Caffeine and Neurologic Recovery Following Surgery and General Anesthesia

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.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: Caffeine Citrate; Drug: Dextrose Water

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.

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Michigan Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.
Placebo Comparator: 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.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Opioid Consumption: Postoperative Opioid Consumption, Oral Morphine Equivalents (mg)	Postoperative opioid consumption, oral morphine equivalents (mg)	through postoperative day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Pain (Patient-reported) as Assessed by Visual Analogue Scale	Visual Analogue Scale (mm, 0-100, 0 = no pain, 100 = worst pain imaginable)	Data gathered from postoperative day 0-3. Final results were based on all values combined over this time period, per protocol.
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	Data gathered from postoperative day 0-3. Final results were based on all values combined over this time period, per protocol.
Time Until Anesthetic Emergence	Time from surgical dressing on to anesthetic emergence (min)	Duration of time from surgical dressing completion to anesthetic emergence (min); generally expected to be between 10 and 60 minutes
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)	baseline through postoperative day 3
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)	baseline through postoperative day 3
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.	morning of surgery baseline compared to postanesthesia care unit. Postanesthesia care unit measurement approximately 60 minutes after end of surgery
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)	postoperative day 3
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)	postoperative day 3
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).	By afternoon of postoperative day (POD) 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Caffeine Intake: Number of Caffeinated Beverages (n) Consumed	Number of caffeinated beverages (n) consumed	postoperative day 0-7
Subacute Opioid Consumption: Postoperative Subacute Opioid Consumption, Oral Morphine Equivalents (mg)	Postoperative subacute opioid consumption, oral morphine equivalents (mg)	postoperative days 4-7
Sleep Disturbances: Incidence (%) of New, Self-reported Sleep Disturbances	Incidence (%) of new, self-reported sleep disturbances	postoperative days 0-3
EEG Spectral Power: Spectral Power (dB) Measured on EEG	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
EEG Connectivity: Connectivity (Weighted Phase Lag Index, wPLI) Measured on EEG	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
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).	30 days after surgery
Persistent Opioid Use	Incidence of continued opioid use (%) on postoperative day (POD) 30	Postoperative day (POD) 30
Quality of Recovery Survey	Self-report outcome measure evaluating recovery after surgery and anesthesia. Scoring ranges from 3-18, 3=poor 18=excellent	Postoperative day (POD) 1
Richards Campbell Sleep Questionnaire (RCSQ)	Self-report instrument for measuring sleep quality. Visual Analogue Scale (mm, 0-100, 0 =Deep sleep , 100 =Light sleep)	Preoperative (once before surgery on day of surgery)

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Principal Investigator: Phillip Vlisides, MD, Assistant Professor of Anesthesiology

Publications and helpful links

General Publications

• Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012 Jul 5;367(1):30-9. doi: 10.1056/NEJMoa1112923.
• Bickel H, Gradinger R, Kochs E, Forstl H. High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study. Dement Geriatr Cogn Disord. 2008;26(1):26-31. doi: 10.1159/000140804. Epub 2008 Jun 24.
• Pandharipande P, Cotton BA, Shintani A, Thompson J, Pun BT, Morris JA Jr, Dittus R, Ely EW. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma. 2008 Jul;65(1):34-41. doi: 10.1097/TA.0b013e31814b2c4d.
• Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, Bohnert ASB, Kheterpal S, Nallamothu BK. New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg. 2017 Jun 21;152(6):e170504. doi: 10.1001/jamasurg.2017.0504. Epub 2017 Jun 21. Erratum In: JAMA Surg. 2019 Mar 1;154(3):272.
• Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL. Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin. 2014 Jan;30(1):149-60. doi: 10.1185/03007995.2013.860019. Epub 2013 Nov 15.
• Weiser TG, Haynes AB, Molina G, Lipsitz SR, Esquivel MM, Uribe-Leitz T, Fu R, Azad T, Chao TE, Berry WR, Gawande AA. Estimate of the global volume of surgery in 2012: an assessment supporting improved health outcomes. Lancet. 2015 Apr 27;385 Suppl 2:S11. doi: 10.1016/S0140-6736(15)60806-6. Epub 2015 Apr 26.
• Litaker D, Locala J, Franco K, Bronson DL, Tannous Z. Preoperative risk factors for postoperative delirium. Gen Hosp Psychiatry. 2001 Mar-Apr;23(2):84-9. doi: 10.1016/s0163-8343(01)00117-7.
• Robinson TN, Raeburn CD, Tran ZV, Angles EM, Brenner LA, Moss M. Postoperative delirium in the elderly: risk factors and outcomes. Ann Surg. 2009 Jan;249(1):173-8. doi: 10.1097/SLA.0b013e31818e4776.
• Lynch EP, Lazor MA, Gellis JE, Orav J, Goldman L, Marcantonio ER. The impact of postoperative pain on the development of postoperative delirium. Anesth Analg. 1998 Apr;86(4):781-5. doi: 10.1097/00000539-199804000-00019.
• Kundermann B, Krieg JC, Schreiber W, Lautenbacher S. The effect of sleep deprivation on pain. Pain Res Manag. 2004 Spring;9(1):25-32. doi: 10.1155/2004/949187.
• Vaurio LE, Sands LP, Wang Y, Mullen EA, Leung JM. Postoperative delirium: the importance of pain and pain management. Anesth Analg. 2006 Apr;102(4):1267-73. doi: 10.1213/01.ane.0000199156.59226.af.
• Karp JF, Reynolds CF 3rd, Butters MA, Dew MA, Mazumdar S, Begley AE, Lenze E, Weiner DK. The relationship between pain and mental flexibility in older adult pain clinic patients. Pain Med. 2006 Sep-Oct;7(5):444-52. doi: 10.1111/j.1526-4637.2006.00212.x.
• Dolan R, Huh J, Tiwari N, Sproat T, Camilleri-Brennan J. A prospective analysis of sleep deprivation and disturbance in surgical patients. Ann Med Surg (Lond). 2016 Jan 6;6:1-5. doi: 10.1016/j.amsu.2015.12.046. eCollection 2016 Mar.
• Avidan MS, Maybrier HR, Abdallah AB, Jacobsohn E, Vlisides PE, Pryor KO, Veselis RA, Grocott HP, Emmert DA, Rogers EM, Downey RJ, Yulico H, Noh GJ, Lee YH, Waszynski CM, Arya VK, Pagel PS, Hudetz JA, Muench MR, Fritz BA, Waberski W, Inouye SK, Mashour GA; PODCAST Research Group. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet. 2017 Jul 15;390(10091):267-275. doi: 10.1016/S0140-6736(17)31467-8. Epub 2017 May 30. Erratum In: Lancet. 2017 Jul 15;390(10091):230.
• Nelson AM, Battersby AS, Baghdoyan HA, Lydic R. Opioid-induced decreases in rat brain adenosine levels are reversed by inhibiting adenosine deaminase. Anesthesiology. 2009 Dec;111(6):1327-33. doi: 10.1097/ALN.0b013e3181bdf894.
• Gauthier EA, Guzick SE, Brummett CM, Baghdoyan HA, Lydic R. Buprenorphine disrupts sleep and decreases adenosine concentrations in sleep-regulating brain regions of Sprague Dawley rat. Anesthesiology. 2011 Oct;115(4):743-53. doi: 10.1097/ALN.0b013e31822e9f85.
• Osman NI, Baghdoyan HA, Lydic R. Morphine inhibits acetylcholine release in rat prefrontal cortex when delivered systemically or by microdialysis to basal forebrain. Anesthesiology. 2005 Oct;103(4):779-87. doi: 10.1097/00000542-200510000-00016.
• Pisani MA, Murphy TE, Araujo KL, Slattum P, Van Ness PH, Inouye SK. Benzodiazepine and opioid use and the duration of intensive care unit delirium in an older population. Crit Care Med. 2009 Jan;37(1):177-83. doi: 10.1097/CCM.0b013e318192fcf9.
• Vlisides PE, Li D, McKinney A, Brooks J, Leis AM, Mentz G, Tsodikov A, Zierau M, Ragheb J, Clauw DJ, Avidan MS, Vanini G, Mashour GA. The Effects of Intraoperative Caffeine on Postoperative Opioid Consumption and Related Outcomes After Laparoscopic Surgery: A Randomized Controlled Trial. Anesth Analg. 2021 Jul 1;133(1):233-242. doi: 10.1213/ANE.0000000000005532.

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2018
• Primary Completion (Actual): November 21, 2019
• Study Completion (Actual): January 17, 2020

Study Registration Dates

• First Submitted: June 8, 2018
• First Submitted That Met QC Criteria: July 3, 2018
• First Posted (Actual): July 5, 2018

Study Record Updates

• Last Update Posted (Actual): October 6, 2021
• Last Update Submitted That Met QC Criteria: September 9, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Depression; Pain; Anxiety; Cognitive Impairment; Affect; Opioid Use; Delirium; Opioid-Related Disorders; Opioid Dependence; Pain, Postoperative; Anxiety Disorders; Opioid Abuse; Opioid-use Disorder; Delirium on Emergence
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Caffeine; Caffeine citrate
• Other Study ID Numbers: HUM00135919

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No