Opioid analgesics provide effective treatment for noncancer pain, but many physicians have concerns about adverse effects, tolerance, and addiction. Misuse of opioids is prominent in patients with chronic back pain and early recognition of misuse risk could help physicians offer adequate patient care while implementing appropriate levels of monitoring to reduce aberrant drug-related behaviors. In this review, we discuss opioid abuse and misuse issues that often arise in the treatment of patients with chronic back pain and present an overview of assessment and treatment strategies that can be effective in improving compliance with the use of prescription opioids for pain. Many persons with chronic back pain have significant medical, psychiatric and substance use comorbidities that affect treatment decisions and a comprehensive evaluation that includes a detailed history, physical, and mental health evaluation is essential. Although there is no “gold standard” for opioid misuse risk assessment, several validated measures have been shown to be useful. Controlled substance agreements, regular urine drug screens, and interventions such as motivational counseling have been shown to help improve patient compliance with opioids and to minimize aberrant drug-related behavior. Finally, we discuss the future of abuse-deterrent opioids and other potential strategies for back pain management. Chronic back pain negatively impacts every facet of daily living. Chronic back pain, defined as pain that lasts longer than 6 months, has been seen to interfere with individual's quality of life, by interrupting sleep, employment, social functioning, and many other daily activities. Patients with chronic back pain typically report feelings of depression, anxiety, irritability, sexual dysfunction, and decreased energy. Often chronic back pain adversely affects family roles and contributes to worry about financial limitations and future disability –5.Studies analyzing factors affecting health and illness have shown that chronic pain, of which chronic back pain is the most prominent, is a widespread international problem –8. More Opioid analgesics have been used to help manage acute as well as cancer-related pain . This clThe National Comorbidity Survey of Psychiatric Disorders collected epidemiological data, indicating a lifetime prevalence of 7.5% for drug dependence (illicit or prescription drugs) and 14.1% for alcohol dependence for individuals in the United States . The Diahttp://www.cdc.gov/HomeandRecreationalSafety/pdf/poision-issue-brief.pdf,  Accessed 4/16/10). A literature review done by Strain [There has been a steady increase in the use of opioids in the United States . This hay Strain  reportedThe pain literature suggests that physicians are able to better provide suitable treatment and care to patients with chronic pain once substance misuse causes are recognized . Misuse In this paper, we review opioid abuse and misuse issues that often arise in the treatment of patients with chronic noncancer back pain and discuss assessment and treatment strategies that can be effective in improving compliance with the use of prescription opioids for pain. The intent of this review paper is to provide a brief overview of studies on the assessment and treatment of abuse risk on opioid prescribing for chronic noncancer pain. This paper is not a systematic review, but rather a critical discussion of current assessment techniques and procedures within the clinical setting. The paper is divided into the following subsections: (1) definition of terms, (2) adverse effects of opioid therapy, (3) medical comorbidity among pain patients, (4) initial medical assessment, (5) psychiatric comorbitidity, (6) substance abuse assessment, (7) urine toxicology screens, (8) opioid therapy agreement, (9) abuse-deterrent opioids, (10) interventions for high-risk patients, and (11) future considerations.Substance misuse is the use of any drug in a manner other than how it is indicated or prescribed, while substance abuse is defined as the use of any substance when such use is unlawful or when such use is detrimental to the user or others. Addiction is a behavioral pattern of substance abuse characterized by overwhelming involvement with the use of a drug. Addiction is generally understood to be a chronic condition from which recovery is possible; however, the underlying neurobiologic dysfunction, once manifested, is believed to persist [Physical dependence is a common phenomenon of all mammals taking opioids characterized with physical withdrawal symptoms when an opioid is discontinued. Tolerance is also a commonly observed phenomenon when taking opioids over time in which the individual becomes used to the drug and has a need for increasing doses to maintain the same effect. Both physical dependence and tolerance are typically found among patients who use opioids for chronic pain and are unrelated to true addiction. Finally, aberrant drug-related behavior is behavior suggestive of a substance abuse and/or addiction disorder. Examples are selling prescription drugs, prescription forgery, stealing or “borrowing” drugs from others, injecting oral formulations, obtaining prescription drugs from nonmedical sources, multiple episodes of prescription “loss,” repeatedly seeking prescriptions from other clinicians, evidence of deterioration in function , and repeated resistance to change therapy despite evidence of physical and psychological problems.A clear definition of terms helps to minimize confusion and to clarify the objectives of therapy with patients taking opioid analgesics for pain . Substan persist , 23. AddSeveral authors have shown that the majority of those taking opioids for the treatment of pain typically do not develop addiction or substance use disorders , althougThere are a number of adverse effects associated with chronic opioid therapy including nausea, sedation, and opioid-induced bowel dysfunction. There has been a suspected relationship between opioid therapy and a number of conditions such as endocrine deficiencies , dose-reMany patients with chronic severe intractable back pain may present with several significant medical comorbidities that can affect the course of treatment. Some of the most common comorbidities include asthma, chronic obstructive pulmonary disease, diabetes mellitus, coronary artery disease, hypertension, ulcers, kidney, bladder, and liver problems, or cancer. When patients are asked to rate their level of pain, comorbid conditions may contribute to this rating.Some individuals suffering from chronic back pain have a history of unhealthy behaviors including minimal exercise, poor diet, and smoking cigarettes. Over time, they experience weight gain and deconditioning. Many chronic pain patients are on multiple medications prescribed by multiple providers, which include blood thinners, blood pressure and heart disease medications, inhalers, and antidepressants. Several chronic pain patients have allergies and reactions to some medications. They may also have medical devices implanted and wear prostheses. It is essential for clinicians to assess and identify current and past medical conditions to avoid any complications.It should be required for all patients considered for opioid therapy to undergo an extensive initial evaluation, including a thorough medical history, review of past medical records, a urine toxicology screen, and physical examination. For most patients, a psychological evaluation should be conducted, including completion of screening questionnaires. The comprehensive evaluation process should involve identifying other controlled substance prescribers. Opioid prescriptions should only rarely be prescribed to patients on their first visit, and it is important for patients to be informed of the comprehensive assessment process and the policy not to prescribe opioids until all information is obtained. A urine toxicology screen should be obtained at the first visit and compared with the patient's recent medication intake in order to identify any opioid misuse. A diagnosis of the patient's back pain should be documented to provide clinicians with the primary pain site and probable cause of pain. It is essential for all of the patient's providers to communicate with one another in order to properly and effectively manage the patient's care. It is important for clinicians to examine several factors, including a patient's age and gender, to provide the best clinical assessment and treatment for the patient. There is evidence to suggest that younger individuals who are prone to impulsivity have a greater risk for misuse of opioids , 35, 36.Many chronic intractable back pain patients report feelings of depression, anxiety, irritability and have a history of physical or sexual abuse, or a past history of a mood disorder , 39. CloOne study conducted by Arkinstall and colleagues found a 50% prevalence of mood disorder in patients who were prescribed opioids, showing this to be a common diagnosis for chronic pain patients . AnotherPatients with chronic pain and psychopathology, especially those with chronic low back pain, typically have poorer pain and disability outcome from treatments –53. In sMany patients with substance use disorders also have affective disorders. Attempting to manage a comorbid affective disorder may result in decreased substance abuse behaviors, although they may be at risk of relapse –60. HasiThe US Department of Justice recommended efforts to improve identification of abuse and diversion of controlled substances by health care providers . PhysiciThere are a variety of assessment measures that can be used to help identify those patients who are prone to misuse their pain medications . Structuα = .86; AUC  =  .74) and were sufficiently similar to values found with the initial sample. A cut-off score of 18 revealed a sensitivity of  .80 and specificity of  .52. Results of a cross-validation suggest that the psychometric parameters of the SOAPP-R are not based solely on the unique characteristics of the initial validation sample [The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a 24-item self-administered screening tool developed and validated for those persons with chronic pain who are being considered for long-term opioid therapy. The SOAPP-R is designed to predict aberrant medication-related behaviors , 70. Thin sample . α) was.83, which is comparable to the.86 obtained in the original sample [The Current Opioid Misuse Measure (COMM) is a 17-item questionnaire developed and validated for patients who have already been prescribed opioids for chronic pain . The COMl sample . Resultsl sample . Both thOther validated measures have also been developed to screen patients with pain for addiction risk potential. The 5-item Opioid Risk Tool (ORT), a brief checklist completed by the clinician, is a validated questionnaire that predicts which patients will display aberrant drug-related behaviors , 74. ScoIt is important to note that scores of any clinical assessment tool used to determine abuse risk are not necessarily reason to deny opioids, but rather provide an estimate of the level of appropriate monitoring for the patient. Thus, although these clinical assessments are useful to estimate risk of noncompliant opioid use, the results are most useful to help determine how closely to monitor patients during opioid therapy.Patients who are typically at a lower risk for misusing opioids include those who are older, generally compliant, have a record of rarely misusing any medication, show stable mood, are thoughtful and responsible, and generally have an easy-going personality. Risk factors for opioid misuse include (1) family or personal history of substance abuse, (2) young age, (3) history of criminal activity and/or legal problems , (4) frequent contact with high-risk individuals or environments, (5) history of previous problems with employers, family, and friends, (6) history of risk-taking/thrill-seeking behavior, (7) smoking cigarettes, (8) history of severe depression or anxiety, (9) multiple psychosocial stressors, and (10) previous drug and/or alcohol rehabilitation see . PatientClinicians use urine drug screens in order to closely monitor patient's adherence to their prescribed opioid medication. Highly sensitive and specific urine screens  help to identify presence and quantities of prescription medications, presence of illegal substances, and/or absence of prescribed medications. Even though many patients prescribed opioids do not misuse their medication, it still is important to document compliance for all patients on chronic opioid therapy by obtaining a urine screen at least yearly. The combination of urine screens, self-report questionnaires, and behavioral observation methods has allowed physicians to properly identify which patients are misusing their prescribed opioids. One study gathered urine toxicology results among 122 patients who were prescribed opioids for noncancer pain and found abnormal results in 43% of this sample . AnotherIncreasingly, patients with chronic pain are using marijuana for the treatment of their symptoms, and evidence of THC in the urine has become more prevalent . There iControlled-substance agreements are frequently used in clinics to clarify the roles of the patients and providers and to ultimately improve patient compliance with their opioid medication. These documented agreements provide education and mutual consent among patients and providers and inform patients of their responsibilities when using prescribed pain medication. A controlled-substance agreement should state that the patient is only allowed to remain in the program if they adhere to the termed conditions . The folThe core elements to the controlled substances agreement should be made clear so the patient knows exactly what is expected of them. When the patient signs this agreement, they are acknowledging their consent to the proposed treatment plan and agree to adhere to the specific conditions and responsibilities set by the clinic. It is imperative for all individuals placed on chronic opioid therapy to read and sign an opioid therapy agreement. In this way, patients can be informed of their responsibilities and work to remain compliant with their prescribed medication while avoiding complications. Physicians should periodically request that the patients complete an opioid compliance checklist, which serves to remind patients of their responsibilities for using opioids for pain . Gourlay and colleagues created a rational approach to opioid therapy for the treatment of chronic pain using universal precautions . This coSeveral new opioid formulations that are designed to prevent or deter the abuse of opioids are currently in development, and two have been approved for marketing  and a new formulation of the extended-release oxycodone (OxyContin)) . Abuse-dThere are still many issues that are yet to be addressed about their integration into clinical practice and their true abuse liability in real-world scenarios. The cost of these new preparations will likely present a challenge, particularly for insurance carriers and pharmacy managers attempting to justify their use based on cost-benefit analyses. The only substantial real-world experience with these types of formulations is with Suboxone even though this combination of buprenorphine and naltrexone is not approved for the treatment of pain. One study suggested dose escalation is typically greater with pure formula opioids and is not associated with the clinical severity of low back pain, or pain resulting from surgery . http://www.choosehelp.com/news/getting-high-on-suboxone-the-fda-says-its-happening-ex-nida-director-blames-doctors.html, Accessed April 23, 2010). Yet even with a certain level of abuse, Suboxone therapy is still considered the safest treatment for opioid addiction. One double-blind study compared buprenorphine transdermal system to placebo and found this treatment to be effective for the management of moderate to severe chronic low back pain for patients who have previously received opioids for their pain [Another study suggested that introduction of Suboxone did not reduce buprenorphine injection in Malaysian substance abusers . Recent eir pain . The SubN = 21) or experimental compliance treatment consisting of monthly urine screens, compliance checklists, and individual and group motivational counseling . Twenty patients who met criteria indicating low potential for misuse were recruited to a low-risk control group (Low-Risk Control). Patients were followed for six months and completed pre- and poststudy questionnaires and monthly electronic diaries. Outcomes consisted of the percent with a positive Drug Misuse Index (DMI), which was a composite score of self-reported drug misuse (Prescription Drug Use Questionnaire), physician-reported abuse behavior (Addiction Behavior Checklist), and abnormal urine toxicology results. After six months, significant differences were found between groups with 73.7% of the High-Risk Control patients demonstrating positive scores on the DMI compared with 26.3% from the High-Risk Experimental group and 25.0% from the Low-Risk Controls (P < 0.05). The results of this study demonstrate support for the benefits of a brief behavioral intervention in the management of opioid compliance among chronic back pain patients at high-risk for prescription opioid misuse. At followup, none of the subjects was dismissed from the clinic due to aberrant drug behavior, which was possibly a partial effect of the attention from being in a study and completing monthly electronic diaries. Overall, this study demonstrated a positive effect of improving opioid compliance, particularly among those patients at high risk for misuse of opioids. The results of this study are encouraging and suggest that compliance training and very careful monitoring of those patients determined to be at high risk for opioid misuse can be incorporated as part of an anesthesia-based multidisciplinary pain program to help improve compliance with opioids and to reduce the number of those individuals who are discharged from treatment because of aberrant drug-related behavior. Although further research is needed, this trial demonstrates that substantial improvement in compliance with prescription opioids for many high-risk pain patients is possible within a pain management center.Chronic pain patients who show aberrant drug-related behavior often are discontinued from treatment when they are noncompliant with their use of opioids for pain. A randomized trial of patients prescribed opioids for noncancer back pain who showed risk potential for or demonstration of opioid misuse was conducted to see if close monitoring and cognitive behavioral substance misuse counseling could increase overall compliance with opioids . Forty tAs the world population ages and life expectancy increases, greater attention will be given to managing medical comorbidities, including chronic back pain. The practice of pain management will likely be changing within the next five to ten years in a number of ways. First, opioids will continue to be prescribed as a treatment for noncancer back pain; however, a balance will likely be reached in effectively managing pain while also addressing the problems with addiction, overdose, and death that these medications can cause. In line with this change, new formulas of abuse-deterrent opioids will continue to be developed and greater attention will be given to educating physicians and patients about proper dispensing, storing, and disposing practices associated with the use of opioids. Also, healthcare practitioners will be encouraged to have specialty training and certification in the proper dispensing of opioids. Second, software programs with interactive, dynamic education for prescribers, pharmacists, and patients will continue to be developed and made available to the general public. Greater attention will also be given to outcome studies on the risk factors that predict misuse of opioids. Third, many other fruitful and exciting areas of study will improve the way pain is managed. Genetics testing holds much promise for the identification of markers for potential opioid misuse. Our understanding of opioid-induced hyperalgesia and craving within certain individuals will also contribute to the identification of sensitive markers for opioid misuse. In particular, complex endogenous chemical reactive systems that affect tolerance and potential opioid misuse will likely be reliably identified. Also, longitudinal investigations on demographic factors such as gender, ethnic origin, and personality predispositions that influence the use of opioids will improve practice guidelines. Fourth, additional studies on other treatments for back pain such as the use of cannabinoids and their role in symptom reduction could add to the current pain management armamentarium. Also, the development of other delivery systems such as topical preparations will offer a wider array of treatment options. The exciting area of nanotechnology to deliver a drug to a particular area should also greatly enhance treatment options. Finally, a greater understanding of how an acute back pain problem develops into a chronic pain syndrome with subtle effects that this process has on centralized mechanisms will open up interventions that are currently not available. Although the management of chronic back pain will always be a challenge, the future will likely hold answers for improved treatment for those who suffer with chronic pain.Comprehensive assessment and monitoring is recommended for all patients who are on long-term opioid therapy for chronic back pain. The close monitoring of patients who are at greatest risk for misuse of their prescribed medication should contain a treatment protocol that includes an opioid agreement, regular urine toxicology screens, compliance checklists, pill counts, and, if indicated, motivational counseling. Careful monitoring and use of abuse-deterrent opioids will hopefully decrease the abuse potential of prescribed opioids; however, risk of opioid misuse and addiction will remain, and close attention to screening and documentation of treatment outcomes will continue to be the gold standard of opioid therapy.


Chronic pain is increasingly recognized as a consequence of stroke. This study aimed to describe the prevalence and pain types of new onset chronic pain (“novel pain”) in patients with stroke compared with a randomly selected reference group from the general population and to identify factors associated with pain development in stroke patients.In a population-based follow-up design, development of chronic pain after stroke was assessed by a questionnaire sent to consecutive stroke patients, registered in a Danish national stroke database, two years after their stroke. A randomly selected sex- and age-matched reference group from the same catchment area received a similar questionnaire about development of new types of chronic pain in the same time period. A total of 608 stroke patients and 519 reference subjects were included in the study.Development of novel pain was reported by 39.0% of stroke patients and 28.9% of reference subjects , and was associated with low age and depression in a multivariate model. Daily intake of pain medication for novel pain was reported by 15.3% and 9.4% of the stroke and reference population, respectively. Novel headache, shoulder pain, pain from increased muscle stiffness, and other types of novel pain were more common in stroke patients, whereas joint pain was equally common in the two groups.Development of chronic pain is more common in stroke patients compared with sex- and age-matched reference subjects. Evaluation of post-stroke pain should be part of stroke follow-up. Stroke is the third leading cause of mortality and the major cause of long-term disabilities, such as hemiparesis, language problems and cognitive deficits, in the developed world Post stroke pain (PSP) is often considered to be identical to central post stroke pain (CPSP) also known as thalamic pain e.g. . HoweverWe combined clinical data from a national database of consecutive patients admitted with a stroke with data from a postal questionnaire mailed 2 years after stroke. The aim of the study was 1) to describe the prevalence and pain types of new onset chronic pain (“novel pain”) in stroke patients compared with a randomly selected sex- and age-matched reference group from the general population and 2) to identify factors associated with pain development in stroke patients. Part of this study has been reported elsewhere All hospitalized acute stroke patients in Denmark are diagnosed according to the WHO criteria (ICD-10) and registered in a National Indicator Project database (NIP) All patients hospitalized with a stroke diagnosis in the County of Aarhus  between March 1, 2004 and February 28, 2005 The questionnaire included sections on demographics, medical and stroke history, increased muscle tone and spasms, sensory symptoms, pain, and concomitant diseases  was defined as constant or remitting pain lasting more than 3 months and with onset at or after the stroke in patients and within the last 2 years in reference subjects. Subjects reporting development of novel pain were asked specifically about pain due to increased muscle stiffness, headache, shoulder pain, other joint pain, or “other pain” and to fill out a section on pain interference, including questions on how the pain affected their sleep, quality of life, mood, social life, and activities of daily living. Each pain interference item was rated on a 5 point scale: not at all, a little, some, quite a lot, and very much.Subjects indicating development of “other pain” were asked to indicate the area of pain on a body chart; to score the intensity of their worst pain within the last week on a numeric rating scale (NRS) from 0–10, where 0 equals “no pain” and 10 “worst possible pain”; and to answer questions about the pain quality (from S-LANSS) The study was approved by the local ethical committee , the steering group of the NIP database, and the Danish Data Protection Agency (ID 2006-41-6779) and was performed according to the Declaration of Helsinki. An accompanying letter was sent out with the questionnaire. Only patients who gave written consent to further contact were solicited by telephone. This procedure was approved by the ethical committee.Only subjects who had completed the screening question on novel pain  were included. Pain frequencies are based on the total number of included responders unless otherwise stated; responders with missing information to an item were excluded from the specific analysis.Age was divided into 3 strata . Statistical analysis was performed using Intercooled Stata version 9.1 software . Data are presented as mean and standard deviation (SD), with 95% confidence intervals (CI) or as median with 10% and 90% percentiles (p10-90) or range. P-values less than 0.05 were considered statistically significant. Parametric data were analyzed using Student's t-test. Non-parametric data were analyzed using Mann-Whitney and Kruskal-Wallis (rank sum). Dichotomous data were analyzed using Pearson's chi-square test and Fisher's exact test. Odds ratios are presented with 10% and 90% CI. A logistic regression analysis was performed to clarify the impact of variables identified to be associated with development of novel pain in the whole cohort and in stroke patients separately.A total of 1411 patients were registered with stroke in the database. Of the 964 surviving stroke patients, 644 returned the questionnaires (response rate of 66.8%); 550 returned the primary questionnaire and 94 the reminder . A totalA total of 570 out of 957 reference subjects returned the questionnaire (59.6%): 517 returned the primary questionnaire and 53 the reminder. Of the responders, 51 were excluded due to either stroke (n = 42) or an incomplete pain section (n = 9), leaving 519  included reference subjects (54.2%) .The median response proportion to each question was 94.7% (range 82.2–100%). The lowest response proportion was observed in the questions describing the impact of pain on social life.Stroke patients had a higher response proportion than reference subjects. There was no statistically significant difference in gender distribution and age between stroke patients and reference subjects . Female Development of novel pain after stroke or within the last 2 years was reported by 39.0% (35.1–43.0%) of stroke patients compared with 28.9% (25.0–33.0%) of reference subjects, OR 1.57 (1.21–2.04) . The higIn a univariate model, stroke was associated with a higher odds ratio (1.57) for development of novel pain as compared to the reference group , model 1Daily intake of pain medication was required by two-thirds of the subjects with development of novel pain, corresponding to the use of daily pain medication for novel pain in 15.3% of the stroke population and 9.4% of the reference population (p = 0.003). Pain interference was higher in stroke patients compared with reference subjects with respect to quality of life (p = 0.006), mood (p = 0.003), social life (p<0.001), and activities of daily living (p<0.001), but not with respect to interference of sleep (p = 0.69) (mean response rate 83.5% (81.9–85.3%)). In the subjects reporting development of novel pain, there was a significant association between high pain interference and depression in stroke subjects (p<0.001), but not in control subjects (p = 0.15).Development of headache was more common in stroke patients than in reference subjects , OR 4.97 (2.62–10.23) , Table 2Development of shoulder pain was more common in stroke patients than in reference subjects , OR 1.64 (1.12–2.40) . In stroDevelopment of pain from other joints was equally common in stroke patients and reference subjects , OR 1.25 (0.92–1.69), but more common in women compared with men (p = 0.002). Novel pain from multiple other joints was common in stroke patients and included pain in hips, ankles, feet, knees, neck, back, wrist, fingers and elbows.Muscle stiffness or spasms were reported by 32.8% of stroke subjects compared with 9.8% of reference subjects (p<0.001), OR 4.50 (3.16–6.46). Pain directly due to muscle stiffness or spasms was reported by more than half of the subjects with these symptoms, corresponding to 17.4% of stroke patients and 5.2% of reference subjects (p<0.001), OR 3.82 (2.41–6.28) .In stroke patients, 22.9% had developed other pains  compared with 13.5% of reference subjects (p<0.001), OR 1.90 (1.37–2.64) . In stroThe localization of other pain is summarized in Stroke patients were more likely to report development of more than one concomitant pain type compared with controls . The likelihood of reporting several novel pain types concomitantly decreased significantly with age in stroke patients (p<0.001), but not in reference subjects (p = 0.40).The stroke diagnosis did not differ between stroke patients with or without development of novel pain (p = 0.32), but the median SSS score on admission was lower, i.e. indicating a more severe stroke, in stroke patients reporting novel pain than in patients without novel pain (p = 0.0018) . A histoIn a multiple logistic regression of all included stroke patients (n = 608) , low ageTo our knowledge, this is the first published population-based study on PSP including a control group. Stroke patients compared with age and sex-matched reference subjects more often reported development of novel pain including pain due to increased muscle stiffness, headache, shoulder pain, and other types of novel pain. Two-thirds of the patients with development of novel pain were taking daily pain medication, corresponding to 15% of the total stroke population. Taken together these findings indicate that novel pain after stroke is a symptom with a major impact on the stroke patient, in addition to the other well-known motor and cognitive sequelae that often accompany stroke. Former studies have shown that stroke represents the disease condition associated with the highest degree of disability In an univariate model in this study, stroke patients were more likely to report development of chronic pain following stroke (39.0%) compared with reference subjects (28.9%), developing pain within the last 2 years (OR: 1.57). The difference between the two groups  can be interpreted as the proportion of pain that is stroke related, and supports findings from other studies per se. The difficulty in dissecting the relationship between depression and pain in general and pain due to stroke in particular is underscored by the fact that a) risk of depression is increased after stroke When correcting for possible confounders in a multiple regression analysis that included depression, there was a significant reduction in the difference in odds between stroke patients and reference subjects. These findings suggest that the higher odds for pain development in stroke patients were partly due to an associated depression, rather than stroke In this study, and also in a recent study The presence of specific subtypes of pain was assessed by asking about pain due to increased muscle stiffness including spasms, headache, shoulder pain, other joint pain, and “other pain”. The reported proportion of muscle stiffness or spasms was higher in stroke patients compared with reference subjects (OR: 4.50), and more than half of these subjects reported pain directly due to these symptoms. Our findings are in accordance with previous studies reporting a prevalence of spasticity of 17–38% using clinical assessment scales The strength of this study is the inclusion of a sex- and age-matched reference group randomly chosen in the same area as the stroke population. The inclusion of a control group is important, as chronic pain is common in all population groups, and in particular among the elderly The present study population was selected from a stroke database including 95% of all stroke patients in the area The present study has a few shortcomings. The response rate was not high, but is consistent with response rates of other questionnaire studies in stroke survivors In conclusion, pain represents an important disability following stroke. In this population-based study, which included a sex and age-matched reference group, about 40% of the stroke patients had developed chronic pain within two years of their stroke and this pain was associated with depression and low age.Figure S1English translation of the questionnaire to the stroke subjects.(DOCX)Click here for additional data file.Figure S2English translation of the questionnaire to the reference subjects.(DOC)Click here for additional data file.Figure S3Localization of other novel pain. The reported location of worst “other pain” in stroke patients (red bars) and reference subjects (blue bars). A hemibody distribution of pain, i.e., pain localized to one side of the body, with or without involvement of the face and trunk, and pain in parts of both upper and lower limbs, was more common in stroke patients than in reference subjects , whereas pain with other localizations, including wide spread pain, pain in multiple sites, back pain and neck pain, was more common in reference subjects .(TIF)Click here for additional data file.Table S1Characterization of the included stroke patients at time of stroke based on NIP data.(DOC)Click here for additional data file.Table S2Characterization of stroke patients and reference subjects with development of all types of novel pain and subtypes of pain.(DOC)Click here for additional data file.


The setting is a high-volume single center hospital, specializing in TEP hernia repair. All patients are operated on by one of four surgeons. Adult male patients (≥18 years of age) with primary, reducible, unilateral inguinal hernias and no contraindications for TEP repair are eligible for inclusion in the study. The primary outcome is substantial chronic postoperative pain, defined as moderate to severe pain persisting ≥ 3 months postoperatively . Secondary endpoints are the individual development of pain until three years after the TEP procedure, the quality of life (QoL), recurrence rate, patient satisfaction and complications.Large prospective randomized controlled studies with a long follow-up evaluating the incidence of chronic postoperative pain following implantation of lightweight and heavyweight mesh in endoscopic (TEP) hernia repair are limited. By studying the presence of pain and quality of life, but also complications and recurrences in a large patient population, a complete efficiency and feasibility assessment of both mesh types in TEP hernia repair will be performed.The TULP study is registered in the Dutch Trial Register (NTR2131) Inguinal hernia repair is one of the most common surgical procedures worldwide. In The Netherlands, approximately 30,000 hernia repairs are performed annually. The lifetime risk of undergoing a hernia operation is 27 % for men and 3 % for women . The incChronic pain after inguinal hernia surgery is a common complication. The incidence of chronic postoperative pain after inguinal hernia repair, as described in the literature, varies significantly 10 to 30 %), which is partially explained by the lack of a clear definition 0 to 30 %. The effIn experienced hands, endoscopic hernia repair techniques are associated with significantly less postoperative pain and an earlier return to normal activities compared to conventional (Lichtenstein) hernia repair ,6,7. TotIn addition, since TEP is associated with less chronic postoperative pain compared to a conventional repair (Lichtenstein), an endoscopic TEP hernia repair with implantation of a lightweight mesh could, therefore, be an appealing technique in the prevention of chronic postoperative pain after groin hernia surgery.The aim of this manuscript is to describe the rationale and design of a large, prospective, double blind, randomized clinical study comparing the results of chronic postoperative pain and quality of life following endoscopic TEP hernia repair with a heavyweight (Prolene) and a lightweight mesh (Ultrapro).This is a prospective, double blind, randomized clinical trial involving a high-volume hospital in The Netherlands specialized in the TEP technique for inguinal hernia repair . All hernia operations are performed by four experienced TEP surgeons. Adult ≥18 years) male patients with primary, unilateral inguinal hernias, eligible for TEP hernia repair, are allocated to either lightweight mesh  or heavyweight mesh  by randomization. The total follow-up of patients is three years. A flowchart of the study with the estimated recruitment targets is shown in Figure 8 years mA total number of 950 patients will be included in the trial (see “Sample size considerations”). Patients are recruited during their first visit at the outpatient clinic of the participating hospital. Patients are screened for eligibility according to the criteria listed in Table The study information is sent to patients after an appointment is made for an initial consultation. The appointment with one of four surgeons specialized in TEP hernia repair is scheduled within one week. After screening for eligibility criteria, informed consent is obtained and the patient is included in the study. Preoperative patient data are obtained by the coordinating investigator Table .Patients are randomly assigned to either Ultrapro or Prolene mesh in the operating room  by computerized block randomization. Follow-up of patients will take place according to the intention-to-treat principle. The patient, coordinating investigator and the surgeon involved in the follow-up of enrolled patients are blinded for the allocated mesh. Obviously, the operating surgeon cannot be blinded to the study because of the characteristic composition of the two meshes. To avoid bias, the mesh type is not mentioned in the operating chart. In addition, the follow-up is not by the operating surgeon, but by one of the other three surgeons specialized in hernia repair.The perioperative care and surgical technique do not differ between the study groups and are not different from the standard procedure. There are no other interventions than the implantation of a lightweight mesh (Ultrapro) or a heavyweight mesh (Prolene) during the TEP endoscopic procedure. General anesthesia is applied in all patients. The operative details of the TEP technique have been described previously ,17. The Prolene® is a non-soluble, so-called heavyweight mesh. It is thStructure: Monofilament with small poresPolymer: Polypropylene2Weight: 80 to 85 g/mDimensions: 10 x 15 cmUltrapro® is a lightweight mesh ; the monStructure: Monofilament with large pores (3 to 4 mm)Polymer: Polypropylene (PP) and Monocryl (Poliglecapron)2 , when necessary and avoid strenuous physical activity  during the first post-operative week. There are no other  restrictions. The type and amount of analgesics used during the first postoperative week are kept in a pain diary.Several questionnaires are used for the assessment of pain and quality of life .1) To assess the presence of postoperative pain, the following validated questionnaires are used:Inguinal Pain Questionnaire  Brief Pain Inventory, Short Form  ,20Carolinas Comfort Scale  Numerical Rating Scale 2) To measure the health related Quality of Life (QoL) the following validated questionnaires are used:Short Form (36) Health Survey  EuroQol 5D  et al.[3) Finally, to assess the presence of pain related to sexual function, the PSF  questionnaire is used, which is a Dutch translation of the questionnaire similar to the one previously described by Aasvang et al. and baseet al. to assesThe patient is requested to record – on a daily basis during the first week immediately following surgery – the pain experienced, as well as the type and amount of analgesics used.The NRS is used to assess the amount of experienced pain, where 0 = no pain and 10 = extremely painful. BPI and SF-36 questionnaires are filled in at Day 1 and Day 7 following surgery, to determine the effect of pain on daily activities.After 6 weeks and 3, 12, 24 and 36 months, the IPQ, BPI, CCS, NRS, PSF, SF-36 and EQ-5D questionnaires are completed by the patients. To prevent bias, the questionnaires will be completed at home, or at the visit to the outpatient clinic at three months and one year postoperatively, in the absence of the surgeon or coordinating investigator, before the clinical assessment at the outpatient clinic. Patient satisfaction with the operative procedure is assessed at one week and three months after surgery on a 0 (= very unsatisfactory) to 10 (= very satisfactory) Likert scale.All patients are examined in the outpatient department by one of the four surgeons (different from the operating surgeon) and the coordinating investigator at three months and one year after surgery. The physical examination is, if necessary, supplemented with an Ultrasound or MRI scan in patients with groin pain and/or complaints suggestive of a recurrent hernia.All visits include standardized clinical evaluation  by Loos ) and regComplications after surgeryShort term Long term The presence of a recurrent herniaThe presence of a contra-lateral herniaOther non-hernia related problems in the groin region Postoperative painCharacteristics of painThe relation of pain to daily activities, physical activity and/or sexual activityPossible treatment of painMesh feelingSensibility disorders in the inguinal/scrotal/thigh/umbilical region or elsewhereThe primary endpoint is the presence of moderate to severe chronic pain three months after an endoscopic preperitoneal (TEP) hernia correction, as measured by the NRS. The definition of the International Association for the Study of PAIN (IASP) is used with chronic postoperative pain being defined as pain still present at the site of the operation three months after the primary surgery and different from the pain before the operation. Pain is measured on a 0 (= no pain) to 10 (extremely painful) scale. In accordance with the literature, the following cut-off values for pain are used: Mild pain: NRS 1 to 3Moderate pain: NRS 4 to 6Severe pain: NRS 7 to 10Moderate to severe pain is considered as clinically relevant . Only moDuration of hospital stayComplications: intra-operative, post-operative period (until three months after surgery), long-term Time to resume daily activities and return to workRecurrent herniaContra-lateral herniaDevelopment of pain over time as measured by the NRS score at the first week following TEP repair and 6 weeks, 12, 24 and 36 months postoperativelyDevelopment of pain over time as measured by the BPI, IPQ and CCS questionnaires: the presence of pain in the first week postoperatively and after 6 weeks, 3 months, 12, 24 and 36 monthsDevelopment of pain, sensitivity disorders  and or discomfort . Before the start of this study, every surgeon had performed over 20 procedures with an Ultrapro mesh, to prevent the occurrence of a ‘learning curve’ effect with a new mesh in the study period. Serious adverse events (SAE), other than SAEs that might eventually occur following endoscopic TEP repair  are not expected to occur in this trial.The most common definition of chronic postoperative pain is from the International Association for the study of pain (IASP), where chronic pain is defined as pain lasting longer than three months following the primary operation, and other than the pain that was experienced preoperatively. The hypothesis is that the incidence of chronic pain is lower after implantation of a lightweight mesh (Ultrapro) than after implantation of a heavyweight mesh (Prolene). Based on a pilot study in our hosopital the assumption is made that 23% of the patients with a Prolene mesh will experience pain three months after TEP repair. In the Ultrapro group a reduction of 7.5% in the incidence of pain is expected. With a two-sided alpha of 0.05 and a power of 0.80, a total of 429 patients are to be included in each allocation group. Based on previous experience, a loss to follow-up of 10% is expected. Therefore, a total of 950 patients will be included in the TULP trial.t-test , Mann–Whitney analysis  or Chi-square analysis . The individual development of pain over time will be analyzed with repeated measurement strategies. Effect estimators are described with 95 % confidence intervals. Significance is set at a level of p ≤ 0.05.Data will be analyzed according to the intention-to-treat principle. SPSS software  will be used for statistical analysis. Descriptive statistics are used for baseline data. The incidence of the primary endpoint (moderate to severe chronic pain three months after endoscopic TEP repair as based on a NRS 4 to 10) will be compared between the Ultrapro and Prolene mesh group by means of Chi-square analysis. The comparisons of pain will be adjusted for analgesics used as a secondary supporting analysis. The number-needed-to-treat to prevent one case of chronic pain will be calculated. In an additional multiple logistic regression model, the effect of treatment on the primary endpoint will be assessed in relation to important risk factors for pain . SecondThe TULP trial is a prospective, randomized controlled (RCT) clinical trial of a lightweight mesh (Ultrapro) and a heavyweight mesh (Prolene) in endoscopic TEP hernia repair designed to analyze the outcomes regarding chronic postoperative pain and quality of life.Although a limited number of randomized studies assessing the outcomes after implantation of a lightweight and heavyweight mesh in endoscopic TEP hernia repair has been published previously, the TULP trial is, to our knowledge, the first randomized controlled trial with a large patient population and a long-term follow-up assessing pain as a primary endpoint and the effect of pain on quality of life. The main challenges that we anticipate are the recruitment and follow-up of trial participants, . We aim to maximize participant follow-up by face-to-face contact (at three months and one year after TEP repair) and telephone contact as a reminder to return the questionnaires.There are some limitations of this study. Due to the different characteristics of the meshes, blinding of the operating surgeon is not possible. Nevertheless, the investigator-related bias for the (primary) endpoints is expected to be negligible, since both the coordinating investigator as well as the surgeon involved in the follow-up of the patients, are blinded for the type of mesh. In this study, the same investigator will be present during all patient visits at the outpatient clinic in order to improve consistency of the results and reduce the loss-to-follow-up rates.In addition, the setting of this study is a high volume center, specialized in endoscopic TEP hernia repair. Despite an inclusive set of patients, a criticism might be that the findings may not be easily generalized to other, less experienced, TEP surgeon settings. On the other hand, the TEP technique has a long(er) learning curve. Expertise is, therefore, a prerequisite in performing TEP and most centers deliver TEP in the hands of expert surgeons, which enables extrapolation of the results of this study.This prospective, double blind, randomized clinical trial is designed to compare the incidence of chronic postoperative pain following the implantation of heavyweight (Prolene) and lightweight (Ultrapro) mesh in endoscopic TEP hernia repair. As the presence of pain in the groin region, quality of life, return to daily activities and work, patient satisfaction, complications and recurrences are assessed in a large cohort of patients with a sufficient long follow-up period, this study will provide a complete efficiency and feasibility assessment of both meshes in endoscopic TEP hernia repair.This study has been approved by the regional Medical Ethics Committee  and the local Ethics Board of the Diakonessenhuis Utrecht, the Netherlands. This study is performed in accordance with the ethical standards of the Declaration of Helsinki. Recruitment of patients started on 12 March 2010. To date (1 July 2011), 569 patients have been included in the study. Depending on the number of patients needed to be included in the trial (see sample size considerations), recruitment of the 950 patients is currently expected to end in June 2012. Analysis and reporting of data are subsequently expected eight months (outcomes three months after TEP repair) and three and one half years (outcomes three years after TEP repair) later to be complete (October 2012 and October 2015 respectively). The TULP study is registered in the Dutch Trial Register (NTR2131).ASA score: American Society of Anesthesiologists score; BMI: body mass index; BPI: Brief Pain Inventory; BP-SF: Brief Pain Inventory, Short Form; CCS: Carolinas Comfort Scale; CONSORT: Consolidated Standards of Reporting Trials; EPD: electronic patient chart; EQ-5D: EuroQoL 5D; IASP: International Association for the Study of PAIN; IIEF: International Index of Erectile Function; IPQ: Inguinal Pain Questionnaire; NRS: numerical rating scale; PSF: Pain-related Sexual Function Questionnaire; QoL: quality of live; RCT: randomized controlled trial; SAE: serious adverse events; SF-36: Short-form 36; TAPP: Transabdominal preperitoneal; TEP: totally extraperitoneal.All authors of this manuscript, and the individuals mentioned in the ‘Acknowledgment’ section, hereby confirm that a Research Grant has been assigned to the Diakonnessenhuis Utrecht/Zeist, or more specifically to the Hernia Centre Zeist, by Johnson & Johnson. The Research Grant is intended to support all (completed) manuscripts on the results and complications of the Totally Extraperitoneal (TEP) endoscopic hernia repair. The Grant will not exceed an amount of € 40.000.This study itself is not directly the subject of the above mentioned Research Grant or any other financial sponsorship. Johnson & Johnson or any other party has and will have no access to data upon which the manuscript is based. A copy of the manuscript will only be provided at acceptance of the manuscript. Johnson & Johnson has no influence on the (subject of) this study whatsoever. Objectivity of data is, therefore, guaranteed and there is no conflict of interest.There are no (other) commercial associations that might pose a conflict of interest in connection with the submitted article.NS provided the conception and design of the article and contributes in the coordination of the study (as the coordinating investigator). NS and JPJB are responsible for the design of the initial protocol and follow-up of the study. JPJB is also responsible for revising the manuscript critically for important intellectual content. SGE provided the statistical analysis and advice. EJMMV, PHPD and GJC were all responsible for the acquisition of data and critically revising the manuscript. All authors gave final approval of the version to be published.


Procedural burn pain is the most intense acute pain and most likely type of burn injury pain to be undertreated due to the physician’s fear of the adverse effect of analgesia and lack of anesthetist present. At our institution, in most of the cases, local burn detersion and debridement were performed at the ward level without any analgesics. This article describes a study designed to test the analgesia effect of a fixed nitrous oxide/oxygen mixture on burn dressing pain.The experiment was carried out in three centers. The patients were given a number from 1 to 240. A randomization list was produced by a statistician according to our preliminary study. Due to the severity of the pain suffered, ethically it was decided to help as many as possible, so patients given the letters A, B or C were treated using a canister with the appropriate letter containing preprepared nitrous oxide/oxygen mixture (NOOM). Those with D were given oxygen only, from an identical-looking canister labeled D. Neither patients, nor doctors, nor nurses, nor data collector knew what was in each canister, thus they were all blind. The nursing officer who implemented the intervention handed the doctors envelopes containing the patients’ name and allocation of A, B, C or D. Thus, patients receiving NOOM or oxygen were in the ratio 3:1. Parameters, including pain severity, blood pressure, heart rate, digital oxygen saturation and the Chinese version of the burn specific pain anxiety scale (C-BSPAS), were taken before, during and after dressing for each group. A video and audio record was taken individually for later communication coding and outcome analysis. Rescue analgesic was recorded.Based on the findings from our previous qualitative study that physician’s reluctance to order narcotic analgesia is due to its adverse effect and from our pilot experiment, this study aims to test the hypothesis that a fixed nitrous oxide/oxygen mixture will promote better burn dressing pain alleviation and outcomes. Analyses will focus on the effects of the experimental intervention on pain severity during dressing (primary outcomes); physiological parameters, C-BSPAS and acceptance of both health care professionals and patients (secondary outcomes). If this model of analgesia for burn pain management implemented by nurses proves successful, it could potentially be implemented widely in hospital and prehospital settings and improve patients’ satisfaction and quality of life.. Burn injuries are caused by contact with flame, steam, hot fumes, hot liquid, a hot surface, electrical current, or extremely acidic or alkaline chemicals. In China, there are 5 to 10million burn victims each year . Acute pA China National Knowledge Infrastructure search of the Chinese-language publications from 1994 to 2011 was conducted using the keywords ‘burn pain’ ‘pain management’, and ‘pain control’. This search produced 898 results, of which 21 were found to be relevant to the treatment of burn pain. Seven of the twenty-one were reported using nonpharmacological intervention with three reported by our team using wrist acupuncture to relieve procedure pain for patients undergoing dressing . Our preHowever, nurses, being around patients’ bedsides and taking care of patients 24 hours a day, are concerned about patients’ comfort. Fortunately, we learned that diluted nitrous oxide is of analgesic effect, so we hypothesized that it may be the most suitable analgesic to meet the need of burn dressing pain management. The analgesia effect of a fixed nitrous oxide/oxygen mixture on burn dressing pain (AEFNOOMBDP) study is a nurse-led, patient-participated, multicenter randomized controlled trial. This article describes the rationale underlying the study, the AEFNOOMBDP study protocol, the design and administration of the study, and the planned analytic approach. Results from the study are expected to be published in 2012.20) is an inhaled anesthetic gas possessing analgesic properties at lower concentrations. It is an effective, short-acting analgesic with few side effects and is widely used in obstetrics departments and has also been used prior to a variety of minor surgical procedures [20 research in prehospital emergency medical service (EMS) systems across the United States [20 possesses several properties that make it ideal for bedside use in the accident and emergency department. It is easy to administer, requires no intravenous access before its administration, and the patient may control the level of analgesia by removing the gas. It possesses a rapid onset of clinical effect (less than two minutes), and after termination of administration, its effect disappears almost as quickly. It has very few side effects, all of which are self-limited and are generally resolved with termination of exposure to the gas. N20 is widely used in facilities possessing anesthesia services. The apparatus to deliver the gas is inexpensive and portable, and easy for nursing staff to manipulate. But its use in burn dressing pain analgesia alone is rarely reported. We hypothesize that nitrous oxide/oxygen mixture (NOOM) does not completely abolish the pain felt during wound dressing, but rather lessens the intensity and severity of any discomfort that is felt.Nitrous oxide  (n = 60) and group UTN  n = 180) intervention on burn procedure pain in three burns centers under audit for quality control. Research members will be deployed to each study field for measurement taking and evaluating of the results. We choose to randomize individual patients and double-blind because pain threshold varies individually and also due to the placebo effect of the cylinder. The overall study design is depicted in Figure 80 intervEthical approval was obtained from Shanghai’s Changhai Hospital Ethics Committee CHEC2011-105). Verbally consenting patients completed a study enrollment pack containing a written consent form and a Chinese versioned burn specific pain anxiety scale (C-BSPAS). Patients eligible for enrollment in the study included all cognitively intact, Chinese speakers aged three to sixty-five from participating burn centers, selected for 1 to 70% of total body surface area (TBSA) burn and who reported moderate to severe burn dressing pain .TBSA was diagnosed by doctors. Moderate pain severity was defined as a score of four or greater  for worst pain during dressing. Specific inclusion and exclusion criteria are presented in Table 1-105. Ve2) and C-BSPAS were taken two minutes prior to intervention, during dressing, immediately after dressing, and 10 minutes after dressing. Video and audio recordings were taken individually for later communication coding and outcome analyzing. Rescue analgesic was recorded.Process of allocation concealment; The experiment was carried out in three centers. The patients were given a number from 1 to 240. A randomization list was produced by a statistician according to our preliminary study. Due to the severity of the pain suffered, ethically it was decided to help as many as possible, so patients given the letters A, B or C were treated using a canister with the appropriate letter containing preprepared NOOM. Those with D were given oxygen only, from an identical-looking canister labeled D. Neither patients, nor doctors, nor nurses, nor data collector knew what was in each canister, thus they were all blind. The nursing officer who implemented the intervention handed the doctors envelopes containing the patients’ name and allocation of A, B, C or D. Thus patients receiving NOOM or oxygen were in the ratio 3:1. A sample size of 240 was established and randomized into two groups, for which patients with at least moderate pain severity  during dressing were randomly assigned to receive usual pain treatment plus oxygen (UTO = 60) and usual pain treatment plus preprepared NOOM  intervention two minutes before dressing based on the current clinical practice, respectively. For each group, intervention outcome including pain severity (VAS), blood pressure (BP), heart rate (HR), digital oxygen saturation (SpOBlinding: The double-blind RCT list was held by a researcher. The researcher (a nursing officer), who held the randomizing list was blind too. The list only showed groups A, B, C and D, but did not indicate what treatment these letters stood for. Oxygen intervention was used as a control group. The rules were that the cessation of blinding would take place only after all the trials had been completed.Indicators present for the expected change in pain between the control and treatment interventions will be examined. The anticipated pain score (VAS) during dressing will be reduced to three to five in the UTN group. The physical parameters such as blood pressure, digital oxygen saturation should be maintained within normal range in the treatment group. The anticipated C-BSPAS will be much lower in the treatment group than that in the control group, and both patients’ and doctors’ satisfaction with the use of the treatment intervention should be obtained after dressing.Demographic characteristics were assessed using administrative records, the screening interview, and the enrollment interview. Pain severity was evaluated with VAS  on the Changhai pain scale, where zero represents no pain and ten unbearable pain. The scale chosen for pain assessment was categorized as mild (VAS 0 to 4.0), moderate (VAS 4.1 to 6.0) and severe (VAS >6.1)). Physiological parameters: heart rate, blood pressure and digital oxygen saturation were monitored with Infinity Vista XL . Psychological reactions were measured with the C-BSPAS using five items focusing on dressing-pain-related anxiety. Patient’s satisfaction and the health care professional’s acceptance of diluted nitrous oxide on burn dressing analgesia were audio recorded with an aigo R5518 digital voice recorder . Clinical data, including burns diagnosis, analgesic prescription and hospital cost were obtained via a chart review using a standardized form.A prospective sample size calculation was performed by a senior academic statistician using SAS POWER procedure during the protocol-writing stage. It aimed to determine a target sample size that would provide 90% power for two-tailed testing (at a type-1 error rate of 5%) of each of the measures. According to the result of our preliminary study, a sample size of 12 was targeted as being sufficient to achieve the required effective sample size, but to meet the Chinese Food and Drug Administration standard for safety and feasibility of nursing staff implementing this inhalation analgesic, the targeted sample size of 240 was recommended.The first patient was enrolled on 14 October 2011. A DSMB was established shortly after the project launch and met several times during the data collection period. Members included two pain management specialists; four burns-trained nursing officers and doctors; and a senior academic statistician who served as the Board's chair.In subsequent publications, we will report results pertaining to the analgesic effects of NOOM on burn dressing pain. Primary outcomes will include: 1) pain severity during dressing, measured as the mean of average and worst pain, and 2) burns-dressing-induced anxiety. The physiological parameters and satisfaction of both health care providers and patients are considered as secondary outcomes. Finally, exploratory analyses will assess the interaction between the intervention and age, sex, and racial minority. The primary estimates of the effects of the intervention on each of these outcomes will come from repeated measure analyses, following the intent-to-treat principle.The AEFNOOMBDP study is a multi-site randomized control trial of a nurse-instructed and patient-controlled intervention designed to reduce pain severity during dressing for burn survivors. Due to special dislike of opioids analgesic in both physicians and patients, burn dressing pain is untreated in China. It is difficult to change attitudes within a short time and most doctors said that burn pain was inevitable and there was no way to control it. Patients screaming out due to dressing pain can be seen. Our previous qualitative study showed that Chinese burn physicians were eager for a safe, effective and economic analgesic regime to control burns dressing pain. Literature suggested that it was safe for a nursing team to provide diluted nitrous oxide analgesia.A major challenge encountered during implementation of the study was the barrier from the institution and anesthetists due to the confusion of the anesthesic effect of pure nitrous oxide with the analgesic effect of diluted pure nitrous oxide. Seeking approval, we initially recruited ambulatory patients in the outpatient dressing room and took video and audio records to convince the consultants and physicians prior to our preliminary study.In summary, the AEFNOOMBDP study is in its initial stage and is currently being carried out in one of the three burn centers. Nursing staff were trained to deliver diluted nitrous oxide during burn dressing. Subsequent analyses will focus on the effects of the experimental intervention on dressing pain, anxiety and satisfaction from both doctors and patients.The study protocol was proposed and carried out in one of the three burn centers.Li Yuxiang, Tang Lu and Yu Jianqiang contributed equally to this work.The authors declare that they have no competing interests.LYX and TL generated the idea and orchestrated implementation of the protocol. ZJJ managed the project and contributed to the design and statistical analysis plan. ZWF planned the clinical conversation analysis. THT, NW and HXY contributed specialty expertise in pain management. XSC, XZF, WY Sand DXY coordinated implementation of the study at the multicenter site. YJQ and YM coordinated implementation at the academic site. ZWN and MXQ contributed to all aspects of design and analytical planning. WGY, HWJ and MGX served as lead health educators for training nursing staff. All authors read and approved the final version of the manuscript.


Abdominal pain in chronic pancreatitis (CP) is the most common symptom with a highly unfavorable impact on the quality of life. It has been shown that bilateral thoracoscopic splanchnicectomy (BTS) may produce marked pain relief for the majority of patients. The aim of this study was to evaluate the effectiveness of BTS in pain control and quality-of-life improvement in patients with a severe form of CP.Between April 2000 and April 2009, a total of 30 patients qualified for BTS due to CP-related pain. Their age ranged from 28 to 60 years. A 12-month follow-up period was planned for all the patients enrolled. To evaluate effectiveness of BTS, an 11-point Numeric Rating Scale (NRS) and the Quality of Life Questionnaire C-30 (QLQ-C30) in its basic form, developed by European Organization for Research and Treatment of Cancer, were used. An NRS value between 0 and 3 was considered a positive postoperative pain control result.p < 0.05) at 12 months was achieved in 24 patients (80 %). The initial change in quality of life was not significant but it gradually improved with time .The bilateral splanchnicectomy procedure was performed successfully in 27 of 30 qualified patients. A positive effect based on decreased pain (This study showed that BTS is safe and efficacious for pain alleviation in patients with severe CP. It may significantly increase the chances of a long-lasting, life-changing improvement in the quality of life. Chronic pancreatitis (CP) is a long-lasting inflammatory process responsible for irreversible degeneration of pancreatic tissue, which is gradually replaced with fibrous tissue . CP riskWith the exception of autoimmune and some obstructive forms of the disease, there is no causative treatment for CP. Its symptomatic management is based on pain control, pancreatic enzyme supplements, compensation of carbohydrate metabolism disturbances, and prevention of malnutrition. A vital part of the treatment process is abstinence from alcohol and smoking cessation, as well as obeying strict dietary rules. As pain management in CP has proven to be challenging, invasive methods like celiac plexus neurolysis and surgical denervation of the pancreas have been proposed for cases where resection and drainage procedures are not indicated or when their benefit-to-risk ratio has deemed them not plausible . UnilateIn this study we aimed to assess the efficacy of bilateral thoracoscopic splanchnicectomy in providing pain relief and quality-of-life (QOL) improvement in the immediate postoperative period and during 1 year of follow-up in patients with severe chronic pancreatitis.The study protocol was reviewed and approved by the Institutional Ethics Committee. Of the 52 consecutive patients hospitalized between April 2000 and April 2009 in the Clinic of General and Digestive Tract Surgery, Medical Center for Postgraduate Education in Warsaw due to the symptoms of CP, 30 underwent the bilateral thoracoscopic splanchnicectomy (BTS) procedure. The diagnosis of CP was based on the clinical assessment , as well as the results of the imaging studies . All patients met the specific inclusion criteria: diagnosed small-duct CP, poor or no response to noninvasive treatment, average pain intensity >7 points in NRS, and sufficient mental capacity to fill out the Quality of Life Questionnaire. They all agreed to participate in the study and signed the informed consent form. Patients with large pancreatic cysts, significantly distended pancreatic duct (when drainage procedures are recommended), diagnosed massive adhesions in the pleural cavity, and intellectual disability were excluded from the study. Following the procedure, a follow-up period was set at 12 months for all the patients included in the study; it was based on the prescheduled outpatient visits in the pain clinic. Three of the patients had been unsuccessfully treated with neurolysis of the celiac plexus in another center. Pain intensity was measured using the Numeric Rating Scale (NRS), which ranged from 0 to 10, where 0 was no pain and 10 was the worst pain imaginable. Quality of life was assessed using the Quality of Life Questionnaire version 30 (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC) . The orit test or the Mann–Whitney U test, depending on the difference of variances of the tested samples. The Kolmogorov–Smirnov test was used to test for normality. To investigate the relationship between NRS and QLQ-C30 results, Pearson’s correlation was calculated. For all data analysis, p < 0.05 was considered statistically significant.All the patients were informed about the purpose and the protocol of the study. How to use the NRS and fill out the QLQ-C30 questionnaire was thoroughly explained to them. Cronbach’s α was used to test the reliability of the answers. Cronbach’s α is a coefficient of internal consistency that is calculated using three variables: number of test items (questions), interitem variance, and variance of the sum of answers. The value of 0.7 or above is indicative of good reliability. Statistical analysis used to establish the significance of changes in pain intensity and QOL was based on the The surgical procedure used was based on the technique described by Cuschieri et al. . After cn = 28) completed the 12-month follow-up period. None of the patients reported procedure-related pain, which could be diagnosed as intercostal neuralgia requiring treatment. The change in NRS-assessed pain severity is shown in Fig. p < 0.05), and the NRS score remained at a relatively similar level for the rest of the follow-up . Of the 28 subjects whose complete data were available at 12 months, 10 had completely discontinued analgesics, 16 had significantly reduced the dose of pain medication, and 2 patients treated with neurolysis of the celiac plexus had stayed on the same dose of pain medication. Of the 25 patients in whom bilateral splanchnicectomy was technically performed and who completed the full observation period, 24 patients (96 %) achieved significant pain reduction at 12 months (NRS 0–3). With respect to the whole study population, the success rate at 1 year was 24 of 30 (80 %). Bilateral splanchnicectomy was successfully performed in 27 of the 30 patients who qualified for the procedure; hence, the statistical analysis was done on data derived from 27 cases. The demographics of the study group are given in Table p > 0.05) postoperatively, and the tendency toward improved QOL continued throughout the follow-up period, resulting in a score of 70.53 ± 20.47 (p < 0.001) at 12 months. The correlation between NRS results and the QLQ-C30 pain scale outcomes was calculated in order to confirm good correspondence between the means of pain measure used in the study. As shown in Fig. p < 0.05, and 60.21 ± 28.52 vs. 77.38 ± 23.44, p < 0.05, respectively). In 12 patients, the improvement in QOL was sufficient enough for them to fully return to work and continue their professional life. Cronbach’s α for most of the multiquestion scales of QLQ-C30 was above 0.7, apart from physical (0.58) and role (0.55) scales, indicating good overall reliability of the questionnaire outcome.Improvement in QLQ-C30—measured quality of life is shown in Fig. This study has shown the good effect of bilateral splanchnic denervation in controlling chronic pancreatitis-related pain and quality-of-life improvement. The complexity of the pain’s origin and of the routes it follows is the possible reason for the low effectiveness of the therapy aimed solely at pancreatitis , 23.The afferent pain pathway from the pancreas starts in the celiac plexus and runs to the sympathetic trunci on both sides of the spine and on to the central nervous system. Splanchnic nerves arise from the thoracic sympathetic ganglia: the greater splanchnic nerve at T6–T9 and the lesser splanchnic nerve at T10–T11. In some cases the least splanchnic nerve might be identified stemming from the 11th–12th thoracic ganglion . SplanchUnlike neurolysis of the celiac plexus, it was indicated that complete transection of the splanchnic nerves within the thoracic cavity was capable of providing long-lasting or even permanent pain relief in chronic pancreatitis. The least invasive technique of denervation is thoracoscopic splanchnicectomy (TS). The first TS was performed by Wittmoser . In 1993Debilitating pain in chronic pancreatitis is difficult to manage not only because of the complex nature of the disease but also because it usually occurs in a troublesome group of patients, in whom compliance and quality-of-life assessment may prove to be more challenging than usual. In this study, variation in pain intensity and QOL was successfully measured over 12 months in 28 (93.3 %) cases. Possible immediate analgesic effectiveness of BTS is reported to be as high as 80 %, with minimal risk of complications (morbidity rate 10 %) , 27, 28.The present study summarizes the results of a 1-year follow-up of patients who underwent BTS in our center over 10 years. The follow-up continues and its results will hopefully add to the discussion on the long-term efficacy of this relatively minor and feasible procedure for attenuating intractable pain in chronic pancreatitis. It seems that the important task for the future is to identify possible factors predictive of outcome that would guide the clinicians in the decision-making process when it comes to matching the right patient with the right treatment.


Comfrey has a centuries-old tradition as a medicinal plant. Today, multiple randomized controlled trials have demonstrated the efficacy and safety of comfrey preparations for the topical treatment of pain, inflammation and swelling of muscles and joints in degenerative arthritis, acute myalgia in the back, sprains, contusions and strains after sports injuries and accidents, also in children aged 3 or 4 and over. This paper provides information on clinical trials and non-interventional studies published on comfrey to date and further literature, substantiating the fact that topical comfrey preparations are a valuable therapy option for the treatment of painful muscle and joint complaints. Copyright © 2012 John Wiley & Sons, Ltd. For centuries, comfrey has been used as a traditional medicinal plant for the treatment of painful muscle and joint complaints . ComfreySymphytum officinale L. positively for the treatment of blunt injuries  fraction (> 1000 kD) in a test model of fibroblasts in a collagen matrix. Both inhibited shrinkage of the collagen matrix  or the leaves (Symphyti folium) are also utilized for medical purposes . The indSymphytum × uplandicum Nyman, Traumaplant®) was examined for its wound-healing effects (n = 137) with fresh abrasions. The subjects included 64 patients of up to 20 yr of age . An otherwise identical low-dose preparation  was used as a reference.A topically applied preparation containing 10% active ingredient from the aerial parts of comfrey (p < 5 × 10−21) was found. From linear regression time to complete healing was determined to be 2.97 days faster with verum than with the reference . The physicians rated efficacy as good to very good in 93.4% of cases, as compared with 61.7% in the group treated with the reference product (p = 2 × 10−11). A subgroup analysis found no significant influence of abrasion area, gender or age on healing effects, albeit that a tendency towards better effects with increasing age was observed. No adverse effects or problems with drug tolerability were observed.After 2 to 3 days, a significantly and clinically relevantly faster initial reduction in wound size of 49 ± 19% versus 29 ± 13% per day in favour of verum  was used as a reference. This double-blind, reference-controlled, randomized, multicentre trial included 215 patients with pain in the lower and upper back. The primary efficacy parameter was pain in motion, assessed with the aid of a visual analogue scale. Secondary efficacy parameters included pain at rest, pain on palpation and functional impairment. With high concentrations of the treatment product, amelioration of pain on active motion (p < 5 × 10−9), pain at rest (p < 0.001) and pain on palpation (p = 5 × 10−5) was significantly more pronounced than with the reference product and was clinically highly relevant. A number needed to treat of 3.2 was calculated from the study results. Global efficacy was significantly better (p = 1 × 10−8) and onset of effect was faster (p = 4 × 10−7) with the high-concentration product. Tolerability of the highly concentrated study product was reported good to excellent in all patients.The same topical Symphytum x uplandicum Nyman], corresponding to 25 g of fresh herb per 100 g of cream) in acute ankle joint distortions, particularly with regard to pain reduction (p < 0.001) on days 3, 4 and 7. Compared with the reference product, reduction of swelling on days 3 and 4 was equally significant (p < 0.01). One comment on the trial emphasized that using a comparator containing very little of the active ingredient instead of a placebo might be a good approach for clinical trials with herbals, when blinding is difficult  is well established. Relevant medicinal products are now marketed in more than 10 countries and the present licences include the topical treatment of pain, inflammation and swelling of muscles and joints in the case of degenerative arthritis, acute myalgia in the back, sprains, contusions and strains after sports injuries and accidents, also in children aged 3 and over. Corresponding randomized clinical trials and non-interventional studies studied the efficacy of comfrey root extract ointment for treatment of various muscle and joint complaints , 2007.A double-blind, placebo-controlled, multicentre, randomized clinical trial with parallel group design was conducted over a period of 5 days (The primary efficacy variable was the area under the curve (AUC) of the Visual Analogue Scale (VAS) on active standardized movement values at visits 1 to 4. The pain intensity on VAS was assessed at performance of standardized, muscle group specific tests. The secondary objectives were back pain at rest using assessment by patient on VAS, pressure algometry , global assessment of efficacy by the patient and the investigator, intake of analgesic medication and functional impairment measured with the Oswestry Disability Index.p < 0,001). Compared with placebo, superiority of the verum treatment was significant with regard to secondary efficacy variables (each p < 0.001). Both the AUC of the reported back pain at rest, the AUC of the pressure algometry in the trigger point as well as the global assessment of the efficacy by the patients and the investigators showed a clinically relevant effect in reducing acute back pain. For the first time, a fast-acting effect of the ointment (1 h) was also observed. After 1 h the pain intensity had already decreased about 33.0% in the comfrey group  and 12.0% in the placebo group  indicating an early onset of the treatment effect. A total of seven patients experienced adverse events in the course of the clinical trial, four in the comfrey extract group and three in the placebo group. Eczema, cold, nausea and rhinitis occurred in the verum group, headache (n = 2) and pruritus in the placebo group. All adverse events were of mild severity.There was a significant treatment difference between comfrey root extract and placebo regarding the primary and secondary variables. The pain intensity on active standardized movement decreased on average (median) approximately 95.2% in the comfrey extract group  and 37.8% in the placebo group  . The secondary target criterion reduced by 60.4 mm (58.0%) in the verum group and 14.7 mm (14.1%) in the placebo group, the difference of 45.7 mm (43.9%) again being significant (p < 0.001).Pain, functional impairment and stiffness are the most important symptoms patients seek to relieve. Therefore, the primary target variable was the VAS sum score of pain at rest and pain on movement. A secondary target variable was the Western Ontario and McMaster Universities (WOMAC) score. During the course of the study, the total score of the primary target variable decreased by 51.6 mm (54.7%) in the verum group and 10.1 mm (10.7%) in the placebo group, a significant difference of 41.5 mm (44.0%) between groups (p < 0.001 for each parameter). A total of 22 AEs occurred in 22 patients . No adverse drug reaction was reported in the active therapy group.Superiority of improvement in the verum group was also evident with respect to four explorative secondary parameters: SF-36 , angle measurement (mobility of the knee), CGI  and global assessment of efficacy by physicians and patients  and at the final assessment the reductions in tenderness compared with initial values were 2.44 kp/cm2 in the verum group compared with only 0.95 kp/cm2 in the placebo group. Compared with placebo, superiority of the verum treatment was significant with regard to reduction in pressure pain , ankle oedema , ankle mobility  and global efficacy (p < 0.0001). A comment valued the trial as a well-executed and designed randomized clinical trial (RCT) with clearly shown beneficial effects  received either a 6-cm-long ointment layer of the aforementioned comfrey root extract cream (n = 82) or of diclofenac gel containing 1.16 g of diclofenac diethylamine salt . On day 4, a statistically significant reduction of the pain on pressure (p = 0.0449), and on day 4 (p = 0.0368) and day 7 (p = 0.0074) a statistically significant reduction of the pain on movement was recorded. Further, the physicians (p = 0.0130) as well as the patients (p = 0.0111) rated the global efficacy of the comfrey preparation significantly higher than the efficacy of the diclofenac gel.A re-evaluation of the trial data in accordance with Committee for Proprietary Medicinal Products guidelines  even revComments on the trial appreciated the proof of efficacy compared with the chemical comparator  and refen = 20) or with placebo (n = 21)  were treated topically with the same cream as above  on the process of healing of experimentally induced UV-B erythema were studied in 29 volunteers in a controlled pharmacological trial . The antThe results of the non-interventional studies are in line with the results of the aforementioned clinical trials. In particular, data for children aged 3 to 12 yr is available.In a non-interventional study of a comfrey root extract cream containing 35% of a comfrey root extract ) the tolerability and efficacy were examined in 306 children aged 3 to 12 yr . The preIn a post-marketing surveillance study, 163 patients with a mean age of 45.3 yr applied the same comfrey root extract cream for several conditions, the most frequent being contusions (33.1%), painful joint complaints (27.6%), sprains (26.4%) and painful muscle complaints 23.3%; . Most paIn a simultaneous surveillance study, 162 patients applied a similar preparation, a paste containing 30% of the above mentioned fluid extract of comfrey roots . They alA cream consisting of a combination of 35% of comfrey root fluid extract and 1.2 % methyl nicotinate is available in Germany, Luxembourg and Switzerland. A further simultaneous non-interventional study of this preparation included 162 patients . The meaA total data analysis of the previous three post-marketing surveillance studies is also available . The finThe effects of dermatological preparations containing 5% or 10% of a comfrey root extract  on the process of healing of experimentally induced UV-B erythema were studied in 29 volunteers in a controlled trial. The antiinflammatory potency of the extract was found to be equal to or greater than that of diclofenac. A positive correlation could be demonstrated between efficacy and the concentration of a caffeic acid derivative in the extract, but not for allantoin .Comfrey root has also been used for knee joint injuries and non-active gonarthrosis, as well as in the treatment of tendinitis syndrome, insect bites, mastitis, fractures, skin inflammation, multiple abscesses of sweat glands, gangrenous ecthymas, furuncles, dicubital ulcers and chronic varicose ulceration, as prior studies and individual case reports reflect  for a pyrrolizidine alkaloids (PA)-free comfrey root liquid extract  mentioned comfrey in his enlarged version of hysitian . He statToday, this historical statement is widely supported by modern clinical data. Several recent randomized clinical trials substantiate the efficacy of topical comfrey preparations in the treatment of pain, inflammation and swelling of muscles and joints in the case of degenerative arthritis, acute myalgia in the back, sprains, contusions and strains after sports injuries and accidents, also in children aged 3 and over.Christiane Staiger is an employee of Merck Selbstmedikation GmbH. A few products in the company's portfolio contain comfrey root extract.