Results
Study selection
A total of 1,048 publications was retrieved and screened by two
investigators (SV, JG or CV). Subsequently, 41 studies were assessed for
eligibility based on their full text (SV, CV), of which ten studies
fulfilled the selection criteria and were included in this review
(Fig. 1 ).44-53 We approached the first author
of two studies with unavailable full text articles. However, none of
them responded. In total, thirty-one full text articles were excluded.
The majority of the excluded studies did not report on our predefined
outcomes (n=9).54-62.
Characteristics of included studies
Study characteristics and the risk of bias of the ten included studies
are summarized in Table 1 . The studies included a total of 422
participants aged between 6 and 21 years old. All participants had SCD
including the genotypes HbSS, HbSC, HbSĂ-thalassemia and HbSD. Studies
were published between 1987 and 2020. All studies were performed in the
USA. The type of intervention studied were psychological interventions
(n=7), physical intervention (n=1) and integrative medicine (n=2). In
this review, psychological interventions included CBT and
biofeedback.44,45,47,48,51-53 The physical
intervention included the practice of yoga51, and
integrative medicine was provided in the form of massage and virtual
reality46,50. In total, five different types of
interventions were studied including CBT
(n=5),44,48,51-53 biofeedback
(n=2),45,47 yoga (n=1),49 massage
(n=1)50 and virtual reality (n=1).46Eight studies were performed in the outpatient clinic
(n=6)44,45,47,51-53 or at home
(n=2),48,50 while two studies were performed during
hospital admission.46,49
In the outpatient clinic, children received one single training session
in four studies,45,46,52,53 in the remaining studies
the number of sessions ranged between 2 and
13.44,47-51. The duration of the intervention period
that included both the training session and the practices ranged from 30
days45,50,52 to 4.5 months.44Duration of follow-up after the non-pharmacological invention ranged
from 1 to 12 months. Pain-related outcomes were assessed using
self-reported daily pain diaries in seven
studies,45,47,48,50-53 in one of them outcomes were
electronically monitored.53 In the other three
studies, pain was reported personally to researcher(s) while inpatient
or by telephone assessment.
All studies primarily focused on pain. They examined either the
frequency of pain (n=2)45,48, the intensity of the
reported SCD-related pain on a 5- or 10-point pain scale
(n=4),44,46,49,50 or both pain outcomes
(n=4).47,51-53 Four studies clearly defined the type
of pain they were targeting, namely acute pain in three
studies,46,47,49 and chronic pain in one
study.44 The remaining six studies did not specify the
type of SCD-related pain they were
targeting.45,48,50-53 Therefore, we decided to state
this pain as daily pain. In total, eight studies investigated the
secondary outcomes that we specified, with seven of them investigating
health service use44,47-52 and four the use of
analgesics.47,49,51,52 In total, four of the studies
studied both health service and analgesic
use.47,49,51,52
Quality assessment of included studies
In this review, five RCTs48-51,53 and five
QED44-47,52 studies were included. The quality of the
five RCTs had a mean score of 9.0 out of 13 points. The five included
QED studies scored an average of 7.6 out of 10 points. Scores per study
are shown in Table 1 . The detailed scoring is listed inSupplemental Figure S2 . In RCTs, the lack of
follow-up48-50 and selective reporting were the main
reasons for a risk of bias.50,51,53 Three studies did
not report on blinding of outcome and allocation concealment, so risk of
bias could not be scored on these items.48,50,51 Only
one study blinded their outcome assessors for the
intervention.49 In QED studies, four out of five
studies did not include a control group45-47,52 and
two studies did not have a follow-up causing a risk of
bias.46,52 In total, five out of the ten studies
achieved a follow-up rate of at least 80% of the patients.
Summary of main findings
Effects of interventions
Five studies reported significant reductions in pain-related outcomes
after a study period between 1 and 12
months,44,46,47,50,52 while one study reported a
significant reduction in analgesic use.47 None of the
included articles reported a significant reduction of health service
use. In the following paragraphs the results will be discussed according
to setting (in- or outpatient) and type of intervention.
Outpatient setting
Psychological interventions
Among the five studies that investigated
CBT,44,48,51-53 two showed improvements on
pain-related outcomes.44,52 First, Dobson et al.
showed that after guided imagery, a technique within CBT, the intensity
of daily reported pain decreased from 2.4 (SD 1.2) to 0.7 (SD 1.2) on a
5-point scale (p < 0.01). In addition, the number of painful
episodes per month decreased significantly, from 5.6 (SD 3.3) to 2.5 (SD
4.1; p = 0.003). However, no significant changes were reported in the
number of ED visits and hospital admissions.52 Second,
Sil et al. reported reduced chronic SCD pain intensities on a 10-point
scale from 5.5 (SD 2.2) to 3.8 (SD 2.8. p = 0.009). The other three CBT
studies did not show any effects on pain, health service or analgesic
use.48,51,53 One study used electronic devices to
provide CBT electronically (e-CBT) and to record outcomes digitally. In
this study, there were large discrepancies between self-reported and
device-reported frequencies of skill practice; children reported
approximately two to four times more skill practice than what the device
recorded.53The efficacy of biofeedback was examined by two studies, with one
showing a significant reduction of the pain-related
outcomes.45,47 This study by Cozzi et al. studied the
effect of biofeedback on acute pain at home.47 Pain
intensities reduced from 1.9 to 0.5 (SD not reported) on a 5-point scale
(p < 0.001) and the number of self-treated crises per month
decreased from 2.2 to 0.4 (p < 0.05). Furthermore, the number
of days on which analgesics were taken in a month was reduced from 8.0
to 1.3 (p < 0.001), but health service use did not change
compared to baseline.
Integrative medicine
Lemanek et al. investigated massage as integrative medicine at the
outpatient clinic. They reported a significant decrease of pain-related
outcomes after massage (p = 0.05), however no specific outcomes or
effect sizes were reported.49 Therefore, this result
was not classified as significant.
Inpatient settings
In the inpatient setting, the effect of yoga and virtual reality were
studied for uncomplicated VOCs.46,49 Children reported
a reduction in acute pain intensity on a 10-point scale after a single
VR session from 7.3 (SD 2.7) to 5.8 (SD 3.2, p < 0.001). Yoga
reduced pain intensity from 5.6 to 5.0 (p = 0.029) after an average of
2.5 sessions. No differences were found in LOS and opioid use after
yoga.