Caffeine is well-tolerated during anesthetic emergence but is unlikely to reduce early postoperative opioid consumption, according to results of a randomized clinical trial published in Anesthesia & Analgesia.

Findings from rat model studies have shown that caffeine may produce acute analgesic benefits and reduce postoperative mechanical hypersensitivity. The findings suggest caffeine may be a promising intervention to improve pain and neuropsychological functioning after surgery.

To further evaluate caffeine’s effects, researchers conducted a randomized, placebo-controlled trial. The Caffeine, Pain, and Change in Outcomes After Surgery trial (CAPACHINOS, identifier NCT03577730) was conducted at Michigan Medical School in Ann Arbor to determine if intraoperative caffeine reduces postoperative opioid consumption and to analyze the effects of caffeine on neuropsychological outcomes in a postoperative setting.

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Study participants were adult patients (aged ≥18 years) who underwent laparoscopic colorectal or gastrointestinal surgery; they were randomized in the 2-arm parallel group trial design with a 1:1 allocation of placebo or caffeine. The participants shared similar anesthetic plans, durations of surgery, postoperative opioid requirements, and length of hospital stay. Participants received either the placebo, a timed infusion of 40 mL dextrose 5% in water (D5W), or caffeine citrate (200 mg caffeine equivalent).

The final cohort included 60 patients (each group n=30), the majority of whom underwent colorectal surgery. In terms of cumulative opioid consumption through postoperative day 3 (measured in oral morphine equivalents, milligrams), there were no significant differences between the caffeine and placebo groups (median, 77 mg vs 51 mg; interquartile range [IQR], 33-182 mg vs 15-117 mg); the estimated difference based on unadjusted group comparisons was 55 mg (95% CI, -9 to 118).

Following post hoc adjustments for age, sex, American Society of Anesthesiologists Physical Status Score, patient history of anxiety or depression, and open surgical conversion, participants in the caffeine group demonstrated a significant increase in opioid consumption (87 mg; 95% CI, 26-148).

In an assessment of the longitudinal effects of caffeine over time, no significant group-by-time interactions were noted.

Secondary trial outcomes through the first 3 postoperative days included the Visual Analog Scale (0-100 mm) that measured pain scores at rest (0.1 mm), with either deep breathing (-0.8 mm) or movement (-6.5 mm).

Neuropsychiatric outcomes were not statistically different in terms of postoperative delirium incidence or postanesthesia care unit (PACU) Trail Making Test scores. Similarly, there were no noted differences in the proportion of new positive postoperative screens for either depression or anxiety, with similar perioperative Positive and Negative Affect Schedule (PANAS) scores between groups. The time between end of surgical closure and anesthetic emergence in minutes was similar between the caffeine group (8 minutes) and placebo group (10 minutes).

Results of a longitudinal analysis conducted to compare opioid consumption on postoperative days 4 through 7 showed no significant differences between the groups over time. Self-reported sleep disturbances, instances of persistent opioid use by 30 days postdischarge, and scores of the Veterans RAND 12-item health survey were also similar.

Investigators also conducted an expanded exploratory analysis of 65 available randomized patients, including 5 excluded from the primary analysis, to characterize electroencephalographic patterns. This analysis showed an increase in parietal alpha power in the caffeine group (19 dB) vs the placebo group (17 dB).

PACU alpha frontal-parietal connectivity was significantly higher in the caffeine group (0.08) compared to the placebo group (0.04). The median fold-change in frontal-parietal connectivity from baseline was significantly higher in the caffeine group (0.72) compared to the placebo group (0.48).

The results led to an additional post hoc exploratory analysis to evaluate incidence of PACU delirium and PACU discharge readiness between groups. PACU delirium was significantly lower in the caffeine group (12%) compared to the placebo group (33%). The time until PACU discharge readiness, measured in minutes, were similar between the caffeine (67 min) and placebo (72 min) groups.

No patients in the caffeine group required antihypertension medications during emergence or PACU admission. No new arrythmias were reported in the caffeine group, and hemodynamic profiles between the groups were similar.

Adverse events were generally mild to moderate and were “unlikely to be related to caffeine administration.”

Study limitations include relatively small sample size, single center trial, and inability to adjust for all baseline and intraoperative imbalances, as well as the exclusion of patients with chronic pain or opioid tolerance and the fixed dose of caffeine administered.

“Caffeine appears unlikely to decrease early postoperative opioid consumption,” the researchers concluded. “There were otherwise no differences in neuropsychological outcomes or 30-day exploratory outcomes between the groups, though caffeine may enhance neuropsychological arousal after surgery.”


Vlisides PE, Li D, McKinney A, Brooks J, Leis AM, Mentz G, et al. The effects of intraoperative caffeine on postoperative opioid consumption and related outcomes after laparoscopic surgery: a randomized controlled trial. Anesth Analg. Published online May 3, 2021. doi:10.1213/ANE.0000000000005532