Radiotherapy is a very effective tool in the treatment of painful bone metastases. The aim of this study was to compare the palliative effect of radiotherapy between the standard fractionation schedule 20 Gy over 5 fractions (20Gy/5fr) and the high biological dose schedule 27 Gy over 3 fractions (27Gy/3fr) which is frequently used in Stereotactic body radio-surgery (SBRT). Patients were randomized to receive (20Gy/5fr)or (27Gy/3fr). The primary aim of the study was pain relief using the numeric rating scale (NRS), after three months of radiation therapy. Secondary end points include pain relief immediately after finishing radiation therapy (within one week), and narcotic relief after three months of radiation therapy. Twenty-two patients with painful bone metastases were included. 12 patients received (20Gy/5fr) and 10 patients received (27Gy/3fr). Male patients were predominant on both arms (81.8%) with a mean age of 58 years [ranging between 19-72 years]. For pain relief after three months of radiation therapy, partial pain relief was documented in 9 patients (75%) with (20Gy/5fr) and in 8 patients (80%) with (27Gy/3fr) with a p- value of 0.6. Additionally, narcotic relief after three months was equal for both groups. For immediate pain relief, partial pain relief was seen in one patient (8%) with (20Gy/5fr) versus seven patients (70%) with (27Gy/3fr) with a p value of 0.06. The increase in immediate pain relief in the 27Gy arm was numerically but not statistically significant. SBRT and standard fractionation radiation therapy had equal effectiveness for pain relief, when the assessment was done after three months of radiation therapy. Interestingly, SBRT had a better immediate pain relief.  Painful bone metastasis is a major problem for cancer patients. In addition to pain, the high incidence of presence of skeletal related events like pathological fracture, spinal cord compression and hypercalcaemia can lead to major disability of cancer patients. Data from lung and breast cancer patients proved that patients with bone metastases had a shorter overall survival than patients without bone metastases. .External beam radiation therapy is one of the main lines of palliative treatment of bone metastases; it can provide 50-70% partial pain relief and 15-25% complete pain relief. Different dose schedules are used, ranging from 40 Gy over 20 fractions, 30 Gy over 10 fractions, 20 Gy over 5 fractions and only a single fraction 8 Gy. Published data proved that all had an equivalent palliative effect. However, the use of a single-fraction was associated with more pathological fractures and the need for re-irradiation. On the other hand, new data support the use of stereotactic body radiotherapy (SBRT) for the palliation of bone metastases. With this technique, we can deliver high radiation dose per fraction. It is safe, achieves good tumor control and palliation of pain. The dose of radiation therapy in SBRT was also variable, ranging from 24 Gy in a single fraction, 27 Gy in three fractions, or 30 Gy in five fractions. Accordingly, we have two different approaches; the traditional radiation therapy or the high biological dose using SBRT. We planned to do a pilot randomized phase II trial comparing both approaches. We chose 20 Gy over 5 fractions as the best suitable schedule for the traditional approach and 27 Gy over three fractions for SBRT approach. In order to know which is more beneficial for our patients, we chose pain relief at three months as the primary end point.The study protocol was approved from the center scientific committee. It was a prospective randomized phase II pilot study comparing 20 Gy over 5 fractions versus 27 Gy over 3 fractions, as a different schedule of radiation therapy for painful bone metastasis.Patient populationTwenty-two patients were recruited according to inclusion and exclusion criteria. Patients were eligible if they were 18 years of age or older and had histologically proven primary malignancy and radiographic evidence of bone metastasis. For example, in the case of spinal metastasis, the presence of spinal instability or neurological deficit may preclude patients from the study as the results may be biased by the surgical treatment required. A maximum of three distinct bone metastases were allowed. Karnofsky performance status of at least 40 was allowed. A Lesion less than 5mm from spinal cord may make SABR regimens difficult to apply due to danger of exceeding spinal cord tolerance. The main exclusion criteria were previous radiation therapy to the affected painful site, pathologic fracture or impending fracture of the treatment site, if there was a clinical or radiographic evidence of spinal cord or cauda equine compression. Haematological tumours are excluded from the study since they are more radiosensitive and respond well to lower doses per fraction and total doses. Patients receiving bone-supporting drugs such as Bisphosphonates or denosumab were included.Aim of the studyThe aim of this study was to compare the pain-relieving efficacy of 20 Gy in 5 fractions versus 27 Gy in 3 fractions in patients with painful bone metastases. The primary aim of the study was pain relief using numeric rating scale (NRS) after three months of radiation therapy. Secondary end points include pain relief one week after finishing radiation therapy, narcotic relief after three months of radiation therapy.Pain assessmentBaseline pain assessment by using a numerical rating scale from 0 to 10 where 0 indicates no pain and 10 indicates severe pain. Patients rated their pain from 0 to 10 prior to start of radiation therapy. The score is recorded along with the analgesic used and its dose. Radiation therapy steps and techniqueRadiation therapy technique was done by the following stepsCT scanCT scanning was carried out with the patient lying comfortable and supine. Midline and lateral laser lines were used for target localization, with radio-opaque markers being utilized for visualization of the reference points on the CT image. Centres were tattooed for reproducibility. Images were then transferred to the treatment planning system (Eclipse version 11). ContouringGross tumor volume (GTV) was delineated guided by available diagnostic imaging modality  and a margin of 0.3cm (Planned tumor volume or PTV) was taken around the GTV. Risk structures were contoured according to the site of the bone lesion indicated for radiation therapy.PlanningPatients were planned either by 3D conformal or VMAT modalities, CT simulationVirtual CT simulation is done before start of treatment guided by the tattoo done earlier and the Digital reconstructed radiograph (DRR).VerificationOn the treatment machine daily online Electronic portal image device (EPID) was done to ensure proper positioning of the patients, as seen in Treatment given and Follow up Patients in the (20Gy/5fr) schedule received their fractions on five consecutive days. While in (27Gy/3fr) schedule, they received fractions on an every other day basis. After finishing the radiation treatment and after three months period, patients were asked to score their pain using NRS and the type of analgesic used and its dose was noted.Response categoriesPain relief can be classified into one of four categories.1) Complete pain relief: a pain score of 0 by NRS at the treated site with no increase in analgesic intake in comparison to baseline analgesic intake.2) Partial pain relief: a pain score reduction of 2 or more from baseline by NRS at the treated site without increasing analgesic intake, or analgesic reduction of 25% or more from baseline without an increase in pain.3) Stationary pain relief: any response that is not categorized as complete, partial pain relief, or pain progression.4) Pain progression: increase in pain score of 2 or more above baseline by NRS at the treated site, or an increase of 25% or more in analgesic intake compared with baseline.Statistical MethodsData were collected, tabulated and statistically analyzed using a personal computer with (SPSS) version 22 program. . P value of ≤ 0.05 was considered statistically significant. Chi-square test was used to assess whether the distribution of a categorical variable is significantly different between two or more groups. Tests of chi-square were used to determine whether there is an association between two categorical variables and used to detect any difference between the two test groups. The Wilcoxon test was used to test the null hypothesis that the median of the differences between pairs of observations is equal to zero.This pilot study was carried out in Kasr Al-Ainy Center of Clinical Oncology and Nuclear medicine (NEMROCK) during the period between May 2018 and January 2019.Twenty-two patients with painful bone metastases were included. Twelve patients received (20Gy/5fr) and 10 patients received (27Gy/3fr). Male patients were predominant on both arms (81.8%) with a mean age of 58 years [ranging between 19-72 years]. Only two patients in (20Gy/5fr) and one patient in (27Gy/3fr) were on chemotherapy. Different baseline characteristics of both groups are illustrated in Pain relief All 22 patients underwent pain relief assessment immediately and after three months of radiation therapy. Complete pain relief was not documented in any patient in both groups. Partial pain relief after three months was comparable with a p-value of 0.6. Immediate partial pain relief was seen in seven patients (70%) of 27Gy/3fr schedule versus only one patient (8%) in 20Gy/5fr schedule with a p-value of 0.06. The increase in immediate pain relief in the 27Gy arm was numerically but not statistically significant. Pain relief after 3 months of radiation therapy and immediate pain relief are illustrated in Although pain severity is significantly decreased in both arms, the need for analgesia remained the same for both groups when assessment was done three months after radiotherapy with the exception of one patient who developed pain flare and increased the dose of analgesics. Regarding the possible confounders as age, sex, being on active treatment and receiving bone supporting agents, all these factors did not affect the significance of pain score reduction with p- values 0.7, 0.1, 0.67 and 0.66 respectively which excluded these factors as confounders in both groups.This is a pilot prospective randomized phase II study for patients with painful bone metastasis, between two different radiotherapy schedules, 20Gy/5Fr versus 27Gy/3Fr. Accordingly, it is a comparison between the traditional palliative dose of radiation therapy using 2D or 3D techniques 20Gy/5Fr and the newly developed high biological dose, which is recently used by SBRT technique 27Gy/3Fr. Our question in this study was very clear and simple, which schedule is better for our patients. We used pain control after three months of radiation therapy as the primary end point. There is no other parameter to tell us which is better; except the patients themselves. So, we depend on NRS in pain relief assessment. We have selected pain relief after three months of radiation therapy as the primary end point, like many previous trials including The Radiation Therapy Oncology Group (RTOG) trial 97-14 , as it is the most reliable, simple and clear objective. Interestingly, we found that immediate pain relief after just finishing radiation therapy is very important as the primary aim was palliation, and the timing of palliation is very crucial for our patients. Our study documented that immediate pain relief was evidently better in (27Gy/3fr) schedule. However, both groups are equally effective according to the pain assessment that was done three months after the radiation therapy. Thus, we reached a conclusion that high biological dose can provide faster pain relief. This prompts the recommendation of performing future trials with larger study populations to confirm this finding. Other important parameters that should be taken into consideration include; cost of the treatment, time taking for delivery of radiation therapy, availability of the new machines and the palliative aim of treatment. All these parameters are in favor with the use of traditional schedules of radiation therapy. Accordingly, in order to apply SBRT we have to have significant better results in comparison to the traditional techniques. Delivering SBRT with high dose per fraction using sophisticated techniques in radiation therapy requires meticulous care starting from the patient selection, fixation technique up to the daily verification methods. This raised a point that using SBRT for pain control is equally as effective as traditional radiotherapy techniques and hence to control pain symptom is not essential.We have not reported any case with complete pain relief, which opposes what was documented in the literature of approximately 15-25% complete pain relief . The explanation is that most of our patients are metastases from relatively radio-resistant primary tumors, hepatocellular carcinoma, sarcoma, and hormone-refractory prostate cancer. Additionally, most of our patients are not receiving concomitant active treatment. We believe that the small sample size may be a contributing factor.Almost all the patients remained on the same dose of analgesics after the 3 months possibly because no patient attained complete response based on our assessment and criteria except for one patient who developed pain flare and increased the dose of analgesics. Again, it can be explained by the type of patients and the relatively no concomitant active treatment.There was no statistically significant correlation found between age, sex, receiving bone-supporting agents, being on active treatment and response to pain possibly due to the low sample size. However, you can see the real palliative effect of radiotherapy when you do not give concomitant active treatment.The main limitation of this study is the limited number of patients. However, up to our knowledge this is the first study to do this comparison. In the near future, we are going to do this trial over a large number of patients in order to know which group of patients, which can benefit from high biological dose. And we can select one or two primary tumor e.g. breast or lung cancer, in order to get reliable results. A possible recommendation for larger studies in the future with longer follow-up may be the use of skeletal-related events occurrence  as an assessment tool comparing the utility of both fractionation schedules.In conclusion, although, we had an immediate better pain relief with SBRT. We did not find any difference in pain relief after three months of radiation therapy between SBRT and traditional palliative schedules. The traditional palliative schedules should continue to be the practice of our daily life in the treatment of painful bone metastases.


Low back pain (LBP) is the most prevalent musculoskeletal problem, which implies a high rate of chronicity. The chronicity of symptoms can lead to pain expansion. The main objective of this study was to assess whether there were differences between patients with nonspecific chronic LBP (CLBP) who sought healthcare compared to those who did not in terms of pain expansion.Ninety individuals participated in the study and were divided into three groups: 30 patients who sought care; 30 patients who did not seek care; and 30 asymptomatic individuals. The primary variable analyzed was pain expansion. Secondary physical and psychological variables were assessed later, and a regression analysis was performed.Patients who sought help showed significant differences in pain expansion and pain intensity compared with the group who did not seek help, with a medium effect size (0.50–0.79). The regression model for the care-seeking group showed that dynamic balance with the left leg and depression were predictors of percentage pain surface area (34.6%). The combination of dynamic balance, range of movement in flexoextension and depression were predictors of widespread pain (48.5%).Patients who soughtcare presented greater pain expansion than patients whodidnot. A combination of functional and psychological variables can significantly predict pain expansion in patients with nonspecific CLBP who seek help. Betweenhe pain” .Among the characteristics found in this population, it has been observed that individuals with chronic low back pain (CLBP) can present functional alterations, such as changes in dynamic stability or range of motion, physical alterations and somatosensory disturbances . All theCWP is defined as pain present on both sides of the body, involving an expansion to the upper limbs, the lower limbs and the axial skeleton . CWP is The main objective of this study was to assess whether there were differences between patients with nonspecific CLBP who sought health care compared with those who did not, in terms of pain expansion. The secondary objective was to determine which factors predictive of greater pain expansion are present in patients with nonspecific CLBP based on their search for care.This study was cross-sectional with a non-probabilistic sample, with the aim of assessing somatosensory, physical and psychosocial variables in patients with nonspecific CLBP who seek care or not and asymptomatic individuals. The trial was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement . FollowiThe participants were recruited between April 2017 and January 2018. The sample was recruited from our university campus and the local community through flyers, posters, social media and outpatients of a primary healthcare center in Madrid, Spain.A consecutive nonprobabilistic convenience sample of 90 individuals was recruited. Participants were classified into the following groups: group 1 was composed of 30 patients with nonspecific CLBP who did not seek care; group 2 was composed of 30 patients with nonspecific CLBP who sought care; and group 3 was composed of 30 asymptomatic individuals. The symptomatic participants were assigned to one group or the other according to whether they sought care from a health professional for their musculoskeletal condition. Those patients who at no time went to any health professional for their problem were classified in the non-care-seeking group. These patients were recruited via flyers placed at the university center and in the local community. The patients who had gone to a primary care doctor due to the presence of CLBP were assigned to the care-seeking group, given they had an intention to be treated.Patients with nonspecific CLBP were selected if they met the inclusion criteria defined by the National Institute for Health and Care Excellence in the LBP Guidelines defines the nature of LBP as “Tension, soreness and/or stiffness in the lower back region for which it is not possible to identify a specific cause of the pain. Several structures in the back, including the joints, discs and connective tissues, may contribute to symptoms” . The folIndividuals were excluded if they met any of the following exclusion criteria: (a) comorbidities, such as the presence of neurological signs , systemic rheumatic disease  or central nervous system disease; (b) the presence of psychiatric diagnosis or severe cognitive impairment; (c) illiteracy; (d) understanding or communication difficulties; and (e) insufficient Spanish language comprehension to follow measurement instructions.Finally, asymptomatic individuals were excluded if they had a history of spinal pain, another condition of chronic pain or had a diagnosis of any systemic disease.After consenting to participate, all the participants received a sociodemographic questionnaire to complete on the day of the measurement, which collected sex, date of birth and educational level. Next, each participant completed a set of self-report measures, and we evaluated the pain drawings in both the care-seeking and non-care-seeking groups.Next, the evaluator conducted a semi-structured interview with each of the patients in which questions were asked about their symptomatology , demographics and certain questions to determine whether they were in search of treatment, based on previous literature . Once thFinally, a physiotherapist instructed the patients regarding the physical test to be performed, and they were supervised during the session. The first test that was performed was an evaluation of the range of movement in flexoextension (ROMFE) and lateral flexion movements (ROMLF). The protocol for measuring range of motion consisted of the following process: the patient was placed in a standing position with arms along the body; the physiotherapist marked the spinous process of T12 and S2 to place the mobile device; the patient was then asked to perform a maximum trunk flexion , followeThe final test that was performed was the evaluation of dynamic balance by means of the Y Balance Test (YBT). This test was performed in a single-limb stance while simultaneously moving the nonstanding limb in 3 different directions: anteriorly, posteromedially and posterolaterally . The comP < 0.001. The inter-rater reliability for the measurement was ICC = 0.989; 95% CI [0.980–0.994]; P < 0.001 (Pain drawings (PPSA and WP) were assessed using open-source software to calculate the total body area in each pain diagram , which h < 0.001 .r = 0.94, P > 0.001)  .The frequency of pain was evaluated based on the number of days with pain during the last month .The frequency of medication was evaluated based on the number of days the patient had taken medication for LBP in the last month .The physical activity (PA) level was measured using the International Physical Activity Questionnaire in its short version. It consists of 9 items that quantify the time that the individual devotes to perform any PA of vigorous or moderate intensity. This questionnaire presents an ICC of 0.76 (95% CI) .The range of motion was evaluated with a digital inclinometer based on the mobile application, iHandy. It has been shown to have good intrarater and inter-rater reliability, with ICC over 0.80 (95% CI) .Dynamic balance was measured using YBT. The YBT has shown good to excellent intrarater (0.85–0.91) and inter-rater (0.99–1.00) reliability .Aanxiety and depression levels were assessed using the Hospital Anxiety and Depression Scale (HADS). The scale has two subscales of 7 items each that measure anxiety and depression . The HADFear of movement was assessed using the 11-item Spanish version of the Tampa Scale of Kinesiophobia (TSK-11), which has a Cronbach’s alpha of 0.78 . The finPhysical disability due to LBP was assessed using the Spanish version of the Roland-Morris Disability Questionnaire (RMDQ), which presented an internal consistency  of 0.84 to 0.93 and test–retest reliability ranging between 0.72 and 0.91 .d) of 0.66. The sample size was estimated with G*Power 3.1.7 for Windows  , and an effect size of 0.66. A total sample size of 60 patients (30 non-care seekers with nonspecific CLBP and 30 care seekers with nonspecific CLBP) was estimated to ensure reliability.We conducted a pilot study to determine the effect size between non-care seekers with nonspecific CLBP and care seekers with nonspecific CLBP using a pain drawing. The pilot study included 15 patients from each group and obtained an effect size (Cohen’s Germany) . We opteThe sociodemographic and clinical variables of the participants were analyzed. The data were summarized using frequency counts, descriptive statistics, summary tables and figures.- test was used for the nonspecific CLBP group comparisons . Cohen’s d effect sizes were calculated for a post hoc analysis of the outcome variables. According to Cohen’s method, the magnitude of the effect was classified as small (0.20–0.49), medium (0.50–0.79) or large (0.80).The data analysis was performed using the Statistics Package for Social Science . The categorical variables are shown as frequency and percentage. The quantitative results of the study are represented by descriptive statistics . For all variables, the z-score was assumed to follow a normal distribution based on the central limit theorem, given the groups had more than 30 participants . Studentpost hoc test with Bonferroni correction. We calculated the partial eta-squared  was used to analyze numerical variables among the asymptomatic participants, the care-seeking group and the non-care-seeking group . Significant ANOVA findings were followed up using a ectively .p-values using the Benjamini–Hochberg method was used . The FDR correction ensures that in no case, if working with 95% confidence, will there be more than 5% of variables in which a false positive has occurred , A total of 90 participants completed the study . t-test (for independent samples) revealed significant differences between the groups for PPSA  and WP . Statistically significant differences were observed in the pain drawing, with pain expansion greater in care seekers  and 2. St =  − 2.35; q = 0.03; d =  − 0.73) and frequency of medication  between care seekers and non-care seekers, with higher intensity in care seekers. Data with respect to physical, somatosensory and psychosocial variables are summarized in Regarding the secondary variables, the strongest results showed significant differences in pain intensity , the association between depression and the number of pain sites  and the association of the same variable with PPSA . Finally, a negative correlation was also established between the ROMFE and the PPSA  and between the days of medication intake and the number of pain sites   .In contrast, in the group of patients with nonspecific CLBP who did not seek care, we found no correlation between the main variable of the study and variables of a functional or psychological nature .The regression models for the criteria variables (PPSA and WP) are presented in The main differences between the patient groups analyzed in this study concerned pain expansion. Individuals who sought care had almost double the number of regions affected by pain than those who did not seek care.The body pain diagram is a tool that provides relevant information. Its use has also been considered for assessing the psychological state of patients due to the greater the number of pain areas and the greater impact that psychological factors exert on the clinical condition . In our Along these lines, our results found that those patients with greater pain expansion who also sought care presented a significantly greater restriction of movement compared with the other groups. Other studies have shown that individuals with LBP had greater restriction of movement and slower speed of execution compared with asymptomatic individuals . This reIn terms of dynamic stability, our results demonstrated significant differences between both symptomatic groups with respect to the asymptomatic group. The evidence available thus far shows that dynamic balance is reduced in patients with LBP . MoreoveIt is important to define, taking into account the results obtained, which factors can influence the search for care in patients with CLBP. Numerous studies have determined that the rate of transition from non-CWP to CWP varies from 9% to 25% . A recenThe most recent systematic review determined that due to the current methodological heterogeneity, it is difficult to clearly determine which social factors might lead to the search for health care. Even so, it is estimated that the prevalence rate of health system use by LBP in Europe is lower than in other countries such as the United States . In relaOn the other hand, certain characteristics of the pain experience, such as pain intensity, are factors related to the search for health care . Given tSimilarly, one study on patients with CLBP determined that impaired functionality and disability are factors positively associated with care seeking . TherefoPsychological factors also have a great influence on patients with chronic pain; the most influential are fear of movement, anxiety and depression. The results of this study showed significant differences between all study groups; fear of movement was the most notable difference between individuals with CLBP seeking help and asymptomatic individuals, with a large effect size. In relation to our results, one study had shown that in patients with temporomandibular dysfunction, the decision to seek care was correlated with higher pain intensity and greater fear of movement . This ouThese results could also be due to a statistically significant difference in the level of physical activity (PA) between groups, which can contribute to an alteration of the pain inhibitory system; however, it has also been observed that patients with chronic pain who perform PA can improve their symptomatology and physical function . Even soIn contrast, the combination of psychological variables such as fear of movement and disability as well as pain intensity, predicted dynamic stability in 43.8% of the individuals with chronic hip pain . These dFinally, taking into account the prognostic factors in CLBP, the presence of depression and anxiety influence the maintenance and recurrence of symptoms . A studyThis study has several limitations. First, the patients seeking help in this study presented a lower level of PA compared with asymptomatic individuals and with patients with nonspecific CLBP who did not seek help. A systematic review had determined that the evidence is limited in terms of improvement in pain severity as a result of exercise, instead determining that there is an improvement in physical and psychological variables through this intervention . AnotherWe recommend a more exhaustive evaluation based on somatosensory variables  in the future to determine the presence of a central sensitization process.Another limitation is the selection of patients. Individuals with a medical diagnosis of fibromyalgia were excluded. It is possible that there were some cases with similar characteristics to this pathology, which should be taken into account. Schaefer et al. had concluded that future studies are necessary, to determine the presence of fibromyalgia or CWP, given errors can be made in sample selection due to the fact that these are different clinical conditions according to the International Classification of Functioning, Disability and Health .p-values using the Benjamini–Hochberg method .One of the main limitations of this study is the possibility of a type I error, which has been solved by adjusting the Finally, the results of the present study should be interpreted with caution, given it is a cross-sectional study; thus, causal relationships cannot be established.The results of this study show that patients who sought care presented greater WP than patients who did not seek care. In addition, psychological and disability factors have a greater influence on the experience of pain in patients with nonspecific CLBP who seek care, as well as their having a reduced range of motion and less ability to discriminate two points. The CRD L, depression and days of medication per month were covariates of PPSA (34.6% of variance), and the composite reach distance percentage of the left leg, depression and ROMFE were covariates of WP (48.5% of variance) for patients with nonspecific CLBP who sought care.10.7717/peerj.8756/supp-1Data S1Click here for additional data file.


Pregabalin is commonly used to relieve neuropathic pain. However, data are lacking on its efficacy for the treatment of chronic cancer pain. The purpose of this study was to determine the analgesic efficacy of pregabalin combined with morphine in the management of pancreatic cancer pain.This study reviewed patients who were prescribed morphine and 150 mg/d pregabalin between 1 January 2017 and 10 November 2018 in our institute. The primary outcomes of this study were the average pain score and dose of morphine. Secondary outcomes included characters of breakthrough cancer pain, functional interference related to pain, anxiety/depression status, and incidence of treatment‐related adverse events during the study.p <  0.001). The change of functional interference score related to pain was significantly different between combination and monotherapy group . Patients in combination therapy group had experienced shorter duration of breakthrough cancer pain than those in monotherapy group . The incidence of somnolence, dizziness, and cognitive dysfunction were significantly higher in the combination group compared to monotherapy group. No serious treatment‐related side effects were observed.A total of 240 patients with pain related to pancreatic cancer were included in the study. The results showed that patients of both combination therapy group  and monotherapy group (morphine) achieved similar analgesic efficacy, demonstrated by NRS  at the end of the study. Mean daily dose of morphine used in the combination group was significant lower compared to monotherapy group (39.5 ± 16.0 mg vs. 61.5 ± 19.3 mg, net difference 23.5, 95% CI: 18.4–28.6, The findings of this study supported the use of pregabalin with morphine to relieve pain in patients of pancreatic cancer. Cancer related pain is difficult to manage and caused significant lower quality of life in pancreatic cancer patients. Pregabalin has been widely used for the management of neuropathic pain including cancer related neuropathic pain. This study demonstrates that pregabalin and morphine combination achieved satisfactory analgesic effect with significant lower dose of morphine compared to morphine treatment alone. The finding of this study provides evidence for using pregabalin with morphine in the palliative treatment of pancreatic cancer pain. The prevalence of cancer pain is approximately 50% at the early stage and is 75% at advanced stage.To reduce the dose and minimize side effects of opioid medications, multimodal analgesia combining various analgesics with different mechanisms is used in chronic cancer pain management. Adjuvant drugs such as hormone steroids, nonsteroidal anti‐inflammatory drugs (NSAIDs), antidepressants, and anticonvulsants are commonly applied with opioid medications in the treatment of chronic cancer pain.22.1The study was conducted at the Department of Pain Medicine in Harbin Medical University Cancer Hospital between 1 January 2017 and 16 November 2018. The protocol was approved by the Institutional Review Board of Harbin Medical University Cancer Hospital. We identified patients with a diagnosis of pancreatic cancer in our hospital electronic information system. The data were collected and reviewed by research assistants and student. During this period, a total of 368 patients of pancreatic cancer were admitted for analgesic treatment in our department. Patients of pancreatic cancer were included in this study if they had pain symptom related to local pancreatic cancer lesion. Patients with neuropathic pain caused by chemotherapy were not included. Patients with other conditions that might induce pain such as biliary obstruction, cholangitis, or infection, change of analgesic therapy with the potential to influence pain such as addition of anticonvulsants, antidepressants, or NSAIDs during the study were not included. Patients were excluded if they lacked follow‐up data. After selection, 240 patients were included in the study. Patients were divided into two groups according to analgesic type: monotherapy  and combination therapy .2.2Two groups of patients were reviewed based on the medications used. Patients in the combination group received Morphine Hydrochloride Sustained‐Release Tablet  orally every 12 h with pregabalin Capsules  75 mg twice a day. Patients in the monotherapy group received Morphine Hydrochloride Sustained‐Release Tablets orally every 12 h alone. Immediate release Morphine Hydrochloride Tablets  were provided for the rescue management of breakthrough pain. The dosage of Morphine Hydrochloride Sustained‐Release Tablets was determined by titration to control Numerical Rating Scale (NRS) score less than or equal to 3.2.3The primary outcome were pain reduction on the basis of NRS score and dosage of morphine by week 4. NRS score was assessed on a 0–10 numerical scale with 0 corresponding to “no pain” and 10 to “the worst possible pain.” Mean dosages of daily morphine were recorded. Secondary outcomes included assessment of functional interference related to pain ,2.4p < 0.05 statistically significant. Analysis of covariance and a repeated measures model were used to analyze NRS, dose of morphine, BPI score, and HADS score. Characters of breakthrough cancer pain and adverse events outcomes were compared between groups using x2 test and Cramer's V.All the statistical analyses were calculated using SAS, 9.2 software (SAS Institute). Patient demographics and characteristics were expressed as mean , number and percentage. We considered 3The patient disposition is shown in Table p = 0.27). After 4 weeks, the mean NRS score had decreased to 2.4 ± 0.9 in the combination group and 2.6 ± 0.9 in the monotherapy group (p = 0.184).Table p < 0.001).Table 2p < 0.001, Cramer's V:0.36).Table p = 0.813). The reduction of mean BPI interference total score was significantly greater in combination group than monotherapy group . There was significant difference in change of HADS score between combination group and monotherapy group .Table 2p = 0.001; Cramer's V:0.22). Patients in the combination group experienced more cognitive disturbance , somnolence , and dizziness  than the patients in the monotherapy group. No serious adverse events including angioedema, seizure, decreased level of consciousness, respiratory depression, or increased suicide risk were reported.Table 4Our study is the first to demonstrate that coadministration of pregabalin with morphine achieved satisfactory analgesic efficacy in patients of pancreatic cancer with reduced dose of morphine. This finding has considerable implications for clinical practice because pregabalin has been increasingly used in the setting of cancer‐related pain. However, the use of pregabalin in patients with cancer pain are usually from anecdotal experience with limited or no evidence from clinical trials.The mechanism of pancreatic cancer pain is complex. Inflammation in tumor microenvironment, direct infiltration of sensory neurons by tumor, and neuroplastic changes in the sensory neurons all contribute the background pain and unpredicted breakthrough pain episodes in patients of pancreatic cancer.Several studies have shown the analgesic efficacy of using pregabalin in perioperative setting.In this study, both groups achieved satisfactory analgesic effect. The pain intensity reduction compared to baseline in the combination group and monotherapy group was 4.0 and 3.7, respectively. The mean daily dose of morphine in the combination group was 39.5 mg which was significantly lower compared to the 61.50 mg in monotherapy group. Addition of pregabalin resulted similar analgesic effect with 36% reduction of morphine dose in patients with pancreatic cancer pain. The dose change usually starts from 25% to 50% of the baseline when titrating the dose of morphine,Cancer pain is usually accompanied with psychological distress such as anxiety and depression. In this study, we used HADS to assess the change of anxiety and depression before and after the analgesic treatment. We found that patients in the combination therapy group have better improvement of HADS score than the monotherapy group. The established application of pregabalin for general anxiety may contribute the improved HADS score. We have also found that pregabalin and morphine combination treatment resulted in notable improvement in quality of life versus morphine monotherapy. Patients in the combination group had significant less pain‐related interference with patients’ normal work, sleep, and enjoyment of life. This finding is consistent with previous reports of combination of gabapentinoid with morphine improved quality of life.Patients in the combination group experienced more adverse events than those in the monotherapy group. The incidence of somnolence, dizziness and cognitive dysfunction occurred more frequently in the combination group. The effect of pregabalin in the central nervous system may contribute to the increased incidence of adverse events. However, the side effects related to pregabalin are generally mild and tolerable. No serious side effects such as angioedema, seizure, decreased level of consciousness, respiratory depression, and increased suicide risk severe side effects were observed in the study.Breakthrough pain caused by pancreatic cancer has a significant impact on the patient's life. The mechanism of breakthrough pain has not been fully understood. Persistent noxious stimuli such as inflammation‐induced peripheral and/or central sensitization may partly contribute to the incidence of breakthrough cancer pain. No change of the number of episodes or intensity of breakthrough pain were found in this study with the coadministration of pregabalin with morphine compared to monotherapy group. However, the duration of breakthrough pain episodes in the combination group was significantly shorter than the monotherapy group.There are some limitations in this study. This study is a retrospective study and a randomized prospective study is needed to validate our findings. The dose of pregabalin in this study was fixed at 75 mg twice a day. This dose was used in our clinical practice to ensure no serious sedation or respiratory difficulty occurred. A personalized higher dose of pregabalin may achieve better analgesic efficacy. The follow‐up period of this study was 4 weeks. A longer follow‐up period is needed to validate the analgesic efficacy and impact on quality of life of pregabalin in patients with pancreatic cancer.In conclusion, this retrospective study showed that pregabalin and morphine combination therapy achieved satisfactory analgesic efficacy with lower dosages of morphine in patients with pancreatic cancer pain. Our results supported the use of pregabalin with morphine in patients who have pancreatic cancer‐related pain.The authors declare that they have no conflict of interest.This study was conducted in accordance with principles for human experimentation as defined in the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines, and approved by the Institutional Review Board of Harbin Medical University Cancer Hospital. Informed consent from the patients was waived by the IRB because the nature of this retrospective study was reanalyzing of existing data which does not involve any potential risks and benefits to the patients.


What are indication-specific opioid prescribing rates for nonsurgical acute or chronic pain or postoperative pain conditions and pain related to cancer or sickle cell disease?In this cross-sectional analysis examining data from 18 016 259 patients with private insurance and 11 453 392 patients with Medicaid benefits, opioid prescribing rates, days’ supply, and daily dosage varied widely across clinical indications and by insurance type.Potential inconsistencies between indication-specific prescribing patterns and relevant clinical recommendations highlight opportunities for selection of safer and more effective pain treatment options. Although opioids can be effective medications in certain situations, they are associated with harms, including opioid use disorder and overdose. Studies have revealed unexplained prescribing variation and prescribing mismatched with patient-reported pain for many indications.To summarize opioid prescribing frequency, dosages, and durations, stratified across numerous painful medical indications.Retrospective cross-sectional analysis of 2017 US administrative claims data among outpatient clinical settings, including postsurgical discharge. Participants had any of 41 different indications associated with nonsurgical acute or chronic pain or postsurgical pain or pain associated with sickle cell disease or active cancer and were enrolled in either private insurance (including Medicare Advantage) in the OptumLabs Data Warehouse data set (n = 18 016 259) or Medicaid in the IBM MarketScan Multi-State Medicaid Database (n = 11 453 392). OptumLabs data were analyzed from October 2018 to March 2019; MarketScan data were analyzed from January to April 2019.Nonsurgical acute or chronic pain or postsurgical pain; pain related to sickle cell disease or active cancer.Indication-specific opioid prescribing rates; days’ supply per prescription; daily opioid dosage in morphine milligram equivalents; and for chronic pain indications, the number of opioid prescriptions.During the study period, of 18 016 259 eligible patients with private insurance, the mean (95% CI) age was 42.7 (42.7-42.7) years, and 50.3% were female; of 11 453 392 eligible Medicaid enrollees, the mean (95% CI) age was 20.4 (20.4-20.4) years, and 56.1% were female. A pain-related indication under study occurred in at least 1 visit among 6 380 694 patients with private insurance (35.4%) and 3 169 831 Medicaid enrollees (27.7%); 2 270 596 (35.6% of 6 380 694) privately insured patients and 1 126 508 (35.5% of 3 169 831) Medicaid enrollees had 1 or more opioid prescriptions. Nonsurgical acute pain opioid prescribing rates were lowest for acute migraines  and highest for rib fractures , with variable days’ supply but similar daily dosage across most indications. Opioid prescribing for a given chronic pain indication varied depending on a patient’s opioid use history. Days’ supply for postoperative prescriptions was longest for combined spinal decompression and fusion  or spinal fusion  and was shortest for vaginal delivery .Indication-specific opioid prescribing rates were not always aligned with existing guidelines. Potential inconsistencies between prescribing practice and clinical recommendations, such as for acute and chronic back pain, highlight opportunities to enhance pain management and patient safety. This cross-sectional study uses administrative claims data for outpatient clinical settings, including postsurgical discharge, from patients with private insurance or Medicaid beneficiaries to summarize opioid prescribing frequency, dosages, and durations for numerous painful medical indications. In 2017, more than one-third of the 47 600 opioid overdose deaths in the US involved prescription opioids.8 However, there is variation in opioid prescribing practices across indications that does not match the level of evidence for treatment effectiveness. For example, chronic pain indications are the most common indications for which opioids are prescribed, despite evidence being insufficient to demonstrate long-term benefit of opioids for chronic pain.6 Furthermore, prescribing characteristics, such as initial days’ supply, have been associated with the likelihood of continued opioid use regardless of clinical factors such as pain etiology.9 Opioid prescribing has been shown to vary even across similar patients and indications within the same institution.10 Unexplained prescribing variation and reports that patients often use only a fraction of opioids prescribed postoperatively11 suggest there are opportunities to reduce unnecessary opioid prescribing.Guidelines provide recommendations to help clinicians and patients determine when the benefits of opioids might outweigh the risks and inform dosage and duration.14 For example, a recent systematic review found that approximately one-third of cancer patients did not receive sufficient pharmacologic pain therapy,12 and several studies document delays and barriers among patients with sickle cell disease (SCD) receiving analgesics, including opioids.14At the same time, there have been reports of undertreatment or delay in pain treatment in instances in which the benefits of opioids might outweigh the risks.The objective of the present study was to estimate rates and amounts of opioids prescribed for specific indications to outpatients in the United States. Findings can provide greater insight into current prescribing practices, prescribing variance across indications and populations, and indications for which amplification of recommendations could improve pain management and patient safety.15 and MarketScan Multi-State Medicaid Database (MMD). The OLDW covers 14% of the commercially insured population and 21% of the Medicare Advantage  population throughout the US in 2016 and 2017. The OLDW population is nationally representative of privately insured patients with regard to age and sex. It covers all census regions although it overrepresents the South and Midwest. The MMD data set contains all Medicaid beneficiaries (fee for service and managed care) enrolled between 2016 and 2017 in 9 anonymized states distributed across census regions. This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline and the RECORD  guideline for cross-sectional studies. The CDC National Center for Injury Prevention and Control determined that the research was conducted with existing data without individual identifiers; thus, the activity is research but does not involve human subjects and therefore institutional review board approval was not required.We conducted a retrospective cross-sectional analysis of national deidentified administrative claims data from OptumLabs Data Warehouse (OLDW)The study period for identifying any index diagnosis was from January 1, 2017, to December 31, 2017, for OLDW and from October 1, 2016, to September 30, 2017, for MMD. Additional details on data sources, access, and sampling can be found in eAppendix 1 in the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis and Current Procedural Terminology codes are described in eAppendix 1 and eAppendix 2 in the We identified 41 different indications associated with pain, including acute and chronic conditions, surgical procedures, SCD, and cancer. Lists of indications, their selection criteria, and their associated 16 We calculated daily morphine milligram equivalents (MME) for opioid prescriptions using days’ supply and quantity dispensed from opioid claims and MME conversion factors.16 We developed algorithms to link patients’ opioid prescriptions to their medical encounters (“visits”) for each indication using data such as patient identification, visit date, dispensing date, clinician identification, and index diagnosis  presented the research protocol and incorporated recommendations from the National Center for Injury Prevention and Control Board of Scientific Counselors, a federal advisory committee, based on expert input from the Board of Scientific Counselors Opioid Prescribing Estimates Workgroup ; the mean with its 95% CI and the median with its interquartile range (IQR) of daily opioid dosage in MME; and the mean (95% CI) and median (IQR) days of opioids supplied. For SCD and cancer, we calculated prescribing rates overall and by age group. For postsurgical and nonsurgical acute pain indications, which generally represent individual events at a single point in time, reported outcome data  reflect prescriptions supplied for a specific procedure or visit, meaning that the prescribing rate is anchored to visits or procedures. For chronic pain indications, SCD, and cancer, for which a single patient may receive multiple prescriptions for the same indication over time, reported outcome data  are anchored to patients, reflecting all prescriptions supplied to a specific patient for visits related to that indication during the 3 months following the index diagnosis. Prescribing measures among chronic pain and postsurgical indications were stratified by opioid use history. Long-term opioid therapy (LTOT) was defined as having (1) 3 or more opioid prescriptions in the 3 months prior to the index visit; (2) more than 60 total days of opioid supply; and (3) a gap between the end of one prescription and the next prescription of less than 10 days. Patients not receiving LTOT were those whose prescriptions did not meet LTOT criteria. Only patients not receiving LTOT were included in the nonsurgical acute pain analysis to increase confidence in opioid prescription linkage to the acute indication. All analyses were conducted using SAS software, version 9.4 (SAS Institute Inc), and Stata SE, version 14 (StataCorp). OptumLabs data were analyzed from October 2018 to March 2019; MarketScan data were analyzed from January to April 2019.Among 18 016 259 patients with private insurance and 11 453 392 Medicaid enrollees during the study period, 50.3% privately insured  to 44.8% (rib fractures) of visits , slightlWe identified 1 474 731 unique privately insured patients  to 28.3% (chronic radicular back pain), overall lower than rates for patients with Medicaid, which ranged from 13.4% (irritable bowel syndrome) to 44.0% (chronic radicular back pain). Mean days’ supply ranged from 17.4 to 34.9 days (privately insured) and 13.5 to 36.6 days (Medicaid); patients with back pain, neck pain, and fibromyalgia received longer days’ supplies  than other patients not receiving LTOT with chronic pain across both patient samples. An approximate mean dosage of 30 MME/d was associated with most conditions.We categorized 12.6% of privately insured patients and 20.0% of Medicaid enrollees with chronic pain as already receiving LTOT prior to the study index diagnosis. Among them, 60.4% (privately insured) and 61.2% (Medicaid) had the same chronic pain indication in the lookback period prior to the study index diagnosis, suggesting that for the majority of patients already receiving LTOT, it is likely that their LTOT was for this same preexisting chronic pain indication. Patients already receiving LTOT were highly likely to continue to receive opioids coincident with a visit for a chronic pain diagnosis, ranging from 63.4% of privately insured patients (66.4% for Medicaid insured) with irritable bowel syndrome to 87.7% of patients (90.4% for Medicaid insured) with chronic nonradicular back pain. Most patients already prescribed LTOT with 1 or more prescriptions linked to a visit for a chronic pain diagnosis received sufficient opioids for at least half the days of the 3 months following the visit across both patient populations. For privately insured patients already prescribed LTOT, mean daily dosage exceeded 50 MME per day for all conditions except irritable bowel syndrome  and osteoarthritis or joint cartilage conditions , in contrast to Medicaid enrollees who received fewer than 50 MME per day for the chronic conditions under study.In total, we identified 385 254 surgical procedures among privately insured patients and 285 996 among Medicaid enrollees. Overall, opioids were prescribed at hospital discharge for 66% of these procedures for the privately insured patients and 55% for Medicaid enrollees . The lowAcross both patient populations, patients already receiving LTOT who underwent surgery nearly always were prescribed opioids to treat postsurgical pain. Also, postsurgical mean days’ supply and mean daily dosage was nearly universally higher among patients already receiving LTOT across both patient populations  and Medicaid-enrolled patients (44.9%) with SCD received an opioid prescription overall . HoweverA third of privately insured patients with cancer received an opioid prescription compared with more than half (56.6%) of patients with Medicaid. Patients with Medicaid received a higher days’ supply and dosage compared with privately insured patients  .Opioids were prescribed for fewer patients and visits, and in lower amounts, for children aged 18 years or younger compared with adults for most indications . CompareOpioids were prescribed in a lower percentage of visits for adults aged 65 years or older for dental pain, renal colic, most surgical procedures, and cancer compared with other adults, but prescribing rates were similar to those for other adults for most other nonsurgical acute and chronic pain indications . Days’ s18 chronic20 and acute back pain,20 musculoskeletal strains or sprains,21 and dental pain23 with no more than 3 to 7 days of opioids when needed for acute pain.6 Opioid prescriptions were issued to patients for all of these indications across both study populations in this analysis. We found that across both patient populations, patients with fibromyalgia not already receiving LTOT were typically prescribed at least a full month’s supply of opioids; that 28.3% (privately insured) and 44.0% (Medicaid) of patients with chronic radicular back pain not already receiving LTOT were started on opioids; and that opioid prescriptions with mean treatment durations of 11.8 (privately insured) and 9.9 days (Medicaid) were issued for acute low back pain.In our analysis, we linked opioid prescriptions to 13% to 16% of nonsurgical acute pain visits, 30% to 50% of patients with chronic pain indications, 55% to 66% of surgical procedures, 43% to 45% of patients with SCD, and 32% to 57% of patients with cancer, with rates, days’ supply, and daily dosage varying widely across indications. For many indications, opioid prescribing rates, days’ supply, and dosage did not align with evidence-based guidelines and practice-informed recommendations. For example, published guidance recommends nonopioid treatment of fibromyalgia,6 Previous analyses have found associations between longer durations of opioid therapy and higher opioid dosages,24 potentially reflecting increasing dosages as patients develop tolerance to pain-relieving effects of opioids. It is important for clinicians to increase long-term opioid dosages only when it is clear that benefits of increasing dosage will outweigh risks.6 Once patients are receiving high opioid dosages long term, it can be difficult to reverse course.25 Successful dosage reduction is likely to require strong collaboration between the patient and clinician, behavioral support, multimodal pain treatment, and time (often months to years) to taper slowly enough to minimize withdrawal symptoms.26For many patients with chronic pain conditions receiving LTOT, daily dosages of opioids exceeded 50 MME, a threshold beyond which the risk for adverse events, including overdose, is increased.27 recommends up to 10 tablets of oxycodone, 5 mg, at discharge for opioid-naive patients after laparoscopic cholecystectomy, totaling 75 MME. One tablet taken every 4 hours would exhaust a 10-tablet supply in less than 2 days; we found 4.7 (privately insured) and 4.8 (Medicaid) days’ supply provided to patients not receiving LTOT. Numerous studies report that patients frequently take fewer opioids than prescribed.31 Therefore, larger amounts of prescribed opioids suggest excess opioids potentially accessible to others, increasing risks of misuse and overdose. To minimize risks of excess opioids while meeting individual pain control needs, 1 institution32 calculates postsurgical discharge opioid prescriptions based on inpatient opioid use on the day prior to discharge.Postoperative opioid prescribing at hospital discharge exceeds published recommendations for nearly all surgical procedures included in this analysis. For example, the Michigan Surgical Quality Collaborative33 for which opioids are recommended.34 It is possible that many patients with cancer in our sample did not have pain or had pain that was managed effectively with nonopioid treatment. However, some patients might not have received pain management proportionate to their pain severity, as has been reported previously.12Among patients with cancer, about one-third in private insurance and about half in Medicaid were prescribed opioids. One study of outpatients with recurrent or metastatic cancer found that 62% reported moderate to severe pain,14 and might have affected some patients. However, claims data cannot identify whether prescriptions were associated with acute sickle cell crisis or with chronic pain. Privately insured adults and those with Medicaid diagnosed as having SCD were much more likely than children to receive opioids, and adults received substantially higher opioid dosages and for longer durations than children did. This finding is consistent with previous studies35 and likely reflects increased incidence of SCD complications as individuals age. Other studies have found that adults and patients with Medicaid were less likely to fill hydroxyurea prescriptions or receive specialty care for SCD,35 suggesting that lack of access to care may be associated with complications such as vaso-occlusive crisis and with a need to treat complications with opioids. In addition, clinicians often do not offer multimodal pain management for SCD pain,14 and many adults with SCD use opioids for chronic pain as well as for acute pain crises,14 which may increase tolerance and opioid requirements when patients experience acute pain. Other research has found that opioid use among SCD patients has been substantial but stable across recent years (2008-2012), while use increased in the broader US population, and that opioid-related overdose deaths among individuals with SCD were substantially lower than among individuals with other diseases associated with pain.35 Because of the unique challenges in managing painful SCD complications, readers of the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain were referred to other guidelines specific to SCD for more guidance.36 Despite this, there have been reports of inappropriate misapplication of CDC guideline recommendations to patients with SCD14 as well as with cancer pain,37 and the CDC has released statements emphasizing that the intended, stated scope of the guideline did not include pain in the setting of acute cancer or acute sickle cell crisis.37Among patients with SCD, fewer than half with either insurance type were prescribed opioids. Suboptimal management of acute SCD pain has been reported38Overall, opioid prescribing rates were higher among Medicaid than privately insured patients, but Medicaid patients were prescribed lower daily dosages and shorter durations. These findings merit closer examination; they may reflect greater use of drug utilization strategies by Medicaid in comparison with commercial payers, such as prior authorization and condition or referral requirements for use of nonopioid medications and nonpharmacologic therapies.Caution is needed in interpreting several aspects of this analysis. We relied on claims data and were unable to assess clinical details, such as pain severity or function, or to assess opioid prescriptions not covered by insurance. Other pain treatments that patients may have received, such as nonopioid medications or nonpharmacologic treatments, were not directly assessed. We did not assess uninsured patients, those with fee-for-service Medicare, or those whose prescriptions were covered under other means, including cash payments or other insurance plans. Variation in plans and inability to identify specific state Medicaid populations in the MMD data limit interpretation of prescribing rates in the context of opioid prescribing policies, such as prior authorization and duration limits. We used a linkage procedure to connect opioid prescriptions to the most likely indications at the patient or visit level; some prescriptions could have been misattributed to specific indications that were not the actual intent of the prescription or intended for an indication not included in our analysis. However, the patients identified using our list of pain indications accounted for the vast majority (87.7%) of total opioid prescriptions among privately insured patients in the OLDW data set in 2017. Dental procedures in OLDW were those covered by medical benefits and may not be representative of dental procedures for which medical claims are not billed. By contrast, the Medicaid data included direct claims from dentists, limiting direct comparisons between insurance plans. In the SCD analysis, we are unable to differentiate between LTOT for SCD and opioids prescribed to treat an acute vaso-occlusive crisis, and the small number of patients with SCD and private insurance may not represent the general SCD population. The amount of time that elapsed between the date of an inpatient surgical procedure and hospital discharge may affect the amount of pain medication prescribed for an individual patient at the point of discharge. Our outcome of interest was overall prescribing for specific indications, rather than prescribing by individual prescribers owing to data set limitations, which may affect estimates of precision. Lastly, prescribing rates do not reflect national estimates of overall opioid prescribing; rates are based on specific patient populations for specific indications, and geographic constraints of the data sources used in this analysis may limit national application of calculated rates.This comprehensive analysis of opioid prescribing across a broad variety of indications suggested that prescribing patterns for some indications were incongruent with existing evidence-based clinical guidelines. These results may reflect low clinician awareness of applicable guidelines or reluctance to adhere to guidance. Implementation guidance that emphasizes evidence-based recommendations has the potential to better align opioid prescribing practices with evidence on opioid benefits and risks and improve pain management and patient safety.


Introduction: Severe, often sudden-onset headache is the principal presenting symptoms of aneurysmal subarachnoid hemorrhage (aSAH). We hypothesized that gabapentin would be safe and tolerable for aSAH-induced headaches and would reduce concurrent opioid use.Methods: We performed a single-center, double-blind, randomized, placebo-controlled trial  from November 24, 2014, to June 24, 2017, where aSAH patients received either dose-escalating gabapentin or oral placebo, both alongside a standard of care pain regimen. After 7 days, patients had the option to continue in an open-label period until 14 days after enrollment or until discharge from the intensive care unit. Our primary endpoint was the efficacy of gabapentin in reducing headache numeric pain scores and opioid usage in patients with aSAH compared to the placebo group. We identified 63 potential patients with aSAH for the study. After applying stringent exclusion criteria, 16 eligible patients were enrolled into one of two arms.Results: The study ended prematurely after reaching a pre-specified funding period and an unexpected drop in aSAH cases. There was a trend toward lower headache numeric pain scores and opioid use in the gabapentin treated arm; however this was not significantly different. Gabapentin was well tolerated by participants and no adverse effects were reported.Conclusions: While there was a trend toward lower pain scores and opioid requirement in the gabapentin group, the study was underpowered to detect a difference. Larger multicenter trials are required to evaluate the efficacy of gabapentin to reduce opioid requirements after aSAH. Aneurysmal subarachnoid hemorrhage (aSAH) comprises ~6–8% of all strokes, with at least 30,000 new cases per year in Western countries . aSAH usOpioids are typically used for the management of aSAH-related pain in the hospital, and are frequently prescribed at discharge . RecentlGabapentin is an antiepileptic drug with well-known pain-modulating efficacy and is used successfully for neuropathic pain and perioperative pain indications , thus weWe conducted a randomized, double-blind, placebo-controlled study to investigate safety and tolerability of gabapentin use for aSAH-related headache. Moreover, we aimed to assess the efficacy of gabapentin for headache treatment in patients with aSAH and its potential for reducing opioid use.ClinicalTrials.gov (NCT02330094). The study was internally funded and was determined by the FDA and Mayo Clinic IRB to be IND-exempt, since our use of gabapentin fell within the drug's primary indication for pain reduction (neuropathic and non-neuropathic) and not with the intent of providing evidence for a change in label indication. We also provided evidence of safety and tolerability from our prior retrospective study to the FDA (This study was designed as part of a research scientific thesis (L. P. D.) for the Mayo Clinic Center for Clinical and Translational Science research program. It was reviewed for scientific merit by the Mayo Clinic Neuroscience Focused Research Team, received Mayo Clinic Institutional Review Board (IRB) approval, and was registered on  the FDA .Patients were eligible to participate if they were 18 years of age or older, had an aSAH, were able to swallow pills and verbalize pain score, and had a numeric pain score (NPS) of at least 5 prior to randomization. Informed consent was obtained from all patients. Exclusion criteria included gabapentin use prior to hospital admission for aSAH, creatinine clearance (CrCl) <30 mL/min, pregnancy, history of severe depression defined by DSM IV criteria, or incapacitation or inability to provide consent.After IRB approval, we evaluated aSAH cases admitted to the Neuroscience ICU (NeuroICU) at Mayo Clinic in Jacksonville, Florida, from November 24, 2014, to June 24, 2017. Enrollment was performed within 72 h of hospital admission and after meeting inclusion criteria.The Mayo Clinic Department of Pharmacy implemented allocation for the double-blind drug or placebo concealment and used permuted block randomization to ensure an equal number of patients in each group as the study progressed. Gabapentin and placebo medications, provided by the central pharmacy, were compounded and repackaged to look identical.A bedside nurse recorded the NPS  every 4 h per hospital policy. The total score over 24 h was averaged as the daily NPS. Only headache and neck pain (meningismus) were included in the study to calculate the pain score. After consent and enrollment, nursing staff recorded data collection sheets with daily NPS scores and standard of care (SOC) management plans. SOC pain management plans were implemented by the NeuroICU team of residents, attendings, nurse practitioners, and physician assistants. A decrease in NPS of >50% from the previous day's NPS was defined as good pain control and would not require escalation of gabapentin or placebo for that day.We reviewed CrCl, blood urea nitrogen, and liver function tests from the medical record performed as SOC by the treating team. The team reviewed patient computed tomography, computed tomography angiography, transcranial Doppler, and vasospasm interventions . aSAH severity was assessed at baseline using the modified Fisher scale.The gabapentin group was given active medication with possible escalation according to CrCl . GabapenAfter the 7-day study period, patients were unblinded and could crossover to receive gabapentin if their head and neck pain was still not well controlled with the SOC pain management regimen alone . GabapenWhenever CSF was collected by SOC via an external ventricular drain or lumbar puncture, we measured white (WBC) and red blood cell (RBC) counts to calculate the CSF WBC/RBC ratio, and culture and sensitivity for evidence of bacterial meningitis.We calculated total morphine equivalent (ME) dose every day with an opiate conversion table  16)..16).We used the modified Brigham and Women's Hospital Management of Postoperative Pain Patients discharge questionnaire (BWQ) , which hOur previous retrospective study demonstrated a 25% difference in NPS daily score between gabapentin and placebo groups and a mean (SD) daily pain score of 26 (5.84) at day 4 . For ourP-value of 0.05.The primary endpoint for this trial was 7 days of treatment with or without gabapentin and SOC, and the treatment groups were compared using a 2-tailed test with a 2 test for independence. Daily average NPS score, opioid requirement, and gabapentin dose were plotted graphically  was used for statistical analysis.From November 24, 2014, to June 24, 2017, we screened 63 patients with aSAH, of whom 16 met final eligibility criteria and were enrolled into the trial. Our study was stopped prematurely due to a decline in recruitment and a pre-specified time period being met.n = 8) and placebo (n = 8) groups. Median (range) age was 51  years and 12 (75%) were women: four (50.0%) in the gabapentin group and all eight (100.0%) in the placebo group (P = 0.02). Overall, there was no significant difference in median (range) age between groups ; however, the gabapentin group had higher aSAH severity scores (P = 0.01) as measured by modified Fisher Scale. All patients enrolled in the trial had imaging studies to confirm an aSAH diagnosis. The most common type of aneurysm noted was middle cerebral artery (n = 5), followed by anterior communicating artery (n = 4). Four patients in the gabapentin group were reported with baseline chronic pain symptoms, and one was on chronic pain medication. Baseline demographic factors compared between the groups are provided in Sixteen patients were randomized evenly into gabapentin . Similarly, there was a nonsignificant trend in median NPS, intravenous fentanyl use, and MEs. When comparing NPS at day 7, there was a trend for the gabapentin group to have lower pain scores than the placebo group , which continued at day 14  (P = 0.60] (The median (range) average NPS for the gabapentin and placebo groups from enrollment through day 7 were 5.4  and 5.7 , respectively ( = 0.81] . However = 0.60] .P = 0.40) or median NPS scores (P = 0.38). The same analysis was performed for the other variables, but the results were not statistically significant for particular opioids used .The median (range) dose of gabapentin at the end of day 7 was 900  mg . Rapid eP = 0.66], although there was a trend toward a better satisfaction score.For statistical calculation, we transformed the BWQ score  into a uThere was one episode of nausea and agitation recorded in each group. In the placebo group, there was also one episode of delirium and one of vomiting . There wThere is little known regarding the CSF WBC/RBC ratio in aSAH patients aside from our prior retrospective gabapentin study . While iThe current study investigated the use of gabapentin vs. placebo for headache pain relief in patients with aSAH while admitted to a NeuroICU as gabapentin can be used safely for days to weeks for pain management. This is the first randomized trial to date reporting the use of gabapentin to reduce headache pain in these patients. Headache pathophysiology after aSAH is complex and involves influences from raised intracranial pressure and potential hydrocephalus initially to delayed, sterile neuroinflammatory response from blood products irritating the meninges . NumerouGabapentin is commonly used for its anti-nociceptive effects, especially in anesthesia during the perioperative period, and has been shown to reduce analgesic, particularly opiate, consumption and associated AEs . The 201Although the exact molecular mechanisms of action by which gabapentin mediates its effects are not yet fully understood, current evidence suggests that it binds to and modulates the α2 δ-1 subunit of voltage-gated calcium channels { #21; 2323 #1055;Our trial has several strengths, including the randomized, double-blind, placebo-controlled design and the 7-day single crossover. The initial 7-day period was designed to assess the primary endpoint, which was pain reduction and reduced opioid use, while still maintaining effective pain management. Although there was a trend toward opioid reduction, the study was ultimately underpowered and stopped after an interim analysis and pre-specified funding period ended, which showed non-inferiority of safety, tolerability, and pain endpoints. A confounding factor in our study was that the gabapentin group started with higher aSAH severity scores than the placebo group. Moreover, there were more women in the placebo control group - although this reflects the gender distribution of aSAH cases and will need to be addressed in future studies.This data can be used as a pilot study to design a larger prospective and multicenter clinical trial. Inclusion and exclusion criteria were stringent, excluding many patients with aSAH; however, a homogenous population was required. Another limitation to our study is the subjective nature of NPSs. While vital signs and other measured variables may suggest more physiologic pain, NPSs can be influenced by factors such as anxiety, depression, and baseline pain tolerance, which affect reporting by patients. Furthermore, we had to exclude comatose and nonverbal patients with aSAH as they would have been unable to respond, which contributed to lower enrollment volumes. Nonetheless, the study was designed in a randomized fashion to help account for these covariates in both groups.Our study investigated use of gabapentin vs. placebo for headache in patients with aSAH able to verbalize their NPS while admitted to a neuroICU. This study confirms our previous retrospective study demonstrating that gabapentin is safe and tolerable in patients with aSAH , howeverThis is the first preliminary randomized controlled trial of gabapentin vs. placebo for headache and meningismus in patients with aSAH in a NeuroICU environment. While the study was underpowered for efficacy, there was a trend toward lower concurrent opioid use and lower overall NPS reporting in the gabapentin group. Gabapentin appears safe and tolerable for patients with aSAH to manage major headache pain and meningismus.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Mayo Clinic Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.LD contributed to conception and design, experiments, collection, analysis and interpretation of data, drafting and critical revision of the manuscript, and collection/generation of tables and figures. MT contributed to analysis and interpretation of data and critical revision of the manuscript. DJ contributed to experiments, collection of data, and critical revision of the manuscript. EE contributed to conception and design, experiments, collection, analysis and interpretation of data, and drafting and critical revision of the manuscript. DH contributed to collection, analysis and interpretation of data, and critical revision of the manuscript. NT, PK, and OA contributed to collection of data and critical revision of the manuscript. DM and JM contributed to conception and design, experiments, and critical revision of the manuscript. WF contributed to conception and design, experiments, collection, analysis and interpretation of data, drafting and critical revision of the manuscript, and collection/generation of tables and figures. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.