Pain, Postoperative
Conditions
Keywords
Arthroplasty Surgery, Genotype-Guided Pain Management
Brief summary
This will be a randomized, open-labeled pilot pragmatic clinical trial. Patients undergoing arthroplasty surgery will be recruited from the University of Florida (UF) Health Gainesville and the Villages Orthopedic clinics for CYP2D6 pharmacogenetic testing to manage post-surgical pain. Patients will be randomized 2:1 to either usual care or genotype-guided care. The aims of the study were to: 1) test the feasibility of a genotype-guided opioid prescribing approach for patients undergoing an outpatient surgical procedure, a group at high risk for persistent opioid use; and 2) evaluate the effect of genotype-guided post-surgical pain management on pain control and opioid prescribing.
Detailed description
This study was a randomized, open-label, type 2 hybrid implementation effectiveness trial conducted to test the hypothesis that CYP2D6 genotype-guided management of post-surgical pain 1) was feasible, and 2) reduced the use of codeine, tramadol, hydrocodone, and oxycodone in Poor Metabolizers (PMs), Intermediate Metabolizers (IMs), and Ultrarapid metabolizers (UMs). In addition to the reduced use of opioids listed above, we aimed to see if participants had improved post-operative pain control in PMs/IMs and reduced Drug Enforcement Administration (DEA) Schedule II (C-II) opioids in Normal Metabolizers (NMs). Patients scheduled to undergo arthroplasty surgery were recruited from the UF Health Gainesville and the Villages Orthopedic clinics. Patients were randomized 2:1 to a genotype-guided versus usual care approach. For patients with CYP2D6 PM, IM or UM phenotype based on genotype or drug interactions, a recommendation to avoid hydrocodone, tramadol, codeine, and oxycodone were made. In NMs, tramadol was recommended, given evidence of its lower potential addiction risk than C-II opioids. Patient-Reported Outcomes Measurement Information System (PROMIS) measures were administered at baseline (within 30 days of surgery) and 2 weeks ± 4 days post-surgery for patients in each arm. Pain scores and assessments of physical functioning, emotional functioning, and mobility from the PROMIS measures and utilization of pain medications during the 2-week period following surgery were also compared between groups.
Interventions
GENETICCYP2D6-guided opioid therapy
Using a standardized consult note, recommendations were made to avoid tramadol, hydrocodone, codeine, and oxycodone in PMs, IMs, and UMs and to use an alternative opioid (e.g. morphine, hydromorphone) or non-opioid (e.g. NSAID). Consideration of tramadol as the first-line opioid will be recommended for NMs.
Sponsors
University of Florida Health
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Scheduled to undergo total joint arthroplasty at area hospital * Primary unilateral total hip or knee arthroplasty scheduled within approximately 6 months of the initial evaluation clinic visit
Exclusion criteria
* Patients scheduled to undergo a revision or bilateral procedure * Receiving chronic opioid therapy, defined as the use of opioids on most days for \> 3 month * Allergy to opioids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Agreed to Participate | 12 months | The feasibility of clinical implementation was measured by the percentage of approached patients who agreed to be the study. This was measured by the number of patients approached and the number of patients who enrolled in the study. |
| Percentage of Participants With a Clinical Phenotype Warranting Alternative Therapy | An average of 2 weeks after genotype sample collection | The feasibility of implementing a genotype-guided opioid prescribing approach for participants undergoing an elective surgical procedure was analyzed by the percentage of participants in the genotype-guided arm and usual care arm with a high-risk CYP2D6 phenotype. CYP2D6 phenotypes were based on CYP2D6 genotype and phenoconversion. High-risk CYP2D6 phenotypes were poor metabolizers (PM), intermediate metabolizers (IM), ultrarapid metabolizers (UM), and ranged phenotypes such as normal to ultrarapid metabolizers and intermediate to ultrarapid metabolizers. |
| Percentage of Participants in the Genotype-guided Arm for Whom a Clinical Phenotype-guided Recommendation Was Accepted by the Clinician | An average of 2 months after genotype results returned | The feasibility of clinical implementation was measured by the percentage of participants in the genotype-guided arm for whom a clinical phenotype-guided recommendation was accepted by the clinician. Study recommendations were considered accepted for participants with a high-risk phenotype if an alternative opioid (e.g., hydromorphone, morphine) was prescribed. For CYP2D6 normal metabolizers (NM), consult recommendations were accepted if tramadol was prescribed. Participants were typically prescribed a tramadol-based regimen where in most cases hydrocodone, or another opioid, was prescribed concomitantly with tramadol as is usual practice at the clinics where participants were enrolled. Participants whose genotype resulted after the preoperative appointment were excluded from the analysis of acceptance of consult recommendations. Data for this outcome were only collected from participants in the genotyped-guided arm with CYP2D6 results returned prior to the preoperative appointment. |
| Opioid Utilization | 2 weeks after surgery | Opioid consumption was calculated as the difference between participant-reported opioid pills prescribed at the preoperative appointment and opioid pills remaining at the 2-week time point. This difference was calculated for each opioid and then expressed as morphine milligram equivalents (MME) using standard conversion factors and the medication strength of the prescribed opioid analgesic. If a participant was prescribed multiple opioids, MMEs were calculated for each opioid and then summed to give a total MME value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Pain Intensity | 2 weeks after surgery | Composite pain intensity was compared between the genotype-guided arm and usual care arm 2 weeks after surgery. The first two scales in the PROMIS Pain Intensity item bank assess pain intensity utilizing a 7-day recall period (items include the phrase the past 7 days) while the third scale asks the patient to rate their pain intensity right now. Each of the 3 scales (worst pain, average pain, and current pain) used to calculate the composite pain intensity score has a range of 1 to 5, with the following text assigned to the numeric scale, 1 -had no pain, 2 -mild, 3 -moderate, 4 -severe, and 5 -very severe. The mean composite pain intensity ranges from 1-5. The higher the composite pain score, the more pain and thus worse outcomes. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Genotype-guided Opioid Therapy For participants randomized to the genotype-guided arm, a CYP2D6 phenotype and pharmacist consult note will be provided to physicians to assist in opioid prescribing. | 154 |
| Usual Care For participants randomized to the usual care arm, providers will follow usual care prescribing practices for post operative opioid prescribing. | 80 |
| Total | 234 |
Baseline characteristics
| Characteristic | Genotype-guided Opioid Therapy | Usual Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 93 Participants | 40 Participants | 133 Participants |
| Age, Categorical Between 18 and 65 years | 61 Participants | 40 Participants | 101 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 12 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 131 Participants | 65 Participants | 196 Participants |
| Region of Enrollment United States | 154 Participants | 80 Participants | 234 Participants |
| Sex: Female, Male Female | 91 Participants | 46 Participants | 137 Participants |
| Sex: Female, Male Male | 63 Participants | 34 Participants | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Opioid Utilization
Opioid consumption was calculated as the difference between participant-reported opioid pills prescribed at the preoperative appointment and opioid pills remaining at the 2-week time point. This difference was calculated for each opioid and then expressed as morphine milligram equivalents (MME) using standard conversion factors and the medication strength of the prescribed opioid analgesic. If a participant was prescribed multiple opioids, MMEs were calculated for each opioid and then summed to give a total MME value.
Time frame: 2 weeks after surgery
Population: Study population that completed a 2-week post-surgery follow-up survey.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Participants Approached for the Study, Prior to Randomization | Opioid Utilization | 200 morphine milligram equivalents |
| Usual Care | Opioid Utilization | 230 morphine milligram equivalents |
p-value: 0.047Wilcoxon (Mann-Whitney)
Primary
Percentage of Participants in the Genotype-guided Arm for Whom a Clinical Phenotype-guided Recommendation Was Accepted by the Clinician
The feasibility of clinical implementation was measured by the percentage of participants in the genotype-guided arm for whom a clinical phenotype-guided recommendation was accepted by the clinician. Study recommendations were considered accepted for participants with a high-risk phenotype if an alternative opioid (e.g., hydromorphone, morphine) was prescribed. For CYP2D6 normal metabolizers (NM), consult recommendations were accepted if tramadol was prescribed. Participants were typically prescribed a tramadol-based regimen where in most cases hydrocodone, or another opioid, was prescribed concomitantly with tramadol as is usual practice at the clinics where participants were enrolled. Participants whose genotype resulted after the preoperative appointment were excluded from the analysis of acceptance of consult recommendations. Data for this outcome were only collected from participants in the genotyped-guided arm with CYP2D6 results returned prior to the preoperative appointment.
Time frame: An average of 2 months after genotype results returned
Population: Participants in the genotyped-guided arm with CYP2D6 results returned prior to the preoperative appointment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Participants Approached for the Study, Prior to Randomization | Percentage of Participants in the Genotype-guided Arm for Whom a Clinical Phenotype-guided Recommendation Was Accepted by the Clinician | 21 Participants |
| Usual Care | Percentage of Participants in the Genotype-guided Arm for Whom a Clinical Phenotype-guided Recommendation Was Accepted by the Clinician | 101 Participants |
Primary
Percentage of Participants With a Clinical Phenotype Warranting Alternative Therapy
The feasibility of implementing a genotype-guided opioid prescribing approach for participants undergoing an elective surgical procedure was analyzed by the percentage of participants in the genotype-guided arm and usual care arm with a high-risk CYP2D6 phenotype. CYP2D6 phenotypes were based on CYP2D6 genotype and phenoconversion. High-risk CYP2D6 phenotypes were poor metabolizers (PM), intermediate metabolizers (IM), ultrarapid metabolizers (UM), and ranged phenotypes such as normal to ultrarapid metabolizers and intermediate to ultrarapid metabolizers.
Time frame: An average of 2 weeks after genotype sample collection
Population: Participants enrolled and randomized who underwent a total joint arthroplasty procedure, completed the study, and were genotyped.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Participants Approached for the Study, Prior to Randomization | Percentage of Participants With a Clinical Phenotype Warranting Alternative Therapy | High-Risk CYP2D6 Phentoype | 35 Participants |
| Participants Approached for the Study, Prior to Randomization | Percentage of Participants With a Clinical Phenotype Warranting Alternative Therapy | Normal CYP2D6 Phenotype | 119 Participants |
| Usual Care | Percentage of Participants With a Clinical Phenotype Warranting Alternative Therapy | High-Risk CYP2D6 Phentoype | 28 Participants |
| Usual Care | Percentage of Participants With a Clinical Phenotype Warranting Alternative Therapy | Normal CYP2D6 Phenotype | 46 Participants |
Primary
Percentage of Patients Who Agreed to Participate
The feasibility of clinical implementation was measured by the percentage of approached patients who agreed to be the study. This was measured by the number of patients approached and the number of patients who enrolled in the study.
Time frame: 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Participants Approached for the Study, Prior to Randomization | Percentage of Patients Who Agreed to Participate | Agreed to participant and enrolled into the study | 260 Participants |
| Participants Approached for the Study, Prior to Randomization | Percentage of Patients Who Agreed to Participate | Declined to participant in the study | 22 Participants |
Secondary
Composite Pain Intensity
Composite pain intensity was compared between the genotype-guided arm and usual care arm 2 weeks after surgery. The first two scales in the PROMIS Pain Intensity item bank assess pain intensity utilizing a 7-day recall period (items include the phrase the past 7 days) while the third scale asks the patient to rate their pain intensity right now. Each of the 3 scales (worst pain, average pain, and current pain) used to calculate the composite pain intensity score has a range of 1 to 5, with the following text assigned to the numeric scale, 1 -had no pain, 2 -mild, 3 -moderate, 4 -severe, and 5 -very severe. The mean composite pain intensity ranges from 1-5. The higher the composite pain score, the more pain and thus worse outcomes.
Time frame: 2 weeks after surgery
Population: Participants that completed the pain intensity survey 2 weeks after surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants Approached for the Study, Prior to Randomization | Composite Pain Intensity | 2.6 units on a scale | Standard Deviation 0.8 |
| Usual Care | Composite Pain Intensity | 2.5 units on a scale | Standard Deviation 0.7 |
p-value: 0.638t-test, 2 sided