Cancer-induced bone pain (CIBP) affects one third of patients with cancer. Radiotherapy remains the gold-standard treatment; however, laboratory and clinical work suggest that pregabalin may be useful in treating CIBP. The aim of this study was to examine pregabalin in patients with CIBP receiving radiotherapy.A multicenter, double-blind randomized trial of pregabalin versus placebo was conducted. Eligible patients were age ≥ 18 years, had radiologically proven bone metastases, were scheduled to receive radiotherapy, and had pain scores ≥ 4 of 10 . Before radiotherapy, baseline assessments were completed, followed by random assignment. Doses of pregabalin and placebo were increased over 4 weeks. The primary end point was treatment response, defined as a reduction of ≥ 2 points in worst pain by week 4, accompanied by a stable or reduced opioid dose, compared with baseline. Secondary end points assessed average pain, interference of pain with activity, breakthrough pain, mood, quality of life, and adverse events.P = .816). There were no statistically significant differences in average pain, pain interference, or quality of life between arms. There were differences in mood (P = .031) and breakthrough pain duration (P = .037) between arms. Outcomes were compared at 4 weeks.A total of 233 patients were randomly assigned: 117 to placebo and 116 to pregabalin. The most common cancers were prostate , breast , and lung . In the pregabalin arm, 45 patients (38.8%) achieved the primary end point, compared with 47 (40.2%) in the placebo arm (adjusted odds ratio, 1.07; 95% CI, 0.63 to 1.81; Our findings do not support the role of pregabalin in patients with CIBP receiving radiotherapy. The role of pregabalin in CIBP with a clinical neuropathic pain component is unknown. Standard analgesics  may be useful in controlling background pain; however, they are often ineffective in treating breakthrough pain.4Cancer-induced bone pain (CIBP) is the most common type of cancer pain, affecting one third of patients.5 Many patients with CIBP do not achieve acceptable levels of analgesia.Radiotherapy is the gold-standard treatment for CIBP; however, meta-analyses have demonstrated that only 25% of patients will achieve complete pain relief, whereas 41% will achieve partial pain relief, with onset of analgesia taking 4 to 6 weeks.6 Focal bone cancer pain models are used currently, and these provide a robust model (with features similar to CIBP in humans). Through these, it has become evident that the underlying pathophysiology of CIBP differs from that in standard neuropathic or inflammatory pain models, although containing elements of both as well as involving additional factors arising from host–cancer cell interactions.8 Excitability in dorsal horn sensory processing pathways is markedly increased, resulting in both electrophysiologic and behavioral hypersensitivity.9 This means that painful and nonpainful peripheral nerve input  result in ongoing and stimulus-evoked pain that can be exacerbated by movement.Animal models have been developed to understand the pathophysiology of CIBP.α2-δ subunit of calcium channels  could act to reduce pain transmission. Expression of the α2-δ1 subunit in dorsal root ganglia is increased after peripheral nerve injury, where it is thought to facilitate channel trafficking to the plasma membrane and thereby contribute to development of central sensitization and pain hypersensitivity.12 Pregabalin and gabapentin have proven efficacy in a variety of chronic pain models , probably through a reduction in excitatory neurotransmitter release and central sensitization.13 Animal studies have also reported efficacy in CIBP models, suggesting that pregabalin and gabapentin may be of value clinically in treating CIBP.9Animal models have been used to assess whether agents used for neuropathic pain could correct the abnormal dorsal horn neuronal architecture and minimize the central sensitization, which also exists in CIBP—particularly whether drugs that bind to the 17 This may be the result of emerging animal studies but may also be because of anecdotal findings. In palliative care, many of the drugs used in routine clinical practice have limited or no evidence supporting their use, but they are embedded in clinical practice. Therefore, it is fundamental that pregabalin be examined in a robust clinical trial within the relevant population before it becomes more widely adopted as a treatment for CIBP.In the clinical setting, pregabalin is being used increasingly to treat CIBP.α2-δ calcium channel ligands may have a role in CIBP in humans, mirroring the preclinical findings.Following this translational paradigm, and given the need to improve management of CIBP and the need to assess the role of pregabalin fully in the clinical setting, a randomized double-blind trial of pregabalin  versus placebo in conjunction with palliative radiotherapy for CIBP was conducted. Our hypothesis was that This was a multicenter, double-blind randomized trial of pregabalin versus placebo in conjunction with palliative radiotherapy for CIBP. Eligible patients were age ≥ 18 years, had radiologic evidence of metastatic bone disease, and were scheduled to receive radiotherapy for ≥ one site of clearly identifiable bone pain. Other key inclusion criteria were: life expectancy > 2 months, pain score (worst pain) ≥ 4  at the site of pain, scheduled to be treated with radiotherapy at that site, and ability to provide written informed consent. The main exclusion criteria were: current gabapentin or pregabalin use, significant renal impairment (creatinine clearance < 60 mL/min), and receiving wide-field irradiation. Patients who had any change in anticancer therapy before entering the trial with the potential to influence pain during the trial were excluded. Initially, radiotherapy to vertebral sites was an exclusion criterion, but this was subsequently removed as a major protocol modification, as discussed and approved by the trial steering committee, after 14 patients had been consented. The trial was conducted in five cancer centers in the United Kingdom: the Beatson West of Scotland Cancer Centre (Glasgow), Edinburgh Cancer Centre (Edinburgh), Velindre Cancer Centre (Cardiff), Princess Alexandra Tayside Cancer Centre (Dundee), and Mount Vernon Hospital (London).After giving consent, patients entered a run-in phase  where their analgesia was optimized before radiotherapy to ensure, where possible, there were minimal changes in analgesia after random assignment and radiotherapy and to allow the effect of the intervention  alone to be assessed. In such cases, patients would have stable pain; however, this would still be suboptimal, necessitating the need for radiotherapy.Some patients had stable pain control and analgesic requirements before random assignment. Others had to have analgesics modified before random assignment. At the point of receiving radiotherapy, patients were only randomly assigned if they still met the eligibility criteria, with critically worst pain score ≥ 4 (0-to-10 NRS).The radiotherapy regimen was either 8 Gy in one fraction or 20 Gy in five fractions, as per the decision of the patient's oncologist. Baseline assessments were performed in the 24 hours before the first fraction. Random assignment was carried out after the baseline assessments and before radiotherapy. Patients received either pregabalin or placebo and were given a 35-day supply of medication. Patients were instructed to take one capsule of the trial medication twice daily (12 hours apart). Each capsule contained either 75 mg of pregabalin or placebo. The trial medication was supplied free by Pfizer.Patients were contacted every 2 to 3 days to encourage compliance with the medication and monitor for any adverse events. Every 7 days from baseline , a formal assessment of analgesia was undertaken. Where a clinically meaningful improvement in pain had not occurred , the dose of the trial medication was increased as follows: baseline (day 1), pregabalin or placebo 75 mg twice daily; day 8, pregabalin or placebo 150 mg twice daily; day 15, pregabalin or placebo 225 mg twice daily; and day 22, pregabalin or placebo 300 mg twice daily.End points were assessed at 1, 2, 3, and 4 weeks after the first fraction of radiotherapy. Analyses relate to assessments at 4 weeks unless otherwise stated.19The primary end point was improvement in CIBP at the site of radiotherapy by week 4. An improvement was a reduction of ≥ 2 points on a 0-to-10 NRS for worst pain, accompanied by a stable or reduced opioid medication dose, compared with baseline. A decrease of ≥ 2 points on a 0-to-10 NRS is accepted as a clinically meaningful improvement in pain in studies of analgesic interventions and is in keeping with guidelines on end points in clinical trials in bone metastases.20 analgesic requirements, tolerability of pregabalin, global quality-of-life scores (using EuroQol thermometer),21 and mood .22Secondary end points included: assessment of worst and average pain, assessment of functional interference of pain in day-to-day living (using Brief Pain Inventory [BPI]),This analysis was based on the objective of showing superiority of pregabalin versus placebo in improving CIBP using the primary end point. An intention-to-treat approach was used.χ2 test with α of 0.05% and 80% power.The null hypothesis tested was that there was no difference in analgesia between the trial arms. A sample size of 206 patients was planned, based on the assumption that 50% of patients in the placebo arm would improve . To detect an improvement to 70%  in the pregabalin arm, 103 patients were required to complete each arm, using a two sided The primary analysis used a conservative approach, where any patient who did not complete the trial was assumed not to have achieved the primary end point of ≥ 2-point drop in worst pain score against a background of stable or reduced opioid dose. This meant that all randomly assigned patients could be included in the primary intention-to-treat analysis. However, this approach tends to attenuate any true treatment effect, so the target sample size was increased to 260. This would give 80% power at the 5% significance level to detect a more conservative treatment effect of 18%. The safety population included all patients who received any dose of the trial medication, and adverse event reporting was continued until 30 days after trial completion.v multiple), cancer type (breast or prostate v other tumor types), and site of bone metastasis (vertebrae v nonvertebrae).Random assignment was implemented by the Cancer Research UK Clinical Trials Unit Glasgow using a minimization algorithm with a random element, based on: fractionation regimes . The primary end point  was analyzed using logistic regression, adjusting for the three factors specified in the minimization algorithm. The continuous secondary outcome measures were examined using analysis of covariance, adjusting for the baseline value of the measure together with the three minimization factors. Treatment effects are reported as adjusted point estimates together with the corresponding 95% CIs and The trial had ethics committee approval (United Kingdom 07/MRE00/59) and was conducted in accordance with the Declaration of Helsinki. It was registered with the European Union Drug Regulating Authorities Clinical Trials and ISRCTN databases.From August 13, 2008, to April 30, 2012, 233 patients were randomly assigned. The trial was stopped early  on the basis of slow recruitment, evidenced by the fact that only one in eight patients screened was consented, as seen in the CONSORT diagram . The maiPatient demographics are listed in P = .816). The observed absolute difference in response rates was 1.4% in favor of placebo (40.2% v 38.8%), with a 95% CI ranging from 13.9% in favor of placebo to 11.2% in favor of pregabalin. In the pregabalin group, 18 patients (15.5%) did not achieve the 2-point reduction in worst pain but rather remained on a stable or decreased opioid dose; 21(18.1%) had an increase in opioid dose, and 32 (27.6%) could not be assessed (assumed nonresponse). In the placebo group, 14 patients (11.9%) did not achieve the 2-point reduction in worst pain but instead remained on a stable or decreased opioid dose; 31 (26.5%) had an increase in opioid dose, and 25 (21.4%) could not be assessed (assumed nonresponse).In the pregabalin arm, 45 patients (38.8%) achieved the primary end point, compared with 47 (40.2%) in placebo arm .P = .150).P = .606). The adjusted mean difference between trial arms for BPI Interference score was −1.8 . There was a difference in HADS score between study arms , but no difference in Euroqol score (P = .825).P = .037).19This large clinical trial does not demonstrate an analgesic benefit from pregabalin in patients with CIBP receiving radiotherapy. Individual pain measures were similar across both arms, and the consistency of neutral primary and secondary end points supports that the study was sufficiently powered to detect a difference. Despite the trial under-recruiting, the primary result comfortably excludes the 20% advantage to pregabalin, which was the basis of the power calculation, and indeed, the 95% CIs were compatible with, at most, an 11.2% improvement in response rate, which would not be clinically meaningful.Of note, patients in the pregabalin arm experienced improvements in mood and reduced duration of breakthrough pain episodes. However, these must be considered in the context of the large CIs present and the established role of pregabalin for treating anxiety.α2-δ calcium channel ligands in rodent models of CIBP, there had been limited clinical validation.9 A case report examined gabapentin in CIBP and suggested possible benefit.14 It was followed by a randomized trial of pregabalin versus placebo, which suggested potential value of pregabalin in CIBP, although firm conclusions could not be drawn.15 Another study suggested pregabalin in combination with mirtazapine may be beneficial; however, it advised additional trials.16 Nevertheless, despite the limited evidence, pregabalin is often prescribed for CIBP, with some reviews of CIBP management recommending the use of pregabalin if there is a neuropathic component to the pain.17 However, our findings do not support a role for pregabalin in CIBP, and we suggest that its clinical role in CIBP be reconsidered.The current findings will have considerable implications for clinical practice, because pregabalin is being used increasingly in the setting of CIBP. Although basic science work was encouraging, with a possible therapeutic role for 23 In clinical trials of patients with peripheral neuropathic pain, gabapentinoids have consistently demonstrated significant benefit.26 However, only a minority of patients achieved substantial pain relief, with many not responding. Patients with CIBP generally have multiple serious morbidities and a more complex array of factors contributing to their hypersensitivity, as a result of immunologic responses to the cancer. Their pain state is more complex and may be less readily reversible by pharmacologic interventions. Animal models may also not respond to therapeutic intervention either qualitatively or quantitatively in the same way as patients with CIBP. These and other reasons may have resulted in the lack of translation of our findings seen herein.The challenges of translating laboratory findings clinically, in pain, include the difficulty in replicating multidimensional pain in animals and the subjectivity of testing in laboratory conditions.27 However, although there may have been a greater number responding, the relative difference between the two arms would not be expected to change across a period from 4 to 8 weeks. The optimal dose of pregabalin in this setting of advanced cancer is not known, and again, it could be argued that higher doses or longer trial duration should have been used. Patients were, however, titrated to the maximum-tolerated dose, which resulted in 67% of patients achieving a dose of ≥ 300 mg daily for at least 3 weeks. These aspects have to be considered in the context of high attrition, which may have increased further with longer trial duration. We also acknowledge that patients who have CIBP with neuropathic features may be more likely to benefit from pregabalin than those without; however, this was outside the scope of our trial. In our trial, we looked at those patients referred to radiation oncology for consideration of palliative radiotherapy for uncontrolled CIBP. Clearly, patients treated successfully with pregabalin or gabapentin, because of CIBP with clinical neuropathic features, would not have reached radiation oncology and therefore screening in this study. Undertaking pain trials in in patients with cancer is challenging, but our trial succeeded by using a rigorous, well-designed protocol, a small number of centers, and focused patient follow-up.The trial had some limitations. All patients had metastatic cancer, and as such, many had different sites of pain. We focused on the area of pain corresponding to the radiotherapy site, and pain assessments were performed accordingly. Also, patients' overall conditions were deteriorating, in keeping with the advanced nature of their disease, and therefore, quality-of-life parameters could have changed. The end point measures were assessed 4 weeks after radiotherapy. It has been advocated that the optimal time for assessing response to radiotherapy for CIBP is 8 weeks, and we cannot be certain that additional differences would not have been evident if the trial had assessed end points at this time.28 on the need for trials in patients with advanced cancer. Currently, the majority of symptom control practice is based on either historical anecdote or low-level evidence, and the lack of research is paradoxical to its importance.29 There is a need for well-designed clinical trials that either support or  refute practice. We have demonstrated that undertaking symptom control trials in patients with cancer is feasible.Despite the neutral findings, we support the opinion of Hardy et alIn conclusion, our findings do not support the role of pregabalin in patients receiving radiotherapy for CIBP. Future trials examining pregabalin in CIBP with a neuropathic pain component would be of interest.


An epidemic of overdoses and deaths from opioids is fuelled by increased prescribing and sales in North America. Tatum Anderson reports. He didn’t know it at the time, but Dr Andrew Kolodny had begun to witness the beginnings of a major drug addiction crisis in the United States of America (USA).A public health expert on drug dependency at New York City’s health department in the early 2000s, Kolodny worked in poor neighbourhoods from South Bronx to central Brooklyn blighted by crack cocaine and heroin.“It was while we were working on the illicit drugs problem that we noticed drug overdose deaths were increasing in middle-class communities in the New York City area,” he says.Before 1995, the prescription of opioid painkillers in the USA was limited to people with pain from advanced cancer, severe injuries or after major surgery.That restraint was founded on the fear that patients might become addicted and the bitter experience of two opioid epidemics: in the early 1900s when heroin was sold legally for various ailments and an epidemic of illegal heroin dependency in the 1960s during the Vietnam War.Opioids are a class of drug used to reduce pain. They include heroin, as well as prescription pain relievers, such as oxycodone, hydrocodone, codeine, methadone and morphine.In 1986, a study based on 38 patients suggested that these powerful prescription drugs could be used safely with minimal rates of addiction for chronic pain, and a few pain specialists began advocating for broader use of them in this way, says Kolodny, who is now the director of nongovernmental organization Physicians for Responsible Opioid Prescribing and a researcher at Brandeis University in Massachusetts.This movement to increase opioid prescribing was catalysed in the 1990s by patient and professional groups that received funding from pharmaceutical companies, he says. Since then, the USA has been facing a growing epidemic of opioid dependency, including a rise in heroin use and record high levels of opioid overdose deaths. From 1999 to 2015, more than 183 000 people died from overdoses related to prescription opioids and in 2012, more than 250 million opioid prescriptions were written in the USA, according to the Centers for Disease Control and Prevention (CDC), more than enough for the entire population of 319 million people.Some of these prescriptions were for palliative care or acute pain, but many more were for patients with chronic non-cancer pain, such as backache, headaches and fibromyalgia. Patients like Dan Schoepf, a self-employed contractor, who was first prescribed oxycodone for a severe back injury by a pain physician in Long Beach, California in 1999. As time wore on he needed ever larger doses to relieve the pain because of increasing tolerance.“Sometimes I used up my supply of prescribed medicines too quickly and went into withdrawal, until I received my next prescription,” Schoepf says. “When I ran out, I couldn’t talk to anyone [because] I was so sick. I couldn’t live with the drugs, I couldn’t live without them and I was destroying my family.”Then, 13 years later, Schoepf was offered physiotherapy. The pain stopped and he received addiction treatment that got him off the opioids for good.The over-prescription of opioids for chronic, non-cancer pain outside palliative care is driving the epidemic of opioid dependency in the USA, according to Dr Debra Houry, Director of the CDC’s National Center for Injury Prevention and Control.“When I was in medical school we didn’t know that these medications were so addictive and we were encouraged to treat pain.”Debra Houry“When I was in medical school we didn’t know that these medications were so addictive and we were encouraged to treat pain. Now we have better evidence that they aren’t safe for long-term prescribing,” Houry says.The number of patients with chronic pain prescribed opioids for long periods of time has increased in other high-income countries as well, including Australia and the United Kingdom of Great Britain and Northern Ireland. But it is mainly the USA and Canada that are seeing epidemics of dependency and a large toll of overdose deaths.Meanwhile, in much of the rest the world, there is little or no access to opioid analgesics for patients dying of cancer, even though codeine and morphine are included on WHO’s model list of essential medicines for use in palliative care. Health-care providers underestimate the risk of addiction of opioids and they overestimate the benefits, says Houry, a former emergency room physician.Getting doctors to consider alternatives to opioids is a strategy Houry’s group at the CDC is taking, one of the many USA agencies tasked with fighting the opioid dependence epidemic, including the Department of Justice and the Office of the President. “Alternative methods other than opioids should be used first. Instead the very first thing … doctors [in this country] do is go straight to the opiates and straight to the oxy,” Schoepf says, referring to oxycodone, a commonly prescribed opioid.In Canada, prescription opioid overdose deaths increased fivefold in the province of Ontario between 1991 and 2014 and about 2000 Canadians died from this cause in 2015 alone. “This enormous problem has arisen from severe and systematic medical system and practice excesses, combined with ineffective regulatory and policy actions,” says Benedikt Fischer, a senior researcher at Toronto’s Centre for Addiction and Mental Health.In the USA, the CDC recently launched a programme that aims to improve the performance of underused prescription drug monitoring programmes. Under these programmes, state-run electronic databases are used by doctors and sometimes nurses to track the prescribing and dispensing of controlled prescription drugs to patients so that suspected abuse can be identified.Some USA states link prescription drug monitoring programmes with patient electronic medical health records, so that doctors can more easily look up a patient’s prescription history. Others alert physicians when they see that one of their patients has been requesting prescriptions from different providers, known as “doctor shopping”.Not all prescription drug monitoring programmes let physicians see what other prescriptions patients are receiving in real-time. Where such programmes exist, they are not used enough, Fischer adds.Medical examiners and coroners can also use prescription drug monitoring programmes to find out which doctors may have prescribed opioids recently to a patient.Last year, CDC released guidelines recommending evidence-based pain management techniques, such as physical therapy; and non-opioid medications, such as anti-inflammatories, as first-line treatment for chronic pain.If prescribing opioids, it recommended that physicians ensure that patients are fully aware of the risks, start them at the lowest possible effective dose and avoid doses above a certain level. CDC is also working with medical schools and nursing colleges to ensure that students are taught safe opioid prescription and pain management.In addition, CDC launched the Prevention for States programme in 2015 supporting 16 of the country’s 50 federal states to prevent prescription drug overdoses. It supports interventions such as incorporating CDC guidelines into health-care systems, carrying out policy re-evaluations to assess whether to use naloxone, an overdose reversal drug, and gathering data to better target overdose hotspots.Data on the effects of these initiatives on opioid deaths are still being gathered but preliminary reports are promising, says Houry. Physicians in the State of Illinois, for example, used the prescription drug monitoring programme three times more per month compared with the previous year.Some analyses suggest that a similar trend of prescription drug overdoses is under way in the United Kingdom of Great Britain and Northern Ireland (UK). Dr Cathy Stannard, a pain consultant in the United Kingdom, dismisses these saying that there are some prescription painkiller deaths in the country, but that adherence to guidelines prevents more overdoses and deaths. Deaths from the synthetic opioid painkiller, tramadol, increased between 1996, when one death was reported, and 2014 when 240 deaths were reported, according to the UK Office of National Statistics. In 2015, tramadol overdose deaths decreased to 208. “The National Health Service structure in the United Kingdom, where general practitioners tend to have close relationships with patients, might help restrict doctor-shopping too,” says Stannard, a consultant in Complex Pain and the Pain Transformation Programme Clinical Lead at the National Health Service Gloucestershire Clinical Commissioning Group.“The solution lies in reforming the health-care system to incentivize doctors to talk to patients, educate patients and spend more time with them, not just to prescribe pills and perform surgeries.”Anna LembkeDrug dealer MD published last year, highlights the country’s epidemic of prescription opioid dependency. Stronger health and social systems are needed in the USA to address the prescription opioid epidemic, according to Dr Anna Lembke, whose book  “The solution lies in reforming the health-care system to incentivize doctors to talk to patients, educate patients and spend more time with them, not just to prescribe pills and perform surgeries,” says Lembke, an Assistant Professor of Psychiatry and an addiction specialist at Stanford University.Many doctors do not know how to diagnose or treat addiction and are unable to help patients who become dependent on opioids. A new approach to managing pain is needed, she says: “We need to change our narratives around pain, encourage notions of resilience and understand the limits of modern medicine”.


Complex Regional Pain Syndrome (CRPS) is an invalidating chronic condition subsequent to peripheral lesions. There is growing consensus for a central contribution to CRPS. However, the nature of this central body representation disorder is increasingly debated. Although it has been repeatedly argued that CRPS results in motor neglect of the affected side, visual egocentric reference frame was found to be deviated toward the pain, that is, neglect of the healthy side. Accordingly, prism adaptation has been successfully used to normalize this deviation. This study aimed at clarifying whether 7 CRPS patients exhibited neglect as well as exploring the pathophysiological mechanisms of this manifestation and of the therapeutic effects of prism adaptation. Pain and quality of life, egocentric reference frames , and neglect tests  were repeatedly assessed prior to, during, and following a one-week intense prism adaptation intervention. First, our results provide no support for visual and motor neglect in CRPS. Second, reference frames for body representations were not systematically deviated. Third, intensive prism adaptation intervention durably ameliorated pain and quality of life. As for spatial neglect, understanding the therapeutic effects of prism adaptation deserves further investigations. Complex Regional Pain Syndrome is a usually lateralized chronic pain condition, which occurs following a potentially mild nociceptive event  or even without any triggering factor . The paiAlthough the precise mechanisms underlying CRPS may vary from individual to individual, including biological pathways that underlie aberrant inflammation or vasomotor dysfunction, it is generally accepted that, besides the peripheral pathology, maladaptive plastic processes in the central nervous system are crucially involved , 7. IndeOne of the most common and disabling symptoms is underuse of the affected limb, which has been related to a kind of motor neglect, described by Galer et al. : movemenAnother very promising and intriguing perspective concerning CRPS is prism adaptation therapy. This proposal was also based on similarities between spatial neglect and CRPS . As a maThis analysis of the available literature can be summarized in 3 main points. First, the parallels and the differences between neglect patients and CRPS patients need to be specifically investigated. Second, prism adaptation seems to be a promising method to alleviate CRPS patients, but to our knowledge only two studies are available and insufficient data is available about follow-up of these patients. Sumitani et al.  followedThe main objective of the present study was to investigate the characteristics of spatial cognition alterations presented by CRPS patients. To do so, we explored different aspect of spatial neglect before and after a prism adaptation therapy. Perceptual aspects were explored with classical paper-and-pencil neglect tests as well as not only visual but also manual straight-ahead demonstrations. Motor aspects (extinction or “neglect-like” deficits) were explored using two specific tasks monitored by quantitative motion analysis. Our second objective was to explore the efficiency of prism adaptation rehabilitation on CRPS pain on a larger sample and with a longer follow-up than what was previously published, with a special emphasis on quality of life in order to assess the functional potential of this rehabilitation technique. We used a posology of two prism adaptation sessions per day in order to optimize the duration of aftereffects. Our third objective was to monitor the evolution of visual and manual straight-ahead pre-, per-, and postprism adaptation in order to investigate their dynamical relationship and explore their potential causal links.Seven consecutive patients reffered from pain or postsurgery consultations and suffering from CRPS following a surgery or a traumatic event were included in the study from January 2014 to October 2015. All of the patients fulfilled the Budapest criteria for the diagnosis of CRPS and provided written informed consent to participate in the study. Two additional patients were excluded because of conversion etiology or pulling out.The inclusion criteria were age ranging from 18 to 90 years; CRPS type 1 or 2 concerning the hand, wrist, and forearm; traumatic or surgical etiology; chronic evolution of longer than 2 months. The exclusion criteria were severe psychiatric disorder; ongoing sympathetic nerve blockade cycle; inclusion in another interventional study regarding CRPS.The patients' characteristics are detailed in This is an open, monocentric, interventional, usual care study involving a single group of patients who all underwent prismatic adaptation rehabilitation. Pain was measured using two complementary ways. First, at the inclusion and follow-up consultations and before and after each prism adaptation session, we used the basic VAS . Second, when the patients stayed home between inclusion and rehabilitation and then between rehabilitation period and follow-up consultation, they collected by themselves their level of pain using adapted VAS: on a ten-centimeter-long line, they marked their level of pain using the same conventions as for VAS, twice a day during a period of 10 days (in the morning and in the evening). The patients were asked to hide each previous line in order to avoid a possible bias. Patients brought the sheet back at the consultation and the examiner measured each line to the nearest millimeter, resulting in values between 0 and 100, as for the classical VAS. Data was analyzed using regression analysis for preadaptation values and two-way ANOVA and repeated measures ANOVA with planned comparisons for the follow-up values.For the last included patient, we followed the idea of a previous patient and asked her to visually represent her pain on her hand picture every treatment day and at inclusion and follow-up consultations. Drawing and coloring were performed on real-size pictures of her own hand  using a simple color code. Green was used to represent the skin areas with no pain, yellow was used for light pain, orange was used for moderate pain, and red was used for intense pain. This procedure provides a vivid way to better follow up pain evolution during treatment.A questionnaire was given to patients before the beginning of rehabilitation and at the beginning of the follow-up consultation . This dahttp://OptiquePeter.com/) producing a 15° optical deviation of the visual field toward the healthy side of the body [PA was carried out by wearing a pair of glasses  appeared at eye level at approximately 30° alternatively to the right or the left of the objective body midline (OM). This red dot was moved from right to left or vice versa at about 3°/second. The participants were asked to stop the dot, using verbal command, when the position crossed their midsagittal plane (vSM). The vSM position was computed between vSM and OM in degrees of visual angle. A rightward deviation was signed positive while a negative value indicates a leftward shift. Ten trials for each condition (100 cm and 200 cm) were performed at inclusion, before and after each prism adaptation session, and at follow-up consultation. Mean and standard deviation were computed for each session and condition.The patients were comfortably seated in front of a table. A chin rest maintained the trunk in an upright position and the head straight. The patients were asked to point in darkness at the “straight-ahead” position, that is, in the direction of an imaginary line dividing their body into two equivalent halves. The patients spread out their arm without any speed or amplitude constraint. The patients wore a metallic thimble on their index finger. When the finger touched the table surface covered with carbon isoresistive paper, tension between the thimble contact point and the reference electrode was measured (see ). Then, One of our predictions was that MSA might be deviated toward the painful side. As there were 5 right CRPS and 2 left CRPS, we normalized the data so as to obtain two groups of means. First, we pooled the data on the basis of the affected and healthy hand. In order to obtain homogeneous values, we logically also used the opposite value of the left CRPS data .Open loop pointing (OLP) accuracy measurement was carried out under the same conditions of darkness and with the same devices. The luminous visual target was aligned with the patients' sagittal axis. The instruction given to the patients was to place their index finger (right and left hand) at the target drip-line as precisely as possible without time constraint. Data collection and processing were similar to MSA.The patients were seated in front of a table, with an A4 sheet of paper lying on the table and aligned with their body axis on which a centered 200 mm long and 2 mm thick line was printed. The patients were asked to mark the middle of the line without any computation or external help. The distance was calculated by measuring the shift in millimeters between the reported point and the objective midline. A leftward shift had a negative value and a rightward shift had a positive value. Ten measures were obtained with each hand at inclusion, before and after each prism adaptation session, and at follow-up consultation. We used the same method described for manual straight-ahead to obtain two groups of normalized data: affected and healthy hand, based on right CRPS group.The two pretests for spatial parameters  were used to explore their reliability by means of correlation. In order to investigate whether left and right CRPS patients would exhibit left or right biases, Yates Chi-2 tests were performed for each parameter.Subjects sat in a comfortable armchair facing a table, with hands lying on the table with the palms down. In this resting position, they were blindfolded and asked to listen to a metronome sound at 120 beats per min during a period of 10 seconds and to remember it. After a go signal given by the experimenter, they were asked to tap with their index finger on the table at the previously heard frequency during a period of 30 seconds. This tapping test was performed in three different conditions. In the “opened-eyes” and the “closed-eyes” conditions, the two hands were 28 cm apart and positioned symmetrically on their side. In the “crossed hands” condition, eyes were closed and the right hand was positioned over the left hand for the first run and under the left hand for the second run.For each condition, movements were recorded using three different blocks in the following order: right index alone, left index alone, and both indexes simultaneously. This series of three blocks was repeated twice so that two runs were collected for each combination of condition and block. Thus, each participant performed a total of 18 trials (3 conditions × 3 blocks × 2 runs).We used an optoelectronic Vicon MX Giganet system composed of eight infrared stroboscopes and 100 Hz infrared cameras to record 3D motion of passive markers during the finger tapping test. One passive infrared reflecting marker was placed upon the nail of the two index fingers. Each data acquisition began with the go signal given by the experimenter and ended automatically after 30 seconds. After recording and tridimensional reconstruction, the spatial positions of each marker were filtered using a Butterworth low-pass filter at 6 Hz cut-off frequency. The spatial position of the index nail marker was used to compute the relevant movement kinematic parameters: movement amplitude and time intervals between taps .For each condition and for each patient, a mean value was computed for each individual tap using the two runs so as to respect a potential extinction effect along the task. Further analyses used this series of averaged values over the two runs.∗ left/right hand). Controls and patients data were analyzed separately because of variance inhomogeneity for this task.The data was analyzed with repeated measures and two-way ANOVA  were printed on it. The patients held a pen in each hand and were asked to listen to a 60/min beat throughout each trial. They were requested to simultaneously draw circles with each hand, crossing the reference point at each beat. Three conditions were recorded: full vision, that is, eyes open and pen on ; hand vision, that is, eyes open and pen with cap ; and no vision, that is, eyes closed . In each condition, clockwise circles were drawn with the left hand and counterclockwise circles were drawn with the right hand simultaneously in a block and vice versa in a second block. Instruction was to draw large circles, filling most of the available space on the page. So each participant performed a total of 6 trials (3 conditions × 2). We used the same optoelectronic Vicon MX Giganet system. Data acquisition and reconstruction were identical to the previous task. Two passive infrared reflecting markers were placed over the pen lead and on the cap, depending on the condition. The spatial position of the pen marker was used to reconstruct ellipses drawn by the subjects. Customized software was used to compute the ellipses characteristics: perimeter, angle, center coordinates, horizontal extent , surface, and horizontal drift and its direction. The most relevant parameters to compare ellipse size produced by each hand were therefore ellipse perimeter, surface, and horizontal extent. In addition, the horizontal drift of the ellipses was examined, that is, the most relevant dimension to explore neglect-like behavior.∗condition∗hand). For this task, comparisons between controls and patients were possible thanks to the comparable standard deviation in both groups with three-way ANOVA (group∗condition∗hand).This data was analyzed with three-way ANOVA and  is represented with error bars.R's < 0.58; all p's > 0.14). Therefore, no preintervention trend would interfere with potential amelioration of this symptom following the intervention. The mean level of pain before intervention was 58.8 ± 12.6 on the VAS the day before the beginning of intervention and significantly differed from zero (t(6) = 12.3; p < 0.0001).Concerning the pain level before intervention, it was important to check whether the level of pain was stable before prism adaptation. For none of the patients, the individual analysis of regression on pain level over time showed a significant slope  = 6.72; p < 0.001), indicating a significant impact on quality of life.The mean initial Sickness Impact Profile for the patients was 38.7 ± 15.3 points  and significantly differed from zero  = 0.01; p = 0.96), VSA2m  = 0.12; p = 0.76), and LMSA  = 0.14; p = 0.72) were found. The best reliability was found for RMSA  = 2.92; p = 0.15). Average values obtained for right and left CRPS patients are presented in Before adaptation, spatial reference frames deviation in CRPS was explored twice . Altogether, we conclude that no systematic bias of reference frame was obtained in our patient sample.In order to investigate whether left and right CRPS patients would exhibit left or right biases, Yates Chi-2 tests were performed for each parameter. None of them provided significant results  < 1.35; all p > 0.25).Line bisection before adaptation tended to be overall accurate: the affected hand performed with a 0.5 ± 0.4 mm bias and then 1.6 ± 0.5 mm bias at the second test, and the healthy hand showed 0.7 ± 0.3 mm bias and then −1.0 ± 0.3 mm bias at the second test. None of these deviations were statistically significant , as shown in F = 1.18; p = 0.3; period: F = 1.16; p = 0.3). Crucially, no group∗hand interaction was found for amplitude  = 0.35; p = 0.57) or for period  = 2.46; p = 0.15). This means that, before adaptation, patients did not differ from controls in terms of tapping performance which is crucial because it stands in sharp contrast with the neglect prediction.Means for the three conditions for controls and pre- and postadaptation patients are presented in The circle drawing task further explored motor extinction and motor neglect. Indexes of ellipse size  investigated whether patients performed smaller circles with their affected hand, that is, motor extinction. Horizontal drift measured the difference between the last and first circle drawn, and the direction of this drift would provide an argument for neglect if it was congruent between the two hands. For this task, the most likely condition to exhibit extinction or neglect was again the closed-eyes condition as no visual feedback is provided.The most obvious result in ∗pre-post) on the pre- and postvalues for each session showed a main effect of adaptation )  = 16.56; p < 0.01). As can be seen in y = −0.04x + 5.38; t(6) = −0.40; p = 0.71), but the preadaptation values tended to drift gradually toward the right  = 3.0; p < 0.03). This suggests that the effect of an adaptation session was partially retained until the next session. Although the magnitude of these effects seems to decrease over time, there was no significant interaction between pre-post and session  = 0.89; p = 0.53). Despite the evolution of pretest values, planned comparison between the inclusion and follow-up consultation values was not significant  = 0.15; p = 0.71), suggesting that the modification of the open loop pointing did not fully stabilize and at least partially resolved in between the end of the treatment and the follow-up consultation.During the prism adaptation period, the most relevant parameter to evaluate the reality of adaptation is the presence of aftereffects. These aftereffects are quantified by open loop pointing performed with the adapted hand (AHOLP). Concerning this parameter, the repeated measures ANOVA (session∗pre-post) on the open loop pointing which showed no significant main effect of pre-post  = 1.98; p = 0.21) or interaction  = 0.39; p = 0.90).As in most experiments, the aftereffects obtained with the adapted hand did not transfer to the nonadapted hand, as shown by the repeated measures ANOVA  = 7.76; p = 0.06) and marginally significant effect of the session∗pre-post interaction  = 2.2; p = 0.053). The session∗pre-post  interaction was significant for NAHMSA  = 2.74; p < 0.02) which means the aftereffects amplitude varied. For none of these four parameters, the planned comparisons between inclusion and follow-up consultation were significant.Other parameters can be classically modified by prism adaptation: the visual straight-ahead at one meter (VSA1m), visual straight-ahead at two meters (VSA2m), manual straight-ahead for adapted hand (AHMSA), and manual straight-ahead for nonadapted hand (NAHMSA). The same analyses were performed as for the OLP for these four parameters and showed only marginally significant effect of pre-post for VSA1m  = 4.77; p < 0.0006). As shown in F = 2.58; p = 0.16), which implies that the affected hand solicitation during each session of prism adaptation did not increase pain in a short term.Concerning the evolution of pain during the period of prism adaptation, two-way (session ∗ pre-post) ANOVA was realized on VAS values during the week of intervention . This analysis showed a highly significant main effect of session  = 3.42; p < 0.0001) showing that the level of pain during the whole observation period was not stable. Then, planned comparisons allowed us to further specify the timing of pain amelioration. A comparison between pre- and peradaptation values showed a significant difference between these two groups  = 7.92; p < 0.05) showing that pain substantially diminished during and after prism adaptation. Then, a comparison between the last adaptation session (ADA8) values and all the postadaptation values showed no significant difference  = 3.98; p = 0.18), implying that pain benefit remained stable over the follow-up period. Congruently, comparison between pre- and postintervention level of pain was significant  = 14.15; p < 0.01), as well as preadaptation values compared to the follow-up consultation pain level  = 12.31; p < 0.02) further supporting the reliability of the benefit over time.Finally, repeated measures ANOVA performed on the whole pain data available  was highly significant  with a simple color code . QualitaF = 5.61; p < 0.0005) which is simply congruent with the fact that the different categories of this score do not include the same number of items. More importantly, a main effect of pre-post was also observed  = 8.2; p < 0.05). The preglobal score was 38.7 ± 5.76 points (mean ± SEM) while postscore was only 28.6 ± 4.64 points, that is, resulting in an improvement of 10 points on the SIP scale. This result demonstrates a substantive improvement of quality of life following the intervention. The interaction between category and pre-post was only marginally significant  = 1.83; p = 0.066). The most improved SIP subscores corresponded to emotional behavior, social interactions, body care and movement, and alertness behavior, as shown in On the Sickness Impact Profile scale, the two-way  ANOVA showed a main effect of category  = 0.05; p = 0.83) or on SIP  = 0.04; p = 0.85).Interestingly, no significant correlations were found between the ADA1 posteffects on AHOLP and the global efficiency on pain  repeated measures ANOVA showed only a marginal effect of session  = 2.24; p = 0.061). Surprisingly, we did not find a main effect of pre-post  = 2.65; p = 0.18). finger tapping task, patients did not significantly differ from controls in terms of initial hand asymmetry  and unimanual condition (motor neglect). In addition, a bimanual circle drawing task was used  in orderThe circle drawing task further explored several aspects of motor extinction and motor neglect. Indexes of ellipse size  investigated motor extinction while horizontal drift explored motor neglect. Congruently with the previous task analysis, no arguments for motor extinction or motor neglect were found and so patients did not differ from controls in terms of hand asymmetry. In Punt et al.'s bimanual condition , a neuroAltogether, these kinematic results clearly invalidate the motor neglect hypothesis heralded by several authors –16, 25 s∗hand significant interaction crucially implies that the hand difference observed during the pretest in both patients and controls for the circle task was not affected by the prism adaptation therapy.This study design also offered the opportunity to test how parameters of the circle drawing task and finger tapping task that were not initially affected by CRPS evolved under prism adaptation. The absence of adaptationIn addition, a counterintuitive observation made in both patients and controls in the circle task was that although no hand asymmetry was obtained in the no-vision condition, the left hand tended to draw larger ellipses when more visual feedback was provided. This reliable trend suggests that it is the visual control of the hand movement (and path) that paradoxically contributes to this hand asymmetry. This important result will deserve further investigations in order to disentangle attentional and motor control sources of explanation. perceptual neglect or motor extinction or motor neglect. Contrary to the classic neglect-like hypothesis, we did not find perceptual neglect-like behavior or antineglect as well, as suggested by Sumitani et al. [To summarize the spatial cognition examination before intervention, this CRPS patients group did not demonstrate any argument for significanti et al. . Our resOur second goal was to explore the concrete effectiveness of prism adaptation which was suggested at several levels. We observed a gradual reduction of initial pain initiated during the adaptation treatment week. This amelioration provided a significantly positive outcome after adaptation that was fully maintained at the follow-up consultation 2 weeks later. This statistical reduction of pain was also clinically relevant because the initial pain (VSA: 58.8 ± 4.8 mm) appeared to stabilize at the follow-up consultation (VSA: 38 ± 8.3 mm), producing an average reduction by about 36% of pain.To our current knowledge, only two studies have been published: the first by Sumitani et al.  with 5 pn = 7) of CRPS patients undergoing prism adaptation as rehabilitation and the first sample followed up after the end of the rehabilitation period. We managed to follow up all patients between 15 and 20 days after the last adaptation day whereas the longitudinal single case was followed up for 8 weeks without treatment in Sumitani et al.'s study [Our group is thus far the largest series  and most of them had been submitted to at least 3 types of therapeutic interventions. The patients who showed the best benefit were not the least chronic ones: the patient (number 4) with 90% improvement had CRPS for 17 months. Interestingly, the clinical outcome for patients did not seem to be related to the type of CRPS: the two patients with CRPS type 2 had pain score improved by 48% and 10%. This is interesting because so far only type 1 CRPS had been reported to benefit from prism adaptation , 35.Qualitatively, this pain reduction was described by one of the patients producing a drawing of her own hand. This representation showed an impressive global reduction of pain, which decreased from moderate pain concerning nearly the whole hand to no pain at all except for a very tiny weak pain area at follow-up. This reduction occurred with respect to the initial mosaic pattern pain distribution, which did not correspond to any nervous territory/area. Strikingly, improvement even further went on after stopping the prism adaptation therapy. This last point is congruent with the group data analysis showing the persistence of benefits along the last follow-up period and also with the knowledge about prism effect on neglect symptoms , 38, 46.Major information provided by our study deals with the concrete effects of prism adaptation on CRPS patients' quality of life. In this group, the Sickness Impact Profile showed a statistically significant improvement of 26%. Emotional behavior, social interactions, body care and movement, and alertness behavior were particularly concerned. At the individual level, the benefits ranged from 0% to 54%, with 3 patients presenting improvement inferior to 20% and 4 patients between 24% and 54%. Despite being subjective, this evaluation describes objective activities of everyday life and it indicates substantial enhancement of everyday living for this initially disabled group.Altogether, the very positive outcome of this interventional study on pain and ADL calls for designing larger controlled multicentric studies to assess the clinical stake and the individual responsiveness of chronic and acute CRPS patients. Evidence collected by two previous studies , 35 and Our third goal was to monitor straight-ahead demonstrations throughout prism adaptation therapy, so as to explore their potential causal links with clinical and neuropsychological parameters.The main result is the confirmation that CRPS patients adapted to prism, as shown by significant sensorimotor posteffects represented by open loop pointing for the adapted hand (OLPAH). Their mean adaptation during the first exposure was 3.6°, that is, smaller than normal subjects undergoing the same amount of deviation (about 7° in ). ContraAdditional analyses were aimed at exploring the causal link between sensorimotor and clinical measures. No significant correlation was obtained between the sensorimotor aftereffect of the first prism adaptation session and the final gain on pain and quality of life. This is consistent with knowledge about prism adaptation clinic efficiency on neglect after stroke, which has never proved to be correlated with the magnitude of sensorimotor aftereffects , 48.In brief, this study provided detailed analysis of the largest CRPS group before, during, and following an intense prism adaptation intervention. At the pathophysiological level, patients' spatial cognition was explored using various sensitive and quantitative tools and providing no systematic left-right asymmetry pattern, in sharp contrast to the clear expectations expressed in the literature. At the therapeutic level, prism adaptation is confirmed to be a very promising method to alleviate CRPS pain. Our study reveals that intense prism adaptation intervention produces sustainable therapeutic effects on pain and subsequent benefits on quality of life.It has now become timely to design and realize controlled trials to test the effectiveness and durability of this promising, intense prism adaptation intervention, to explore predictive parameters of patients' responsiveness and neurophysiological mechanisms of this therapeutic effect. Ultimately tailoring interventions on the basis of CRPS subgroups  is a key


Radiosurgery is now an established method of satisfactory pain control in patients with trigeminal neuralgia (TN). The Varian Truebeam STx  linear accelerator (LINAC) system is an arc-based, frameless stereotactic radiosurgery system used for the treatment of TN. To our knowledge, there has been only one published series of patient histories that documents the use of a frameless LINAC system for the treatment of TN. We describe the treatment parameters, patient outcomes, and complications associated with the treatment of TN.All patients treated with the Truebeam system for TN between 2012 and 2015, with at least a six-month follow-up, were identified. A dose of 90 Gy was delivered to the isocenter using a 0.5 cm diameter cone. The cisternal segment of the trigeminal nerve was placed at the location of the LINAC isocenter using an ExacTrac™  image guidance system. The radiosurgical dose, Barrow Neurologic Institute pain score (BNI PS), symptom recurrence, magnetic resonance imaging (MRI) radiographic changes, and other complications, including Barrow Neurologic Institute facial numbness score (BNI FN), were analyzed.A total of 18 patients—15 women and 3 men—with a mean age of 58 years  were treated at our institution. Fourteen patients (78%) had a BNI PS of IIIb or better, which was considered successful treatment. Twelve patients had excellent (BNI PS I) pain relief and two patients had good  pain relief. The pain of four patients recurred after a mean of 10 months.Truebeam radiosurgery can provide effective and safe treatment for patients suffering from TN. The efficacy appears similar to other frame- and frameless-based systems Trigeminal neuralgia (TN) affects up to 12 out of every 100,000 people. Various classifications have been proposed to describe TN and facial pain syndromes; Burchiel , frame-bFrameless radiosurgery has been used successfully as a method of treatment for TN -9. CyberThe Varian Truebeam  system is a LINAC-based platform that has been used for the treatment of TN -10. ChenAll data acquisition and analysis was approved by the Institutional Review Board. A total of 21 patients were treated with the Truebeam system for TN refractory to medical or surgical procedures. Three patients were lost to follow-up. Two of these patients had complete resolution of their symptoms at 56 and 99 days, respectively, based on the BNI PS. One patient noted that her pain was unchanged at her two-month follow-up. These patients were not included in our analysis. In our remaining cohort of 18 patients, clinical outcomes were assessed at a mean follow-up time of 27.5 months . Demographic and treatment information was obtained through a retrospective chart review. Post-treatment follow-up data was collected through outpatient patient charts or through phone interviews.All patients underwent pretreatment evaluation, including comprehensive clinical history-taking, physical evaluation, and appropriate imaging studies, including a fast imaging employing steady-state acquisition (FIESTA) MRI scan. Patients who failed medical therapy, were ineligible, or declined surgery were offered radiosurgery. A total of 18 patients—15 women (83%) and three men (17%)—were included in this study. Ten patients (56%) had TN type 1, four patients (22%) had TN type 2, and four patients (22%) had TN type 5 (history of multiple sclerosis (MS)). The average age at treatment was 56.3 years, with a median age of 58 years (range: 22-84 years). Five patients (28%) had undergone unsuccessful prior nonmedical intervention, which included microvascular decompression, radiofrequency or retrogasserian glycerol rhizotomy, and prior radiosurgery at a different institution. Pain distribution and selected demographic characteristics are presented in Table Treatment planningAn MRI was obtained at 2-21 days prior to treatment. Patients were immobilized with an S-frame mask  and thin slice (1.5 mm) axial computed tomography (CT) images were obtained at the time of simulation using helical acquisition by a 16-slice Philips Brilliance  CT scanner. CT images were fused with FIESTA axial slices (0.8-mm slice thickness) for target delineation. The trigeminal nerve root was identified on the FIESTA MRI. The brainstem was contoured on consecutive axial slices on CT with the aid of MRI fusion. A five mm diameter BrainLab  cone was used for treatment in all cases. A total of seven 6 MV flattening filter-free noncoplanar arcs were designed to deliver 90 Gy to the isocenter of the cisternal segment of the trigeminal nerve root. The segment of the trigeminal nerve root treated was determined based on the dose isodose lines (IDL) which corresponded to the 50% IDL (45 Gy) abutting the brainstem. This corresponded roughly to the dorsal root entry zone, which is approximately 3 mm from the edge of the brainstem.Prior to treatment, Winston-Lutz testing was performed to confirm radiation, mechanical, and imaging isocenter coincidence with a tolerance of 0.5 mm. All patients were treated in a single treatment session. Patients were positioned supine on the treatment couch using a frameless thermoplastic mask. Stereoscopic orthogonal radiographic images using ExacTrac™ stationary x-ray tubes were obtained to verify the position with a tolerance of 0.75 mm and 1 degree of rotation. Six-degrees-of-freedom positional changes were applied based on these radiographs. A kV cone beam CT scan was performed to confirm the stereoscopic x-ray setup.ExacTrac™ x-ray verification images were taken every 10-20 arc degrees during treatment delivery. If the verification alignment suggested a mismatch greater than 1 mm, treatment was interrupted and patient repositioning performed.All patients received 10 mg dexamethasone prior to treatment and were discharged on the same day after treatment with a solumedrol dosepak. Initial follow-up for all patients was done between three and six months after treatment. Patients were seen sooner if there were any concerns or relapse of pain. Follow-up data was collected after an initial visit through a phone interview or outpatient clinic documentation. Patients were evaluated for the level of pain control, response rate, time to pain relief, the occurrence of hypesthesia, and time to pain recurrence.Post-radiosurgery pain was assessed using BNI PS, as shown in Table Successful treatment was defined as a BNI score of I-IIIb. A BNI score of I was deemed an excellent outcome, while a BNI score of II-IIIb and recurrence after one year was a good outcome. Treatment failure was defined as a BNI score of IV or V, with recurrence prior to one year. Recurrence was defined as a relapse to a prior lower level after a higher level was achieved after initial treatment Table .A post-radiosurgery MRI scan was obtained approximately two months after radiosurgery. An MRI was obtained sooner in situations of new neurologic changes or treatment failure. A Fischer’s exact test and univariate analysis were used to determine the correlation between patient co-morbidities and treatment success. A P value of <0.05 was used for statistical significance.The median BNI PS was four prior to radiosurgery. Five (28%) patients had BNI PS III, nine (50%) patients had BNI PS IV, while four (22%) patients had BNI PS V.Six patients (33%) had pain distribution involving both the maxillary (V2) and mandibular (V3) divisions. Five patients (28%) had V3 pain, four (22%) had V2, two (11%) had ophthalmic (V1) division and V2 pain, and one (6%) had pain in the V1, V2, and V3 distributions. Patients were followed for an average of 27.5 months . At the 12-month follow-up, 17 patients (94%) reported some improvement in pain. At the last follow-up, 13 patients (72%) had successful pain relief (BNI PS I-IIIb). Eleven of these patients had excellent pain relief (BNI PS I) and two patients had good pain relief . Symptom recurrence was noted in four patients. This occurred within one year and the cases were deemed treatment failures. The mean time to failure was 10 months. One patient had a preoperative BNI PS of III, two patients had a BNI PS of IV, and one patient had a BNI PS of V. One patient with BNI PS III and a history of MS was re-treated with radiosurgery at 240 days and remained pain free (BNI PS I) at his nine-month follow-up. The remaining three patients did not wish to undergo further radiosurgery.Ten patients (56%) had TN type 1. Eight patients had excellent results, one patient had good results, and one patient had a recurrence of symptoms. Four patients had MS. Prior to treatment, two of these patients had a BNI PS of III and two patients had a BNI PS of IV. Three patients with MS had successful radiosurgical outcomes. One patient experienced a recurrence of his symptoms but after a second radiosurgery treatment, he has remained pain free. Three ultimately had excellent (BNI PS I) pain relief and one had good (BNI PS II) pain relief.Five patients failed prior radiosurgical or surgical treatment for TN before undergoing radiation at our institution. Four patients had prior microvascular decompression (MVD) and one patient underwent Gamma Knife radiosurgery at another institution. Three of these patients had complete resolution of their pain after radiosurgery, with pain relief for a mean duration of 27.6 months .There were four patients with a BNI PS of V prior to treatment, of which three had complete resolution of symptoms with an average follow-up of 27.8 months . One patient with a BNI PS of V had temporary pain relief for 16 months but the pain reoccurred. A pain-free survival curve based on preoperative BNI PS is shown in Figure The mean time to pain relief in all patients was 82 days . Patients with MS had a mean time to pain relief of 47.5 days . Patients with previous surgical intervention had a mean time to pain relief of 22 days . Overall, patients experienced an average of 22.5 months of pain relief (median of 24.3 months).Seven patients (39%) had nonbothersome facial numbness (BNI FN II), and one patient had bothersome facial numbness with a persistent itching sensation in her eye (BNI FN III). Interestingly, none of the patients who underwent prior radiosurgery treatment (two patients) experienced facial numbness. One patient reported dry eye syndrome, which resolved after nine months.3 (range: 0.036 cm3 – 0.15 cm3). The average volume of the trigeminal nerve encompassed by the 90% IDL (81 Gy), 50% IDL (45 Gy), and 13.3% IDL (12 Gy) were 0.014 cm3 (range: 0.007 cm3–0.022 cm3), 0.033 cm3 (range: 0.014 cm3–0.057 cm3), and 0.057 cm3 (range: 0.029 cm3–0.088 cm3), respectively. A typical isodose distribution is shown in Figure 3 (range: 0.070 cm3 – 0.178 cm3) . Six patients 33%) had evidence of contrast enhancement within the treated volume (50% IDL), as seen in Figure 3% had evTreatment modalities for TN consist of conservative medical therapy, surgical decompression, ablative procedures, and radiosurgery. Surgical intervention carries risks such as hemorrhage, infections, and cranial nerve palsies with morbidity rates of up to 3% -14. ThesThe configurations of frame-based systems, including Gamma Knife, use rigid fixation of the head and have established Gamma Knife as a safe and efficient treatment option for TN . The oveCyberKnife and select LINAC-based systems can use frameless-based positioning for the accurate delivery of radiation. Using the ExacTrac™ x-ray system, head position monitoring can be performed on-demand during radiation delivery. We found that frameless image-guided radiosurgery provides convenience when acquiring imaging and a shorter set-up time on the day of radiation. It is also painless, which is similar to other published studies .Radiosurgery involves a focused beam arrangement directed to the trigeminal nerve at the root entry zone at the anterolateral portions of the pons. The isocenter receives the maximum point dose, which is most frequently advocated for at the dorsal root entry zone, approximately 2-3 mm from the edge of the brainstem. The root entry zone is advocated as the ideal location of treatment, given the histologic changes in the nerve from the compact axonal fibers and oligodendrocytes layers of myelin in the central nervous system to the Schwann cells of the peripheral nervous system . Other tGiven the proximity to the brainstem and other critical neural structures, validation was an important step toward the acceptance of frameless radiosurgery as an accurate method for intracranial radiosurgery. The targeting error during frameless radiosurgery is comparable to frame-based treatment methods, with reports ranging from a 0.26-0.32 mm error in translation -18.Various nerve lengths, volumes, and dosing in the treatment of TN have been described in the literature. An increase in length or volume has not been correlated to better outcomes. With Gamma Knife, longer portions of the nerve were treated using larger collimator sizes with the hope of increased efficacy but this only caused a higher incidence of facial numbness . SimilarThe optimal dose for treatment of TN has varied in the literature. It has been suggested that doses of more than 70 Gy have better sustained pain relief than those treated with less than 70 Gy using Gamma Knife . RadiatiPain relief latency also varies depending on the dose and system used. Time to pain relief remains shortest using CyberKnife, with reports of pain relief in as little as 7-14 days to 2 months ,21. ThisPain relief and the rates of facial numbness in both CyberKnife and LINAC-based systems are comparable to Gamma Knife radiosurgery. Patients undergoing CyberKnife have excellent pain relief of 50%-72% for two years following treatment ,27-28. FFacial numbness remains the most common complication after radiosurgery to treat TN. Facial numbness has been reported in 23.8%-35% which has been correlated to prior surgery and a larger collimator ,26. In oIn our study, we found successful pain relief in 72% of patients after a median follow- up of 28.5 months, similar to the reports of other LINAC or CyberKnife studies. Post-treatment MRIs revealed enhancement at the root entry zone in six patients, five of which had excellent results; yet, this was not a statistically significant (p<1.0) predictor of treatment success.The limitations of this study include the difficulty in evaluating and comparing radiosurgery literature, as each published report uses different outcome measures for treatment success, different dosing strategies, and different ways of defining complications. Although attempts at standardizing patient outcomes have made great progress, a uniform method of measuring success has yet to be determined. This is evident when looking at the Chen et al. series, where excellent results were defined as BNI PS I and II . AnotherAlthough Gamma Knife is considered the gold standard radiosurgery treatment for TN, the Truebeam system provides a frameless alternative. The safety and efficacy established in this analysis demonstrates an important opportunity for centers to provide effective treatment of TN in the absence of a Gamma Knife platform. The novelty of this system is that it is a frameless system, and it adds to the body of the literature.TN can be effectively and safely treated using the Varian Truebeam system, with results similar to that published in the literature. Although statistically significant findings were not present, patients with TN type 1 tend to recover better than those with other forms of TN; they also experience longer pain-free survival. In addition, patients with prior surgical or radiosurgical treatment may benefit from further radiation with the Truebeam system. Patients with prior radiation treatment did not have an increased incidence of facial numbness. The follow-up results of over two years are promising for the continued success of the Truebeam system for the treatment of TN.


Pain levels in patients with osteoarthritis (OA) of the knee are commonly assessed by using a numeric scoring system, but results may be influenced by factors other than the patient’s actual physical discomfort or disease severity, including psychosocial and demographic variables. We examined the possible relation between knee-pain scores and several psychosocial, sociodemographic, disease, and treatment variables in 355 patients with knee OA.The pain-evaluation instrument was a 0- to 10-point rating scale. Data obtained retrospectively from the patients’ medical records were demographic characteristics, body mass index (BMI), concomitant disorders, illicit and prescription drug use, alcohol use, smoking, knee OA treatment, and severity of knee OA indicated by Kellgren-Lawrence (KL) radiographic grade. Univariate and multivariate analyses were performed to determine whether these variables correlated with reported pain scores.On univariate analysis, higher pain scores were significantly associated with Native American or Hispanic ethnicity; a higher BMI; current prescription for an opioid, antidepressant, or gabapentinoid medication; depression; diabetes mellitus; fibromyalgia; illicit drug use; lack of health insurance; smoking; previous knee injection; and recommendation by the clinician that the patient undergo knee surgery. Neither the patient’s sex nor the KL grade showed a correlation. On multivariate analysis, depression, current opioid prescription, and Native American or Hispanic ethnicity retained a significant association with higher pain scores.Our results in a large, ethnically diverse group of patients with knee OA suggest that psychosocial and sociodemographic factors may be important determinants of pain levels reported by patients with knee OA. More than nine million people in the United States have symptomatic knee osteoarthritis (OA) , with paFactors that have been assessed for their possible relation to reports of OA-associated pain include age, sex, body mass index (BMI), race/ethnicity, substance abuse, and psychological variables such as depression, hopelessness, overall well-being, and social stress ,7–10. ThWith approval from the Human Research Review Committee of The University of New Mexico Health Sciences Center (HRRC#13–523), we reviewed the medical records of all 611 new patients who presented to our orthopaedics clinic and received a primary diagnosis of knee OA between 1st January 2013 and 31st December 2013. In each case, the diagnosis was confirmed by an evaluation of the patient’s medical history, a physical examination, radiographic studies, or a combination of these methods. Patients with a concurrent ligamentous injury, inflammatory arthritis, or bilateral knee OA were excluded from the study; therefore, 355 were enrolled. Institutional review board waived the need for patient consent, and data was accessed anonymously with no patient identifiers.At their initial presentation, all patients had been asked to describe their pain level with respect to a number from 0 to 10, with 0 representing “no pain” and 10 “the worst pain imaginable.” This numeric scale is commonly used to assess arthritic pain . Aside fAt the time of the medical-record review, radiographs obtained during the initial patient visit were assessed by a musculoskeletal radiologist who was blinded to all patient information in the records, including pain scores. The radiologist assigned each image a KL grade of 0, 1, 2, 3, or 4 on the basis of the extent of degenerative changes observed.In estimating the appropriate sample size for the study, we assumed that most clinicians would consider a difference in pain score of 2 to be clinically important and we wanted to limit the type I error to 0.05 or lower and achieve a power of 90%. Because we anticipated simultaneous analysis of up to 22 independent variables, we used a type I error of 0.002 . Under these assumptions, we calculated that the study should include about 310 patients.Standard summary statistics were calculated for all variables. Univariate analysis was used initially to assess the possible relation between pain score and each independent binary variable studied. The Student t test or Mann-Whitney U test was applied as appropriate. Analysis of variance was used to examine the possible relation between pain score and each of the following: age, BMI, race or ethnic group, and KL grade. A p value of <0.05 was considered to indicate a statistically significant difference.2 analysis. The variables were removed sequentially until only those that had a significant relation with pain score remained in the model. All statistical analyses were performed with Statgraphics Centurion XV software .Multivariate analysis was performed by using a general linear model algorithm and maximum-likelihood estimation. Variables that were significantly associated with pain score in the univariate analysis were sequentially fitted into the model with use of adjusted R2 . The overall mean (standard deviation [SD]) pain score was 5.0 (2.9). The mean pain scores in white, Native American, Hispanic, “other,” and black patients were 4.5 (3.0), 6.3 (2.7), 6.4 (2.5), 4.7 (3.1), and 5.8 (2.8), respectively. The “other” category included two patients who indicated that they were Asian and twenty-seven who reported that they were “other” than white, Native American, Hispanic, or black. The most common KL score was 3, indicating moderate OA.On univariate analysis, age had a significant inverse relation to pain score, with younger subjects having significantly higher scores (p = 0.03). Compared with white patients, Hispanic or Native American patients had significantly higher pain scores .In a univariate analysis of a large, diverse cohort of patients with knee OA, we found that several psychosocial, sociodemographic, disease, and treatment variables were each significantly associated with higher reported knee-pain scores. A subsequent multivariate analysis showed a significant association between higher pain scores and Hispanic or Native American ethnicity, opioid agent prescription, and depression. There was no relation between pain score and KL grade, a discordance also observed in several earlier studies –6. Many Other research has examined a possible link between knee OA-associated pain and race/ethnicity. A study by Creamer et al.  includedStudies of arthritis-associated pain in Native Americans are scarce; however, in an investigation by Kramer et al.  in whichThe association between current opioid agent prescription and higher pain scores possibly stems from neuromodulation of pain sensitivity resulting from chronic opioid use ,16. It iOur multivariate analysis also found a significant relation between higher pain scores and depression. Previous studies found that depression affects reported pain in patients with rheumatoid arthritis , and an In agreement with earlier findings ,8, the sObesity, a known risk factor for development of OA, has been linked to an increased severity of OA-related pain, although Somers et al.  found thThe association between higher pain scores and uninsured status is probably related to socioeconomic status because OA pain and symptomatic knee OA have been correlated with lower income levels  and the Our study had the usual limitations of a retrospective, observational investigation. In addition, there may have been interactions among the variables assessed that our study design could not identify. Some factors not examined, such as whether the patient was currently involved in a workers’ compensation evaluation, might have influenced pain-score reports. Additionally, our study had a small number of black patients, with a large percentage of Hispanic and Native American patients. This unique ethnic distribution, however, is a reflection of our state’s composite population. Finally, the pain-evaluation method that was used was a simple numeric rating scale. This assessment can be administered quickly, but it may not sufficiently characterize a patient’s pain experience.Despite these limitations, our results indicate that psychosocial and sociodemographic factors significantly affect patients’ reports of their level of OA-related knee pain and that patients with OA do not constitute a homogenous group for which the same management approaches will suffice. Management should be tailored to the individual and characterized by more extensive patient education regarding the specific factors contributing to their pain, as well as discussion of appropriate expectations for pain-level. The usefulness of a pain assessment based primarily on a numeric pain score is of variable utility. Extensive reliance on such an assessment in clinical decision-making may be inappropriate, especially when invasive procedures are contemplated. With the limitations that come with the visual analog scale, clinicians could consider employing various self-reported and physical measures recommended by the Osteoarthritis Research Society International (OARSI) such as the Dallas Pain Questionnaire or the WOMAC Questionnaire. Ultimately, pain-treatment decisions should not be based primarily on KL grade but the entire patient presentation.Although clinicians cannot modify some of the factors associated with higher pain scores in our study, they can increase their insight into the possible causes of an observed discrepancy between a patient’s clinical appearance with respect to comfort and his or her pain score and perhaps mitigate the influence of factors that can be changed. Clinicians who are aware of the psychosocial and sociodemographic characteristics that affect their patients’ reports of OA-related knee pain will thereby be able to provide more effective, patient-centered care.S1 DatasetRaw data extracted from the chart review for all patients who met study inclusion criteria.(XLS)Click here for additional data file.


Chronic pain is associated with increased stress in families and has its own impact on the relationship between members of the family. Among couples, if one of them suffers from chronic pain, this may influence marital satisfaction in both of them and given the importance of marital satisfaction in the prediction of successful treatment outcome, it is important to investigate pain and personality-related factors contributing to inter-individuals variation in marital satisfaction.Participants in this study were recruited from Atieh Hospital and Rasa Pain Clinic, Tehran, Iran in the year 2013. Chronic pain patients and their spouses were asked to complete a battery of questionnaires including measures on pain cognition and marital satisfaction. Using correlation and regression analysis factors with the highest level of contribution to marital satisfaction were investigated.Spouses’ level of rumination about patients’ pain has been found to be positively correlated with marital satisfaction in patients. In addition, patients’ depression has been found to be the best predictor of level of marital satisfaction in patients. In addition, patients’ level of depression, disability and perceived helplessness has been found to be the best predictors of marital satisfaction in their spouses.To improve marital satisfaction among chronic pain patients, their support-seeking needs should be satisfied through involvement of their spouses in the process of treatment. To improve marital satisfaction among patients’ spouses, we should help patients regain their ability, improve their mood, and make patients believe that they have access to the support of their caregivers. Chronic pain condition exerts profound impact on both patients and their significant others, mainly spouses . Indeed,Given the existing literature and proposed important role of marital satisfaction in the enhancement of pain treatment outcomes, identifying factors that contribute to marital satisfaction in both patients and their spouses seems to be of great significance. Moreover, marital satisfaction decline in chronic pain patients and their spouses after the onset of pain condition , 2. TherThe present study aimed to investigate factors that might contribute to both spouses’ marital functioning since pain and relationship difficulties are mutually related to one another.Participants with musculoskeletal pain and their spouses (n=284) were recruited from Atieh Hospital and Rasa Pain Clinic, Tehran, Iran in 2013. The study was approved by University research Ethics Committee and Mental Health Center of Atieh Hospital.Patients had to be older than 18 yr, be in constant pain for at least three months. Patients were excluded if they had brain injury or major cognitive dysfunction. All participants in this study provided informed consent and participated in the study voluntarily.Chronic pain patients were predominantly female  with an age average of 45.89 yr (SD=11.90). Their spouses were on average 47.51 yr old (SD=12.25). The couples had been married for a mean of 22.99 yr (SD=13.42). Chronic pain patients reported a mean pain duration of 46.33 (SD=65.69) months. The most common location for patients to experience pain was back and knee.Patients and their spouses completed a battery of questionnaires including pain intensity (VAS), fear of movement, pain catastrophizing, disability, depression, and Marital Adjustment Test (MAT). All measures showed good internal consistency –at or above 0.70 for the current study.The VAS is a 10 cm un-graded horizontal line with two anchors from 0 indicating “the minimum intensity of pain” to 100 indicating “the maximum intensity of pain”. Chronic pain patients were asked to indicate their current pain intensity on the scale, while their spouses were asked to indicate their interpretation of patients’ current pain. This scale has consistently demonstrated good validity and sensitive to change .PCS is a 13-Item self-report scale that measures three dimensions of pain catastrophizing: Rumination, Magnification, and Helplessness. Respondents have to rank each statement on a 5-point Likert scale ranging from 0  to 4  with respect to past painful experiences and indicate the degree to which they experienced those thoughts and feelings . ChronicFear of movement was assessed with Tampa Scale of Kinesiophobia, the patient and spouse versions , 19]. ItThe RDQ is a 24-item checklist designed to assess disability caused by pain. Patients were asked to mention whether each statement applied to them in the last 24 h. The RDQ score ranges from 0 (no disability) to 24 (maximum disability). In the current study, a modified version of RDQ was used for a heterogeneous group of chronic pain patients, the wording “my back pain” was changed to “my pain”, this modified version has shown good validity in pain samples . This meBoth spouses’ depressive symptoms were assessed with the depression subscale of DASS  which inMarital satisfaction was assessed by using Marital Adjustment Test (MAT). The 15-item MAT is commonly used as a measure of marital satisfaction. Greater scores indicate higher satisfaction, whereas lower scores reflect greater marital discord. Scores on the scale range from 2 to 158. Respondents are asked questions related to the degree of happiness with the marriage, agreement with the spouse on matters such as finances and the degree to which the respondent engages in outside activities with the spouse. The MAT has demonstrated good validity, inter-item reliability and test–retest reliability. For the current sample, internal consistency was good for both partners .Patients’ depressive symptoms, fear of movement, rumination, and magnification were correlated negatively and significantly with their marital satisfaction, showing that higher pain-related problems are associated with lower marital satisfaction in Patients. Patients’ rumination and depressive symptoms were negatively and significantly correlated with spouses’ marital satisfaction, showing that higher levels of depression and rumination about pain in patients are associated with lower levels of marital satisfaction in their Spouses. Pain intensity, disability, and helplessness were not significantly correlated with patients and spouses’ marital satisfaction.Spouses’ depressive symptoms were negatively and significantly correlated with both spouses’ marital satisfaction, while spouses’ rumination was positively and significantly correlated with patients’ marital satisfaction. Higher levels of depression in caregivers is associated with lower levels of marital satisfaction for both patients and caregivers, while higher levels of rumination about patients’ pain is associated with higher levels of satisfaction in them. Spouses’ interpretation of pain intensity, magnification, and helplessness were not significantly correlated with both spouses’ marital satisfaction.A hierarchical regression was used to test the hypothesis that pain beliefs  contribute unique variance to marital satisfaction over and above pain variables.First, we examined the correlation between demographic variables  and the dependent variable  to determine whether demographics should be entered as covariates. Gender was significantly correlated with healthy spouses’ marital satisfaction, but not patients’ marital satisfaction. Therefore, step 1 of the hierarchical regression for spouses’ marital satisfaction included education, step 2 consisted of pain variables , step 3 consisted of depressive symptoms, and step 4 consisted of pain catastrophizing subscales .As shown in Patients’ disability and depressive symptoms accounted for 37% of variance in their marital satisfaction, whereas their pain catastrophizing did not contribute to their marital satisfaction. Spouse pain variables did not significantly contribute to patients’ marital satisfaction. Spouses’ depressive symptoms and rumination accounted for 18% of variance in patients’ marital satisfaction.As shown in This study aimed to test whether patients and their spouses’ pain catastrophizing contributed uniquely to their marital satisfaction after controlling other pain related variables correlated with marital satisfaction. Patient’ depressive symptoms accounted for an incremental variance in their marital satisfaction beyond that accounted for by pain variables, while their pain severity, rumination, magnification, and helplessness did not contribute to their marital satisfaction. Taken together, patients’ marital satisfaction is better explained by their depressive symptoms and disability. The role of depressive symptoms in predicting patients’ marital satisfaction as found in the current study is in congruence with the findings that depression has a significant impact on chronic pain patient’s relation satisfaction . That paInterestingly, spouses’ rumination was positively correlated with patients’ marital satisfaction. Such findings can be explained by the fact that content of the rumination items  are representative of persistent thoughts about patients pain as well as spouses’ care and concern for patients’ health. Hence, rumination may result in a feeling of empathy and understanding of patients’ pain (pain affects spouses too), which may contribute to patients’ marital satisfaction as they are likely to receive more support and attention from their spouses.Patients’ disability, depressive symptoms, and helplessness significantly explained spouses’ marital satisfaction, while their pain severity did not contribute to spouses’ marital satisfaction. Such findings lend support to the notion that pain-related disability is more likely to predict spouses’ marital satisfaction as it leads to functional impairment and might adversely affect family atmosphere through role changes. Indeed, pain adversely affects couples’ relationships as it gets chronic, but pain-related disability and its consequences are more likely to interfere with daily life. For example, helplessness beliefs are related to patients’ feelings of lack of control over pain that results in more avoidant behaviors, and disability . TherefoSpouses’ depressive symptoms explained a significant proportion of variance in their own marital satisfaction, while their interpretation of patients’ pain severity, fear of movement, rumination, magnification, and helplessness did not contribute to their marital satisfaction. Perhaps these variables have an indirect effect on spouses’ marital satisfaction by exacerbating depressive symptoms that seems to be a key factor contributing to marital satisfaction. Spouses who catastrophize are more likely to experience depressive symptoms since it is difficult for them to distract their attention from patients’ pain .This study simultaneously examined the predicting role of both patients’ and spouses’ pain catastrophizing on their marital satisfaction while controlling for pain variables and depressive symptoms.The current study may suffer from a number of limitations taken into account for the interpretation of findings. First, data for the current study gathered in one time point. Marital satisfaction is a dynamic concept that can change over the time dependent upon a number of variables . We were not able to repeat assessment in different time points and include all the other variables into account. In addition, we were not able to track changes in marital satisfaction over the time and to investigate its association with changes in pain cognition and mood of subjects. This also influenced our analyses and interpretation of findings of those analyses. In the future studies, longitudinal designs may help us to better investigate the causal relationship between the changes in mood and pain and changes in marital satisfaction.More focus on couples’ psychological states, especially their negative beliefs and depressive symptoms, may provide significant benefit in patients’ treatments through enhancing their marital satisfaction. Such outcomes seem to be a key step toward treatment enhancement as research shows that increase in marital satisfaction is related to better long-term treatment outcomes for both patients and their spouses. The findings of this study also place emphasis on the importance of considering spouses alongside patients both in pain research and in treatment to achieve better outcomes.Ethical issues  have been completely observed by the authors.