and their implications available to patients who wish to know this 
information and have consented for the release of that information to them once we do our final 
analyses.  In some cases individual subjects may benefit from this information if future surgical 
procedures are necessary. Patients presenting for surgical procedures in the future may benefit from the 
research if the models mapping genotype to pain response phenotype are predictive with the requisite 
precision.
9.4.
Alternatives to Participation
Alternatives if the patient decides not to participate in this study include the standard of care of impacted 
third molar surgical removal w/o using pharmacogenomic testing for guided-acute surgical pain 
management.
10. CONFIDENTIALIATY OF DATA AND INFORMATION STORAGE 
All subjects screened and enrolled in this study will be identified by an assigned study number only. 
All study records will be maintained in a locked office. Information collected will be treated as 
confidential, as provided by law. The study records will be made available for review only to the 
Institutional Review Board. The subjects’ names or any identifier will not be used in published 
information relating to this study.  
To minimize potential risks to the subject’s confidentiality, all protected health information will be 
collected in accordance with the HIPAA guidelines and a signed research authorization will be obtained 


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from the subject prior to enrollment.  All study-related records will be kept in a secured research record 
room or the secured study coordinators office suite.  These records will be available only to the research 
staff involved in the clinical research of the subject, and representatives from regulatory agencies.  
Subject confidentiality will be protected to the extent permitted by law.  Data labeled with subject 
identifiers will not be released without the knowledge and consent of the subject.  Electronic databases 
with subject identifier will also be user-access protected.  All samples collected for analysis will be 
labeled with a coded subject number, sample identifier and date/time of collection.  Subjects will not 
be individually identifiable by the subject number. Our data storage in locked cabinets and password 
protected computers and files will prevent unauthorized access, use, and disclosure of data, identifiers, 
and links to identifiers.
11. RESEARCH INFORMATION IN MEDICAL RECORDS
After completion of the study pharmacogenetic results will not be included in the medical record of 
each research participant. However, research related documentation for study participation and consent 
form will be included in the subjects’ records.
12. DATA ANALYSIS AND MONITORING
12.1. Sample Size Determination
Assuming that a 15% reduction in pain outcomes signifies that the pharmacogenomics test has produced 
a significant effect, we will need 238 subjects total. 119 in each group to achieve 90% power at an alpha 
level of 0.05.
12.2. Planned Statistical Analysis
Specific Aim 1. (Pain control outcomes)
Pain Severity Rating (SPID), Dental Pain Relief Rating (DPRR) and Onset of Perceptible and 
Meaningful Relief on 12 hour period.
The primary analysis will assess the change in the pain severity rating, measuring the time-weighted 
sum of all observations (SPID) over the entire 6 hour period. This will be analyzed by comparison 
among the 2 groups, using ANCOVA model with factors for treatment, sex, Baseline pain intensity 
score and treatment-by-Baseline pain intensity score interaction. 
Dental Pain Relief Rating (DPRR) will be analyzed in three ways including 1) The time-weighted sum 
of all observations (TOTPAR) over the first 6 hours of treatment and 2) the entire 12-hour period for 
comparison among the two groups, using ANCOVA model with factors for treatment, sex, Baseline 
pain intensity score, and treatment-by-Baseline pain intensity score interaction and 3) individual scores 
at each evaluation period will be analyzed for comparison between the 2 groups using ANCOVA model 
with factors for treatment, sex, Baseline pain intensity score, and treatment-by-Baseline pain intensity 
score interaction. 
Finally, relief scores associated with the onset of perceptible and meaningful relief will be analyzed for 
comparison among the 2 groups the two groups, using ANCOVA model with factors for treatment, sex, 
Baseline pain intensity score, and treatment-by-Baseline pain intensity score interaction. 
Onset of Perceptible and Meaningful Pain Relief. Time to onset of perceptible and to meaningful pain 
relief product-limit (Kaplan-Meier) survival curves will be analyzed for comparison among the 2 
groups using log-rank test. Time to onset of perceptible and meaningful pain relief will be assessed by 
each group using the stopwatched method. For patients who drop out, the time to onset of perceptible 
and meaningful pain relief will be censored at Hour-6. For patients who take rescue medication before 


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reaching time to onset of perceptible and meaningful pain relief, the time to relief will be assigned and 
event time (in hours) 6.1 + 0.1/(time rescue medication was taken -time selected medication was taken). 
This rule for handling data for patients that took rescue medication affects only upper limit to the 
confidence interval. Multiple comparisons between groups will be performed if a significant treatment 
effect exists. 
Time to rescue medication. Time to rescue medication product limit (Kaplan-Meier) survival curves 
will be analyzed for comparison among the 2 groups using log-rank test. For patients who remain in 
the study and do not take rescue medication within 12 hours, the time will be censored at Hour-12. 
Multiple comparisons between the 2 groups will be performed if a significant treatment effect exists. 
Overall Global Evaluation. Global evaluation scores will be analyzed for comparison among the 2 
groups, using ANCOVA model with factors for treatment, sex, Baseline pain intensity score, and 
treatment-by-Baseline pain intensity score interaction.
Specific Aim 2. (Opioid analgesics prescription reduction)
We will examine the number of patients receiving standard of care with opioid analgesics and those 
receiving pharmacogenomic-testing-driven-prescribed medications. We will use Fisher’s exact test 
analysis in this specific aim.  
       Other secondary analysis includes:
Vital signs and demographics. 
Vital signs, including blood pressure, heart rate, oral temperature, and respiratory rate, will be 
summarized at Baseline and during the post-dosing period. Demographic data will be compared 
statistically to assess the treatment group comparability at Baseline. Variables with continuous 
distribution (i.e., age, etc.) will be analyzed by analysis of variance (ANOVA). Categorical data (i.e., 
sec, race, etc.) will be analyzed by the chi-square test with Yates’ correction. Baseline pain severity 
will be analyzed by ANOVA.  
12.3. Data and Safety Monitoring
This is a clinical trial with not minimal risk to participants. All expected adverse events are related to 
the standard of care administration of local anesthesia and pain relief medications for the planned 
surgical procedure and are recorded as part of the patient record.  Adverse events will be recorded in 
the patient’s study record, assessed for relatedness and reported to the IRB on determination that they 
meet IRB criteria for reporting. Hans Malmström, DMD will monitor this study for safety issues related 
to the participating subjects.  
13. REFERENCES
1.
Denisco RC, Kenna GA, O'Neil MG, Kulich RJ, Moore PA, Kane WT, et al. Prevention of 
prescription opioid abuse: the role of the dentist. Journal of the American Dental Association. 
2011; 142(7):800–10. PMID: 21719802.
2.
National Institute on Drug Abuse. Topics in Brief: Prescription Drug Abuse—A Research Update 
from the National Institute on Drug Abuse. National Institute of Health, 2011 December 2011. 
Report No.
3.
Hersh E.V, Kane W.T, O’Neil M.G, Kenna G.A, Katz N.P, Gulobic S, Moore P.A. Prescribing 
Recommendations for the Treatment of Acute Pain in Dentistry. Compend Contin Educ Dent. 
2011 Apr; 32(3):22, 24-30; quiz 31-2.


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4.
Qi D.S, May L.G, Zimmerman B, Peng P, Atillasoy E, Brown J.D, Cooper S.A. A randomized, 
double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg 
for the treatment of postsurgical dental pain. Clin Ther. 2012 Dec;34(12):2247-2258.
5.
Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain
relievers—-United States, 1999–2008. MMWR—Morbidity & Mortality Weekly Report. 2011; 
60 (43):1487–92. PMID: 22048730.
6.
Rasubala L, Pernapati L, Velasquez X, Burk J, Ren Y-F. Impact of a Mandatory Prescription Drug 
Monitoring Program on Prescription of Opioid Analgesics by Dentists. PLoS One. 2015; 10(8): 
e0135957.
7.
Barden J, Edwards JE, McQuay HJ, et al. Attenuation of pain in a randomized trial by suppression 
of peripheral nociceptive activity in the immediate postoperative period. Anesth Analg. 2002; 
95(5): 1351-1357.
8.
Cooper SA. Comparative analgesic efficacies of aspirin and acetaminophen. Arch Intern Med. 
1981;141(3): 282-85.
9.
Moore P.A, Nahouraii H.S, Zovko J.G, Wisniewski S.R, Dental Therapeutic Practice patterns in 
the U.S. II. Analgesics, corticosteroids, and antibiotics. Gen Dent. 2006; 54(3):201-207.
10. Tufts Health Care Institute Program on Opioid Risk Management. Executive Summary. The Role 
of Dentists in Preventing Opioid Abuse. Tufts Health Care Institute Program on Opioid Risk 
Management 12th Summit Meeting. March 11-12 2010. Available at 
www.thci.org/opioid/mar10docs/executivesummary.pdf. Accessed January 20 2016. 
11. Ren Z-Y, Xiu X-Q, Bao Y-P, He J, Shi L, Deng J-H, Gao X-J, Tang H-L, Wang Y-M, Lu L. The 
Impact of Genetic Variation on Sensitivity to Opioid Analgesics in Patients with Postoperative 
Pain: A Systematic Review and Meta-Analysis. Pain Physician 2015; 18:131-152.
12. Uribe-Rivera A, et al. Predictive genomics to personalize opioid analgesia in oral and 
maxillofacial surgery. Translational Science 2015. Abstract/Poster presentation.
13. Neunzig I, Göhring A, Drăgan C-A,  Zapp J,  Peters F.T, Maurer H.H, Bureik M. Production and 
NMR analysis of the human ibuprofen metabolite 3-hydroxyibuprofen. J Biotechnol 2012 Feb 27; 
157(3):417-20.
14. Hamman MA, Thompson GA, and Hall SD (1997) Regioselective and stereoselective metabolism 
of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 54:33– 41.
15. Mazaleuskaya L.L, Theken K.N, Gong L, Thorn C.F, FitzGerald G.A, Altman R.B, Klein T.E. 
PharmGKB summary: ibuprofen pathways. Pharmacogenet Genomics. 2015 Feb; 25(2):96-106.
16. Davies NM. Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin Pharmacokinet. 1998 
Feb; 34(2):101-54.
17. Lloyd MD, Yevglevskis M, Lee GL, Wood PJ, Threadgill MD, Woodman TJ. α-Methylacyl-CoA 
racemase (AMACR): metabolic enzyme, drug metabolizer and cancer marker P504S. Prog Lipid 
Res. 2013; 52: 220–230.
18. Jiang Z, Fanger G.R, Woda B.A, Banner B.F, Algate P, Dresser K, Xu J, Chu P.G. Expression of 
alpha-methylacyl-CoA racemase (P504s) in various malignant neoplasms and normal tissues: a 
study of 761 cases. Hum Pathol. 2003 Aug; 34(8):792-6.
19. Qu X, Allan A, Chui G, Hutchings T.J, Jiao P, Johnson L, Leung W.Y, Li P.K, Steel G.R, 
Thompson A.S, Threadgill M.D, Woodman T.J, Lloyd M.D. Hydrolysis of ibuprofenoyl-CoA and 
other 2-APA-CoA esters by human acyl-CoA thioesterases-1 and -2 and their possible role in the 
chiral inversion of profens. Biochem Pharmacol. 2013 Dec 1; 86(11):1621-5.
20. Sakaguchi K, Green M, Stock N, Reger T.S, Zunic J, King C. Glucuronidation of carboxylic acid 
containing compounds by UDP-glucuronosyltransferase isoforms. Arch Biochem Biophys 2004; 
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21. Martin B.K, Meinert C.L, Breitner J.C.S. Double placebo design in a prevention trial for 
Alzheimer’s disease. Controlled Clinical Trials 23 (2002) 93–99. 

ICF_001.pdf: 
RSRB Case Number: 00058833
Page 1 of 9
Version Date: 5/24/2017
CONSENT FORM
Utility of Pharmacogenomic Testing and Postoperative Dental Pain 
Outcomes
Principal Investigator:  Yanfang, Ren, D.D.S, MPH, PhD   
This consent form describes a research study, what you may expect if you 
decide to take part and important information to help you make your 
decision.  Please read this form carefully.
The study staff will explain this study to you.  Please ask questions about anything 
that is not clear before you agree to participate.   You may take this consent form 
home to think about and discuss with family or friends. 
➢Being in this study is voluntary – it is your choice.
➢If you join this study, you can change your mind and stop at any time.
➢If you choose not to take part, your routine medical care will not be changed in 
any way.
➢There are risks from participating and you should understand what these mean 
to you.
Introduction
You are being asked to take part in this study because you are between the ages 
of 18-35 and are having at least one impacted lower jaw wisdom teeth removed.
This study is being conducted by Dr. Yanfang Ren at the University of Rochester’s 
Department of General Dentistry and Urgent Care at Eastman Institute for Oral 
Health
Purpose of Study
•
The purpose of this study is to determine whether testing for your genetic 
make-up can help dentists to select the appropriate pain medications to 
MEDICINE of THE HIGHEST ORDER
RSRB Approval Date: 6/16/2020
Expiration Date: 6/15/2021


RSRB Case Number: 00058833
Page 2 of 9
Version Date: 5/24/2017
manage dental pain after your wisdom tooth or teeth extraction. If you do 
not reach a certain level on the dental pain scale 6 hours after the numbness 
in your mouth wears out, you will be withdrawn from the study and standard 
of care procedures will be carried out. In addition, saliva samples that were 
taken from you, will be discarded and will not be stored. If you are withdrawn 
from the study, you will receive US$50 for your time and participation. 
Description of Study Procedures
If you choose to participate and qualify for the study, the following will happen:
Screening visit:
•
First, your medical chart will be reviewed to determine if you are eligible to 
participate in this study. 
•
If eligible, you will be asked to read a consent form, ask questions about the 
research. If agree, you will be asked to sign the consent form and a copy 
will be handed out to you.
•
Once you enroll in the study genetic testing will be carried out. This testing 
consists of spitting approximately 5mL (the equivalent of a tablespoon 
amount) of saliva into a special laboratory tube. A special kit with supplies 
to carry out these activities will be used only for you. 
•
The special laboratory tube with saliva will be sent to a laboratory outside 
the University of Rochester with only a code that will identify you for this 
study; no additional personal information will be needed. This laboratory will 
study your saliva for a specific genetic make-up. 
•
The genetic testing results, with only a study code with no additional 
personal information of yours, will be sent to a specialist (examiner) involved 
in the study at Eastman Institute for Oral Health. Dr. Ren and research 
investigators involved in your surgery (for this study) will not know which 
pain medication will be given to you after your surgery. 
•
You will be asked to answer questions such as your response to pain 
medications in the past, and how you typically respond to pain. 
•
You will also be asked about family history of taking pain medications, etc. 
Then, a complete physical examination will be carried out and intervention 
will be scheduled. 
Surgery and post-surgery visit:
•
You will have no food after midnight, except for clear liquids up to 2 hours 
prior to surgery. You will be reported to the clinic on the morning of your 
surgery. 
•
Before the surgery, if you are female we will ask you to take a pregnancy 
test.
•
After your wisdom teeth are removed, you will be monitored in the clinic for 
pain.  This may take up to 6 hours for the numbness to wear off and for you 
to start feeling pain.  You will be asked to rate your pain on a scale of 0-
100mm. If your pain is rated more than 50mm you will be assigned 1 of the 
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two groups in the study. You will be randomly assigned (like the flipping of 
a coin) to one of the following: 
o
Control group where you will receive a single dose of a pain 
medication 
called 
Vicodin®(hydrocodone/acetaminophen 
5mg/650mg) or
o
Experimental group where you may receive a single dose of 
acetaminophen (Tylenol®) 650 mg or ibuprofen (Motrin®) 400mg, 
depending on your specific genetic testing. 
Neither you nor the study team will know which group you have been assigned to 
or what medication you are given. To prevent you from recognizing the medication, 
you will wear a mask over your eyes before you take the medication. 
•
You will be asked to complete some questions about rating your pain on a 
scale of 0-100mm. These questions are to be completed 15 minutes, 30 
minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours 
after having taken the study medication. Also, during these times, the study 
investigators will take vital signs. 
•
Additionally, three to four (3-4) minutes after you take the study medication, 
you will be given two stopwatches and asked to stop one when you first feel 
pain relief.  You will also be asked to stop the 2nd stopwatch when you feel 
much better pain alleviation. At the end of the six hour period, you will be 
asked to provide an overall evaluation of the study medication.  
In the event that the study pain medication is not effective we will give you a 
non-blinded second medication (rescue medication) named Percocet® 
(oxycodone/acetaminophen 5/325mg) which is considered also standard of 
care for pain associated with wisdom teeth removal. We will ask you 
additional questions about your pain after the medication is given.
 
You will be dismissed once the investigators determine you are ready to leave the 
clinic with the following criteria: 
1) Your pain is controlled, 
2) You are not showing an adverse effect of pain medications, such as excessive 
sleepiness or drowsiness and 
3) You have a companion with you all the time. 
You will be given standard home care instructions about wisdom teeth removal 
including how to contact general dentistry and dental urgent care dentists for any 
concerns.  
Although this is a 12-hour study, you can contact a dental provider any time after 
your procedure, if you have questions or surgical pain continues. Dental staff 
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contact information will be provided in the postoperative instructions given to you 
when you are sent home and ready to leave the dental clinic. Genetic results will 
not be given to you, but, any incident related to this study will be managed 
according to guidance stated in the protocol document. Also, if you agree your 
genetic sample will be stored for future research. 
The following information about your study participation will be included in your 
electronic health record.:
•
Documenting you are in this study
•
A copy of your signed consent form
Information about Genetic Testing
We are asking your permission to store and share your saliva sample collected 
during the course of this study for future testing. These future tests are not yet 
planned, and may or may not be related to this study. These future tests may 
include testing in relation to your genetic profile.  
The purpose of storage and sharing of samples and data for future testing is to 
make information and samples available to other researchers for use in health 
research.  Collecting, storing and sharing information and making it available for 
other studies may help people in the future.   
The results of future tests performed on stored or shared samples or reports 
resulting from the analysis of your research samples will not be given to you or 
your doctor and they will not be put in your dental record.  They will not identify 
you and will not affect your routine dental care.
There is no benefit to you from the storage of samples and information.  
If you decide to allow storage, your samples and information may be stored for 
an unknown length of time. Although your stored research samples will not be 
sold, the information obtained from the research performed on your samples may 
in the future lead to the development of commercial products.  You will not 
receive any money from research using your stored samples and information.
There may be unknown risks associated with the storage of samples and 
information.  While we will not use information that is traditionally used to identify 
you, people may develop ways in the future that would allow someone to link 
your medical information in our databases back to you. There may also be other 
privacy risks that we have not foreseen.  We will make every attempt to protect 
your confidentiality and to make sure that your personal identity does not become 
known.
Your decision regarding the storage of samples for future testing, or the 
information resulting from the analysis of your samples will not affect your ability 
to participate in this study.  
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☐ Yes, you may store my saliva sample for future genetic research.
☐ No, you cannot store my saliva sample for future genetic research
Number of Subjects
Approximately 238 subjects will take part in this study.  
Duration of the Study
Your participation in the study will last about 12 hours, plus the time for 
consenting and genetic testing that involves approximately, 30 minutes before 
wisdom teeth extraction(s). 
Risks of Participation
Potential risks of participating in this research study are those risks associated 
with routine wisdom tooth/teeth extraction, side effects of pain medications that 
include; nausea, allergic reaction, sleepiness, constipation and dizziness.
Also, you can also experience delay in receiving pain medications or 
ineffective pain control from your participation in this study.
You may be withdrawn from this study after the 6 hours if you do not meet the 
pain threshold.
Because this study will involve collecting personal information that can identify 
you, including your genetic profile, there is a possibility for invasion of privacy 
and loss of confidentiality. To minimize this risk, we will assign a number instead 
of your name or other personal information we collect about you. All these 
information will be stored in a secure manner accessible to study personnel only.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results.  You 
can search this website at any time. 
Benefits of Participation  
You will not benefit from participating in this study. 
Alternatives to Participation 
Instead of being in this research study you may choose not to participate and 
receive standard of care medications for pain management.
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Costs 
You and/or your insurance company will be responsible for paying for any 
tests/procedures/exams that are done as part of your standard care.   You are 
encouraged to discuss your coverage with your insurance provider.
 Payments
You will be paid a total of $50 for participation in the study, even if you do not get 
randomized.
Reimbursement for Travel Expenses 
You will be offered a parking voucher to cover any parking expenses.
Compensation for Injury 
If you are directly injured by medical procedures needed because of this study, 
and you receive medical care for the injury, you may need to pay for that care.  
You will be reimbursed for reasonable and necessary medical costs for such 
care, but you might not be reimbursed for care covered and paid for by a third 
party like your health insurance provider, or costs such as required co-payments 
or deductibles related to that coverage.  No other funds have been set aside to 
pay for such things as lost wages or expenses due to a current underlying illness 
or condition.
If your research injury is paid for by the University,we will collect your name, date 
of birth, gender, and Medicare Health Insurance Claim Number or Social Security 
Number to determine your Medicare status. This information will be used only in 
accordance with the law. If you are a Medicare beneficiary, information about the 
study you are in, and any payments made related to your injury, will be reported 
to the Centers for Medicare & Medicaid Services (CMS), in accordance with CMS 
requirements.  This information will not be used for any other purpose
Confidentiality of Records  
Every effort will be made to maintain the confidentiality of your medical and 
research records related to this study.  The monitor, the auditor, the Institutional 
Review Board (IRB), and other regulatory authority(ies) will be granted direct 
access to your original medical and research records for verification of clinical 
trial (research study) procedures or study data without violating your 
confidentiality, to the extent permitted by the applicable laws and regulations.  By 
signing this consent form, you or your legally authorized representatives are 
authorizing such access.
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The data from the study may be published; however, you will not be identified by 
name. Your identity will remain confidential unless disclosure is required by law.  
If you have never received a copy of the University of Rochester Medical Center 
(URMC) and Affiliates Notice of Privacy Practices, please ask the investigator for 
one. 
What information may be used and given to others?
The study doctor will get your personal and medical information.  For example: 
•
Research records
•
Records about phone calls made as part of this research
•
Records about your study visits
•
Past and present dental records related to the study
•
Results of dental X-rays
Who may use and give out information about you?
•
The study doctor and the study staff
•
URMC and Affiliates
Your information may be given to: 
•
The Department of Health and Human Services
•
The University of Rochester 
•
Admera Labs
Why will this information be used and/or given to others?
•
To do the research 
•
To study the results 
•
To see if the research was done right  
If the results of this study are made public, information that identifies you will not 
be used.
What if I decide not to give permission to use and give out my health 
information?
Then you will not be able to be in this research study.
May I review or copy my information?
Yes, but only after the research is over.
How long will this permission be valid?
This permission will last indefinitely. 
May I cancel my permission to use and disclose information?
Yes.  You may cancel your permission to use and disclose your health information 
at any time.  You do this by sending written notice to the study doctor.  Upon 
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receiving the written notice, the study team will no longer use or disclose your 
health information and you will not be able to stay in this study.  Information that 
has already been gathered may need to be used and given to others for the validity 
of the study.  
May I withdraw from the study?
Yes.  If you withdraw your permission to be in the study, no new health information 
identifying you will be gathered after that date.  Information that has already been 
gathered may still be used and given to others.  
Is my health information protected after it has been given to others?
No.  There is a risk that your information will be given to others without your 
permission.
 
Contact Persons
For more information concerning this research or if you feel that your 
participation has resulted in any emotional or physical discomfort, please contact: 
Dr. Yanfang Ren, Principal Investigator at 585-273-5588.
Please contact the University of Rochester Research Subjects Review Board at 
265 Crittenden Blvd., CU 420628, Rochester, NY 14642, Telephone (585) 276-
0005 or (877) 449-4441 for the following reasons:
•
You wish to talk to someone other than the research staff about your 
rights as a research subject;
•
To voice concerns about the research;
•
To provide input concerning the research process;
•
In the event the study staff could not be reached.
Voluntary Participation
Taking part in this study is voluntary.  You are free not to participate or to 
withdraw at any time, for whatever reason.  No matter what decision you make, 
there will be no penalty or loss of benefits to which you are entitled.  In the event 
that you do withdraw from this study, the information you have already provided 
will be kept in a confidential manner.
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SIGNATURE/DATES
After reading and discussing the information in this consent form you should 
understand:
•
Why this study is being done;
•
What will happen during the study;
•
Any possible risks and benefits to you;
•
Other options you may have instead of being in the study; 
•
How your personal information will be protected;
•
What to do if you have problems or questions about this study.
Subject Consent
I have read (or have had read to me) the contents of this consent form and have 
been encouraged to ask questions.  I have received answers to my questions.  I 
agree to participate in this study.  I have received (or will receive) a signed copy 
of this form for my records and future reference.
Subject Name (Printed by Subject)
Signature of Subject
Date
Person Obtaining Consent
I have read this form to the subject and/or the subject has read this form.  I will 
provide the subject with a signed copy of this consent form.  An explanation of 
the research was given and questions from the subject were solicited and 
answered to the subject’s satisfaction.  In my judgment, the subject has 
demonstrated comprehension of the information.  I have given the subject 
adequate opportunity to read the consent before signing.
Name and Title (Print)
Signature of Person Obtaining Consent
Date
RSRB Approval Date: 6/16/2020
Expiration Date: 6/15/2021