Acute Pain Genomic Study

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01557751
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Dental and Craniofacial Research (NIDCR) (NIH)
• Enrollment: 156
• Location: 1
• Arm: 1
• Duration (Months): 178
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

In preparation for future large-scale genome wide association studies, reliable methods must be developed for measuring perceived pain and for estimating the effects of potentially confounding factors such as appropriate covariates. The major objectives of our pilot investigation are to develop optimal methods to characterize the primary endpoint of the study-knee pain, and to gather preliminary data on genetic markers in the human genome that are associated with a certain pain phenotype. The specific issues for this study will be to carry out a preliminary gene association analysis of acute perioperative pain in individuals undergoing total knee replacement and to define a pain phenotype that is composed of multidimensional domains such as opioid consumption, inflammatory markers, anxiety level, degree of catastrophizing, etc. This pain phenotype has to be sensitive enough to pick up changes in pain experience that can be attributed to single nucleotide polymorphisms.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis; Postoperative Pain	Genetic: Whole blood for genotyping	N/A

Detailed Description

In spite of advances in postoperative management and the standardization of postoperative care, there is a wide variability in the degree of pain relief achieved which cannot be accounted for. The aim of this study is to devise a method for defining a pain phenotype sensitive enough to detect differences in genetic makeup between individuals who undergo a standard surgical procedure (total knee replacement). This methodology will serve as a pilot study for future genome wide association studies. Given the multidimensional aspects of pain experience, the phenotype will be combined of various dimensions comprising postoperative pain. Reports about single nucleotide polymorphisms (SNPs), which account for some of the variability of pain, have been reported in the literature using different pain models. To test the sensitivity of our method of phenotyping, the investigators aim to determine if variability in our clinical phenotypes can be explained by some of the SNPs published in the literature. Patients scheduled for elective unilateral primary total knee arthroplasty will be asked to report on various clinical pain variables, fill psychometric questionnaires, be subjected to quantitative sensory testing, genotyped for a genes associated with pain, and additional SNPs. A composite pain profile will be composed for each patient initially examining five candidate genes and related SNPs to find out the SNPs that are significantly associated with given pain phenotypes. Samples will be banked for future study of other genes associated with pain. Other clinical variables will be collected (e.g. opioid consumption). At six and twelve months, psychological questionnaires and pain questionnaires will be sent to patient. A model using pain during physical therapy as the dependent variable will be fit to the data. Knee joint fluid, urine, and serum will be collected from approximately 30% of the subjects who provide their additional consent cytokine and other inflammatory marker analysis. All biological specimens will be banked for future analysis. This is a pilot, preliminary study which will assess patients prospectively and attempt to correlate markers on genes and single nucleotide polymorphisms with patient phenotypes. This method which will serve as the foundation for a future genome wide association study of pain. This is a preliminary, developmental, prospective follow-up study to develop a tool that will be sensitive and specific enough to be used in a large-scale candidate genome association pain study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Preliminary Studies for Whole Genome Association Study (WGAS) in Acute Perioperative Pain
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Dec 1, 2016
• Anticipated Study Completion Date: Dec 1, 2024

Arms and Interventions

Arm

Intervention/Treatment

Other: Total knee arthroplasty subjects who are genotyped All patients will have whole blood drawn for genotyping, and participate in the various assessments (psychosocial questionnaires, qualitative sensory testing, etc).

Genetic: Whole blood for genotyping; This study requires genotyping by extracting DNA from blood sample. A blood sample will be drawn once during visit 2 (day of surgery) or any other time prior to that after the signing of informed consent. Four vacutainers of which hold 8.5 mL will be drawn during this time totaling approximately 34 mL of blood which completes the genomic sampling portion of the study.

Outcome Measures

Primary Outcome Measures

1. NRS-Pain With Movement on POD 2 [Postoperative day (POD) 2]

   The primary endpoint is the pain reported by subjects, using the NRS-Pain with movement on the second day after surgery.The assumption behind this study is that certain genetic variants (e.g. single-nucleotide polymorphism (SNP) are responsible for part of total variation of certain clinical phenotypes (e.g. post-operative pain here). Numeric Rating Score Pain Assessment (0-10 scale where 0 indicates no pain at all and 10 indicates the worst pain imaginable) on Post Op Day 2, Pain with Movement

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age >18

• Undergoing a primary, unilateral total knee arthroplasty for the first time

• Willing and able to provide informed consent

• Caucasian

• Non-hispanic

Exclusion Criteria:

• Contraindication or refusal for peripheral nerve blocks

• Any chronic pain condition which may confound the study per investigator's opinion

• Chronic opioid dependence per investigator's opinion

• Any diagnosis for total knee arthroplasty other than degenerative joint disease or osteoarthritis

• Evidence of clinical dementia, dementia, delirium, or any cognitive disorder which inhibits the subject's ability to comprehend and cooperate with researchers

• Revision or any knee surgery that is not a primary, unilateral, elective total knee arthroplasty being performed for the first time

• Any criteria that in the investigator's opinion would prohibit the subject from following

• Hispanic ethnicity

• Any race other than caucasian

• Subjects with knee flexion contracture (which is clinically defined for the purpose of our protocol as more than 15 degrees of knee contracture)

• Pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UPMC Presbyterian Shadyside	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• University of Pittsburgh
• National Institutes of Health (NIH)
• National Institute of Dental and Craniofacial Research (NIDCR)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Belfer I, Wu T, Kingman A, Krishnaraju RK, Goldman D, Max MB. Candidate gene studies of human pain mechanisms: methods for optimizing choice of polymorphisms and sample size. Anesthesiology. 2004 Jun;100(6):1562-72.
• Buvanendran A, Kroin JS, Berger RA, Hallab NJ, Saha C, Negrescu C, Moric M, Caicedo MS, Tuman KJ. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology. 2006 Mar;104(3):403-10. Erratum in: Anesthesiology. 2006 Apr;104(4):900.
• Chan VW, Clark AJ, Davis JC, Wolf RS, Kellstein D, Jayawardene S. The post-operative analgesic efficacy and tolerability of lumiracoxib compared with placebo and naproxen after total knee or hip arthroplasty. Acta Anaesthesiol Scand. 2005 Nov;49(10):1491-500.
• Curatolo M, Petersen-Felix S, Arendt-Nielsen L. Sensory assessment of regional analgesia in humans: a review of methods and applications. Anesthesiology. 2000 Dec;93(6):1517-30.
• Dina OA, Hucho T, Yeh J, Malik-Hall M, Reichling DB, Levine JD. Primary afferent second messenger cascades interact with specific integrin subunits in producing inflammatory hyperalgesia. Pain. 2005 May;115(1-2):191-203.
• Dionne RA, Berthold CW. Therapeutic uses of non-steroidal anti-inflammatory drugs in dentistry. Crit Rev Oral Biol Med. 2001;12(4):315-30. Review.
• Granot M, Ferber SG. The roles of pain catastrophizing and anxiety in the prediction of postoperative pain intensity: a prospective study. Clin J Pain. 2005 Sep-Oct;21(5):439-45.
• Gueorguieva RV, Sanacora G. Joint analysis of repeatedly observed continuous and ordinal measures of disease severity. Stat Med. 2006 Apr 30;25(8):1307-22.
• Kalff JC, Türler A, Schwarz NT, Schraut WH, Lee KK, Tweardy DJ, Billiar TR, Simmons RL, Bauer AJ. Intra-abdominal activation of a local inflammatory response within the human muscularis externa during laparotomy. Ann Surg. 2003 Mar;237(3):301-15.
• Khan AA, Owatz CB, Schindler WG, Schwartz SA, Keiser K, Hargreaves KM. Measurement of mechanical allodynia and local anesthetic efficacy in patients with irreversible pulpitis and acute periradicular periodontitis. J Endod. 2007 Jul;33(7):796-9. Epub 2007 Mar 26.
• Max MB, Stewart WF. The molecular epidemiology of pain: a new discipline for drug discovery. Nat Rev Drug Discov. 2008 Aug;7(8):647-58. doi: 10.1038/nrd2595. Epub 2008 Jun 27. Review.
• Reynolds LW, Hoo RK, Brill RJ, North J, Recker DP, Verburg KM. The COX-2 specific inhibitor, valdecoxib, is an effective, opioid-sparing analgesic in patients undergoing total knee arthroplasty. J Pain Symptom Manage. 2003 Feb;25(2):133-41.
• Rolke R, Baron R, Maier C, Tölle TR, Treede -DR, Beyer A, Binder A, Birbaumer N, Birklein F, Bötefür IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihöfner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006 Aug;123(3):231-243. doi: 10.1016/j.pain.2006.01.041. Epub 2006 May 11. Erratum in: Pain. 2006 Nov;125(1-2):197.
• Silverman DG, O'Connor TZ, Brull SJ. Integrated assessment of pain scores and rescue morphine use during studies of analgesic efficacy. Anesth Analg. 1993 Jul;77(1):168-70.
• Tegeder I, Adolph J, Schmidt H, Woolf CJ, Geisslinger G, Lötsch J. Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype. Eur J Pain. 2008 Nov;12(8):1069-77. doi: 10.1016/j.ejpain.2008.02.004. Epub 2008 Apr 18.
• Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, Lötsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov;12(11):1269-77. Epub 2006 Oct 22.

• Responsible Party: Jacques E. Chelly, Professor of Anesthesiology (with Tenure) and Orthopedic Surgery, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01557751
• Other Study ID Numbers: PRO09050171; N08PC10039; 1406-0408-CT-20481
• First Posted: Mar 19, 2012
• Last Update Posted: Mar 17, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Jacques E. Chelly, Professor of Anesthesiology (with Tenure) and Orthopedic Surgery, University of Pittsburgh: Total knee arthroplasty; Total knee replacement; Genetics of pain
• Additional relevant MeSH terms: Osteoarthritis; Pain, Postoperative

Study Results

Participant Flow

Arm/Group Title	Total Knee Arthroplasty Subjects Who Are Genotyped
Arm/Group Description	All patients will have whole blood drawn for genotyping, and participate in the various assessments (psychosocial questionnaires, qualitative sensory testing, etc). Whole blood for genotyping: This study requires genotyping by extracting DNA from blood sample. A blood sample will be drawn once during visit 2 (day of surgery) or any other time prior to that after the signing of informed consent. Four vacutainers of which hold 8.5 mL will be drawn during this time totaling approximately 34 mL of blood which completes the genomic sampling portion of the study.
Period Title: Overall Study
STARTED	156
COMPLETED	153
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Total Knee Arthroplasty Subjects Who Are Genotyped
Arm/Group Description	All patients will have whole blood drawn for genotyping, and participate in the various assessments (psychosocial questionnaires, qualitative sensory testing, etc). Whole blood for genotyping: This study requires genotyping by extracting DNA from blood sample. A blood sample will be drawn once during visit 2 (day of surgery) or any other time prior to that after the signing of informed consent. Four vacutainers of which hold 8.5 mL will be drawn during this time totaling approximately 34 mL of blood which completes the genomic sampling portion of the study.
Overall Participants	156
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	92 59%
>=65 years	64 41%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	64.23
Sex: Female, Male (Count of Participants)
Female	90 57.7%
Male	66 42.3%
Region of Enrollment (Count of Participants)
United States	156 100%

Outcome Measures

1. Primary Outcome

Title	NRS-Pain With Movement on POD 2
Description	The primary endpoint is the pain reported by subjects, using the NRS-Pain with movement on the second day after surgery.The assumption behind this study is that certain genetic variants (e.g. single-nucleotide polymorphism (SNP) are responsible for part of total variation of certain clinical phenotypes (e.g. post-operative pain here). Numeric Rating Score Pain Assessment (0-10 scale where 0 indicates no pain at all and 10 indicates the worst pain imaginable) on Post Op Day 2, Pain with Movement
Time Frame	Postoperative day (POD) 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Total Knee Arthroplasty Subjects Who Are Genotyped
Arm/Group Description	All patients will have whole blood drawn for genotyping, and participate in the various assessments (psychosocial questionnaires, qualitative sensory testing, etc). Whole blood for genotyping: This study requires genotyping by extracting DNA from blood sample. A blood sample will be drawn once during visit 2 (day of surgery) or any other time prior to that after the signing of informed consent. Four vacutainers of which hold 8.5 mL will be drawn during this time totaling approximately 34 mL of blood which completes the genomic sampling portion of the study.
Measure Participants	156
Mean (Full Range) [units on a scale]	2.83

Adverse Events

Arm/Group Title	Total Knee Arthroplasty Subjects Who Are Genotyped
Arm/Group Description	All patients will have whole blood drawn for genotyping, and participate in the various assessments (psychosocial questionnaires, qualitative sensory testing, etc). Whole blood for genotyping: This study requires genotyping by extracting DNA from blood sample. A blood sample will be drawn once during visit 2 (day of surgery) or any other time prior to that after the signing of informed consent. Four vacutainers of which hold 8.5 mL will be drawn during this time totaling approximately 34 mL of blood which completes the genomic sampling portion of the study.
All Cause Mortality
	Total Knee Arthroplasty Subjects Who Are Genotyped
	Affected / at Risk (%)	# Events
Total	0/156 (0%)
Serious Adverse Events
	Total Knee Arthroplasty Subjects Who Are Genotyped
	Affected / at Risk (%)	# Events
Total	0/156 (0%)
Other (Not Including Serious) Adverse Events
	Total Knee Arthroplasty Subjects Who Are Genotyped
	Affected / at Risk (%)	# Events
Total	0/156 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.