ORIGINAL ARTICLE
Who can benefit from virtual reality to reduce experimental pain? A crossover study in healthy subjects N. Demeter1, N. Josman1, E. Eisenberg2,3, D. Pud4 1 2 3 4
Department of Occupational Therapy, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel Institute of Pain Medicine, Rambam Health Care Campus, Haifa, Israel The Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Faculty of Social Welfare and Health Sciences, University of Haifa, Israel
Correspondence Naor Demeter E-mail: [email protected] Funding sources This study was supported by a grant from the Dean of the Faculty of Social Welfare and Health Sciences, University of Haifa, Israel. Conflicts of interest None declared.
Accepted for publication 14 December 2014 doi:10.1002/ejp.678
Abstract Background: The present study aimed to identify predicting factors affecting experimental pain stimuli reduction by using ‘EyeToy’, which is an Immersive Virtual Reality System (IVRS). Methods: Sixty-two healthy subjects (31 M, 31 F) underwent a battery of pain tests to determine each participant’s baseline sensitivity to nociceptive. The battery included thermal pain tests (hot and cold) as well as a paradigm to induce conditioned pain modulation (CPM). Later on, each subject participated in two study conditions in random order: (1) An exposure to tonic heat stimulation (46.5 °C/135 s) to the ankle while participating in VR environment which included an activity requiring limb movements; (2) Same heat stimulation with no exposure to VR. Six pain measures were taken during each study condition (baseline, test 1–5). Results: An interaction of time 9 treatment was found (RM ANOVA, F(5, 305) = 24.33, p < 0.001, g² = 0.28). Specifically, the reduction in pain score between baseline and test 1 was significantly greater in VR condition than in control (p < 0.001). The maximal pain reduction in both conditions was between baseline and test 1. Hierarchical regression revealed gender and the extent of CPM as predictive factors for pain reduction in the VR condition (6.1% and 7.5%, respectively). Conclusions: It can be concluded that VR can serve as an effective manipulation for pain reduction in individuals with efficient CPM and in women. These findings constitute a promising platform for future research and hold potential for the improvement and facilitation of clinical treatment.
1. Introduction Distraction from pain is defined as directing one’s attention away from the sensations or emotional reactions produced by a noxious stimulus (McCaul and Mallot, 1984; van Damme et al., 2010). Virtual reality (VR), an advanced technology used in rehabilitation settings, has also become increasingly utilized in inhibiting pain. It is one example of a
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distraction paradigm (Hoffman et al., 2000) which includes the use of computer hardware and software, in addition to adjunct technologies, to create interactive simulations and environments. VR users have the opportunity to engage in settings that resemble and feel similar to real world interactions (Witmer and Singer, 1998), with most VR platforms delivering primarily visual and auditory feedback. Visual information is commonly displayed by headmounted displays (HMD), projection systems or flat
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What’s already known about this topic? • Previous studies have shown that virtual reality (VR) can be used for pain reduction. • Most of the studies were based on clinical pain patients. What does this study add?
• The current study provides evidence for pain reduction via VR among a sample of healthy subjects. • Virtual reality can serve as effective manipulation for pain reduction in individuals with efficient conditioned pain modulation and in women.
screen, desktop systems of varying size (Weiss et al., 2004). Most previous studies examining the effect of VR on pain have been based on burn pain patients. The pioneer in this area was Hoffman et al. (2008), who developed an immersive VR environment designed for pain relief named ‘snow-world,’ an environment presenting a three-dimensional snowed-in canyon, inducing an icy-cold feeling. Several studies demonstrated the effectiveness of the technique in relieving pain in burn patients during wound care (Hoffman et al., 2004, 2008) and physical therapy (Sharar et al., 2007; Carrougher et al., 2009). In the laboratory setting, there is also some evidence showing the efficacy of VR in reducing experimental multimodal evoked pain in healthy subjects (Magora et al., 2006; Rutter et al., 2009; Dahlquist et al., 2010). Another example considered a manifestation of pain inhibition based on a psychophysical protocol is conditioned pain modulation (CPM). CPM describes a state whereby the response to a given noxious test stimulus is attenuated by another conditioning stimulus that is simultaneously administered to a remote area of the body. CPM is a ‘bottom-up’ activation of the pain-modulatory mechanism, as part of the descending endogenous analgesia system (Yarnitsky et al., 2010). CPM may be at least partly dependent on a distraction effect. To date, there is no evidence to support associations between the magnitude of CPM and a continuous cognitive distractive task, utilizing by VR. Therefore, since both CPM and VR are two effective methods which endogenously reduce perceived pain from experimental stimuli, the aim of the present study was to test whether the magnitude of CPM can serve as a predictive factor for the magnitude of 2 Eur J Pain (2015) –
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pain reduction by VR. An additional aim was to examine other factors that might predict a pain response following a VR task, such as baseline thermal pain perception and gender. The rationale in examining gender as a potential factor is derived from well-established evidence showing gender differences in pain perception on the one hand (Fillingim, 2005), together with inconsistent findings regarding gender differences in response to VR or other distracting manoeuvres (Hoffman et al., 2008; Moont et al., 2010). Our working hypotheses were that: (1) the magnitudes of pain reductions due to VR as well as due to CPM paradigm are related to one another; (2) women will exhibit higher thermal pain intensities (Fillingim, 2005) and will react more positively to VR-induced pain reduction (Gear et al., 1996). Identifying such predictors may help identify those who might benefit from VR for pain reduction.
2. Materials and methods 2.1. Subjects Sixty-two healthy subjects (31 males, 31 females, mean age = 24.2 SD = 3.7 years) were recruited by advertisement at the University of Haifa. Inclusion criteria for study subjects were as follows: (1) Age 18–35 years; (2) Hebrew speakers; (3) Free from any type of chronic or acute pain; (4) Not taking any medication except for contraceptive agents; (5) Free of hearing/visual impairment; and (6) Possess the ability to communicate and understand the purposes and instructions of the study.
2.2. Experimental pain models 2.2.1. Cold pressor test – cold pain threshold, tolerance and intensity The Cold pressor test (CPT) apparatus (Heto CBN 830 Lab equipment, Allerod, Denmark) is a temperature-controlled water bath with a maximum temperature variance of 0.5 °C, which is continuously stirred by a pump. Subjects were instructed to place their right hand in the CPT in a still position. A stopwatch was simultaneously activated, and subjects were requested to keep their hands in the cold water for as long as they could. A cut-off time of 180 s was set for safety reasons. Subjects were instructed to indicate the exact point in time when the cold sensation began to elicit pain. The time until the pain was first perceived was defined as the time to pain onset © 2015 European Pain Federation - EFICâ
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(seconds). In the current study, water temperature of the CPT was 5 °C. Immediately after hand withdrawal, subjects were asked to mark their maximal pain intensity on a 0–100 numerical pain scale (NPS), where 0 represented ‘no pain’ and 100 represented the ‘worst pain one can imagine.’ The latency of intolerability (spontaneous hand removal) was defined as pain tolerance (seconds). Tolerance for subjects who did not withdraw their hand for the entire 180 s was recorded as 180 s. 2.2.2. Thermal thresholds and heat pain intensity Cold and heat pain thresholds were determined with the method of limits on a Medoc TSA-2001 device (Medoc, Ramat Yishai, Israel). A Peltier thermode, size 30 9 30 mm, was attached to the skin above the thenar eminence. The baseline temperature was set at 32.0 °C and was increased or decreased at a rate of 1 °C/s. Stimulator temperature range was 0–50 °C. Subjects were instructed to press a switch when the stimulus was first perceived as painful heat or cold. Three readings were obtained for each thermal modality (cold and hot), and their averages were determined as the pain threshold scores. The thermal sensory analyser (TSA) was used also to determine the intensity of noxious heat stimulation. Subjects were exposed to tonic heat stimulation (46.5 °C, for 120 s) on the medial part of the left ankle and were asked to report the perceived pain intensity (NPS 0–100).
Predictors for pain reduction by virtual reality
The CPM test paradigm was performed as follows: first, heat stimulation was delivered and the subjects verbally reported the level of NPS at the point when the temperature reached 46.5 °C. This was considered the ‘baseline test stimulation’ (baseline-BL). Subjects were then asked to immerse their right hand into the CPT. Following 30 s of immersion, while the hand was still in the CPT, the second test stimulation was delivered and pain intensity was recorded again (test 1). As was found in some of our previous reports (Ram et al., 2008; Treister et al., 2010), the effect of CPM was the gap between BL and test 1 (BL-1). 2.2.4. VR application
To induce the CPM effect, phasic heat stimulations were given and considered the ‘test stimulation’, whereas cold stimulation was used as a ‘conditioning’ stimulation. In our laboratory, there is extensive experience using this kind of paradigm for inducing CPM.
The VR application chosen for the current study is named ‘EyeToy’. It is a popular application released by Sony, Inc. (Tokyo, Japan) in the early 2000s for use with a Play Station 2 platform. ‘EyeToy’ is an immersive Virtual Reality System (IVRS), in which the user is completely immersed in the computer-generated world, and has an impression that he/she has ‘stepped inside’ the synthetic world. Virtual objects are displayed on a standard TV monitor, while ‘EyeToy’ relays real-time images of the user, and detects the participant’s movement. Originally developed for entertainment purposes, IVRS platforms portend great potential for rehabilitation purposes. Important benefits include the fact that clients view themselves, instead of being represented as an avatar. In addition, active client movement is enhanced (Rand et al., 2008) as no impeding special equipment, such as gloves or sensors, need to be worn. ‘EyeToy’ was chosen for this study as an economical, off-the-shelf VR application readily available to the public. The ‘EyeToy’ includes a variety of motivating environments, and is known for containing negligible to no side effects, such as cyber sickness (Sveistrup et al., 2003; Kushner, 2004).
2.2.3.1. Test stimulation
2.2.5. VR procedure chosen for the current study
A TSA thermode was attached to the skin above the right thenar eminence. Five heat pain stimuli of 46.5 °C (starting from 37 °C in an increasing and decreasing rate of 10 °C/s), each lasting 4 s, with interstimulus intervals of 12 s were delivered. After each stimulus, the subject was asked to report the pain intensity he or she felt, using a 0–100 NPS.
The specific ‘EyeToy’ environment chosen for the current study is called ‘Backlash’ taken from ‘EyeToy Kinetic’ (EyeToy games CD). The VR procedure was as follows: subjects were instructed to stand in a demarcated area while viewing a large monitor displaying a game and were required to maintain whole body balance while interacting with the virtual stimuli. A single vision-based tracking camera captured and converted user movements for further processing. The users live on-screen video image corresponded in real time to his movements (Rand et al.,
2.2.3. Assessment of CPM
2.2.3.2. Conditioning stimulation
The left hand was immersed into the CPT (12 °C) for 30 s. © 2015 European Pain Federation - EFICâ
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2005). The task included on ‘Backlash’ environment required visual attention to the entire screen and rapid movement of the subject’s arms and legs, to hit four paddles, two paddles on each side of the screen, and prevent their contact with the central circle. At the outset, only one paddle must be hit. Activity demands are subsequently increased, and a few paddles must be hit by the subject on each trial. Success in this task is measured by the number of paddles hit and those prevented from contacting the central circle on the screen (Fig. 1 illustrates the VR task). Notably, since a Peltier thermode was attached to the lateral left ankle, subjects were instructed to use their right leg only, while performing the VR task.
2.3. Study design The study was approved by the ethics committee of the University of Haifa, Faculty of Social Welfare and Health Sciences. After meeting all inclusion criteria, each subject received a detailed explanation regarding the study procedure and goals, and signed an informed consent form to participate in the study. Subjects were identified only by number. Each subject underwent a set of painful test stimuli for training and an introduction to VR environments. Ten minutes later, a battery of pain tests was administered to determine each participant’s baseline sensitivity to pain. The battery included a measuring of heat and cold pain thresholds (TSA), sensitivity to noxious cold stimulus (CPT) (time to pain onset, tolerance and intensity) and CPM, as explained above. All tests were conducted in a random order with an interval of 5 min between tests. Immediately afterwards, each subject underwent two separate experimental conditions, presented in random order: (1) VR and (2) Control (No VR).
Figure 1 VR environment. VR environment includes a VR-based activity named ‘Backlash’, taken from ‘EyeToy Kinetic’ disc, by Sony. The activity consists of a subject standing in the middle of a TV screen and hitting paddles to prevent them from touching the central circle.
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During each condition (VR and control), the subject was exposed to tonic noxious heat stimulation (46.5 °C, for 140 s) applied to the medial part of the left ankle. Heat pain intensities (NPS 0–100) were documented six times: 10 (BL-baseline), 40 (test 1), 70 (test 2), 100 (test 3), 130 (test 4) s from the beginning of the heat stimulation as well as 10 s after the stimulation was completed (test 5). The exposure to the VR environment lasted 120 s parallel to the heat stimulation, beginning 10 s after commencement of the heat application (right after the first NPS report). Consequently, four NPSs were measured during participation in VR. An interstimulus intervention of 5 min was provided between conditions. During control condition, the subjects were exposed to tonic noxious heat stimulation only, without any distracting task. This was aimed to investigate the pattern of pain response per se across the noxious stimulation to avoid bias in drawing conclusions in case of pain habituation (Fig. 2).
2.4. Statistical analyses Descriptive statistics (mean SEM) were used to describe subjects and study variables (i.e. all pain measurers). Repeated measure (RM) ANOVA was performed to examine differences in the extent of pain reduction between the two study conditions. To examine differences between six heat pain intensity measurements (within factors), a Bonferroni post hoc test was conducted. To examine an interaction effect, a repeated contrast was conducted. The maximal pain reduction was calculated separately for each study condition (i.e. DVR, DControl). A Spearman
Figure 2 Illustration of study design.
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correlation test was performed to examine correlations between all pain measures taken before the two study conditions and pain reduction following VR. A stepwise hierarchical regression was conducted to examine predictor variables of pain reduction following VR including gender and each of the baseline pain measures. Results were considered significant at the 0.05 level. Findings are presented as mean SEM.
3. Results 3.1. Effect of VR participation on pain intensity – comparison between sessions Pain scores during study conditions are depicted in Table 1. No significant differences were found between the two pain scores at baseline (t(122) = 0.06, p = 0.95). Repeated measures ANOVA found a significant main effect of treatment [F(1, 61) = 43.86, p < 0.001, g² = 0.42] in which pain scores were higher during control condition. In addition, a significant main effect of time was found [F(5, 305) = 63.08, p < 0.001, g² = 0.55]. A Bonferroni post hoc test showed a significant difference between BL score and all other scores, and a significant difference between test 5 and all other scores. Notably, even if pain score increased in test 5, it was still lower than BL score. Finally, a significant interaction effect of treatment 9 time was found [F(5, 305) = 24.33, p < 0.001, g² = 0.28]. Contrast test showed that the reduction in pain score between BL and test 1 was significantly greater in VR condition than in control. A significant difference between conditions was found also between test 2 and test 3; in VR, there was hardly a change while in control, pain score increased. In addition, there was a significant difference between test 4 and test 5 showing an increase in pain ratings in VR condition only. This means that there was a significant reduction in pain once the VR begun,
Table 1 Descriptive values of heat intensity scores during study conditions. VR BL Test Test Test Test Test
1 2 3 4 5
63.6 32.8 29.0 30.0 33.0 47.8
Control
3.3 3 2.7 2.9 3.2 3.5
Values are expressed as mean SEM.
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63.9 48.4 48.0 52.6 56.4 55.3
3.2 3.2 3.3 3.5 3.7 4
whereas an elevation in pain occurred once VR was discontinued. Although the differences in control condition were significant, they were smaller than the differences found during the VR session (See Fig. 3, Table 1). The maximal pain reduction in both conditions was between BL and test 1. Therefore, we calculated the difference between these two measures at each condition. These values were called DVR or DControl and were used (as a single value for each session) for the correlation analyses.
3.2. Correlations between baseline pain measures and DVR All baseline pain measures that were taken before the two study conditions for the entire sample, as well as by gender are depicted in Table 2. In VR condition, Spearman correlation showed a significant negative correlation between DVR and heat pain threshold (r = 0.27, p = 0.03), meaning that those with a greater change in pain during VR condition had a lower heat pain threshold. In addition, a significant positive correlation was found between DVR and heat pain intensity (r = 0.33, p = 0.01), meaning that those with a greater change in pain score during VR condition scored higher heat pain intensity. Finally, there was a significant positive correlation between DVR and CPM (r = 0.39, p = 0.002), meaning that those with a greater change in pain score during VR condition showed higher magnitude of CPM. All other correlations were not significant. See Table 3.
3.3. Regression analyses To identify predictive variables for pain reduction, a stepwise hierarchical regression analysis was conducted for each of the study conditions. In the VR condition, it was found that gender explained 6.1% of the pain decrease variance, meaning that pain decreased more in female subjects than in male subjects. CPM added another 7.5% of the explained variance, meaning that the extent of CPM predicted pain decrease. Table 4 depicts the standardized regression coefficients (b), R2 and change R2. In the control condition, no predicting variables were found (F(4, 56) = 1.89, p = 0.13).
4. Discussion The main findings of this study were (1) pain ratings were significantly reduced during the VR environment; (2) CPM was identified as a predictor for the magnitude of pain reduction while participating in Eur J Pain
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Figure 3 Heat pain intensity during the two study conditions. Asterisks represent differences between the VR condition and control condition within two adjacent time points. Two-way RM ANOVA, **p < 0.01, ***p < 0.001.
Table 2 Descriptive values of baseline pain measures of the entire sample and by gender. Total (n = 62) Cold pain intensity Cold pain tolerance (s) Cold pain threshold (s) Cold pain threshold (°C) Heat pain threshold (°C) Heat pain intensity CPM
79.8 46.2 5.4 8.4 47.1 46.1 24.3
Female (n = 31)
14.0 54.0 3.6 6.2 2.9 5.2 18.9
87.0 21.3 4.5 10.3 45.8 57.0 33.6
Male (n = 31)
12.0* 14.7* 2.0 7.3 3.8 5.1 16.9*
83.4 33.8 4.9 9.3 46.5 51.6 28.9
1.7 5.2 0.4 0.9 0.4 3.7 2.4
CPM, conditioned pain modulation. The values are expressed as mean SEM. *p < 0.05 between male and female.
Table 3 Correlations (r) between pain reduction in two study conditions and baseline pain measurers. DVR Cold pain intensity Cold pain tolerance (s) Cold pain threshold (s) Cold pain threshold (°C) Heat pain threshold (°C) Heat pain intensity CPM
0.22 0.30* 0.04 0.08 0.27 0.33* 0.39*
DControl 0.11 0.14 0.15 0.09 0.10 0.10 0.21
CPM, conditioned pain modulation. *p < 0.05.
VR; (3) Women were found to be more sensitive to pain in some of the pain measures and experienced greater benefits from VR. 6 Eur J Pain (2015) –
Table 4 Stepwise hierarchical regression for predicting variables of pain decrease in VR condition. Model 1
Model 2
Variable
B
SE B
b
B
SE B
b
Gender CPM R2 F for change in R2
9.21
4.70
0.25*
6.53 0.29
4.70 0.13 0.136 5.01*
0.18 0.28*
0.061 3.84*
*p ≤ 0.05. CPM, conditioned pain modulation.
There is compelling evidence beginning from the early 2000s for the effectiveness of the VR technique on pain relief in various clinical pain conditions (Hoffman et al., 2000; Chan et al., 2007; Mott et al., © 2015 European Pain Federation - EFICâ
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2008; Schmitt et al., 2011). For example, Hoffman’s water-friendly VR technology (Hoffman et al., 2004) was found to decrease both sensory and affective pain ratings of a burn patient undergoing wound care in a hydrotherapy tub. VR has also been shown to have pain relieving effects for experimentally evoked pain (Le Bars et al., 1979; Rutter et al., 2009; Dahlquist et al., 2010). In their study of the effectiveness of interactive versus passive distraction delivered via a VR type head-mounted display helmet for children experiencing experimental cold pain, Dahlquist et al. (2007) found that children who experienced either passive or interactive distraction demonstrated significant improvements in both pain tolerance and pain threshold relative to their baseline scores. The interactive distraction condition was significantly more effective than the passive one. In contrast, children who underwent a second cold pain trial without distraction showed no significant improvements in pain tolerance or threshold. The present study provides further support for the pain relief effect of VR on pain. It is important to mention the advantages of the VR application used in the current study. The ‘EyeToy’ constitutes an affordable and readily available, off-the-shelf product, generating negligible cyber-sickness side effects in comparison to other VR technologies, such as HMD-based applications (Rand et al., 2008). The current study identified two predictors among all parameters that may contribute to its effect. The first predictor was the magnitude of CPM. Our results showed the more efficient CPM was, the more pain reduction was demonstrated during VR. Although no evidence was found in the literature regarding CPM and VR, a few studies have shown that CPM is not attributed to a distraction effect. In a laser-evoked potential study, Kakigi (1994) found no difference in CPM when asking subjects to direct their attention to the test pain rather than to the conditioning pain (hot water). Similarly, such attention manipulation by Staud et al. (2003) did not further reduce thermal wind-up pain in men. In addition, in their comparison of three experimental manipulations on pain, CPM, distraction and a combined manipulation of CPM and distraction, Moont et al. (2010) found that combined manipulation had a significant further pain inhibition effect compared to CPM alone. The authors concluded that modulation of pain was not due to a cognitive attention requirement to the conditioning pain and that CPM and distraction are independent. Quiton and Greenspan (2007) did find pain reduction to thermal test stimuli was predicted by a distraction effect when © 2015 European Pain Federation - EFICâ
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instructing subjects to focus their attention on an electrical conditioning stimulation. As far as we could ascertain, this is the first study to examine the relationship between CPM and pain during VR. Since the anterior cingulate cortex (ACC) is known to be involved in both pain and attention mechanisms, we assume this could be one possible mechanism-based justification for the relationship found between pain relief and VR. The ACC is activated by moderate to severe pain stimulation and is involved in the subjective perception and the emotional aspects of pain (Casey et al., 1994). Regarding attention, imaging studies showed that attentional modulation of pain involves orbitofrontal cortex, ACC, insula and PAG (Talbot et al., 1989; Posner and Rothbart, 1992; Bantick et al., 2002). The ACC is activated in tasks requiring conflict resolution between anatomically separate cognitive processing systems, such as in the colour/word conflict in the classic Stroop test (Botvinick et al., 1999; Petrovic et al., 2000) or in the VR task. In a previous study that examined associations between CPM and distraction (not through VR), it was claimed that although both pain and attention may involve the ACC, there may be some separation of the cortical areas within the ACC, and the descending pathways involved may result in some differential activation between the two mechanisms (Moont et al., 2010). This claim was based on an earlier fMRI study focusing at pain and attention activation in the ACC of healthy adults, which provided evidence that the posterior part of ACC (BA24) is involved in pain, whereas a larger and more anterior location is involved in other attention-demanding cognitive tasks (Davis et al., 1997). One way or another, the fact that there is a common neuro-anatomical structure involved in endogenously reduce perceived pain by two different modes, justify extensive exploration for the relationship between these two manners. Our finding in which one mode (the magnitude of CPM) predicts the effect of the other (pain relief by distracting via VR) is novel and warrant further RCT and imaging investigations to be able to draw solid conclusions. The second predictor identified for an efficient response to VR was gender. Some evidence has shown that VR can be an effective pain reduction technique for both men and women (Hoffman et al., 2003). A review of the literature did not reveal any further evidence regarding gender differences in pain response to VR, per se. However, several studies have examined gender differences in pain response during other distracting modalities. Moont et al. (2010) Eur J Pain
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examined the effect of distraction on pain in healthy volunteers. They found that a visually distracting task was more efficient in reducing pain in men than in women, and suggested distraction might serve as an effective strategy for coping with pain for men. Keogh et al.(2000) examined the effect of two different attentional strategies (focused vs. avoidance) in the responses of men and women to cold pain; they found attentional focusing in a painful stimulation to be a useful strategy for men. The current study revealed that women were more likely to benefit from VR as a pain reduction technique. This finding is in agreement with evidence related to gender differences in response to analgesia, which shows that although more sensitive to pain (Fillingim, 2005), women gain better analgesia than men by opioids (Sarton et al., 2000; Fillingim and Gear, 2004; Pud et al., 2006). Based on the potential ‘analgesic properties’ hidden in the VR technique, one can expect that women will better benefit from VR than men. The inconsistency in the aforementioned findings, the use of different methods and settings and the fact that no study has tested gender differences in response to VR on pain, to date, leaves this question open and warrants further studies. The lack of predicting value for pain reduction during VR by the rest of the baseline ‘static’ psychophysical tests (i.e. thermal threshold, intensity, tolerance) indicates that the baseline pain perception is not likely to predict who would be a good candidate for distraction manipulations. On the other hand, the ‘dynamic’ advanced psychophysical paradigm (i.e. CPM) is a potentially efficient measure for this purpose. Another interesting finding arising from the study is the significant decrease in pain ratings during control condition. This decrease might be attributed to the phenomenon of habituation. Habituation is indicated by a decrease in response to sustained or repetitive stimulation (Ernst et al., 1986; Milne et al., 1991). It occurs in all modalities of the senses, and it is not specific for noxious stimulation. It can possibly result from either central or peripheral desensitization (Greffrath et al., 2007). In conclusion, this novel study obtained evidence for significant pain reduction during exposure to VR environment. A combination of women and efficient CPM are the most likely profile for benefitting from the VR as a pain relief technique. Based on our finding, we suggest CPM may have clinical relevance in an era of personalized medicine, and may serve as a useful paradigm for identifying those with efficient CPM who may benefit from VR for analgesic 8 Eur J Pain (2015) –
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purposes in some clinical states. Although this study provides novel results, it is limited by deducing the findings into clinical pain states. Hence, future research in clinical populations is required to verify our conclusions. Acknowledgements Part of this study was submitted by the first author to the University of Haifa, Department of Occupational Therapy in partial fulfilment of the requirement for the master’s degree.
Author contributions N.D. – obtained the Ethics Committee approval, implemented the study protocol and oversaw data collection, contributed to the analysis plan, discussed the results, drafted the article and gave her final approval of the version to be published. N.J. – conceptualized and integrated the study as a whole given her unique expertise in studying Virtual Reality. In addition, N.J. contributed to the analysis plan, discussed the results, commented on the manuscript and gave her final approval of the version to be published. E.E. – conceptualized and integrated the study as a whole given his unique expertise in studying PAIN. In addition, E.E. discussed the results and contributed to the writing and editing of the manuscript. D.P. – conceptualized and integrated the study as a whole given her unique expertise in studying PAIN. In addition, D.P. contributed to the analysis plan, discussed the results and commented on the manuscript.
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van Damme, S., Legrain, V., Vogt, J., Crombez, G. (2010). Keeping pain in mind: A motivational account of attention to pain. Neurosci Biobehav Rev 32, 204–213. Davis, K.D., Taylor, S.J., Crawley, A.P., Wood, M.L., Mikulis, D.J. (1997). Functional MRI of pain- and attention-related activations in the human cingulate cortex. J Neurophysiol 77, 3370–3380. Ernst, M., Lee, M.H., Dworkin, B., Zaretsky, H.H. (1986). Pain perception decrement produced through repeated stimulation. Pain 26, 221–231. Fillingim, R.B. (2005). Individual differences in pain responses. Curr Rheumatol Rep 7, 342–347. Fillingim, R.B., Gear, R.W. (2004). Sex differences in opioid analgesia: Clinical and experimental findings. Eur J Pain 8, 413–425. Gear, R.W., Gordon, N.C., Heller, P.H., Paul, S., Miaskowski, C., Levine, J.D. (1996). Gender differences in analgesic response to the kappaopioid pentazocine. Neurosci Lett 205, 207–209. Greffrath, W., Baumg€ artner, U., Treede, R.D. (2007). Peripheral and central components of habituation of heat pain perception and evoked potentials in humans. Pain 132, 301–311. Hoffman, H.G., Doctor, J.N., Patterson, D.R., Carrougher, G.J., Furness, T.A. (2000). Virtual reality as an adjunctive pain control during burn care in adolescent patients. Pain 85, 305–309. Hoffman, H.G., Garcia-Palacios, A., Kapa, V.A., Beecher, J., Sharar, S.R. (2003). Immersive virtual reality for reducing experimental ischemic pain. Int J Hum Comput Int 15, 469–486. Hoffman, H.G., Patterson, D.R., Magula, J., Carrougher, G.J., Zeltzer, K., Dagadakis, S., Sharar, S.R. (2004). Water-friendly virtual reality pain control during wound care. J Clin Psychol 60, 189–195. Hoffman, H.G., Patterson, D.R., Seibel, E., Soltani, M., Jewett-Leahy, L., Sharar, S.R. (2008). Virtual reality pain control during burn wound debridement in the hydrotank. Clin J Pain 24, 299–304. Kakigi, R. (1994). Diffuse noxious inhibitory control: Reappraisal by pain-related somatosensory evoked potentials following CO2 laser stimulation. J Neurol Sci 125, 198–205. Keogh, E., Hatton, K., Ellery, D. (2000). Avoidance versus focused attention and the perception of pain: Differential effects for men and women. Pain 85, 225–230. Kushner, D. (2004). Computing gets physical. Technol Rev 107, 57–61. Le Bars, D., Dickenson, A., Besson, J. (1979). Diffuse noxious inhibitory controls (DNIC). Effects on dorsal horn convergent neurons in the rat. Pain 6, 283–304. Magora, F., Cohe, N.S., Shochina, M., Dayan, E. (2006). Virtual reality immersion method of distraction to control experimental ischemic pain. IMAJ 8, 261–265. McCaul, K.D., Mallot, J.M. (1984). Distraction and coping with pain. Psych Bull 95, 516–533. Milne, R.J., Kay, N.E., Irwin, R.J. (1991). Habituation to repeated painful and non-painful cutaneous stimuli: A quantitative psychophysical study. Exp Brain Res 87, 438–444. Moont, R., Pud, D., Sprecher, E.G., Sharvit, G., Yarnitsky, D. (2010). “Pain inhibits pain” mechanisms: Is pain modulation simply due to distraction? Pain 150, 113–120. Mott, J., Bucolo, S., Cuttle, L., Mill, J., Hilder, M., Miller, K., Kimble, R.M. (2008). The efficacy of an augmented virtual reality system to alleviate pain in children undergoing burns dressing changes: A randomized controlled trial. Burns 34, 803–808. Petrovic, P., Petersson, K.M., Ghatan, P.H., Stone-Elander, S., Ingvar, M. (2000). Pain-related cerebral activation is altered by a distracting cognitive task. Pain 85, 19–30.
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Posner, M.I., Rothbart, M.K. (1992). Attentional mechanisms and conscious experience. In Neuropsychology of Consciousness, A.D., Milner, M.D., Rugg, eds. (San Diego, CA: Academic Press) pp. 91–111. Pud, D., Yarnitsky, D., Sprecher, E., Rogowski, Z., Adler, R., Eisenberg, E. (2006). Can personality traits and gender predict the response to morphine? An experimental cold pain study. Eur J Pain 10, 103–112. Quiton, R.L., Greenspan, J.D. (2007). Sex differences in endogenous pain modulation by distracting and painful conditioning stimulation. Pain 132, S134–S149. Ram, K.C., Eisenberg, E., Haddad, M., Pud, D. (2008). Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain – New perspective of opioid-induced hyperalgesia. Pain 139, 431–438. Rand, D., Kizony, R., Feintuch, U., Katz, N., Josman, N., Rizzo, A.A., Weiss, P.L. (2005). Comparison of two VR platforms for rehabilitation: Video capture versus HMD. Presence-Teleop Virt 14, 147–160. Rand, D., Kizony, R., Weiss, P. (2008). The Sonyplaystation II EyeToy: Low cost virtual reality for use in rehabilitation. J Neurol Phys Ther 32, 155–163. Rutter, C.E., Dahlquist, L.M., Weiss, K.E. (2009). Sustained efficacy of virtual reality distraction. J Pain 4, 391–397. Sarton, E., Olofsen, E., Romberg, R., den Hartigh, J., Kest, B., Nieuwenhuijs, D., Burm, A., Teppema, L., Dahan, A. (2000). Sex differences in morphine analgesia: An experimental study in healthy volunteers. Anesthesiology 93, 1245–1254. Schmitt, Y.S., Hoffman, H.G., Blough, D.K., Patterson, D.R., Jensen, M.P., Soltani, M., Carrougher, G.J., Nakamura, D., Sharar, S.R. (2011). A randomized, controlled trial of immersive virtual reality analgesia, during physical therapy for pediatric burns. Burns 37, 61–68. Sharar, S.R., Carrougher, G.J., Nakamura, D., Hoffman, H.G., Blough, D.K., Patterson, D.R. (2007). Factors influencing the efficacy of virtual reality distraction analgesia during postburn physical therapy: Preliminary results from 3 ongoing studies. Arch Phys Med Rehabil 88, S43–S49. Staud, R., Robinson, M.E., Vierck, C.J. Jr, Price, D.D. (2003). Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 101, 167–174. Sveistrup, H., McComas, J., Thornton, M., Marshal, S., Finestone, H., McCormick, A., Babulic, K., Mayhew, A. (2003). Experimental studies of virtual reality-delivered compared to conventional exercise program for rehabilitation. Cyberpsychol Behav 6, 245–249. Talbot, J.D., Duncan, G.H., Bushnell, M.C. (1989). Effects of diffuse noxious inhibitory controls (DNICs) on the sensory-discriminative dimension of pain perception. Pain 36, 231–238. Treister, R., Eisenberg, E., Gershon, E., Haddad, M., Pud, D. (2010). Factors affecting – and relationships between – different modes of endogenous pain modulation in healthy volunteers. Eur J Pain 14, 608–614. Weiss, P., Rand, D., Katz, N., Kizony, R. (2004). Video capture virtual reality as a flexible and effective rehabilitation tool. J Neuroeng Rehabil 1, 1–12. Witmer, B.G., Singer, M.J. (1998). Measuring presence in virtual environments: A presence questionnaire. Presence 7, 225–240. Yarnitsky, D., Arendt-Nielsen, L., Bouhassira, D., Edwards, R.R., Fillingim, R.B., Granot, M., Hansson, P., Lautenbacher, S., Marchand, S., Wilder-Smith, O. (2010). Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14, 339.
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Who can benefit from virtual reality to reduce experimental pain? A crossover study in healthy subjects N. Demeter1, N. Josman1, E. Eisenberg2,3, D. Pud4 1 2 3 4
Department of Occupational Therapy, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel Institute of Pain Medicine, Rambam Health Care Campus, Haifa, Israel The Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Faculty of Social Welfare and Health Sciences, University of Haifa, Israel
Correspondence Naor Demeter E-mail: [email protected] Funding sources This study was supported by a grant from the Dean of the Faculty of Social Welfare and Health Sciences, University of Haifa, Israel. Conflicts of interest None declared.
Accepted for publication 14 December 2014 doi:10.1002/ejp.678
Abstract Background: The present study aimed to identify predicting factors affecting experimental pain stimuli reduction by using ‘EyeToy’, which is an Immersive Virtual Reality System (IVRS). Methods: Sixty-two healthy subjects (31 M, 31 F) underwent a battery of pain tests to determine each participant’s baseline sensitivity to nociceptive. The battery included thermal pain tests (hot and cold) as well as a paradigm to induce conditioned pain modulation (CPM). Later on, each subject participated in two study conditions in random order: (1) An exposure to tonic heat stimulation (46.5 °C/135 s) to the ankle while participating in VR environment which included an activity requiring limb movements; (2) Same heat stimulation with no exposure to VR. Six pain measures were taken during each study condition (baseline, test 1–5). Results: An interaction of time 9 treatment was found (RM ANOVA, F(5, 305) = 24.33, p < 0.001, g² = 0.28). Specifically, the reduction in pain score between baseline and test 1 was significantly greater in VR condition than in control (p < 0.001). The maximal pain reduction in both conditions was between baseline and test 1. Hierarchical regression revealed gender and the extent of CPM as predictive factors for pain reduction in the VR condition (6.1% and 7.5%, respectively). Conclusions: It can be concluded that VR can serve as an effective manipulation for pain reduction in individuals with efficient CPM and in women. These findings constitute a promising platform for future research and hold potential for the improvement and facilitation of clinical treatment.
1. Introduction Distraction from pain is defined as directing one’s attention away from the sensations or emotional reactions produced by a noxious stimulus (McCaul and Mallot, 1984; van Damme et al., 2010). Virtual reality (VR), an advanced technology used in rehabilitation settings, has also become increasingly utilized in inhibiting pain. It is one example of a
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distraction paradigm (Hoffman et al., 2000) which includes the use of computer hardware and software, in addition to adjunct technologies, to create interactive simulations and environments. VR users have the opportunity to engage in settings that resemble and feel similar to real world interactions (Witmer and Singer, 1998), with most VR platforms delivering primarily visual and auditory feedback. Visual information is commonly displayed by headmounted displays (HMD), projection systems or flat
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What’s already known about this topic? • Previous studies have shown that virtual reality (VR) can be used for pain reduction. • Most of the studies were based on clinical pain patients. What does this study add?
• The current study provides evidence for pain reduction via VR among a sample of healthy subjects. • Virtual reality can serve as effective manipulation for pain reduction in individuals with efficient conditioned pain modulation and in women.
screen, desktop systems of varying size (Weiss et al., 2004). Most previous studies examining the effect of VR on pain have been based on burn pain patients. The pioneer in this area was Hoffman et al. (2008), who developed an immersive VR environment designed for pain relief named ‘snow-world,’ an environment presenting a three-dimensional snowed-in canyon, inducing an icy-cold feeling. Several studies demonstrated the effectiveness of the technique in relieving pain in burn patients during wound care (Hoffman et al., 2004, 2008) and physical therapy (Sharar et al., 2007; Carrougher et al., 2009). In the laboratory setting, there is also some evidence showing the efficacy of VR in reducing experimental multimodal evoked pain in healthy subjects (Magora et al., 2006; Rutter et al., 2009; Dahlquist et al., 2010). Another example considered a manifestation of pain inhibition based on a psychophysical protocol is conditioned pain modulation (CPM). CPM describes a state whereby the response to a given noxious test stimulus is attenuated by another conditioning stimulus that is simultaneously administered to a remote area of the body. CPM is a ‘bottom-up’ activation of the pain-modulatory mechanism, as part of the descending endogenous analgesia system (Yarnitsky et al., 2010). CPM may be at least partly dependent on a distraction effect. To date, there is no evidence to support associations between the magnitude of CPM and a continuous cognitive distractive task, utilizing by VR. Therefore, since both CPM and VR are two effective methods which endogenously reduce perceived pain from experimental stimuli, the aim of the present study was to test whether the magnitude of CPM can serve as a predictive factor for the magnitude of 2 Eur J Pain (2015) –
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pain reduction by VR. An additional aim was to examine other factors that might predict a pain response following a VR task, such as baseline thermal pain perception and gender. The rationale in examining gender as a potential factor is derived from well-established evidence showing gender differences in pain perception on the one hand (Fillingim, 2005), together with inconsistent findings regarding gender differences in response to VR or other distracting manoeuvres (Hoffman et al., 2008; Moont et al., 2010). Our working hypotheses were that: (1) the magnitudes of pain reductions due to VR as well as due to CPM paradigm are related to one another; (2) women will exhibit higher thermal pain intensities (Fillingim, 2005) and will react more positively to VR-induced pain reduction (Gear et al., 1996). Identifying such predictors may help identify those who might benefit from VR for pain reduction.
2. Materials and methods 2.1. Subjects Sixty-two healthy subjects (31 males, 31 females, mean age = 24.2 SD = 3.7 years) were recruited by advertisement at the University of Haifa. Inclusion criteria for study subjects were as follows: (1) Age 18–35 years; (2) Hebrew speakers; (3) Free from any type of chronic or acute pain; (4) Not taking any medication except for contraceptive agents; (5) Free of hearing/visual impairment; and (6) Possess the ability to communicate and understand the purposes and instructions of the study.
2.2. Experimental pain models 2.2.1. Cold pressor test – cold pain threshold, tolerance and intensity The Cold pressor test (CPT) apparatus (Heto CBN 830 Lab equipment, Allerod, Denmark) is a temperature-controlled water bath with a maximum temperature variance of 0.5 °C, which is continuously stirred by a pump. Subjects were instructed to place their right hand in the CPT in a still position. A stopwatch was simultaneously activated, and subjects were requested to keep their hands in the cold water for as long as they could. A cut-off time of 180 s was set for safety reasons. Subjects were instructed to indicate the exact point in time when the cold sensation began to elicit pain. The time until the pain was first perceived was defined as the time to pain onset © 2015 European Pain Federation - EFICâ
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(seconds). In the current study, water temperature of the CPT was 5 °C. Immediately after hand withdrawal, subjects were asked to mark their maximal pain intensity on a 0–100 numerical pain scale (NPS), where 0 represented ‘no pain’ and 100 represented the ‘worst pain one can imagine.’ The latency of intolerability (spontaneous hand removal) was defined as pain tolerance (seconds). Tolerance for subjects who did not withdraw their hand for the entire 180 s was recorded as 180 s. 2.2.2. Thermal thresholds and heat pain intensity Cold and heat pain thresholds were determined with the method of limits on a Medoc TSA-2001 device (Medoc, Ramat Yishai, Israel). A Peltier thermode, size 30 9 30 mm, was attached to the skin above the thenar eminence. The baseline temperature was set at 32.0 °C and was increased or decreased at a rate of 1 °C/s. Stimulator temperature range was 0–50 °C. Subjects were instructed to press a switch when the stimulus was first perceived as painful heat or cold. Three readings were obtained for each thermal modality (cold and hot), and their averages were determined as the pain threshold scores. The thermal sensory analyser (TSA) was used also to determine the intensity of noxious heat stimulation. Subjects were exposed to tonic heat stimulation (46.5 °C, for 120 s) on the medial part of the left ankle and were asked to report the perceived pain intensity (NPS 0–100).
Predictors for pain reduction by virtual reality
The CPM test paradigm was performed as follows: first, heat stimulation was delivered and the subjects verbally reported the level of NPS at the point when the temperature reached 46.5 °C. This was considered the ‘baseline test stimulation’ (baseline-BL). Subjects were then asked to immerse their right hand into the CPT. Following 30 s of immersion, while the hand was still in the CPT, the second test stimulation was delivered and pain intensity was recorded again (test 1). As was found in some of our previous reports (Ram et al., 2008; Treister et al., 2010), the effect of CPM was the gap between BL and test 1 (BL-1). 2.2.4. VR application
To induce the CPM effect, phasic heat stimulations were given and considered the ‘test stimulation’, whereas cold stimulation was used as a ‘conditioning’ stimulation. In our laboratory, there is extensive experience using this kind of paradigm for inducing CPM.
The VR application chosen for the current study is named ‘EyeToy’. It is a popular application released by Sony, Inc. (Tokyo, Japan) in the early 2000s for use with a Play Station 2 platform. ‘EyeToy’ is an immersive Virtual Reality System (IVRS), in which the user is completely immersed in the computer-generated world, and has an impression that he/she has ‘stepped inside’ the synthetic world. Virtual objects are displayed on a standard TV monitor, while ‘EyeToy’ relays real-time images of the user, and detects the participant’s movement. Originally developed for entertainment purposes, IVRS platforms portend great potential for rehabilitation purposes. Important benefits include the fact that clients view themselves, instead of being represented as an avatar. In addition, active client movement is enhanced (Rand et al., 2008) as no impeding special equipment, such as gloves or sensors, need to be worn. ‘EyeToy’ was chosen for this study as an economical, off-the-shelf VR application readily available to the public. The ‘EyeToy’ includes a variety of motivating environments, and is known for containing negligible to no side effects, such as cyber sickness (Sveistrup et al., 2003; Kushner, 2004).
2.2.3.1. Test stimulation
2.2.5. VR procedure chosen for the current study
A TSA thermode was attached to the skin above the right thenar eminence. Five heat pain stimuli of 46.5 °C (starting from 37 °C in an increasing and decreasing rate of 10 °C/s), each lasting 4 s, with interstimulus intervals of 12 s were delivered. After each stimulus, the subject was asked to report the pain intensity he or she felt, using a 0–100 NPS.
The specific ‘EyeToy’ environment chosen for the current study is called ‘Backlash’ taken from ‘EyeToy Kinetic’ (EyeToy games CD). The VR procedure was as follows: subjects were instructed to stand in a demarcated area while viewing a large monitor displaying a game and were required to maintain whole body balance while interacting with the virtual stimuli. A single vision-based tracking camera captured and converted user movements for further processing. The users live on-screen video image corresponded in real time to his movements (Rand et al.,
2.2.3. Assessment of CPM
2.2.3.2. Conditioning stimulation
The left hand was immersed into the CPT (12 °C) for 30 s. © 2015 European Pain Federation - EFICâ
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2005). The task included on ‘Backlash’ environment required visual attention to the entire screen and rapid movement of the subject’s arms and legs, to hit four paddles, two paddles on each side of the screen, and prevent their contact with the central circle. At the outset, only one paddle must be hit. Activity demands are subsequently increased, and a few paddles must be hit by the subject on each trial. Success in this task is measured by the number of paddles hit and those prevented from contacting the central circle on the screen (Fig. 1 illustrates the VR task). Notably, since a Peltier thermode was attached to the lateral left ankle, subjects were instructed to use their right leg only, while performing the VR task.
2.3. Study design The study was approved by the ethics committee of the University of Haifa, Faculty of Social Welfare and Health Sciences. After meeting all inclusion criteria, each subject received a detailed explanation regarding the study procedure and goals, and signed an informed consent form to participate in the study. Subjects were identified only by number. Each subject underwent a set of painful test stimuli for training and an introduction to VR environments. Ten minutes later, a battery of pain tests was administered to determine each participant’s baseline sensitivity to pain. The battery included a measuring of heat and cold pain thresholds (TSA), sensitivity to noxious cold stimulus (CPT) (time to pain onset, tolerance and intensity) and CPM, as explained above. All tests were conducted in a random order with an interval of 5 min between tests. Immediately afterwards, each subject underwent two separate experimental conditions, presented in random order: (1) VR and (2) Control (No VR).
Figure 1 VR environment. VR environment includes a VR-based activity named ‘Backlash’, taken from ‘EyeToy Kinetic’ disc, by Sony. The activity consists of a subject standing in the middle of a TV screen and hitting paddles to prevent them from touching the central circle.
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During each condition (VR and control), the subject was exposed to tonic noxious heat stimulation (46.5 °C, for 140 s) applied to the medial part of the left ankle. Heat pain intensities (NPS 0–100) were documented six times: 10 (BL-baseline), 40 (test 1), 70 (test 2), 100 (test 3), 130 (test 4) s from the beginning of the heat stimulation as well as 10 s after the stimulation was completed (test 5). The exposure to the VR environment lasted 120 s parallel to the heat stimulation, beginning 10 s after commencement of the heat application (right after the first NPS report). Consequently, four NPSs were measured during participation in VR. An interstimulus intervention of 5 min was provided between conditions. During control condition, the subjects were exposed to tonic noxious heat stimulation only, without any distracting task. This was aimed to investigate the pattern of pain response per se across the noxious stimulation to avoid bias in drawing conclusions in case of pain habituation (Fig. 2).
2.4. Statistical analyses Descriptive statistics (mean SEM) were used to describe subjects and study variables (i.e. all pain measurers). Repeated measure (RM) ANOVA was performed to examine differences in the extent of pain reduction between the two study conditions. To examine differences between six heat pain intensity measurements (within factors), a Bonferroni post hoc test was conducted. To examine an interaction effect, a repeated contrast was conducted. The maximal pain reduction was calculated separately for each study condition (i.e. DVR, DControl). A Spearman
Figure 2 Illustration of study design.
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correlation test was performed to examine correlations between all pain measures taken before the two study conditions and pain reduction following VR. A stepwise hierarchical regression was conducted to examine predictor variables of pain reduction following VR including gender and each of the baseline pain measures. Results were considered significant at the 0.05 level. Findings are presented as mean SEM.
3. Results 3.1. Effect of VR participation on pain intensity – comparison between sessions Pain scores during study conditions are depicted in Table 1. No significant differences were found between the two pain scores at baseline (t(122) = 0.06, p = 0.95). Repeated measures ANOVA found a significant main effect of treatment [F(1, 61) = 43.86, p < 0.001, g² = 0.42] in which pain scores were higher during control condition. In addition, a significant main effect of time was found [F(5, 305) = 63.08, p < 0.001, g² = 0.55]. A Bonferroni post hoc test showed a significant difference between BL score and all other scores, and a significant difference between test 5 and all other scores. Notably, even if pain score increased in test 5, it was still lower than BL score. Finally, a significant interaction effect of treatment 9 time was found [F(5, 305) = 24.33, p < 0.001, g² = 0.28]. Contrast test showed that the reduction in pain score between BL and test 1 was significantly greater in VR condition than in control. A significant difference between conditions was found also between test 2 and test 3; in VR, there was hardly a change while in control, pain score increased. In addition, there was a significant difference between test 4 and test 5 showing an increase in pain ratings in VR condition only. This means that there was a significant reduction in pain once the VR begun,
Table 1 Descriptive values of heat intensity scores during study conditions. VR BL Test Test Test Test Test
1 2 3 4 5
63.6 32.8 29.0 30.0 33.0 47.8
Control
3.3 3 2.7 2.9 3.2 3.5
Values are expressed as mean SEM.
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63.9 48.4 48.0 52.6 56.4 55.3
3.2 3.2 3.3 3.5 3.7 4
whereas an elevation in pain occurred once VR was discontinued. Although the differences in control condition were significant, they were smaller than the differences found during the VR session (See Fig. 3, Table 1). The maximal pain reduction in both conditions was between BL and test 1. Therefore, we calculated the difference between these two measures at each condition. These values were called DVR or DControl and were used (as a single value for each session) for the correlation analyses.
3.2. Correlations between baseline pain measures and DVR All baseline pain measures that were taken before the two study conditions for the entire sample, as well as by gender are depicted in Table 2. In VR condition, Spearman correlation showed a significant negative correlation between DVR and heat pain threshold (r = 0.27, p = 0.03), meaning that those with a greater change in pain during VR condition had a lower heat pain threshold. In addition, a significant positive correlation was found between DVR and heat pain intensity (r = 0.33, p = 0.01), meaning that those with a greater change in pain score during VR condition scored higher heat pain intensity. Finally, there was a significant positive correlation between DVR and CPM (r = 0.39, p = 0.002), meaning that those with a greater change in pain score during VR condition showed higher magnitude of CPM. All other correlations were not significant. See Table 3.
3.3. Regression analyses To identify predictive variables for pain reduction, a stepwise hierarchical regression analysis was conducted for each of the study conditions. In the VR condition, it was found that gender explained 6.1% of the pain decrease variance, meaning that pain decreased more in female subjects than in male subjects. CPM added another 7.5% of the explained variance, meaning that the extent of CPM predicted pain decrease. Table 4 depicts the standardized regression coefficients (b), R2 and change R2. In the control condition, no predicting variables were found (F(4, 56) = 1.89, p = 0.13).
4. Discussion The main findings of this study were (1) pain ratings were significantly reduced during the VR environment; (2) CPM was identified as a predictor for the magnitude of pain reduction while participating in Eur J Pain
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Figure 3 Heat pain intensity during the two study conditions. Asterisks represent differences between the VR condition and control condition within two adjacent time points. Two-way RM ANOVA, **p < 0.01, ***p < 0.001.
Table 2 Descriptive values of baseline pain measures of the entire sample and by gender. Total (n = 62) Cold pain intensity Cold pain tolerance (s) Cold pain threshold (s) Cold pain threshold (°C) Heat pain threshold (°C) Heat pain intensity CPM
79.8 46.2 5.4 8.4 47.1 46.1 24.3
Female (n = 31)
14.0 54.0 3.6 6.2 2.9 5.2 18.9
87.0 21.3 4.5 10.3 45.8 57.0 33.6
Male (n = 31)
12.0* 14.7* 2.0 7.3 3.8 5.1 16.9*
83.4 33.8 4.9 9.3 46.5 51.6 28.9
1.7 5.2 0.4 0.9 0.4 3.7 2.4
CPM, conditioned pain modulation. The values are expressed as mean SEM. *p < 0.05 between male and female.
Table 3 Correlations (r) between pain reduction in two study conditions and baseline pain measurers. DVR Cold pain intensity Cold pain tolerance (s) Cold pain threshold (s) Cold pain threshold (°C) Heat pain threshold (°C) Heat pain intensity CPM
0.22 0.30* 0.04 0.08 0.27 0.33* 0.39*
DControl 0.11 0.14 0.15 0.09 0.10 0.10 0.21
CPM, conditioned pain modulation. *p < 0.05.
VR; (3) Women were found to be more sensitive to pain in some of the pain measures and experienced greater benefits from VR. 6 Eur J Pain (2015) –
Table 4 Stepwise hierarchical regression for predicting variables of pain decrease in VR condition. Model 1
Model 2
Variable
B
SE B
b
B
SE B
b
Gender CPM R2 F for change in R2
9.21
4.70
0.25*
6.53 0.29
4.70 0.13 0.136 5.01*
0.18 0.28*
0.061 3.84*
*p ≤ 0.05. CPM, conditioned pain modulation.
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2008; Schmitt et al., 2011). For example, Hoffman’s water-friendly VR technology (Hoffman et al., 2004) was found to decrease both sensory and affective pain ratings of a burn patient undergoing wound care in a hydrotherapy tub. VR has also been shown to have pain relieving effects for experimentally evoked pain (Le Bars et al., 1979; Rutter et al., 2009; Dahlquist et al., 2010). In their study of the effectiveness of interactive versus passive distraction delivered via a VR type head-mounted display helmet for children experiencing experimental cold pain, Dahlquist et al. (2007) found that children who experienced either passive or interactive distraction demonstrated significant improvements in both pain tolerance and pain threshold relative to their baseline scores. The interactive distraction condition was significantly more effective than the passive one. In contrast, children who underwent a second cold pain trial without distraction showed no significant improvements in pain tolerance or threshold. The present study provides further support for the pain relief effect of VR on pain. It is important to mention the advantages of the VR application used in the current study. The ‘EyeToy’ constitutes an affordable and readily available, off-the-shelf product, generating negligible cyber-sickness side effects in comparison to other VR technologies, such as HMD-based applications (Rand et al., 2008). The current study identified two predictors among all parameters that may contribute to its effect. The first predictor was the magnitude of CPM. Our results showed the more efficient CPM was, the more pain reduction was demonstrated during VR. Although no evidence was found in the literature regarding CPM and VR, a few studies have shown that CPM is not attributed to a distraction effect. In a laser-evoked potential study, Kakigi (1994) found no difference in CPM when asking subjects to direct their attention to the test pain rather than to the conditioning pain (hot water). Similarly, such attention manipulation by Staud et al. (2003) did not further reduce thermal wind-up pain in men. In addition, in their comparison of three experimental manipulations on pain, CPM, distraction and a combined manipulation of CPM and distraction, Moont et al. (2010) found that combined manipulation had a significant further pain inhibition effect compared to CPM alone. The authors concluded that modulation of pain was not due to a cognitive attention requirement to the conditioning pain and that CPM and distraction are independent. Quiton and Greenspan (2007) did find pain reduction to thermal test stimuli was predicted by a distraction effect when © 2015 European Pain Federation - EFICâ
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instructing subjects to focus their attention on an electrical conditioning stimulation. As far as we could ascertain, this is the first study to examine the relationship between CPM and pain during VR. Since the anterior cingulate cortex (ACC) is known to be involved in both pain and attention mechanisms, we assume this could be one possible mechanism-based justification for the relationship found between pain relief and VR. The ACC is activated by moderate to severe pain stimulation and is involved in the subjective perception and the emotional aspects of pain (Casey et al., 1994). Regarding attention, imaging studies showed that attentional modulation of pain involves orbitofrontal cortex, ACC, insula and PAG (Talbot et al., 1989; Posner and Rothbart, 1992; Bantick et al., 2002). The ACC is activated in tasks requiring conflict resolution between anatomically separate cognitive processing systems, such as in the colour/word conflict in the classic Stroop test (Botvinick et al., 1999; Petrovic et al., 2000) or in the VR task. In a previous study that examined associations between CPM and distraction (not through VR), it was claimed that although both pain and attention may involve the ACC, there may be some separation of the cortical areas within the ACC, and the descending pathways involved may result in some differential activation between the two mechanisms (Moont et al., 2010). This claim was based on an earlier fMRI study focusing at pain and attention activation in the ACC of healthy adults, which provided evidence that the posterior part of ACC (BA24) is involved in pain, whereas a larger and more anterior location is involved in other attention-demanding cognitive tasks (Davis et al., 1997). One way or another, the fact that there is a common neuro-anatomical structure involved in endogenously reduce perceived pain by two different modes, justify extensive exploration for the relationship between these two manners. Our finding in which one mode (the magnitude of CPM) predicts the effect of the other (pain relief by distracting via VR) is novel and warrant further RCT and imaging investigations to be able to draw solid conclusions. The second predictor identified for an efficient response to VR was gender. Some evidence has shown that VR can be an effective pain reduction technique for both men and women (Hoffman et al., 2003). A review of the literature did not reveal any further evidence regarding gender differences in pain response to VR, per se. However, several studies have examined gender differences in pain response during other distracting modalities. Moont et al. (2010) Eur J Pain
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examined the effect of distraction on pain in healthy volunteers. They found that a visually distracting task was more efficient in reducing pain in men than in women, and suggested distraction might serve as an effective strategy for coping with pain for men. Keogh et al.(2000) examined the effect of two different attentional strategies (focused vs. avoidance) in the responses of men and women to cold pain; they found attentional focusing in a painful stimulation to be a useful strategy for men. The current study revealed that women were more likely to benefit from VR as a pain reduction technique. This finding is in agreement with evidence related to gender differences in response to analgesia, which shows that although more sensitive to pain (Fillingim, 2005), women gain better analgesia than men by opioids (Sarton et al., 2000; Fillingim and Gear, 2004; Pud et al., 2006). Based on the potential ‘analgesic properties’ hidden in the VR technique, one can expect that women will better benefit from VR than men. The inconsistency in the aforementioned findings, the use of different methods and settings and the fact that no study has tested gender differences in response to VR on pain, to date, leaves this question open and warrants further studies. The lack of predicting value for pain reduction during VR by the rest of the baseline ‘static’ psychophysical tests (i.e. thermal threshold, intensity, tolerance) indicates that the baseline pain perception is not likely to predict who would be a good candidate for distraction manipulations. On the other hand, the ‘dynamic’ advanced psychophysical paradigm (i.e. CPM) is a potentially efficient measure for this purpose. Another interesting finding arising from the study is the significant decrease in pain ratings during control condition. This decrease might be attributed to the phenomenon of habituation. Habituation is indicated by a decrease in response to sustained or repetitive stimulation (Ernst et al., 1986; Milne et al., 1991). It occurs in all modalities of the senses, and it is not specific for noxious stimulation. It can possibly result from either central or peripheral desensitization (Greffrath et al., 2007). In conclusion, this novel study obtained evidence for significant pain reduction during exposure to VR environment. A combination of women and efficient CPM are the most likely profile for benefitting from the VR as a pain relief technique. Based on our finding, we suggest CPM may have clinical relevance in an era of personalized medicine, and may serve as a useful paradigm for identifying those with efficient CPM who may benefit from VR for analgesic 8 Eur J Pain (2015) –
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purposes in some clinical states. Although this study provides novel results, it is limited by deducing the findings into clinical pain states. Hence, future research in clinical populations is required to verify our conclusions. Acknowledgements Part of this study was submitted by the first author to the University of Haifa, Department of Occupational Therapy in partial fulfilment of the requirement for the master’s degree.
Author contributions N.D. – obtained the Ethics Committee approval, implemented the study protocol and oversaw data collection, contributed to the analysis plan, discussed the results, drafted the article and gave her final approval of the version to be published. N.J. – conceptualized and integrated the study as a whole given her unique expertise in studying Virtual Reality. In addition, N.J. contributed to the analysis plan, discussed the results, commented on the manuscript and gave her final approval of the version to be published. E.E. – conceptualized and integrated the study as a whole given his unique expertise in studying PAIN. In addition, E.E. discussed the results and contributed to the writing and editing of the manuscript. D.P. – conceptualized and integrated the study as a whole given her unique expertise in studying PAIN. In addition, D.P. contributed to the analysis plan, discussed the results and commented on the manuscript.
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