Skip to main content
Download PDF

Influence of a chronic beta-blocker therapy on perioperative opioid consumption – a post hoc secondary analysis

BMC Anesthesiology volume 24, Article number: 80 (2024) Cite this article

Abstract

Background

Beta-blocker (BB) therapy plays a central role in the treatment of cardiovascular diseases. An increasing number of patients with cardiovascular diseases undergoe noncardiac surgery, where opioids are an integral part of the anesthesiological management. There is evidence to suggest that short-term intravenous BB therapy may influence perioperative opioid requirements due to an assumed cross-talk between G-protein coupled beta-adrenergic and opioid receptors. Whether chronic BB therapy could also have an influence on perioperative opioid requirements is unclear.

Methods

A post hoc analysis of prospectively collected data from a multicenter observational (BioCog) study was performed. Inclusion criteria consisted of elderly patients (≥ 65 years) undergoing elective noncardiac surgery as well as total intravenous general anesthesia without the use of regional anesthesia and duration of anesthesia ≥ 60 min. Two groups were defined: patients with and without BB in their regular preopreative medication. The administered opioids were converted to their respective morphine equivalent doses. Multiple regression analysis was performed using the morphine-index to identify independent predictors.

Results

A total of 747 patients were included in the BioCog study in the study center Berlin. 106 patients fulfilled the inclusion criteria. Of these, 37 were on chronic BB. The latter were preoperatively significantly more likely to have arterial hypertension (94.6%), chronic renal failure (27%) and hyperlipoproteinemia (51.4%) compared to patients without BB. Both groups did not differ in terms of cumulative perioperative morphine equivalent dose (230.9 (BB group) vs. 214.8 mg (Non-BB group)). Predictive factors for increased morphine-index were older age, male sex, longer duration of anesthesia and surgery of the trunk. In a model with logarithmised morphine index, only gender (female) and duration of anesthesia remained predictive factors.

Conclusions

Chronic BB therapy was not associated with a reduced perioperative opioid consumption.

Trial registration

This study was registered at ClinicalTrials.gov (NCT02265263) on the 15.10.2014 with the principal investigator being Univ.-Prof. Dr. med. Claudia Spies.

Peer Review reports

Background

Chronic beta-blocker (BB) therapy plays a central role in the treatment of cardiovascular disease, which is one of the leading causes of morbidity and mortality in western societies. BBs are indicated in the treatment of chronic heart failure [1] in supraventricular tachyarrythmias, coronary artery disease as well as post myocardial infarction [2]. Due to their competitive antagonism at G-protein coupled beta-adrenoceptors, they suppress sympathetic innervation and thus have negative chronotropic, dromotropic, inotropic and lusitropic effects, thereby reducing heart rate and cardiac workload. BB treatment in the aforementioned cardiovascular diseases therefore results in a reduction of mortality [3]. In this context, it is worth mentioning that an increasing number of patients with cardiovascular risk factors with ongoing BB treatment are scheduled for noncardiac surgery [4].

Opioids play an integral role in anesthesiological and analgesia management. They are considered the cornerstone of general anesthesia in surgical patients presenting with preexisting cardiovascular diseases. Experimental data has demonstrated that opioids may migitate the cardioprotective effects during myocardial ischemic situations [5, 6]. Opioid receptors, also members of the G-protein-coupled receptor superfamily, are co-expressed with beta-adrenergic receptors [7]. Interestingly, there seems to be an interaction between the adrenergic and opioidergic system in the form of a cross-talk between both G-protein coupled receptors [8]. Moreover, there have been some meta-analyses showing perioperative opioid sparing effects of a short-term treatment of the short-acting BB Esmolol [9,10,11]. Its application resulted in a reduced postoperative pain intensity and postoperative nausea and vomiting (PONV) [10, 11]. In contrast, there is currently little understanding of the impact of a long-term “chronic” BB therapy on perioperative opioid use.

Thus, this retrospective study aimed to examine whether a chronic BB therapy is associated with a lower perioperative opioid consumption and improved perioperative outcomes with regard to perioperative parameters.

Methods

Study design

This study was designed as a post hoc analysis based on the study “Biomarker Development for postoperative Cognitive Impairment in the Elderly (BioCog)”, a multicenter, prospective clinical observational study with the aim to develop biomarkers to assess the risk and predict the occurrence of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) [12]. All procedures involving humans were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments. The study was approved by the local ethics committee at Charité – Universitätsmedizin Berlin (EA 2/092/14) on the 31.07.2014 and registered at ClinicalTrials.gov (NCT02265263) on the 15.10.2014 with the principal investigator being Univ.-Prof. Dr. med. Claudia Spies. Informed written consent was obtained from all patients. Data collection for the entire BioCog study took place between October 2014 and June 2019 at the Department of Anesthesiology and Intensive Care Medicine at Campus Charité Mitte and Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, Germany, and the Department of Intensive Care Medicine at the University Medical Center Utrecht, Netherlands. We adhered to the CONSORT guidelines and the STROBE checklist.

Study population

The following patients were screened for inclusion in the post hoc secondary analysis to examine whether a chronic BB therapy had an influence on perioperative opioid consumption: elective non-cardiac surgery (general, thoracic, orthopedic, trauma, gynecologic, urologic, ear nose, throat, neurosurgical, dermatologic) with an anesthesia duration of ≥ 60 min, total intravenous general anesthesia without additional regional anesthesia. Only BioCog study participants from Berlin, Germany, were included in the secondary analysis. Patients, who fulfilled the inclusion criteria, were divided into two groups, whether they received a chronic BB therapy as a regular medication at the time of study inclusion or not, and compared to each other. Additionally, we exluded patients with chronic pain from our post hoc analysis to harmonise the study cohort. In the main study, patients were advised to take their BB on the morning of surgery and to resume BB treatment as quickly as possible postoperatively.

Study protocol

The study protocol has been previously described [12]. Preoperative data were collected from the preoperative visit as well as the individual patient file and included age, gender, weight, Body Mass Index (BMI), American Society of Anesthesiologists Physical Status (ASA PS), type of planned surgery, consumption of alcohol and/or nicotine, preexisting medical conditions and regular medication intake. Perioperative data were extracted from the electronic patient data management system (COPRA6®). This included the duration of anesthesia, administered medications, cumulative opioid application including all opioids administered from the beginning of anesthesia until the end of recovery room treatment, length of stay in the recovery room, PONV, incidence of intolerable pain and rate of admission to the intensive care unit (ICU)/postanaesthesia care unit (PACU). Postoperative data included length of hospital stay and rate of complications based on the Clavien-Dindo-Classification [13, 14]. For the ease of use, complications were divided into the following categories: 1) no complication, 2) complications (without death), 3) death. The follow-up period was from the beginning of treatment in the recovery room or ICU/PACU until discharge from hospital or death of the patient.

Postoperative pain was examined using the Numeric Rating Scale (NRS), Behavioral Pain Scale (BPS), BPS non intubated (BPS-NI), or the Critical-Care Pain Observation Tool (CPOT) [15,16,17]. For an easier description of postoperative pain, multiple scores were compiled into one cumulative pain score for the BioCog study. This score only differentiates between tolerable and intolerable pain until the 7. postoperative day. The former was defined as a pain with NRS > 4 or BPS/BPS NI > 5 or COPT > 2 in one of the postoperative visits, which were undertaken twice daily in the morning and evening until the 7. postoperative day.

Opioid and beta-blocker equivalents

Opioids identified from anesthesia protocols included Fentanyl, Remifentanil, Morphine and Piritramid. Perioperative administered opioids were converted to their respective morphine equivalent dose according to their therapeutic potency [18]. For better comparability, the morphine index was also determined, defined as the cumulative perioperative morphine consumption divided by BMI. For comparison of the different BB, the value of the achieved target dose in percent was calculated, according to the guideline of the European Society of Cardiology (ESC) for the diagnosis and treatment of acute and chronic heart failure of 2016 [19].

Statistical analysis

All statistical analyses are exploratory in nature and not considered confirmatory. Statistical analysis was done using SPSS® Statistics 25 (SPSS, Inc., Chicago, IL). Graphics were created using both SPSS and Excel. All binary and categorical variables are reported as absolute and relative frequencies, continuous non-normally distributed variables are listed as median with interquartile range (IQR). Normal distribution was tested using histograms and the Kolmogorov-Smirnov test. Testing for differences between two independent groups was done using Mann-Whitney U test for continuous non-normally distributed variables and Pearson chi-square test for categorical non-normally distributed variables.

A simple linear regression analysis was used to test whether beta-blockade or the dose of BB therapy had an effect on perioperative opioid consumption. Multiple regression analysis was used to identify risk factors for predicting an increased or decreased morphine index. Subsequently, a normal distribution of the data used was obtained by regressing the morphine index, which allowed further precision of the confounder adjustment. The individual significant predictors were then graphically represented using bivariate regression analysis and grouped boxplots.

Results

Patient characteristics

In total, 747 patients were recruited for inclusion in the BioCog study in Berlin. Thereof, 247 patients were exluded for post hoc analysis, as their respective anesthesia protocol was recorded with an older version of the patient data management system where an exact calculation of the perfusor-controlled opioid administration, as is the case with Remifentanil, was not possible. Of the remaining 439 analyzed protocols, 106 patients fulfilled the inclusion criteria of which 37 patients had a long-term BB therapy (Fig. 1). Baseline characteristics were similar between groups (Table 1).

Fig. 1
figure 1

Patient enrollment

Full size image
Table 1 Baseline characteristics of the study population
Full size table

Preexisting medical conditions are displayed in Table 2. Patients with chronic BB therapy presented with significantly more arterial hypertension, chronic renal failure and hyperlipoproteinemia.

Table 2 Prevalence of preexisting medical conditions of the study population
Full size table

Perioperative data

Data of the perioperative phase and incidence of complications are shown in Tables 3 and 4, respectively. Patients on chronic BB therapy did not differ significantly from patients without BB therapy regarding the cumulative total opioid dose during surgery. Similarly, median anesthesia times were similarly distributed. There were no differences in the amount of administered blood products, catecholamines, antihypertensive agents and atropine. Postoperatively, no differences concerning intolerable pain, PONV as well as recovery room length of stay between both groups were detected. Admission to ICU or PACU as well as length of stay in the ICU or PACU (BB: 0 days (0–0.1); no BB: 0 days, p = 0.608) in median and hospital length of stay (BB: 6 (3.5–9) days; no BB: 6 (3.5–9) days, p = 0.828) in median did not differ between both groups. The incidence of postoperative complications are given in Table 4, revealing no significant differences between groups.

Table 3 Perioperative data of the study population
Full size table
Table 4 Incidence of postoperative complications
Full size table

Influences on perioperative opioid consumption

There was no correlation between doses of chronic BB therapy and increasing morphine equivalents (Supplementary Fig. 1).

Using multiple regression analyses independent predictors for the amount of perioperative opioid consumption, expressed by the morphine index, were examined (Table 5). Chronic BB therapy had no influence on the opioid consumption, whereas age, gender, anesthesia duration as well as type of surgery had. Their respective influence on the morphine index is given by the regression coefficient. Regarding age, each year yielded an increase of the morphine index by 0.547 mg/BMI, whereas female gender leads to a reduction of the morphine index by 9.104 mg/BMI (Table 5). Intracranial surgery as well as thoracic, abdominal and pelvic surgery were associated with an increased morphine index compared to surgery involving the extremities.

Table 5 Multiple regression analysis of morphine index (n = 106)
Full size table

Discussion

This retrospective post hoc analysis of the BioCog study was not able to detect an influence of chronic BB therapy on perioperative opioid consumption amongst noncardiac surgical patients undergoing general anesthesia. Age, gender, duration of anesthesia and type of surgery were confirmed to be of predictive value concerning an increased consumption of perioperative opioids.

Recently, there have been several studies indicating that short-term perioperative BB therapy with Esmolol can reduce perioperative opioid consumption [9, 10, 20,21,22,23], which cannot be translated to our “chronic” setting. Possible explanations could be that compared to patients on chronic BB therapy, these patients were younger and did not exhibit cardiovascular comorbidities or other similar risk factors. It is known that reactivity of beta-adrenergic receptors decreases with increasing age, termed beta-adrenoceptor desensibilisation, as demonstrated in animal and human studies. Beta-adrenoceptor desensibilisation is theorisized to be due to phosphorylation of receptor structures in agonist-receptor binding states leading to a decrease of receptor density and subsequent internalization, which has also been described amongst heart failure [24,25,26]. This further leads to a reduced autonomic modulation of the cardiac system during physical activity [27] and possibly to a diminished perioperative sympathetic reaction to pain. This change in receptor structure and function is one of the main causes of chronic BB therapy to counteract internalization.

Nonetheless, Starr et al. showed that chronic BB therapy was associated with a lower prescription of postoperative opioids within the first 30 days of surgery in a large retrospective cohort study of American veterans undergoing total knee arthroplasty implantation [28]. Furthermore, selective as well as non-selective BB were associated with a reduced postoperative morphine equivalent dose up to 30 days. However, compared to our study, Starr et al. only examined the postoperative period beginning from the first postoperative day analysing oral opioid medication. Moreover, chronic BB therapy was assumed if patients were prescribed BB within 90 days before surgery or during hospitalisation and/or within the first 90 days postoperatively. With regard to our study, we are not able to make any statement about the duration of the use of BB therapy preoperatively. Additionally, postoperative prescription rate concerning opioids differ between the United States and Germany, which may additionally explain the divergent study results [29].

A possible reason for the potential of a reduced perioperative consumption under BB therapy might be the concept of a cross-talk between beta-adrenergic and opioid receptors. In animal models, these receptors are co-expressed at the sarcolemma of cardiomyocytes [30,31,32]. This might explain that Esmolol was shown to diminish sympathetic excitation perioperatively caused by PONV in the literature [9,10,11]. However, it is unclear if these effects could also apply to a chronic BB therapy.

Additionally, stimulation of δ- and κ-opioidreceptors not only mediated cardioprotective effects against ischemic and hypoxia-induced injury in animal models, but also limited the positive inotropic and chronotropic effects of catecholamines [8, 33,34,35,36,37,38,39,40]. A clinical transitional study showing a possible interaction between both receptors in the human body is still lacking. We were also not able show significant differences in perioperative use of catecholamines, antihypertensive drugs and cardiovascular complications with and without beta-blockade in our study. The reason for that could be the relative small sample size in the BB group. However, in a large cohort study by Ahl et al. patients presenting for emergent colonic cancer surgery also did not differ regarding perioperative complications whether they were on chronic beta-blockade or not [41].

Beyond our primary study we were able to show that several factors were associated with an increased opioid usage. One of these specific factors was gender. Gender-specific differences in pain perception have been described in the literature. Regarding postoperative pain ambiguous results were reported [42,43,44,45,46,47,48,49]. However, none of these studies is methodologically comparable to our investigation. Physiologically, gonadal steroid hormones (e.g. estradiol, testosterone) have a modulating effect on pain perception and analgesia. They can influence the pharmacokinetics and pharmacodynamics of opioids by altering absorption and distribution as well as metabolism of opioids to active and inactive metabolites [50, 51]. Oestrogens can attenuate the effects of endogenous and exogenous opioids by binding directly to opioid receptors [52].

Type of surgery was also associated with an increased perioperative morphine index, especially in abdominal surgery. Yet, the ratio of abdominal to peripheral surgery was 25:76, this uneven cohort as well as longer surgery and anesthesia duration might have obscured the results. Nevertheless, our results are in contrast to an observational study by Ekstein et al., which compared abdominal to orthopedic surgery. The authors found no differences regarding intraoperative cumulative doses of fentanyl, but higher postoperative pain scores after orthopedic surgery [53].

To our knowledge, there exist only few studies investigating perioperative opioid consumption in elderly patients up to now [54]. Pathophysiologically several mechanisms might be an explanation for the observed association between age and opioid consumption. With increasing age, a large propotion of metabolically active tissue is converted to fat leading to altered distribution volumes of lipo- and hydrophilic drugs [55]. Cardiac output decreases with a change in distribution from kidneys and liver to heart and brain [56]. Renal parenchyma and renal clearance as well as liver mass and hepatic blood flow decreases [57, 58]. All these result in a significantly lower clearance, prolonged terminal elimination half-time and higher serum concentrations of opioids in elderly compared to younger patients [59]. However, it remains unclear why more opioids were administered (or needed) by the older patients in our study. Also amongst older patients, Remifentanil was deployed more often than other opioids as part of the anesthesia plan due to its favourable effects, e.g. short-half life, organ-independent degradation, etc. As Remifentanil was calculated with an morphin equivalent of 200, it had a significant impact on the calculated morphine equivalent dose compared to other opioids.

Limitations

There are several limitations applying to our study. Concerning its post hoc design, an adequate power analysis and sample size calculation was not performed. Secondly, chronic beta-blockade was only defined by its preoperative existence, not by its duration before surgery. We also did not record the total duration of the chronic BB treatment. Compared to other studies, different pharmacokinetics between oral intake in chronic blockade versus intravenous application in acute beta-blockade may result in varying bioavailability. Aggregation of perioperatively administered opioids into a morphine equivalent dose without taking into consideration that pharmacokinetic differences exist between different opioids must be considered the greatest limitation. We also exluded patients who received regional anesthesia and did not analyse alternate multimodal strategies for opioid reduction in our study, as these were too heterogenous between the different types of surgery and the two campuses of which data were analysed. We might also missed other confounding factors regarding analgesic therapy, e.g. influence of non-steroidal anti-inflammatory drugs, which might have been not used in patients with vascular disease, leading to a higher use in patients with BB obscuring the effect of the latter. There was no study specific protocol for intra- and postoperative pain management due to the retrospective nature of the post hoc analysis. Due to the limited sample size, it could be possible that an effect of a chronic BB therapy on opioid consumption might not have been detected in our cohort. Therefore, prospective trials with larger sample sizes are needed to investigate this question further. Finally, there was a great amount of heterogeneity regarding types of surgery included resulting in a heterogenous study group as well as different BB that were taken in the chronic BB group. We did not collect information about the exact indication for chronic BB intake as well as about the proportion of patients who complied to the recommendations concerning perioperative BB intake. We did not analyze the effect of individual risk factors on outcome as sample size was too small. Also, we cannot for sure certify the comparability of similar procedures, i.e. procedure per specialism.

Conclusions

In our study being one of the first to examine the influence of a chronic beta-blockade on perioperative opioid consumption, we could not show an association between these two. There is a need for randomized controlled trials and adequately powered prospective studies to examine this question further before any conclusions can be made.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to German data protection laws.

Abbreviations

ASA PS:

American Society of Anesthesiologists Physical Status

BB:

Beta-Blocker

BMI:

Body mass index

BPS:

Behavioral Pain Scale

BPS-NI:

Behavioral Pain Scale non intubated

COPD:

Chronic obstructive pulmonary disease

CPOT:

Critical-Care Pain Observation Tool

ESC:

European Society of Cardiology

ICU:

Intensive care unit

IQR:

Interquartile range

NRS:

Numeric Rating Scale

PACU:

Postanaesthesia care unit

POCD:

Postoperative cognitive dysfunction

POD:

Postoperative delirium

PONV:

Postoperative nausea and vomiting

TIA:

Transient ischemic attack

References

  1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–726.

    Article  CAS  PubMed  Google Scholar 

  2. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2018;39(2):119–77.

    Article  PubMed  Google Scholar 

  3. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54(19):1747–62.

    Article  CAS  PubMed  Google Scholar 

  4. Ahl R, Ismail AM, Borg T, Sjölin G, Forssten MP, Cao Y, et al. A nationwide observational cohort study of the relationship between beta-blockade and survival after hip fracture surgery. Eur J Trauma Emerg Surg. 2022;48(2):743–51.

    Article  PubMed  Google Scholar 

  5. Headrick JP, See Hoe LE, Du Toit EF, Peart JN. Opioid receptors and cardioprotection – “opioidergic conditioning” of the heart. Br J Pharmacol. 2015;172:2026–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dehé L, Shaqura M, Nordine M, Habazettl H, von Kwiatkowski P, Schluchter H, et al. Chronic naltrexone therapy is associated with improved cardiac function in volume overloaded rats. Cardiovasc Drugs Ther. 2021;35(4):733–43.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pepe S, van den Brink OWV, Lakatta EG, Xiao RP. Cross-talk of opioid peptide receptor and beta-adrenergic receptor signalling in the heart. Cardiovasc Res. 2004;63(3):414–22.

    Article  CAS  PubMed  Google Scholar 

  8. Pepe S, Xiao RP, Hohl C, Altschuld R, Lakatta EG. ‘Cross talk’ between opioid peptide and adrenergic receptor signaling in isolated rat heart. Circulation. 1997;95(8):2122–9.

    Article  CAS  PubMed  Google Scholar 

  9. Gelineau AM, King MR, Ladha KS, Burns SM, Houle T, Anderson TA. Intraoperative esmolol as an adjunct for perioperative opioid and postoperative pain reduction: a systematic review, meta-analysis, and meta-regression. Anesth Analg. 2018;126(3):1035–49.

    Article  CAS  PubMed  Google Scholar 

  10. Watts R, Thiruvenkatarajan V, Calvert M, Newcombe G, van Wijk RM. The effect of perioperative esmolol on early postoperative pain: a systematic review and meta-analysis. J Anaesthesiol Clin Pharmacol. 2017;33(1):28–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Thiruvenkatarajan V, Watts R, Calvert M, Newcombe G, Van Wijk RM. The effect of esmolol compared to opioids on postoperative nausea and vomiting, postanesthesia care unit discharge time, and analgesia in noncardiac surgery: a meta-analysis. J Anaesthesiol Clin Pharmacol. 2017;33(2):172–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Winterer G, Androsova G, Bender O, Boraschi D, Borchers F, Dschietzig TB, et al. Personalized risk prediction of postoperative cognitive impairment - rationale for the EU-funded BioCog project. Eur Psychiatry. 2018;50:34–9.

    Article  CAS  PubMed  Google Scholar 

  13. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery. 1992;111(5):518–26.

    CAS  PubMed  Google Scholar 

  14. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Payen JF, Bru O, Bosson JL, Lagrasta A, Novel E, Deschaux I, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med. 2001;29(12):2258–63.

    Article  CAS  PubMed  Google Scholar 

  16. Chanques G, Payen JF, Mercier G, de Lattre S, Viel E, Jung B, et al. Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale. Intensive Care Med. 2009;35(12):2060–7.

    Article  PubMed  Google Scholar 

  17. Gélinas C, Ross M, Boitor M, Desjardins S, Vaillant F, Michaud C. Nurses’ evaluations of the CPOT use at 12-month post-implementation in the intensive care unit. Nurs Crit Care. 2014;19(6):272–80.

    Article  PubMed  Google Scholar 

  18. Aktories K, Förstemann U, Hofmann F, Starke K. Allgemeine und spezielle pharmakologie und toxikologie. München: Elsevier; 2017.

    Google Scholar 

  19. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200.

    Article  PubMed  Google Scholar 

  20. Celebi N, Cizmeci EA, Canbay O. Intraoperative esmolol infusion reduces postoperative analgesic consumption and anaesthetit use during septorhinoplasty: a randomized trial. Rev Bras Anestesiol. 2014;64(5):343–9.

    Article  PubMed  Google Scholar 

  21. Ozturk T, Kaya H, Aran G, Aksun M, Savaci S. Postoperative beneficial effects of esmolol in treated hypertensive patients undergoing laparoscopic cholecystectomy. Br J Anaesth. 2008;100(2):211–4.

    Article  CAS  PubMed  Google Scholar 

  22. Morais VBD, Sakata RK, Huang APS, Ferraro LHDC. Randomized, double-blind, placebo-controlled study of the analgesic effect of intraoperative esmolol for laparoscopic gastroplasty. Acta Cir Bras. 2020;35(4):e202000408.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chia YY, Chan MH, Ko NH, Liu K. Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy. Br J Anaesth. 2004;93(6):799–805.

    Article  CAS  PubMed  Google Scholar 

  24. White M, Roden R, Minobe W, Khan MF, Larrabee P, Wollmering M, et al. Age-related changes in beta-adrenergic neuroeffector systems in the human heart. Circulation. 1994;90(3):1225–38.

    Article  CAS  PubMed  Google Scholar 

  25. Xiao RP, Tomhave ED, Wang DJ, Ji X, Boluyt MO, Cheng H, et al. Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. J Clin Invest. 1998;101(6):1273–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rengo G, Perrone-Filardi P, Femminella GD, Liccardo D, Zincarelli C, de Lucia C, et al. Targeting the Beta-adrenergic receptor system through G-protein-coupled receptor kinase 2: a new paradigm for therapy and prognostic evaluation in heart failure: from bench to bedside. Circ Heart Fail. 2012;5(3):385–91.

    Article  CAS  PubMed  Google Scholar 

  27. Scarpace PJ, Shu Y, Tümer N. Influence of exercise training on myocardial beta-adrenergic signal transduction: differential regulation with age. J Appl Physiol (1985). 1994;77(2):737–41.

    Article  CAS  PubMed  Google Scholar 

  28. Starr JB, Backonja M, Rozet I. Beta-blocker use is associated with a reduction in opioid use 30 days after total knee arthroplasty. Pain Physician. 2019;22(5):E395–406.

    Article  PubMed  Google Scholar 

  29. Preissner S, Siramshetty VB, Dunkel M, Steinborn P, Luft FC, Preissner R. Pain-prescription differences - an analysis of 500,000 discharge summaries. Curr Drug Res Rev. 2019;11(1):58–66.

    Article  PubMed  Google Scholar 

  30. Ventura C, Bastagli L, Bernardi P, Caldarera CM, Guarnieri C. Opioid receptors in rat cardiac sarcolemma: effect of phenylephrine and isoproterenol. Biochim Biophys Acta. 1989;987(1):69–74.

    Article  CAS  PubMed  Google Scholar 

  31. Holaday JW. Cardiovascular effects of endogenous opiate systems. Annu Rev Pharmacol Toxicol. 1983;23:541–94.

    Article  CAS  PubMed  Google Scholar 

  32. Tang J, Yang HY, Costa E. Distribution of met5-enkephalin-Arg6-Phe7 (MEAP) in various tissues of rats and guinea pigs. Life Sci. 1982;31(20–21):2303–6.

    Article  CAS  PubMed  Google Scholar 

  33. Xiao RP, Pepe S, Spurgeon HA, Capogrossi MC, Lakatta EG. Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells. Am J Physiol. 1997;272(2 Pt 2):H797-805.

    CAS  PubMed  Google Scholar 

  34. Wong TM, Shan J. Modulation of sympathetic actions on the heart by opioid receptor stimulation. J Biomed Sci. 2001;8(4):299–306.

    Article  CAS  PubMed  Google Scholar 

  35. Yu XC, Wang HX, Pei JM, Wong TM. Anti-arrhythmic effect of kappa-opioid receptor stimulation in the perfused rat heart: involvement of a cAMP-dependent pathway. J Mol Cell Cardiol. 1999;31(10):1809–19.

    Article  CAS  PubMed  Google Scholar 

  36. Sheldon RJ, Nunan L, Porreca F. Differential modulation by [D-Pen2, D-Pen5]enkephalin and dynorphin A-(1–17) of the inhibitory bladder mobility effects of selected mu agonists in vivo. J Pharmacol Exp Ther. 1989;249(2):462–9.

    CAS  PubMed  Google Scholar 

  37. Qi JN, Mosberg HI, Porreca F. Modulation of the potency and efficacy of mu-mediated antinociception by delta agonists in the mouse. J Pharmacol Exp Ther. 1990;254(2):683–9.

    CAS  PubMed  Google Scholar 

  38. Schoffelmeer AN, Yao YH, Gioannini TL, Hiller JM, Ofri D, Roques BP, et al. Cross-linking of human [125I]beta-endorphin to opioid receptors in rat striatal membranes: biochemical evidence for the existence of a mu/delta opioid receptor complex. J Pharmacol Exp Ther. 1990;253(1):419–26.

    CAS  PubMed  Google Scholar 

  39. Traynor JR, Elliott J. Delta-Opioid receptor subtypes and cross-talk with mu-receptors. Trends Pharmacol Sci. 1993;14(3):84–6.

    Article  CAS  PubMed  Google Scholar 

  40. Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning and morphine-induced cardioprotection involve the delta (delta)-opioid receptor in the intact rat heart. J Mol Cell Cardiol. 1997;29(8):2187–95.

    Article  CAS  PubMed  Google Scholar 

  41. Ahl R, Matthiessen P, Cao Y, Sjolin G, Ljungqvist O, Mohseni S. The relationship between severe complications, beta-blocker therapy and long-term survival following emergency surgery for colon cancer. World J Surg. 2019;43(10):2527–35.

    Article  PubMed  Google Scholar 

  42. Aubrun F, Salvi N, Coriat P, Riou B. Sex- and age-reltaed differences in morphine requirements for postoperative pain relief. Anesthesiology. 2005;103(1):156–60.

    Article  CAS  PubMed  Google Scholar 

  43. Zheng H, Schnabel A, Yahiaoui-Doktor M, Meissner W, Van Aken H, Zahn P, et al. Age and preoperative pain are major confounders for sex differences in postoperative pain outcome: a prospective database analysis. PLoS One. 2017;12(6):e0178659.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hrebinko KA, Myers SP, Tsang WL, Doney L, Lazar S, Teng C, et al. Sex comparisons in opioid use and pain after colorectal surgery using enhanced recovery protocols. J Surg Res. 2020;253:105–14.

    Article  CAS  PubMed  Google Scholar 

  45. Cavallaro PM, Fields AC, Bleday R, Kaafarani H, Yao Y, Sequist TD, et al. A multi-center analysis of cumulative inpatients opioid use in colorectal surgery patients. Am J Surg. 2020;220(5):1160–6.

    Article  PubMed  Google Scholar 

  46. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10(5):447–85.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Craft RM, Mogil JS, Aloisi AM. Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain. 2004;8(5):397–411.

    Article  CAS  PubMed  Google Scholar 

  48. Niesters M, Dahan A, Kest B, Zacny J, Stijnen T, Aarts L, et al. Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain. 2010;151(1):61–8.

    Article  PubMed  Google Scholar 

  49. Cepeda MS, Carr DB. Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg. 2003;97(5):1464–8.

    Article  PubMed  Google Scholar 

  50. Baker L, Ratka A. Sex-specific differences in levels of morphine, morphine-3-glucuronide, and morphine antinociception in rats. Pain. 2002;95(1–2):65–74.

    Article  CAS  PubMed  Google Scholar 

  51. South SM, Wright AW, Lau M, Mather LE, Smith MT. Sex-related differences in antinociception and tolerance development following chronic intravenous infusion of morphine in the rat: modulatory role of testosterone via morphine clearance. J Pharmacol Exp Ther. 2001;297(1):446–57.

    CAS  PubMed  Google Scholar 

  52. Schwarz S, Pohl P. Steroids and opioid receptors. J Steroid Biochem Mol Biol. 1994;48(4):391–402.

    Article  CAS  PubMed  Google Scholar 

  53. Ekstein MP, Weinbroum AA. Immediate postoperative pain in orthopedic patients is more intense and requires more analgesia than in post-laparotomy patients. Pain Med. 2011;12(2):308–13.

    Article  PubMed  Google Scholar 

  54. Pesonen A, Suojaranta-Ylinen R, Hammarén E, Kontinen VK, Raivio P, Tarkkila P, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106(6):873–81.

    Article  CAS  PubMed  Google Scholar 

  55. Funk RD, Hilliard P, Ramachandran SK. Perioperative opioid usage: avoiding adverse effects. Plast Reconstr Surg. 2014;134(4 Suppl 2):32S-S39.

    Article  CAS  PubMed  Google Scholar 

  56. Bender AD. The effect of increasing age on the distribution of peripheral blood flow in man. J Am Geriatr Soc. 1965;13:192–8.

    Article  CAS  PubMed  Google Scholar 

  57. Aymanns C, Keller F, Maus S, Hartmann B, Czock D. Review on pharmacokinetics and pharmacodynamics and the aging kidey. Clin J Am Soc Nephrol. 2010;5(2):314–27.

    Article  CAS  PubMed  Google Scholar 

  58. Schmucker DL. Age-related changes in liver structure and function: Implications for disease? Exp Gerontol. 2005;40(8–9):650–9.

    Article  CAS  PubMed  Google Scholar 

  59. Bentley JB, Borel JD, Nenad RE, Gillespie TJ. Age and fentanyl pharmacokinetics. Anesth Analg. 1982;61(12):968–71.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This paper includes results of the doctoral thesis entitled “Influence of beta blocker Therapy on perioperative opioid consumption” submitted by Luisa Margarete Rothe to the faculty of Charité – Universitätsmedizin Berlin in 2022.

Funding

Open Access funding enabled and organized by Projekt DEAL. The research leading to these results has reveived the funding from the European Community’ s FP7 under grant agreement n. 602461.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt Universität zu Berlin, Hindenburgdamm 30, Berlin, 12203, Germany

    Ralf F. Trauzeddel, Lukas Dehé & Sascha Treskatsch

  2. IS Global Campus Cliníc Rosselló, Barcelona Institute for Global Health, 132, 7è, Barcelona, 08036, Spain

    Luisa M. Rothe

  3. Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany

    Michael Nordine

  4. Department of Anesthesiology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt Universität zu Berlin, Augustenburger Platz 1, Berlin, 13353, Germany

    Kathrin Scholtz, Claudia Spies, Daniel Hadzidiakos, Georg Winterer & Friedrich Borchers

  5. Hochschule Osnabrück, University of Applied Sciences, Osnabrück, Germany

    Jochen Kruppa

Authors
  1. Ralf F. Trauzeddel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luisa M. Rothe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Nordine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lukas Dehé
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathrin Scholtz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claudia Spies
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel Hadzidiakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Georg Winterer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Friedrich Borchers
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jochen Kruppa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sascha Treskatsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RFT analysed and interpretated the data; drafting the article; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. LMR acquired data; analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MN revised the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. LD revised the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. KS analyzed and interpreted the data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CS made substantial contribution to conception and design, acquisition, analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DH made substantial contribution to conception and design of the study; acquisition, analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GW made substantial contribution to conception and design of the study; acquisition, analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. FB made substantial contribution to conception and design of the study; acquisition, analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JK made substantial contribution to conception and design of the study; analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. ST made substantial contribution to conception and design of the study; acquisition, analysis and interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolve.

Corresponding author

Correspondence to Sascha Treskatsch.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the local ethics committee at Charité - Universitätsmedizin Berlin (EA 2/092/14) on the 31.07.2014. Informed written consent was obtained from all patients before study inclusion.

Consent for publication

Not applicable.

Competing interests

LMR, MN, LD, KS, DH, GW, FB, JK declare no competing interests. RFT, CS and ST disclosed all their financial and non-financial relationships and activities within 36 months of manuscript submission in the ICMJE disclosure forms submitted with the manuscript.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trauzeddel, R.F., Rothe, L.M., Nordine, M. et al. Influence of a chronic beta-blocker therapy on perioperative opioid consumption – a post hoc secondary analysis. BMC Anesthesiol 24, 80 (2024). https://0-doi-org.brum.beds.ac.uk/10.1186/s12871-024-02456-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s12871-024-02456-2

Keywords

BMC Anesthesiology

ISSN: 1471-2253

Contact us