Veelal heeft het voorkeur om patiënten met een cervicaal radiculair syndroom (CRS) primair te behandelen met conservatieve (niet-operatieve) therapieën. Als onderdeel van een conservatief traject kunnen zorgverleners naast bewegingsadviezen, fysiotherapie en pijnmedicatie ook een interventionele pijnbehandeling geven. Een interventionele pijnbehandeling kan bestaan uit epidurale corticosteroïde-injecties. Door pijnverlichting probeert men een operatieve interventie te voorkomen, aangezien het natuurlijk beloop van een CRS meestal gunstig is.

De achtergrond voor epidurale corticosteroïde-injecties is gebaseerd op de veronderstelling dat CRS gepaard gaat met een ontstekingsreactie, welke bijdraagt aan de radiculaire pijnklachten. De aanname is dat de injecties pijnstillend en ontstekingsremmend werken. Injecties kunnen transforaminaal of interlaminair toegediend worden.

Epidurale corticosteroïde-injecties worden in de praktijk veelvuldig toegepast. Momenteel is echter de (toegevoegde) waarde van epidurale corticosteroïde-injecties, als behandeling of als add-on therapie, voor patiënten met CRS onduidelijk. Vanwege mogelijke complicaties, dienen zowel effectiviteit als veiligheid in kaart gebracht te worden, alvorens aanbevelingen kunnen worden geformuleerd.

Deze module gaat over patiënten met cervicaal radiculair syndroom. Raadpleeg bij nekpijn zonder radiculaire pijn de betreffende richtlijn. Diagnostische facetten van epidurale corticosteroïde-injecties worden buiten beschouwing gelaten.

1. Pain (critical)

2. Patient satisfaction (critical)

3. Complications (critical)

4. Use of medication (important)

5. Functioning (important)

6. Disability

7. Quality of life (important)

8. Surgery sparing effect (important)

MSQ, Medication Quantitative Scale; NDI, Neck Disability Index; NRS, Numeric Rating Scale; VAS, Visual Analogue Scale

Results

1. Pain (critical)

Five studies reported on pain (Anderberg, 2007; Bureau, 2014; Cohen, 2014; Manchikanti, 2012; Stav, 1993). Results are presented in three post-intervention terms: a) short term: until 30 days, b) mid-term: >30 days to 3 months, and c) long term: >3 months to 1 year. A brief overview of the main characteristics is provided in Table 2.

Table 2. Overview on post-intervention terms

NRS: Numeric rating scale; VAS: Visual Analogue Scale

1a. Short term arm pain (post-treatment: 30 days)

Four studies reported on pain up to 30 days (Anderberg, 2007; Bureau, 2014; Cohen, 2014; Stav, 1993).

Local anaesthetic with steroids vs. local anaesthetic alone

Anderberg (2007) reported results for one, two and three weeks after injection. One week after injection, eight out of twenty (40%) participants in the intervention group and seven out of twenty (35%) participants in the control group reported a reduction. This resulted in a risk ratio of 1.14 (95%CI 0.51 to 2.55). Two weeks after injection, in seven (35%) participants in the steroid treatment group, and in six (30%) participants in the control group the effect was maintained. This resulted in a risk ratio of 1.17 (95%CI 0.48 to 2.86). These effects were not clinically relevant. Three weeks after injection, in six participants in the intervention group (30%) and six participants in the control group (30%) the effect was maintained. This resulted in a risk ratio of 1.00 (95%CI 0.39 to 2.58). Results are depicted in figure 1.

Figure 1. Mean differences for arm pain, local anaesthetic with steroids versus anaesthetic alone
(follow-up: 1-3 weeks)

Transforaminal vs. intra-articular facet corticosteroid injections

Bureau (2014) reported results for four weeks after baseline. In the TFSI-group, mean VAS-scores reduced with 9.8% (95%CI -11.5 to 31.2). In the IFSI-group, VAS-scores reduced with 45.3% (95%CI 21.4 to 69.2). The analysis resulted in a mean difference of -35.50 (95%CI -66.1 to -4.89) favouring the IFSI-group. This difference was clinically relevant. Results are depicted in figure 2.

Figure 2. Mean differences in pain, transforaminal versus intra-articular facet corticosteroid injections.

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported results for arm pain one month after injection. In the epidural steroid injection group, the mean score was 4.2 (SD 2.59). In the combined group, mean score was 3.5 (SD 2.59). In the group with conservative treatment, the mean score was 4.3 (SD 2.69). The mean difference between the epidural steroid group and the conservative treatment group was 0.1 (95%CI -0.87 to 1.07). The mean difference between the combination group and the conservative treatment group was 0.80 (95%CI -0.17 to 1.77). Results are depicted in figure 3.

Figure 3. Mean differences in arm pain, epidural steroids with hand without conservative treatment versus conservative treatment alone.

After 1 month, 29 (53.7%) of the participants in the epidural steroid group, 30 (51.7%) participants in the conservative treatment group and 33 (64.7%) participants in the combined group reported a successful treatment outcome. The risk ratio between the group receiving conservative treatment and the group receiving epidural steroids was 1.04 (95%CI 0.73 to 1.47). The risk ratio between the group receiving conservative treatment and combination treatment was 1.25 (95%CI 0.91 to 1.72) are depicted in figure 4.

Figure 4. Risk ratios for successful treatment outcome, epidural steroids with and without conservative treatment versus conservative treatment alone

Cervical epidural steroid injection vs. steroid injections into posterior neck muscles

Stav (1993) reported results for one week after injection. Very good and good scores were considered as pain relief.

After one week, in the cervical epidural steroid group 19 out of 25 participants (76%) experienced pain relief, compared to 6 out of 17 participants (35%) in the posterior neck-muscle steroid group. This resulted in a risk ratio of 2.15 (95%CI 1.09 to 4.25), favouring the cervical epidural group. This difference was clinically relevant. Results are depicted in figure 5.

Figure 5. Risk ratios for pain relief, cervical epidural steroid injection versus steroid injection into posterior neck muscles

 1b. Mid-term arm pain (post-treatment: >30 days to 3 months)

Two studies reported on pain after 30 days up to 3 months (Cohen, 2014; Manchikanti, 2012).

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported results for 3 months after injection. 18 (36.7%) of the participants in the epidural steroid group, 15 (26.8%) participants in the conservative treatment group and 29 (56.9%) participants in the combined group reported a successful treatment outcome. This resulted in a risk ratio of 1.37 (95%CI 0.78 to 2.42).

The risk ratio between the group receiving conservative treatment and combination treatment was 2.12 (95%CI 1.29 to 3.48), favouring the combined group. These differences were clinically relevant. Results are depicted in figure 6.

Figure 6. Mean differences for arm pain 3 months after injection, Epidural steroids with or without conservative treatment versus conservative treatment alone.

Cervical interlaminar injections with anaesthetic and betamethasone vs. anaesthetic alone

Manchikanti (2012) reported results for three months after injection. After 3 months, the mean difference between anaesthetic with betamethasone group and the anaesthetic group was 0.1 (95%CI -0.40 to 0.60). Results are depicted in figure 7.

Figure 7. Mean difference for pain 3 months after injection, Cervical interlaminar injections with anaesthetic and betamethasone versus anaesthetic alone

1c. Long term arm pain (post-treatment: >3 months to 1 year):

Three studies reported on pain over 3 months up to one year after injection (Cohen, 2014; Manchikanti, 2012; Stav, 1993).

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported results for 6 months after injection. 12 (25.5%) of the participants in the epidural steroid group, 13 (23.6%) participants in the conservative treatment group and 22 (44%) participants in the combined group reported a successful treatment outcome. The risk ratio between the epidural steroid group and the conservative treatment group was 1.08 (95%CI 0.55 to 2.13).

The risk ratio between the group receiving conservative treatment and combination treatment was 1.86 (95%CI 1.05 to 3.29), favouring the combined group. This difference was clinically relevant. Results are depicted in figure 8.

Figure 8. Risk ratio for successful treatment outcome, Epidural steroids with or without conservative treatment versus conservative treatment alone

Cervical interlaminar injections with anaesthetic and betamethasone vs. anaesthetic alone

Manchikanti (2012) reported results for 6 months after injection. After 6 months, the mean difference between the anaesthetic group and the group receiving betamethasone plus anaesthetic was -0.40 (95%CI -0.92 to 0.12). After 12 months, the mean difference was -0.20 (95%CI -0.74 to 0.34). Results are depicted in figure 9.

Figure 9. Mean difference for pain, Cervical interlaminar injections with anaesthetic and betamethasone versus anaesthetic alone.

Cervical epidural steroid injection vs. steroid injections into posterior neck muscles

Stav (1993) reported results for one year after injection. Very good and good scores were considered as pain relief.

After one year, in the cervical epidural group 17 out of 25 participants (68%) experienced pain relief, compared to 2 out of 17 (12%) participants in the posterior neck-muscle group. This resulted in a risk ratio of 5.78 (95%CI 1.53 to 21.84), favouring the cervical epidural group. This difference was clinically relevant. Results are depicted in figure 10.

Figure 10. Risk ratio for pain relief, Cervical epidural steroid injection versus steroid injections into posterior neck muscles

1d. Short term neck pain (post-treatment: 30 days)

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported results for neck pain one month after injection. In the epidural steroid injection group, the mean score was 4.6 (SD 2.59). In the combined group, mean score was 3.5 (SD 2.77). In the group with conservative treatment, the mean score was 4.7 (SD 2.49). The mean difference between the epidural steroid group and the conservative treatment group was 0.10 (95%CI -0.83 to 1.03).

The mean difference between the combination group and the conservative treatment group was 1.20 (95%CI 0.23 to 2.17), favouring the combined group. This difference was clinically relevant. Results are depicted in figure 11.

Figure 11. Mean differences for neck pain 30 days after injection, Epidural steroids with or without conservative treatment versus conservative treatment alone.

2. Patient satisfaction (critical)

One study reported on patient satisfaction (Cohen, 2014).

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported on patient satisfaction using the global perceived effect (GPE). The GPE was considered positive when both, arm pain was reduced since baseline for two points or more, and the participant was satisfied with the treatment. This was measured with the two statements “my pain has improved/worsened/stayed the same since my last visit” and “I am satisfied/not satisfied with the treatment I received and would/would not recommend it to others”. A positive GPE was reported in 33 (61.1%) participants in the epidural steroid group, in 37 participants (72.6%) in the combined group and in 35 (60.3%) participants in the conservative group.

The risk ratio between the epidural steroid group and the conservative group was 1.01 (95%CI 0.75 to 1.37). The risk ratio between the combined group and the conservative treatment group was 1.07 (95%CI 0.87 to 1.32). Results are depicted in figure 12.

Figure 12. Risk ratio for positive Global Perceived Effect, Epidural steroids with or without conservative treatment versus conservative treatment alone.

3. Complications (critical)

Five studies reported on complications (Anderberg, 2007; Bureau, 2014; Cohen, 2014; Manchikanti, 2012; Stav, 1993).

Local anaesthetic with steroids vs. local anaesthetic alone

Anderberg (2007) reported no serious complications. Five out of 40 patients reported minor complications. One participant experienced an allergic skin reaction, and four participants experienced increase in radicular pain for some days after injections. None of the participants reported any persisting negative effects three weeks after the intervention.

Transforaminal vs. intra-articular facet corticosteroid injections

Bureau (2014) reported that one participant in the TFSI-group had tinnitus and vertigo after the intervention. In both groups, one participant reported having headaches in the two days following the injections. For adverse events, results were presented for participants as treated. The participant reporting headache in the IFSI-group actually received TFSI. Thus, all participants reporting adverse events received TFSI.

 Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported that ten complications occurred in eight participants receiving epidural steroids or combined treatment. Two headaches were reported, one wet-tap (not associated with neurological sequalae), one participant experienced prolonged post procedure pain, and in two participants the neurological symptoms worsened for less than two weeks. Furthermore, one rash, two vasovagal episodes and one case of tachycardia (resolved with assurance) were reported.

Cervical interlaminar injections with anaesthetic and betamethasone vs. anaesthetic alone

Manchikanti (2012) did not report on complications per arm. One participant had a subarachnoid puncture, intravascular penetrations appeared in three participants, and one participant reported soreness for seven days.

Cervical epidural steroid injection vs. steroid injections into posterior neck muscles

In Stav (1993), two participants in the intervention-group and two participants in the control-group experienced worse pain after one week. This did not change after 1 year.

Outcomes for complications were not pooled, because complications were often not reported per group, the low number of events, and definitions of complications were not similar enough to ensure a clinical meaningful answer.

4. Use of medication (important)

Four studies reported on use of medication (Bureau, 2014; Cohen, 2014; Manchikanti, 2012; Stav, 1993).

Transforaminal vs. intra-articular facet corticosteroid injections

Bureau (2014) reported pain outcomes using the Medication Quantitative Scale-scale (MQS-scale) at four weeks after injection. At baseline, subjects were instructed continuing with their usual medication. However, mean differences were presented for different groups by baseline VAS-score. For this reason, this outcome could not be graded.

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported use of medication in whether a participant reduced their opioid use with ≥20%, or completely quit using non-opioids. The study did not provide information on whether changed intake of opioids was based on prescription or initiative of the participant. Reduced medication use was reported in 15 (34.9%) participants in the epidural steroid group, 16 (35.6%) participants in the conservative treatment group, and in 23 (54.8%) participants in the combined group. The risk ratio between the epidural steroid group and the conservative group was 1.01 (95%CI 0.55 to 1.83).

The risk ratio between the combined group and the conservative group was 1.54 (95%CI 0.86 to 1.89). Results are depicted in figure 13.

Figure 13. Risk ratio for reduced opioid intake, Epidural steroids with or without conservative treatment versus conservative treatment alone.

Cervical interlaminar injections with anaesthetic and betamethasone vs. anaesthetic alone

Manchikanti (2012) reported medication use in changes in intake of morphine equivalents. The study did not provide information on whether changed intake of opioids was based on prescription or initiative of the participant. Baseline morphine intake was 53.8 (SD 36.1) in the betamethasone group, and 57.0 (SD 46.1) in the anaesthetic group. At 3 months, mean difference in medication use was -0.80 (95%CI -7.67 to 6.07). At 6 months, mean difference in medication use was -2.50 (95%CI -9.49 to 4.49). At 12 months, mean difference in medication use was -0.80 (95%CI -8.04 to 6.44). Results are depicted in figure 14.

Figure 14. Mean differences for intake of morphine equivalents Cervical interlaminar injections with anaesthetic and betamethasone versus anaesthetic alone.

Cervical epidural steroid injection vs. steroid injections into posterior neck muscles

Stav (1993) reported on medication use in whether a participant reduced their daily dose of analgesics. The study did not provide information on whether changed intake of medication was based on prescription or initiative of the participant. After one-week, reduced use of analgesics was reported in 81.7% of the participants in the cervical epidural steroid group, and in 8.6% of the participants in the posterior neck-muscle group. After one year 63.9% participants in the cervical epidural steroid group reduced their use of analgesics compared to 9.4% of the participants in the posterior neck-muscle group. Upon subsequent calculation, these percentages could not be translated to risk ratios. These results were therefore not graded.

5. Functioning (important)

Cervical interlaminar injections with anaesthetic and betamethasone vs. anaesthetic alone

Manchikanti (2012) reported on functioning using employment characteristics. Results are presented in (table 3), however these results could not be evaluated using GRADE.

Table 3. Employment characteristics

Cervical epidural steroid injection vs. steroid injections into posterior neck muscles

Stav (1993) reported on functioning using recovery of capacity for work. After one week, recovered capacity for work was reported in 69.4% of the participants in the cervical epidural steroid group and in 12.8% of the participants in the posterior neck-muscle group. After one year, 61.3% participants in the cervical epidural steroid group recovered capacity for work, compared to 15.9% of the participants in the posterior neck-muscle group. Upon subsequent calculation, these percentages could not be translated to risk ratios. These results were therefore not evaluated using GRADE.

6. Disability

Three studies reported on disability (Bureau, 2013; Cohen, 2014; Manchikanti, 2012) using the Neck Disability Index (NDI).

6a. Short term disability (post-treatment: 30 days)

Transforaminal vs. intra-articular facet corticosteroid injections

Bureau (2014) reported results for four weeks after baseline, using the NDI range 0-50. In the TFSI-group, mean NDI-scores reduced with 9.6% (SD 64.0). In the IFSI-group, NDI-scores reduced with 24.3% (SD 70.1). This corresponds with a decrease of 4.8 points in the TFSI-group (95%CI -17.2 to 7.6) and a decrease of 12.15 points in the IFSI-group (95%CI -25.75 to 1.45). The analysis resulted in a mean difference of -14.7 (95%CI -49.9 to 18.4).

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported results for disability one month after injection, using the NDI range 0-100. In the epidural steroid injection group, the mean score was 33.4 (SD 13.8). In the group with conservative treatment, the mean score was 32.0 (SD 12.2). In the combined group, mean score was 28.4 (SD 13.3). The mean difference between the epidural steroid group and the conservative treatment group was -1.40 (95%CI -6.18 to 3.38).

The mean difference between the combination group and the conservative treatment group was 3.60 (95%CI -1.17 to 8.37).

6b. Mid-term disability (post-treatment: >30 days to 3 months)

Cervical interlaminar injections with anaesthetic and betamethasone vs. anaesthetic alone

Manchikanti (2012) reported results for 3 months after baseline using the NDI range 0-100. At baseline, mean score in the anaesthetic group was 29.6 (SD 5.3) and 29.2 (SD 6.1) in the betamethasone group. In the anaesthetic group, mean score after 3 months was 14.7 (SD 5.5) and mean score in the betamethasone group was 15.6 (SD 6.3). The analysis resulted in a mean difference of 0.90 (95%CI -1.33 to 3.13).

6c. Long term disability (post-treatment: >3 months to 1 year)

Cervical interlaminar injections with anaesthetic and betamethasone vs. anaesthetic alone

Long term results were reported by Manchikanti (2012). After 6 months, the mean score in the anaesthetic group was 13.8 (SD 5.4) and the mean score in the betamethasone group was 15.3 (SD 6.9). The mean difference between the anaesthetic group and the betamethasone group was 1.50 (95%CI 0.73 to 3.72). After 12 months, the mean score in the anaesthetic group was 13.8 (SD 5.7) and the mean score in the betamethasone group was 15.1 (SD 7.0). The mean difference between the anaesthetic group and the betamethasone group was 1.30 (95%CI -0.98 to 3.58). Results are depicted in figure 15.

Figure 15. Mean differences of Neck Disability Index-scores

7. Quality of life (important)

The outcome quality of life was not reported in the included studies.

8. Surgery sparing effect (important)

One study reported on cervical surgery sparing effect (Cohen, 2014).

Epidural steroids with or without conservative treatment vs. conservative treatment alone

Cohen (2014) reported whether a participant proceeded for surgery within one year of treatment. Surgery within one year of treatment was reported in 3 (5.5%) participants in the epidural steroid group, in 4 (6.8%) participants in the conservative treatment group and in 3 (5.5%) participants in the combined group. Both risk ratios comparing epidural steroids or combined treatment with conservative treatment, were 1.24 (95%CI 0.29 to 5.30).

Figure 17. Risk ratio’s for proceeding for surgery within one year of treatment, Epidural steroids with or without conservative treatment versus conservative treatment alone.

Level of evidence of the literature

1. Pain (critical)

1.1 Short term

The level of evidence regarding the outcome measure pain (short term) started as high because it was based on RCTs and was downgraded by three levels to very low because lack of blinding (Cohen, 2014) (-1, risk of bias), clinical heterogeneity (-1, inconsistency), and crossing of both thresholds of clinical decision-making (Cohen, 2014; Anderberg; 2007) (-1, imprecision).

1.2 Mid term

The level of evidence regarding the outcome measure pain (mid-term) started as high because it was based on RCTs and was downgraded by three levels to very low because lack of blinding (Cohen, 2014) (-1, risk of bias), clinical heterogeneity (-1, inconsistency) and crossing of one threshold of clinical decision-making (Cohen, 2014) (-1, imprecision).

1.3 Long term

The level of evidence regarding the outcome measure pain (long-term) started as high because it was based on RCTs and was downgraded by three levels to very low because lack of blinding (Cohen, 2014; Stav, 1993) (-1, risk of bias) clinical heterogeneity (-1, inconsistency) and crossing of one threshold of clinical decision-making (Cohen, 2014; Stav, 1993) (-1, imprecision).

2. Patient satisfaction (critical)

The level of evidence regarding the outcome measure patient satisfaction started as high because it was based on RCTs and was downgraded by three levels to very low because lack of blinding in a self-reported outcome without any compensating RCTs of adequate quality (Cohen, 2014) (-2, risk of bias) and crossing of both thresholds of clinical decision-making (-1, imprecision).

3. Complications (critical)

The level of evidence regarding the outcome measure complications started as high because it was based on RCTs and was downgraded by three level to very low because of methodological shortcomings (Cohen, 2014 and Stav, 1993) (-1, risk of bias), strong heterogeneity in outcome-definition (-1, inconsistency) and a low number of events (-1, imprecision).

4. Use of medication (important)

The level of evidence regarding the outcome measure medication use started as high because it was based on RCTs and was downgraded by three levels to very low because lack of blinding (Cohen, 2014) (-1, risk of bias) and intervals crossing borders of clinical relevance (Cohen, 2014; Manchikanti, 2012) (-2, imprecision).

5. Functioning (important)

The level of evidence regarding the outcome measure functioning was not assessed.

6. Disability

The level of evidence regarding the outcome measure disability started as high because it was based on RCTs and was downgraded by three levels to very low because lack of blinding (Cohen, 2014) (-1, risk of bias), clinical and statistical heterogeneity (-1, inconsistency) confidence intervals crossing borders of clinical relevance (Bureau, 2014; (-1, imprecision).

7. Quality of life (important)

The level of evidence regarding the outcome measure quality of life was not assessed.

8. Surgery sparing effect (important)

The level of evidence regarding the outcome measure cervical surgery started as high because it was based on an RCT and was downgraded by three levels to very low because lack of blinding (Cohen, 2014) (-1, risk of bias) and confidence interval crossing both borders of clinical relevance (-2, imprecision).

A systematic review of the literature was performed to answer the following question: What is the efficacy of epidural steroid injections compared to care as usual in patients with cervical radiculopathy?

P: Patients with cervical radiculopathy (acute or sub-acute)

I: (Add on) epidural corticosteroid injections with or without local anaesthetic injection (transforaminal/midline or interlaminar)

C: Other conservative treatment possibilities

O: Pain, patient satisfaction, complications, use of medication, functioning, disability, quality of life, surgery sparing effect

Relevant outcome measures

The guideline development group considered pain, patient satisfaction, and complications as a critical outcome measure for decision making; and use of medication, functioning (return to work), quality of life and surgery sparing effect as important outcome measures for decision making.

The working group defined the outcome measures as follows:

• Patient satisfaction: Likert-scale or global perceived effect (GPE)
• Functioning: Return to work
• Quality of life: Validated questionnaires

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

The working group defined a 10% difference for both continuous outcome measures and dichotomous outcome measures informing on relative risk (RR ≤ 0.91 and ≥ 1.1), and standardized mean difference (SMD=0,2 (small); SMD=0,5 (medium); SMD=0,8 (large)) as minimal clinically (patient) important differences. This decision was based on the minimal important change scores described in the article by Ostelo (2008), in accordance with the Dutch Lumbosacral Radicular syndrome guideline (NVN, 2020).

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 1990 until 25 April 2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 382 hits. Studies were selected based on the following criteria:

• Systematic review (searched in at least two databases, and detailed search strategy, risk of bias assessment and results of individual studies available), randomized controlled trial comparing epidural steroid injections with other conservative treatment possibilities;
• Patients aged ≥ 18 years;
• Full-text English or Dutch language publication;
• Studies including ≥ 20 patients (ten in each study arm); and
• Studies according to PICO

Initially, 37 studies were selected based on title and abstract screening. After reading the full text, 32 studies were excluded (see the table with reasons for exclusion under the tab Methods), and five studies were included.

Results

Five studies were included in the analysis of the literature. A comprehensive overview of study characteristics is depicted in Table 1. Important study characteristics and results are summarized in the evidence table. The assessment of the risk of bias is summarized in the risk of bias table.