Sensory stimulations potentializing digital therapeutics pain control

For the past two decades, using Digital Therapeutics (DTx) to counter painful symptoms has emerged as a novel pain relief strategy. Several studies report that DTx significantly diminish pain while compensating for the limitations of pharmacological analgesics (e.g., addiction, side effects). Virtual reality (VR) is a major component of the most effective DTx for pain reduction. Notably, various stimuli (e.g., auditory, visual) appear to be frequently associated with VR in DTx. This review aims to compare the hypoalgesic power of specific stimuli with or without a VR environment. First, this review will briefly describe VR technology and known elements related to its hypoalgesic effect. Second, it will non-exhaustively list various stimuli known to have a hypoalgesic effect on pain independent of the immersive environment. Finally, this review will focus on studies that investigate a possible potentialized effect on pain reduction of these stimuli in a VR environment.

Many virtual reality (VR) definitions have been proposed in the past few decades, from short straightforward to more complex explanations.Honzel et al. elegantly summarized it as follows: an immersive computer-generated environment designed to be perceived as real by the user (56).Meanwhile, Digital Therapeutics (DTx) has been defined as an "evidence-based therapeutic interventions that are driven by high-quality software to treat, manage, or prevent a disease or disorder […] used independently or in concert with medications, devices, or other therapies to optimize patient care and health outcomes" (138).Interestingly, DTx benefit from VR technologies in the healthcare system (21), particularly since the COVID-19 pandemic, which led to a more digitalized model (22).Thus, VR has been increasingly studied, notably in acute or chronic pain analgesia situations (128).
The hypoalgesic power of VR has been extensively highlighted in recent meta-analysis and reviews not only in the adult population (1,9,16,17,25,47,72,76,78,102) but also in pediatric patients (28).In addition, benefits affecting several modalities of quality of life have been reported (e.g., stress, anxiety), suggesting VR as a good nonpharmacological therapeutic tool (95,76,150).The goal of this review is to verify if the addition of different auditory and visual stimulations frequencies [e.g., binaural beats (BBs), hypnosis] have additive effects on VR efficacy.The first part of this review will exclusively focus on pain studies that investigated the hypoalgesic effects of VR in acute or chronic pain conditions, followed by the physiological evidence supporting this effect.
The second part will non-exhaustively list several sensory stimuli used to promote analgesia as stand-alone treatments.Finally, the third part of this review will aim to investigate studies combining one or many of the sensory stimuli previously described in a VR environment (Table 1).

Analgesic power of virtual reality 1.Acute pain
Pain is a perception mechanism aiming to alert the organism of nociceptive stimuli potentially compromising its survival.Since 2020, its definition has been revised by the International Association for the Study of Pain (IASP) as follows: "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" (106).
To our knowledge, the first evidence of VR analgesia on acute pain came from the work of Hoffman et al. in the early 2000s.First, they reported a decrease of the perceived pain following a VR session in two adolescent patients during burn wound care (Figure 1) (50).Second, using magnetic resonance imaging (MRI), they highlighted that VR effectively lowered brain activity in areas related to pain (i.e., anterior cingulate cortex, primary and secondary cortex, insula, and thalamus) in 14 healthy participants (51).Third, they reported the importance of choosing a good quality VR headset to improve the efficiency of the device (52).Fourth, they have shown that VR significantly reduces pain compared to opioids, with a potentialized effect when both are being coupled (53).Following these results, they continued to provide significant evidence concerning the hypoalgesic power of VR through pain measurements and cerebral imaging, mainly in burn victims or children receiving painful procedures (2,3,5,7,54,55).Following the release of these pioneer studies performed by Hoffman et al., many teams have now shown a hypoalgesic effect of VR in acute pain situations, such as venipuncture, lumbar puncture, women during labor, or dental surgery (15,45,38,118).
In accordance with these results, recent reviews are increasingly reporting the benefits of VR for acute pain analgesia (1,25,47,58,72,76,78,102). For instance, it has been shown that VR is able to significantly increase thermal pain tolerance (46) or significantly decrease experimental pain intensity using electrical-and thermal-induced stimuli (119).Moreover, it has been highlighted that three sessions a day of 30 min of VR is also efficient to reduce pain during a rehabilitation protocol after knee surgery (63).Interestingly, the addition of VR with local anesthesia in patients undergoing dental surgery can significantly reduce oxygen saturation, intraoperative pulse rate, and postoperative visual analog pain scale results (126).
However, it is important to notice that some studies did not find significant results regarding a hypoalgesic effect of VR on some acute pain stimulation.Indeed, Walker et al. investigated the efficacy of VR distraction during a cystoscopy, without a significant decrease of pain questionnaire scores between the VR and control groups (145).The authors suggested that these results could likely be due to a lack of immersion, which is the main mechanism of action during a VR experience (see Section 1.2).In addition, Smith et al. tested the pressure pain during various contextual conditions and did not show statistical differences on participants' pain thresholds (121).However, the authors mentioned that they investigated pain sensitivity instead of pain intensity, which could explain their results.Importantly, these disparate results also highlight the difficulty for VR studies to properly choose the best methods (e.g., protocol of administration, VR apparatus), thus leading to difficulties to compare the results between studies.
Interestingly, the VR hypoalgesic effects observed on acute pain are not limited to the duration of the application.It has been reported that this effect can last up to 1 h post-VR application following either a cardiac surgical or an episiotomy repair procedure (59, 86).Further investigations are required to evaluate this lasting hypoalgesic effect of VR on acute pain (    Chronic pain can be defined as a persistent or recurrent pain, lasting for at least 3 months (136,137).Chronic pain can lead to critical dysfunctions in both peripheral and central nervous systems, such as gray and white matter loss, increase or decrease of the activity in major cerebral areas, or alterations of synaptic neurotransmission (124, 108).In addition, chronic pain may severely affect the quality of life of patients living with it, from nutrition and physical activity to sleep disorders and mental wellbeing (91, 85).Importantly, chronic pain can appear through aging and in patients presenting specific diseases (77).
While current results are converging toward the efficacy of VR to diminish acute pain, reviews are also looking to the potential hypoalgesic power of VR on chronic pain (47,78,102).Interestingly, major significant VR benefits on pain ratings or pain relief have been reported in various chronic conditions, such as musculoskeletal pain, neuropathic pain, cervical/thoracic/ lumbar spine pain, hip pain, pervasive pain, or interstitial cystitis (63,65).
A study on six fibromyalgia patients has shown that pain reduction was significantly greater in the VR group compared to the control group (10).Another study has highlighted that VR immersion can significantly reduce pain perceived in patients living with chronic migraines in a hospital waiting room (135).Similarly, VR benefits have been found in children with chronic headaches (120).Another one has shown a major decrease of pain intensity in patients suffering from chronic pain (148).Also, an improvement of pain intensity, frequency, duration, and intrusion in patients living with phantom limb pain after 12 VR sessions has been reported (92).In addition, pain intensity was significantly decreased after a 6-week VR session in patients with subacromial impingement syndrome (97).Recently, a 56-day study has highlighted a significant decrease of pain intensity in patients living with chronic low back pain (40).
The duration of the hypoalgesic effect of VR on chronic pain varies across the studies (78).The benefits have been demonstrated to last up to (i) 1 month (97); (ii) 1 to 3 months (120, 135); (iii) 1, 3, and 6 months (92); or even (iv) 6 months (10) post-treatment, potentially suggesting a long-term efficacy of VR on chronic pain.Finally, it is important to notice that some studies did not find significant results regarding the hypoalgesic effects of VR, or at least sustainable ones (113), on unspecified chronic pain conditions (63,148).
In conclusion, ample evidence attests to the many benefits of VR on acute and chronic pain analgesia, while some pointed out the lack of an effect.Nevertheless, the study of this technology in these pain conditions is still under investigation in various pathologies, allowing us to better understand the limits of its hypoalgesic power (Table 1).

Physiological evidence supporting the analgesic efficacy of VR
The exact mechanisms through which VR is procuring the hypoalgesic effects previously mentioned on acute and chronic pain are still unclear, although it seems that the main one is immersion (18,74).This concept needs to be differentiated from distraction.Indeed, it has recently been shown that immersive VR significantly increases heat-pain tolerance limits, as well as improves mood, situation anxiety, and pain unpleasantness, while a distraction control only increased the pain tolerance limits without affecting the other modalities (18).In addition, the authors highlighted that the increase of the heat-pain tolerance limits by VR was related to an increase of sympathetic and parasympathetic responses (e.g., heart rate variability standard deviation from normal to normal, galvanic skin responses).Interestingly, it has also been shown that VR cues related to "virtual water temperature" (i.e., color red for hot and blue for cold) can significantly influence the pain perception of thermal stimuli (68).Using the same nociceptive thermal stimulation, a virtual hot water signal was perceived as significantly more painful than a virtual cold signal, likely through top-down endogenous mechanisms.
This hypoalgesic ability of VR leads us to compare it to traditional medication.To date, the most common analgesics prescribed for pain are opioids (89).Notably, repetitive opioid use can lead to an increase of postoperative acute pain episodes (37) as well as major aversive effects, such as addiction or overdose death (112).Thus, the current worldwide opioid crisis has led to an urgency to find new non-pharmacological hypoalgesic solutions, in which VR appears to be effective (132).As previously mentioned, VR can be as efficient as opioids to reduce pain, with a potentialized efficiency when used adjunctively (53).In addition, VR can effectively reduce opioid administration during painful wound care procedures (82).Thus, the current emergence of various DTx using VR is very interesting in terms of novel hypoalgesic strategies.
One of the main counter-indications of VR is the adverse effect known as "cybersickness," mainly causing nausea symptoms in VR users (70,81,144,146).It seems that this motion sickness could be due to a conflict between the sensory stimuli or autonomic responses (e.g., visual system, vestibular system) (70).Interestingly, a recent review highlighted a close relationship between cybersickness and the feeling of presence in a VR environment: the more the cybersickness experienced, the less immersed the VR user will be (146), which could prevent any hypoalgesic effects of DTx using VR.
Several sensory (i.e., auditory, visual, olfactory, gustatory, tactile) stimuli can be transmitted to users through a VR apparatus in order to increase immersion within the virtual environment (1, 68), allowing the transmission of various stimulations [e.g., hypnosis, binaural beats, colored noise, bilateral alternative stimulation (BAS)], thus potentially being able to increase the VR hypoalgesic power.

Sensory stimuli
Among the various sensory stimuli that DTx may use to induce a hypoalgesic effect, VR technologies for pain treatment frequently include therapeutic scripts as well as sound and light frequencies in the virtual environment (83).It is difficult to separate the efficacy of VR from the effects of some visual or auditory stimuli since they are presented together in most of the studies.We will introduce a non-exhaustive description of psychological (i.e., hypnosis), auditory (i.e., binaural beats, colored noise), and visual (i.e., bilateral alternative stimulation) stimuli that are the most used in VR, but can be used as a stand-alone treatment (Table 1).

Hypnosis
The definition of hypnosis has frequently evolved throughout the years, mainly to increase its comprehension, in order to allow its use, notably, in scientific studies (29).One of the more recent is the following: "A state of consciousness involving focused attention and reduced peripheral awareness characterized by an enhanced capacity for response to suggestions" (29).Several clinical studies have highlighted the benefits of hypnosis in several situations (e.g., pain, depression, motor paralysis, phobia) (8,103,105,129,142).
Analgesia through hypnosis has majorly been investigated during surgeries for "hypnosedation" (35,69,142).A pioneer retrospective study has shown that adding hypnosedation to a conscious intravenous sedation coupled with a local anesthesia improves both perioperative pain and anxiety relief during various plastic surgery (e.g., breast augmentation, correction of mammary ptosis, liposuction) compared to medical sedation alone (32).These results were confirmed a few years later during a prospective study (33).More recently, a critical review of nearly 30 randomized controlled clinical trials (RCTs) highlighted that hypnosis was consistently able to decrease pain in acute painful conditions compared to standard care and attention control groups (69).The authors also mentioned that hypnosis was at least as efficient to comparable adjunct psychological or behavioral therapies in the same context.Importantly, it has been shown that hypnosis was able to significantly reduce pain intensity in patients suffering from chronic pain following a spinal cord injury, compared to noninvasive electrical stimulation (60,62).Hypnosis has been reported to more effectively reduce the pain intensity in chronic low back pain participants using self-hypnosis training compared to biofeedback (127).Finally, a recent review and meta-analysis reported that hypnosis was moderately able to manage pain in musculoskeletal and neuropathic pain patients, suggesting that deeper investigations were necessary to conclude on the hypoalgesic power of hypnosis on chronic pain conditions (73).
In addition to its hypoalgesic power, hypnosis can effectively impact the patient's quality of life, as well as multiple medical spheres (e.g., pain, medication consumption, physiological parameters, recovery and professional activity restart latency, emotional distress) (8,61,73,110,111,125,129,134,142), suggesting a cerebral effect across various brain areas.Importantly, it has been reported that hypnosedation was able to reduce both the affective and sensory components of pain (i.e., unpleasantness, intensity) compared to control conditions (33,34,36,103,105).Several studies focusing on brain electrical signals have highlighted changes in brain activity due to hypnosis-induced states (60,62,104,149).Functional MRI (fMRI), positron emission tomography (PET), and laser-evoked potential (LEP) studies reported various changes in functional brain connectivity in participants during ongoing hypnosis (8).Interestingly, these changes mainly occurred in brain areas related to consciousness (e.g., anterior and posterior cingulate cortex, medial frontal cortex, precuneus) (8,61,140).Another study using hypnosis suggested that experimental pain will become less unpleasant even if the intensity stayed the same and was able to demonstrate the possibility to reduce brain imaging activity in regions related to affective components of pain (e.g., cingulate cortex and insula) without affecting the sensorydiscriminative regions (e.g., somatosensory cortices) (103).
However, we must notice that there are some limits surrounding the clinical use of hypnosis.First, protocols using hypnosis frequently take a long time to administer to participants, and measurements are often limited to solely behavioral responses, without considering the subjective experience of the participants, especially to assess their hypnotizability (61, 141).This limit can lead to another constraint, which is that the number of participants often quite small (141, 143).In addition, methods can be subject to limitations, as some variations can occur across most studies, notably on the number of hypnosis sessions and intervention length or timing (especially regarding the induction phase), thus complicating interpretations and comparisons between the studies of this field (69).Although hypoalgesic benefits previously reported are promising, further studies will help expand these results in various acute and chronic pain conditions (Table 1).

Binaural beats
BBs can be defined as a perceived third frequency resulting from the difference between two different frequencies applied in each ear (e.g., a frequency of 253 Hz in the right ear and a 250 Hz one in the left ear will result in a third frequency of 3 Hz perceived in the brain) (19).Interestingly, it has been shown that this auditory stimulus can elicit an evoked synchronous response reproducing the same frequency and waveform of the stimulus entering the central auditory pathway as a brain oscillation (19).Thus, five different types of BBs have been listed, depending on their frequency: delta (i.e., 0.1-4 Hz), theta (i.e., 4-8 Hz), alpha (i.e., 8-13 Hz), beta (i.e., 13-30 Hz), and gamma (i.e., >30 Hz).To our knowledge, only theta-and alpha-BBs have been reported being able to elicit a hypoalgesic effect.
Theta-BB (i.e., 4-8 Hz) can significantly decrease the severity of perceived chronic pain compared to neutral sound (151).In this study, 36 patients suffering from different types of chronic pain had to listen to a 6 Hz BB tone for 20 min during 14 successive days, while a sham intervention group listened to a non-BB tone of 300 Hz.The results indicated reduced perceived pain severity exclusively in the theta-BB group.Although the pain scores were reduced in both groups, the authors observed a 77% larger reduction of the mean pain scores in favor of the theta-BB group (151).
Concerning alpha rhythms (i.e., 8-13 Hz), several studies indicate that a global suppression of alpha oscillations in somatosensory, motor, and visual areas are observed in response to both transient and tonic painful stimuli (98,101).In some studies, pain intensity ratings were correlated with a decrease in alpha power (6,87).More recently, a study has shown that listening to alpha-BB for 10 min significantly decreased the ratings of experimentally induced pain, compared to a control group (27).The authors also discovered that this effect was maximized for 10 Hz frequencies, compared to 8 and 12 Hz.However, the same study found no statistically significant differences with the control group for several aspects of the quality of life (e.g., anxiety, wellbeing, drowsiness), although these results contradict another study that found that alpha rhythm stimulation reduces both stress and anxiety (13).Interestingly, they also noted an improvement in heart rate variability via parasympathetic reinforcement, highlighting the ability of BBs to act on physiological variables as well.Thus, by reducing stress, anxiety, and physiological parameters, alpha rhythm stimulation could potentially decrease pain perception.In addition to their involvement in pain, a recent study pointed out the link between alpha rhythm and memory, by showing that listening to alpha-BB for 15 min can enhance memory recall (88).
However, it is important to notice that we found three studies that failed to promote brain oscillations following theta-, alpha-, beta-, or gamma-BBs, listening for durations of (i) 2 min ( 43), (ii) 3 min (75), or (iii) 5 min (39).Based on these findings, more studies are needed to investigate the potential hypoalgesic power of all types of BB in order to choose protocols adequately for brain oscillation-induced states (Table 1).

Colored noise
The "color" of a noise is a terminology used to classify different noises according to their power spectrum density (i.e., frequency of a sound), similar to light waves classification (26).For instance, if we decide to draw the sound wave diagram for "pink noise" by transposing it into a diagram of light waves, it would correspond to a pink light.As such, warm colors are assigned to lowfrequency sounds, while cold colors are related to high-frequency sounds.To our knowledge, only white and pink noises have been related to pain analgesia studies (Table 1).
White noise has been extensively studied on sleep, mainly in infants and children (122), as well as intensive care unit patients (31,123), although, at high intensity, it has been revealed in rodents that white noises can be harmful to the organism, creating anxiety-like behaviors as well as inducing apoptosis, chromatolysis, cytoplasmic organelle destruction, and glial activation brain structures (153).Concerning studies on pain, a team compared the effect of an MRI scanner noise to white noises on the sensory-discriminative (i.e., intensity, localization) and the motivational-affective (i.e., unpleasantness) components of pain (11).They showed that both the MRI scanner noise and white noises significantly reduced unpleasantness ratings, whereas the ability to locate pain was not significantly affected.Interestingly, they assume that, by acting solely on the motivational-affective component of pain, without affecting the sensory-discriminative one, noises may have therapeutic implications by diminishing the distress associated with the pain unpleasantness, while maintaining the capacity to localize the pain to avoid further injury.Another study demonstrated that the pain score was lowered with white noises in newborns (i.e., 38-42 weeks old) during an acute painful procedure (i.e., blood draw), compared to control conditions (67).Similar results were discovered to relieve procedural pain caused by vaccination in premature infants compared to a control group (71).Unfortunately, the impact of white noise in adults has mostly been studied regarding higher cognitive functions, such as semantic priming (4) or recognition memory tasks (107), and not pain.
Pink noise has been studied extensively in relation to sleep (12,90,93,94,152).A study recently investigated the effects of pink noise on pain in a rat model of chronic pain (12).They measured mechanical allodynia responses before and after exposure to pink noise and observed a statistically significant decrease in behavioral pain response in rats exposed to pink noise.It is important to notice that pink noise has also been used as a control stimulation, compared to music, in a study aiming to investigate the hypoalgesic effect of music on fibromyalgia pain (41).The results indicated a reduction in pain and an increased functional mobility in the music group, whereas there was no change in the pink noise control group.Consecutively, it is difficult to conclude the hypoalgesic power of pink noises.
To our knowledge, no scientific data have been published in order to highlight the potential hypoalgesic power on acute or chronic pain for other types of noise, including red, black, gray, green, blue, and purple noise (26).Concerning brown noise, we found only one study that has been published with stimulation close enough to brown noise, but relative to consciousness and not pain (115).They showed high stability of a Ganzfeld-induced state (i.e., altered state of consciousness through visual and auditory perceptual field homogenization following an unstructured sensory input), white noise displaying the highest overall global scores.Interestingly, the authors suggest that, based on their results, white noise could be very effective to homogenize the auditory field while ignoring potential environment distraction (115).

Bilateral alternative stimulation
Bilateral alternative stimulation (BAS) is a visual technique mainly applied during a psychotherapeutic approach called eye movement desensitization and reprocessing (EMDR) for post-traumatic stress disorder (PTSD) treatment (139,147), although growing evidence tends to highlight possible applications of EMDR to relieve pain in patients living with acute or chronic painful conditions (44,80,130,131,42,114).
We found a recent review of two RCTs related to acute pain and EMDR (114).The first one found that one session of EMDR was efficient to diminish acute experimental pain intensity (i.e., cold pain pressor), as well as to improve the pain threshold, bettering pain tolerance and reducing anxiety (48).The second one highlighted that one 60-min session 2 h post-abdominal surgery in an emergency service effectively decreased pain intensity (79).
A systematic review reported that EMDR has been efficient in decreasing pain intensity in several studies with patients suffering from various chronic pain conditions (e.g., phantom limb pain, headache, musculoskeletal pain, fibromyalgia) (130).An RCT pilot study also highlighted that EMDR effectively diminished pain intensity, sometimes for up to 6 months, in patients suffering from non-specific chronic back pain after 10 sessions of EMDR (42).In addition, nine weekly sessions of 1 h of EMDR can effectively decrease pain levels and their affect, as well as increase pain control in patients suffering from chronic pain for at least 6 months (44).In 38 patients living with chronic pain, it has been shown that 12 weekly EMDR sessions of 90 min were able to significantly decrease the amount of medication needed and to improve the quality of life (e.g., pain, physical activity, vitality, social interaction, emotional management) (80).
Little is known concerning the possible mechanisms through which EMDR might diminish pain.Pioneer EMDR protocols from Shapiro highlight eight phases to optimize the efficacy of the technique: (i) history and treatment plan, (ii) introduction to EMDR protocol and development of coping strategies, (iii) evaluation of the treatment targets, (iv) desensitization and reprocessing, (v) incorporation of positive cognitions, (vi) body scan (and the reprocessing of any remaining negative bodily sensations), (vii) relaxation (i.e., re-establishing emotional stability if distress has been experienced, and for use between sessions), and, finally, (viii) re-evaluation (116,117,114,139).Interestingly, Grant and Threlfo specified that to facilitate relaxation and to change pain sensations, EMDR was usually accompanied by suggestions to ask the patient to shift their attention from the pain to the BAS (44).An fMRI study reported that BAS can either increase or decrease the activation of limbic structures (i.e., right amygdala, left dorsolateral prefrontal), thus highlighting the effect of EMDR on emotion processing in healthy participants (49).Interestingly, it seems that visual BAS are more effective than auditive BAS on memory tasks (57).
Finally, it is important to note that, despite an increased amount of evidence showing the benefits of EMDR on pain, studies usually do not use an active control group to address the results, and their monocentric design leads to small sample sizes (131).These results thus need to be extended in future investigations to confirm the potential hypoalgesic power of BAS (Table 1).

Sensory stimuli associated with virtual reality
In this review, we previously highlighted how VR or isolated sensory stimuli (i.e., hypnosis, binaural beats, colored noise, bilateral alternative stimulation) can elicit a hypoalgesic effect.This section aims to investigate the hypoalgesic power of combining these stimuli in a VR environment (Table 1).

Virtual reality and hypnosis
As hypnosis has been used for many decades, since the 21st century, its use in a 3D environment following the emergence of VR was rapidly tested in the early 2000s (78,110,111,134).In 2010, Patterson et al. investigated how a hypnotic induction and hypoalgesic suggestions delivered by a customized VR hardware/ software would be able to assess analgesia in patients with physical trauma at the hospital (96).They showed that pain intensity ratings, as well as pain unpleasantness, were significantly lowered in the group with VR and hypnosis compared to the groups with only VR or standard care alone, up to 8 hours post-treatment.Interestingly, a recent review and meta-analysis on hypnosis suggests that VR could potentiate the efficacy of hypnosis, especially in low hypnotic suggestibility patients (73).This observation is partially based on an RCT that highlighted that hypnosis with 3D VR animation can improve the user's mood, as well as reduce both the tiredness and the level of cortisol, measured through a salivary test (133).Meanwhile, it has recently been shown that hypnosis added with VR can effectively reduce pain, as well as anxiety and fatigue, in patients undergoing cardiac surgery (110,111).However, it is important to notice that a study recently showed that human care was preferable to hypnosis through VR in patients undergoing electrophysiology and pacing procedures to improve their comfort (20).
Nevertheless, authors have highlighted some limits surrounding VR hypnosis induction, notably in case-series designs, such as an absence of a randomized distribution and a control group as well as possibly a small sample size (30).The methods can also be affected, since choosing the proper amount of VR sessions to induce hypnosis can often be limited across studies (110,111).Further studies are needed to clarify all the possibilities of VR hypnotic induction on pain analgesia, but recent findings tend to encourage its use for alleviating patient's pain (14) (Table 1).

Virtual reality and binaural beats
To our knowledge, only a few studies recently investigated the potentializing effect of BB through VR (Table 1).In 2019, Perales et al. reported that some BBs (i.e., delta, theta, alpha) coupled with a VR environment can act on the sympathetic nervous system modalities (e.g., electrodermal activity) in healthy participants, in addition to other physiological parameters (e.g., temperature, heart rate) for children living with chronic pain (99, 100).The authors mention that these changes could introduce the user into an effective relaxation mood, potentially leading to an improvement in the perception of pain.More recently, they confirmed these results by showing a potentialized effect of VR with BB for chronic pain in children, but surprisingly not on the physiological modalities (i.e., heart rate, galvanic skin response), possibly due to study design limitations (109).Interestingly, it has recently been highlighted that BB in a VR environment can also drastically decrease the main aversive event of VR use, cybersickness, suggesting a potentially better efficacy of DTx using VR and BB (23).

Virtual reality and colored noise
As mentioned above, VR greatly benefits from immersion to generate its efficacy (18, 74).To our knowledge, studies that specifically investigated a potentialized effect of colored noise on VR analgesia are quite rare (Table 1), although we found one study that showed that adding sounds to a VR game can significantly increase pain tolerance for experimental thermal pain compared to the sounds or the VR game separately (64).However, the authors specified that "sounds" cited referred to the game's music, thus preventing us from concluding the specific hypoalgesic effect of white or pink noise when incorporated into a VR environment.Interestingly, it has recently been shown that shifting a music volume to the same frequency (i.e., 0.1 Hz) as the VR environment motion does not influence the body sway assessed by position measurements, suggesting a lack of effect of colored noise on cybersickness (24).

Virtual reality and bilateral alternative stimulation
To our knowledge, only one study has investigated more specifically the effect of transmitting EMDR techniques through a VR environment (Table 1).Kaminska et al. reported in 2020 that BAS in VR can significantly reduce the acute stress level as well as mood improvements in healthy adult volunteers, leading to be considered a great tool when added to a relaxation training program (66).Even if it is difficult to conclude with only one study, it seems that BAS through VR could benefit analgesia.

Conclusion
In this review, we highlighted (i) the hypoalgesic power of VR only, (ii) the hypoalgesic power of various sensory stimuli only (i.e., hypnosis, binaural beats, colored noise, bilateral alternative stimulation), and (iii) the potentialized hypoalgesic power of these sensory stimuli in a VR environment.In the first part, we have summarized many studies that showed with self-reported scales scores and cerebral imaging that VR can effectively reduce pain perception, both in healthy participants and during acute and chronic pain conditions, likely through the immersive capacity of VR.In addition, we found that the hypoalgesic effect of VR is sometimes as powerful as strong pharmacological analgesics (i.e., opioids).In the second part, we highlighted (i) how hypnosis can elicit an hypoalgesic effect as well as an improvement of the quality of life of participants, (ii) that some BB (i.e., theta, alpha) can effectively produce an hypoalgesic effect, likely by acting on cerebral oscillations, (iii) the low but existing hypoalgesic power of some colored noise (i.e., white, pink), and (iv) how an EMDR technique (i.e., BAS) may both decrease pain and improve the quality of life of some patients suffering from acute or chronic pain.In the final part, we reported the short but emerging scientific literature investigating the potentialized hypoalgesic effect of combining previous sensory stimuli evoked with a VR environment.
A potential limit to our review is the difficulty to compare all these modalities (i.e., VR only, stimuli only, VR and stimuli) as the methods are different across studies, even in the same fields of research.Moreover, the small sample size and the lack of information on the effect size in several studies are limiting a final conclusion on the clinical relevance of these studies.Another limit could be the non-exhaustivity of the sensory stimuli chosen in this review.Further reviews should investigate the hypoalgesic power of a plethora of other sensory stimuli (e.g., odors, textures, biofeedback) or cognitive approaches (e.g., cardiac coherence, mindfulness breathing) and their probable potentialized effect while being coupled with VR technologies.The fact that some studies report a hypoalgesic effect of the VR session outlasting hours and even months may be explainable by several mechanisms.For instance, the activation of endogenous pain modulation may outlast the effect by minutes or even hours.However, the longer effects may be explained by some life habit changes such as moving more freely and more frequently after the positive effect of VR.More studies are needed to characterize the different variables that may contribute to the long-term effect of VR.
We recently published an RCT (NCT04650516) where we highlighted that a VR treatment comprised of some sensory stimuli mentioned above (e.g., BB, BAS) effectively diminished the mean pain intensity in 45 patients diagnosed with moderateto-severe endometriosis-related chronic pelvic pain, up to 4 h post-treatment, as well as reducing the mean perceived pain, compared to a 2D digital control (84).These results encourage us to conclude that VR with added sensory stimuli can be a good addition to an arsenal for alleviating pain.However, since the control was with the same 2D environment without the additional stimuli, we can only conclude the potential effects of the combination of these stimuli.Future studies are needed to better characterize the potentializing effect of adding BB, BAS, EMDR, or different sound frequencies on the hypoalgesic effect of VR.
In conclusion, our review suggests that adding sensory stimuli to VR can be a great opportunity for a plethora of DTx in order to alleviate patients from painful symptoms.It suggests that we can

TABLE 1
(56) of the articles that refer to the different stimulations with and without VR for acute and chronic pain.SnowWorld, a 3D virtual reality environment designed in the early 2000s for analgesia purposes in burnt victims [adapted from Honzel et al.(56)].