Use of electronic health data to identify patients with moderate-to-severe osteoarthritis of the hip and/or knee and inadequate response to pain medications.

BACKGROUND: No algorithms exist to identify important osteoarthritis (OA) patient subgroups (i.e., moderate-to-severe disease, inadequate response to pain treatments) in electronic healthcare data, possibly due to the complexity in defining these characteristics as well as the lack of relevant measures in these data sources. We developed and validated algorithms intended for use with claims and/or electronic medical records (EMR) to identify these patient subgroups. METHODS: We obtained claims, EMR, and chart data from two integrated delivery networks. Chart data were used to identify the presence or absence of the three relevant OA-related characteristics (OA of the hip and/or knee, moderate-to-severe disease, inadequate/intolerable response to at least two pain-related medications); the resulting classification served as the benchmark for algorithm validation. We developed two sets of case-identification algorithms: one based on a literature review and clinical input (predefined algorithms), and another using machine learning (ML) methods (logistic regression, classification and regression tree, random forest). Patient classifications based on these algorithms were compared and validated against the chart data. RESULTS: We sampled and analyzed 571 adult patients, of whom 519 had OA of hip and/or knee, 489 had moderate-to-severe OA, and 431 had inadequate response to at least two pain medications. Individual predefined algorithms had high positive predictive values (all PPVs ≥ 0.83) for identifying each of these OA characteristics, but low negative predictive values (all NPVs between 0.16-0.54) and sometimes low sensitivity; their sensitivity and specificity for identifying patients with all three characteristics was 0.95 and 0.26, respectively (NPV 0.65, PPV 0.78, accuracy 0.77). ML-derived algorithms performed better in identifying this patient subgroup (range: sensitivity 0.77-0.86, specificity 0.66-0.75, PPV 0.88-0.92, NPV 0.47-0.62, accuracy 0.75-0.83). CONCLUSIONS: Predefined algorithms adequately identified OA characteristics of interest, but more sophisticated ML-based methods better differentiated between levels of disease severity and identified patients with inadequate response to analgesics. The ML methods performed well, yielding high PPV, NPV, sensitivity, specificity, and accuracy using either claims or EMR data. Use of these algorithms may expand the ability of real-world data to address questions of interest in this underserved patient population.

Dual-Acting Peripherally Restricted Delta/Kappa Opioid (CAV1001) Produces Antinociception in Animal Models of Sub-Acute and Chronic Pain.

BACKGROUND: The development of highly efficacious alternatives to mu-opioid analgesics represents an urgent unmet medical and public health need. In the presence of inflammation both delta- and kappa-opioid agonists, acting on peripheral sensory neurons, mediate analgesia. The dual-acting, peripherally restricted kappa/delta-opioid agonist, CAV1001, was tested in four rodent pain models. METHODS: Experiment 1 - Formalin testing in mice. Three doses (1-10 mg/kg) of CAV1001 or ICI204448 at 30 minutes were tested after formalin injection. Spontaneous nocifensive responses were video recorded. Experiment 2 - Complete Freund's Adjuvant (CFA)-induced arthritis. CFA was injected into the ankle joint of rats. Joint compression thresholds (JCT) were measured. CAV1001 was compared to celecoxib. Experiment 3 - Spinal nerve ligation (SNL) in rats. Paw compression thresholds (PCT) were measured. CAV1001 was compared to gabapentin. Experiment 4 - MMRT-1 bone cancer implantation into the rat tibia. Weight-bearing was assessed. CAV1001 was compared to morphine. RESULTS: In Phase 2 of the formalin model, CAV1001 (1 mg/kg) significantly reduced pain behaviors to a degree comparable to the peripherally restricted kappa-opioid agonist, ICI204448 (10 mg/kg). CAV1001 (10 mg/kg) effectively eliminated pain behaviors associated with phase 2. In the CFA-induced arthritis model, a significant increase in JCTs, similar to the comparator celecoxib, was observed with CAV1001 at 1 mg/kg at 2 hours; CAV1001 (10 mg/kg) was effective at 1 hour. In the SNL model, both the comparator gabapentin and CAV1001 (5 mg/kg) significantly reduced PCT at 2 hours, but at 4 hours, the CAV1001 thresholds improved to baseline. CAV1001 10 mg/kg significantly improved weight bearing at 4-hour post-dosing compared to baseline following MMRT-1 implantation. CONCLUSION: CAV1001 demonstrated efficacy in several different preclinical pain models. Time- and dose-dependent differences in the efficacy of CAV1001 amongst these rodent pain models parallel the degree of underlying inflammation.

Ease-of-care from the physical therapists' perspective comparing fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia in postoperative pain management.

AIM: To compare the ease-of-care (EOC) examining time efficiency, convenience and satisfaction of fentanyl iontophoretic transdermal system ([ITS] IONSYS®) and morphine intravenous patient-controlled analgesia (iv. PCA) in postoperative pain management using a validated physical therapist (PT) EOC questionnaire. MATERIALS & METHODS: This meta-analysis assessed EOC of fentanyl ITS versus morphine iv. PCA using data from two randomized, active-comparator studies (fentanyl ITS: n = 720 and morphine iv. PCA: n = 739) which used the PT EOC questionnaire (22 items grouped into three subscales; time efficiency, convenience and satisfaction). Each item was scored on a 6-point Likert scale. For time efficiency, PT whose average scores were ≤2 on all items of the time efficiency and convenience subscales or ≥4 on both satisfaction items were considered responders. RESULTS: There were EOC questionnaires from 264 (fentanyl ITS) and 254 (morphine iv. PCA) PTs. There were significantly greater proportions of PTs classified as responders for fentanyl ITS than morphine iv. PCA for overall EOC (81.0 vs 55.7%, respectively), time efficiency (83.1 vs 59.5%, respectively), convenience (87.4 vs 72.0%, respectively) and satisfaction (51.9 vs 30.0%, respectively), all p < 0.0001. CONCLUSION: In this meta-analysis, fentanyl ITS is associated with a superior EOC profile (overall, time efficiency, convenience and satisfaction) from the PTs' perspective when compared with morphine iv. PCA.

Patient considerations in the use of transdermal iontophoretic fentanyl for acute postoperative pain.

Opioids are commonly used in the management of moderate-to-severe postoperative pain. Patient-controlled analgesic techniques are recognized as preferred administration methods. Previously, research has focused on intravenously administered opioids via a programmable pump. More recently, an iontophoretic transdermal system (ITS), which is patient controlled, has been developed. The focus of this review is on pain management using the fentanyl ITS during the 24-72-hour time period immediately following surgery. Fentanyl ITS offers a needle-free alternative to traditional intravenous (IV) patient-controlled analgesia (PCA) system that is as effective and safe as IV PCA. This system is easy to use for both patients and nurses. The use of fentanyl ITS is generally associated with a better ease-of-care profile, including a greater ease of mobility, from a patients' perspective when compared with morphine IV PCA.

Back Pain and Neuraxial Anesthesia.

The incidence of back pain after neuraxial anesthesia in the adult population is not different from that after general anesthesia. The pain is usually mild, localized in the low back, rarely radiates to the lower extremities, and has a duration of only a few days. The risk factors for development of back pain include the lithotomy position, multiple attempts at block placement, duration of surgery longer than 2.5 hours, body mass index ≥32 kg/m, and a history of back pain. However, there is no permanent worsening of preexisting back pain after neuraxial anesthesia. The back pain has been attributed to tears in the ligaments, fascia, or bone with localized bleeding; immobility of the spine; relaxation of the paraspinal muscles under anesthesia; flattening of the normal lumbar convexity; and stretching and straining of the lumbosacral ligaments and joint capsules. The addition of an anti-inflammatory drug to the local anesthetic used for skin infiltration may decrease the incidence and severity of back pain. The use of spinal or epidural anesthesia in the adult, non-obstetric and obstetric populations should depend on the advantages offered by the technique and not on the occurrence of back pain after the procedure. Additional studies are needed to confirm the efficacy of epidural dexamethasone, or other steroids, or the addition of an anti-inflammatory drug to the local anesthetic infiltration for the prevention of back pain after neuraxial anesthesia. Future studies should involve a physician with expertise in the evaluation of chronic low back pain to help identify the cause of the back pain and institute appropriate treatment(s).

Fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia for pain management following orthopedic surgery: A pooled analysis of randomized, controlled trials.

OBJECTIVE: To compare the efficacy and safety of patient-controlled pain management following orthopedic surgery using either fentanyl iontophoretic transdermal system (ITS) or morphine intravenous (i.v.) patient-controlled analgesia (PCA). SETTING: Acute Care Hospital. PATIENTS: Three-open-label, multicenter, randomized, active-controlled, parallel-group phase 3B studies (N = 2095) were conducted that compared fentanyl ITS with morphine i.v. PCA for postoperative pain in hospitalized postoperative patients. A subgroup of orthopedic surgery patients (N = 1,216) was pooled for this analysis; of which 819 completed treatment. INTERVENTIONS: A total of 590 patients received fentanyl ITS (40 µg/dose) and 626 patients received morphine i.v. PCA (1 mg/dose) for up to 72 hours. MAIN OUTCOME MEASURES: Efficacy measures included the patient global assessment (PGA) and the investigator global assessment (IGA) of the method of pain control. RESULTS: Patients had a mean age of about 60 years, were predominantly Caucasian (90.5 percent), and the majority underwent hip replacement (80.3 percent). There were more patients treated with fentanyl ITS who rated their pain control method as "excellent" compared to morphine i.v. PCA at 24 hours postsurgery (44.8 percent vs 33.0 percent, respectively; p < 0.001), 48 hours (37.5 percent vs 25.3 percent, respectively; p < 0.001), and at the last assessment (54.3 percent vs 39.6 percent, respectively; p < 0.001). There were more investigators who rated treatment with fentanyl ITS as "excellent" compared to morphine i.v. PCA at the last assessment (57.4 percent vs 36.9 percent, respectively; p < 0.001). CONCLUSIONS: Following orthopedic surgery, patients and investigators more frequently reported global assessment of pain control as "excellent" on the PGA and IGA assessments with fentanyl ITS than with morphine i.v. PCA.

Neuropathic pain and pharmacological treatment.

Neuropathic pain is a serious chronic condition strongly affecting quality of life, which can be relieved but cannot be cured. Apart from symptomatic management, treatment should focus on the underlying disorder. The estimated prevalence is at least 1% to 5% of the general population. Neuropathic pain is characterized both by spontaneous and evoked pain. A diagnosis of neuropathic pain can usually be established based solely on history and neurological examination. Ancillary investigations may include EMG and computerized tomography/magnetic resonance imaging scans, depending on the localization of the suspected lesion. A limited number of agents, primarily directed at symptom control, are currently approved for use in neuropathic pain. A mechanism-based approach to pharmacological intervention supports the use of polypharmacy in neuropathic pain.

Noradrenergic reuptake inhibition in the treatment of pain.

INTRODUCTION: Noradrenergic reuptake inhibitors can be effective analgesics, finding application in a wide variety of clinical pain settings. Due to a shift toward noradrenergic-mediated pain pathways following nerve injury, they are particularly well suited to the treatment of neuropathic pain. This phenotypic shift makes neuropathic pain difficult to control with opioids alone; some noradrenergic reuptake inhibitors have demonstrated synergy with opioids. Agents currently in early clinical trials are discussed and include both novel delivery of old drugs and the development of new drugs. AREAS COVERED: This review was limited to noradrenergic reuptake inhibitors and analgesia. Literature search included the terms adrenergic, noradrenergic, reuptake, inhibitors, analgesia, NET, norepinephrine transporter, and pain using Medline, Google scholar, Web of Knowledge, www.clinicaltrials.gov, and Pharmaprojects (Informa UK Ltd. 2012). EXPERT OPINION: Topical drug delivery and the use of combinations of agents both topically and systemically are under active investigation. The intrathecal delivery of noradrenergic reuptake inhibitors, allowing delivery directly to the central nervous system thus limiting systemic exposure, represents an exciting avenue of investigation. Gaps in current knowledge have complicated the development of prophylactic therapies for susceptible individuals or preemptive intervention. Disease-modifying agents and selective inhibitors would facilitate these treatment strategies.

Perioperative use of etoricoxib reduces pain and opioid side-effects after total abdominal hysterectomy: a double-blind, randomized, placebo-controlled phase III study.

OBJECTIVE: To evaluate the effects of two different doses of etoricoxib delivered perioperatively compared with placebo and standard pain management on pain at rest, pain with mobilization, and use of additional morphine/opioids postoperatively. RESEARCH DESIGN AND METHODS: In this double-blind, placebo-controlled, randomized clinical trial, we evaluated postoperative pain following total abdominal hysterectomy over 5 days in patients receiving placebo or etoricoxib administered 90 min prior to surgery and continuing postoperatively. Patients were randomly assigned to receive either placebo (n = 144), etoricoxib 90 mg/day (n = 142), or etoricoxib 120 mg/day (n = 144). Average Pain Intensity at Rest over days 1-3 (0- to 10-point numerical rating scale [NRS]) was the primary efficacy endpoint. Secondary endpoints included Average Pain Intensity upon Sitting, Standing, and Walking over days 1-3 (0- to 10-point NRS) as well as Average Total Daily Dose of Morphine over days 1-3. CLINICAL TRIAL REGISTRATION: This trial is registered on www.clinicaltrials.gov (NCT00788710). RESULTS: The least squares (LS) means (95% CI) for the primary endpoint were 3.26 (2.96, 3.55); 2.46 (2.16, 2.76); and 2.40 (2.11, 2.69) for placebo, etoricoxib 90 mg, and etoricoxib 120 mg, respectively, significantly different for both etoricoxib doses versus placebo (p < 0.001). Patients on etoricoxib 90 mg and 120 mg required ~30% less morphine per day than those on placebo (p < 0.001), which led to more rapid bowel recovery in the active treatment groups by ~10 hours vs. placebo. A greater proportion of patients on etoricoxib (10-30% greater than placebo) achieved mild levels of pain with movement, defined as pain ≤3/10. LIMITATIONS: A key limitation for this study was that movement-evoked pain measurements were not designated as primary endpoints. CONCLUSION: In patients undergoing total abdominal hysterectomy, etoricoxib 90 mg and 120 mg dosed preoperatively and then continued postoperatively significantly reduces both resting and movement-related pain, as well as reduced opioid (morphine) consumption that led to more rapid bowel recovery.

Identification and management of pain medication abuse and misuse: current state and future directions.

Long-term opioid therapy poses a risk for abuse and misuse in some patients. Identifying which patients may potentially be at risk prior to initiation of therapy, and identifying patients in whom these problems develop during therapy, are significant challenges. Outcome prediction is impeded by the complexity of the problem, where considerable heterogeneity results from psychological and socioeconomic factors, as well as interindividual variation in biological pathways due to genetic and epigenetic factors. Screening tools designed to detect opioid misuse and urine drug testing are both used clinically; scant evidence currently exists to allow the formulation of an algorithm for judicious use of these tools. Moreover, these tools may not be addressing the underlying alterations in biological pathways that occur owing to the development of chronic pain or in response to chronic opioid administration. An evidence-based algorithmic approach to risk mitigation that can be applied in a cost-effective manner to guide therapy is urgently needed.

The effect of initial local anesthetic dose with continuous interscalene analgesia on postoperative pain and diaphragmatic function in patients undergoing arthroscopic shoulder surgery: a double-blind, randomized controlled trial.

BACKGROUND: Interscalene block (ISB) is commonly performed using 20-40 mL of local anesthetic. Spread to adjacent structures and consequent adverse effects including paralysis of the ipsilateral hemidiaphragm are frequent. Pain ratings, analgesic requirements, adverse events, satisfaction, function and diaphragmatic excursion were compared following interscalene block (ISB) with reduced initial bolus volumes. METHODS: Subjects undergoing arthroscopic rotator cuff repair were randomized to receive 5, 10, or 20 mL ropivacaine 0.75% for ISB in a double-blind fashion (N = 36). Continuous infusion with ropivacaine 0.2% was maintained for 48 h. Pain and diaphragmatic excursion were assessed before block and in the recovery unit. RESULTS: Pain ratings in the recovery room were generally less than 4 (0-10 NRS) for all treatment groups, but a statistically significant difference was noted between the 5 and 20 mL groups (NRS: 2.67 vs. 0.62 respectively; p = 0.04). Pain ratings and supplemental analgesic use were similar among the groups at 24 h, 48 h and 12 weeks. There were no differences in the quality of block for surgical anesthesia. Dyspnea was significantly greater in the 20 mL group (p = 0.041). Subjects with dyspnea had significant diaphragmatic impairment more frequently (Relative risk: 2.5; 95%CI: 1.3-4.8; p = 0.042). Increased contralateral diaphragmatic motion was measured in 29 of the 36 subjects. Physical shoulder function at 12 weeks improved over baseline in all groups (baseline mean SST: 6.3, SEM: 0.6; 95%CI: 5.1-7.5; 12 week mean SST: 8.2, SEM: 0.46; 95%CI: 7.3-9.2; p = 0.0035). CONCLUSIONS: ISB provided reliable surgical analgesia with 5 mL, 10 mL or 20 mL ropivacaine (0.75%). The 20 mL volume was associated with increased complaints of dyspnea. The 5 mL volume was associated with statistically higher pain scores in the immediate postoperative period. Lower volumes resulted in a reduced incidence of dyspnea compared to 20 mL, however diaphragmatic impairment was not eliminated. Compensatory increases in contralateral diaphragmatic movement may explain tolerance for ipsilateral paresis. TRIAL REGISTRATION: clinicaltrials.gov. identifier: NCT00672100.