Association of preoperative opioid use and postoperative complications following breast reconstruction.

BACKGROUND: Previous studies in orthopedics and general surgery have linked negative patient outcomes with preoperative opioid use. In this study, we investigated the association of preoperative opioid use on breast reconstruction outcomes and quality of life (QoL). METHODS: We reviewed our prospective registry of patients who underwent breast reconstruction for documented preoperative opioid use. Postoperative complications were recorded at 60 days after the first reconstructive surgery and 60 days after the final staged reconstruction. We used a logistic regression model to assess the association between opioid use and postoperative complications, controlling for smoking, age, laterality, BMI, comorbidities, radiation, and previous breast surgery; linear regression to analyze RAND36 scores to evaluate the impact of preoperative opioid use on postoperative QoL, controlling for the same factors; and Pearson chi-squared test to assess factors that may be associated with opioid use. RESULTS: Of the 354 patients eligible for inclusion, 29 (8.2%) were prescribed preoperative opioids. There were no differences in opioid use by race, BMI, comorbidities, previous breast surgery, or laterality. Preoperative opioids were associated with increased odds of postoperative complications within 60 days after the first reconstructive surgery (OR: 6.28; 95% CI: 1.69-23.4; p = 0.006) and within 60 days after the final staged reconstruction (OR: 8.38; 95% CI: 1.17-59.4; p = 0.03). Among patients using opioids preoperatively, the RAND36 physical and mental scores decreased but were not statistically significant. CONCLUSION: We found that preoperative opioid use is associated with increased odds of postoperative complications among patients who underwent breast reconstruction and may contribute to clinically significant declines in postoperative QoL.

Adverse Effects Associated with Patient-Controlled Analgesia with Ketamine Combined with Opioids and Ketamine Infusion with PCA Bolus in Postoperative Spine Patients: A Retrospective Review.

Objective: There has been increasing use of ketamine at subanesthetic doses as an adjunct to opioids in perioperative pain management. There are several known adverse drug effects (ADEs) associated with ketamine. However, the incidence of ADEs with ketamine infusions with patient-controlled analgesia (PCA) boluses compared with combined opioid and ketamine PCAs is not well described. The objectives of this study were to compare the incidence and type of ADEs in postoperative spine surgery patients on ketamine infusions with as-needed PCA boluses to patients on combined opioid and ketamine PCAs. Methods: The medical records of patients who underwent spine surgery between March 2016 and March 2020 who were postoperatively treated with a ketamine infusion and as-needed PCA boluses and parenteral opioids or treated with a combined opioid and ketamine PCA were reviewed. Perioperative information including patient characteristics and preoperative morphine equivalent daily dose (MEDD) were collected. Patient charts were reviewed for ADEs including psychological and neurological side effects, nausea, and new-onset tachycardia. Results: A total of 315 patients met the inclusion criteria and were included in the final analysis. Of these patients, 121 experienced at least one ADE (38%). Sixteen of the 68 ketamine infusion with PCA bolus patients (24%), 77 of the 203 hydromorphone and ketamine patients (38%), and 28 of the 44 morphine and ketamine patients (64%) experienced an ADE [p<0.01]. In patients with preoperative MEDD ≤ 90, nausea was the only ADE that differed significantly among the three groups. Conclusion: This retrospective analysis suggests that postoperative spine patients treated with a ketamine infusion with as-needed PCA boluses and parenteral opioids were associated with fewer ADEs when compared to an intravenous combined opioid and ketamine PCA. In patients with preoperative MEDD ≤ 90, nausea with and without emesis was the only ADE that showed statistically significant difference amongst the three groups.

Estimates of Probabilities of Successful Development of Pain Medications: An Analysis of Pharmaceutical Clinical Development Programs from 2000 to 2020.

BACKGROUND: The authors estimate the probability of successful development and duration of clinical trials for medications to treat neuropathic and nociceptive pain. The authors also consider the effect of the perceived abuse potential of the medication on these variables. METHODS: This study uses the Citeline database to compute the probabilities of success, duration, and survivorship of pain medication development programs between January 1, 2000, and June 30, 2020, conditioned on the phase, type of pain (nociceptive vs. neuropathic), and the abuse potential of the medication. RESULTS: The overall probability of successful development of all pain medications from phase 1 to approval is 10.4% (standard error, 1.5%). Medications to treat nociceptive and neuropathic pain have a probability of successful development of 13.3% (standard error, 2.3%) and 7.1% (standard error, 1.9%), respectively. The probability of successful development of medications with high abuse potential and low abuse potential are 27.8% (standard error, 4.6%) and 4.7% (standard error, 1.2%), respectively. The most common period for attrition is between phase 3 and approval. CONCLUSIONS: The authors' data suggest that the unique attributes of pain medications, such as their abuse potential and intended pathology, can influence the probability of successful development and duration of development.

Infectious Complications of Dorsal Root Ganglion Stimulation: A Systematic Review and Pooled Analysis of Incidence.

BACKGROUND AND OBJECTIVES: Dorsal root ganglion stimulation (DRGS) is a newer form of neuromodulation that targets the dorsal root ganglion. DRGS has superior efficacy in complex regional pain syndrome compared to spinal cord stimulation (SCS) and may have efficacy in other forms of chronic pain. While decades of safety data are available for SCS, there is less available safety information for DRGS. The objectives of this systematic review and pooled analysis of incidence are to determine the overall incidence of DRGS infections, incidence at each stage (trial vs implant vs revision), infection characteristics, and outcomes. MATERIALS AND METHODS: A comprehensive search of databases from January 1980 to January 2021 was conducted. RESULTS: Ten studies met inclusion criteria. Eight studies reported patients with trial data (n = 291), ten studies reported patients with implant data (n = 250), and seven studies reported data with revisions (n = 26). The pooled incidence of trial infections was 1.03% (95% CI 0.35-2.99%), implant infections was 4.80% (95% CI 2.77-8.20%), revision infections was 3.85% (95% CI 0.20-21.59%), and overall infections was 2.82% (95% CI 1.62-4.54%). There was a statistically significant difference in infection rates between the trial, implant, and revision stages, X2 (2, N = 567) = 8.9839, p = 0.01. CONCLUSIONS: This is the first systematic review and pooled analysis that followed PRISMA guidelines to report infectious complications of DRGS by stage (trial vs implant vs revision). DRGS trial appears to be low risk for infection but that risk is significantly increased with DRGS implant. Our findings highlight the need for further study of infectious complications, their risks, and optimal prophylaxis.

Changes in Patient Satisfaction Scores During the Early COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has caused a rapid and widespread application of telemedicine services in the outpatient setting. Prior to COVID-19, patient satisfaction was measured with Consumer Assessment of Healthcare Providers and Systems (CAHPS) Clinician & Group Survey (CG-CAHPS) and was then measured with the Press Ganey telemedicine survey. Both surveys ask about a patient's likelihood to recommend a particular medical practice, which is a useful, but imperfect, surrogate for overall satisfaction. The purpose of this analysis was to identify any changes in patient satisfaction scores with the implementation of telemedicine services. A retrospective analysis of our institution's experience during the early months of the COVID-19 pandemic compared to the months immediately prior to the pandemic was conducted. The percent of patients with a "Top box" response to survey questions regarding their likelihood to recommend a medical practice were compared. A total of 14 430 CG-CAHPS results collected in November 2019 through February 2020 were compared to 22 009 telemedicine survey results collected between March and May 2020. In general, most medical specialties incorporated telemedicine but suffered a decrease in their patient's likelihood to recommend a medical practice during the first few months of the pandemic. However, the magnitude of this decrease was variable by medical specialty. Physical medicine and rehabilitation and pain medicine had relatively poor scores prior to the pandemic which did not statistically change. Oncology was the sole medical specialty that continued to have unchanged high patient satisfaction scores. These data provide insights for the refinement of telemedicine.

Anti-nerve growth factor antibodies for the treatment of low back pain.

INTRODUCTION: The treatment of chronic low back pain (cLBP) often involves multimodal pharmacologic and non-pharmacologic strategies. There remain shortcomings with these tools with regards to both effect size and side effects. AREAS COVERED: In an effort to better address cLBP, anti-nerve growth factor (NGF) monoclonal antibodies (mAbs) are nearing marketing approval. This class of medications has been primarily evaluated for osteoarthritis, but are being examined at higher doses for use in cLBP. We review the efficacy of this class in treating LBP as well as their potential side effects based on nine phase II or III published clinical trials. Five trials evaluated Tanezumab and four trials evaluated Fasinumab, with seven trials evaluating nonspecific LBP, one evaluating sciatica related cLBP, and one evaluating vertebral fracture related cLBP. EXPERT OPINION: The results of available clinical trials indicate modest effectiveness with regard to reduction of pain in the low back, and improved functionality, compared to placebo in keeping with the effect size of other pharmacologic treatment modalities. Rapidly progressive osteoarthritis was infrequently reported. However, the continued observation of this serious side effects warrants careful patient selection and balancing the risks and benefits of anti-NGF mAbs in treating cLBP.

Workplace Violence in the Setting of Pain Management.

In the context of the opioid crisis, increased attention has been placed on the risk of violence in outpatient pain medicine clinics. The primary objective of this study was to determine the prevalence and characteristics of workplace violence in a mixed group of clinicians (ie, practicing physicians, resident and fellow physicians in training, nurse practitioners, physician assistants, psychologists) participating in a workplace violence education session at a national pain conference held March 6 through March 10, 2019. A published survey instrument developed to assess workplace violence among pain management clinicians was offered to all 70 attendees, and 58 (82.9%) completed the survey. The mean age of respondents was 47.5 years, and 23 of 56 (41.1%) were female. Of the 58 respondents, 48 (82.8%) reported calling security at least once in the past year, and 39 of 57 (68.4%) reported being threatened with bodily harm. Among those threatened (multiple responses possible per respondent), 41 of 78 responses (52.6%) reported verbal threats, 11 of 78 (14.1%) reported being threatened with an object, and 11 of 78 (14.1%) reported threats of physical violence. Of 59 reponses, 15 (25.6%) endorsed carrying a weapon or using protective equipment. When asked about the clinical context of threats, 37 of 77 responses (48.1%) cited opioid management, 9 (11.7%) cited Workers' Compensation, 6 (7.8%) cited disability request, and 4 (5.2%) cited litigation related to an automobile accident. The observations from this survey suggest that clinicians practicing pain medicine experience workplace violence and threats of violence on a frequent basis. It is imperative for clinicians to acknowledge the risk of workplace violence and to recognize high-risk clinical scenarios. Future research should be directed toward developing and implementing data-driven risk mitigation strategies aimed at reducing the rate of workplace violence in outpatient pain clinics.

Emerging concepts on the use of ketamine for chronic pain.

Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine's action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine's analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine's ability to modulate the affective-motivational dimension of pain.

Survey of Spinal Cord Stimulation Hardware Currently Available for the Treatment of Chronic Pain in the United States.

Background: The number of spinal cord stimulator (SCS) units sold in the United States (US) for the treatment of chronic pain has increased with a corresponding expansion in the number of different SCS platforms available. Each marketed stimulator has several unique features, indications, and limitations, which distinguish one from the other and makes the selection of appropriate hardware possible for optimal patient care. There are an even greater number of similar and overlapping features between SCS. Measures: We used market analysis techniques to survey the currently available SCS technology. We then reviewed published device specifications and manuals for comparison of features. Outcomes: As of 2020, there are nine commonly used SCS platforms made by four manufacturers including four SCS units from Abbott, three from Boston Scientific, and one each from Medtronic and Nevro. Conclusions: A working understanding of each SCS product's nuances is needed for selecting the most appropriate device with which to manage chronic pain patients. Here we present a brief survey of currently available SCS hardware in the US and the features that make each product unique.

The effect of patient satisfaction scores on physician job satisfaction and burnout.

Physician burnout is recognized as reversible with the potential to negatively influence quality of care and patient outcomes. The study objective was to evaluate associations between patient satisfaction scores (PSS) and physicians' perceptions of job satisfaction and burnout via a physician survey. Eighty two out of 107 report PSS are institutionally tracked, with 23/107 and 39/107 reporting PSS utilization in financial compensation or performance review, respectively. Fifty four out of 107, report pressure to emphasize PSS; 63/107, report PSS having negative effect on job satisfaction; 31/107 considered leaving their job or career due to PSS and 84/107 report PSS contribute to burnout. In the cohort of physicians treating patients with spine pain who responded to this survey, PSS are associated with decreased job satisfaction and increased burnout.

Morphine decreases the function of primary human natural killer cells by both TLR4 and opioid receptor signaling.

BACKGROUND: Opioids are commonly used to provide analgesia for cancer pain, and functional opioid receptors have been identified on natural killer (NK) cells, the lymphocytes responsible for surveillance and elimination of cancer cells. Opioids also bind to other lymphocyte receptors, such as Toll-like receptor (TLR)-4. Here, we characterized the effects of morphine on primary human NK cell cytotoxicity and mediator release, which occur through classical opioid receptor or TLR4 signaling. METHODS: Purified primary human NK cells were pretreated with inhibitors of opioid receptors or TLR4 before being cultured with target tumor cell line K562 in the presence or absence of morphine. Apoptosis of K562 cells in each treatment condition was measured with an Annexin V flow cytometry-based assay and compared to that of K562 cells cultured with NK cells alone. Supernatant concentrations of 13 cytokines and cytotoxic mediators were measured with a multiplex bead-based flow cytometry assay. RESULTS: Exposure of NK cells to morphine decreased their ability to induce apoptosis in K562 cells. Pretreating the NK cells with either naloxone, a mu- and kappa-opioid receptor antagonist, or TAK-242, a selective inhibitor of TLR4 signaling, prevented this effect. Paradoxically, morphine increased the concentration of interleukin-6, granzyme A, and granzyme B in cell supernatants. Pretreatment of NK cells with TAK-242 prevented the morphine-induced increase in interleukin-6, whereas pretreatment with naloxone inhibited the morphine-induced increase in granzymes A and B. CONCLUSIONS: Both classical opioid receptors and TLR4 participate in morphine-induced suppression of NK cell cytotoxic activity. These studies have important implications for maintenance of immune function during management of cancer pain.

Suppression of Human Natural Killer Cells by Different Classes of Opioids.

BACKGROUND: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized. METHODS: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester-labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction. RESULTS: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5] enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells. CONCLUSIONS: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not observed after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with µ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by µ- and κ-receptor agonism and that suppression is similar with many clinically used opioids.

Cannabis for the Treatment of Chronic Pain in the Era of an Opioid Epidemic: A Symposium-Based Review of Sociomedical Science.

OBJECTIVE: This manuscript reviews medical literature published pertaining to the management of chronic pain with medical marijuana therapy (MMJ), with an emphasis on the social, medical, and legal aspects of therapy. DESIGN: Narrative review of peer-reviewed literature. METHODS: The 3rd Symposium on Controlled Substances and Their Alternatives for the Treatment of Pain was held in Boston on February 27, 2016, with a focus on MMJ for the treatment of chronic pain. Invited speakers had diverse backgrounds, including pain management, addiction psychiatry, neurology, and legal authorities. The purpose of this conference and this subsequent narrative review is to provide a medical, legal, and logistical framework for physicians and other health care providers to refer to when considering the initiation of medical marijuana therapy. RESULTS: The invited speakers each covered a unique aspect of MMJ therapy for the treatment of chronic pain. These presentations highlighted the current data for and against the use of MMJ as a pain therapy. Optimal patient selection and screening, in addition to policy developments, were discussed. CONCLUSIONS: Increasing interest in MMJ for chronic pain underscores a need for primary care and pain physicians to better understand the indications and evidence for its use free from cultural bias. Given a lack of full conclusive clinical utility, continued research is needed to better understand how to best utilize MMJ therapy for the treatment of chronic pain. Policy initiatives, such as enumerated indications, should follow medical science in order to prevent another abused substance epidemic.

Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future.

The field of spinal cord stimulation is expanding rapidly, with new waveform paradigms asserting supraspinal sites of action. The scope of treatment applications is also broadening from chronic pain to include cerebral ischemia, dystonia, tremor, multiple sclerosis, Parkinson disease, neuropsychiatric disorders, memory, addiction, cognitive function, and other neurologic diseases. The role of neurostimulation as an alternative strategy to opioids for chronic pain treatment is under robust discussion in both scientific and public forums. An understanding of the supraspinal mechanisms underlying the beneficial effects of spinal cord stimulation will aid in the appropriate application and development of optimal stimulation strategies for modulating pain signaling pathways. In this review, the authors focus on clinical and preclinical studies that indicate the role of supraspinal mechanisms in spinal cord stimulation-induced pain inhibition, and explore directions for future investigations.

HIV treatment is associated with a two-fold higher probability of raised triglycerides: Pooled Analyses in 21 023 individuals in sub-Saharan Africa.

BACKGROUND: Anti-retroviral therapy (ART) regimes for HIV are associated with raised levels of circulating triglycerides (TG) in western populations. However, there are limited data on the impact of ART on cardiometabolic risk in sub-Saharan African (SSA) populations. METHODS: Pooled analyses of 14 studies comprising 21 023 individuals, on whom relevant cardiometabolic risk factors (including TG), HIV and ART status were assessed between 2003 and 2014, in SSA. The association between ART and raised TG (>2.3 mmol/L) was analysed using regression models. FINDINGS: Among 10 615 individuals, ART was associated with a two-fold higher probability of raised TG (RR 2.05, 95% CI 1.51-2.77, I2=45.2%). The associations between ART and raised blood pressure, glucose, HbA1c, and other lipids were inconsistent across studies. INTERPRETATION: Evidence from this study confirms the association of ART with raised TG in SSA populations. Given the possible causal effect of raised TG on cardiovascular disease (CVD), the evidence highlights the need for prospective studies to clarify the impact of long term ART on CVD outcomes in SSA.

Neuropathic Pain Medication Use Does Not Alter Outcomes of Spinal Cord Stimulation for Lower Extremity Pain.

INTRODUCTION: Spinal cord stimulation (SCS) for the treatment of lower extremity pain is believed to the result of increased activity in the descending inhibitory and decreased activity in the ascending excitatory tracts. Evidence suggests that the analgesia afforded by SCS may be altered using certain neuropathic pain medications that also modulate neurotransmitters in these sensory tracts. We hypothesize that neuropathic pain medications may alter the response to SCS therapy. METHODS: One hundred and fifteen subjects undergoing SCS therapy for lower extremity pain were retrospectively examined. The pharmacologic profile, including stable use of neuropathic and opioid medications, were recorded. Three separate logistic regression models examined the odds ratio of primary outcomes; a successful SCS trial, a 50% decrease in pain or a 50% reduction in opioid use one year after implant. RESULTS: Neither the use of opioids or neuropathic pain medications were associated with changes in the odds of a successful SCS trial or a 50% pain reduction. A higher dose of chronic opioids use prior to a trial was associated with greater odds of having a 50% reduction in opioid use following implant. OR 1.02, 95% CI 1.01-1.02, p-value < 0.01). CONCLUSIONS: The use of neuropathic pain medications did not change the odds of either a successful SCS trial, or of experiencing a 50% reduction in pain at one year. The association between higher opioid doses and greater odds of a 50% reduction in opioid use may be the reflective of SCS's ability to reduce opioid reliance in chronic pain patients.

Chronic Opioid Therapy Modifies QST Changes After Ketamine Infusion in Chronic Pain Patients.

The long-term effects of opioids on sensitization processes are believed to be mediated through the N-methyl-D-aspartate receptor. Quantitative sensory testing (QST) changes observed after a ketamine infusion have been previously described but the effect that chronic opioids will have is not known. The results of this prospective randomized factorial trial compared the thermal QST changes observed after a .05 mg/kg ketamine infusion or a saline placebo in chronic pain subjects who were either opioid-naive or were chronically using opioids for chronic noncancer pain are presented. No baseline QST differences were noted between the 4 groups at baseline. Comparison of changes preinfusion with postinfusion QST measurements resulted in decreased average change in temporal summation response between opioid subjects who received a placebo compared with those who received a ketamine infusion (-5.22, SD = 9.96 vs 13.81, SD = 19.55; P = .004). Additionally, the average change in temporal summation was decreased among subjects who received a ketamine infusion and were not chronically using opioids compared with subjects who were using chronic opioids and received a placebo infusion (-1.91, SD = 13.25 vs 13.81, SD = 19.55; P = .007). The results indicate that low-dose ketamine infusions produce subtle changes in QST phenotypes that are modified by the chronic use of opioids. This illustrates the potential diagnostic and therapeutic value of ketamine in the setting of chronic opioid use. PERSPECTIVE: The presented data further our understanding of modulation of sensory perception in the setting of chronic opioid use and the role of the N-methyl-D-aspartate receptor. The use of low-dose ketamine infusions may be useful for the treatment as well as diagnosis of opioid-related neuropathic conditions.

Opioid Reduction Following Interventional Procedures for Chronic Pain: A Synthesis of the Evidence.

The past decade has witnessed the tremendous growth of procedures to treat chronic pain, which has resulted in increased third-party scrutiny. Although most of these procedures appear to be associated with significant pain relief, at least in the short and intermediate term, their ability to improve secondary outcome measures, including function and work status is less clear-cut. One of these secondary outcome measures that has garnered substantial interest in the pain and general medical communities is whether interventions can reduce opioid intake, which is associated with significant risks that in most cases outweigh the benefits in the long term. In the article, we examine whether procedural interventions for chronic pain can reduce opioid intake. Most studies that have examined analgesic reduction as a secondary outcome measure have not separated opioid and nonopioid analgesics, and, among those studies that have, few have demonstrated between-group differences. Reasons for failure to demonstrate opioid reduction can be broadly classified into procedural, design-related, clinical, psychosocial, biological, and pharmacological categories, all of which are discussed. In the future, clinical trials in which this outcome is examined should be designed to evaluate this, at least on a preliminary basis.