This study reports on physicians’ experiences with chronic pain management. For over a decade prescription opioids have been a primary treatment for chronic pain in North America. However, the current opioid epidemic has complicated long-standing practices for chronic pain management which historically involved prescribing pain medication. Caring for patients with chronic pain occurs within a context in which a growing proportion of patients suffer from chronic rather than acute conditions alongside rising social inequities.Our team undertook an ethnographic approach known as institutional ethnography in the province of Ontario, Canada in order to explore the social organization of chronic pain management from the standpoint of primary care physicians. This paper reports on a subset of this study data, specifically interviews with 19 primary care clinicians and 8 nurses supplemented by 40 hours of observations. The clinicians in our sample were largely primary care physicians and nurses working in urban, rural and Northern settings.In their reflections on providing care for patients with chronic pain, many providers describe being most challenged by the work involved in helping patients who also struggled with poverty, mental health and addiction. These frustrations were often complicated by concerns that they could lose their license for inappropriate prescribing, thus shifting their work from providing treatment and care to policing their patients for malingering and opioid abuse.Our findings show that care providers find the treatment of patients with chronic pain–especially those patients also experiencing poverty–to be challenging at best, and at worst frustrating and overwhelming. In many instances, their narratives suggested experiences of depersonalization, loss of job satisfaction and emotional exhaustion in relation to providing care for these patients, key dimensions of burnout. In essence, the work that they performed in relation to their patients’ social rather than medical needs seems to contribute to these experiences. Their experiences were further exacerbated by the fact that restricting and reducing opioid dosing in patients with chronic pain has become a major focus of care provision. An empirical understanding of the materiality of physicians’ work is crucial for understanding–and ultimately addressing–these evidently socio-medical conditions.Chronic pain is a significant health concern globally, affecting an estimated 20 percent of adults worldwide , and is Like other chronic disease sufferers, patients with chronic pain have been found to use more health services than the average Ontarian, and to incur higher medical costs overall . Yet desFurthermore, evidence suggests that more broadly, chronic disease sufferers and high-cost health system users are disproportionately of lower SES ,16. For Our current analysis focuses on physicians’ and other primary care providers’ reflections on their experiences of providing care to patients with chronic pain. While evidence suggests that the care that is provided to these patients often fails to meet patients’ hopes and expectations for pain relief and recovery , 20, ourThis article draws on data from an ongoing institutional ethnography  of the cPeople’s everyday lives are sites of interface between individuals and a vast network of institutional relations, discourses, and work processes. The object of interest in institutional ethnographic research is that interface between embodied individuals and institutional relations . IE emphOur interviews were supplemented with observations at four sites. These interviews followed an open-ended interview guide that was piloted prior to commencement of the study to ensure flow of topic areas. Following IE’s emphasis on what Smith describes as “work knowledge”, interview questions were organized around eliciting details about the work that clinicians performed in carrying out care for patients they deemed to be complex . We askeRigorous ethnographic research combines interview and observational data to reach a deeper understanding of how forms of knowledge, rationality, and experience are sustained, produced, and contested through everyday practices and institutions . By obseThe procedural steps involved in analyzing data in an IE study are similar to those practiced in many other qualitative research approaches. Data is transcribed and coded so that it can be analyzed. Codes identify features of the data that are pertinent to the research questions and organize data into more concise ideas that can be eventually grouped into topics. They are often recurrent keywords or concepts that are supported by interview data (i.e. quotes). Codes reflect our analytic interest in explicating how the work that is performed by an actor in one situation  is coordinated extra-locally. Through interviews, the IE researcher identifies a series of texts and discourses that are present in the language of participants as they describe their everyday work practices.The first several transcripts and field notes were inductively coded by FW and KR independently; the researchers then met to compare their codes and achieve consensus on items to be included in a coding framework which was then applied by KR to the remaining interviews. Coding by multiple team members is a useful way of developing reflexivity rather than a tool to confirm the ‘truth’ of the data. Reflexivity used in this way refers to the process by which we critically examine our own assumptions about the world. Through comparison of our developing understanding of the transcript data, each member of the coding team has an opportunity to check their own assumptions and ideas. At the same time FW and KR de-briefed weekly to discuss each new interview. Larger team meetings were held at several key points during which we discussed and reflected on our emergent understanding of the data. These larger meetings were led by FW, an experienced sociologist and IE researcher, and included a multidisciplinary research team that comprised a post-doctoral fellow who held a PhD in medical anthropology [KR], a PhD pain psychologist [JC], two academic primary care physicians . Several of these meetings were joined by an IE trained nurse [CD], a medical student [JER], and a PhD candidate working in health psychology [EO]. Data analysis was an interactive, inductive, and collaborative process that involved identifying emergent themes and theorizing the implications of this for our broader research topic. Nvivo 10 software was used for storage and organization of data.Our findings are organized around physicians’ experiences providing care to chronic pain patient, and are presented in a narrative style that demonstrates care providers’ changing role vis a vis care provision, the frustrations they experience in trying to effectively provide care for patients that they find challenging, and their struggles to effectively respond to situations that they feel helpless to address. We have drawn on the many examples in which physicians describe having to manage issues of poverty and marginalization in their work rather than strictly patient’s health concerns. We also note in their stories many examples of loss of job satisfaction, emotional exhaustion and, at the extreme end of the continuum, depersonalization.We begin this section by sharing an extended account in which a physician discusses a patient who undoubtedly faces far more barriers to health than do many Canadians. However, similar examples featured regularly among the interviews that we collected with health care providers working in primary care and warrant including this account. This particular narrative highlights that while our research aims to examine the current context and work of providing care for patients with chronic non-cancer pain in the province, it necessarily also entails investigating the relationship between pain and poverty, as well as the challenges posed by socio-economic status (SES) differentials between doctors and patients.The one that’s just off the forefront of my head is a client who has a very significant personality disorder, so antisocial, has a lot of anger based on just long-standing childhood trauma, and has a lot of other comorbidities, the most recent being an amputation to his leg because of recurrent infections because of his diabetes and also hep C. So he was someone who had lots of pain, and a lot of it was due to the infections in his leg. … He’s in a wheelchair, he doesn’t really know how to use it, he’s on Suboxone, which is a medication that he was getting for both [narcotic] addiction and pain but it’s not enough for his pain at this point so he actually does need pain medication. But he can’t leave his apartment because there’s stairs, and … the washroom is downstairs … and it’s a mess. I mean, we’re trying really hard to get him into accessible housing as a priority, but it doesn’t seem to be happening. So I’m spending a lot of time advocating for him … But that’s an example of me putting hours and hours into helping a client who has lots of other medical issues going on, and I would love to be able to focus on that, but because he doesn’t have housing that’s appropriate that’s taking over the forefront of my energy the patient is quiet, morose, and unstylishly dressed in drab clothing, with holes in one shoe. Rather than a winter coat he had on three layers of sweatshirts under a light jacket. (…) The family physician asks him about his housing situation, recalling that at his last appointment the patient was concerned about losing his apartment” .In this paper we suggest that aspects of poverty, such as those described in the example above, are a ubiquitous feature of primary care provision, and this is likely intensifying as a growing proportion of patients suffer from chronic rather than acute conditions alongside rising social inequity. This was regularly documented in care providers’ narratives, and was and confirmed observational fieldnotes such as “Although many patients clearly struggled with poverty and marginalization, in clinical contexts patient care takes place at the level of the individual, honing in on patient behavior rather than the social inequities that inform the circumstances of people’s lives. In the extended quote above, for example, the physician describes a patient living in substandard housing and refers to both “childhood trauma” and “personality disorder” in the same sentence. While the reference to childhood trauma would suggest that the patient’s behavior is shaped by experiences beyond their control–and while some personality disorders are associated with childhood trauma–the socio-cognitive nature of both personality disorders and non-physical trauma challenge the parameters of what is typically understood as biomedical pathology. Accordingly, physicians are more likely to view people as being responsible for having personality disorders (because they are enduring character traits) as opposed to, for instance, schizophrenia, which they recognize as a disease.Many of the participants we interviewed described a disjuncture between patients’ hopes and expectations for pain management and the reality of what physicians can provide in way of treatment, especially in the current climate in which they are under pressure to restrict opioid prescriptions, the historical mainstay of treatment for patients with chronic pain. Most primary care physicians expressed sentiments such as the following, in which the physician links the fact that the “patient is suffering” with their lack of effective treatment and ongoing pressure to not prescribe opioids.Well, lots of them are difficult because the patient is suffering and you don’t have effective treatment for them … It can also be difficult if they also have expectations of things that you’re going to do that either you don’t think is effective for them, or there’s not an evidence base for. I suppose a specific instance in chronic pain is use of opiates, where you’re trying to judge that and it’s difficult to know whether the person is drug-seeking or whether they’re needing it for their pain .Several physicians alluded to the work of trying to determine if “the person is drug-seeking”, as in the excerpt above, but were often vague about specifically how this was accomplished. Especially for physicians who were trained in an era when prescription opioids were the gold standard for chronic pain treatment, such anxieties were further complicated by a lack of support in helping their patients’ transition away from prescription opioids. This conundrum is summarized by the following family doctor:They’ve heard [that high doses of opioids are risky], but they don’t know what to do. So let’s say they’re prescribing a high dose to a patient, and they’re worried about it, so they say to the patient, “Jeez, maybe we should taper,” and the patient says, “But I got terrible pain, and if you taper me my pain will be even worse. I need this drug. How could you do this to me!?” And the doctor has never been trained in how to say no to a patient .Saying no to patients as an aspect of clinical work was one of many informal activities that physicians in our study referenced as being particularly difficult to enact. Physicians also cited the difficulty of testing, measuring, or accurately evaluating a patient’s pain in the absence of any clear bio-markers. In the account below the physician describes how challenging it is to ensure she does not “inappropriately prescribe narcotics,” especially when she struggles to trust “what the patient is telling”. She does not find the work of medicine “exhausting” but rather the efforts that are spent “sorting out organic gain from secondary gain”. This adjudicating of the legitimacy of patient’s requests for pain medication is a growing area of focus for most providers, as she describes:The one thing I still struggle with all the time is just the subjectivity again of chronic pain. I think it’s just because it’s more subjective than objective, so it can be challenging in that perspective. And, especially with our population that we deal with because we deal with many high-risk patients, sorting out organic pain from secondary gain from other issues or pain, is something that’s manifesting as pain but is actually depression or something else, it’s exhausting. …And, again in [this city] we have a really high diversion rate of our medications. We’re super high as far as the province goes for narcotic prescriptions, so that’s just always looming in the back of your head. You don’t want to be inappropriately prescribing narcotics .Frustrations about the subjective nature of pain were complicated by concerns some physicians had about malingering patients, and patients who might abuse opioids. These concerns sometimes stemmed from fears of harming the patient through overdose or prescribing drugs that might end up on the street, a fear the following physician describes as “an awful dilemma”,Patients on very high doses of narcotics], these are mistakes … it’s not even a mistake. You [the family physician] are in between a rock and a hard place with this stuff. You are a compassionate individual who doesn’t want to leave your patients in pain, you’re also aware that if you continue down this road you run the risk of killing your patient. What an awful dilemma to be in .And similarly, in the following account the physician describes “lying awake at night” worrying about opioid abuse and opioid prescriptions:So I think opioids–like, opioid abuse and opioid prescription–is a really, really big issue. You know, definitely I lie awake at night thinking about it. Like, it’s one of those things that I think is a huge problem, and particularly because it’s very difficult to know what to do, right? (…) , he even asked me, the first thing he wanted, he said, “Okay, well, how many appointments is it going to take until we get up to the dose that I was on?” …and he knows the drill, right, he knows what is needed. And so it’s hard when he says, you know, “Opioids are not my drug of choice, like, I always did crack,” and so you’re kind of simultaneously trying to build a rapport with a new patient and tell them that you trust and you believe them and you want them to come to you, while also denying them something that they want and invalidating them and …so it’s tricky .Descriptions of these “tricky” aspects of providing care were common among physicians in our study, and featured in a number of observations as well. It gives rise to a peculiar tension between the work of trying to “build rapport” with patients and communicate trust while simultaneously “invalidating them”. In addition, in these examples the physicians begin to describe the extraordinary work performed by patients who “know the drill” in terms of how they must accommodate the various requirements of different physicians in order to try and get what they believe they need for pain relief.Concerns about opioid misuse were often ascribed to The College of Physicians and Surgeons (CPSO) Opioid Strategy, recently launched in response to the 2017 Canadian Guideline for Opioids for Chronic Non-Cancer Pain . This seI’m sort of afraid to [prescribe opioids]. Just the medical-legal aspects of opioids. You always hear about prescribers losing their licenses as a result of prescribing opioids and them being used in an inappropriate manner. It happened to one attending in my hometown (…) he had to start independent practice, like in a walk-in, and there are all these restrictions on his license and it was in the paper. I don’t want to be one of the people who ends up in the back of the CPSO [College of Physicians and Surgeons of Ontario] magazines or anything like that .Although such concerns were shared by many physicians, their narratives also showed they are hamstrung by the lack of supports for opioid therapies, the limited alternatives to opioids, and apprehensions about the risks that opioids can entail. The following observational fieldnote extract illustrates this challenge:I don’t agree with not prescribing at all. As I understand it, pain is subjective. I can’t measure it in any way. But it’s real, and we can do something to reduce it. I think most docs who don’t want to prescribe don’t want to because it’s a ton of work managing someone on opioids, and it’s really challenging to get them off of it. But we don’t have the support for that, and it takes a huge amount of time. It would take a huge amount of my time. And I didn’t go into med school to become a babysitter. .[Young rural family physician] indicated that he would be doing paperwork in the evening, and that some of it had to do with prescription opioids. I asked him what his “stance” is on opioids, clarifying that we’ve encountered a range of perspectives on the appropriateness of prescribing opioids and that some physicians seem uncomfortable prescribing them at all. This is his response, as recorded by hand: This physician’s statement that he “didn’t go into medical school to become a babysitter” further highlights how the work physicians are now being asked to perform is not exclusively medical and thus introduces both a type and volume of work for which they were not trained or prepared and often do not want. For example, it is worth emphasizing that this physician equates the work associated with managing someone on opioids as “babysitting” rather than caring. We noted that similar concerns about opioid misuse were even more ubiquitous and explicit with patients of low SES:I constantly struggle on wanting desperately to believe the patients of their pain, but having that fear that it’s being diverted. Medications are being diverted or not used appropriately all the time. So, the subjectivity of it I find I struggle with all the time. And, again when I graduated residency it was everyone is innocent until proven guilty type thing. But, I feel in our high-risk clinic almost it’s guilty until proven innocent, and that saddens me as a physician .In summary, patients with chronic pain have largely been treated with opioid-based treatments that have led to escalating addiction and death, further burdening these patients, and leading their physicians to feel often “sad” and overwhelmed in providing care for them.As demonstrated in the excerpt at the beginning of this article, the theme of poverty and marginalization featured prominently in the interviews we conducted. Poverty was presented as a powerful barrier to providing optimal care to patients with chronic pain, and many providers noted that disadvantaged patients were heavily represented among their patients with chronic pain.The following example provides a rich description of the kinds of patients that frequently feature in clinician’s narratives about chronic pain patients. In the following account, the challenges posed by low SES are compounded by the limited services available outside major urban centres:Patient has] long-term lower finances in the family, has never had a job with proper benefits, is unable to work because of his pain, has diabetes, can’t pay for his medications because of not having benefits, is awaiting surgery which probably will not happen for another year for his back because of our lack of specialists here in town and lack of available surgeons. Basically he’s [now] in a state where we can start helping. But, in order to try to actually get him to a place where he’s going to be healthy is probably going to take at least a year and a half or two years by the time we can get some more benefit programs in place for him …. We’ve got our community health workers and our systems in place to help him access drug benefits. We can help him with his financial benefits and we can hopefully try to get him in for the surgery as soon as possible, and then he’s going to have the recovery from that. But, he’s so de-conditioned at this point and his health with the diabetes is so poor, we worry about what his recovery from the surgery is going to be like. So, yeah, very complex, complex client. Very, very nice man, very patient with the whole system, but obviously very frustrated with it too . was heavily focused on the patient’s lifestyle. They had a long talk about getting out of the house, and it became clear that the patient only goes out for essential errands such as buying groceries and filling prescriptions. The physician encouraged the patient to try to find other reasons to leave the house, and asked the patient if he had anyone he could meet up with socially. The patient said that there are a few guys he could call, but that they usually want to meet at bars and this is a “trigger” for him. In the ensuing dialogue it became clear that the patient struggles with addiction, and he admitted to using “a bit” in the past couple months .Moreover, with chronic pain patients in particular, patients’ reluctance or inability to make lifestyle changes, combined with a strong patient preference for medical forms of pain relief, was a common challenge for clinicians and one that often leaves them unable to “go home at the end of the day and feel satisfied” in the care they provided.This sort of frustration features in this abridged interview excerpt, in which a family doctor describes a patient with whom she is having a “hard time”:One of the ones that I’ve had a hard time with he’s young, probably 35, very, very overweight. He’s got a history of chronic low back pain, he has had a MRI showing some nerve root impingement, he’s been seen by a couple of neurosurgeons, and has been recommended to get surgery. He refuses because he’s too scared to have the surgery. He’s been on Percocet for a number of years. The issue with him was that he was just so paranoid of the health care system that he just wouldn’t even consider the other options [besides Percocet]. …So I’m really trying to do some self-management with him, because obviously his obesity is contributing to his pain, and there’s just no getting him motivated to move around (..) So yeah, it’s been difficult with him because there’s a huge wall, he’s just, like, no, that’s it, I just want this [Percocet], I’m done, I’m not going to do anything else. I have a hard time with that .Perhaps due to such frustrations related to the “huge wall” physicians perceive between themselves and patients, several interviewees were dismissive of some patients with chronic pain. However, most recognized that while lifestyle-related changes are indeed helpful for people with chronic pain, it is not realistic to expect most people to make those changes without access to services not currently funded, especially so if they are living in poverty.In keeping with IE’s emphasis on an expanded definition of work, our findings demonstrate the shifting nature of the work performed by care providers causes them frustration, exhaustion and compromised job satisfaction. These are key characteristics of what has been termed physician burnout . In the Most often these responses were described in relation to a changing work environment in which providing care now frequently revolves around restricting and reducing opioid dosing in patients with chronic pain. The College of Physicians and Surgeons (CPSO) launched an Opioid Strategy  in direcThe College will continue to work with the Ministry of Health as necessary to identify levels of opioid prescribing and investigate prescribing practices that may be harmful to patients. The College is aware that while investigations may identify instances of risk of harm to patients when opioid prescribing is continued, there is also a very real risk of harm to patients when opioid prescribing is discontinued. Understanding and questioning prescribing practices is not intended to discourage appropriate opioid prescribing and we are urging physicians to not suddenly cease prescribing to patients currently on opioid therapy.how specifically opioids should be discontinued or not. Yet the emphasis on “investigations” renders clear that oversight will be enacted in relation to physicians prescribing practices and that penalties may be imposed. The concerns with appropriateness of opioid use raise issues regarding the fundamental justification of medicine in treating chronic pain as well as patient poverty. It seems that in the context of opiates and chronic pain, concerns about the limits of clinician judgment and worries about legitimacy are creating untenable issues for clinicians.These guidelines are vague, with little direction around when and Furthermore, even when patients with chronic pain have straightforward medical problems, our findings show that primary care providers are often unable to effectively facilitate these treatments because their patients struggle with more pressing and immediate concerns, such as housing , 33. TheEvidence indicates that health care providers rarely share the same socio-economic background as such patients . This isThe Renewal of Generosity by Arthur Frank [No one teaches “The Art of Medical Decision Making With Limited Funds” or “Medical Compromise with Cultural Strictures”. Medical practice in a community of poor people often seems a solitary specialty without research, common cause, or shared-experience. I and my few partners are isolated professionally, with no way to even to assess our own record … As a physician for the poor, I know there will be no “professional advancement”. The bottom rung of the ladder is the same as the top rung: working as a clinic doctor, seeing patients day-to-day.” (quoted in ur Frank ).In addition, few studies related to care of patients with chronic pain include any discussion of gender or race. In an important study, Mendoza and her colleagues conducted an ethnographic case study of Staten Island, analyzing popular media press and interviews with physicians and pharmacists . They noLow-income patients often are unable to access treatments such as physiotherapy, massage, and even mental health care that are frequently offered instead of opioids. As our participants state, more affluent people have access to these therapies through private insurance or have the means to pay out-of-pocket. Restricting access to these services to the wealthy is a joint outcome of what is a trend in health care reform. The Ontario health care system is increasingly characterized by economic-rationalist discourse, and thus by neoliberal reforms –51. Key The physicians in our study provide numerous examples of the tension they feel between wanting to believe and trust their patients, being aware of their difficult life circumstances, and yet increasingly being directed to suggest alternative health therapies that are far beyond the reach of most patients. The subjective nature of pain also adds to the difficulties they have in believing their patients’ accounts. In their excellent ethnographic study of U.S. clinicians’ experience of contending with pain in their everyday practice, Crowley-Matoka and colleagues describe how “pain and pain medications remain both incompletely medicalized and ineffectively medicalizing in American biomedicine ”. Our fiIn our analysis we traced how care is standardized through textually established policies that must be enacted across multiple locations. Recent undertakings enacted jointly by the CPSO and the Ontario Ministry of Health in an effort to provide provincial oversight of opioid prescribing were frequently evident in interviews both directly and indirectly. There are a number of ways in which our research shows the harmful effects of this. Examples such as physicians who are dismissive of patients suggest that such ideologies are present in Ontario system and may be increasing due to the pressure on physicians to police their patients who suffer from chronic pain, ironically to avoid being policed themselves by their professional College. This leads to physician dissatisfaction and in many cases distress as their work shifts away from diagnosis and healing.It also leaves both physicians and patients troubled by the inadequate care that is being provided and a growing sense of helplessness as physicians are left to manage rising social inequities without support or training , the symInstitutional ethnography is a particular qualitative approach that allows researchers to link the everyday experiences of participants working lives to the wider institutional factors influencing that experience through an examination of texts including discourse. In our study we were able to link physician accounts of stress, emotional exhaustion and even depersonalization with the many examples they provided of treating patients with low SES, within the context of changing legislation by their professional Colleges. We noted how much of the work that physicians described was about gatekeeping or policing patient access to chronic pain medication rather than the work of healing. This puts the provider in a conflicted position relative to their patients in need as the institutional priority is restricting or withholding therapies once widely prescribed and now recognized as risky.While our findings have profound implications for patient care in Ontario, we have not focused on patients and thus cannot authoritatively speak to how our findings may implicate them. Indeed, in this article their experiences as they are presented here are in most cases refracted through the voice of their physicians. Such perspectives are unlikely to reflect a comprehensive understanding of patient experience. Future research could be aimed at understanding the experiences of patients of low SES with chronic pain in order to better understand how their work is hooked into and organized by these same institutional priorities.We have drawn together discourses on health and social inequality and the rising literature on physician well-being. Indeed, the pervasiveness of poverty among chronic pain patients means that care providers are being asked to mediate across class lines, to help people whose problems they have not been trained to solve. This results in a lot of anguish and worry for them.While the association between wealth and health has long been recognized, solutions for this are increasingly being sought through medicine, and in this process are frequently recast as medical problems–such as an opioid crisis–rather than as issues of public health. In addition, while opioid tapering is recommended as the antidote to this problem, and while sanctions are levelled against physicians who over-prescribe, there are currently few alternative therapies available that are affordable for many patients. We would argue that this represents a medicalization of poverty that diverts attention and resources from social services and education and toward clinical treatment where physicians are poorly situated to manage the situation. The provision of stronger supports, rather than potential sanction, would offer much needed assistance to those physicians dealing with the crisis of growing inequity on the front lines. In addition, if physicians are to taper or stop prescribing opioids for their patients, there must be fully funded alternatives for them to offer. Without this funding in place, the current regulations and guidelines risk estranging physicians from the very patients who most need their care and will contribute to both patient suffering and threaten physician well-being in the future.S1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file.


Pain is the most common complaint for an emergency department (ED) visit, but ED pain management is poor. Reasons for poor pain management include providers’ concerns for drug-seeking behaviors and perceptions of patients’ complaints. Patients who had objective findings of long bone fractures were more likely to receive pain medication than those who did not, despite pain complaints. We hypothesized that patients who were interhospital-transferred from an ED to an intensive care unit (ICU) for urgent surgical interventions would display objective pathology for pain and thus receive adequate pain management at ED departure.This was a retrospective study at a single, quaternary referral, academic medical center. We included non-trauma adult ED patients who were interhospital-transferred and underwent operative interventions within 12 hours of ICU arrival between July 2013 and June 2014. Patients who had incomplete ED records, required invasive mechanical ventilation, or had no pain throughout their ED stay were excluded. Primary outcome was the percentage of patients at ED departure achieving adequate pain control of ≤ 50% of triage level. We performed multivariable logistic regression to assess association between demographic and clinical variables with inadequate pain control.We included 112 patients from 39 different EDs who met inclusion criteria. Mean pain score at triage and ED departure was 8 (standard deviation 8 and 5 [3]), respectively. Median of total morphine equivalent unit (MEU) was 7.5 [5–13] and MEU/kg total body weight (TBW) was 0.09 [0.05–0.16] MEU/kg, with median number of pain medication administration of 2 [1–3] doses. Time interval from triage to first narcotic dose was 61 (35–177) minutes. Overall, only 38% of patients achieved adequate pain control. Among different variables, only total MEU/kg was associated with significant lower risk of inadequate pain control at ED departure .Pain control among a group of interhospital-transferred patients requiring urgent operative interventions, was inadequate. Neither demographic nor clinical factors, except MEU/kg TBW, were shown to associate with poor pain management at ED departure. Emergency providers should consider more effective strategies, such as multimodal analgesia, to improve pain management in this group of patients. Although pain is the most common complaint for emergency department (ED) visits,Pain undertreatment is multifactorial; it has been linked to providers’ concern for drug-seeking behaviorsWe performed a retrospective study using a convenience sample of non-traumatic, interhospital adult patients who were transferred from a referring ED to any ICU at a quaternary, academic center for urgent surgical interventions, defined as having surgery within 12 hours of arrival. We included interhospital-transferred patients from referring EDs between July 2013 to June 2014 who were taken to the operating room urgently within 12 hours of arrival. We excluded patients who required mechanical ventilation in the ED and ED records missing pain assessment at ED triage or departure. We also excluded patients who reported no pain throughout their ED stay. The study was approved by our institutional review board.a priori as pain level, reported on 11-point verbal scale (0–11), at ED departure that was equal or less than 50% from triage levels. Pain reduction at equal or less than 50% was considered clinically meaningful to ED patients in previous studies.Primary outcome was percentage of patients receiving adequate pain control at ED departure. Adequate pain control was defined What do we already know about this issue?Pain management in the emergency department has been inadequate, but patients with objective findings for pain were more likely to receive pain medicine.What was the research question?Whether patients, who were transferred to a quaternary academic center for urgent surgical intervention, would receive adequate pain management.What was the major finding of the study?Pain management among patients with surgical pathology was inadequate. Emergency providers (EPs) did not employ effective strategies for pain management in these patients.How does this improve population health?EPs should employ effective strategies, including multimodal analgesia, to improve pain management among patients who needed surgical interventions.Investigators , who were not blinded to the study hypothesis, were first trained by the principal investigator (PI) (QKT) for data extractions. Data were extracted to a standardized Microsoft Access form  and 40% was randomly reviewed by the PI to maintain interrater agreement of at least 90% for systolic blood pressure, heart rate, and pain at ED triage, ED departure and medication administration. The team met every month to discuss data extraction issues and to adjudicate disagreements between junior investigators and the PI until data collection was completed.ED records from patients who were taken to the operating room within 12 hours of ICU arrival were identified and examined for data extraction. Independent variables extracted from patients’ ED records included demographic factors ; clinical data . The continuous infusion did not include vasopressors, which were part of the SOFA score. To evaluate the opioid dose that patients received, we converted the doses of the different parenteral or intravenous (IV) opioids to morphine equivalent unit (MEU), as previously described.13a priori selected therapeutic interventions, such as total MEU, MEU per kilogram (kg), and time interval to first narcotics, that may have clinically affected outcomes, to be included in the multivariable logistic regression. Independent variables were first evaluated in univariable analyses; we excluded those with weak association with outcome variable  from the multivariable logistic regressions. All p-value ≤0.05 were considered statistically significant. We performed all statistical analyses using Sigma Plot version 14 .Data were expressed as mean and standard deviation (SD) or median with interquartile range (IQR), where appropriate. The effect of variables on inadequate pain control was assessed using multivariable logistic regression. We We electronically identified 195 patients who were transferred to any adult ICU at our institution between July 2013 and June 2014; 112 patients who were transferred from 39 unique EDs met inclusion criteria and were included in the final analysis . The majMost patients (66%) received only narcotics, and the median number of administered doses was 2 [1–2]. The median number of pain assessment was 3 [2–5]. The majority of administered pain medications were narcotics (66%), while the time interval from triage to first dose of narcotics was 61 (35–177) minutes. Median of total MEU administered was 7.5 [5–13] and median of total MEU per body weight was 0.09 [0.05–0.16] MEU/kg body weight .Overall, emergency providers (EP) poorly managed pain in this high-risk group of patients. Pain control was adequate in only 38% of patients and inadequate in 62% , with thWe also performed a subgroup analysis of patients presenting with severe pain (triage pain 8–10) only, to avoid the confounding factor of whether the patient refused pain treatment. There were 74 (66%) patients presenting with severe pain. Thirty patients (41%) had adequate pain control at ED departure. Comparing to all patients, median of total MEU  or MEU/kg of body weight  was not significantly different. Multiple logistic regression adjusting for the same clinically-significant factors showed that no interventions by EPs were associated with adequate pain control .Our study showed that among patients who were transferred from EDs to ICUs for urgent surgical interventions, only 38% achieved meaningful reduction of pain level at ED departure, defined as 50% or less of triage levels. We identified one factor, total MEU/kg total body weight, associated with adequate pain control. However, we identified three potential barriers for adequate pain management in the EDs. Our findings suggested that pain control for this group of ED patients with time-sensitive diseases was inadequate.In our study, the median time interval from triage to IV morphine was 61 minutes (range 35–177). A previous prospective, multicenter study showed that the median time from ED triage to any analgesic administration for ED patients presenting with moderate to severe painPain management has been shown to be poor in the ED.Our study also identified the lack of multimodal analgesia among our patient population, who only received either narcotic or nonsteroidal anti-inflammatory drug (NSAID) pain medication. A recent study showed that a combination of ibuprofen and acetaminophen was equally effective as a single dose of opioids among patients with severe extremity pain.19Our study had several limitations. First, we did not have a control group to compare the efficacy of pain management in non life-threatening situations to these patients who would need transfer for urgent surgical intervention. Secondly, we did not assess the effect of ethnicity on inadequate pain control among our group of critically ill patients. A previous study suggested that African-American patients who were not taking opioids at home were less likely to achieve a 50% pain score reduction than other patients, even with similar analgesic dosage.5Our study consisted of a heterogenous group of patients with a limited sample size; therefore, it did not allow us to investigate which disease states would be at higher risk for inadequate pain control. Although patients included in our study required urgent surgical intervention, the sample size of mortality was low (9%), which did not allow us to examine the association of poor analgesia with outcome, as refractory pain was shown to be associated with poor outcomes in some disease states such as aortic dissection.Pain control among a group of interhospital-transferred patients requiring urgent operative interventions, was inadequate. No demographic or clinical factors, except total morphine equivalent unit per kg body weight, was associated with adequate pain management at ED departure. Emergency providers should consider a more effective strategy, such as multimodal analgesias, to improve pain management in this group of patients.


JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.Fibrodysplasia ossificans progressiva (FOP) is an ultra‐rare, inherited, connective tissue disease with ∼800 documented cases worldwide. The principal pathological feature of FOP is the transition of skeletal muscle, tendons, ligaments, and fascia into cartilage and bone. This heterotopic ossification (HO) is often preceded by painful soft tissue swellings or flare‐ups that may last several months. For many individuals, experiencing a flare‐up may represent a worsening of their condition and contribute to feelings of anxiety or suppressed affect, both of which are well‐recognized to exacerbate pain perception. To date, much remains unknown regarding the dynamics of pain and emotional health in FOP during flare‐up and also quiescent, non–flare‐up disease phases. In order to elucidate the occurrence and effect of pain in FOP, this study analyzed Patient‐Reported Outcomes Measurement Information System–based questionnaires completed by 99 patients participating in the international FOP Registry over a 30‐month period. We observed that although moderate to severe pain  was commonly associated with flare‐ups (56% to 67%), surprisingly, 30% to 55% of patients experienced similar pain levels during non–flare‐up states. In those patients reporting pain levels of ≥4, 45% to 74% of patients report experiencing anxiety, depression, or irritability, with 36% to 48% reporting emotional problems during no to mild pain states. Furthermore, independent of the flare‐up status, the severity of pain in FOP patients was found to be significantly anti‐correlated with emotional health, physical health, and overall quality‐of‐life. These findings strongly suggest the need for an improved understanding of pain and emotional health in FOP during flare‐up and quiescent periods. © 2019 The Authors.  Fibrodysplasia ossificans progressiva (FOP) is an ultra‐rare  and disabling inherited disorder that arises from missense mutations of the type I bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1).Flare‐ups and injury to the musculoskeletal system are undoubtedly principal sources of pain in FOP, yet past reports have noted the presence of recurrent severe headache , neuropathic pain of the lower extremities, and somatosensory abnormalities .In the current study, we aimed to test the hypothesis that although high levels of pain may be periodically driven by a flare‐up event, perception of pain along with a patient's emotional health are altered during non–flare‐up states. Furthermore, we explored how emotional and physical health as well as quality‐of‐life in FOP patients varied as a function of pain severity. Understanding pain in patients diagnosed with FOP will assist in defining an initial paradigm that may enhance the evaluation of these patients in the clinic and may provide an important first step toward the use of objective measures of pain in this patient population.This investigation utilized patient reported data from the FOP Connection Registry. This international registry, spanning 42 counties, was initiated in July 2015 and has aimed to capture FOP patient demographics and disease information on a voluntary basis. The core objectives of this global initiative are to (i) organize the FOP community for potential participation in clinical investigations, (ii) cogitate patient experiences, (iii) inform on treatment outcomes, and (iv) provide a more detailed understanding of the emotional, cognitive, and physical health in FOP patients over time.Participation in the FOP registry was open to all adolescent and adult patients diagnosed with the disease by a physician or confirmed with genetic testing. No exclusion criteria were utilized. Each patient  provided informed consent prior to participation into the registry. Approval of the patient portal, protocol, and informed consent form was obtained from the Chesapeake/Advarra Institutional Review Board . Ethics approval specific to the current study was also obtained from the Boston Children's Hospital Institutional Review Board.The FOP patient cohort currently analyzed does not include all individuals within the registry, but rather those adult patients (≥18 years of age) who were able to provide information on demographics, disease‐specific information  and flare‐up status as well as those individuals who completed the Patient‐Reported Outcomes Measurement Information System (PROMIS) database questionnaires relevant to the focus of this investigation. We also included only FOP patients who remained enrolled in the registry across a 30‐month period  who provided data through the patient portal at enrollment, 6‐month, 12‐month, 18‐month, 24‐month, and 30‐month time points.Pain: “How would you rate your pain on average?”Scale: 0 = no pain; 10 = worst imaginable painCategory 1: No to mild pain: 0 to 3Category 2: Moderate to severe pain: ≥4Emotional health: “How often have you been bothered by emotional problems such as feeling anxious, depressed or irritable?”Scale: Never, rarely, sometimes, often, or alwaysCategory 1: Never and rarely Category 2: Sometimes, often or always Mental health: “In general, how would you rate your mental health, including your mood and your ability to think?”Scale: Excellent, very good, good, fair, or poorCategory 1: Excellent, very good, and good Category 2: Fair or poor Physical health: “In general, how would you rate your physical health?”Scale: Excellent, very good, good, fair, or poorCategory 1: Excellent, very good, and good Category 2: Fair or poor Quality‐of‐life: “In general, what would you say your quality‐of‐life is?”Scale: Excellent, very good, good, fair, or poorCategory 1: Excellent, very good, and good Category 2: Fair or poor Sleep (Non‐PROMIS based): “Do you experience poor sleep quality, take a long time to fall asleep, snore, have excessive leg movements during sleep, or wake up with shortness of breath or difficulty breathing?”Scale: Yes, no, or unsureNeuropathic pain (Non‐PROMIS based): “Have you experienced new or continuing health issues related to the brain and nerves symptoms?” (brief description of neuropathic pain given).Scale: Yes, no, or unsureIn addition to flare‐up status, multiple metrics from the PROMIS‐based questionnaires and other sources were assessed. Between enrollment and 30 months, patients completed the following questions, where responses were subdivided into two categories:n), arithmetic mean, standard deviation, median, minimum, and maximum. Categorical variables were tabulated with frequencies and percentages. Statistical comparisons between two independent binomial proportions were performed using Fisher's exact test, whereas Spearman's rank correlation coefficients were calculated to explore the association between the cohorts or health‐related measure . Statistical significance was assessed at the 5% level.Summaries for continuous variables were reported with the number of observations . Moderate to severe pain levels were in fact frequently associated with the occurrence of flare‐up; however, it is important to note that as high as 55% of patients  who did not experience a flare‐up reported pain ≥4 . Furthermore, from the pool of 99 FOP patients, 13% of individuals at enrollment noted neuropathic pain.In order to elucidate the relationship between flare‐up status and the reported pain severity, FOP patients were subdivided at each time point into patients with and without flare‐up as well as those who experienced no to mild (0 to 3 rating) and moderate to severe 4 to 10 rating) pain levels  occurred in FOP patients with flare‐up, but overall a low percentage of patients reported mental health issues in either flare‐up condition . A higher percentage of patients reported emotional problems in the flare‐up group at each time point; however, cases of anxiety, depression, or irritability were common in the non–flare‐up condition as well, particularly at enrollment and 6‐month time points .A). Across the 30‐month evaluation period, upward of 74% and 48% of patients reported experiencing emotional deficits in the moderate to severe and no to mild pain level subpopulations, respectively . Likewise, FOP patients living with pain also consistently reported a higher degree of fair to poor physical health  and quality of life . Issues related to mental health were not frequent in either low or high pain states , indicating generally intact cognitive capabilities at the group‐level and over time. In Supplemental Fig. 1B‐E, the percentage of FOP patients in either pain state and who did not report emotional, mental, or physical health problems are depicted.FOP patients experiencing moderate to severe pain more frequently reported emotional problems. However, experiencing anxiety, depression, or irritability was a substantial issue in the no to mild pain cohort Fig. A. Acrosely Fig. B. Likewn = 28) and 55% (n = 18) of FOP patient experiencing no sleep problems reported feeling anxiety, depressed, or irritable.In addition to the focus on flare‐up and pain, the association between psychosocial functioning and other health‐related parameters were evaluated. It is noted that apart from the enrollment time point, experiencing fair to poor emotional health did not lead to substantially more FOP patients reporting lower than normal physical health or poor quality of life . As expected, a higher percentage of patients reporting fair to poor quality of sleep did experience emotional and cognitive health problems, yet individuals without sleep problems experienced similar emotional health issues . For example, at enrollment and 6‐month follow‐up, 51%  reporting neuropathic pain; however, caution should be used in interpreting this specific finding, because a neuropathic pain phenotype was not identified during a clinical examination or with tools such as the PainDETECT questionnaire.FOP patients may experience multiple flare‐ups and HO lesions across time and, in some instances, within the same anatomical location.Very little is known regarding the mechanism(s) that drive pain either during or between flare‐up events in FOP, which can contribute to the difficulty in efficiently providing FOP patients with effective analgesia. To date, a variety of analgesic options with mixed efficacy across modalities have been and are commonly employed in FOP.The FOP registry has utilized PROMIS, a system developed by the National Institutes of Health that provides a standardized, flexible, and reliable test bank of patient‐reported outcomes for clinical research.A number of novel insights into the dynamics of flare‐up, pain, emotional health, mental health, physical health, and overall quality of life have been gained from analyzing the FOP Registry. Yet the information gathered and presented herein must be considered with the following limitations in mind. First, following the 6‐month follow‐up time point, the total number of FOP patients subsided substantially. For example, whereas 52 total FOP patients with or without flare‐up and in either pain subpopulation were analyzed at 6 months, this number was reduced to 27 at the 30‐month follow‐up. The cause of this decrease is multifactorial and may stem from the recent launch of the registry, patients lost to follow‐up, or incomplete clinical questionnaires, and patient characteristics . Study participants who entered and remained active throughout the 30‐month period were also likely to be on various medications. Variability in medications consumed across patients and time points may have impacted flare‐up, pain, and other health‐related measures. Finally, although flare‐up episodes in some cases are clearly evident, in some circumstances these subcutaneous events may be difficult to detect in an objective manner. Currently, there is an absence of validated methods and clinical biomarkers that can be used to detect and monitor flare‐ups in FOP patients. If such methodologies were available, it would potentially be more feasible and accurate to determine whether and how pain, emotional health, and related health measures track with flare‐up episodes in FOP.All authors state that they have no conflicts of interest.Supporting Data S1.Click here for additional data file.


Alternatives to postoperative, narcotic pain management following implant-based, postmastectomy breast reconstruction (IBR) must be a focus for plastic surgeons and anesthesiologists, especially with the current opioid epidemic. Paravertebral blocks (PVBs) are a regional technique that has demonstrated efficacy in patients undergoing a variety of breast cancer–related surgeries. However, a specific understanding of PVB’s efficacy in pain management in patients who undergo IBR is lacking.A systematic search of PubMed, EMBASE, and Cochrane Library electronic database was conducted to examine PVB administration in mastectomy patients undergoing IBR. Data were abstracted regarding: authors, publication year, study design, patient demographics, tumor laterality, tumor stage, type, and timing of reconstruction. The primary outcome was PVB efficacy, represented as patient-reported pain scores. Secondary outcomes of interest include narcotic consumption, postoperative nausea and vomiting, antiemetic use, and length of stay.The search resulted in 1,516 unique articles. After title and abstract screening, 29 articles met the inclusion criteria for full-text review. Only 7 studies were included. Of those, 2 studies were randomized control trials and 5 were retrospective cohort studies. Heterogeneity of included studies precluded a meta-analysis. Overall, PVB patients had improved pain control, and less opioid consumption.PVBs are a regional anesthesia technique which may aid in pain management in the breast reconstructive setting. Evidence suggests that PVBs aid in controlling acute postoperative pain, reduce opioid consumption, and improve patient length of stay. However, some conflicting findings demonstrate a need for continued research in this area of pain control. Opioid prescriptions to opioid-naive patients following minor surgery are increasing,21 with these patients having a 4.1% chance of chronic opioid use at 1 year.25 Furthermore, among surgical patients, female gender remains a potential factor for chronic opioid usage due to exhibiting more pain.30Due to the current opioid epidemic in the United States, the use of opioid analgesics has faced intense scrutiny.33 However, there is little evidence and consensus on the efficacy of PVBs in breast cancer patients undergoing prosthetic PMR. The purpose of this study was to conduct a systematic review to assess the effectiveness of PVB in IBR patients with a diagnosis of breast cancer.Such risk factors may contribute to opioid misuse in IBR patients with poorly controlled pain. To improve upon postoperative pain management following PMR in the context of a national, opioid epidemic, it is timely and necessary to understand alternative options. First described in the early 1900s, thoracic paravertebral blocks (PVBs) are a regional anesthetic block where local anesthesia is injected adjacent to thoracic vertebra and beneath the costotransverse ligament to block thoracic spinal nerves after they emerge from the intervertebral formina . We reported in accordance with the preferred reporting items for systematic reviews and meta-analysis guidelines.A comprehensive search was performed using PubMed, EMBASE, and Cochrane Library electronic databases with publication end date of October 2018. No language restrictions were applied. The bibliographies of selected articles were manually checked for relevant references.Studies were included if they described PVB use in prosthetic PMR (TE or implant) following immediate or delayed mastectomy, among women older than 18 years with a diagnosis of breast cancer. Review articles, case reports, conference or meeting abstracts, editorial comments, studies describing PVB for mastectomy only, autologous tissue-based breast reconstruction (ABR), cosmetic breast surgery, and male patients were excluded.Two authors (T.P. and S.D.) independently assessed all titles and abstracts. Studies were subjected to full-text review by 2 authors (T.P. and S.D.) if at least 1 reviewer marked it for inclusion based on the above inclusion criteria. Consensus was reached when all reviewers agreed to include or exclude the study.Data abstraction for the following were retrieved: authors, publication year, study design, patient demographics, tumor laterality, tumor stage, type and timing of reconstruction, and comorbidities. The primary outcome of interest for review was PVB efficacy at pain control. Secondary outcomes of interest included PVB-related complications, morphine consumption, PONV, antiemetic use, and LOS.34 and the methodological index for nonrandomized studies .35Two authors (T.P. and S.D.) performed an independent assessment of the methodological quality and risk of bias in the included studies using the Cochrane Collaboration Risk of Bias tool Although all of the articles included an adequate endpoint relevant to our analysis in this review, there was significant variation in the format in which outcomes were reported. As a result, meta-analysis was not conducted and comparisons among studies were made in a qualitative manner, grouped by outcomes of interest to this study.37 and 5 were retrospective reviews.41 The combined, 7 studies resulted in a total of 877 patients, of which 478 had administration of PVB  alone in 6 studies41 with the seventh study comparing PVB with liposomal bupivacaine (LB) wound infiltration.40 All 5 of the retrospective cohort studies used ultrasound-guided administration of PVB,41 whereas both RCTs used anatomical landmarks to administer PVB.37 Regarding the administration of PVB, 5 studies reported multilevel injections,41 whereas the remaining 2 studies reported single-level injections.39 Due to heterogeneity in outcome definitions, it is unclear if level of administration impacts postoperative pain or opioid use. All 5 of the retrospective cohorts used bupivacaine in the PVB procedures41; however, 1 RCT used levobupivacaine37 and the other RCT used ropivacaine.36The systematic search resulted in 1,516 unique articles. After screening by title and abstract, 29 articles met the inclusion criteria for full-text review. A total of 7 studies were included. Fig.  Two studQuality assessment of the cohort studies using modified MINORS score yielded a range of 18–22. The most common deficiency was lack of prospective calculation of sample size, likely due to the retrospective nature of these studies. The 2 RCTs were reviewed according to Cochrane’s Risk of Bias tool and deemed to have low bias.36Pain scores were reported in 3 studies Table . One stu40 Strazisar et al. studied changes in postoperative pain stratified by activity levels. Resting PVB patients had a significantly lower median VAS score compared with GA-alone patients only in the recovery room. However, “on activity” (activity with the upper extremity), PVB patients had significantly lower median pain scores than GA-alone patients at all postoperative time periods . On activity, median VAS scores on the day of surgery were significantly lower for PVB patients than for GA-alone patients; there was no significant difference in median scores for the first postoperative day between these groups.37 Abdelsattar et al. compared a PVB treatment group to a LB control group, reporting a significantly lower, average VAS pain score only at day 0 among the LB group versus the PVB group. The pain scores were not significantly different for the other postoperative assessment days.40Strazisar et al. and Abdelsattar et al. evaluated pain using the VAS.37 Specifically, Strazisar et al. reported that on average, patients who received PVB with levobupivacaine consumed significantly less piritramide in the first 24 hours after surgery compared with GA-alone patients.37 Wolf et al. reported average, total fentanyl administered preoperatively and intraoperatively, noting that PVB patients were administered less fentanyl compared to patients with GA alone.36Opioid use was reported as consumption of narcotics or morphine equivalents (MEs) in 6 of the 7 studies Table . Both RC41 Aufforth et al. also reported that PVB patients who underwent immediate TE PMR consumed less ME than GA-alone patients during the first postoperative day; however, this difference was not seen between the 2 groups in the recovery room or 0 days following surgery.38Additionally, 2 retrospective studies showed that PVB patients received less postoperative narcotics compared with the comparator. For patients undergoing bilateral PMR, Fahy et al. reported on average, PVB patients consumed significantly less ME than those given GA alone; however, this difference was not observed in patients undergoing unilateral mastectomy with PMR.39 Lastly, Abdelsattar et al. found that PVB patients consumed a significantly higher average of ME compared to LB-only patients in the postanesthesia care unit (PACU) but had no significant difference in postoperative opioid consumption days 0–2.40Glissmeyer et al. reported that PVB patients received less ME compared to non-PVB patients; however, no statistical analysis was conducted.40 Similarly, Fahy et al. reported no significant difference in LOS between patients with PVB compared to GA alone/non-PVB patients, following a multivariate analysis.41Two studies reported LOS as proportion of patients with a LOS less than 36 hours. Abdelsattar et al. reported no significant difference in LOS between the LB group versus the PVB group.33 Strazisar et al. reported that there was no significant difference in LOS between the local PVB group and the standard treatment group.37 Glissmeyer et al. reported PVB patients had shorter LOS (1.3 days) compared to those without PVB (2 days); however, this study did not perform a statistical analysis to determine significance.39One study reported LOS in hours while 2 studies measured LOS in days. Coopey et al. reported that, on average, patients undergoing prosthetic PMR with PVB had a significantly shorter LOS compared to the non-PVB group, regardless of laterality  or type (TE versus immediate implant placement) of PMR.36Lastly, Wolf et al. reported that on general LOS, no significant difference in length of hospital stay was found between the PVB treatment and control groups.36Wolf et al. investigated postoperative nausea scores (reported as NRS ranging from 0 to 10), reporting no significant difference in average scores between the PVB group and the GA-alone group at various intervals (immediately following surgery and up to 22 hours postoperatively). Additionally, they reported no significant difference in the average number of vomiting episodes in the PACU or at time of discharge between the 2 groups.41 Coopey et al. reported a significantly lower proportion of patients with postoperative nausea in the PVB group compared to the non-PVB group, but found no significant difference in the proportion of patients with postoperative vomiting. However, this study did not quantify antiemetic use between the 2 groups.33Fahy et al. used postoperative antiemetic administration as a proxy for postoperative nausea. Analyses showed the PVB group receiving significantly less antiemetics than the GA-alone group, even after controlling for laterality of PMR.40 Strazisar et al. also reported that PVB patients on average consumed significantly less metoclopramide than GA patients.37 Lastly, Wolf et al. found no significant difference in average consumption of antiemetics among PVB patients compared to GA-alone patients.36Abdeslsattar et al. reported a significantly lower proportion of LB patients using antiemetic medication one day following PMR compared to PVB patients.46 In 2016, the CDC released clinical guidelines for chronic pain management, aiming to decrease misuse, abuse, and overdose from opioids. However, there remains minimal guidance for physicians on the management of acute pain, specifically in the perioperative and acute postoperative setting.48 Regional anesthetic techniques, such as PVBs, are an example of a possible method to reducing postoperative pain and initial narcotic utilization with well described, minimal complications.49 This review demonstrates that this technique not only may favor positive postoperative outcomes, but also displays the heterogeneity of existing studies and their slightly conflicting results.In light of the US opioid epidemic, there is an intense focus on finding alternatives to effective postoperative pain control following surgery.37 Furthermore, 4 of 5 studies indicate significant decreases in postoperative nausea and antiemetic consumption. There is positive evidence of PVB’s impact on opioid consumption. Lastly, there is not enough evidence to state PVB significantly reduces LOS with 4 of 6 studies showing no significant difference between PVB and non-PVB groups.41PVB was shown to positively reduce acute postoperative pain and reduce PONV/antiemetic medication consumption in IBR patients. However, there is not enough evidence to draw strong conclusions regarding PVB’s impact on opioid consumption and LOS. Two of 3 studies reporting pain show PVB reduces acute postoperative pain (during the recovery room and within the first postoperative day following PMR) compared to GA alone.38 a finding supported by 2 retrospective studies also indicating significant decreases in opioid consumption among the PVB group.41 However, 1 study showed a decrease in opioid consumption but lacked statistical analysis,39 while another study conversely reports significantly higher consumption of opioids in the PVB group versus the control group receiving LB in the PACU.40 Abdelsattar et al did not use contemporary groups for comparison and found no difference in opioid consumption at later postoperative time points. Due to the strength of evidence from the included RCTs in addition to some evidence from observational studies, PVB does seem to reduce acute postoperative opioid consumption.The 2 RCTs show an overall significant decrease in acute postoperative opioid consumption,50 As such, these patients require more narcotics and other analgesics for their pain management.8 Suboptimal pain management is associated with further negative effects: slowed recovery, increased morbidity, prolonged opioid use during and after hospitalization, impaired physical function, and lowered quality of life.52 Increased, acute postoperative pain is a significant predictor of chronic pain syndromes, which negatively impact quality of life and affects nearly 50% of patients with breast cancer.54 One study reviewed long-term chronic pain, reporting PVB patients had less pain compared to GA alone at 3 months following PMR37; however, the mechanism for developing chronic pain among breast cancer patients following PMR is poorly understood.Several studies have shown that IBR patients are at risk for significant, postoperative pain compared to ABR patients.55 Surgical technique is another possible mechanism for the development of chronic pain in IBR patients. The predominant technique, placement of the implant under the pectoralis muscle, has been associated with increased pain compared to the prepectoral method.7 Manipulation of the muscle could lead to higher rates of referred pain7 or muscle spasming.57 Lastly, psychological factors and psychological vulnerability to pain perception are significantly associated with greater postoperative pain intensity.59Possible factors contributing to the development of chronic pain in this patient population may include: pain due to surgical scars, chest wall pain, upper-arm pain, shoulder discomfort, and/or a neuropathic component that develops into a complex, regional pain syndrome.38 As well, Fahy et al. did not distinguish between mastectomy only patients versus mastectomy plus reconstruction patients; nor did this study detail the scoring system used.41 For LOS, Aufforth et al. displayed a significantly lower LOS for the PVB group versus the non-PVB group and no significant difference in the proportion of patients with PONV. However, these results refer to all included patients, not simply IBR patients.38The results of this systematic review support PVB’s value as an alternative to opioids for controlling postoperative pain among IBR patients. However, this review was limited by the quantity and quality of the available literature. The significant heterogeneity in the results prevented the conduct of a meta-analysis. Aufforth et al. found no significant difference in average pain scores on all postoperative days between the PVB and non-PVB groups, whereas Fahy et al. reported no significant difference in average pain scores between their experimental groups, on the day of surgery. However, Aufforth et al. did not specifically distinguish patients who only underwent IBR.The majority of the included studies were retrospective and observational. Other limitations of reviewed studies include: studies with small sample sizes, use of varying anesthetic agents for PVB injection along with different anesthetics for the control group, the lack of standard postoperative protocols for pain management, lack of controlling for the impact of sentinel lymph node biopsy or axillary lymph node dissection on pain, and different measurement scales for each outcome of interest. An additional limitation is lack of reported costs incurred from using PVB. From a policy perspective, understanding the costs of introducing an intervention is an important factor in considering its overall benefits and should be included in future studies.61 However, to draw strong conclusions about PVB’s effectiveness in IBR patients is dependent on further research. A systematic review conducted by Offodile et al. assessing the effectiveness of PVB in PMR (both IBR and ABR) patients was overall consistent with our findings. The review of Offodile et al. was limited by number and quality of included studies  and heterogeneity of results. Therefore, they reported on the trends of PVB’s efficacy showing some positive impact in improving pain management, decreasing opioid consumption, and reducing LOS while not impacting PONV.62In multiple meta-analyses that included patients undergoing an array of breast surgery procedures (from breast-conserving surgery to cosmetic), PVB has been shown to be a superior and effective treatment for postoperative pain management, limiting opioid consumption, and reducing LOS and PONV compared to GA alone.Despite the limitations, this review is a rigorous synthesis of current literature. Overall, the limited number of studies and heterogeneity of results necessitates further research in examining PVB as an alternative to narcotic, postoperative pain control in the prosthetic PMR patient.Given the current opioid crisis, there is a growing emphasis on non-narcotic alternatives in the perioperative setting. In prosthetic PMR, PVBs may provide an alternative analgesic approach to improve postoperative pain and enhance recovery. Evidence suggests that PVB reduces acute, postoperative pain, improves PONV, and may have a positive impact on reducing opioid consumption. There is not enough evidence to support that PVB is associated with a decreased LOS. More high-quality studies are needed to assess the effects of PVB on perioperative opioid consumption, quality of recovery, and chronic pain in IBR patients.


Post-translational modifications (PTMs) generate a tremendous protein diversity from the ~ 20,000 protein-coding genes of the human genome. In chronic pain conditions, exposure to pathological processes in the central nervous system could lead to disease-specific PTMs detectable in the cerebrospinal fluid (CSF). In a previous hypothesis-generating study, we reported that seven out of 260 CSF proteins highly discriminated between neuropathic pain patients and healthy controls: one isoform of angiotensinogen (AG), two isoforms of alpha-1-antitrypsin (AT), three isoforms of haptoglobin (HG), and one isoform of pigment epithelium-derived factor (PEDF). The present study had three aims: (1) To examine the multivariate inter-correlations between all identified isoforms of these seven proteins; (2) Based on the results of the first aim, to characterize PTMs in a subset of interesting proteins; (3) To regress clinical pain data using the 260 proteins as predictors, thereby testing the hypothesis that the above-mentioned seven discriminating proteins and/or the characterized isoforms/fragments of aim (2) would be among the proteins having the highest predictive power for clinical pain data.CSF samples from 11 neuropathic pain patients and 11 healthy controls were used for biochemical analysis of protein isoforms. PTM characterization was performed using enzymatic reaction assay and mass spectrometry. Multivariate data analysis  was applied on the quantified protein isoforms.We identified 5 isoforms of AG, 18 isoforms of AT, 5 isoforms of HG, and 5 isoforms of PEDF. Fragments and glycosylated isoforms of AT were studied in depth. When regressing the pain intensity data of patients, three isoforms of AT, two isoforms of PEDF, and one isoform of angiotensinogen “reappeared” as major results, i.e., they were major findings both when comparing patients with healthy controls and when regressing pain intensity in patients.Altered levels of fragments and/or glycosylated isoforms of alpha-1-antitrypsin might mirror pathophysiological processes in the spinal cord of neuropathic pain patients. In particular, we suggest that a putative disease-specific combination of the levels of two different N-truncated fragments of alpha-1-antitrypsin might be interesting for future CSF and/or plasma biomarker investigations in chronic neuropathic pain.The online version of this article (10.1186/s12883-018-1116-2) contains supplementary material, which is available to authorized users. Biomarkers would be useful for diagnosis and prognosis of different pain conditions, for the evaluation of treatment response, and for the development of drugs; they could also serve as surrogate endpoints  [A substantial part of our knowledge about the pathophysiology of pain has been acquired through animal experiments. Although there are obvious similarities between species, there are also differences, and translating evidence from animals to humans in this field is far from trivial . The quedpoints) .Post-translational modifications (PTMs) generate a tremendous protein diversity from the ~ 20,000 protein-coding genes of the human genome, the complexity of the proteome being several orders of magnitude greater than the coding capacity of the genome –5. AfterGlycosylation, i.e. when a carbohydrate is attached to a protein, is one type of PTM . The glyIn chronic pain conditions, exposure to pathological processes in the central nervous system (CNS) could perhaps lead to a disease-specific fragmentation process detectable in the cerebrospinal fluid (CSF). Protein fragments are also interesting because their smaller size would enable them to cross the blood-brain barrier (BBB) easier than full-length proteins, and hence fragments would probably be easier to detect in blood .To examine the multivariate inter-correlations between all identified isoforms of these seven proteins, using multivariate data analysis by projection (MVDA) , 19. TheBased on the results of the first aim above, to characterize PTMs in a subset of interesting proteins. Because protein fragments seem especially promising as biomarkers (their generation by disease-specific processes could reduce the overlap between diagnostic groups) , specialReturning to MVDA and focusing on the patients, to regress clinical pain parameters (pain intensity and pain duration), using all the proteomic data (260 proteins) of our previous study as predictor variables . We wantNeuropathic pain is defined as pain caused by a lesion or disease in the somatosensory nervous system . In a prHence, the purpose of the study was not to conduct clinical biomarker research at the validation stage; instead, this was a pre-clinical exploratory study in the early discovery stage , 20.The patients have been described extensively in a previous paper . All paiAfter informed consent, the following data were registered: basic demographic data; pain diagnosis; pain duration; present and past medical history; concomitant medication. A medical examination was performed. All patients had at least probable post-traumatic/post-surgical neuropathic pain according to the criteria published by Treede et al. , and allFor an overview of patients vs healthy controls, see Table Healthy controls were recruited by local advertisement at the Faculty of Health Sciences, Linköping University, Sweden, and by contacting healthy subjects from earlier studies. After informed consent, a structured interview was conducted to ensure the absence of any significant medical condition. The following areas were specifically assessed in the interview: earlier major trauma; back, joints, muscles or skeletal disease; heart or vascular disease; lung or bronchial disease; psychiatric symptoms; neurological, ear or eye disease; digestive tract disease; kidney, urinary or genital disease; skin disease; tumor or cancer; endocrine disease; hematological disease; birth defects; other disease, disability or allergy. Moreover, the presence of a known bleeding disorder was specifically inquired for.The absence of a chronic pain condition was ensured by a structured questionnaire covering sociodemographic data, presence of pain now, location of pain now, generalization of pain, presence of intermittent pain, duration of persistent pain. The questionnaire also covered anxiety and depressive symptomatology using Hospital Anxiety and Depression Scale , coping °C until analysis.For every subject in this study, intrathecal access was obtained by lumbar puncture with a 27 GA pencil-point Whitacre needle  and a 10 ml sample of CSF was drawn in five numbered syringes of 2 ml each. Each sample was immediately cooled on ice and transported to the Painomics® laboratory, Linköping University Hospital, centrifuged and divided in aliquots and stored at − 70The comparative proteomic study between patients and healthy controls was performed as described in our previously study . BrieflyN-glycosidase PNGase F (Sigma Aldrich) at 37 °C overnight using conditions recommended by the supplier and as has been described in detail elsewhere [For the characterization of the different protein isoforms, a pooled CSF sample from patients and a pooled sample from healthy subjects were used. The samples were desalted, lyophilized and dissolved in urea sample buffer solution, as has been described in detail elsewhere . Proteinlsewhere . The propI/MW (http://www.expasy.org/proteomics). The calculated pI/MW of the fragment was controlled to be in agreement with the apparent mass and pI on the 2D-gel.The interesting protein spots were excised from the gels, trypsinated and identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) using Linear Trap Quadropole (LTQ) Orbitrap Velos Pro hybrid (Thermo Fisher Scientific) in conjunction with nano flow HPLC system . Data processing of the spectra was performed using MaxQuant software, and the generated mass list was searched against SwissProt human protein sequence database as previously described . When idTraditional univariate statistical methods can quantify level changes of individual substances but disregard interrelationships between them and thereby ignore system-wide aspects. Therefore, we used SIMCA version 13.0  for MVDA computations. Conceptually, imagine a multidimensional space where each protein is a dimension (“k” dimensions). Each subject (patient or control) will be a point in this k-dimensional space. Due to a combination of technological development (rendering high “k”) and practical/economic constraints (leading to a low number of subjects “n”), todays data tables in the omics field often have a low subjects-to-variables ratio (n < <<k). Classical regression techniques like multiple linear regression (MLR) or logistic regression (LR), which were developed in the early days of the twentieth century, are not suited for such high-dimensional and multi-collinear data. Hence, todays data table often break one of the underlying assumption behind MLR and LR, namely that the predictor (X) variables are fairly independent. MLR and LR also assume that a high subject-to-variables ratio is present , and they have difficulties coping with missing data. Due to the above-mentioned drawbacks of classical regression techniques (with regression coefficients becoming unstable and their interpretability breaking down), the modern MVDA methods of Principal Component Analysis (PCA) and Orthogonal Partial Least Squares (OPLS) regression were used instead. PCA and OPLS can handle subject-to-variables ratios < 1, and they cope well with both multi-collinearity and missing data. OPLS is a recent, easier-to-interpret modification of Partial Least Squares (PLS). The MVDA workflow and the reporting of parameters necessary for evaluating model quality were in accordance with the paper published by Wheelock & Wheelock . For alln = 11) and healthy controls (n = 11), focusing on all the isoforms of the seven proteins mentioned in the introduction. Each isoform had previously been quantified by SOD [2 Critical 95%) and by distance to model in X-space (DModX). The R2 value indicates how well the model explains the dataset, and cross-validated Q2 is a measure of the predictive power of the model. If R2 is substantially greater than Q2 (a difference > 0.3 is mentioned in the literature) [For Aim 1 we used PCA, which is the foundation of all latent variable projection methods, separately for patients (d by SOD . In a muerature) , the roberature) .A PC relates to each original variable by a loading, which has a value between − 1 and + 1. Variables with high loadings (ignoring the sign) are considered to be of large or moderate importance for the PC under consideration. Hence, PCA is a data visualization technique that models the correlation structure of a dataset, presenting the relationship between variables in a loading plot. On a loading plot, variables close to each other are positively correlated, and variables that are unimportant for the model are found around the origin of the plot  .For Aim 3, OPLS was used to regress (predict) two clinical variables in patients: VASPI last week and pain duration. Hence, the outcome variable (Y) was one of these two clinical variables, whereas the predictor variables (X:s) where the relative quantification of 260 proteins by SOD in accordance with our previous study . ConcernIn OPLS, the importance of each variable for the model can be measured as a Variable Influence on Projection (VIP) value. This indicates the relevance of each X-variable pooled over all dimensions and Y-variables – the group of variables that best explain Y. Variables with VIP ≥ 1.0 and having a 95% confidence interval not including zero are usually considered significant, but in this study VIP≥ 1.5 was used. The direction of the relationship (positive or negative) was determined by sign of the corresponding loading.For traditional univariate statistics, all computations were made using IBM® SPSS® Statistics version 23. Spearman’s rho correlation coefficient was used for bivariate correlation analysis, and Mann-Whitney U test or Fisher’s exact test were used for comparing groups . A two-sided significance level of 0.05 was chosen.We identified 5 isoforms of AG, 18 isoforms of AT, 5 isoforms of HG, and 5 isoforms of PEDF – amounting to a total of 33 proteins. Hence, we generated a SIMCA data table consisting of 22 individuals (rows) and spot optical densities from 33 proteins (columns). To enable quick identification when looking at loading plots (see below), AG, AT, HG, or PEDF was added to the original spot number. Moreover, on basis of their location on the gels, five groups of AT were identified, which were referred to by Roman numeral I-V; AT5106 did not belong to any group  was computed. The model had one PC . No multivariate outliers were found. The loadings column plot of the model is depicted in Fig. n = 11). The model had one PC . No multivariate outliers were found. The loadings column plot of the model is depicted in Fig. AG3409: In healthy controls, AG3409 is separated from the four other isoforms of AG, and these four isoforms inter-correlated positively, ie the loading values  were siAT5106: In Fig. IV_AT1505: In both patients and healthy controls, IV_AT1505 is close to zero, meaning that this isoform does not contribute much to the two PCA models. IV_AT1505 also remains fairly isolated from the other isoforms of group IV. The remaining isoforms of group IV of AT positively inter-correlate in a similar way in both health and disease.HG1211, HG1203, HG2205: No clear correlation structure was discernable for these three isoforms. The same was true for the two other isoforms of HG.PEDF3308: It was difficult to discern a clear pattern concerning PEDF3308 and its isoforms.First, an unsupervised PCA model for healthy controls .Based on the above-mentioned correlation between AT5106 and I_AT111 , we decided to focus the biochemical part of the present paper on characterizing some of the post-translational modifications and fragments of AT. The 18 isoforms of AT are highlighted in Fig. AT5106 and I_AT111, which were positively inter-correlated in patients by PCA, were both confirmed to be N-terminal truncated fragments. IV_AT1505 was N-glycosylated.2 = 0.99, Q2 = 0.43), and the results are summarized in Table First, pain intensity data in patients (“VASPI last week”) was regressed, using the 260 proteins from our earlier study as predictor variables (X-variables). The OPLS model on 11 patients with “VASPI last week” as outcome variable (Y-variable) rendered three components (Rand a significant Spearman’s rho correlation coefficient:p = 0.008), Fig. PEDF3308 had VIP = 2.38, which was the second-highest VIP of the model (rank 2 out of 260 proteins). The bivariate correlation between “VASPI last week” and PEDF3308 was positive . Going back to Fig. p = 0.026); in healthy controls, no such correlation existed between I_AT110 and I_AT111 .I_AT110 had VIP = 1.83 (rank 13 out of 260 proteins). The bivariate correlation between “VASPI last week” and I_AT110 was negative , Fig. I_AT111 had VIP = 1.75 (rank 19 out of 260 proteins). The bivariate correlation between “VASPI last week” and I_AT111 was negative , Fig. AG3409 had VIP = 1.73 (rank 20 out of 260 proteins). The bivariate correlation between “VASPI last week” and AG3409 was positive .Moreover, PEDF3211, which was one of the five isoforms of PEDF in Aim 1 above, also had a very high VASPI-VIP , albeit with a non-significant Spearman’s rho , and the results are summarized in Table p = 0.233).Then, pain duration in patients was regressed using the 260 proteins from our earlier study as predictor variables (X-variables). The OPLS model on 11 patients with “pain duration” as outcome variable (Y-variable) had 3 components . The renin-angiotensin system seems to be involved in nociception processing [Although we chose to focus on AT isoforms in the present study, future work on the isoforms of AG and PEDF would be interesting. Concerning AG3409, which had the highest discriminative power between groups in our previous study , it is nocessing , 37, andocessing –40; invesecond-highest VIP of the model (rank 2 out of 260 proteins). PEDF3308 correlated positively with VASPI (Fig. PEDF3308 was down-regulated in patients in our previous study . In the total levels of a particular protein is probably often too simplistic, and an “old” and well-known protein like AT might very well, due to PTMs, mirror disease-specific processes. The familiarity of AT should not make one a priori consider it uninteresting as a biomarker.Going back to AT, one might wonder why such a well-known protein would be a specific biomarker for a pathological pain condition. In this context, it is important to remember that PTMs are very important physiologically. PTMs modulate enzyme activity, protein turnover and localization, protein-protein interactions, various signaling cascades, DNA repair, and cell division . It is bIn the words of Pavlou et al., we have studied “a small number of samples from diseased and nondiseased groups” in order to “identify molecules exhibiting discriminating potential” . To corrOn the basis of the findings reported in the present paper, we present the hypothesis that fragments and/or glycosylated isoforms of alpha-1-antitrypsin might be considered as potential biomarkers of the pathophysiological processes in the spinal cord of neuropathic pain patients. The biomarker potential of protein fragments should be taken into account by pain researchers. Biomarkers with high specificity and sensitivity are difficult to find, and the combinatorial power of a panel of different biomarkers has been suggested as a solution this problem . This isAdditional file 1:Figure S1. Two dimensional gel electrophoregram of CSF proteins. The marked spot numbers refer to the identified proteins in Tables