For the majority of patients with osteoarthritis, total hip (THA) arthroplasty results in a significant reduction in pain, emotional distress, and disability and a significant improvement in their quality of life. Little is known about how these recovery-related changes impact the spouse or the marital relationship. Methods: Twenty-nine couples whose spouse underwent a THA (29 THA) participated in a semi-structured retrospective interview designed for this study. They were each asked to recall the level of pain before and after surgery and to provide a numerical rating score for questions pertaining to the level of disability in seven different activities of daily living. Couples were also asked to list in order of importance the five ways in which the surgery affected their overall quality of life. Results: The spouses estimated their partner’s pain, both pre- and postoperatively, to be significantly higher level than the patient’s perception. The spouses perceived a greater improvement in family/home responsibilities, recreation and social activities, and in their occupation than that noted by the partner. After the arthroplasty, the spouses indicated that their lives had improved with respect to doing more activities/leisure (72%), because their partner had less suffering (59%), they had more independence/less caregiving (55%), it improved their marital relationship (52%), they had a better social/family life (28%), and they were able to travel (28%). Conclusions: This study indicates that THA result in a significant improvement in quality of life not only for the patients, but also for their spouses. The pain of arthritic disorders occurs in a social and environmental context; therefore, the pain and disability of arthritis not only can affect the patient but also the spouse . IndividSpouses of individuals with chronic illness most frequently assume the role of informal caregivers . InformaFor the vast majority of individuals with osteoarthritis, joint replacement surgery will result in significant reductions in pain, emotional distress, and disability and there will be a significant improvement in their function . Little We undertook a study to evaluate the spouse’s perception of the patient’s pain and disability before and after hip replacement surgery and to assess the degree to which patients and their spouses perceive themselves to be disabled, both preoperatively and postoperatively. In addition, we determined the ways in which the spouse’s personal and marital life improved after the patient’s successful hip arthroplasty.The study sample comprised 29 heterosexual couples (58 respondents). The average age of the patients was 68 years old  and 67 years  for the spouses. There were 14 male patients and 15 female patients, and 15 female spouses and 14 male spouses. All the 29 THAs were performed by the senior author (M.T.). Patients had been living with a diagnosis of osteoarthritis for an average of 7 years , while the average waiting time to receive an operation was 8.9 months . On average, couples had been married for 36.7 years . The levels of education and number of children are also summarized in p value of p < 0.05 was deemed statistically significant. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.Hospital institutional review board approval  was obtained prior to the onset of the study. Hip arthroplasty patients were identified either from our arthroplasty database or were recruited for the study at their 6-week follow-up visit and consented to participate. All patients in the study were operated on by a single surgeon (M.T.), using the same implants and at a single institution. All patients in the study had to be 3–12 months following their surgery, had a diagnosis of osteoarthritis (OA), were married or co-habiting with their spouse for at least 5 years prior to surgery, and were between 65 and 85 years of age. Patients were excluded if they either received an arthroplasty for a diagnosis other than OA, were divorced, had other chronic pain or illnesses that significantly affected their ability to ambulate, had other lower extremity joints that required replacement, or had a serious postoperative complication that affected their recovery. Couples participated in a semi-structured interview, and the interview took place either in clinic or was conducted over the telephone. The interviews took place an average of 11.8 months after surgery . In total, 4 couples were interviewed 3 months postoperatively, 6 couples at 6 months, 2 couples at 9 months, 5 couples at 12 months, and 12 couples over 1 year postoperatively. During the interview, couples were interviewed separately. This was done in the early postoperative period, so that the spouse and the patient could readily recall the pain and disability, but after the patient had recovered from surgery and was fully functional (Harris Hip Score of 100). The interview was done when the patient had a full recovery with no pain or limitations, indicated by their normal Harris Hip Score of 100. The patients ranged in age from 65 to 85, resulting in the time to obtain a normal Harris Hip Score being between 3 and 12 months, at which time the interview was done. Basic descriptive analysis for nominal data was used, and a paired Student’s T test was used to compare pre-operative and post-operative pain and PDI scores, and a Interview: A semi-structured interview was developed for the purpose of this study. Interview questions were generated to address patients’ and spouses’ perceptions of patients’ pain severity, as well as pain-related disability preoperatively and postoperatively at the time of the survey. The spouses were also asked to provide demographic data for the duration of their marriage, level of education, and number of children. Finally, the spouses and the patients were asked to list in order of importance the five ways in which the surgery affected their overall quality of life.Pain Severity: Patients and spouses were asked to rate the severity of the patient’s pain on a 0–10 numerical rating scale (NRS) with the endpoints (0) no pain, and (10) unbearable pain.no disability and (10) total disability. The PDI has been shown to be internally reliable and significantly correlated with objective indices of disability . Ite. Ite8]. lity and  total dip = 0.05). Postoperatively, at the time of the survey, the patients felt their pain had improved to 0.9, while their spouses continued to report their pain as significantly worse, being 1.4 (p = 0.05).All patients reported that they had completely recovered from their surgery at the time of the study. Overall, the patients rated the level of their preoperative pain significantly lower than did their spouse. The patients rated the level of their preoperative pain as 7.4 out of 10, while their spouses rated their preoperative pain as 8.3 (p < 0.001), and spouses reported a mean improvement of 28.7 points  (p < 0.001).PDI scores averaged 33.6 for the patients preoperatively . The patFor patients, the most common significant ways in which the surgery affected their quality of life, in order of importance, was the noticeable improvement in mobility (93%), the fact that they could resume their favorite leisure and sporting activities (76%), their remarkable improvement in pain (72%), and improvement in their social and family lives (38%) . AbilityThis survey study highlights the many benefits of hip arthroplasty surgery, not only for the patient, but also for their spouse. It also underlines the differences in perceived pain and levels of disability in relation to activities of daily living between both the patient and their spouse. When compared to patients, spouses reported higher levels of pain, both preoperatively and at the time of the survey. The spouses also perceived a greater overall reduction in pain-related disability across activities of daily living. Importantly, we have demonstrated that the subjective benefits of surgery extend to spouses of arthroplasty patients. After the surgery, the spouses indicated that their lives had improved with respect to partaking in physical and leisure activities with their spouse. They also perceived less partner suffering and had more independence with less caregiving, and consequently, the surgery improved their marital relationship.The discrepancy between pain perceptions reported by patients and their spouses has been previously reported in several studies in a couples context ,12,13,14Although the exact etiology for the differences in pain perceptions and levels of disability remain unclear, this study has shown that there are many positive effects of hip arthroplasty for the spouse. When asked the five most important ways in which the surgery affected their lives specifically, the spouses responded positively, and recurring themes arose such as improved leisure activities, less caregiving, more independence, and less perceived suffering.The results of this study indicate that the patient’s pain and function are most affected by their arthritis. This is in line with the present indications for joint replacement, primarily pain and loss of function. Preoperatively, patients are generally able to modify their lives to varying degrees in order to accommodate their arthritis. Therefore, it is reasonable to expect that the patients and their spouses in this study found the greatest benefit of the hip replacement was related to the pain reduction and increased mobility after the total hip replacement. This differs from more life threatening or chronic disease where life modification is drastic or not possible. In these cases, mood/well-being can be significantly affected as well.The limitations of this study pertain to the survey nature of it. Consequently, it does not shed light on the particular causes for the disparities between the questionnaire responses of the patients and their spouse. In addition, as this study is retrospective in nature and only done after the arthroplasty, it may be limited by recall bias of both the patient and their spouse. In addition, the Harris Hip Score was only used in this study to include/exclude patients. It did not give any information on patient’s satisfaction or health-related quality of life (HRQoL). The inclusion of only patients with a Harris Hip Score of 100 may have excluded patients with severe comorbidities and postoperative complications, which can impact the generalizability of the study findings. Furthermore, the quality of the marital relationship and the psychological status of the couples were not determined, so it was not possible to determine whether or not these couples are representative of a normal clinical sample. Finally, the relatively small number of couples in this study may limit the conclusions of this study, as well as the generalizability of these findings to couples of differing socioeconomic status, ethnicity, and duration of marriage.It has become clear that since its inception in the 1960s by Sir John Charnley, total hip arthroplasty has evolved into a reliable and reproducible surgical procedure to restore the patient’s function . The agiIn the era of patient-centered care, it should be recognized that a hip arthroplasty has the potential to improve the quality of life and marital relationship not only for the patient, but for the spouse as well.


P = .003, .039, and .006 for the back neck, shoulder, and lower back, respectively). Application of the structured exercise would alleviate the patients’ position-induced postoperative physical burden, by reducing pain and discomfort.Face-down posture after vitrectomy physically burdens patients. Despite being of significant concern for patients, the intraoperative pain and discomfort has not been of great interest to retinal surgeons or researchers. This randomized controlled trial evaluated the effect of a 3-day novel structured exercise on reducing musculoskeletal pain from the face-down posture in 61 participants (31 in the exercise group) who underwent vitrectomy. Among the subjects, the median age was 62 years, 42 were female, 42 had macular holes, and 19 had retinal detachments. Participants in the exercise group received initial education on the exercise and performed three daily active exercise sessions. After the sessions, the exercise group had median numeric pain scores of 2, 1, and 1 at the back neck, shoulder, and lower back, respectively, while the control group had corresponding scores of 5, 3, and 4, respectively. The exercise group reported significantly lower pain scores ( Its appropriate duration remains controversial; however, it is generally advised to maintain FDP for ≥ 3 days, depending on the retinal condition.Face-down positioning (FDP) is a standard posture recommended after vitrectomy and intraocular tamponade for macular holes and retinal detachments. With postoperative FDP, intraocular gas or oil mechanically pushes the retina against the retinal pigment epithelium, keeping the sensory retina attached, and isolating a retinal tear or macular hole from the vitreous fluid2. Patients positioned face-down complain of neck, shoulder, and back pain, as well as mental stress, a sense of psychological isolation, and anxiety2. Some also experience pressure ulcers and ulnar neuropathies4. Associated pain and discomfort may thus lead to reduced compliance. Seno et al.5 reported that FDP maintenance after vitrectomy and gas tamponade varied considerably among patients. The reduced proper posture holding time caused by discomfort from the posture could decrease its therapeutic effect, thereby negatively affecting the clinical outcome of the surgery.Postoperative FDP and immobilization cause considerable physical and psychological burden to patientsFDP-related musculoskeletal pain has not been a major concern for researchers, despite being of substantial concern for patients. Limited studies have quantitatively investigated FDP-related musculoskeletal pain, and little effort has been made to reduce the FDP-related pain. To our knowledge, no previous study has suggested or evaluated a proper posture and structured rehabilitation exercise for reducing FDP-related pain. We hypothesized that application of the structured exercise in patients on FDP would lessen their physical stress and improve postoperative satisfaction. In this study, we devised a novel structured rehabilitation exercise program and validated the effects of exercise on FDP-related musculoskeletal pain after retinal surgery for macular holes and retinal detachments.This prospective, single-masked, randomized clinical trial was performed at the Samsung Medical Center, Seoul from September 3 to December 14, 2020. It was approved by the institutional review board of Samsung Medical Center (no. 2019-03-157), was registered at ClinicalTrials.gov (identifier: NCT04535622), and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants. A total of 70 participants were enrolled in the study and the process of recruitment and allocation is described in Fig. The study included participants aged ≥ 18 years diagnosed with retinal detachment  or macular hole and admitted to the hospital for vitrectomy. Patients aged ≥ 80 years, with preexisting musculoskeletal disorders or poor best-corrected visual acuity in the opposite eye (less than 20/200 in the Snellen chart), which would make it difficult for them to follow instructions and participate, or those not scheduled for FDP and who decided to maintain sitting position postoperatively  were excluded. All participants were admitted to the hospital 1 day preoperatively and were randomized into either the exercise or control groups. They underwent vitrectomy performed by a surgeon (S.W.K.) who was blinded to the group allocation. A structured rehabilitation exercise program was applied to the exercise group. Exercise education and training were conducted by a physiotherapist affiliated with the Department of Physical and Rehabilitation Medicine after vitrectomy and the pain score was assessed. All other procedures and management were the same in both groups. Conventional painkillers, nonsteroidal anti-inflammatory drug skin patches, and positioning pillows were provided to both groups on a pro re nata basis. The patients were followed-up until postoperative day 3 and then discharged. The detailed hospital course of the two study groups is illustrated in Supplemental Fig. 6. The exercises were performed within the range of each individual muscle’s strength and fitness. The patients were asked to maintain proper FDP and perform self-exercise sessions three times daily. The physical therapist provided feedback to the participants on the next day of education.The exercise education program was designed through a collaboration between the Department of Ophthalmology and the Department of Physical and Rehabilitation Medicine at the Samsung Medical Center to reduce muscular fatigue at the neck, shoulder, and waist, and to strengthen the muscles and joints while performing FDP. It comprised education on the following: (1) performing proper FDP without putting too much physical stress, and 2) exercise methods while maintaining FDP. The detailed methods are illustrated in Fig.  exerciseThe randomization process was implemented by an independent clinical trial consultant. The patients were randomized in a 1:1 ratio using a block randomization method with permutated blocks of 4 or 6 in size. Subjects were allocated blocks based on pre-allocated codes placed in sealed opaque envelopes that were opened by a trial coordinator during the randomization step. Based on the code, each subject was randomized to either the control or the exercise group. Owing to the nature of the intervention, the participants, healthcare professionals, and researchers could not be blinded to the group allocation. Only the data manager, trial statisticians, and surgeon at the time of surgery were masked to the allocation.7. The primary endpoints were musculoskeletal pain scores at the back neck, shoulder, and lower back on postoperative day 3. The secondary endpoints included musculoskeletal pain scores at the back neck, shoulder, and lower back on postoperative days 0, 1, and 2. Additionally, a satisfaction survey on the exercise program was conducted for the exercise group on postoperative day 3. The questionnaire included items regarding whether the exercise program helped the patients’ postoperative recovery, whether the patients would like to receive this program again in case of re-operation, whether they would recommend the program to other patients, and their overall satisfaction level  scoring system, wherein the pain level was quantified on a scale of 0 (no pain) to 10 (worst possible pain). The NRS is a valid and frequently employed method of musculoskeletal pain assessment, and its high validity and reliability have been reported by many studies8. Based on the clinical assumption that structured exercise programs would have effects comparable to or greater than those obtained via complementary therapy on FDP-related pain, we conducted a sample size calculation expecting an effect size of 0.9 based on post-treatment pain scores in the aromatherapy and control groups of the previous study8. The estimated sample size, power, and Bonferroni-corrected significance level were 32 patients, 90%, and 0.05, respectively. Considering a 10% loss to follow-up, we recruited 35 patients in each arm.No relevant studies have previously described the effect of structured exercise on FDP-related pain. One previous study performed complementary therapy and quantitatively evaluated FDP-related painP-values of < 0.05 were considered statistically significant.Statistical analysis was performed using SPSS . The Chi-square test and Wilcoxon rank-sum test were used to analyze the baseline characteristics of both groups. The Wilcoxon rank-sum test was used to compare the musculoskeletal pain scores. Bonferroni’s correction for multiple testing was applied to compare the pain scores assessed at three different sites . A total of 70 participants were enrolled Fig. . Eight sP = 0.003, 0.012, and 0.012, respectively). Conversely, the pain scores on postoperative days 0, 1, and 2 did not significantly differ between the two groups.The NRS pain scores in the study groups are shown in Table Figure According to the satisfaction survey at discharge, 26 (87%) of the 30 subjects in the exercise group were satisfied with the exercise program. Detailed data on the satisfaction questionnaire are shown in Supplemental Fig. P = 1.000 by Fisher’s exact test) and no musculoskeletal pain, except for three patients with retinal detachment who were lost to follow-up. No participants complained of musculoskeletal pain at the 1-month follow-up.No associated complications or complaints were noted. At the 1-month follow-up, all participants presented successful anatomical outcomes  may have successful closure rates equivalent with those of FDP in macular hole surgery10. Other attempts have been made to reduce the posture-holding time, including the use of long-acting and short-acting gases13. Additionally, there have been some trials on adjusting the position or modifying the FDP period using optical coherence tomographic images in the gas-filled eye16. Attempts have also been made to compare the effects of gas and silicone oils19. However, meta-analyses comparing the clinical outcomes between postoperative FDP and non-FDP after macular hole surgery consistently indicated that FDP was necessary, especially for holes > 400 μm21. Regarding retinal detachment, a recent multicenter clinical trial suggested that compared with support-the-break positioning, FDP was associated with reduced rates of macular displacement and binocular diplopia after macula-involving retinal detachment repair22. Furthermore, strict FDP is still needed to avoid cataract and glaucoma development in gas-filled eyes26. In summary, postoperative FDP is still valid and necessary for improving surgical outcomes in many vitreous surgeries. Therefore, efforts are needed on understanding the discomfort caused by FDP, and reducing this physical burden.FDP causes significant discomfort to patients, and many efforts have been made to minimize the duration of FDP maintenance, or avoid strict prone posture after vitrectomy for retinal detachments and macular holes. Several studies have compared a strict FDP with other alternative postures. Chen et al.28, which are now generally implemented in the clinical setting. Passive interventions, such as painkillers and nonsteroidal anti-inflammatory drug patches, can also assist patients in maintaining FDP. Some clinics provide patients with brief instructions on the body posture to reduce discomfort, increase satisfaction, and motivate patients to exercise. However, these instructions are relatively informal and not systematically standardized. Hence, our study is important in that it proposed a structured instruction for proper posture and exercise and validated its efficacy for the first time.Although FDP causes serious physical burden, pain, and mental isolation in patients, very few methods to counteract the posture-related discomfort have been reported. The introduced strategies involve the use of assistive devices, such as pillows, desks, and bedsIn our study, the final back neck, shoulder, and lower back pain scores were significantly lower in those who received exercise education and performed regular structured exercise. In contrast, the pain scores on postoperative days 0, 1, and 2 did not significantly differ between the two groups. In the control group, the overall pain score continued to rise until the third day after surgery, whereas in the exercise group, the total pain score increased only on the first day after surgery and decreased continuously for the next 2 days. This result may indicate that exercise does not immediately reduce FDP-related physical pain, but has a long-term pain-relieving effect, emphasizing the importance of prolonged regular exercise. This is an encouraging result, considering that many patients need to maintain FDP for over 3 postoperative days. Unfortunately, we only observed the pain scores up to 3 days after surgery and were unable to assess the subsequent physical burden to the participants. However, the trend of the pain scores from postoperative day 1 to day 3 strongly suggests a benefit of structured exercise on FDP-related pain even after discharge. Questions may arise as to whether the reduced pain is attributable to the effects of the exercise itself or to the additional attention provided by the physical therapist. However, the physical therapist visited the patients once immediately after surgery and once for feedback on the first day after surgery, and it was on the third day after surgery that the two groups began to exhibit significant pain differences. If attention caused the improvement, the pain scores on the first or second postoperative days would also have significantly differed between the groups. Therefore, we believe that the structured exercise is mainly attributable to the alleviation of physical burden in the exercise group.The reduction in musculoskeletal pain, which was our primary goal, was reaffirmed by evaluating patient satisfaction. Most patients were highly satisfied with the exercise program and were willing to participate in it again if they had to receive vitrectomy with postoperative FDP. They also responded that they would recommend this program to other patients. Therefore, this exercise program serves as a good example of promoting cooperation among different medical departments in the age of fusional medical care.30. Although the schedule for FDP is generally 3–10 days, the maintenance of the posture itself is physically challenging and may induce significant pain, fatigue, and physiological/psychological responses31. Therefore, reduction of physical burden is important for the patients’ experience, and the present study provides an effective method to achieve this goal.At the 1-month follow-up visit, all participants exhibited successful anatomical outcomes and did not complain of further musculoskeletal pain. Since the present study was initially designed to evaluate the influence of the structured exercise program on patient’s physical pain, its sample size might not have been sufficient to achieve enough statistical power for comparing the anatomical outcomes and long-term musculoskeletal effects of the positioning in the two groups. Additionally, even without significant influence on anatomical outcomes, structured exercise for FDP-related pain is still necessary. Not only the surgical outcomes, but also postoperative physical/psychological burdens are major concerns of patients undergoing retinal surgeryThe strength of our study is that it is the first to introduce a structured exercise for FDP-related musculoskeletal pain and to report its efficacy. We provided detailed instructions of the exercise sessions for widespread application. Our study also has several limitations. First, we analyzed the results after a relatively short period of FDP. Second, it was a single-center study, and the patient population was limited to those with macular holes and retinal detachments. Thus, caution is needed before generalizing the results to other retinal disorders or extended periods. However, the difference in pain scores between the two groups gradually widened, strongly suggesting a benefit of the exercise on musculoskeletal pain even after 3 days. Finally, this study was conducted in an inpatient hospital setting, raising the concern about the program’s utility in an outpatient-based vitrectomy setting. However, even at the hospital, the overall exercise was conducted by the patients themselves, following the initial education. The same initial education can be provided via brochures or as multimedia in an outpatient-based setting, and similar beneficial effects may be achieved if the provided instructions are followed.In conclusion, the newly developed exercise program effectively reduced FDP-related musculoskeletal pain and yielded high patient satisfaction. A proper exercise program may increase patients’ compliance to FDP, thereby improving the surgical outcomes in some complex vitreous surgery cases. Moreover, the physical and psychological burden caused by FDP are important components of patient management, and greater attention should be paid to the patients’ experience in future research regarding retinal surgery.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.


Endovascular interventions (EVI) are increasingly performed as minimally-invasive alternatives to surgery and have many advantages, including a decreased need for general anesthesia. However, EVI can be stressful for patients and often lead to anxiety and pain related to the procedure. The use of local anesthetics, anxiolytics, and analgesic drugs can help avoid general anesthesia. Nevertheless, these drugs have potential side effects. Alternative nonpharmacological therapies can improve patients’ experience during conscious interventions and reduce the need for additional medications. The added value of virtually augmented self-hypnosis (VA-HYPO) and its potential to reduce pain and anxiety during peripheral and visceral arterial and venous EVI is unknown. This is a prospective two-arm trial designed to randomize 100 patients in two groups according to the use or not of VA-HYPO during peripheral EVI as a complementary nonpharmacological technique to improve patient comfort. The main objective is to compare per-procedural anxiety, and the secondary aim is to compare the rated per-procedural pain in both groups. The potential significance is that VA-HYPO may improve patients’ experience during peripheral and visceral arterial and venous EVI and other minimally invasive interventions performed under local anesthesia.Trial registration: Our study is registered on clinicaltrials.gov, with trial registration number: NCT04561596. Endovascular interventions (EVI) are minimally invasive therapies gaining interest in many indications. EVI are increasingly replacing surgery and vastly reduce the need for general anesthesia. Indications for percutaneous interventions are many and varied; typical examples include treatments for venous disorders , aneurysPeriprocedural anxiety and pain are most commonly managed with rapid-acting opioid analgesics and/or hypnotic sedative drugs –14. WithNonpharmacological pain and anxiety management approaches have been developed as adjunctive treatment –18. HypnIn experimental and clinical experience, virtual reality is considered a valuable tool to decrease anxiety and reduce pain by diverting attention from painful stimuli , 26. It TM) providing a video screen and sound system aiming to achieve digital sedation. For this study, patients follow the "Aqua" module reproducing a scuba diving experience and breath exercises in a virtual reality environment. For this purpose, a monocentric open-label prospective randomized trial with two arms is designed.This prospective study is based in a single Swiss academic hospital and seeks to evaluate whether virtually augmented self-hypnosis (VA-HYPO) lowers anxiety and pain in the setting of percutaneous peripheral and visceral arterial and venous EVI. VA-HYPO is performed using a head-mounted device . Patients referred to cardiothoracic or neuroradiology intervention are not eligible.Exclusion criteria: no or limited study language comprehension, deafness or visually impaired patient, the anticipated need for a sedative medication, a history of motion sickness or a psychiatric disease such as paranoia, schizophrenia, deep water phobia, and dementia. We will also exclude patients who do not tolerate the virtual reality mask during a preoperative visit.The sequentially numbered, opaque, sealed envelope (SNOSE) method was used for randomization with a 1:1 allocation before the intervention. A person not involved with patient recruiting will print the allocation sequence and prepare the envelopes (AMJ).One group of participants will wear the virtual reality mask with the autohypnosis program running during the EVI. The other group will benefit from the intervention in standard conditions without the virtual reality mask.The study will run in an open-label fashion because information cannot be withheld from trial participants and operators. Participants included in the virtual reality arm will wear the head-mounted device, and awareness regarding self-hypnosis is inevitable.Study timetable: the first patient was included in August, 2020. The recruitment is expected to be completed by the end of May, 2022.All vascular punctures are performed under local anesthesia and using ultrasound guidance. The puncture site depends on the clinical indication and is at the operator’s discretion. The typical vascular access is the common femoral artery for peripheral and visceral arterial interventions. The most common venous accesses are the common femoral vein and brachial veins.Arterial vascular accesses usually benefit from vascular closer devices, at the operator’s discretion, while venous accesses are controlled by manual compression.The schedule of enrolment, interventions, and assessment is presented in The percutaneous EVI is performed as usual except for the autohypnosis software that will run during the intervention in the virtual reality group.The medical team will provide pain and anxiolytic medication if needed during the intervention at the operator’s discretion and depending on the patient’s condition.Immediately after the intervention, participants will fill a second self-questionnaire (postoperative questionnaire) to report anxiety and pain felt during the intervention Tables  and 2.A clinical visit at 3 months, as part of the standard clinical protocol, is planned for late assessment. Participants will fill a third self-questionnaire on anxiety , the visThe study flowchart from referral to the last clinical visit is provided in The primary outcome is the rated per procedural anxiety, measured by the Spielberger Anxiety State Inventory in French . The SpiThe secondary outcome is the rated per procedural pain measured by the visual analog pain scale. The visual analog pain scale rates pain from 0 to 10, 0 being no pain, and 10 being the worst pain imaginable .Both outcomes will be measured on day 1, before and after the intervention, and 3 months after the intervention.The other outcomes of interest will be measured on day 1. Those outcomes are age and sex, side effects of virtual reality, the amount of drugs administered for pain and anxiety, the number of participants that did not tolerate the mask before randomization, and the number of participants where the mask has been taken off . We will measure the prevalence of cybersickness, our safety outcome on day 1.Patient-relevant outcomes, including amputation, mesenteric or renal ischemia, and death, will be reported 90 days after EVI.Data are coded and processed with Research Electronic Data Capture (REDCap), a broadly used HRA-compliant data collection application , 32. DatTo date, in the literature, the only recognized side effect of virtual reality is cybersickness , a condiThe prevalence of cybersickness is not known because of the diverse software and hardware that deliver virtual reality.The manufacturer of the Oncomfort system also warns the users of the potential risks of:claustrophobiaproblems with orientationsweating of the facesleepinessThe prevalence of the above risks is not known.The present study intends to compare vascular radiologic interventions with or without a virtual reality mask with a specific program to release stress and tension from patients undergoing certain procedures.We will collect device deficiencies and adverse events, including all serious adverse events. Adverse events will be thoroughly investigated and documented in the medical record and the case report form (CRF) during the entire study period.There is no follow-up period needed for this study since virtual reality has no known long-term adverse effect.Quantitative discrete data will be the Spielberger anxiety state self-questionnaire results, rated visual analog pain scale, age, the amount of drugs administered for pain and anxiety. We will compare the means of the discrete quantitative data with two-sided student tests.Qualitative data are participants that did not tolerate the mask before randomization, participants that had to take off the mask, and the occurrence of cybersickness. We will compare the occurrence of qualitative data between both groups with the Wilcoxon signed-rank test.th, 2020 (protocol number 2020–00728). The study is compliant with the principles of the declaration of Helsinki and was registered on ClinicalTrials.gov (NCT04561596). Only patients who give written informed consent will be included. A data safety monitoring committee is not required per the ethics protocol since the study is open-label.The study protocol  received approval from the ethical committee of the Canton de Vaud (CER-VD) on July 27The study is open in the recruiting phase. No interim analysis is currently planned.Several authors have already investigated the effects of virtually augmented self-hypnosis (VA-HYPO) during medical procedures and found a significant improvement in patients’ experience of both anxiety and pain , 23–27. TM) is lightweight, portable, and fast to set up and may be amenable to widespread clinical use with no additional human resources. Furthermore, the device can be controlled entirely by the operations in a sterile manner during the EVI procedure. The VA-HYPO trial aims to evaluate the impact of VA-HYPO on anxiety and pain during peripheral EVI, compared with peripheral EVI performed without VA-HYPO.Of note, patients’ experience in percutaneous image-guided therapies is not restricted to pain and anxiety that procedures could generate. Pain memory is also an essential determinant as patients might have multiple treatments with potentially multiple sessions in their life. Essentially, EVI requires puncturing one or more vessels with needles. Non-conscious memory of needle-induced pain can be shaped very early after the time of birth and influence subsequent responses to pain stimuli , 29. FurThe clinical impact of the present study is potentially high, with improved patient wellbeing during peripheral EVI. We expect the results to be scientifically robust because of the prospective nature of the study, with randomization and following power analysis. The placebo effect could confound our results because of the impossibility of conducting a blinding procedure. However, we are interested in the net effect of virtually administered autohypnosis on perprocedural anxiety and pain; the placebo effect can contribute to a clinically significant improvement of procedural tolerance. Furthermore, past experiences with needle puncture were not assessed due to broad landscape covered not only by EVI, but any procedure performed under local anesthesia such as dental care, as well as subcutaneous or intramuscular injection or even surgery.Once terminated, we will submit the study results to a peer-reviewed scientific journal for publication. If significant enough, we will communicate the results to the public by means of scientific broadcasts.We will implement substantial amendments only after approval by the external Ethics Committee.


This perceived added value was higher for respondents experienced with the device . Respondents preferred monitoring with the device on every  or most  visits to the outpatient clinic, or even more often than on every visit . Monitoring RA using an optical spectral transmission device is seen by patients as a possibly valuable addition to the monitoring process of inflammatory activity during visits to an outpatient clinic. Their main reason was that the device can increase insight into their current disease status. More insight may support patients in discussing treatment options with their rheumatologist.To enable patients with rheumatoid arthritis (RA) and their healthcare professionals to choose the optimal treatment, it is crucial to accurately assess the current state of inflammatory activity. The objectives of this study were to (1) investigate the perspective of RA patients on their insight into the current status of their disease, and to (2) investigate the patients’ perspective on the possible added value of a monitoring device based on optical spectral transmission—called the HandScan—that measures the location and severity of joint inflammation. A survey was distributed online among patients with RA in the Netherlands. Four-hundred and eight patients with RA completed the survey. Of these, 298 (73%) felt they have sufficient insight into their current disease status. Most respondents perceived either a large (The online version contains supplementary material available at 10.1007/s00296-021-05026-8. Rheumatoid arthritis (RA) is a chronic condition that can have a severe impact on a person’s quality of life . The maiPatient-centered care is considered very important in the treatment of patients with RA , 5. A keA patient's current RA status is commonly monitored through clinical examination by a trained rheumatologist, blood tests, and a set of imaging techniques for inflammation including MRI and ultrasound . FurtherA device based on optical spectral transmission—the HandScan—has recently been developed for detecting inflammation . OpticalThe first aim of this study was to investigate patients’ opinions about their insight into their current disease status. The second aim was to investigate patients’ opinions on the potential added value of the HandScan to monitor inflammatory activity as part of secondary care.An online survey was conducted from June to August 2020.Patients with RA, 16 years or older, were recruited regardless of any existing experience with the HandScan. Recruitment of a convenience sample took place online by sharing the survey among members and followers of national and local patient associations, via websites, and social media. One of the hospitals that use the HandScan in daily practice sent the link to the survey by email to their patients with RA.Patients received information on the investigators, study purpose, procedure, approximate duration of the survey, data handling and privacy. They could contact the researchers with additional questions. They were required to provide informed consent before starting the survey. Five vouchers of 10 euro were randomly awarded among patients. The vouchers were provided as an appreciation for the effort on the part of the participants. Participants interested in receiving a voucher could enter a raffle to be eligible.The study has been approved by the ethics committee of the faculty of Behavioural, Management and Social Sciences of the University of Twente (req. nr. 200865).The survey was developed with the input of experts on the HandScan  on the technical properties and functionalities. A patient with RA critically examined a draft version of the survey and improvements were made based on the feedback.Topic 1 concerned the current monitoring process, ie the process of monitoring disease status and inflammatory activity.Topic 2 concerned the perceived added value of the HandScan.Topic 3 concerned the patient’s perspective on active involvement of patients in future research for the development of technology. The results of this topic will serve as a first investigation for a future project. As the topics covered in part 3 are out of the scope of the current study, results will not be presented in this paper.The survey was constructed with the survey software Qualtrics XM . Patients could fill out the survey online, download a version to print out, or have a paper version sent to their home upon request. The survey consisted of 31 closed and open-ended questions, covering three different topics and displayed on 9 pages while participants could track their progress. Patients could change their answers and use a button to go back to previous answers.For the complete survey (translated into English) see Supplementary material 1.Only completed surveys were used for analysis.A person who underwent at least one HandScan test and discussed the results with a rheumatologist was considered as having experience with the HandScan.Free-text comments as answers to open-ended questions were categorized. For this goal the first and second authors familiarized themselves with the free-text comments and identified suitable categories. Thereafter they independently assigned 10% of the free-text comments into the created categories. This resulted in an agreement of 92%. Resulting differences were discussed until consensus was reached. The remaining free-text comments were categorized by the first author. Furthermore, for relevant questions, free-text comments were categorized as being ‘positive’ or ‘negative’.Data were analysed using descriptive statistics in SPSS (version 26). Comparisons of the perceived added value of the HandScan between patients with and without experience with the HandScan were analysed using a Chi-square test.n = 279), a desktop (n = 122) or paper (n = 7). Three-hundred and sixty-two respondents had no previous experience with the HandScan (89%), whereas 46 respondents (11%) did. Further characteristics of the respondents of the survey are depicted in Table The completion rate of the survey was 64%, with a large part of drop-outs due to patients who only agreed to participate but not answer any questions. The survey was completed by 408 respondents, on a mobile device (ktop n = 22 or papn = 171 (42%); 3–4 times n = 164 (40%)], and 372 respondents (91%) were satisfied with the number of visits. The most frequently visited healthcare professional was a rheumatologist, followed by a rheumatology nurse.Most respondents visited the outpatient clinics 1–4 times per year [1–2 times Respondents reported that during their visits physicians almost always (96%) asked for a patient’s opinion on the current disease status, and that blood testing was in general conducted (90%). A physical examination of the joints occurred almost always according to 71% of respondents. In general, respondents were satisfied (86%) with the frequency of being asked their opinion, blood tests, and physical examinations. Imaging  occurred either on some visits (42%) or almost never (48%). Two-hundred and eighteen respondents (59%) were satisfied with the frequency of imaging.n = 360, 88%), that they understood the results of the examinations , and also understood what these results could mean for their treatment . Furthermore, 345 respondents (85%) indicated that healthcare professionals took sufficient time to answer their questions. Three-hundred and thirty (81%) respondents trusted the outcomes of the tests to inform decisions on treatment. Respondents who were already examined using the HandScan had more trust in the results of the HandScan for decisions on their treatment, χ2  = 44.6, p < 0.001* than respondents without this experience.Based on the percentage of respondents that answered ‘agree’ or ‘completely agree’, respondents indicated that the healthcare professional discussed the outcomes of the examinations during hospital visits with them  = 47.4, p < 0.001* compared with respondents satisfied with this frequency.Out of the total of 408 respondents, 298 (73%) believed they had sufficient insight into the current status of their RA. Respondents who found the frequency of imaging too low are less likely to feel they have sufficient insight into their RA activity, χ2  = 37.2, p < 0.001*). Respondents indicated in the free-text comments that they would like to receive additional information on their current disease status . A further 26 respondents (23%) would like to receive (more) information on additional or alternative treatment, including information on the effect of nutrition or exercise on disease activity, or the possibilities of using medication with less side effects. A third category included information on side effects of medication and on extra-articular complaints of RA, such as pain and fatigue . Other areas included long-term expectations for symptoms , insight into progress of the disease  and a general desire to have more imaging .One hundred and two respondents (28%) would like to receive additional information from their rheumatologist. The respondents who felt to have insufficient insight were more likely to report to desire additional information  compared to those who felt to have sufficient insight , whereas respondents who gave the process a 6 or higher provided both positive (n = 267) and negative (n = 35) comments. Reasons to be satisfied included receiving sufficient explanations, good collaboration and communication with the rheumatologist , satisfaction with the current status of their disease , trust in the expertise of the rheumatologist , adequate actions by the rheumatologist, personalized treatment  and easy access to the rheumatologist . Reasons to be dissatisfied included free-text comments on the collaboration and communication by the rheumatologist , disagreeing with the rheumatologist’s decisions , difficulties accessing the rheumatologist , that the rheumatologist did not take all complaints into consideration , not liking the treatment , or other .Respondents gave the shared decision-making process on average an 8.1 on a scale from 0–10 . Only 24 respondents (6%) gave a score of 5 or lower, which could be considered as ‘unsatisfactory’. Of all free-text comments  regarding shared decision-making, 267 (78%) could be categorized as positive, 53 (15%) as negative and 22 (6%) were unclear or did not refer to the decision-making process. Respondents who gave the process a score of 5 or lower only provided free-text comments categorized as negative  = 6.7, p = 0.04*). Respondents who thought that the current frequency of imaging was too low, reported greater added value for the HandScan, χ2  = 11.5, p = 0.003* than those satisfied with this frequency. 345 respondents (85%), added 396 free-text comments . The negative comments included the following considerations: the HandScan is limited to the hand and wrist area , the outcome would most likely not affect their treatment , or other . Positive comments included that the HandScan would provide a clear image of (the location of) inflammatory activity, i . Other reasons why the HandScan could add value were the ability to contribute to early recognition of inflammation and adaptation of the treatment , to show progression over time and perhaps predict future developments , and other .When asked about the added value of the HandScan, 240 respondents (59%) reported a large added value, 148 (36%) a small added value, and 20 (5%) no added value. Respondents with experience with the HandScan were more likely to see a large added value than respondents without experience with the HandScan  or possible improvements . These can be found in Table n = 192, 47%), followed by ‘on some hospital visits’ , ‘more often than just during hospital visits’ , or ‘never’ . Nineteen respondents (5%) answered that they had no opinion on this topic. Respondents who thought that the frequency of imaging was too low were more likely to report that they would prefer a HandScan at all check-ups, χ2  = 15.3, p = 0.004*. There was no difference between respondents with and without experience with the HandScan on the preferred frequency of a scan, χ2  = 2.1, p = 0.73.When asked on the preferred frequency of the use of the HandScan in the monitoring process, the most common answer was ‘at every hospital visit’  = 1.7, p = 0.19. Those who preferred the HandScan provided free-text comments in support , in which they considered the HandScan as more objective and accurate , more convenient  and/or as a way of making inflammation visible for the respondents , or useful since the respondents mostly had complaints in their hands/wrists , and other . In the 93 free-text comments on why respondents did not have a preference, they mentioned that if results were similar, both have pros and cons , it depended on the complaints , and they rather pointed out the complaints themselves instead of letting a device determine the symptoms , and other . Some respondents explained that no choice could be made without personally experiencing the HandScan , and 30 respondents (32%) wrote that they would prefer to have both a physical examination and an examination with the HandScan. In 95 free-text comments respondents expressed why a physical examination was preferred. These included the following: that because other joints than the ones in their hands were of importance as well , respondents had more trust in the rheumatologist than in a device . Furthermore some respondents highlighted the importance of human contact during the physical examination  and expressed their opinion that optical technology cannot observe everything  and other . Of note, across all categories, 40 respondents (10%) stated in the comments that they would prefer a combination of the HandScan and a physical examination, even though this answer option was not provided in the survey.Out of the 408 respondents, 131 (32%) preferred the Hand-Scan, 123 (30%) had no preference, and 102 (25%) preferred a physical examination (and 52 respondents (13%) answered no opinion).). There was no difference between respondents with and without experience with the HandScan on whether they preferred the HandScan over a physical examination, The survey results showed that patients were in general satisfied with the current monitoring process. It was suggested by patients that their insight into their disease could be improved and furthermore that the HandScan was a valuable addition to the monitoring process of rheumatoid arthritis in a secondary care setting.The results of the current survey showed that the majority of patients is satisfied with the number of medical appointments, physical examinations and blood tests. However, not all patients are satisfied with their perceived insight into the current status of their disease. They indicated a desire for additional information about the current status of their disease, what this status means for the choice of treatment, and possible  treatments. These results are in line with previous studies among patients with RA that consistently show a high need for information , 18–20.Insight into the current status and possible treatments is an important prerequisite for patient participation in treatment decisions , 21. TheAccording to the patients participating in this survey, increasing the frequency of imaging is one way to obtain more insight into the current status of their RA. More frequent imaging could provide patients with a better understanding of the current level and location of inflammation. A substantial group of patients would like to have more imaging and this was especially true for patients who believed they did not have sufficient knowledge on the current status of their RA. The use of imaging is also recommended by the EULAR for the clinical management of RA. These organizations state that imaging can be useful in disease monitoring, since inflammation as seen on imaging may be more predictive of therapeutic response than clinical features and it can predict future flare-ups of inflammation even when a patient seems to be in remission . Thus, mImaging as part of the monitoring process in RA is mostly done with radiography, ultrasound, CT, MRI, or PET . In geneAlmost all patients saw either a small or large added value of the HandScan in their current monitoring process. This was mostly due to the ability of the HandScan to detect the presence or absence of inflammation for each joint separately and its ability to calculate a score for the severity of the inflammation. Several patients indicated that they would appreciate the opportunity to find out whether their suspicions regarding the cause of pain or the presence of inflammation in a specific joint could be verified or disproven. This type of information can increase the insight into the current situation and can also be used for treatment decisions.Patients were split on their preference for HandScan examinations or physical examinations. The HandScan was considered more objective, accurate and convenient, whereas physical examinations would also include joints outside of the hands and include the expertise of the rheumatologist. These arguments may also explain why a substantial group of patients would prefer a combination of both examinations.Recognizing inflammatory activity early and treating accordingly is important for a tight control of RA . The HanOne important caveat is that the HandScan only measures joints in the hands and wrists. These joints are commonly affected in RA, and in this study almost all patients reported that these joints were involved. Thus although the HandScan does not cover all joints, it will be relevant to a large proportion of the RA population.Some limitations should be considered. First, due to measures surrounding the Covid-19 pandemic most of the recruitment now occurred online, which may have resulted in the exclusion of patients with limited digital literacy. However, data content was not affected as the survey focused on the period before implementation of these measures. Further, although asked about the situation pre-pandemic, we cannot exclude the possibility of patients answering with the situation during the pandemic in mind. Second, 87% of the respondents were women, which is higher than the 67% women among the general RA population . This coPatients with RA are in general satisfied with the current monitoring and decision-making process. However, they believe their understanding of the current status of their disease could be improved and would like to increase the frequency of imaging. More frequent imaging might give patients with RA better insight into their disease activity, empowering them to take a more active role in the decision-making process. Patients believe that frequent imaging based on optical spectral transmission—such as with the HandScan—could be a valuable addition to their monitoring process, especially due to the possibilities to measure the presence and severity of inflammatory activity for each separate joint.Supplementary file1 (DOCX 34 kb)Below is the link to the electronic supplementary material.


This review presents the most common disease entities in which combinations of NSAIDs and spasmolytic drugs are used to reduce pain. The benefits of fixed-dose combination products (FDCs) are that they improve the response in people with insufficient monotherapy. Using the synergy or additive effect of drugs, it is possible to obtain a significant therapeutic effect and faster action with the use of smaller doses of individual drugs. In addition, one active ingredient may counteract adverse reactions from the other. Another essential aspect of the use of FDCs is the improvement of medical adherence due to the reduction in the pill burden on patients. It is also possible to develop a fixed-dosed combination product de novo to address a new therapeutic claim and be protected by patents so that the manufacturer can obtain exclusive rights to sell a particular FDC or a formulation thereof. The proposed fixed-dose combinations should always be based on valid therapeutic principles and consider the combined safety profile of all active substances included in the medicinal product. This review aims to identify which combinations of NSAIDs and spasmolytics have been developed and tested and which combinations are still under development. The pharmacotherapy of pain is often based on the need for polytherapy. There are many advantages of combined pain pharmacotherapy, including, above all, the possibility of obtaining an additive or synergistic effect. On the other hand, combinations allow one to increase the therapeutic effect while reducing the risk of drug-related side effects and using lower doses of individual drugs ,2,3,4.Despite the considerable progress of pharmacotherapy and the introduction of many new drugs, NSAIDs are still widely used and occupy an important place in the broadly understood pain management strategy ,6. NSAIDHowever, special attention should also be paid to the limitations of the use of NSAIDs despite their frequent use. Particular restrictions on use are relevant for the elderly population, people taking anticoagulants, and people with a history of gastrointestinal bleeding and upper gastrointestinal ulcers, as NSAIDs are associated with frequent upper gastrointestinal bleeding ,19,20. ISpasmolytic drugs are characterized by side effects from the parasympathetic system ,28. The The available scientific studies confirm the benefits of the combined administration of antispasmodic drugs and non-steroidal anti-inflammatory agents (NSAIDs) with analgesics and in the treatment of pain accompanying smooth muscle spasms of the urogenital system , gastrointestinal tract  and pathways cholecystitis  ,35,36,37The search for publications on combination drugs for pain therapy containing NSAIDs in combination with substances with spasmolytic activity was based on a selection of those scientific reports that included the assessment of their efficacy and safety.The Medline;®;PubMedThe Science Direct;The Cochrane Library (a database with systematic reviews).Scientific literature and bibliographic databaseswere searched:CENTRAL clinical trials registry;Drugs.com—an international drug information database;DrugBank—an international drug information database. The database is used by scientists and healthcare professionals around the world.Moreover, the following were checked:In the first stage, publications were searched automatically using keywords and related logical terms and then selected manually into the basic set.The search keywords were: fixed-dose combination, polytherapy of pain, combined administration NSAIDs with spasmolytic agents; spasmolytic drugs; antispasmodic effects; combined pain pharmacotherapy; synergy or additive effects of drugs; combination drug with a different mechanism of action; ibuprofen plus drotaverine/alverine; metamizole and hyoscine combination; compare ibuprofen with drotaverine/alverine/hyoscine; ibuprofen plus drotaverine bilayer tablet; addition of spasmolytic agent; painkillers; pain relievers; two-component drugs; muscle relaxant and analgesic effect; multimodal analgesia; adjuvant; spastic pain during colic; abdominal pain; acute infectious gastroenteritis; menstrual pain; dysmenorrhea; alverine; drotaverine; hyoscine; pharmaceutical composition comprising two substances.In addition, publications and patent applications containing commercial trade names of drugs were searched for: Buscopan compositum; Spasmofen; Petro tablets; Algopyrin complex; Quarelin; Drotin-M tablet; Algoflex-M, Vemonis Femi and their counterparts in other countries.Publications not related to combinations of NSAIDs with other substances/combination drugs/the simultaneous administration of drugs with different mechanisms of action, pain polytherapy (publications on monotherapy were excluded);Publications on combinations other than combinations of NSAIDs with substances with a spasmolytic/analgesic effect;Publications that are too general and imprecise in describing conditions that are indications for using combinations of the listed substances;Publications published before 1980;Publications with the description of studies without randomization/placebo/blinding (not meeting the GCP requirements).In stage 2, the following were excluded from the basic set:In the third stage, selected publications were qualified according to the selection criteria used. The publications included in the review were selected based on randomization, placebo, double-blind, or single-blind presence in the trial. They were carried out following the proper clinical trial (GCP) principles and developed based on the Helsinki Declaration and met medical, bioethical, and scientific research standards in research involving humans.Most of the literature data used in this review relate to studies that meet the criteria and standards of clinical research following the GCP requirements. However, single studies were conducted before the introduction of the current GCP regulations.The main aim of the review was to collect and include publications relating to clinical trials on the efficacy and tolerability of the concurrent use of NSAIDs and spasmolytic substances in the treatment of pain.In stage 4, the qualified references were grouped into datasets, in which individual clinical data were assessed using weighting indicators related to selected selection criteria (Randomization (R), Blindness (Z), Clinical effect (E), Serious adverse reaction (C))From 42 references, 21 clinical trials meeting this efficacy criterion were described. The report also presents 12 systematic reviews  confirming the effectiveness of using NSAIDs in combination with other substances in various disease entities, including one review in the form of an expert opinion emphasizing that there are justified, both pharmacological and practical reasons for using combinations of drugs from the group of NSAIDs for pain management.Fourteen compositions of registered, commercially available combination drugs containing a combination of NSAIDs and spasmolytic substances were identified and tabulated, along with commercial names and national availability, and innovative combinations under development/research.p = 0.755). The mean percentage reduction in VPAS at 15 min post-dose was 61.82% in the Spasmofen group and 64.76% in the ketorolac group. In the conducted study, within one hour from administering the therapeutic dose, Spasmofen was related with a statistically significant greater reduction in VPAS (mean% reduction = 92.36%) than ketorolac . Combining an antispasmodic agent with a potent analgesic in the form of a rectal suppository with a good bioavailability profile, although it reaches its maximum effect to some extent slower than when administered intravenously, can provide high effectiveness in reducing pain in renal colic by operating based on two separate mechanisms of action. Spaspofen as a fixed-dose drug, in the form of a rectal suppository, can be a safe, rapid, and effective method of treating acute renal colic in emergency departments [The typical characteristic of renal colic is a sudden, unexpected pain radiating from the groin area, the immediate treatment of which in emergency departments is mainly based on rapid pain relief. Spasmofen contains 100 mg of ketoprofen and 10 mg of hyoscine butylbromide, and it is registered by Amriya Pharmaceutical Industries  in the form of rectal suppositories. This combination is used to relieve severe colic pain quickly and effectively in the renal, hepatobiliary, or gastrointestinal tract. A study by Yakoto in patients who experienced acute renal colic compared using a single dose of Spasmofen rectal suppositories to the administration of a single intravenous (IV) dose of ketorolac tromethamine 30 mg/2 mL. The efficacy of therapy was noted after 60 min in 87.5% of patients treated with Spasmofen and 82.5% of patients treated with ketorolac. However, in the Fisher test, the difference was not statistically significant  with buscopan. The results obtained showed that 80% of patients treated with tenoxicam achieved pain relief after one hour compared to 86% of patients in this study .A study by Kumar et al. aimed to compare the therapeutic effect of using diclofenac and hyoscine in the symptomatic treatment of acute colic. The study showed that 91.7% of patients treated with diclofenac achieved complete pain relief one hour after dosing. However, the studies mentioned above were designed to compare the effect of NSAIDs and hyoscine alone, not as a combination; the results obtained by Ali and Kumar et al. indicate pain relief one hour after treatment in 72.7% and 69.4% of patients treated with hyoscine alone ,41.Combining hyoscine butylbromide with analgesics such as ibuprofen, acetaminophen, and metamizole sodium  has already been marketed in some countries for a decade.It is common in clinical practice to use a combination of NSAID drugs with antispasmodics. Application in the form of injections of NSAIDs and antispasmodics in acute renal colic helps relieve pain while reducing inflammation and swelling at the site of ureteral obstruction. The addition of antispasmodics has been shown to increase the effectiveness of NSAID treatment in acute spasmodic pain. However, the literature on the subject shows that few published studies deal with the safety and effectiveness of such a combination and the advantage of using one of them. Porwal et al. compared dicyclomine combinations with other NSAIDs and showed different efficacy in the acute pain model. The study compared diclofenac and dicyclomine administered intravenously with the combination of dexketoprofen and dicyclomine to treat acute renal colic. The researchers found that the second combination was much more effective and better tolerated than the first drug combination.n = 109) or a fixed-dose combination of diclofenac and dicyclomine (n = 108). The pain intensity was assessed using a visual analog scale (VAS) for eight hours at two-hour intervals. The conducted study showed that the product containing dexketoprofen and dicyclomine showed better efficacy and better tolerance than the fixed-dose combination of diclofenac and dicyclomine in patients diagnosed with acute renal colic when administered intravenously [In this study, a total of 270 patients were randomized to either use a combination of dexketoprofen and dicyclomine intramuscularly  and frequency  of its occurrence. The study showed that hyoscine, paracetamol, and their fixed combination effectively treat recurrent cramping abdominal pain and are well tolerated when administered three times a day continuously for three weeks .A randomized controlled study by Narang was designed to evaluate the efficacy and safety of a combination of 500 mg of paracetamol with 80 mg of drotaverine hydrochloride in the treatment of abdominal pain caused by acute infectious gastroenteritis. The study included a total of 252 adults of either gender with acute infectious diarrhea and moderate-to-severe abdominal pain. Patients were treated with a fixed-dose combination of 500 mg of paracetamol combined with 80 mg of drotaverine hydrochloride or with paracetamol alone in the same dose; drugs were administered three times daily for three days. The mean intensity of the pain difference was observed at 60 min after applying the therapeutic dose and complete pain relief after two hours using the VAS and Verbal Rating Scale.The conducted study showed a statistically significant improvement in using the combination of drotaverine hydrochloride with paracetamol compared to paracetamol alone. Moreover, much faster pain relief was observed in the group treated with the fixed-dose combination .Menstrual pain is a visceral, or diffuse, poorly localized pain with a component of inflammatory pain. The most likely cause of menstrual pain is currently considered to be excessive uterine contractile function due to increased levels of prostaglandins, increased sympathetic tone, and reduced uterine blood flow. The painkillers of choice for women with primary dysmenorrhea are non-steroidal anti-inflammatory drugs (NSAIDs) that reduce prostaglandin synthesis. In patients treated with NSAIDs, including ibuprofen, the levels of prostaglandins in menstrual secretions are reduced . The nonThis type of therapy is effective for approximately 80% of patients. Non-steroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen, act causally in primary therapy dysmenorrhea. Women with primary dysmenorrhea often use NSAIDs in very high doses, exposing themselves to numerous side effects, i.e., irritation of the gastric mucosa, leading to stomach ulcers, nausea, vomiting, and nervous system disorders .In a randomized trial, Dawood demonstrated the greater efficacy of ketoprofen at 12.5 and 25 mg and ibuprofen at 200 mg than a placebo, with a complete recovery of pain at the fourth hour after administering both test drugs . In addiGiven the mechanism of prostaglandin-dependent pain, it can be argued that non-steroidal anti-inflammatory drugs (NSAIDs), that act by inhibiting COX-1 and COX-2, create the ideal therapeutic path. However, the pathomechanism of menstrual pain is more complex and is used in many inhibitions of PG production, which does not cause pain relief. The use of additional cyclooxygenase two inhibitors (Coxibs), despite initial hopes, did not bring the expected results. Two independent studies confirmed the lack of superiority of selective COX-2 inhibitors over non-selective NSAIDs in treating the effects of menstrual pain ,48. The p = 0.989), lornoxicam and alverine citrate were determined to effectively treat primary dysmenorrhea . Thus, the presented results are consistent with the literature on the subject, supporting the use of NSAIDs in the treatment of primary dysmenorrhea. In addition, alverine citrate, which has a smooth muscle relaxant and analgesic effect, appears to be helpful as an adjunct to the treatment of primary dysmenorrhea. However, more advanced and extensive research is required to accurately determine the effect of alverine citrate on primary dysmenorrhea [Özbay assessed the efficacy of lornoxicam, alverine citrate + simethicone versus a placebo in treating dysmenorrhea. The study included 33 patients with primary dysmenorrhoea who took lornoxicam alverine citrate with simethicone and a placebo for two cycles. The pain reduction efficacy was assessed using the visual analog scale (VAS). In the results, the placebo was found ineffective  with ibuprofen (400 mg) (86.8%) than with drotaverine (80 mg) (78.4%) [Drotaverine, like alverine, is a derivative of papaverine. Drotaverine, marketed under the No-spa Hungary . Dębski  (78.4%) .® from Adamed Pharma . Unfortunately, a combination of the above-mentioned medicinal substances, which is the only one available on the European market, fails to meet the chemical purity requirements. The chemical quality deteriorates even further over time, during the medicine storage, as the impurities increase due to the critical active components. Attention should be paid in particular to the high level of impurities of drotaverine derivatives, the limit of which, for a single unknown impurity, is 0.2%. It is, therefore, desirable to provide a pharmaceutical composition comprising these three active substances with good stability or use another combination with a similar spectrum of action [The ternary drug, containing metamizole, drotaverine, and caffeine, is an example of a well-established FDC with potent analgesic and antipyretic properties. The combination of analgesic (metamizole) with antispasmodic (drotaverine) effectively relieves persistent spastic pain during colic, abdominal pain, menstruation, migraine, etc. Caffeine is an adjuvant, commonly used as an adjunct to over-the-counter pain relievers. An adjuvant is a compound that is added to a drug to increase its effectiveness. A study compared the effects of ibuprofen at 400 mg and ibuprofen at the same dose combined with 100 mg of caffeine in patients who had their third molar tooth extracted. The superiority of the two-component preparation over ibuprofen alone was observed in the drug efficacy and speed of action. A review of four studies suggests that a lower dose of ibuprofen (200 mg) combined with 100 mg of caffeine is more effective in treating post-operative pain ,52. The f action .In the last decade, we have observed a high frequency of using spasmolytics and combinations of spasm-analgesics to facilitate cervical dilatation during labor and shorten the first phase and the entire duration of labor. However, anticholinergic spasmolytic drugs have numerous undesirable side effects that can lead to dangerous situations for both the mother and the fetus. Hence, non-anticholinergic spasmolytics are nowadays the preferable choice during pregnancy. Atropine, when given by injection to a woman during pregnancy, increases the fetal heart rate. Dicyclomine has been linked with a few cases of human congenital disabilities. When injected into humans during pregnancy, hyoscyamine increases the fetal heartbeat. The desired antispasmodics are rapid action and long-lasting, do not adversely affect the uterine contractions, and do not risk uterine inertia. They also have minimal side effects on the mother and fetus. More than a few studies focused on various antispasmodic agents to shorten the phase of labor, among which are hyoscine-N-butyl bromide, drotaverine hydrochloride, phloroglucinol, and valethamate bromide.A prospective randomized trial of 146 women in active, spontaneous labor was conducted by Madhu et al. The patients were assigned to three equal groups, in which women were given drotaverine or valethamate, and the control group was given a placebo. According to the protocol, the amniotomy was performed with a 4 cm dilation of the cervix. There was a statistically significant difference in the meantime from intravenous administration to delivery: 183.2 min in the drotaverine group, compared to 206.5 min in the valethamate group and 245 min in the control group. The mean cervical dilatation factor (cm/h) was statistically significant and amounted to 3, 2.4, and 1.9 . There were no statistically significant differences in the duration of the second and third stages of labor. Short-lived side effects, such as fetal–maternal tachycardia, dryness of mouth, and flushing of the face, were noted for valethamate. Both drotaverine and valethamate appear to help cervical dilatation and augment the first stage of labor significantly. However, drotaverine accelerates labor more rapidly and is associated with fewer side effects than valethamate .p < 0.001 for all). In this study, no maternal differences in adverse effects were observed. Kaplan–Meier survival analysis showed a higher probability of swifter delivery among patients treated by drotaverine hydrochloride . Drotaverine hydrochloride effectively and safely shortened the first stage of labor among nulliparous women with active, spontaneous labor [In the conducted study by Ibrahim et al., the role of antispasmodic drug drotaverine in shortening the length of the active first stage of labor among nulliparous women was assessed. At the start of the active phase of labor, drotaverine hydrochloride (40 mg) was administered to one group and placebo to the other group. Patients received a maximum of three doses of the drug, separated by 2 h. There was a significant difference in the assessment of labor pain after the administration of drotaverine, the active phase of labor duration, and the cervical dilatation index between the two groups  to painful stimuli induced by heat, trauma, or inflammation.The use of diclofenac for pain relief in the first stage of labor was associated with a statistically significant reduction in pain scores in both primiparous and multiparous women. However, there was no statistically significant effect of diclofenac administration on the duration of the first and second stages of labor in primiparous and multiparous women, nor were the neonatal or maternal side effects detected .The analgesic efficacy of aceclofenac was evaluated compared to paracetamol in women undergoing episiotomy during labor. A dose of 100 mg of aceclofenac has been shown to be more potent than 650 mg of paracetamol in providing relief from post episiotomy pain, particularly 3 to 5 h after administration. The patients’ severity was assessed using an analog visual test (Huskisson’s test). The antalgic effect of paracetamol showed a similar evolution over time to aceclofenac, but the analgesic efficacy of paracetamol seemed to be much less .The current review presented by Tiwari gives the foundation for selecting an effective combination of aceclofenac (a COX-2 inhibitor) and drotaverine hydrochloride (antispasmodic agent with non-anticholinergic action) as an appropriate choice to amplify the labor over the other proposed combinations . HoweverThere are several combinations of NSAID and antispasmodic agents available in the market or under research. The characteristics of given fixed-dose combinations are presented in A patient’s response to therapy cannot be fully predicted from the drug’s mechanism of action alone. No therapy is optimal for all patients. Therefore, the assessment of effectiveness is only possible based on the observation of individual patients. The combination of various painkillers and adjuvants with different action mechanisms can help optimize the analgesic effect. The implementation of standard pain assessment, the routine use of multimodal analgesia techniques, and the development of combination drugs for pain management are signs promising the continuation of the improvement of pain management in the coming years. Despite the research potential, surprisingly few controlled studies have been conducted using spasmolytic drugs combined with analgesics to treat cramp pain. A small number of drugs are available on the Polish market containing a combination of NSAIDs and spasmolytic substances. Very few combinations of analgesics and antispasmodic agents are available to treat menstrual pains and cramps in Europe. When developing new formulations, particular attention should be paid to the possibility of using the given active compounds in as many countries as possible; for example, drotaverine is not approved for use by the FDA, which significantly reduces the potential market.Moreover, these are available as two different tablets in a single pack. Hence, to provide a compact formulation for patient compliance, there is still a need to prepare a fixed-dose combination of NSAIDs and spasmolytic agents available in an easy-to-administer single tablet dosage form. It is, therefore, desirable to provide a pharmaceutical composition comprising this combination of active substances with good stability. Particular attention should also be paid to the need to perform additional detailed clinical trials aimed at determining the effectiveness of therapy using fixed-dose combinations and determining their safe profile of action. The risk of adverse effects always increases with the number of drugs used; therefore, it seems necessary to perform additional clinical trials before admitting new formulations to the market to verify the safety of use.This review aims to indicate which combinations of NSAIDs and spasmolytics have been developed and tested and which combinations are still under development. It shows a broad potential for future research to develop modern, effective combinations and search for new indications for the existing fixed-dose combination drugs.


Background and Objectives: The anterolateral thigh (ALT) flap is widely used in head and neck reconstruction, but the postoperative thigh sensory function lacks sufficient evaluation. The present study reports the postsurgical pain and cancer-related quality of life (QoL) in different stages of oral cancer patients receiving anterolateral thigh (ALT) flap reconstruction. Materials and Methods: Patients were subgrouped into postoperative early-, mid-, and late-recovery stages  according to the time point of assessment. The QoL was examined using the EORTC C-30. Postsurgical donor and receipt site pain was evaluated through subjective reports and sensory tests. Results: Ninety-four patients were included in the final analysis. The functional and global health-related QoL significantly improved with time after surgery. However, spontaneous pain was reported in 57.7%, 72.3%, and 42% of patients in early-, mid-, and late-recovery stages, mainly in donor sites rather than in receipt sites. The highest incidence of donor site pain after ALT flap reconstruction in oral cancer surgery was in the mid-recovery stage but remained high in the late-recovery stage . Conclusions: The postsurgical pain in the donor site might persist to or exhibit delayed onset one to two years postoperatively but is much improved after postoperatively two years later. A longer postsurgical follow-up for over two years for pain and sensory dysfunction is indicated. Immediate flap reconstruction for oral or maxillofacial defects resulting from radical resection for oral cancer is often needed. The type of reconstruction, type of surgery, and cancer stage may influence the postoperative quality of life (QoL) ,2,3.The anterolateral thigh (ALT) free flap is widely used in reconstructive surgery for head and neck cancer for the advantages of versatile flap designs and minimal donor site morbidity ,5. EarlyThe purpose of this study is to investigate the characteristics and incidence of persistent postsurgical pain in oral cancer patients receiving ALT flap reconstruction, and the relationship with cancer-related QoL at different postoperative stages.This study was approved by the hospital’s Institutional Review Board (KMUH-IRB-20130085) and registered at ClinicalTrials.gov Identifier (NCT02048631). Between July 2013 and February 2014, 357 consecutive adult oral cancer patients who underwent wide excision of oral tumors reconstructed with ALT free flaps were selected in the outpatient department of plastic surgery at Kaohsiung Medical University Hospital, a tertiary medical center. Patients who were older than 70 years of age, impaired in communication, diagnosed with dementia and lacked the ability to complete the questionnaire by themselves were excluded. Written informed consent was obtained from each patient before enrollment in the study.According to the time interval between surgery and evaluation, patients were categorized into the postoperative early-recovery stage (postoperative six months to one year), mid-recovery stage (one to two years), and late-recovery stage (over two years).Patients who underwent free flap surgery received inhalational general anesthesia with nasotracheal intubation. Sevoflurane was used for the maintenance of anesthesia. The operation procedure is briefly described as follows. A wide excision was planned for the tumors and the surrounding tissues, preparing a clear border for free flap reconstruction of facial defects. Several procedures were applied to establish a well-prepared free flap for reconstruction: a hand-held Doppler probe was used to map the suitable perforators in the selected thigh tissue and design a flap according to the size and shape of the defect. The main axis of the ALT flap was marked by a line drawn from the anterior iliac spine to the lateral aspect of the patella. The pedicle of the ALT flap was supplied by the perforator from the descending branch of the lateral circumflex femoral vessels and the flap was centered on the chosen perforators along the main longitudinal axis. The chosen ALT perforators were dissected along the subfascial plane and its whole length muscles were free. Finally, the thin fascial ALT flap was harvested just within the fascia and a small amount of overlying fat. The flap design could be adjusted depending on the findings of a Doppler test. Flap donor areas wider than 8 cm were considered for skin grafts. The donor site was closed directly or received skin grafting with a split-thickness skin graft or a full-thickness skin graft.In the plastic surgery outpatient department for postoperative assessment, all patients were requested to complete a chronic pain-related questionnaire by themselves. Patients were asked to report postsurgical donor and receipt site pain with a numeric rating scale (NRS: 0—no pain and 10—worst pain imaginable), pain locations, self-reported spontaneous pain  with continuous or paroxysmal symptoms, and dysesthesia. Subsequently, stimulus-evoked positive sensory responses were recorded by a registered nurse anesthetist from the contralateral limb to the donor limb, lateral to medial sides, and outer border to the inner part of the surgical sites. Brush and cotton wool were used for light touch-induced pain. Mechanical static pressure-induced pain was measured using 10 g and 2 g von Frey monofilaments  on the donor sites and contralateral thigh alternately, to differentiate the mechanical dysesthesia. Each filament was steadily compressed perpendicular to the skin until filament bending occurred. A pinprick wheel roller  was used for pin-pricking-induced pain. Metal temperature rollers, one warm at 40 °C and the other cold at 25 °C , were used for screening temperature sensibility. The negative phenomena included numbness or hypoalgesia on stimuli-evoked sensory responses on donor and receipt sites.The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire  was used to measure the quality of life for cancer patients. Each patient was asked to complete the core questionnaire sections that incorporate physical, emotional, and social health issues with multi-item scales, including five functional scales, three symptom scales, a global health status, and six single-item scales. Score calculations are based on the Fayers et al. scoring procedures  by firstp < 0.05.Statistical analyses were performed using SPSS software . The chi-square test was used for the comparison of sensory test results between the donor and contralateral sites, and spontaneous pain characteristics between different postoperative stages. The pain intensity NRS was analyzed with one-way ANOVA. The EORTC average scores were compared for each domain using one-way ANOVA. The significance level was set at The study protocol is summarized in Nighty-four patients were enrolled in the final analysis. Most of the patients were in their fifties, and males accounted for more than 90% of the subjects in all three groups . The eduIn the EORTC C-30 assessment, the patients in the postoperative late-recovery stage (>2 years) had the highest scores for global health status, representing the highest quality of life, followed by the patients in the mid-recovery stage (postoperative 1–2 years) and the early-recovery stage (6 months–1 year) after surgery . The rolIn the mechanical and thermal sensory tests, no patient demonstrated sensory dysfunction  in the contralateral thigh. The proportion of sensory dysfunction present in the thigh donor site was significantly high in all three stages and all examined items, including light touch, pressure, pin-prick, and a cold and warm test . The senNearly half of the patients reported spontaneous pain after ALT flap reconstruction for oral cancer surgery in all three stages, which was mainly located in the donor sites (>80%) than in the receipt sites . The paiThe ALT flap is the mainstream in our institute for oral cancer reconstruction because of the advantages of a long vascular pedicle, large skin territory and less donor site morbidity. However, donor site pain has been frequently reported in postoperative patients in our plastic surgery outpatient department. In our study, the global health status in the EORTC-C30 assessment gradually improved with time, although the prevalence of spontaneous pain was highest in the postoperative mid-recovery stage. This revealed an inconsistent trend between the pain and the cancer-related quality of life, which reminded us to evaluate these two components separately in postoperative follow-up.Townley et al.  reportedThe pain intensity and the proportion of patients with moderate pain were highest in the postoperative mid-recovery stage (1–2 years). Although high-intensity acute postoperative pain is one of the main risk factors for persistent postsurgical pain, a delayed onset of persistent postsurgical pain has been observed in several studies ,13,14. OIn the EORTC-C30 assessment, our data showed a significant improvement in postoperative QoL over time in global health status, role functioning, social functioning, and symptoms of insomnia and fatigue. This trend is different from previous research. In a 2-year QoL study on head and neck reconstruction using the radial forearm flap, fibula flap, and scapular flap, the global QoL remained stable before and at 6 and 12 months after surgery [This study has some limitations. First, only the patients followed up in the plastic surgery department were enrolled in our study. In our institute, oral cancer surgery with an immediate ALT flap reconstruction is performed by three medical teams: the otolaryngology team or oral and maxillofacial surgery team for cancer tumor resection, and the plastic surgery team for flap reconstruction. Thus, outpatient tracing could happen in these three separate departments. Bias may occur in patient selection. Second, multiple factors are associated with postoperative QoL after ALT flap reconstruction for oral cancer surgery, including age, gender, radiotherapy, tumor location, and cancer stage ,20,21. IOur study demonstrates a thorough survey of persistent postsurgical pain in oral cancer patients receiving ALT flap reconstruction. The overall cancer-related quality of life in these patients significantly improved with time after the operation. However, the prevalence of spontaneous pain at the donor site remained high and even developed one year after surgery. Therefore, a longer postsurgical follow-up for at least over two years for donor site pain and sensory dysfunction after ALT flap reconstruction in oral cancer patients is indicated.