Pain, Postoperative
Conditions
Keywords
Opioid Use, Opioid Dependence, Opioid-Related Disorders, Opioid Abuse, Opioid-use Disorder, Pain, Pain, Postoperative, Cognitive Impairment, Delirium, Delirium on Emergence, Depression, Anxiety, Anxiety Disorders, Affect
Brief summary
The ongoing opioid epidemic is a public health crisis, and surgical patients are particularly vulnerable to opioid-dependency and related risks. Emerging data suggest that caffeine may reduce pain after surgery. Thus, the purpose of this study is to test whether caffeine reduces pain and opioid requirements after surgery. The investigators will also test whether caffeine improves mood and brain function (e.g., learning, memory) after surgery.
Detailed description
Opioid-related deaths have quadrupled in the last 20 years, and nearly half of these deaths currently involve prescription opioids. Surgical patients often experience moderate-to-severe pain is common after major surgery, and surgery is associated with a 14-fold increased risk of opioid dependency compared to non-surgical controls, even after minor surgery. Furthermore, mood disorders (e.g., depression) are independently associated with persistent opioid use postoperatively, and signs of postoperative depression are common after major surgery. Thus, given these risk factors, surgical patients are at particularly high risk for opioid dependency postoperatively. Interventions that (1) reduce opioid burden, and (2) improve mood and neuropsychological function may mitigate the risk of postoperative opioid dependency. Preliminary laboratory and clinical findings demonstrate that caffeine may reduce pain after surgery, which may translate to lower opioid requirements. The study tests the hypothesis that intraoperative caffeine administration will improve opioid consumption, pain, and neuropsychological recovery in patients undergoing surgery. Through validated assessment measures, the research team will study the effects of caffeine in relation to postoperative opioid requirements, pain, and neuropsychological (e.g., cognition, depression, anxiety) trajectory after surgery.
Interventions
DRUGCaffeine Citrate
Prepared intravenous piggyback solutions of caffeine citrate (200 mg caffeine) will be directly delivered to the operating room prior to the surgery of enrolled participants.
DRUGDextrose Water
Prepared intravenous piggyback solutions of 5 percent dextrose water will be directly delivered to the operating room prior to the surgery of enrolled participants.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This will be a single-center, quadruple-blinded, pilot randomized controlled trial at the University of Michigan Health System.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult (\>/= 18 years old) undergoing non-cardiac, non-neurologic, non-major vascular surgery requiring general anesthesia
Exclusion criteria
* Emergency surgery * Cognitive impairment precluding capacity for informed consent * Uncontrolled cardiac arrhythmias * Seizure disorders * Preoperative opioid use * Diabetes * Liver failure * Pregnancy * Breastfeeding * Severe visual or auditory impairment (may hinder cognitive function testing) * Patients unable to speak English.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Opioid Consumption: Postoperative Opioid Consumption, Oral Morphine Equivalents (mg) | through postoperative day 3 | Postoperative opioid consumption, oral morphine equivalents (mg) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Pain (Patient-reported) as Assessed by Visual Analogue Scale | Data gathered from postoperative day 0-3. Final results were based on all values combined over this time period, per protocol. | Visual Analogue Scale (mm, 0-100, 0 = no pain, 100 = worst pain imaginable) |
| Acute Pain (Observer-reported) as Assessed by Behavioral Pain Scale | Data gathered from postoperative day 0-3. Final results were based on all values combined over this time period, per protocol. | Behavioral Pain Scale, on a scale ranging from 3 to 12 when 3 is no pain and 12 is maximum pain |
| Time Until Anesthetic Emergence | Duration of time from surgical dressing completion to anesthetic emergence (min); generally expected to be between 10 and 60 minutes | Time from surgical dressing on to anesthetic emergence (min) |
| Number of Participants With Depression as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-D) | baseline through postoperative day 3 | Number (n) of participants with positive screens (score ≥8) using the Hospitalized Anxiety and Depression Scale (HADS-D) (n, 0-21, 0 = normal, 21 = presence of severe depression symptoms) |
| Number of Participants With Anxiety as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-A) | baseline through postoperative day 3 | Number (n) of participants with positive screens (score ≥8) using the Hospitalized Anxiety and Depression Scale (HADS-A) (n, 0-21, 0 = normal, 21 = presence of severe anxiety symptoms) |
| Cognitive Function as Assessed by Trail Making Test | morning of surgery baseline compared to postanesthesia care unit. Postanesthesia care unit measurement approximately 60 minutes after end of surgery | Trail Making Test scores (seconds, 10-300,10 = fastest reported completion, 300 = maximum time allowed for completion). The change was calculated from the value at post anesthesia minus value at baseline. Higher values are considered to be worse outcomes. |
| Positive Affect as Assessed by PANAS (Positive and Negative Affect Schedule) | postoperative day 3 | Positive Affect Score (n, 10-50, 10 = least positive affect, 50 = most positive affect) via PANAS (Positive and Negative Affect Schedule) |
| Negative Affect as Assessed by PANAS (Positive and Negative Affect Schedule) | postoperative day 3 | Negative Affect Score (n, 10-50, 10 = least negative affect, 50 = most negative affect) via PANAS (Positive and Negative Affect Schedule) |
| Percentage of Delirious Patients Per Group | By afternoon of postoperative day (POD) 3 | Number (n) of participants who has experienced at least one episode of delirium by the postoperative day 3 time point, as determined by daily Confusion Assessment Method (CAM). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Subacute Opioid Consumption: Postoperative Subacute Opioid Consumption, Oral Morphine Equivalents (mg) | postoperative days 4-7 | Postoperative subacute opioid consumption, oral morphine equivalents (mg) |
| Sleep Disturbances: Incidence (%) of New, Self-reported Sleep Disturbances | postoperative days 0-3 | Incidence (%) of new, self-reported sleep disturbances |
| EEG Spectral Power: Spectral Power (dB) Measured on EEG | time point 1: anesthetic emergence, approximate measurement 5-10 minutes after surgery end. Time point 2: postanesthesia care unit arrival, approximate measurement 20 minutes after end of surgery | Spectral power (dB) measured on EEG |
| EEG Connectivity: Connectivity (Weighted Phase Lag Index, wPLI) Measured on EEG | time point 1: anesthetic emergence, approximate measurement 5-10 minutes after surgery end. Time point 2: postanesthesia care unit arrival, approximate measurement 20 minutes after end of surgery | Connectivity (weighted phase lag index, wPLI) measured on EEG |
| Veterans Rand 12 Survey | 30 days after surgery | Comprehensive survey that reports on general health perceptions, physical functioning, role limitations due to physical and emotional problems, bodily pain, energy /fatigue levels, social functioning and mental health. Specifically, a physical and mental health score are reported, with both score scales ranging from 0 (worst possible outcome) to 100 (best possible outcome). |
| Persistent Opioid Use | Postoperative day (POD) 30 | Incidence of continued opioid use (%) on postoperative day (POD) 30 |
| Quality of Recovery Survey | Postoperative day (POD) 1 | Self-report outcome measure evaluating recovery after surgery and anesthesia. Scoring ranges from 3-18, 3=poor 18=excellent |
| Richards Campbell Sleep Questionnaire (RCSQ) | Preoperative (once before surgery on day of surgery) | Self-report instrument for measuring sleep quality. Visual Analogue Scale (mm, 0-100, 0 =Deep sleep , 100 =Light sleep) |
| Caffeine Intake: Number of Caffeinated Beverages (n) Consumed | postoperative day 0-7 | Number of caffeinated beverages (n) consumed |
Countries
United States
Participant flow
Pre-assignment details
A total of 71 subjects were consented. Data is reported for a total of 60 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Prepared intravenous piggyback solution of caffeine citrate (200 mg caffeine) will be directly delivered to the operating room prior to the surgery of enrolled participants who are randomized to this group.
Caffeine Citrate: Prepared intravenous piggyback solutions of caffeine citrate (200 mg caffeine) will be directly delivered to the operating room prior to the surgery of enrolled participants. | 30 |
| Control Prepared intravenous piggyback solution of 5 percent dextrose water will be directly delivered to the operating room prior to the surgery of enrolled participants who are randomized to this group.
Dextrose Water: Prepared intravenous piggyback solutions of 5 percent dextrose water will be directly delivered to the operating room prior to the surgery of enrolled participants. | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not receive allocated intervention | 1 | 0 |
| Overall Study | Physician Decision | 3 | 1 |
Baseline characteristics
| Characteristic | Experimental | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 7 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 23 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 29 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 29 Participants | 30 Participants | 59 Participants |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 17 Participants | 15 Participants | 32 Participants |
| Sex: Female, Male Male | 13 Participants | 15 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 31 |
| other Total, other adverse events | 8 / 33 | 6 / 31 |
| serious Total, serious adverse events | 2 / 33 | 4 / 31 |
Outcome results
Primary
Cumulative Opioid Consumption: Postoperative Opioid Consumption, Oral Morphine Equivalents (mg)
Postoperative opioid consumption, oral morphine equivalents (mg)
Time frame: through postoperative day 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Cumulative Opioid Consumption: Postoperative Opioid Consumption, Oral Morphine Equivalents (mg) | 77 oral morphine equivalents (mg) |
| Control | Cumulative Opioid Consumption: Postoperative Opioid Consumption, Oral Morphine Equivalents (mg) | 51 oral morphine equivalents (mg) |
p-value: 0.09295% CI: [-9, 118]Generalized estimating equations
Secondary
Acute Pain (Observer-reported) as Assessed by Behavioral Pain Scale
Behavioral Pain Scale, on a scale ranging from 3 to 12 when 3 is no pain and 12 is maximum pain
Time frame: Data gathered from postoperative day 0-3. Final results were based on all values combined over this time period, per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Acute Pain (Observer-reported) as Assessed by Behavioral Pain Scale | 3 score on a scale |
| Control | Acute Pain (Observer-reported) as Assessed by Behavioral Pain Scale | 3 score on a scale |
p-value: 0.32Mixed Models Analysis
Secondary
Acute Pain (Patient-reported) as Assessed by Visual Analogue Scale
Visual Analogue Scale (mm, 0-100, 0 = no pain, 100 = worst pain imaginable)
Time frame: Data gathered from postoperative day 0-3. Final results were based on all values combined over this time period, per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Acute Pain (Patient-reported) as Assessed by Visual Analogue Scale | 40 score on a scale |
| Control | Acute Pain (Patient-reported) as Assessed by Visual Analogue Scale | 39 score on a scale |
Comparison: Analysis for visual analog scale scores at rest presented.p-value: 0.802Mixed Models Analysis
Secondary
Cognitive Function as Assessed by Trail Making Test
Trail Making Test scores (seconds, 10-300,10 = fastest reported completion, 300 = maximum time allowed for completion). The change was calculated from the value at post anesthesia minus value at baseline. Higher values are considered to be worse outcomes.
Time frame: morning of surgery baseline compared to postanesthesia care unit. Postanesthesia care unit measurement approximately 60 minutes after end of surgery
Population: Data at baseline or post-operative point was not available for some participants, so data is reported only for those who had complete baseline and post-operative data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Cognitive Function as Assessed by Trail Making Test | 10 score on a scale |
| Control | Cognitive Function as Assessed by Trail Making Test | 16 score on a scale |
p-value: 0.417Wilcoxon (Mann-Whitney)
Secondary
Negative Affect as Assessed by PANAS (Positive and Negative Affect Schedule)
Negative Affect Score (n, 10-50, 10 = least negative affect, 50 = most negative affect) via PANAS (Positive and Negative Affect Schedule)
Time frame: postoperative day 3
Population: Data at baseline or post-operative point was not available for some participants, so data is reported only for those who had complete baseline and post-operative data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Negative Affect as Assessed by PANAS (Positive and Negative Affect Schedule) | 12 score on a scale |
| Control | Negative Affect as Assessed by PANAS (Positive and Negative Affect Schedule) | 12 score on a scale |
p-value: 0.673Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With Anxiety as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-A)
Number (n) of participants with positive screens (score ≥8) using the Hospitalized Anxiety and Depression Scale (HADS-A) (n, 0-21, 0 = normal, 21 = presence of severe anxiety symptoms)
Time frame: baseline through postoperative day 3
Population: Data at baseline or post-operative point was not available for some participants, so data is reported only for those who had complete baseline and post-operative data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental | Number of Participants With Anxiety as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-A) | 2 Participants |
| Control | Number of Participants With Anxiety as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-A) | 2 Participants |
p-value: 0.985Fisher Exact
Secondary
Number of Participants With Depression as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-D)
Number (n) of participants with positive screens (score ≥8) using the Hospitalized Anxiety and Depression Scale (HADS-D) (n, 0-21, 0 = normal, 21 = presence of severe depression symptoms)
Time frame: baseline through postoperative day 3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental | Number of Participants With Depression as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-D) | 2 Participants |
| Control | Number of Participants With Depression as Assessed by the Hospitalized Anxiety and Depression Scale (HADS-D) | 1 Participants |
p-value: 0.595Fisher Exact
Secondary
Percentage of Delirious Patients Per Group
Number (n) of participants who has experienced at least one episode of delirium by the postoperative day 3 time point, as determined by daily Confusion Assessment Method (CAM).
Time frame: By afternoon of postoperative day (POD) 3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental | Percentage of Delirious Patients Per Group | 7 Participants |
| Control | Percentage of Delirious Patients Per Group | 14 Participants |
p-value: 0.058Chi-squared
Secondary
Positive Affect as Assessed by PANAS (Positive and Negative Affect Schedule)
Positive Affect Score (n, 10-50, 10 = least positive affect, 50 = most positive affect) via PANAS (Positive and Negative Affect Schedule)
Time frame: postoperative day 3
Population: Data at baseline or post-operative point was not available for some participants, so data is reported only for those who had complete baseline and post-operative data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Positive Affect as Assessed by PANAS (Positive and Negative Affect Schedule) | 35 score on a scale |
| Control | Positive Affect as Assessed by PANAS (Positive and Negative Affect Schedule) | 35 score on a scale |
p-value: 0.432Wilcoxon (Mann-Whitney)
Secondary
Time Until Anesthetic Emergence
Time from surgical dressing on to anesthetic emergence (min)
Time frame: Duration of time from surgical dressing completion to anesthetic emergence (min); generally expected to be between 10 and 60 minutes
Population: Data at baseline or post-operative point was not available for some participants, so data is reported only for those who had complete baseline and post-operative data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Time Until Anesthetic Emergence | 8 Minutes |
| Control | Time Until Anesthetic Emergence | 10 Minutes |
p-value: 0.67Wilcoxon (Mann-Whitney)
Other Pre-specified
Caffeine Intake: Number of Caffeinated Beverages (n) Consumed
Number of caffeinated beverages (n) consumed
Time frame: postoperative day 0-7
Other Pre-specified
EEG Connectivity: Connectivity (Weighted Phase Lag Index, wPLI) Measured on EEG
Connectivity (weighted phase lag index, wPLI) measured on EEG
Time frame: time point 1: anesthetic emergence, approximate measurement 5-10 minutes after surgery end. Time point 2: postanesthesia care unit arrival, approximate measurement 20 minutes after end of surgery
Other Pre-specified
EEG Spectral Power: Spectral Power (dB) Measured on EEG
Spectral power (dB) measured on EEG
Time frame: time point 1: anesthetic emergence, approximate measurement 5-10 minutes after surgery end. Time point 2: postanesthesia care unit arrival, approximate measurement 20 minutes after end of surgery
Other Pre-specified
Persistent Opioid Use
Incidence of continued opioid use (%) on postoperative day (POD) 30
Time frame: Postoperative day (POD) 30
Other Pre-specified
Quality of Recovery Survey
Self-report outcome measure evaluating recovery after surgery and anesthesia. Scoring ranges from 3-18, 3=poor 18=excellent
Time frame: Postoperative day (POD) 1
Other Pre-specified
Richards Campbell Sleep Questionnaire (RCSQ)
Self-report instrument for measuring sleep quality. Visual Analogue Scale (mm, 0-100, 0 =Deep sleep , 100 =Light sleep)
Time frame: Preoperative (once before surgery on day of surgery)
Population: Richards Campbell Sleep Questionnaire (RCSQ)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Richards Campbell Sleep Questionnaire (RCSQ) | 58 score on a scale | Standard Deviation 26 |
| Control | Richards Campbell Sleep Questionnaire (RCSQ) | 56 score on a scale | Standard Deviation 28 |
Other Pre-specified
Sleep Disturbances: Incidence (%) of New, Self-reported Sleep Disturbances
Incidence (%) of new, self-reported sleep disturbances
Time frame: postoperative days 0-3
Other Pre-specified
Subacute Opioid Consumption: Postoperative Subacute Opioid Consumption, Oral Morphine Equivalents (mg)
Postoperative subacute opioid consumption, oral morphine equivalents (mg)
Time frame: postoperative days 4-7
Other Pre-specified
Veterans Rand 12 Survey
Comprehensive survey that reports on general health perceptions, physical functioning, role limitations due to physical and emotional problems, bodily pain, energy /fatigue levels, social functioning and mental health. Specifically, a physical and mental health score are reported, with both score scales ranging from 0 (worst possible outcome) to 100 (best possible outcome).
Time frame: 30 days after surgery