Discussion

In this systematic review, we investigated the efficacy of non-pharmacological interventions to reduce SCD-related pain in children with SCD. In half of the ten included studies non-pharmacological interventions improved pain-related outcomes. These interventions included CBT and biofeedback in the outpatient setting, and yoga and VR in the inpatient setting. Despite the heterogeneity of the included studies, these findings support that the addition of non-pharmacological interventions to standard medical care seems promising in further reducing SCD-related pain.
The efficacy of non-pharmacological interventions, and in particular psychological interventions, has been well described in various pain conditions.21,22,63-65 In this review, seven of the included studies investigated psychological interventions. Four of the seven psychological interventions were successful in reducing pain. Two of successful psychological interventions included CBT, implying that this intervention could be useful in targeting SCD-related pain in children.44,52 One of the CBT studies specifically looked at the effect of guided imagery. Guided imagery is expected to be particularly effective in children, because of their capacity for active and creative imaginations and their high degree of suggestibility.66 The other three CBT interventions did not show significant results most likely due to differences in CBT procedures, despite the fact that CBT has the broadest evidence in adults with SCD and in patients with other chronic pain conditions. Schatz. et al focused on electronically delivered CBT. Although authors did not show statistically significant changes on pain-related outcomes, smartphone-assisted skill use was associated with a beneficial effect on next day pain intensity using multilevel modeling.53
In SCD, there are two QED studies examining the effect of biofeedback in children,45,47 and only one small observational study in adults.67 In adults, biofeedback did not show any significant reduction in pain, health service use nor analgesic use.67 In the outpatient setting, massage therapy was also described to result in a significant pain reduction in children with SCD. 50 Although there are two studies with massage therapy in adults with SCD showing positive results on SCD-related pain68,69, this effect remains unclear in children with SCD as the authors did not report any outcomes50.
In the inpatient setting, yoga and the use of VR showed significant positive effects on acute pain in the two included studies.46,49 The effect of yoga on pain reduction was previously explored in the outpatient setting and in other pain conditions.70,71 Remarkably, a survey among children and adolescents with chronic pain, showed that 32% preferred yoga as first choice of complementary medicine.72 According to a systematic review about the effect of yoga, nine out of ten RCTs also reported significant reductions in pain intensity in ambulant adolescents and adults with a variety of pain conditions including lower back pain, osteoarthritis and irritable bowel syndrome.73 The use of VR as a distraction tool may be an effective, and easy-to-use tool in hospitalized children for a VOC. VR is especially appealing for children, as they are often more engaged in magical thinking,74 and become more captivated by imaginative play.75 Despite the positive results after VR, this study still needs replication in children with SCD, as the study was focused on feasibility rather than efficacy.46 Nevertheless, the efficacy of virtual reality in reducing acute pain has previously been well described in children undergoing painful medical procedures and in children hospitalized with burn injuries.76-79
In several studies, painful early life experiences were associated with hypersensitivity to pain and allodynia.37,80,81 Pain experienced during early childhood has been suggested to be a significant contributor to the development of chronic pain in children and adults.82,83, 84-86 Meanwhile both the prevalence and daily opioid dose in SCD patients increase significantly with age.87-89 Therefore, it is important to reduce opioid use with non-pharmacological interventions to target this issue. We address the effect of these interventions by evaluating analgesic and health service use as outcomes. Only one included study reported reduced analgesic use,47 and none of the studies reported a reduced health service use after intervention.44,48-52However, none of the included studies were designed and powered for these outcomes. Also, most studies had a short or even absent period of follow-up to measure these outcomes properly. Furthermore, pain in children in general, is associated with fear of pain, pain anxiety and/ or pain catastrophizing.90 These psychological factors could have played a role in the maintained use of analgesics and frequent hospital visits. These psychological effects were not evaluated in the included studies, so these effects on our outcomes could not be ruled out.
There are several limitations of this systematic review that need to be addressed. Due to the heterogeneity of the included studies, firm conclusions about the effect of non-pharmacological interventions cannot be drawn. Within the various interventions, there were great differences with regards to the method or practice. There are no standardized methods for any of the interventions; there is a lack of methodological robustness. In addition, our included studies evaluated the non-pharmacological interventions as add-on intervention. The effect of the intervention alone has not been studied. Variation in managing pain pharmacologically between centers, makes the comparison between our included studies in this systematic review even more difficult. Also, socio-cultural perceptions, socio-economic status and access to care are important factors, that affect patient recruitment and may therefore have biased selection of patients. This may limit the extrapolation and representativeness of this systematic review.91,92Lastly, the majority of the included studies has small sample sizes ranging from 8 to 101 participants.
Although significant pain reduction was reported in half of the studies after non-pharmacological interventions in children with SCD, specific interventions cannot be strongly recommended yet. We need further studies that address the different subtypes of SCD-related pain (acute, daily, chronic). In addition, to achieve more consistency in future studies, well-designed, adequately-powered studies should incorporate standardized administration and analysis procedures and for each type of non-pharmacological intervention, allowing fair comparison and replication. Lastly, outcome measures such as analgesic use at home and healthcare use should be considered with an adequate duration of follow-up, as these measures accurately reflect the home situation of patients with SCD.
In conclusion, non-pharmacological interventions as a complementary strategy, have the potential to lead to a faster recovery of SCD-related pain with a substantial decrease of side effects and complications; thereby improving quality of life in children with SCD.

Conflict of interest

The authors have no conflicts of interest to declare.

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. We would like to thank the medical information specialist René Spijker for performing the literature search.
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