A Pooled Analysis of Two Randomized,Double‐Blind,Placebo‐Controlled Trials of Milnacipran Monotherapy in the Treatment of Fibromyalgia

Milnacipran has been shown to significantly improve the pain, global well‐being, and physical function of fibromyalgia (FM), and is approved by the U.S. Food and Drug Administration for the management of this disorder. Post hoc analyses of data from two pivotal trials were conducted to further assess the clinical benefits of milnacipran, to determine the impact of baseline pain severity on treatment outcomes, and to confirm the safety and tolerability of this medication in patients with FM. Patients in these trials were randomized to placebo (n = 624), milnacipran 100 mg/day (n = 623), or milnacipran 200 mg/day (n = 837). Two different composite responder analyses were used to evaluate efficacy: a 2‐measure analysis, requiring ≥ 30% improvement from baseline visual analog scale 24‐hour recall pain scores and a Patient Global Impression of Change (PGIC) score of “very much improved” or “much improved”; and a 3‐measure analysis, requiring a ≥ 6‐point improvement from baseline in SF‐36 Physical Component Summary scores in addition to the pain and PGIC criteria. Additionally, a pooled analysis of mean changes from baseline pain scores was conducted in order to evaluate the efficacy of milnacipran over the entire course of treatment. At 3 months, composite responder rates were significantly higher in the milnacipran treatment groups than in the placebo group (2‐ and 3‐measure composite responder analyses: P ≤ 0.001, both doses vs. placebo). These improvements were not dependent on baseline pain severity. Similar composite responder results were observed in patients who continued treatment for up to 6 months. Significant improvements in mean pain scores were seen with both doses of milnacipran vs. placebo as early as 1 week after treatment initiation and were sustained for up to 6 months of milnacipran treatment. The most common adverse events associated with milnacipran were nausea, headache, and constipation.     

A Meta‐Analysis of Pain Response in the Treatment of Fibromyalgia

Objective: This meta‐analysis compared efficacy (pain response) of drugs that are licensed or commonly used in the treatment of fibromyalgia. A meta‐analysis of safety measured via discontinuation because of adverse events was also performed. Methods: We conducted a meta‐analysis of 21 clinical trials to estimate treatment differences vs. placebo, separately, for duloxetine, fluoxetine, gabapentin, milnacipran, pramipexole, pregabalin, either of two tricyclic antidepressants, and tramadol plus paracetamol. Indirect treatment comparisons using mixed treatment comparisons methodology were conducted for all pairwise comparisons. Pain response was analyzed as improvement of at least 30%, and separately of 50%, from baseline. Results: When compared with placebo, statistically significant pain responses (improvement of 30% and 50%) were observed for patients treated with duloxetine, milnacipran 200 mg/day, pregabalin 300 or 450 mg/day, and tramadol plus paracetamol. Treatment with fluoxetine, gabapentin, or milnacipran 100 mg/day resulted in significant findings for the 30% improvement in pain response. The meta‐analysis showed a statistically increased risk of discontinuation because of adverse events for milnacipran 100 and 200 mg/day (both P < 0.001), and pregabalin 300 and 450 mg/day (P = 0.009 and P < 0.001, respectively). All other treatments, except fluoxetine, showed numerically increased risk over placebo for discontinuation because of adverse events. In the indirect comparisons, no pairwise comparison of active treatments reached statistical significance for either pain response end point. Conclusion: All eight active treatments displayed evidence suggesting improvement over placebo in the treatment of pain in patients suffering from fibromyalgia. Indirect comparison of active treatments found no strong differences.     

Measuring the Pain Area: An Intra‐ and Inter‐Rater Reliability Study Using Image Analysis Software

Pain drawings have frequently been used for clinical information and research. The aim of this study was to investigate intra‐ and inter‐rater reliability of area measurements performed on pain drawings. Our secondary objective was to verify the reliability when using computers with different screen sizes, both with and without mouse hardware. Pain drawings were completed by patients with chronic neck pain or neck–shoulder–arm pain. Four independent examiners participated in the study. Examiners A and B used the same computer with a 16‐inch screen and wired mouse hardware. Examiner C used a notebook with a 16‐inch screen and no mouse hardware, and Examiner D used a computer with an 11.6‐inch screen and a wireless mouse. Image measurements were obtained using GIMP and NIH ImageJ computer programs. The length of all the images was measured using GIMP software to a set scale in ImageJ. Thus, each marked area was encircled and the total surface area (cm²) was calculated for each pain drawing measurement. A total of 117 areas were identified and 52 pain drawings were analyzed. The intrarater reliability between all examiners was high (ICC = 0.989). The inter‐rater reliability was also high. No significant differences were observed when using different screen sizes or when using or not using the mouse hardware. This suggests that the precision of these measurements is acceptable for the use of this method as a measurement tool in clinical practice and research.     

Concept Analysis of Pain: Implications Related to Nursing Diagnoses

Pain is a phenomenon that has an impact on clients in a variety of settings. Nurses have many responsibilities related to assessment, diagnosis, intervention, and evaluation when caring for the person experiencing pain. The phenomenon of pain is described through a concept analysis, which is guided by the research tradition of phenomenology. A review of both medical and nonmedical literature provides a broad base of definitions from which the attributes, antecedents, and consequences are derived. The analysis includes the construction of various cases and identification of empirical referents in the phenomenologic tradition. Suggestions for future development and implementation of the concept into clinical nursing practice and clinical nursing research are included.     

Reducing Pain During Emergency Arterial Sampling Using Three Anesthetic Methods: A Randomized Controlled Clinical Trial

BackgroundTaking a sample of arterial blood is widely reported as a cause of significant pain.ObjectivesTo compare three anesthetic methods with standard practice (no anesthesia) to establish which was the most effective in reducing pain caused by radial artery puncture in patients requiring an arterial blood gas test in the emergency department (ED).MethodsA randomized controlled trial was conducted to compare the effectiveness between anesthetic cream, cryoanalgesia, and subcutaneous mepivacaine in reducing pain caused by radial artery puncture in ED patients.ResultsAfter comparing perceived pain during arterial puncture, the lowest median score was obtained in the mepivacaine group (1 interquartile range 0.6–1.3) and the highest median score in the control group (5 interquartile range 4.0–7.0). When comparing the control group with the three intervention groups, the Kruskal-Wallis test showed that mepivacaine (p = 0.023) and cryoanalgesia (p = 0.012) were associated with significantly lower pain scores. The anesthetic cream (p = 0.861) intervention group did not produce a statistically significant median difference compared with the control group.ConclusionsThe results of this study encourage the use of anesthetic methods like cryoanalgesia or mepivacaine for their proven effectiveness in reducing or eliminating pain during arterial puncture.     

A Review of Duloxetine 60 mg Once‐Daily Dosing for the Management of Diabetic Peripheral Neuropathic Pain,Fibromyalgia, and Chronic Musculoskeletal Pain Due to Chronic Osteoarthritis Pain and Low Back Pain

Background: Duloxetine is a selective dual neuronal serotonin (5‐Hydroxytryptamine, 5‐HT) and norepinephrine reuptake inhibitor (SSNRI). It is indicated in the United States for treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and several chronic pain conditions, including management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis (OA) pain and chronic low back pain (LBP). Its use for antidepressant and anxiolytic actions has been extensively reviewed previously. We here review the evidence for the efficacy of 60 mg once‐daily dosing of duloxetine for chronic pain conditions. Method: The literature was searched for clinical trials in humans conducted in the past 10 years involving duloxetine. Results: There were 199 results in the initial search. Studies not in the English language were excluded. We then included only studies of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain (OA and LBP). Studies of painful symptoms reported in mental health studies were excluded. This resulted in 32 studies. Articles that did not include a 60 mg/day daily dose as a study arm were excluded. This resulted in 30 studies, broken down as follows: 12 for diabetic peripheral neuropathy, 9 for fibromyalgia, 6 for LBP, and 3 for OA pain. Conclusions: The studies reviewed report that duloxetine 60 mg once‐daily dosing is an effective option for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic OA pain and chronic LBP. As these pains are often comorbid with MDD or GAD, duloxetine might possess the pharmacologic properties to be a versatile agent able to address several symptoms in these patients. With adequate attention to FDA prescribing guidance regarding safety and drug–drug interactions, duloxetine 60 mg once‐daily dosing appears to be an effective option in the appropriate pain patient population.     

Symptoms of Fibromyalgia According to the 2016 Revised Fibromyalgia Criteria in Chronic Pain Patients Referred to Multidisciplinary Pain Rehabilitation: Influence on Clinical and Experimental Pain Sensitivity

Fibromyalgia (FM) is a condition with chronic widespread pain and signs of generalized pain hypersensitivity. FM has previously been classified according to the American College of Rheumatology-1990 criteria, where the presence of hypersensitivity is estimated by a tender point examination. Because of the limitations of these classification criteria, new diagnostic criteria have been proposed, abandoning this examination. This cross-sectional study investigated the prevalence of FM according to the revised 2016 FM criteria in a large cohort of chronic pain patients. Pain drawings, the FM Symptom Severity Scale, and questionnaires assessing manifestations of pain, pain-related disability, and psychological distress were collected from 1,343 patients with chronic nonmalignant pain referred to a multidisciplinary pain clinic. In addition, assessments of mechanical and thermal pain sensitivity were performed in 496 of the patients. Patients fulfilling the FM criteria (n?=?498, 37%) reported significantly higher levels of pain, pain-related disability, psychological distress, and sensitivity to mechanical and heat stimuli (P?<?.05). Moreover, the proportion using opioids were significantly higher compared with patients not fulfilling the criteria (P?=?.015). Significant associations were found between heat and mechanical pain sensitivity (P?<?.001) indicating that patients who showed higher pain sensitivity to mechanical stimulation also showed higher pain sensitivity to thermal stimulation.

Pain Variability in Fibromyalgia Is Related to Activity and Rest: Role of Peripheral Tissue Impulse Input

Because fibromyalgia (FM) patients frequently report activity-dependent deep tissue pains, impulse input from painful body regions may be relevant for their musculoskeletal complaints. In addition, peripheral impulse input may induce and maintain thermal and mechanical hyperalgesia of FM patients. If so, activity and rest may alternately enhance and diminish intensity of FM pain. However, the effects of exercise on pain are ambiguous in studies of FM. Whereas exercise-only studies demonstrated increased pain and hyperalgesia during and after physical activity, some exercise studies that included rest periods resulted in decreased FM pain and increased function. To further clarify these effects, we examined the effects of alternating exercise with rest on clinical pain and thermal/mechanical hyperalgesia of 34 FM patients and 36 age-matched healthy controls (NC). Using an ergometer, all subjects performed arm exercise to exhaustion twice alternating with 15-minute rest periods. Although strenuous muscle activity was reported as painful by most FM subjects, overall clinical pain consistently decreased during the rest periods. Additionally, FM subjects' pain sensitivity to mechanical pressure decreased after each exercise and rest session. Conclusion: Alternating strenuous exercise with brief rest periods not only decreased overall clinical pain of FM subjects but also their mechanical hyperalgesia. No prolonged worsening of overall FM pain and hyperalgesia occurred despite vigorous muscle activity. Our findings contribute further evidence that FM pain and hyperalgesia are at least partially maintained by muscle impulse input, and that some types of exercises may be beneficial for FM.     

Demographic Predictors of Pain Sensitivity: Results From the OPPERA Study

The demographic factors of sex, age, and race/ethnicity are well recognized as relevant to pain sensitivity and clinical pain expression. Of these, sex differences have been the most frequently studied, and most of the literature describes greater pain sensitivity for women. The other 2 factors have been less frequently evaluated, and current literature is not definitive. Taking advantage of the large Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study cohort, we evaluated the association of sex, age, and self-reported race with 34 measures of pressure, mechanical, and thermal pain sensitivity encompassing threshold and suprathreshold perception. Women were significantly more pain-sensitive than men for 29 of 34 measures. Age effects were small, and only significant for 7 of 34 measures, however, the age range was limited (18–44 years of age). Race/ethnicity differences varied across groups and pain assessment type. Non-Hispanic white individuals were less pain-sensitive than African-American (for 21 of 34 measures), Hispanic (19 of 34), and Asian (6 of 34) individuals. No pain threshold measure showed significant racial differences, whereas several suprathreshold pain measures did. This suggests that racial differences are not related to tissue characteristics or inherent nociceptor sensitivity. Rather, the differences observed for suprathreshold pain ratings or tolerance are more likely related to differences in central nociceptive processing, including modulation imposed by cognitive, psychological, and/or affective factors.

The Use of Ketamine for Acute Treatment of Pain: A Randomized,Double-Blind,Placebo-Controlled Trial

Background

Pain is one of the most common reasons for emergency department (ED) visits in the United States. Ketamine is a sedative with N-methyl-D-aspartate (NMDA) receptor antagonism. Recent literature has suggested that the use of subdissociative dose ketamine (SDDK) may be safe and effective for acute pain.

Randomized Trial of a Low-Literacy Chronic Pain Self-Management Program: Analysis of Secondary Pain and Psychological Outcome Measures

Based on input of rural, largely Hispanic persons with chronic pain, a low-literacy, 6-month self-management program was developed, drawing on elements of existing pain toolkits. In a randomized trial, low-income, primarily Hispanic patients with chronic pain received the program in 6 sessions of 1-on-1 meetings with a trained health educator in clinic or in 8 group lectures by experts in the community. Intention-to-treat analyses in linear mixed-effects models were conducted for 5 secondary outcomes at 6 months, including Brief Pain Inventory pain severity and interference, Patient Health Questionnaire-9, 12-Item Short-Form Survey Mental Component Summary, and Tampa Scale for Kinesiophobia-11. A total of 111 participants were randomized (15.9% of 700 initially eligible from 3 clinics), and 67 (60.4%) completed 6-month measures. Among completers, the clinic arm improved on 4 measures and community arm on 3 measures (all P < .05). Effect sizes were small to moderate (.41–.52). In intention-to-treat analyses, both arms improved on 4 of 5 measures (all P ≤ .001) versus baseline, with clinically significant changes in Brief Pain Inventory pain severity and interference. Improvement in multiple outcomes after this chronic pain self-management program for low-income patients warrants further study.

Characteristics Associated With High-Impact Pain in People With Temporomandibular Disorder: A Cross-Sectional Study

High-impact (disabling) pain diminishes the quality of life and increases health care costs. The purpose of this study was to identify the variables that distinguish between high- and low-impact pain among individuals with painful temporomandibular disorder (TMD). Community-dwelling adults (N?=?846) with chronic TMD completed standardized questionnaires that assessed the following: 1) sociodemographic characteristics, 2) psychological distress, 3) clinical pain, and 4) experimental pain. We used high-impact pain, classified using the Graded Chronic Pain Scale, as the dependent variable in logistic regression modeling to evaluate the contribution of variables from each domain. Cross-validated area under the receiver operating characteristic curve (AUC) quantified model discrimination. One-third of the participants had high-impact pain. Sociodemographic variables discriminated weakly between low- and high-impact pain (AUC?=?.61, 95% confidence interval [CI]?=?0.57, 0.65), with the exception of race. An 18-variable model encompassing all 4 domains had good discrimination (AUC?=?0.79, 95% CI?=?0.75, 0.82), as did a simplified model (sociodemographic variables plus catastrophizing, jaw limitation, and number of painful body sites) (AUC?=?0.79, 95% CI?=?0.76, 0.82). Duration of pain, sex, and experimental pain testing results were not associated. The characteristics that discriminated most effectively between people with low- and high-impact TMD pain included clinical pain features and the ability to cope with pain.

Ibuprofen Provides Analgesia Equivalent to Acetaminophen–Codeine in the Treatment of Acute Pain in Children with Extremity Injuries: A Randomized Clinical Trial

Objectives: This study compared the analgesic effectiveness of acetaminophen–codeine with that of ibuprofen for children with acute traumatic extremity pain, with the hypothesis that the two medications would demonstrate equivalent reduction in pain scores in an emergency department (ED) setting. Methods: This was a randomized, double-blinded equivalence trial. Pediatric ED patients 5 to 17 years of age with acute traumatic extremity pain received acetaminophen–codeine (1 mg/kg as codeine, maximum 60 mg) or ibuprofen (10 mg/kg, maximum 400 mg). The patients provided Color Analog Scale (CAS) pain scores at baseline and at 20, 40, and 60 minutes after medication administration. The primary outcome measured was the difference in changes in pain score at 40 minutes, compared to a previously described minimal clinically significant change in pain score of 2 cm. The difference was defined as (change in ibuprofen CAS score from baseline) – (change in acetaminophen–codeine CAS score from baseline); negative values thus favor the ibuprofen group. Additional outcomes included need for rescue medication and adverse effects. Results: The 32 acetaminophen–codeine and the 34 ibuprofen recipients in our convenience sample had indistinguishable pain scores at baseline. The intergroup differences in pain score change at 20 minutes (−0.6, 95% confidence interval [CI] = −1.5 to 0.3), 40 minutes (−0.4, 95% CI = −1.4 to 0.6), and 60 minutes (0.2, 95% CI = −0.8 to 1.2) were all less than 2 cm. Adverse effects were minimal: vomiting (one patient after acetaminophen–codeine), nausea (one patient after ibuprofen), and pruritus (one after acetaminophen–codeine). The three patients in each group who received rescue medications all had radiographically demonstrated fractures or dislocations. Conclusions: This study found similar performance of acetaminophen–codeine and ibuprofen in analgesic effectiveness among ED patients aged 5–17 years with acute traumatic extremity pain. Both drugs provided measurable analgesia. Patients tolerated them well, with few treatment failures and minimal adverse effects.     

The Effects of Inhalation Aromatherapy on Postoperative Abdominal Pain: A Three-Arm Randomized Controlled Clinical Trial

PurposeThis study compares the effects of inhalation aromatherapy using essential oils of sweet orange and damask rose on postoperative abdominal pain.DesignA randomized three-arm controlled trial.MethodsIn this randomized double-blinded, and parallel-group controlled trial, a total of 120 patients who underwent open abdominal surgeries were enrolled using a sequential sampling method. Participants were then randomly assigned to three groups of sweet orange, damask rose, and placebo (distilled water) using the permuted block randomization. When the patients regained full consciousness, a clean gauze impregnated with four drops of either distilled water or essential oils of sweet orange or damask rose were attached to the collar of the patients, and they were asked to inhale the aroma through normal breathing for 30 minutes. Abdominal pain severity was recorded using the visual analog scale at four time points including before the intervention (baseline) and 4, 8, and 12 hours after the intervention.FindingsPain reduction after sweet orange inhalation was significantly greater than placebo (at 8 and 12 hours after the intervention) and damask rose (at 12 hours after the intervention). The differences in the mean score of pain severity between all before-and-after observations were statistically significant in the three groups, except in the placebo group between the baseline score of pain severity and the pain severity score at 4 hours after the intervention.ConclusionsInhalation aromatherapy using sweet orange seems to be more effective than the damask rose in reducing pain severity after open abdominal surgeries.     

Physiotherapy for Sleep Disturbance in People With Chronic Low Back Pain: Results of a Feasibility Randomized Controlled Trial

Objective

To determine the feasibility of a randomized controlled trial investigating the effectiveness of physiotherapy for sleep disturbance in chronic low back pain (CLBP) (≥12wks).

Design

Randomized controlled trial with evaluations at baseline, 3 months, and 6 months.

Setting

Outpatient physiotherapy department in an academic teaching hospital.

Participants

Participants with CLBP were randomly assigned to a walking program (n=20; mean age ± SD, 46.4±13.8y), supervised exercise class (n=20; mean age ± SD, 41.3±11.9y), or usual physiotherapy (n=20; mean age ± SD, 47.1±14.3y). The 3-month evaluation was completed by 44 participants (73%), and 42 (70%) participants completed the 6-month evaluation.

Interventions

Participants received a physiotherapy-delivered 8-week walking program, an 8-week group supervised exercise class (1 class/wk), or 1-to-1 usual physiotherapy (advice, manual therapy, and exercise).

Main Outcome Measures

Sleep was assessed by the self-reported Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Pittsburgh Sleep Diary, and objective actigraphy.

Results

Groups were comparable at baseline. Most (95%, n=57) of the participants had sleep disturbance. The acceptability of actigraphy was excellent at baseline (58 of 60 participants), but dropped at 3 months (26 of 44 participants). There were improvements on the PSQI and ISI in all groups at 3 and 6 months, with predominantly medium effect sizes (Cohen d=0.2–0.5).

Conclusions

The high prevalence of sleep disturbance indicated the feasibility of good recruitment in future trials. The PSQI would be a suitable screening tool and outcome measure alongside an objective nonobtrusive sleep outcome measure. The effectiveness of physiotherapy for sleep disturbance in CLBP warrants investigation in a fully powered randomized controlled trial.