This study is a prospective, randomized controlled trial with two parallel groups. After randomization, participants will receive either (1) standard care after surgery (control group) or (2) VR based intervention along with standard care for testing the superiority of the intervention delivered through VR environments for reducing postoperative pain.
The study protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (42) instructions and received the ethical approval from the Babes-Bolyai University committee as from the committee of Municipal Hospital of Cluj-Napoca and is retrospectively registered on ClinicalTrials.gov (NCT03776344).
Study sample size
Using G*Power 184.108.40.206 (43), we estimated a minimum of 54 participants (27 in each group) needed to detect an effect size of 0.80, with α = 0.05 and power =0.80. The expected effect size of 0.80 was chosen in the light of the results found by the most recent meta-analyses (29,30), being a conservative effect size given that in their analysis Chan and colleagues (29) found a medium effect size (SMD= -0.49, 95% CI -0.83 to -0.14) and the analysis of Georgescu and colleagues (30) a large effect size was found (g=1.08, 95% CI 0.46 to 1.70) for studies with parallel design aiming to decrease pain at hospitalized patients. However, we expect to have some incomplete or unusable data, especially on the physiological measure, therefore, we aim to recruit 30 participants in each group.
All the participants are recruited from one community hospital from Romania. Starting October 2018, each patient admitted to the hospital for surgery is screened for eligibility criteria to this trial.
The below criteria should be cumulative met in order that a participant be included in the trial.
- Adults aged 18-65 years, after surgery of varicose veins, hernia repair or gallbladder surgery.
- Patient in the acute care units, 1-3 days following surgery.
- Willing and able to provide informed consent and participate in the study visit and study follow-up questionnaire.
Presence of any criteria listed below will conduct at the exclusion of the participant from the trial.
- Patients with neoplastic pathologies.
- Patients with a history of motion sickness.
- Patients with severe visual impairment (i.e. not able to clearly see without glasses; patients with contact lenses will not be excluded).
- Patients with severe/profound cognitive impairments measured with Six-item Cognitive Impairment Test (6CIT).
- Use of strong opioids (i.e. morphine)
- Other reasons for exclusion (Non-Romanian speaking patients, patients with severe psychological problems, etc.)
Randomization and blinding
Randomization is conducted within the type of surgery using a random number generator, with an equal number of participants in the control and experimental group. An independent researcher conducted the randomization sequence and the allocation sequence is stored on a secured computer until the participants are assigned to one of the interventions. For ensuring blindness of medical personnel and participants through the entire procedure every participant is invited in a separate room - the treatment room - where only the research assistant conducting this phase of the study is allowed. In the treatment room those from the experimental group will be exposed to the VR content and psychological along physiological measures will be taken, while those from the control group psychological and physiological measures will be taken without exposure to the VR content. After this, each participant will be conducted to their hospital room. In this manner the participants from the control and experimental group will not be mixed and the entire procedure is secured. In the case that a participant explicitly requests to end the study procedure for any reasons, the procedure will be stopped and will be counted as a dropout. Those patients, who ask to end the procedure earlier, will be asked to respond at a short interview to quantify the reasons.
Recruitment procedure and interventions
The process of recruitment and data collection is presented in Figure 1. The day following the surgical procedure, all patients from the acute care unit who meet the primary criteria for inclusion (i.e., age, type of surgery, type of opioids used, free of visual impairments, able to fluently speak in Romanian and without recorded psychological problems) are invited to participate. Information regarding duration, procedure, implications, and conditions for withdrawing are presented and explained. Those who are interested and sign the informed consent are invited in the treatment room where they complete the Six-item Cognitive Impairment Test for assessing the eligibility regarding executive functions. Subsequently, patients are randomly allocated to one of the two groups:
a) Treatment group: VR based intervention
Patients allocated to the VR based intervention will follow the standard protocol after surgery as prescribed by the current medical personnel and are exposed for 15 minutes to an interactive virtual environment (i.e., Nature Treks© VR). This application is a commercially available app from the Oculus store (available at
https://www.oculus.com/experiences/go/1723271804396968/), promoting relaxation through fifteen highly immersive environments. Every environment recreates a different natural scene (e.g., a tropical beach, savannas at sunset, snowy forests) which can be explored by the patients through a controller. Concomitant with the activities (e.g., walking on the beach, climbing the mountains) environmental effects are changing smoothly to create a vivid experience. Additionally, in some environments (i.e., deep blue and black beginning), patients can freely explore the scenes in 360 degrees for enhancing the feeling of presence and immersion.
As previous studies testing the efficacy of the analgesic effect of VR (34) showed that better immersion is associated with lower scores for pain intensity, the device used is an Oculus Rift® (available at - https://www.oculus.com/). This device is the premium device from Oculus, equipped with a highly immersive headset, one controller, and integrated headphones.
Five minutes before and during the VR exposures, the fluctuations of skin conductance are measured for all patients. Before and after the intervention, pain intensity, relaxation, and VR adverse effects are recorded. Additionally, the catastrophizing level, anxiety, and depression related to health and presence in the VR environment are measured.
b) Control group: standard of care intervention
Patients allocated to the standard of care group follows the treatment after surgery as prescribed by current medical personnel. They are also following the same protocol as the patients in the intervention group regarding psychological and physiological measures. Specifically, they will be conducted in the treatment room, will be asked to indicate the non-dominant hand and the equipment for measuring SC will be setted up. After that, the SC will be measured continuously for 20 minutes without to be exposed to the VR environments. At the end, they will complete de psychological measures and will be conducted in their hospital room.
Data collection procedure
Figure 2 offers an overview of the process of the data collection and measures. All psychological and physiological measures will be collected by a previously trained researcher. The level of pain intensity and relaxation will be collected before and after the exposure to VR environments in the experimental group and before and after the measurement of skin conductance (SC) in the control group. The SC will be measured during the exposure to VR content in the experimental group and for a period of 15 minutes in the control group. For ensuring an accurate baseline for the physiological measure and for controlling the individual differences in SC, the signal of SC for each participant will be taken before the study procedure start for five minutes. During this time, participants will have no other instructions, and the communication will be maintained at the minimum level. The amount of analgesic consumption for each participant will be extracted from the medical records. Excepting for the fluctuations of skin conductance, all measures will be collected through an online platform.
The present study assesses the efficacy of a Nature Track© VR to decrease pain intensity in surgical patients. The primary outcome will be pain intensity measured right before the exposure to the VR content and after. The secondary outcomes will measure the effects of the application on relaxation and the amount of time spent thinking about pain. Also, to allow for an in-depth investigation on the effect of VR environments, the primary outcome will be complemented with measures of the adverse effects, level of immersion and level of presence in the VR.
The pain intensity will be measured using the Numerical Rating Scale (NRS) (44) by asking participants to report their intensity before and after the intervention on a scale from 0 (“no pain”) to 10 (“extremely painful”). To help patients to discriminate between different pain levels, we will ask them to report the mean level of pain intensity in the last 24 hours, the peak of intensity in the same period and the intensity right before the intervention. We chose NRS for this study rather than other measures more extensively used, such as Visual Analog Scales (VAS), due to the consensus of the better psychometrics properties (45–48). The value of pain right before the intervention will be used in the analysis of VR effectiveness.
Concomitantly, as a physiological indicator of postoperative pain we will measure the fluctuations of the SC (49–51). The SC will be measured using the BIOPAC MP150 system (52). The two finger electrodes were attached to the first phalange of the index and medius fingers from the non-dominant hand with Velcro straps. The electrodes were connected to the computer using the USB connection input. In order to ensure good contact with the skin, isotonic gel was added to the electrodes prior to attaching to the fingers. At the beginning, participants were allowed to relax, get ready and comfortable with the experimental structure in a variable time (i.e., five minutes). In this time participants were invited to find a comfortable position for both hands, which they were instructed not to move for the duration of the recording.
As the level of relaxation could affect the perception of the pain intensity, the state of relaxation will be measured using the NRS from 0 (“extremely stressed” to 10 (“relaxed”) before and after the intervention. We chose to measure through an NRS rather than other scale designed to measure relaxation due to his factual effect and similarities with the pain intensity measures.
Time spent thinking about pain
Another factor which can contribute to an increased perception of pain intensity is the time spent thinking about pain (53). Consequently, we will ask patients to report after the interventions, on NRS from 0 (“not at all”) to 10 (“all the time”), the amount of time they spent thinking about their pain during the exposure to the VR content in the experimental group and during the measuring of SC conductance in the control group.
Potential adverse effects will be evaluated using the Simulator Sickness Questionnaire (SSQ) (54). As some of the unintended effects of VR could also be effects of the opioid’s consumptions (e.g., headaches, nausea), we will ask participants to complete the scale twice, before and after the exposure of VR. The SSQ was previously validated and proved robust psychometrics properties (54,55) being the most widely measure of cyber-sickness. The patients will be instructed to answer on a 4-point Likert scale, corresponding to not at all, slight, moderate and strong sensations regarding the occurrence of possible side effects such as general discomfort, fatigue, headache, and dizziness.
Treatment satisfaction and presence
The presence in VR was assessed using Igroup presence questionnaire (IPQ, available at http://www.igroup.org/projects/ipq/). This is a 14 items questionnaire assessing different aspects of presence and immersion into VR world through items such as: “In the computer generated world I had a sense of "being there" or “How aware were you of the real world surrounding while navigating in the virtual world? (i.e. sounds, room temperature, other people, etc.)?”. In the end, once the IPQ completed, the patients will be instructed to answer an additional question (i.e., Are you willing to use VR systems in the future?) with dichotomous response developed by the authors for assessing the willingness for further sessions with VR system.
Covariates and measures for baseline imbalances
The amount of analgesic used will be extracted from the medical records and will be used as a covariate in the estimation of the intervention effect. The usage of opioids will be coded as present and absent. The mean drug metabolism time will be calculated in order to determine if an opioid agent is active, coding 1 if the opioid agent is active and 0 if is out of his action range.
Level of catastrophizing will be measured through the Pain Catastrophizing Scale (PCS) (56). This scale is a self-report measure with 13 items structured in three subscales, namely rumination, magnification, and helplessness, and proved good psychometrics properties. Patients will be instructed to answer on a scale from 0 (“not at all”) to 4 (“all the time”).
Assessment of mood
Anxiety and depression levels will be assessed through the Hospital Anxiety and Depression Scale (HADS)(57). This scale is a self-report measure with 14 items, with half of the items measuring anxiety symptoms (e.g., items targeting tension, panic attacks) and the other half measuring depression symptoms (e.g., items targeting anhedonia or inability to enjoy things or experiences). Responses are recorded on a scale from 0 to 3, and each item has a different response in accordance with the item content.
Cognitive abilities were measured though the Six-item Cognitive Impairment Test (6CIT) (58), a screening tool for measuring the global cognitive status. The items of the 6CIT cover six questions; one assessing the memory (remembering a 5-item name and address), two items including calculation (reciting numbers backward from 20 to 1 and months of the year backward) and three items assessing orientation (year, month, and time of day). The cutoff of seven from the total score was used for excluding patients with low cognitive abilities (59).
Preliminary analyses and preprocessing data of skin conductance
Demographic characteristics and psychological measures will be explored for missing data, and distribution abnormalities. Means and standard deviations will be used to characterize the sample. Baseline imbalances between groups regarding continuous variables (i.e., age, level of pain catastrophizing, anxiety and depression related to health problems) will explored using t-test statistics, and gender respectively the opioids usage using χ2 test. Preprocessing of skin conductance measure will performed using AcqKnowledge 4.1 first though the visual inspection of the raw signal, and then applying the Smoothing function with a smoothing factor of three samples. This function has the same effect as the low pass filter by replacing the high-frequency signal with the mean values across three milliseconds in order to subtract the artifacts, without changing the waves form.
Behavioral data will analyzed using SPSS 20 (IBM Corporation, Armonk, NY) in accordance with the intent to treat principal (Gupta, 2011). Physiological data will be processed using the AcqKnowledge 4.1 software, and for each patient, a difference score in the area under the curve between the last five minutes of measurement and baseline level of SC was extracted. In order to account the changes in pain intensity and relaxation scores, separate repeated measure analysis of variance (RM-ANOVA) will be employed. The effect size of intervention will be estimated by computing a d value using the means and standard deviations (SD) of the control and treatment group. A value of d less than .20 will be considered small, medium when d ≤ .50 and large when d ≥.80. For clinical significance purposes, we will code for each patient the percentages of dropping in pain score, coding with 1 all pre-post differences above 30% on NPRS and 0 differences below this threshold. Subsequently, χ2 test will be employed to determine if are significant differences across the two groups. To estimate differences in time spent thinking about pain, treatment satisfaction, and adverse effects of VR intervention, t-test statistics will be used. Pearson correlation will be employed to examine the relationship between the level of skin conductance and pain intensity (as a difference score between pre-post intervention). A P-value will be used to estimate statistical significance for all analyses.