Multimodale analgesie beoogt het toedienen van analgetica met verschillende werkingsmechanismen voor een additief effect. Standaard worden paracetamol, NSAID (indien geen contra-indicaties) en opioïden toegediend. In de voorgaande hoofdstukken is uitgebreid de waarde van toevoeging van individuele componenten van multimodale analgesie beschreven en onderzocht. Dit waren vooral one-factor-at-a-time studies. Vaak worden in de praktijk deze componenten met elkaar gecombineerd. Hierbij gaat het dus om multimodale farmacologische analgesie. Om deze combinaties goed te kunnen beoordelen is een “factorial study design” nodig, waarbij twee (of meer) interventies (hier: multimodale componenten) tegelijk met elkaar vergeleken worden. Het aantal gepubliceerde factoriële trials over multimodale analgesie is beperkt. Er zijn geen studies bekend die een 3x3 of hoger factorieel design hebben. Het hoogste aantal multimodale componenten, zoals in de voorgaande hoofdstukken beschreven, dat systematisch onderzocht werd is 2 in een 2x2 factorieel design. Hierdoor is het moeilijk om een goed onderbouwde conclusie te trekken over de effectiviteit van de combinatie van 3 of meer van de boven beschreven componenten van multimodale analgesie en werd in deze module gefocust op het effect van de toevoeging van een tweede multimodale component.

Taken together, the following conclusions could be drawn:

• The use of a second multimodal component may further reduce postoperative pain scores at PACU arrival and 24 hours post-surgery in surgical patients, but the evidence is uncertain (very low GRADE; sources: Patel, 2016, Sivaji, 2022; Xu, 2017; Martinez, 2014; Ghadami, 2021, Choi, 2013; Demirhan, 2014; Demirhan, 2013; Momon, 2019; Zengin, 2015)
• The use of a second multimodal component may further reduce postoperative pain scores at 2-4, 6-8 and 12 hours post-surgery in surgical patients (low GRADE; sources: Patel, 2016; Sivaji, 2022; Xu, 2017; Ghadami, 2021; Choi, 2013; Demirhan, 2014; Demirhan, 2013; Zengin, 2015)
• The use of a second multimodal component may further reduce opioid consumption in the total postoperative period in surgical patients (low GRADE; sources: Patel, 2016, Sivaji, 2022; Xu, 2017; Jabbour, 2020, Adhikary, 2021, Martinez, 2014; Abdelgalil, 2018; Demirhan, 2014; Demirhan, 2013; Mathiesen, 2008, Mathiesen, 2009; Momon, 2019; Zengin, 2015)

Description of studies

As shown in table 1, different controls were used, in various surgeries and using different scales to assess postoperative pain. The number of patients per arm ranged from 20 to 99. All studies were single-centered RCTs.

Table 1. Characteristics of studies that compared adding a second multimodal component with controls

Results

1. Postoperative pain

Postoperative pain was assessed at PACU arrival-1h post-surgery, 2-4 hours, 6-8 hours, 12 hours and 24 hours post-surgery. Multiple studies reported pain on other time points as shown in the evidence tables. For these analyses, the most widely used time points are included as predefined in the PICO.

A lower score indicated less pain for all scales. In case data could not be pooled, results were summarized.

1.1 Postoperative pain at PACU arrival – 1 h post-surgery

In total, eight studies reported postoperative pain in the period PACU arrival to 1 h post-surgery (Sivaji 2022, Xu 2017, Martinez 2014, Choi 2013, Demirhan 2013, Demirhan 2014, Momon 2019, Zengin 2015) for a control group (standard care), a second group with standard care plus one multimodal component and a third group with standard care plus two multimodal components.

The weighted mean pain score (VAS/NRS) was 3.76 in the control group; 3.15 in the group with standard care plus one multimodal component and 3.00 in the group with standard care plus two multimodal components.

In addition to the pooled data, additional data reporting pain scores in the period PACU arrival to 1 h post-surgery were found in eleven studies. These studies could not be included in the weighted mean analysis due to the following reasons: no absolute data were presented (only in figures) or the studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components.

The following studies reported postoperative pain scores (VAS/NRS) only in figures:

Guo (2022) reported lower pain scores in the multimodal groups than in the control group.

Koc (2007) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Adhikary (2021) reported similar pain scores across the groups.

Jabbour (2020) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain score in the group with one multimodal component was in between.

Varas (2020) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain score in the group with one multimodal component was in between.

Mendonca (2020) reported a lower pain score in the group with two multimodal components compared to the groups with standard care or standard care plus one multimodal component.

Abdelgalil (2018) reported lower pain scores in the multimodal groups than in the control group.

The following studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components):

Lee (2018) reported a mean pain score of 5.2 in the groups with one multimodal component compared to 4.7 in the group with two multimodal components.

Hassan (2021) reported the same median pain score of 4 in both groups.

Murphy (2021) reported a median pain score of 6 in the group with one multimodal component compared to 3.5 in the group with two multimodal components at PACU admission.

Jabbour (2014) reported in a figure a higher pain score in the group with one multimodal component compared to the group with two multimodal components.

1.2 Postoperative pain 2 – 4 h post-surgery

In total, seven studies reported postoperative pain in the time period 2 – 4h post-surgery (Patel 2016, Sivaji 2022, Xu 2017, Ghadami 2021, Demirhan 2013, Demirhan 2014, Zengin 2015) for a control group (standard care), a second group with standard care plus one multimodal component and a third group with standard care plus two multimodal components.

The weighted mean pain score (VAS/NRS) was 3.42 in the control group; 2.45 in the group with standard care plus one multimodal component and 1.87 in the group with standard care plus two multimodal components.

In addition to the pooled data, additional data reporting pain scores in the time period 2 to 4h post-surgery were found in eleven studies. These studies could not be included in the weighted mean analysis due to the following reasons: no absolute data were presented (only in figures) or the studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components.

The following studies reported postoperative pain scores (VAS/NRS) only in figures:

Guo (2022) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Koc (2007) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Adhikary (2021) reported similar pain scores across the groups.

Jabbour (2020) reported a lower pain score in the group with two multimodal components compared to the group with standard care plus one multimodal component.

Varas (2020) reported similar pain scores across the groups.

Abdelgalil (2018) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Mathiesen (2008) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Mathiesen (2009) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Mathiesen (2011) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

The following studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components):

Hassan (2021) reported a median pain score of 3 in the group with one multimodal component compared to 2 in the group with two multimodal components.

Jabbour (2014) reported in a figure a higher pain score in the group with one multimodal component compared to the group with two multimodal components.

1.3 Postoperative pain at 6 - 8 hours post-surgery

In total, five studies reported postoperative pain in the time period 6 – 8h post-surgery (Patel 2016, Xu 2017, Demirhan 2013, Demirhan 2014, Zengin 2015) for a control group (standard care), a second group with standard care plus one multimodal component and a third group with standard care plus two multimodal components.

The weighted mean pain score (VAS/NRS) was 3.28 in the control group; 2.12 in the group with standard care plus one multimodal component and 1.58 in the group with standard care plus two multimodal components.

In addition to the pooled data, additional data reporting pain scores in the time period 6 to 8h post-surgery were found in eight studies. These studies could not be included in the weighted mean analysis due to the following reasons: no absolute data were presented (only in figures) or the studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components.

The following studies reported postoperative pain scores (VAS/NRS) only in figures:

Guo (2022) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Koc (2007) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Adhikary (2021) reported similar pain scores across the groups.

Varas (2020) reported a lower pain score in the group with two multimodal components compared to the group with standard care. The group with standard care plus one multimodal component had the lowest pain score.

Abdelgalil (2018) reported similar pain scores across the groups.

The following studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components):

Lee (2018) reported a mean pain score of 4,9 in the groups with one multimodal component compared to 4,2 in the group with two multimodal components.

Hassan (2021) reported the same median pain score of 2 in both groups.

Jabbour (2014) reported in a figure a higher pain score in the group with one multimodal component compared to the group with two multimodal components.

1.4 Postoperative pain at 12 hours post-surgery

In total, eight studies reported postoperative pain 12h post-surgery (Patel 2016, Sivaji 2022, Xu 2017, Ghadami 2021, Choi 2013, Demirhan 2013, Demirhan 2014, Zengin 2015) for a control group (standard care), a second group with standard care plus one multimodal component and a third group with standard care plus two multimodal components.

The weighted mean pain score (VAS/NRS) was 3.07 in the control group; 2.15 in the group with standard care plus one multimodal component and 1.81 in the group with standard care plus two multimodal components.

In addition to the pooled data, additional data reporting pain scores 12h post-surgery were found in nine studies. These studies could not be included in the weighted mean analysis due to the following reasons: no absolute data were presented (only in figures) or the studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components.

The following studies reported postoperative pain scores (VAS/NRS) only in figures:

Guo (2022) reported a slightly lower pain score in the group with two multimodal components compared to the groups with standard care or standard care plus one multimodal component.

Koc (2007) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Adhikary (2021) reported the lowest pain score in the standard care group and the highest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between.

Varas (2020) reported similar pain scores across the groups.

Mendonca (2020) reported a lower pain score in the group with two multimodal components compared to the groups with standard care or standard care plus one multimodal component.

Abdelgalil (2018) reported a lower pain score in the group with two multimodal components compared to the groups with standard care or standard care plus one multimodal component.

The following studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components):

Hassan (2021) reported a median pain score of 4 in the group with one multimodal component compared to 2 in the group with two multimodal components.

Murphy (2021) reported a median pain score of 4 in the group with one multimodal component compared to 3 in the group with two multimodal components.

Jabbour (2014) reported in a figure a higher pain score in the group with one multimodal component compared to the group with two multimodal components.

1.5 Postoperative pain at 24 hours post-surgery

In total, eight studies reported postoperative pain in the time period 24h post-surgery (Patel 2016, Sivaji 2022, Xu 2017, Martinez 2014, Ghadami 2021, Choi 2013, Demirhan 2013, Demirhan 2014) for a control group (standard care), a second group with standard care plus one multimodal component and a third group with standard care plus two multimodal components.

The weighted mean pain score (VAS/NRS) was 2.13 in the control group; 1.80 in the group with standard care plus one multimodal component and 1.28 in the group with standard care plus two multimodal components.

In addition to the pooled data, additional data reporting pain scores 24h post-surgery were found in twelve studies. These studies could not be included in the weighted mean analysis due to the following reasons: no absolute data were presented (only in figures) or the studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components.

The following studies reported postoperative pain scores (VAS/NRS) only in figures:

Guo (2022) reported similar pain scores across the groups.

Koc (2007) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the groups with one multimodal component were in between, with small differences between all groups.

Adhikary (2021) reported similar pain scores across the groups.

Mendonca (2020) reported a lower pain score in the group with two multimodal components compared to the groups with standard care or standard care plus one multimodal component.

Abdelgalil (2018) reported similar pain scores across the groups.

Mathiesen (2008) reported similar pain scores across the groups.

Mathiesen (2009) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the group with one multimodal component were in between.

Mathiesen (2011) reported the highest pain score in the standard care group and the lowest pain score in the group with two multimodal components. The pain scores in the group with one multimodal component were in between.

The following studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components):

Lee (2018) reported a mean pain score of 3.6 in the groups with one multimodal component compared to 3,1 in the group with two multimodal components.

Hassan (2021) reported the same median pain score of 1 in both groups.

Murphy (2021) reported a median pain score of 4 in the group with one multimodal component compared to 3 in the group with two multimodal components.

Jabbour (2014) reported in a figure a slightly higher pain score in the group with one multimodal component compared to the group with two multimodal components.

2. Postoperative opioid consumption

The consumption of rescue analgesics (opioids) is reported in a very heterogeneous manner in the included studies. The percentage of reduction of opioid consumption in the total study period (mostly 24h) was calculated. Studies with no use of a postoperative opioid at all in any group were excluded. In total, thirteen studies reported postoperative opioid use (Patel 2016, Sivaji 2022, Xu 2017, Adhikary 2021, Jabbour 2020, Martinez 2014, Abdelgalil 2018, Demirhan 2013, Demirhan 2014, Mathiesen 2008, Mathiesen 2009, Momon 2019, Zengin 2015) for a control group (standard care), a second group with standard care plus one multimodal component and a third group with standard care plus two multimodal components.

The weighted mean percentage of reduction of opioid consumption was 17.65% in the group with standard care plus one multimodal component compared to the group with standard care and 24.11% in the group with standard care plus two multimodal components compared to the group with standard care.

The following studies included no control group with standard care but only two groups (one group with standard care plus one multimodal component and a second group with standard care plus two multimodal components):

Lee (2018) reported a 6.22% reduction of postoperative opioid consumption in the group with two multimodal components compared to the group with one multimodal component.

Hassan (2021) reported a 27.33% reduction of postoperative opioid consumption in the group with two multimodal components compared to the group with one multimodal component.

Murphy (2021) reported a 53.45% reduction of postoperative opioid consumption in the group with two multimodal components compared to the group with one multimodal component.

Jabbour (2014) reported a 29.57% reduction of postoperative opioid consumption in the group with two multimodal components compared to the group with one multimodal component.

Level of evidence of the literature

The literature included in this summary was retrieved using a non-systematic literature search. Therefore, it cannot be stated that all literature regarding multimodal analgesia using the components of modules 10.1 to 10.8 was included in the current summary. The identified literature was summarized per outcome measure. A description of the level of evidence, based on the GRADE guidelines, is provided per outcome measure, making it possible to illustrate the certainty of the results that were retrieved using this non-systematic literature search.

The level of evidence regarding the outcome measure postoperative pain at each time point started as high because the studies were RCTs.

1. Postoperative pain

• The level of evidence regarding the outcome measures postoperative pain at 2-4 hours, postoperative pain at 6-8 hours post-surgery and postoperative pain at 12 hours post-surgery was downgraded by two levels because of conflicting results (inconsistency, -1), and indirectness of evidence (-1). The level of evidence is low.
• The level of evidence regarding the outcome measures postoperative pain at PACU arrival to 1 hour post-surgery and postoperative pain at 24 hours post-surgery was downgraded by three levels because of conflicting results (inconsistency, -1), indirectness of evidence (-1) and the weighted mean effect crossing the border of clinical relevance (imprecision -1). The level of evidence is very low.

2. Postoperative opioid consumption

• The level of evidence regarding the outcome measure postoperative opioid consumption was downgraded by 2 levels because of conflicting results (inconsistency -1) and indirectness of evidence (-1). The level of evidence is low.

A review of the literature was performed to answer the following question:

What is the effectiveness of adding a second multimodal component, as described in 10.1. – 10.8, perioperatively to standard care plus one multimodal component in surgical patients on postoperative pain (and rescue analgesic consumption)?

P: patients                                      Surgical patients

I: intervention                               Adding a second multimodal component, as described in 10.1. – 10.8,

C: control                                       Standard care and standard care plus one multimodal component

O: outcome measure                   1 . Postoperative pain

                                                     2. Rescue analgesic consumption (opioids)

This module was written to integrate modules 10.1 to 10.8, discussing the overarching context of the use of a combination of multimodal components in surgical patients. To provide insight in the literature regarding multimodal analgesia, a non-systematic literature search was conducted in PubMed, combining the search terms “postoperative pain ‘component1’ ‘component2’. Component 1 and 2 indicate all the pharmacological treatments as described in previous modules. It cannot be stated that all literature regarding multimodal analgesia using the components of modules 10.1 to 10.8 is included in the current summary.

Relevant outcome measures

The guideline development group considered postoperative pain as a critical outcome measure for decision making; and adverse outcomes and rescue analgesic consumption as an important outcome measure for decision making. The working group defined the outcome measures as follows:

Postoperative pain at rest: Validated pain scale (Visual Analogue Scale (VAS), Numeric Rating Scale (NRS) or Verbal Rating Scale (VRS)) at PACU admission – 1h post-surgery, 2-4 h post-surgery, 6-8 h post-surgery, 12 and 24 hours post-surgery.

A priori, the working group did not define the other outcome measures listed above but used the definitions used in the studies.

The working group defined one point as a minimal clinically (patient) important difference on a 10-point pain score and 10 mm on a 100 mm pain scale. Regarding postoperative opioid consumption, a difference of 10 mg was considered clinically relevant.

Search and select (Methods)                                                                                 

The database Pubmed was searched with relevant search terms until 1-7-2022. The detailed search strategy is depicted under the tab Methods. Studies were selected based on the following criteria:

• Randomized controlled trials (RCTs)
• Patients ≥ 18 years
• Conform PICO

Results

A total of 24 studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.