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.

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).

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.

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.

Aprepitant vs. multimodal prophylaxis in the prevention of nausea and vomiting following extended-release epidural morphine.

BACKGROUND: Extended-release epidural morphine (EREM) is an effective option for postoperative analgesia following major orthopedic surgery; however, postoperative nausea/vomiting (PONV) is a recognized limitation. The incidence of PONV following prophylactic aprepitant, a neurokinin-1 antagonist, was compared with prophylactic multimodal antiemetic therapy in patients receiving EREM for postoperative analgesia following unilateral primary total knee arthroplasty (TKA). METHODS: Prospectively collected quality assurance data were examined with Institutional Review Board approval. A sequential, open-label, active matched case-control study compared PONV following EREM in patients receiving ondansetron and dexamethasone, and either metoclopramide, diphenhydramine, or prochlorperazine every 6 hours for the 48-hour study period, to patients receiving aprepitant 40 mg given as a single oral dose in the preoperative holding area. Cases were matched for procedure (TKA), age, epidural morphine dose, and known major risk factors for PONV (sex, smoking, previous PONV/motion sickness). RESULTS: Twelve consecutive patients (3 male; 9 female) receiving aprepitant prior to EREM were matched to 12 patients of the same sex of similar age (range 51 to 84 years.) and EREM dose (range 5 to 12.5 mg) receiving the multimodal regime. The incidence of PONV was significantly less for the aprepitant group where 3 of 12 (25%) had PONV compared with 9 of 12 (75%) in the multimodal group (P = 0.039, Fisher's Exact Test; odds ratio = 0.11; 95% CI: 0.018 to 0.706, P = 0.03). CONCLUSION: While aprepitant significantly reduced the incidence of PONV compared with a multimodal antiemetic regime, used alone it did not eliminate PONV.

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.

Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study.

OBJECTIVES: The primary objective of this study was to assess the efficacy and tolerability of tapentadol immediate release (IR) in patients who were candidates for joint replacement surgery due to end-stage joint disease. A secondary objective was to compare tapentadol IR with oxycodone HCl IR with respect to efficacy and prespecified tolerability end points. METHODS: This 10-day, Phase III, randomized, double-blind, active- and placebo-controlled study compared the efficacy and tolerability of tapentadol IR, oxycodone HCl IR, and placebo in patients with uncontrolled osteoarthritis pain who were candidates for primary replacement of the hip or knee as a result of end-stage degenerative joint disease. Patients received tapentadol IR 50 mg, tapentadol IR 75 mg, oxycodone HCl IR 10 mg, or placebo every 4 to 6 hours during waking hours. The primary end point was the sum of pain intensity difference (SPID) over 5 days. Secondary efficacy end points included 2- and 10-day SPID; 2-, 5-, and 10-day total pain relief (TOTPAR); and the sum of total pain relief and pain intensity difference (SPRID). Prespecified noninferiority comparisons with oxycodone HCl IR were performed with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported adverse events (AEs) of nausea and/or vomiting and constipation). RESULTS: Of 666 patients originally enrolled, 659 were included in the efficacy analysis (51% male; 91% white; mean age, 61.2 years; mean weight, 97 kg). Five-day SPID was significantly lower in those treated with tapentadol IR (tapentadol IR 50 mg: least squares mean difference [LSMD] = 101.2 [95% CI, 54.58- 147.89]; tapentadol IR 75 mg: LSMD = 97.5 [95% CI, 51.81-143.26]) or oxycodone HCl IR (LSMD = 111.9 [95% CI, 66.49-157.38]) (all, P < 0.001). Tapentadol IR 50 and 75 mg and oxycodone HCl IR 10 mg were associated with significant reductions in pain intensity compared with placebo, based on 2- and 10-day SPID and 2-, 5-, and 10-day TOTPAR and SPRID (all, P < 0.001). The efficacy of tapentadol IR 50 and 75 mg was noninferior to that of oxycodone HCl IR 10 mg; however, the incidence of selected gastrointestinal AEs (nausea, vomiting, and constipation) was significantly lower for both doses of tapentadol IR compared with oxycodone HCl IR 10 mg (nominal P < 0.001). The odds ratios for nausea and/or vomiting for tapentadol IR 50 and 75 mg relative to oxycodone HCl IR 10 mg were 0.21 (95% CI, 0.128-0.339) and 0.32 (95% CI, 0.204-0.501), respectively; for constipation, the corresponding odds ratios were 0.13 (95% CI, 0.057-0.302) and 0.20 (95% CI, 0.098-0.398). Rates of treatment discontinuation were 18% (28/157) in the tapentadol IR 50-mg group, 26% (43/168) in the tapentadol IR 75-mg group, 35% (60/172) in the oxycodone HCl IR 10-mg group, and 10% (17/169) in the placebo group. In a post hoc analysis, tapentadol IR 50 mg was associated with a significantly lower incidence of treatment discontinuation than was oxycodone HCl IR 10 mg (P < 0.001). CONCLUSIONS: In these patients with uncontrolled osteoarthritis pain who were awaiting joint replacement surgery, tapentadol IR 50 and 75 mg were associated with analgesia that was noninferior to that provided by oxycodone HCl IR 10 mg. Tapentadol treatment was associated with improved gastrointestinal tolerability.

Quality assessment in clinical trials: considerations for outcomes research in interventional pain medicine.

The assessment of quality in clinical trials involves multiple considerations. While compliance with both Good Clinical Practice and International Conference on Harmonisation guidelines is required, variations in many other factors contribute to the overall quality of the report. Principal among these factors is the development of a testable study question. Study questions that are feasible, interesting, novel, ethical, and relevant are desirable. The methodology used to answer the question should be described in sufficient detail and documented to provide for reproducibility and transparency. This is essential for both interpretation of the results and for assessing the applicability of the results to clinical practice. While randomized controlled trials (RCT) are currently the penultimate methodological standard for quality in research study design, they typically do not mimic clinical practice, which can present limitations to their value. This is particularly relevant with respect to interventional therapies, where RCT designs can be associated with scientific and ethical challenges. Well-designed observational studies may overcome some of these drawbacks, but often require very large study populations. Technological advances in communication may permit the pooling of data and the emergence of new standards for interventional pain research.

Evaluation of a single-dose, extended-release epidural morphine formulation for pain after knee arthroplasty.

BACKGROUND: DepoDur is a single-dose, extended-release epidural morphine formulation designed to provide forty-eight hours of pain relief. The drug offers potential advantages over continuous epidural infusions, particularly in patients being treated with anticoagulation therapy. The purpose of this study was to evaluate the efficacy and safety of single-dose epidural DepoDur for pain control following knee arthroplasty. METHODS: In this multicenter, randomized, double-blind, parallel-group study, patients were randomized to receive a single-dose of DepoDur (20 or 30 mg) or a sham epidural injection thirty minutes before administration of general or regional anesthesia for knee arthroplasty. At their first request for postoperative analgesia, patients who had received DepoDur were given an intravenous bolus of hydromorphone followed by placebo patient-controlled analgesia. Patients who had received the sham epidural were given an intravenous bolus of morphine followed by patient-controlled analgesia with morphine. Patient ratings of pain intensity at rest and with activity, their rating of overall pain control, and postoperative opioid use were recorded. The ability to tolerate physical therapy, the range of motion of the knee, and the need for physical support were assessed as well. Adverse events and vital signs were recorded. RESULTS: Of 168 patients randomized to receive the 20-mg injection of DepoDur, the 30-mg injection of DepoDur, or the sham epidural injection, fifty-one, fifty-eight, and fifty-five patients, respectively, were included in the efficacy analysis. Compared with the patients treated with intravenous patient-controlled analgesia with morphine, the patients treated with DepoDur had significantly reduced mean pain-intensity-recall scores during the four to eight, four to twelve, four to twenty-four, and four to thirty-hour postdose intervals (p < 0.05 for all comparisons). The patients treated with DepoDur used approximately a threefold lower amount of postoperative opioids in total, with a significant percentage requiring no supplemental opioids. Adverse events common to all groups were nausea (78%), pyrexia (46%), vomiting (43%), pruritus (43%), and hypotension (36%). Respiratory depression was the most common serious adverse event, with serious respiratory depression observed in four DepoDur-treated patients, who were more than sixty-five years of age. CONCLUSIONS: With appropriate patient selection and monitoring, perioperative single-dose epidural DepoDur was a safe and effective analgesic alternative to postoperative intravenous patient-controlled analgesia following knee arthroplasty, with younger patients benefiting from the 20-mg dose. Additional studies of 10 to 15-mg doses for older patients are warranted.

Fentanyl iontophoretic transdermal system for acute-pain management after orthopedic surgery: a comparative study with morphine intravenous patient-controlled analgesia.

BACKGROUND AND OBJECTIVES: The fentanyl HCl iontophoretic transdermal system (ITS) has been demonstrated in clinical trials to be safe and effective for acute-pain management after several types of major surgery. The current study compared the efficacy, safety, and convenience of fentanyl ITS with morphine intravenous patient-controlled analgesia (IV PCA) for acute-pain management after unilateral total-hip replacement (THR). METHODS: In this multicenter (52 sites), randomized, open-label, active-controlled, phase IIIb study, patients (n = 799) received fentanyl ITS (40 mug fentanyl [10-minute infusion/lockout], up to 6 doses/h) or morphine IV PCA (1-mg morphine bolus [5-minute lockout], up to 10 mg/h) after unilateral THR. The primary efficacy measure was success ratings ("excellent" or "good") on the patient global assessment (PGA) of the method of pain control in the first 24 hours. Pain intensity and adverse events were also assessed. RESULTS: The PGA success ratings (83.0% v 82.2%; difference = 0.9%; 95% CI: -4.4% to 6.1%) and the mean last pain-intensity scores (3.0 v 3.0; difference = 0.0; 95% CI: -0.33 to 0.33) in the first 24 hours were statistically equivalent between fentanyl ITS and morphine IV PCA groups, respectively. The incidence of adverse events was similar between the groups. CONCLUSIONS: Results of this study demonstrate fentanyl ITS and a standard regimen of morphine IV PCA were comparable methods of pain control for management of acute postoperative pain after THR, on the basis of the PGA success ratings and pain intensity in the first 24 hours of treatment.

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.