Therapies that target the prostacyclin pathway are considered effective, yet are complex to dose and may cause dose-limiting side effects for patients with pulmonary arterial hypertension (PAH). Careful side effect management and the ability to discern side effects from worsening disease are essential in order for patients to continue, and benefit from, prostacyclin therapy. This manuscript was developed through a collaborative effort of allied health providers with extensive experience in managing patients with PAH who are treated with medications that target the prostacyclin pathway. This article provides an overview of individual prostacyclin pathway therapies approved in the United States, side effects most commonly associated with these therapies, and practical suggestions for side effect management. Most patients will experience significant side effects on prostacyclin therapy. Creating a proactive and careful side effect management program will increase the likelihood that patients are able to stay on therapy and receive the benefits afforded by prostacyclin therapy. If left untreated, the right ventricle will ultimately fail, leading to death.3Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and vasoconstriction of the pulmonary arterial bed, leading to increasing pulmonary vascular resistance (PVR) over time.5 The broader term “pulmonary hypertension” is categorized into five World Health Organization (WHO) groups according to clinical presentation, pathological findings, and hemodynamic characteristics.5 WHO Group 1 includes patients with PAH, which is the focus of this manuscript and is the only cohort of patients for which prostacyclin therapies are approved.PAH can only be diagnosed by right heart catheterization (RHC) and is defined as a mean pulmonary capillary pressure ≥25mmHg, pulmonary capillary wedge pressure ≤15 mmHg, and a PVR >3 Wood Units.6 Fourteen medications targeting these pathways are approved by the Food and Drug Administration (FDA) for treatment of PAH, seven of which target the prostacyclin pathway.1 Due to the high level of evidence of efficacy, prostacyclin is generally thought to be the standard of care for PH patients with advanced disease.1Three pathways, endothelin, nitric oxide, and prostacyclin, are involved in PAH pathophysiology.2 (PGI2), or prostacyclin. This prostacyclin deficit contributes to the vasoconstriction, vascular proliferation, and platelet aggregation seen in patients with PAH. Prostacyclin's main target, the IP receptor, is expressed in the pulmonary vascular smooth muscle cell layer.7 Activation of the IP receptor stimulates adenylyl cyclase leading to increased cyclic adenosine monophosphate, which increases protein kinase A activity. This leads to vasodilation, antithrombosis, and anti-proliferative effects on vessel walls.613 Synthetic prostacyclin analogues were developed to replace the endogenous prostacyclin deficiency in patients with PAH. The parental PGI2 analogues tend to be more complex to administer and have more side effects than other classes of drugs used to treat PAH; therefore, PGI2 analogues are often reserved for patients with more advanced disease.11In patients with PAH, prostacyclin synthase is reduced leading to inadequate production of prostaglandin I11 with PAH and can lead to discontinuation. This article will review the management of the common side effects of FDA-approved medications that target the prostacyclin pathway 15 was approved in 2008, which was developed for room-temperature stability.Epoprostenol sodium (Flolan®)Both formulations of epoprostenol have a short half-life of 2–3 min and require continuous administration with an ambulatory, infusion pump through a tunneled central venous catheter or a peripherally inserted central catheter (PICC) line.16 A meta-analysis of epoprostenol studies revealed a 70% mortality risk reduction.17 Due to its superior efficacy, epoprostenol is considered first-line therapy for patients with PAH who have advanced disease and/or functional class (FC) IV symptoms.1 Common side effects of epoprostenol include nausea, vomiting, diarrhea, headache, hypotension, flushing, dizziness, jaw pain, and musculoskeletal pain 19 Common side effects include vasodilation (flushing), cough, headache, jaw pain, nausea, hypotension, and vomiting ,21 and extended-release tablets for oral dosing (Orenitram®).22Treprostinil is a tricyclic benzidine prostacyclin available in several formulations: intravenously and subcutaneously (Remodulin®),20Subcutaneous (SQ) treprostinil was approved in 2002 in the US. This formulation has a 4-h half-life and offers patients the benefits of prostacyclin therapy without an invasive central venous catheter and the associated risk of central line blood stream infections. SQ treprostinil is administered through a small catheter inserted under the skin, which is attached to a small pump. Common side effects reported in clinical studies include infusion site pain and reaction, headache, diarrhea, nausea, jaw pain, vasodilation, and hypotension .2020 A notable complication of IV treprostinil is the concern for increased risk of bloodstream infection with gram-negative organisms.23Intravenous (IV) treprostinil was approved by the FDA in 2004. Similar to IV epoprostenol, IV treprostinil is administered via an ambulatory infusion pump through a central venous catheter. IV treprostinil also has a half-life of approximately 4 h. Most common side effects for IV treprostinil are the same as SQ treprostinil, with the exception of site pain and reaction that is not seen with IV administration .20 A not21 This formulation has a half-life of 3–4 h and is administered as an inhaled treatment four times a day using a battery powered device. Inhaled treprostinil is sometimes added to oral therapy for patients who may not be candidates for parenteral therapy.24 Common side effects include cough, headache, nausea, dizziness, flushing, throat irritation, pharynlaryngeal pain, and diarrhea ,flushing .26In order to maximize the benefit of prostacyclin pathway therapies, healthcare providers must identify, accurately assess, and appropriately manage prostacyclin side effects which otherwise may lead to discontinuation of therapy.19 In general, side effects are more common during the titration phase than in the maintenance phase.27 Patients should be educated to expect some side effects, which vary from patient to patient. Advances in treatment options have shown improvements in physical functioning and survival.28 Despite considerable side effects, patients receiving prostacyclin pathway therapies have shown improvement in their quality of life.11Due to the difficult side effect profile, prostacyclin pathway therapies are initiated at low doses and up-titrated slowly, as tolerated, until a maintenance dose is achieved.Recognizing the difference between side effects of prostacyclin pathway therapies and the signs and symptoms of the disease such as worsening right heart failure  is an im30 Pain may be in the form of jaw pain, leg pain, or generalized body pain. The healthcare provider should assess pain severity and quality, to determine if the pain is typical of a prostacyclin pathway therapy side effect or related to another cause.Pain is a potential side effect following dosing with all prostacyclin pathway therapies, which can be a significant burden for patients with PAH and can be challenging to manage. Preclinical studies have shown that prostacyclin is a mediator in inflammation and pain and may produce hyperalgesia.31 Pharmacologic treatments for pain can include acetaminophen, ibuprofen (if not otherwise contraindicated), gabapentin, pregabalin, tramadol, and narcotics such as hydrocodone, fentanyl, or codeine, on a case-by-case basis.32 Gabapentin may be a more successful analgesic for leg pain. If the pain is not relieved with the above measures, a lower dose or different prostacyclin therapy may be tried. If the dose is lowered, an attempt can be made to titrate the dose back up once the pain is controlled. In cases of refractory pain, referral to a pain management or palliative care specialist can be considered.31Depending on the pain severity, pharmacologic or non-pharmacologic interventions may be appropriate. Non-pharmacologic measures include use of a heating pad, massage, acupuncture, acupressure, and relaxation techniques.32 Myalgia, or muscle pain, has been reported in patients receiving prostacyclin pathway therapies and can be treated as other pain is treated. Additionally, a recent consensus statement regarding treatment of leg pain associated with oral treprostinil recommended screening for iron deficiency.32Jaw pain is a side effect unique to prostacyclin pathway therapies and often occurs with the first bite of a meal. It is generally not dose-limiting and can usually be managed by taking slow bites, sucking on a saltine cracker or a hard candy, or chewing gum before eating. Patients should be educated to expect jaw pain.33 Patients may experience headache of varying severity, quality, frequency, and duration. Best practices exist in the evaluation of headache severity.34 Patients with a past history of headache may be more likely to experience headache with dose titration. As is true for all prostacyclin pathway therapy side effects, the rate of dose titration can be slowed to allow for better tolerability. Patients may benefit from scheduled, prophylactic, treatment for headache. For example, before each dose of PO or inhaled prostacyclin pathway therapies or prior to titration of parenteral prostacyclin, patients can be pre-medicated with acetaminophen or other pain medications to attempt to prevent headache onset or reduce severity. If headache is atypical, new, or more severe than expected, consider the possibility of intracranial hemorrhage and check prothrombin time if on warfarin, and consider whether brain imaging or specialist referral is indicated.Headache can be a side effect of all of the medications that target the prostacyclin pathway. Prostacyclin has inflammatory and hyperalgesic properties, with actions very similar to those of prostaglandin E1, which has long been known to cause “vascular-type” headaches.32 If dizziness is leading to pre-syncope or syncope, the healthcare provider should thoroughly evaluate the patient in the clinic or hospital setting.Dizziness has been reported in patients who have received epoprostenol and inhaled treprostinil. In a recent consensus statement about dizziness associated with PO treprostinil, the authors suggest closely monitoring blood pressure, lowering doses of blood pressure medicine, and managing fluid volume status.35 In patients who are taking anti-hypertensive medications, consider whether the dose should be decreased when prostacyclin pathway therapies are started. Patients should monitor their blood pressure and be advised to change positions slowly and report symptomatic hypotension. An inadvertent bolus of prostacyclin may result in hypotension and patients should make their healthcare provider aware immediately if this occurs. In these instances, a temporary decrease in dose may be required. Severe hypotension may require hospitalization and temporary use of vasopressors.Hypotension has been seen following administration of epoprostenol, iloprost, and SQ and IV treprostinil, but is rarely dose-limiting. There may be an increased rate of hypotension in patients on background anti-hypertensives and on combination PAH therapy compared with monotherapy.1 Prostaglandins may influence thyroid function by a direct effect on specific prostaglandin membrane receptors.36 In the selexipag phase 3 clinical trial, new onset hyperthyroidism was reported in eight patients in the selexipag group (1%) and none in the placebo group (P = 0.004).35 Patients with PAH have higher incidence of iron deficiency, cardiac failure, and connective tissue disease complications that predisposes them to anemia.1 Anemia was reported in 8% of the selexipag group and 5% of the placebo group (P = 0.05).35 Baseline medical history of patients in the GRIPHON study,35 in which events denoting anemia as previous or concomitant disease were documented in 11.3% and 11.1% of patients randomized to selexipag and placebo, respectively . Reasons for hyperthyroidism and anemia seen following selexipag treatment are unclear. Serial laboratory follow-up of both measures is recommended for PAH in general.Thyroid disease is common in patients with PAH and may develop during the disease course.37 Nausea is a common side effect of prostacyclin pathway therapies. If nausea occurs at the time of a dose increase, slower titration or temporarily lowering the dose may help reduce nausea. Non-pharmacologic treatments include: eating smaller, more frequent meals and use of ginger-based products, such as ginger ale.38 Anti-emetics can be prescribed to prevent or control nausea. Nausea with inhaled treprostinil may be the result of inadvertent swallowing of the drug, which can be mitigated by rinsing the mouth after each treatment. By selecting the IP receptor, selexipag theoretically has the potential for fewer gastrointestinal side effects, such as nausea and vomiting, that often results from activation of the other prostacyclin receptors by prostacyclins.39 Pregnancy should be ruled out in any woman of child-bearing potential when nausea is not clearly a prostacyclin side effect.24 If nausea is refractory to the above recommendations, consider referral to a gastrointestinal specialist to evaluate for other causes of nausea.Gastrointestinal complaints have been reported as a cause of decreased quality of life in PAH patients.Loss of appetite is often associated with nausea and can lead to weight loss. In the event of significant weight loss, a dietician consultation should be considered. Some interventions include increasing caloric content, consuming small, more frequent meals, or adding a nutritional supplement. Patients with continued weight loss despite these measures should be evaluated for other causes of weight loss.32 For refractory diarrhea, a slower titration or dose reduction may be necessary until symptom relief is obtained. Dietary changes may be implemented such as adding probiotics or fiber, or switching to a gluten-free diet. If diarrhea is severe, an infection such as Clostridium difficile should be excluded. During times of severe diarrhea, the diuretic regimen may need to be reduced to avoid hypovolemia. The healthcare provider should consider referral to a gastroenterologist if the diarrhea is not clearly caused by prostacyclin pathway therapy.All prostacyclin pathway therapies can cause diarrhea, which can usually be managed successfully with scheduled, or as-needed doses, of loperamide.40 Fanning or the use of cool packs may be helpful for some patients. Healthcare providers should educate patients about flushing or rash and provide reassurance that it is not harmful and is rarely dose-limiting.32Vasodilation, or flushing, which may occur after scheduled doses or dose increases, has been observed in patients receiving all of the prostacyclin pathway therapies. Flushing is felt as a warm or hot feeling, sometimes with redness of the skin, which can be generalized or involve only the face. In addition to flushing, patients receiving IV epoprostenol may experience a red rash, which may be constant .40 Fanni24 Patients with pre-existing lung disease such as interstitial lung disease or chronic obstructive pulmonary disease may experience more cough than patients without lung disease.24Cough and throat irritation with inhaled prostacyclins are most likely related to the route of administration.24For patients who develop cough, the specialty pharmacy staff should review proper technique for administration of inhaled prostacyclins. If coughing persists, treatments include throat lozenges or the use of bronchodilators.20 and has also been associated with more advanced PAH.41 Patients with portopulmonary hypertension may have lower platelet counts at baseline and should be followed closely for worsening thrombocytopenia. In rare, severe cases, dose reduction may be necessary or patients could be switched to another PAH therapy. Platelet infusions are rarely necessary. Patients will need routine laboratory testing to monitor for thrombocytopenia and they should report any unusual bleeding.Thrombocytopenia has been associated with epoprostenol, iloprost, and parenteral treprostinil,31 typically peaks two to five days after starting a new infusion site and may last up to 14 days.42 Pain can be associated with erythema, induration, warmth, inflammation, tenderness, mild site bleeding, nodule, or in severe cases, abscess , which is a microemulsion-based gel that has been used to deliver different types of pain drugs topically and transdermally. Additionally, ice packs or lidocaine patches can be used. If site pain has resolved and then recurs days or weeks later, consideration should be made for possible site infection. If site pain is much more severe than usual shortly after placement, consider immediate replacement to another location. Some patients may experience less site pain or reaction with a different catheter type, such as the Cleo® 90  or Quick-set® , which can be managed by the specialty pharmacy staff. Consider preventative measures prior to site change to reduce pain severity, such as dry catheter pre-placement, treatment with analgesics, amitriptyline HCl, or histamine (H1/H2) receptors blockers. If needed, gabapentin or tramadol could be administered within the first week of a site change.31Patients with moderate to severe site pain should be encouraged to maintain sites as long as possible, while monitoring for signs of early infection.23 Patients treated with treprostinil with epoprostenol diluent have been shown to have a lower incidence of gram-negative bloodstream infection than those treated with treprostinil with saline diluent and a similar rate to those treated with epoprostenol.44 Patients should avoid wetting the infusion system connections,42 and a closed-hub system is recommended. Central line infections generally involve removing the infected line and use of a PICC line until the infection has cleared. Peripheral IV lines should be avoided or used for very short durations as they can become painful and are generally too distal from the central circulation. Subcutaneous dosing has a low risk for bacteremia or venous thrombosis, as it does not require central venous access.19Line infections are a known risk for patients receiving intravenous infusions and are a complication of the route of administration, rather than a side effect. Bloodstream infections are most commonly gram-positive infections; however, gram-negative infections have been shown to be higher in patients receiving IV treprostinil than in those receiving IV epoprostenol.Prostacyclin pathway therapies offer significant benefit to patients with PAH in terms of efficacy and survival, but also carry an often difficult-to-manage side effect profile. In order to maintain adherence, it is imperative to carefully manage side effects. At the time the decision is made to initiate a prostacyclin pathway therapy, clinicians should educate patients on what to expect. Most patients will experience some side effects; however, the type and severity will differ from patient to patient. Patients should be counseled to contact their healthcare provider if side effects become too severe, so they can be managed before the need to limit dose increases and to avoid discontinuations. Patients should be reassured that in most cases, side effects will either lessen or abate over time, and the improvement in PAH symptoms will likely outweigh the difficulty faced with side effects during the titration phase.There are many side effect management strategies that healthcare providers can use to manage prostacyclin side effects. Some approaches will work for one patient and not another; thus, it is important to have a clear understanding of options to combat side effects and tailor these to what works for an individual patient. Patients should be provided clear verbal and written instructions on side effect management. Smart phrases can be created in electronic medical record systems to easily provide detailed side effect management instructions to patients with simultaneous documentation in the medical record. Healthcare professionals should foster open communication and educate patients on side effect plans at the time therapy is started. In particular, nurses are in a key position to provide patient support and counseling, thereby helping patients remain on therapy.Limitations of this article include the lack of randomized controlled trials in the management of prostacyclin pathway therapy side effects and thus the recommendations are from other disease states as well as the experience of the authors. The similarities in the management of side effects across multiple experienced PH centers adds strength to these recommendations, but evidence-based support is lacking.Side effect management following prostacyclin pathway therapy can be challenging for both patients and healthcare providers. By anticipating side effects and initiating a proactive plan, healthcare providers can help patients stay on therapy and receive the maximum benefit from prostacyclin therapy.


Excision of all endometriotic lesions is the method of choice in the treatment of severe endometriosis resistant to medical therapy. The infiltrating nature of the disease as well as extensive surgery may, however, cause chronic pain that cannot be relieved by either surgery or hormonal treatment. As a pilot treatment, we tested the effect of sacral neuromodulation (SNM) for four endometriosis patients suffering chronic pelvic pain and pelvic organ dysfunction after radical surgical treatment. Three out of four patients reported improvement in their symptoms during the neuromodulation testing period and a permanent pulse generator was installed. After 2.5 years, all three patients report better quality of life and want to continue with SNM. Sacral neuromodulation (SNM) involves electrical modulation of a sacral nerve root by means of an electrode and a pulse generator. The conventional indications for SNM are urinary retention, urinary incontinence, anal incontinence, and constipation . SeveralEndometriosis is an estrogen-dependent chronic inflammatory disease defined by the presence of functional endometrial tissue outside the uterine cavity. Approximately 4–10% of women are affected during their fertile years suffering from a variety of pelvic pain symptoms and subfertility . EndometEndometriosis can cause pain in many different mechanisms . IrritatCommon to all our four patients was a history of surgically treated deep infiltrating endometriosis in lateral pelvic sidewalls affecting ureters, sacrouterine ligaments, and pelvic nerves. All women had undergone hysterectomy and bilateral salpingo-oophorectomy combined with excision of all macroscopic endometriosis. Thus, adenomyosis as the source of pain was excluded. No recurrent endometriosis was suspected in gynecological examination and transvaginal ultrasound, and the chronic noncyclical pelvic pain was life interfering and resistant to hormonal and medical treatment. Detailed surgical history is presented in The SNM procedure with InterStim II™ system was performed in two stages. In the first stage, a permanent lead was implanted under local anesthesia with fluoroscopic control into S3 or S4 sacral foramina as described in detail earlier [A self-designed disease-related questionnaire was used to assess pelvic pain symptoms as well as bowel and urogenital function before and 3–6 months after SNM procedure. This questionnaire evaluated the presence of abdominal or pelvic pain or dyspareunia; functional bowel symptoms like pain and difficulties on defecation, fecal incontinence, or constipation; urinary symptoms like incomplete bladder emptying, dysuria, and urinary incontinence. In addition, patients were advised to keep daily pain diary and pain medication diary for fourteen days before, during, and after SNM test period. Furthermore, women with permanent pulse generator were asked to evaluate the effect of SNM treatment to pelvic pain symptoms and bowel and bladder function 3–6 months after procedure . Women's subjective satisfaction on SNM was evaluated with numerical rating scale (NRS) . During the treatment and follow-up, women had the possibility for daily contact with study nurse.Main pre-SNM symptoms and self-reported response to treatment are shown in After the test period, three patients reported considerable or excellent improvement (NRS 8-9) in subjective quality of life and were offered to have permanent pulse generator installed. Two women found considerable improvement in bladder symptoms and two women found considerable or excellent relief in dyspareunia. All these three women found that SNM relieved chronic pelvic pain a little, but the pain was easier to tolerate when functional pelvic symptoms eased. Total use of pain medication decreased, but only one woman filled the questionnaire fully adequately regarding NRS values and pain medication.Patient number four did not experience any improvement in symptoms during the test period. Permanent pulse generator was not installed. She did not return any of the questionnaires.We organized a phone call control to all four patients 2.5 years after the test period. All three patients with SNM installed wanted to continue with SNM. None of the patients with SNM were totally symptom-free but they all reported better quality of life by better symptom control enabling working, social life, and travelling. Main pre-SNM symptom for patient 1 was disabling chronic pain and defecation problems. She got excellent help for pain and dyspareunia from SNM but the first modulator had to be removed because of infection. Second modulator gave good pain control but it has not been as good with dyspareunia. For good symptom control, she has needed SNM reprogramming 2-3 times a year. Patient 2 announced that chronic pelvic pain and pain during defecation had eased as well as fecal and urinary incontinence. Patient 3 had excellent help for obstipation and lived a regular life. She was fully satisfied with SNM. Fourth patient has retired in the age of 38 and suffers chronic pelvic pain, functional bowel symptoms, dysuria, and dyspareunia. No spontaneous symptom mitigation has occurred during 2.5 years. She underwent full clinical and radiological reevaluation with MRI year 2015 and has tried all hormonal treatments and pain killers without help.Our clinical experience is that deep endometriotic nodules at area of uterosacral ligaments with infiltration to hypogastric nerves and the ureters create the most difficult disease to treat. Possibilities of surgery are limited by preservation of vascular, urinary, and neural structures. Nature of the pain is often neurogenic and response to hormonal treatment and regular pain medication is poor. Luckily, this end stage is rare but those few patients may end up being quite desperate.SNM has been used for pelvic floor pain and functional pelvic disorders for other indications but not for endometriosis . We deciA self-administered disease-related questionnaire was used to assess problems with bowel and urogenital functions, but the compliance was poor. After the SNM test period, three out of four patients announced significant relief in their symptoms and a permanent pulse generator was implanted. NRS did not turn out to be reliable indicator of pain since the heavy use of pain medication in the beginning of study biased the results. However, three out of four patients were able to reduce pain medication. These three women also felt that problems with defecation and urinary symptoms were alleviated significantly. In addition, two women got a remarkable help for dyspareunia and reported great increase in subjective quality of life. All three patients want to continue with the SNM after 2.5 years. Fourth patient who did not benefit from SNM has not experienced any spontaneous relief in symptoms during 2.5 years.We are fully aware of the placebo effect of SNM. However, since three out of four patients with chronic pelvic pain and pelvic floor dysfunction reported a clinically plausible benefit of this pilot trial, we believe that SNM for end stage endometriosis patients is worth further controlled studies.


Persistent postoperative pain (up to 41 %) and significant practice variation necessitate better patient selection for cholecystectomy. Patient-reported outcome measures (PROMs) are nowadays known to serve as a tool for better patient selection, although variability within these subjective outcomes may be a point for debate. This study determines associations of both the preoperative pain and patient characteristics with PROMs at 24 weeks after cholecystectomy. In order to evaluate variability of PROMs, we also determined consistency of these outcomes in time.This prospective multicenter cohort study included adult patients diagnosed with uncomplicated symptomatic cholecystolithiasis. Twenty-four weeks after surgery, a questionnaire study was carried out, containing Gastrointestinal Quality of Life Index (GIQLI) and Patients’ Experience of Surgery Questionnaire. Results were compared to preoperative data and results 12 weeks post-cholecystectomy. Logistic regression analyses were performed to determine associations. Additional post hoc analysis on associations between preoperative selection criteria and PROMs was done.A total of 360 patients (85 %) responded. Postoperative absence of pain was reported by 59.2 %. Associated characteristics were symptoms ≤1 year prior to surgery [OR 1.85 (95 % CI 1.11–3.09)] and high baseline GIQLI score [OR 1.04 (95 % CI 1.02–1.05)]. General improvement in abdominal symptoms and positive result of surgery were found in 90 %; no preoperative variables were significantly associated. PROMs showed consistency at 12 and 24 weeks postoperatively. Post hoc analysis showed no significant associations.PROM-based preoperative selection criteria need to be considered to select those patients who achieve freedom of pain after surgical treatment of uncomplicated symptomatic cholecystolithiasis. Other patients might consider cholecystectomy as successful, but are less likely to be free of pain. Usefulness of PROMs is underscored as they proved to be consistent in time in evaluating surgical outcome. Cholecystectomy is the current gold standard for symptom relief in uncomplicated symptomatic cholecystolithiasis –3. HowevThe combination of large practice variation and significant persistence of postoperative pain emphasizes the need for more evidence on proper patient selection for cholecystectomy. Persistence of pain after surgery is possibly due to wrong symptom attribution to gallstones or newly arisen symptoms after cholecystectomy . Only whWe aimed to determine the association of preoperative pain and patient characteristics with patient-reported postoperative absence of abdominal pain, improvement in abdominal symptoms in general and success of surgery at 24 weeks after elective cholecystectomy in uncomplicated symptomatic cholecystolithiasis patients. We also aimed to assess the consistency of PROMs after cholecystectomy at 12 and 24 weeks after surgery.This prospective cohort study was conducted at the Radboudumc Nijmegen, St. Elisabeth Hospital Tilburg and Medisch Spectrum Twente Enschede, The Netherlands. Details of the study design were reported previously . BrieflyWe report the second part of the prospective cohort study, in which all patients that had previously returned the preoperative questionnaire were sent a second postoperative questionnaire 24 weeks after surgery. Patients who did not return this questionnaire were contacted. Those who subsequently completed the questionnaire were classified as “late responder.” All non-responders were excluded from analysis.The questionnaire consisted of the GIQLI , 23 and The study was approved by the medical ethics committee of all hospitals and was performed in accordance with the Declaration of Helsinki and with the recommendations in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies .The primary outcome was defined as the absence of abdominal pain 24 weeks after cholecystectomy as reported on the postoperative GIQLI. We dichotomized results in the absence or presence of abdominal pain. Secondary outcomes were patient-reported general improvement in abdominal symptoms and result of surgery 24 weeks after cholecystectomy. We dichotomized results in improvement  or absence of improvement  in abdominal symptoms after cholecystectomy and good  and bad (bad and very bad) results of surgery. We estimated the association of preoperative pain characteristics, patient characteristics and health status with both primary and secondary outcomes. Finally, all outcomes 24 weeks after cholecystectomy and associated variables were compared to the previous 12-week follow-up results. Similarities and differences in the results were described.Based on previous publications –18, we iThe appropriate sample size for the study was calculated based on findings of a systematic review . PersistTo examine significant differences in patient characteristics between responders (including late responders) and non-responders, Chi-square test or Fisher’s exact test for categorical data and Student’s t test for continuous data were used.p value <0.1 in univariable analyses were included in multivariable logistic regression analysis. Backward elimination was used as variable selection method retaining age at time of surgery, gender, study center and preoperative absence of abdominal pain as covariables. The results were reported as adjusted odd ratios (OR) and 95 % CIs. To determine whether the PROMs significantly differed between 12 and 24 weeks after cholecystectomy, McNemar’s test was used. A p value <0.05 was considered statistically significant. All missing values were considered to be at random and were excluded from analyses. All statistics were done with SPSS statistics 20.0 (IBM).To identify which variables were associated with primary and secondary outcomes, logistic regression analysis was applied. Variables with a Based on the results of the regression analyses, we performed a post hoc analysis on the association between the preoperative presence of biliary colic and postoperative PROMs. Since biliary colic is in daily practice defined in different ways, we explored these associations with four commonly used definitions of biliary colic; episodic pain in epigastrium or right upper abdominal quadrant with a duration of at least 30 min without additional features (1), with pain radiating to the back (2), with urge to move (3) and with both pain radiating to the back and urge to move (4). Information on the presence of biliary colic was abstracted from the structured anamnesis. Associations between the presence of biliary colic preoperative and postoperative PROMs were analyzed using univariate and multivariate logistic regression analysis.n = 279). Mean age at surgery was 49.8 years (SD 14.2 years). None of the baseline characteristics of the responders were different from characteristics of non-responders, except for gender and age. Non-responders were more often female (88.9 % p = 0.04) and were younger .We send follow-up questionnaire 24 weeks after surgery to 423 patients. Questionnaires were returned by 360 (85 %) patients: 314 (87.2 %) were returned immediately after 6 months and another 46 (12.8 %) late responders between 8 and 25 months postoperatively. Baseline characteristics of the responders and non-responders are shown in Table p = 0.02) and baseline GIQLI score  remained significantly associated with the absence of abdominal pain after cholecystectomy  patients reported postoperative absence of abdominal pain using the GIQLI. Duration of symptoms ≤1 year prior to surgery, awaking at night and baseline GIQLI score were univariably associated (Table p < 0.001) associated with general improvement in abdominal symptoms.Abdominal symptoms in general were reported as “much better” or “slightly better” by 324 (90.0 %) patients after cholecystectomy. No variables were associated with improvement in abdominal symptoms in general. Postoperative absence of abdominal pain itself was both univariably (Table p < 0.001).The result of cholecystectomy was rated “excellent,” “very good” and “good” by 324 (90.0 %) patients. Baseline GIQLI score and episodic pain were associated in univariable analyses, but not in multivariable analysis (Table p = 0.51). The extent to which patients with the absence or presence of pain at 12- and 24-week follow-up were consistent is shown in Fig. p = 0.86 and p = 0.70 respectively).Three hundred and sixteen of the 360 patients who returned the follow-up questionnaire after 24 weeks had also completed the previous questionnaire at 12 weeks postoperative. There was no significant difference in the absence of abdominal pain reported at 24 and 12 weeks postoperatively . From these 352 patients, 91.7 % had a biliary colic according to the criterium: episodic pain in epigastrium or right upper abdominal quadrant for at least 30 min. 66.9 % had biliary colic with pain radiating to the back, 79.2 % had biliary colic with urge to move, and 58.3 % had biliary colic with both pain radiating to the back and urge to move. None of the criteria for biliary colic were univariably significantly associated with patient-reported absence of abdominal pain after cholecystectomy, general improvement in abdominal symptoms or result of cholecystectomy  and a higher preoperative health status predicted being pain-free after cholecystectomy. Additionally, 90 % of patients reported general improvement in abdominal symptoms and success of surgery. These PROMs were more likely to be reported by patients without abdominal pain after cholecystectomy. All PROMs were consistent in time and did not significantly differ between 12 and 24 weeks after cholecystectomy.A recent systematic review showed patient-reported complete relief of pain after cholecystectomy in 59–100 % of patients measured between 3 and 61 weeks postoperatively , 26–30. The low proportions of patient-reported postoperative pain relief suggest ineffective use of cholecystectomy. Although the Rome III criteria have been formulated to indicate symptomatic cholecystolithiasis patients and subsequent surgery, these criteria are either not sufficient to distinguish the true gallstone-related symptoms or not applied strictly by surgeons, leading to unnecessary surgeries with postoperative pain persistence. A randomized controlled trial is currently being performed to examine the latter hypothesis. Our analysis shows that the criteria for biliary colic used in common practice fail to select the gallstone patient likely to benefit from cholecystectomy. We should consider expanding current criteria to properly differentiate true gallbladder patients that benefit from surgery from non-specific patients less likely to benefit from surgery. The two factors related to positive PROMs, symptoms ≤1 year and a high preoperative health status, combined with the current biliary colic criteria, may be introduced as new selection criteria. These are the patients that should undergo cholecystectomy and are likely to be free of pain after surgery. For patients not meeting these criteria, alternative diagnoses for the abdominal symptoms should be considered and additional watchful waiting may be the suitable alternative treatment. The discrepancy between patients being free of pain (59.2 %) and reporting a successful result of surgery (90 %) however suggest that patients without the absence of pain can be satisfied with the result of surgery if other symptoms have improved. If no other diagnoses are found and patients keep experiencing symptoms, surgery may be considered to improve symptoms, although patients are less likely to be completely free of pain. This would be a shared decision of patient and physician in which the alternative goal of cholecystectomy should be clearly discussed to prevent false patients’ expectations regarding the outcome of surgery.This study comes with strengths and limitations. The length of follow-up and repetition of measuring PROMs at longer follow-up after cholecystectomy to capture variations in responses and create a complete and reliable picture on characteristics associated with these outcomes are unique features. We also used reliable and valid questionnaires to analyze PROMs, minimizing variability in responses  and enhaThe inclusion of the late responders (questionnaires completed 8–25 months postoperatively) in our analysis to maximize response rate might be viewed as a limitation. However, late responders are only a minority (12.8 %) and after exclusion of late responders data, similar results were obtained (data not shown). Another limitation is that gender and age at time of surgery and ASA classification were significantly higher among the responders than non-responders. We cannot exclude that this has affected the results, although no significant associations were seen between gender and age and the study outcomes.In conclusion, this study establishes that the current practice based on the biliary colic as selection criteria fails to predict freedom of abdominal pain following cholecystectomy. To optimize surgical treatment for uncomplicated symptomatic cholecystolithiasis patients, criteria for cholecystectomy should be redesigned to allow use of duration of symptoms and health status as parameters. These criteria select patients likely to truly benefit from surgery and be free of pain after cholecystectomy. For other patients, cholecystectomy may be successful by improving symptoms, but they are less likely to be free of pain. PROMs are a promising tool in the evaluation of these surgical outcomes, as they show to be consistent up and including 3 months after surgery.


Headaches represent over three million emergency department (ED) visits per year, comprising 2.4% of all ED visits. There are many proposed methods and clinical guidelines of treating acute headache presentations. However, data on intravenous acetaminophen usage in these settings are lacking. In this study, we sought to determine the efficacy of intravenous (IV) acetaminophen as an adjunct to a standard therapy for the treatment of patients who present to the ED with a chief complaint of “headache.”We conducted a single site, randomized, double-blind, placebo-controlled trial investigating the clinical efficacy of IV acetaminophen as an adjunct to a standard therapy with prochlorperazine and diphenhydramine for the treatment of patients who present to the ED with a chief complaint of “headache” or variants thereof. (See below for variants). The primary outcome measure of the efficacy of parenteral acetaminophen as an adjunct treatment for headache in addition to a standard therapy was a threshold two-point reduction in visual analog scale (VAS) pain scores on a 1–10 level at 90 minutes. Secondary outcomes measures included assessment of decreased requirement of “rescue” pain medicines, defined as any analgesic medications outside of diphenhydramine, prochlorperazine and acetaminophen, with particular interest to potential opioid-sparing effects with parenteral acetaminophen. Additional secondary outcome measure included time to disposition from arrival in the ED.For the acetaminophen group the initial mean pain score was 8.67, for the placebo group 8.61. At 90 minutes pain score was 2.23 for the acetaminophen group and 3.99 for placebo  [0.8%–16%]. Of 45 patients in each group, we observed at least a threshold two-point decrease in pain score 36/45 (80%) with acetaminophen vs. 25/45 (55%) with placebo (p <0.01) 95% CI [5%–41%], number needed to treat (NNT) = 4). Secondary outcome measure did not demonstrate a difference in length of stay (161 minutes for acetaminophen arm and 159 minutes for placebo). However, 17/45 (38%) of patients who received IV acetaminophen required rescue analgesia, opposed to 24/45 (53%) of patients in the placebo group (p=0.13) 95% CI [−5%–34%].IV acetaminophen when used with prochlorperazine and diphenhydramine to treat acute headaches in the ED resulted in statistically significant pain reduction compared with prochlorperazine and diphenhydramine alone as measured by both threshold of lowering VAS pain score by at least two points (NNT = 4) and overall decline in VAS pain score. Further study is required to validate these results. Headaches represent over three million emergency department (ED) visits per year comprising 2.4% of all ED visits.We conducted a single site, randomized, double-blind, placebo-controlled trial investigating the clinical efficacy of IV acetaminophen as an adjunct to a standard therapy for the treatment of patients who present to the ED with a chief complaint of “headache” or variants thereof. (See below for variants.) Independent of the clinician’s ultimate disposition of the patient, data collection was performed to ascertain the primary outcome measure of the efficacy of parenteral acetaminophen as an adjunct treatment for headache in addition to a standard therapy, with primary end point being threshold two-point reduction in visual analog scale (VAS) pain scores on a 1–10 level at 90 minutes. An estimated 100 patients were needed for the study (50 patients in each group) to achieve adequate power when considering the primary outcome measure. The primary outcome measure would be anticipated to reflect a statistically significant difference in mean pain scores between acetaminophen and placebo greater or equal to two with standard statistical thresholds of p < 0.05 and beta (power) > 0.8. Secondary outcomes measures included assessment of decreased requirement of “rescue” pain medicines defined as any analgesic medications outside of the aforementioned protocol with particular interest to potential opioid-sparing effects with parenteral acetaminophen. Additional secondary outcome measures included decreased time to disposition from arrival in the ED.We obtained institutional review board approval and informed consent documentation prior to beginning patient enrollment. We included a convenience sample of patients age 18–65 years presenting with chief complaint of headache, migraine headache, tension headache, cluster headache or headache not otherwise specified, reporting pain as >4 using a standard 10-point VAS. We excluded patients who consumed a cumulative dose of acetaminophen >2,600 mg within the preceding 24 hours (per manufacturer recommendations), physical or mental disability hindering adequate response to assessment of pain, mental disability limiting ability to give consent, hemodynamic instability or medical condition requiring acute lifesaving intervention, documented or suspected pregnancy or active breastfeeding, any known contraindication to acetaminophen use , brain mass/glioma, intra-cranial hemorrhage, skull fracture and any contraindication or reported allergy to the use of prochlorperazine and/or diphenhydramine.What do we already know about this issue?IV acetaminophen has showed promise in post-operative pain control trials with demonstrated narcotic-sparing effects. It has not yet shown much success for other pain presentations.What was the research question?Can the addition of IV acetaminophen to a “standard” headache cocktail help improve pain control, diminish length of stay, and decrease amount of “rescue’”medications?What was the major finding of the study?IV acetaminophen added to prochlorperazine and diphenhydramine to treat acute headaches in the ED resulted in significant pain reduction when compared with prochlorperazine and diphenhydramine alone, decreasing VAS pain scores by at least 2 points (NNT =4), with overall decline in VAS pain score.How does this improve population health?Non-narcotic treatment of acute pain in the ED is recommended. We evaluated the effectiveness of alternative regimen for a common complaint.Patients presenting to the ED with chief complaint of headache or variant thereof were evaluated by the treating emergency physician, who discussed the study in detail with the patient, reviewed inclusion and exclusion criteria, and obtained informed consent for enrollment. An order set was used in the electronic medical record to initiate a pre-selected order cluster including prochlorperazine 10mg IV bolus, diphenhydramine 25mg IV bolus, 1,000 ml 0.9% normal saline bolus, and “study drug.” The “study drug” was either 100ml 0.9% sodium chloride in a minibag, or 1,000 mg IV acetaminophen transferred from the manufacturer’s vial into a 100 cc minibag, both labeled “study drug.” All patients received prochlorperazine, diphenhydramine, and 1,000 ml 0.9% normal saline immediately from the ED medication-dispensing machine, and then subsequently the “study drug” upon arrival from pharmacy via tube system to ensure blinding. Both IV acetaminophen and placebo were administered via IV infusion over a 15-minute interval as is required by the manufacturer’s dosing administration instructions. The study was double blinded to both physician and patient. Therefore, patients were randomized by the pharmacist to either treatment arm “A” or “B,” where “A” represented acetaminophen, and “B” represented placebo. The pharmacists used a numeric identifier in a logbook to track whether patients received the study drug or placebo.ED nursing staff completed a stratification form that noted the patient age, chief complaint, pain assessment intervals at time of arrival, time of “study drug” administration, reassessment at 30-minute intervals thereafter, and additional reassessment if a “rescue” medication was later used. In the event of adverse reaction to the IV infusion of the “study drug,” the infusion would be stopped and pharmacy contacted if required to “break” the double blinding to determine which medication was administered.One hundred patients were enrolled in the study from November 2014–June 2015. We excluded four enrolled patients from data analysis secondary to age; two were excluded for repeat enrollment  and three were excluded secondary to missing data. One patient who was found to have a brain mass was also excluded.Forty-five patients received placebo and 45 IV acetaminophen. Both groups received 50 mg IV diphenhydramine, 10 mg IV prochlorperazine, and 1,000 ml 0.9% NS bolus. At no time was the study blinding broken secondary to patient side effects. Our patients’ racial demographics are reported in We enrolled 70 men and 20 women with a mean age of 31 and 38 respectively. Age groups of study participants were further divided with notable findings of the majority of males being within ages 18–29, and females being ages 18–39 .Pain scores were analyzed at 0, 30, 60, and 90 minutes after study-drug administration. Pain scores were reported with ascending severity on a 1–10 point VAS. Of the (n=45) patients who received IV acetaminophen, 36 (80%) reported a decrease by pain score reporting of ≥ 2 from presentation at the 90-minute mark. Nine patients reported pain scores that were unchanged from initial presentation, increased, or decreased by <2 at the 90-minute assessment. Of the (n=45) patients who received placebo, 25 (55%) reported a decrease by pain score reporting of ≥ 2 from presentation at the 90- minute mark. Twenty patients reported pain scores that were either increased, unchanged from initial presentation, or decreased by <2 at the 90-minute assessment (p <0.01) 95% confidence interval [CI] (5%–41%) .Forty-one patients required some form of “rescue” medication in addition to the initially administered medications; 17/45 (38%) of patients who received IV acetaminophen required rescue analgesia, as opposed to 24/45 (53%) of patients in the placebo group, which did not reach statistical significance.Seventeen out of the 41 patients who required rescue analgesia received IV ketorolac as part of the rescue regimen: eight in the IV acetaminophen treatment arm and nine in the placebo arm. Nine patients received opioids as part of a rescue formulation: four in the IV acetaminophen treatment arm and five in the placebo arm (p=0.72). The opioids administered included hydrocodone, hydromorphone, meperidine, and fentanyl. Some patients received combination rescue medications including opioids and NSAIDS alone, in combination or in addition to other medications including orphenadrine, triptans, and steroids depending on clinician discretion . The levMean time to clinically significant reduction in pain score as defined by at least a two-point decrease was 49.2 minutes post administration of IV acetaminophen, prochlorperazine and diphenhydramine. Mean time to clinically significant pain reduction was 71.3 minutes post administration of IV 0.9% NS, prochlorperazine and diphenhydramine. Mean pain intensity scoring (VAS) was noted for both groups. For the acetaminophen arm the initial mean pain score was 8.67, for the placebo arm 8.61. At 30, 60, and 90 minutes, corresponding mean pain scores were 6.61, 4.41, and 2.23 for the acetaminophen group, and 7.14, 5.12, 3.99 for the placebo group. A statistically significant difference in mean pain score was not observed until the 90-minute mark ).Mean length of stay (LOS) was 161 minutes for the acetaminophen arm and 159 minutes for the placebo arm. LOS was extrapolated from the time of physician contact to disposition entered in the electronic health record (EHR) and included (in both groups) additional rescue medications and additional reassessment times. The maximum LOS for either treatment arm was 361 minutes. Disposition for two patients was admission and thus associated LOS was excluded from analysis. All other patients were discharged.Treatment of headaches in the clinical setting is difficult and requires an evidence-based and often patient-tailored approach, as there is a paucity of published data suggesting optimal headache therapy.9Clinical strategies using parenteral acetaminophen as an adjunct have become increasingly popular as there are notable opioid-sparing effects demonstrated in surgical and anesthesia literature with minimal side effects and a low risk/benefit ratio.17Minimal literature is present regarding the opioid-sparing effects of parenteral acetaminophen outside of peri-operative settings.5A recently published American Headache Society evidence assessment of migraine pharmacotherapies cited Level A evidence by Lipton et. al. demonstrating the efficacy of 1,000 mg of oral acetaminophen vs. placebo in treatment of acute migraine with regard to pain relief, functional disability, phonophobia and photophobia, though the study population was limited to those with minimal nausea and need for bed rest.21The use of IV acetaminophen as primary therapy for headaches would decrease the pitfalls of using primary NSAIDS such as ketorolac or ibuprofen in cases such as possible headache associated with intracranial hemorrhage where there is a platelet aggregation inhibition,19Reviewing data findings, we obtained various pain scores in 30-minute intervals, of which only the first three pain scores  for a total of 90 minutes post-medication administration were considered. Pain scores were reported on a 1–10 VAS because of previously established integration with the her, thus enhancing data collection and ease of nursing-documented pain assessments essential to the study. Bijur et. al. reported decrease of pain by at least 1.4 as significant when investigating the VAS for pain reporting.The mean age of participants was 31 in males and 38 in females. This is consistent with reported headache-sufferer demographics according to the American Headache Society.1The definition of rescue medications administered in this study included opioids, additional NSAIDS, steroids, orphenadrine, ergotamines, triptans or additional dopamine agonists. LOS was extrapolated from the time to disposition from first provider contact entered electronically per the EHR and included in both groups additional rescue medications and additional reassessment times. The time to disposition for either arm was very similar, which was an unexpected finding given the trend towards superior pain reduction in the acetaminophen group at 90 minutes. This may be attributed to the small size of our study, thus relatively small number of patients requiring rescue analgesia. In theory, those with improved pain reduction should require less rescue medications and would be suitable for discharge sooner. The maximum LOS for either treatment arm was 361 minutes in which the particular patient required significantly longer assessment due to refractory presentation. When compared to the additional subjects this was an outlier and did not greatly alter the data significance.During enrollment, several physicians cited concern with excluding analgesic medications such as ketorolac from initial treatment. Several studies have demonstrated the superiority of combination metoclopramide plus diphenhydramine over NSAIDS,We identified some limitations during trial completion. Our intention was to enroll a consecutive series of eligible patients, but this relied on both patient and physician participation and consent to trial participation, which were both factors not within controlled limits of the study. Based on the projected sample size to achieve appropriate power, a sample size of (n=100) was deemed optimal; due to exclusion criteria and other factors as noted before, a sample size of (n=90) was ultimately available for analysis. While the ultimate study population was smaller than initially intended, we observed a greater outcome effect than anticipated such that statistical significance was still achieved, though this did require 90 minutes until a statistically significant difference was achieved. Individual emergency medicine providers were encouraged to enroll all eligible patients according to the study protocol; however, data displayed non-consecutive enrollment. We speculate this may have been due to some provider reluctance to participate in the study or patient refusal, preventing consecutive series enrollment. The degree of subject refusal was not recorded during the enrollment period for further reflection. At time of patient enrollment, treatment was initiated in both arms with initial administration of prochlorperazine and diphenhydramine within several minutes. In either arm, the “study drug” required the blinded product to be sent from pharmacy to the ED, resulting in subsequent administration to the initial medications as noted above. The level of effect of this on study outcomes is difficult to determine, since as noted in the placebo group the time to significant pain score decrease was slower than the acetaminophen group and pain score decrease more profound in the acetaminophen group, although both arms had delayed “study drug” administration by up to 15 minutes post initial medications. To maximize our sample size and decrease exclusion burden, we did not target a specific subset of headache populations. Total patient LOS was defined as arrival to the ED and time to disposition. The beginning of LOS was not recorded as initial provider assessment and study enrollment, which is certainly a confounding variable. The observed difference in LOS between the two study groups was not substantially different, and it is unclear if further analysis in this regard would have significantly changed the reported LOS between the groups.It would be beneficial to delineate in a larger trial if the observed benefit of IV acetaminophen is specific to certain headache conditions. Going forward, it would be worthwhile to study a head-to-head comparison of IV acetaminophen alone with a standard NSAID or opioid therapy to ascertain if similar efficacy exists in treatment of cephalgia as it was reported in treatment of renal colic by Bektas et. al.5Results may further support evidence suggesting that avoidance of opioids in treatment of headache presentations is wise. It is also worthwhile to note that a cost analysis was not performed in this trial, and all medications were provided without cost to patients involved in the trial. This is important as OFIRMEV® as currently available in clinical practice does carry moderate increase in patient cost compared to therapies that have been traditionally used, and may represent a different or increased billing charge toward the patient. Further investigation is required to weight financial burden versus therapeutic effect.IV acetaminophen when used with prochlorperazine and diphenhydramine to treat acute headaches in the ED resulted in statistically significant pain reduction compared with prochlorperazine and diphenhydramine alone as measured by both threshold of lowering VAS pain score by at least two points (NNT = 4) and overall decline in VAS pain score. Further study is required to validate these results.


Hypermobility of the first carpometacarpal joint is mostly surgically treated with a volar approached stabilization by Eaton, but recent studies indicate the importance of the dorsoradial and intermetacarpal ligaments (DRL and IML) for carpometacarpal joint stability. The aim of this study was to compare a dorsal and volar technique for primary carpometacarpal hypermobility regarding pain and functional outcome.Patients with non-degenerative, painful carpometacarpal hypermobility were included and were randomly assigned to either the volar technique using the FCR, or a dorsal technique using the ECRL. After premature termination of the trial, we followed all patients treated with the volar approach. Pain, strength, and ADL function using DASH and Michigan Hand Questionnaires (MHQ) were measured at baseline and 3 and 12 months after surgery.After including 16 patients, the randomized trial comparing the volar and dorsal technique was terminated because of significant increased pain in the dorsal group. Although none of the other outcome measures were significant in the underpowered comparison, in line with the pain scores, all variables showed a trend towards a worse outcome in the dorsal group. Between 2009 and 2012, 57 thumbs were surgically stabilized. We found significant better pain and MHQ scores, and after 1 year improved grip and key pinch strength. Patients returned to work within 8 (±7) weeks, of which 85 % in their original job.Surgical stabilization of the thumb is an effective method for patients suffering from hypermobility regarding pain, daily function, and strength. We recommend a volar approach.Level of Evidence: Level I, therapeutic study Joint laxity or hypermobility of the first carpometacarpal (CMC) joint is a common disorder. In some cases, this generalized joint hypermobility combined with subluxation of the joint can cause severe pain and can result in osteoarthritis of the first CMC joint later in life –4. This Since it is often assumed that the deep oblique anterior ligament (dOAL), also called the beak ligament, provides the most joint stability, the most commonly used surgical procedures in the treatment of symptomatic hypermobility of the first CMC joint are based on supporting or reinforcing the function of this volar beak ligament , 7. The However, more recent anatomical studies indicate that the dorsoradial ligament (DRL) and the IML are more important for CMC joint stability than the beak ligament . Based oTo our knowledge, a volar approach, focused on reinforcing mainly the function of the volar beak ligament, has never been compared with a dorsal approach, focused on reinforcing the function of the DRL and IML. Therefore, the aim of this study was to directly compare a dorsal and volar approach in a randomized controlled trial for the surgical treatment of symptomatic CMC hypermobility in patients with primary hypermobility in terms of pain, complications, and functional outcome.The study was conducted in 2008 and 2009 as a randomized single-blinded comparative trial of a volar versus dorsal stabilization for CMC joint laxity in the Department of Hand and Wrist Surgery, Diakonessenhuis, Zeist, the Netherlands, with approval of the local scientific committee. High pain scores in the dorsal group lead to prematurely termination of the randomized controlled trial (RCT) (see Results); hence, a cohort study of all patients treated with the volar technique was initiated.After informed consent was obtained, patients were included if they had (1) severe pain during daily use of their thumb, (2) first metacarpal subluxation during physical examination, and (3) a failed conservative treatment such as splinting and physical therapy. X-rays were taken and examined by an independent radiologist to exclude early stages of osteoarthritis (Eaton & Glickel stages I and II). We excluded patients with previous invasive treatments .For the volar technique, we slightly modified the technique of Eaton and Littler , which uFor the dorsal technique, an incision of approximately 5 cm was made from the insertion of the ECRL at the base of second metacarpal towards the radial styloid, preserving the radial superficial nerve. After opening the capsule and creating a bone tunnel in the base of the first metacarpal, a slip of the ECRL was passed through this tunnel, back through a tunnel in the trapezium bone and reattached to itself at the base of the second metacarpal see Fig. . Both thAfter consultation and inclusion in the trial, patients were randomly assigned to a surgeon; both surgeons had their preferable method so randomization was performed at this level. We chose an equal randomization type with the usage of opaque envelopes which were drawn by the doctor’s assistant after consultation, deciding which surgeon would be operating on this patient and therefore which type of technique would be used in the stabilization.Medical history and demographic data of each patient were recorded at first presentation. Independent hand therapists performed measurements at baseline and 3 and 12 months after surgery.Our primary outcome measurements were pain and hand function. Pain was measured using a visual analogue scale (VAS). In the RCT, function was measured with the “Disabilities of the Arm, Shoulder and Hand” (DASH) questionnaire. The DASH score is a frequently used questionnaire for the function of the upper limb  .As secondary outcome measures, grip strength was measured using a hydraulic hand dynamometer and tip, key, and tripod pinch were measured using a pinch gauge meter. In addition, we evaluated overall patient satisfaction with the treatment using a five-level Likert scale and patients were asked 1 year after surgery if they would choose for the same treatment again under the same circumstances. Complications were recorded for a period of 12 months for each patient.t testing, Mann–Whitney U tests, and chi-square statistics, and a P value smaller than 0.05 was considered statistically significant.To compare the two treatment groups, a generalized estimating equations (GEE) approach was used. Using both group allocation and time interval (3 months and 12 months versus preoperative) as predictors, the comparison between the dorsal and volar technique was compared in three dimensions; between both groups, over time and the group × time interaction effect, which evaluates if the change over time is different between both groups. Evaluation of treatment satisfaction and complications were tested using independent Between 2008 and 2009, 16 patients were enrolled in the randomized trial. Table Because of a significant increase in pain after surgical stabilization for CMC joint laxity, using a dorsal approach, compared to an improvement in both pain and function using a volar approach, we abandoned the dorsal approach and continued only using the volar approach.After termination of the RCT, all patients with symptomatic primary hypermobility were treated with the volar technique  and were prospectively followed as a cohort, based on the same inclusion criteria as described for the randomized trial part.The same primary and secondary outcome measures were used as in the randomized trial. In addition, we used the “Michigan Hand Questionnaire”  to allow evaluating both hands separately .P value higher than 0.05 means that the characteristics in the groups with complete data are not significantly different from the group that did not achieved full completion of all measurements.For the retrospective analysis of the cohort, we also used a GEE analysis to evaluate the treatment effect over time. Because not all patients already were at 12 months after surgery, a missing value analysis was performed using the Little’s MCAR (chi-square) test, a P value of the Little’s test was 1.000 indicating that missing values were missing completely at random. Therefore, all cases were used in the analysis.Between 2008 and 2014, 54 patients (57 thumbs) were treated. Patients were predominantly women between 20 and 40 years old  weeks of which 85 % with the same intensity as preoperative. Twelve months after surgery, 6 % rated their treatment as “poor,” 13 % as “average,” 34 % as “good,” and 47 % as “excellent.” Ninety percent of the patients reported that they would choose this surgery again. The complication rate was 19 % of which two patients had major complications; one patient had revision surgery after 3 years because of development of osteoarthritis, another patient as earlier mentioned had multiple revision surgeries because of an extensive infection (Table Due to the premature termination of the randomized controlled trial, statistical power of this study was low. Despite of this, the interim analysis indicating a significant difference in change in pain scores at 3 months between both groups, with a decreased average pain score in the volar group and an increased pain in the dorsal group. Due to the small number of patients included in the RCT, no other conclusions can be drawn because of the absence of other statistical differences between groups. Another limitation of this study is the relatively high percentage of missing data in the cohort study. An important reason for this missing data was that data were measured by the patients’ own hand therapist, some of whom were not integrated in our hand clinic. Furthermore, we missed 12 months pain scores in the RCT part of the study. As a result, we are not able to compare how pain scores would develop in both groups over time. An important limitation of the cohort study was the lack of a control group.To our knowledge, a direct comparison of a dorsal and volar approach for surgical stabilization of the thumb CMC joint has not been reported and so far; no data have been reported in literature on the surgical outcome of a purely dorsal technique. Eggers  describeIn contrast to surgical stabilization for symptomatic CMC hypermobility, for trapeziectomy in osteoarthritis, results of dorsally approached ligament reconstruction can be found as well as a comparison with a volar approach. Ritchie et al.  found siDespite the volar technique  is over Our finding that a dorsal surgical approach results in less optimal outcome than a volar approach may be related to a richer innervation of the dorsal part of the joint. The superficial branch of the radial nerve plays a major role in the sensibility of the CMC joint , embeddeIn summary, the prematurely terminated trial shows a significant increase in pain in the dorsal technique treated group whereas the volar technique group had pain reduction at follow-up. In addition, the large cohort study of the volar technique indicates that patients with symptomatic CMC hypermobility can be treated with a stabilization of this joint, using a volar approach, leading to pain relief and good functional outcome. Based on our results, therefore, we do not recommend a dorsal approach in this specific patient group.


In this paper, we analyze predictive factors for early death from comorbidity (defined as death within 3 years from diagnosis and unrelated to prostate cancer) in patients with localized or locally advanced prostate cancer. Such information may guide individually tailored treatment or observation strategies, and help to avoid overtreatment. We retrospectively analyzed baseline parameters including information on comorbidity and medication use among 177 patients (median age at diagnosis 70 years). Actuarial survival analyses were performed. During the first 3 years, two patients (1.1%) died from progressive prostate cancer after they had developed distant metastases. The risk of dying from other causes (3.4%) was numerically higher, although not to a statistically significant degree. Six patients who died from other causes had age-adjusted Charlson comorbidity index (CCI) scores ≥5 (CCI is a sum score where each comorbid condition is assigned with a score depending on the risk of dying associated with this condition). The main comorbidity was cardiovascular disease. The two statistically significant predictive factors were medication use and age-adjusted CCI score ≥5 . However, medication use was not an independent factor as all patients with age-adjusted CCI score ≥5 also used at least one class of medication. Median survival was 30 months in patients with age-adjusted CCI score ≥5. Prediction of non-prostate cancer death may be important to prevent overtreatment in patients who are more threatened by comorbidity. Our data suggest that simple parameters such as use of medications vs. none, or presence of serious cardiac disease vs. none, are not sufficient, and that age-adjusted CCI scores outperform the other factors included in our analysis.


We evaluated the pain associated with cancer and its impact on pain management, anxiety, and depression in Chinese patients using a controlled cross-sectional study. One hundred and twenty-six cancer outpatients were evaluated from January 2012 to June 2014; 64 reported pain and 62 did not. Patients with cancer eligible for this study were older than 18 years and able to effectively communicate with medical personnel. Patients were administered a questionnaire regarding their medical status. The information collected was used along with patient charts to complete a socio-demographic and clinical characteristic summary for each patient. Results showed that patients who reported pain had mean State-Trait Anxiety Inventory (STAI) scores of 46.38 for state anxiety and 44.64 for trait anxiety, as well as a mean BDI (Beck Depression Inventory) score of 19.17. The pain-free patient group had mean STAI scores of 40.73 for state anxiety and 42.87 for trait anxiety, and a mean BDI score of 15.35. In conclusion, patients who reported pain were more prone to anxiety and depression, with pain severity being a strong predictor of anxiety. Adequate pain assessment and adjustment proved necessary for pain management. Pain is one of the most common symptoms for patients with cancer. Despite established cancer pain management guidelines, more than 50% of patients do not obtain adequate pain relief, and undertreatment of pain is still a widespread problem worldwide12et al.In the early 1990 s, Wang, Two decades have passed since then and we believe that overall pain control has been greatly improved in China, given the gradually increased availability of opioids and better attitudes and skills of physicians regarding cancer pain treatment. However, no published study has reassessed cancer pain and pain treatment in Mainland China in recent years; thus, specific strategies for further improvement remain ambiguous. We have evaluated and analyzed the pain experienced by Chinese patients with cancer and its management. Furthermore, we assessed the level of anxiety and depression in patients who reported experiencing pain.Anxiety and depression are the most common psychological symptoms in patients with cancer pain56Since previous studies have demonstrated that patients with cancer without pain also presented with higher levels of anxiety and depression compared with healthy controls89A controlled cross-sectional study was conducted at the Medical Oncology Department of the First Affiliated Hospital of Chinese PLA General Hospital, a 1000-bed tertiary teaching hospital in Beijing, China. The study protocol was approved by the Ethics Committee and the Institutional Review Board of the First Affiliated Hospital of Chinese PLA General Hospital. Informed consent was obtained from each patient participating in this study after explaining the risks and benefits of the study in an ethical manner. The methods were carried out in accordance with the approved guidelines. All experiments were performed in accordance with the Declaration of Helsinki.Each group had an equal number of outpatients, recruited based on the presence or absence of cancer pain. The authors of this study trained physicians regarding patient enrollment based on complaints, symptoms, and imaging data. Patients with pain were enrolled in the pain group and patients without pain were enrolled in the non-pain group at a 1:1 ratio. Pain status was assessed verbally by asking if the patient experienced pain during the previous week and patients were categorized into the respective groups. Pain assessments were performed with the pain-group patients, evaluating intensity, pattern, and relief.Patients who met the following criteria were considered eligible for inclusion: (1) had received a cancer diagnosis, with no limitation for types of cancer or staging, and no limitation for cancer therapy status; (2) were over 18 years of age; (3) were conscious and able to read, write, and communicate. Patients who had a lifetime history of psychopathology or cognitive impairment were excluded.The study was conducted from January 2012 to June 2014. In total, 130 patients with cancer were enrolled in the study: 65 patients with, and 65 patients without pain. Of these patients, 126 were deemed eligible to participate in the study and were evaluated (64 with pain and 62 without pain). One patient in the pain group and 3 in the pain-free group were excluded due to their apparently contradictory or inconsistent responses on the questionnaires. Patients were enrolled into either the pain or pain-free groups according to their pain status.p = 0.03), and a significantly higher proportion of patients who were not currently receiving anticancer treatment (p = 0.01)  in the pain group ( = 0.01) .All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) for Windows 17.0 . Statistical significance was based on two-sided tests evaluated with 95% confidence intervals. Continuous variables were expressed as means and standard deviations (SD) and were evaluated using the Student’s t-test and one-way analysis of variance (ANOVA). Categorical variables were expressed as numbers and percentages and were evaluated using the Fisher’s exact test and Chi-square test. Mean STAI-S, STAI-T and BDI-II scores of the two groups were analyzed for significant differences. A cutoff value of 14 on the BDI-II was used to identify moderate to severe depressionp ≤ 0.25 and/or r ≥ 0.25). Multiple linear stepwise regression analyses were employed to determine the impact of pain-related variables on anxiety or depression when other identified predictors were controlled . Residual diagnostic tests were performed to evaluate the appropriateness of the selected regression models.A one-way ANOVA was used to identify possible predictors among categorical variables. Correlation coefficients were used for continuous, ordinal, and binary variables. A predictor was considered to be a candidate if it exhibited at least a marginal association , and a significantly higher proportion of patients who were not currently receiving anticancer treatment (p = 0.01) (We observed a significantly poorer ECOG PS for the pain group ( = 0.01) .In the pain group, 62.5% of patients experienced severe pain (40/64), 15.63%) had moderate pain (10/64), and 21.88% indicated mild pain (14/64).Pain severity/interference and the percentage of pain relief for the pain group are presented in The average duration of cancer pain was 15.64 weeks . Almost half (48.44%) of patients had cancer pain for less than 12 weeks, 34.38% for less than 6 months, and 17.19% for more than 6 months.Analgesics administered to patients are listed in Additionally, the PMI scores calculated were −3 for 2 patients, −2 for 4 patients, −1 for 10 patients, 0 for 35 patients, 1 for 3 patients, and 2 for 10 patients. No patients had a PMI value of 3 which might indicate that no patients had complete pain relief. In summary, 25% (16/64) of patients had a negative PMI, and 75% (48/64) had a PMI score of ≥0.p = 0.0001) and depressed mood based on the Beck Depression Inventory II  than did the pain-free group. However, there was no observed significant difference in trait anxiety between the two groups. The prevalence of depression, as measured by the BDI-II with a cutoff value of 14, was significantly higher in the pain group  than in the pain-free group .As shown in p = 0.002), duration of pain , and the worst level of pain intensity .The impact of pain on these two symptoms was studied further using univariate analysis . In patiMultiple linear stepwise regression analyses were performed to examine the psychological impact of pain, measured by the patients’ reported anxiety state and depression and the results are summarized in Tolerances for all independent variables ranged from 0.91 to 0.99. Therefore, multicollinearity did not exist in the two models that were used. Standardized residuals were normally distributed, indicating that there was no discernible pattern of correspondence between the residuals and predicted values. These features were consistent with the assumptions of the linear regression modelIn this study, over 60% of patients in the pain group reported severe pain. The levels for the worst and the average pain intensities experienced by the pain group remained moderate. Pain had a moderate effect on four of the seven interference items and only 47% of participants indicated pain relief. However, more than 90% of patients in the pain group were given analgesics. Among them, 80% were taking strong opioids and 81% received analgesia ATC. Additionally, only a quarter of patients had a negative PMI score. The proportion of negative PMI scores in our study is similar or better than that indicated by two recent multicenter surveys1A seemingly acceptable proportion of negative PMI scores with relatively low patient-reported percentages of pain relief shown in this study led to the reconsideration of the role of the PMI in evaluating pain management and the reasons for inadequate pain control. Given the subjective nature of pain, we believe patient-reported pain relief is the “gold standard” in evaluating pain management. We also agree that negative PMI values always indicate the undertreatment of pain. Studies have shown high congruence between these two variables, but positive PMI scores do not signify adequate pain control2425From this point of view, most cancer pain in the present study was not effectively controlled. Two factors might have resulted in the uncontrolled cancer pain. First is inadequate opioid dose. While a majority of patients in the pain group were prescribed strong opioids, a rational dose escalation was not obviously achieved. The second factor is the underutilization of adjuvant analgesics. Cancer pain is multifactorial and often involves inflammatory and neuropathic components and, therefore, the appropriate use of adjuvant agents is necessary to mitigate the pain. However, most physicians lack experience in the use of these drugs. In Mainland China, these two factors are widespreadSeveral further issues exist that hinder the adequate use of analgesics in China, such as generally low levels of patient compliance for analgesics, a lack of specialized palliative care teams, and a very complicated procedure for opioid prescription. The undertreatment of cancer pain in this study emphasizes the importance of reassessing cancer pain and analgesic regimes, including frequency and dose adjustment. The barriers to adequate pain management also need to be reviewed and gradually overcome.The present study also investigated the influence of cancer pain on anxiety and depression. The relationship between cancer pain and psychological distress has been well studied. Zaza and BaineIn this study, the STAI and BDI-II were applied to assess anxiety and depression. The advantage of these two measurements in evaluating patients with advanced cancer with multiple symptoms has been identified29The present study indicates that, compared to pain-free patients, patients with cancer pain had significantly higher levels of both state anxiety and depression, but not trait anxiety. Furthermore, the prevalence of depression was also significantly higher in patients with pain. Considering the pain status of the participants, the results indicate that uncontrolled pain was a significant risk factor of state anxiety and depression for patients with cancer in Mainland China. Effort has been made to find a controlled study in publication using the STAI and BDI-II simultaneously, without success. Thus, a direct comparison of the levels of state anxiety and depression of patients from the two groups in this study with those from previous publications was not possible. However, an uncontrolled study employing the same pain and psychological measurements as those in our study identified similar levels of anxiety and depression in American patients with cancer painThe necessity of a control group was demonstrated in our study by the pain-free patients reporting some degree of anxiety and depression. The levels of state and trait anxiety of the pain-free group were in agreement with previous studies833In this study, the impact of cancer pain on state anxiety and depression was further clarified. The worst and average pain intensity levels were identified as significant predictors for state anxiety and depression. Based on the degree of variance explained in each regression model, pain intensity correlated much better with anxiety than with depression. This finding was supported by Chung and Tso’s reportIn this study, both anxiety and depression could be predicted by the duration of cancer pain and the patient’s ECOG PS. These findings in Chinese patients with cancer are consistent with the previously reported negative correlation between the length or duration of cancer pain and psychological distress363338In this study, anticancer therapy was a significant predictor of SA. It is noted that this variable and the ECOG PS differed significantly between the pain and pain-free groups. These results indicate that cancer pain decreased patients’ quality of life and may have prevented them from receiving anticancer therapy. Therefore, multicollinearity between pain-related factors and these two variables should be tested. However, the independent variables in the final regression model were not collinear, based on the collinearity diagnostics. This study indicated that cancer pain is a key factor negatively associated with the ECOG PS, not exclusive to patients with advanced cancer. We also believe the subjective feeling of not receiving anticancer therapy may induce an anxious reaction regarding the disease progression or future life expectancy, possibly explaining the negative influence on patients’ anxiety.The impact of other previously identified socio-demographic predictors4041In this study, there were several limitations. Initially, these findings are mainly applicable to Chinese patients with cancer pain experiencing symptoms associated with depression and anxiety. These findings are not representative of patients in other cultures or different regions or locations. Moreover, the use of convenience sampling and the relatively small sample size limit the generalizability of these findings. The potential for sampling bias may exist from the study design as patients were selected based on a specific list of criteria. The participants of the two groups were taken from a limited sample and may not be representative of the entire population. Additionally, other potentially relevant correlates, such as concurrence symptoms, social supports and coping strategies for pain were not analyzed together. The time between intervals of pain in patients might have introduced recall bias in understanding their own pain, depression, and anxiety relative to the cancer pain. In addition, the pain-free group was not evaluated with the ABI-II. Heterogeneity existed between the specific cancer diagnoses received by patients and this may have played a role in the pain, anxiety, and depression responses.Furthermore, the neoplasm stage was not taken into account. Therefore, the variance of SA and depression could only be partially explained by the identified variables. There are some limitations to the study design, particularly in that relying on patient-reported anxiety and depression scales can present a less objective method to quantify and rationalize data, resulting in less statistical significance. Moreover, the methods to screen for anxiety and depression in patients were not diagnostic but symptomatic evaluations. In this respect, some of the patients might not have had a clear diagnosis of anxiety or depression. However, the results of the study did present the current situation of cancer pain control and extend previous findings regarding the impact of cancer pain on anxiety and depression in Chinese patients.In conclusion, despite the relatively low proportion of negative PMI scores, cancer pain was not effectively treated. Compared with the pain-free group, the pain group demonstrated significantly lower ECOG PS, fewer patients receiving anticancer treatment, and higher means STAI-S and BDI-II scores. Predictors of SA and depression included the worst and average levels of pain intensity, duration of cancer pain, ECOG PS, and whether or not anticancer therapy was received. With respect to the proportion of total variance, the worst pain intensity level played the most important role in predicting SA. The frequent assessment of cancer pain and the adjustment of analgesic regimes are critical. Based on these findings, we believe psychological screening should be routinely performed with patients experiencing cancer pain, with poor ECOG PS, and who are not receiving anti-cancer treatment.How to cite this article: Li, X.-M. et al. Psychological distress and cancer pain: Results from a controlled cross-sectional survey in China. Sci. Rep.7, 39397; doi: 10.1038/srep39397 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.