BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury.

Peripheral nerve injury-induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury-induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.

An Overview of Cannabidiol.

Cannabidiol (CBD) is one of the most interesting constituents of cannabis, garnering significant attention in the medical community in recent years due to its proven benefit for reducing refractory seizures in pediatric patients. Recent legislative changes in the United States have made CBD readily available to the general public, with up to 14% of adults in the United States having tried it in 2019. CBD is used to manage a myriad of symptoms, including anxiety, pain, and sleep disturbances, although rigorous evidence for these indications is lacking. A significant advantage of CBD over the other more well-known cannabinoid delta-9-tetrahydroncannabinol (THC) is that CBD does not produce a "high." As patients increasingly self-report its use to manage their medical conditions, and as the opioid epidemic continues to drive the quest for alternative pain management approaches, the aims of this narrative review are to provide a broad overview of the discovery, pharmacology, and molecular targets of CBD, its purported and approved neurologic indications, evidence for its analgesic potential, regulatory implications for patients and providers, and future research needs.

The Basic Science of Cannabinoids.

The cannabis plant has been used for centuries to manage the symptoms of various ailments including pain. Hundreds of chemical compounds have been identified and isolated from the plant and elicit a variety of physiological responses by binding to specific receptors and interacting with numerous other proteins. In addition, the body makes its own cannabinoid-like compounds that are integrally involved in modulating normal and pathophysiological processes. As the legal cannabis landscape continues to evolve within the United States and throughout the world, it is important to understand the rich science behind the effects of the plant and the implications for providers and patients. This narrative review aims to provide an overview of the basic science of the cannabinoids by describing the discovery and function of the endocannabinoid system, pharmacology of cannabinoids, and areas for future research and therapeutic development as they relate to perioperative and chronic pain medicine.

Legal and Regulatory Aspects of Medical Cannabis in the United States.

Federal and state laws in the United States governing the use of cannabis are rapidly evolving. Under federal law, marijuana and its derivatives remain schedule I, defined as substances having no currently accepted medical use and a high potential for abuse. Hemp and its derivatives, in contrast, have been removed from schedule I. At the state level, a majority of states have passed laws legalizing cannabis in some form, although these laws vary from state to state in terms of the extent to which use is permitted, approved medical uses, and the types of regulation placed on commercial activity and quality control. This inconsistency has contributed to uncertainty among medical providers and their patients. In this review, we provide a brief account of the evolution and current state of federal and state laws and regulatory agencies involved in overseeing medical cannabis use in the United States.

Effectiveness of oral versus intravenous tranexamic acid in primary total hip and knee arthroplasty: a randomised, non-inferiority trial.

BACKGROUND: Tranexamic acid (TXA) reduces rates of blood transfusion for total hip arthroplasty (THA) and total knee arthroplasty (TKA). Although the use of oral TXA rather than intravenous (i.v.) TXA might improve safety and reduce cost, it is not clear whether oral administration is as effective. METHODS: This noninferiority trial randomly assigned consecutive patients undergoing primary THA or TKA under neuraxial anaesthesia to either one preoperative dose of oral TXA or one preoperative dose of i.v. TXA. The primary outcome was calculated blood loss on postoperative day 1. Secondary outcomes were transfusions and complications within 30 days of surgery. RESULTS: Four hundred participants were randomised (200 THA and 200 TKA). The final analysis included 196 THA patients (98 oral, 98 i.v.) and 191 TKA patients (93 oral, 98 i.v.). Oral TXA was non-inferior to i.v. TXA in terms of calculated blood loss for both THA (effect size=-18.2 ml; 95% confidence interval [CI], -113 to 76.3; P<0.001) and TKA (effect size=-79.7 ml; 95% CI, -178.9 to 19.6; P<0.001). One patient in the i.v. TXA group received a postoperative transfusion. Complication rates were similar between the two groups (5/191 [2.6%] oral vs 5/196 [2.6%] i.v.; P=1.00). CONCLUSIONS: Oral TXA can be administered in the preoperative setting before THA or TKA and performs similarly to i.v. TXA with respect to blood loss and transfusion rates. Switching from i.v. to oral TXA in this setting has the potential to improve patient safety and decrease costs.

Patients Undergoing Primary, Cementless TKA had Similar Pain, Opioid Utilization, and Functional Outcomes Compared to Matched Patients With Cemented Fixation.

BACKGROUND: Despite renewed interest in cementless fixation of total knee implants, many surgeons have anecdotal concerns about slower recovery and higher early pain scores. We sought to analyze 90-day opioid utilizations, inhospital pain scores, and patient-reported outcome measures (PROMs) in patients undergoing primary cemented versus cementless total knee arthroplasty (TKA). METHODS: We retrospectively identified a cohort of opioid naïve patients undergoing primary TKA for osteoarthritis. There were 186 patients who had cementless TKAs matched 1:6 with 1,116 who received a cemented TKAs based on age (±6 years), body mass index (BMI) (±5), and sex. We compared inhospital pain scores, 90-day opioid utilizations in morphine milligram equivalents (MMEs), and early postoperative PROMs. RESULTS: The cemented and cementless cohorts had similar lowest (0.09 versus 0.08), highest (7.36 versus 7.34), and average (3.26 versus 3.27) pain scores using numeric rating scale (P > .05). They received similar inhospital (90 versus 102, P = .176), discharge (315 versus 315, P = .483), and total (687 versus 720, P = .547) MMEs. They had similar average inpatient hourly opioid consumption (2.5 versus 2.5 MMEs/hour, P = .965). Average refills 90 days postoperatively were similar in both cohorts (1.5 versus 1.4 refills, P = .893). Also, preoperative, 6-week, 3-month, delta 6-week, and delta 3-month PROMs scores were similar between cemented and cementless cohorts (P > .05) CONCLUSION: This matched study demonstrated similar in-hospital pain scores and opioid utilization, total MMEs prescribed within 90 days, and PROMs at 6 weeks and 3 months postoperatively between cemented and cementless TKAs. LEVEL OF EVIDENCE: III, retrospective cohort study.

Preoperative cannabis use does not increase opioid utilization following primary total hip arthroplasty in a propensity matched analysis.

PURPOSE: The recreational and medical use of cannabis is being legalized worldwide. Its use has been linked to an increased risk of developing opioid use disorders. As opioids continue to be prescribed after total hip arthroplasty (THA), the influence that preoperative cannabis use may have on postoperative opioid consumption remains unknown. The purpose of this study was to assess the relationship between preoperative cannabis use and opioid utilization following primary THA. METHODS: We identified all patients over the age of 18 who underwent unilateral, primary THA for a diagnosis of osteoarthritis at a single institution from February 2019 to April 2021. Our cohort was grouped into current cannabis users (within 6 months of surgery) and those who reported never using cannabis. One hundred and fifty-six current users were propensity score matched 1:6 with 936 never users based on age, sex, BMI, history of chronic pain, smoking status, history of anxiety/depression, ASA classification and type of anesthesia. Outcomes included inpatient and postdischarge opioid use in morphine milligram equivalents. RESULTS: Total inpatient opioid utilization, opioids refilled, and total opioids used within 90 postoperative days were similar between the groups. CONCLUSION: In propensity score matched analyses, preoperative cannabis use was not independently associated with an increase in inpatient or outpatient, 90-days opioid consumption following elective THA.

Cannabis and Cannabinoids in the Perioperative Period.

Cannabis use is increasingly common, and with a growing number of jurisdictions implementing legalization frameworks, it is likely that providers will encounter more patients who use cannabis. Therefore, it is important for providers to understand the implications of cannabis use and practical considerations for the perioperative period. Cannabis affects multiple organ systems and may influence intraoperative anesthesia, as well as postoperative pain management. The effects of cannabis and key anesthetic considerations are reviewed here.

Effectiveness of Perioperative Opioid Educational Initiatives: A Systematic Review and Meta-Analysis.

BACKGROUND: Opioids are the most commonly prescribed analgesics in the United States. Current guidelines have proposed education initiatives to reduce the risk of chronic opioid consumption, yet there is lack of efficacy data on such interventions. Our study evaluates the impact of perioperative opioid education on postoperative opioid consumption patterns including opioid cessation, number of pills consumed, and opioid prescription refills. METHODS: The MEDLINE/PubMed, Embase, Cochrane Library, Scopus, and Google Scholar databases were systematically searched for randomized controlled trials (RCTs) assessing the impact of perioperative educational interventions (using either paper- or video-based instruments regarding pain management and drug-induced side effects) on postoperative opioid patterns compared to standard preoperative care among patients undergoing elective surgery. Our end points were opioid consumption (number of pills used), appropriate disposal of unused opioids, opioid cessation (defined as no use of opioids), and opioid refills within 15 days, 6 weeks, and 3 months. RESULTS: In total, 11 RCTs fulfilled the inclusion criteria, totaling 1604 patients (804 received opioid education, while 800 received standard care). Six trials followed patients for 15 days after surgery, and 5 trials followed patients up to 3 months. After 15 days, the opioid education group consumed a lower number of opioid pills than those in the control group (weighted mean difference [WMD], -3.39 pills; 95% confidence interval [CI], -6.40 to -0.37; P =.03; I2 = 69%) with no significant difference in overall opioid cessation (odds ratio [OR], 0.25; 95% CI, 0.04-1.56; P = .14; I2 = 83%). Likewise, perioperative opioid education did not have significant effects on opioid cessation at 6 weeks (OR, 0.69; 95% CI, 0.45-1.05; P = .10; I2 = 0%) and 3 months (OR, 0.59; 95% CI,0.17-2.01; P = .10; I2 = 0%) after surgery, neither reduced the need for opioid refills at 15 days (OR, 0.57; 95% CI, 0.28-1.15; P = .12; I2 = 20%) and 6 weeks (OR, 1.08; 95% CI, 0.59-1.98; P = .80; I2 = 37%). There was no statistically significant difference in the rate of appropriate disposal of unused opioids between both groups (OR, 1.99; 95% CI, 0.66-6.00; P = .22; I2 = 71%). Subgroup analysis by type of educational intervention showed a statistical reduction of opioid consumption at 15 days when implementing multimedia/audiovisual strategies (4 trials: WMD, -4.05 pills; 95% CI, -6.59 to -1.50; P = .002; I2 = 45%), but there was no apparent decrease when using only paper-based strategies (2 trials: WMD, -2.31 pills; 95% CI, -12.21 to 7.59; P = .65; I2 = 80%). CONCLUSIONS: Perioperative educational interventions reduced the number of opioid pills consumed at 15 days but did not demonstrate a significant effect on opioid cessation or opioid refills at 15 days, 6 weeks, and 3 months. Further randomized trials should focus on evidence-based educational interventions with strict homogeneity of material to draw a more definitive recommendation.

Risk of Postdural Puncture Headache in Adolescents and Adults.

BACKGROUND: Spinal anesthesia is known to have numerous benefits, including reductions in nausea and opioid consumption; however, postdural puncture headache (PDPH) remains a significant risk associated with this technique. The literature specifically examining this complication in adolescents is scarce. Our primary objective was therefore (1) to estimate the incidence of PDPH with a 27G pencil-point needle in patients between the ages of 12 and 19 undergoing ambulatory lower extremity procedures and (2) to compare it to the incidence in adults aged 20-45 years. METHODS: After institutional review board (IRB) approval, patients aged 12-45 years undergoing ambulatory lower extremity surgery were approached. Patients undergoing the procedure under combined spinal-epidural (CSE) or spinal anesthesia with a 27G pencil-point needle were eligible for enrollment. Patients were consented before surgery and received a survey via e-mail on postoperative day (POD) 4 inquiring about the presence of a headache. Each headache was described by the participant and assessed for severity, time of onset, duration, location, and whether it was of a postural nature. All patients reporting a postural headache were contacted by a physician author to confirm a diagnosis of PDPH using the International Headache Society diagnostic criteria. RESULTS: A total of 656 patients were included in the analysis. Overall, 3.4% of patients developed PDPH. The percentage developing PDPH was 4.9% (3.0-7.8) among those aged 12-19 years and 1.8% (0.8-3.9) in the 20- to 45-year-old group. After adjusting for covariates, the age group between 12 and 19 years was associated with an almost 3-fold increase in the odds (2.8 [95% confidence interval {CI}, 1.1-7.3]) for the development of PDPH compared to that in the 20-45 age group. One patient in the adult group required an epidural blood patch. CONCLUSIONS: The overall incidence for the development of PDPH in ambulatory patients <45 years of age is low. However, the odds for developing PDPH is significantly higher in teenagers compared to those aged 20-45 years. This increase was not associated with an increase in the need for an epidural blood patch. Providers may incorporate these data in their consent process and have a higher index of suspicion for PDPH in teenagers who report headaches after neuraxial anesthesia.

Postoperative Serum Cytokine Levels Are Associated With Early Stiffness After Total Knee Arthroplasty: A Prospective Cohort Study.

BACKGROUND: Inflammatory cytokines have been implicated in organ fibrosis; however, their role in the development of arthrofibrosis after total knee arthroplasty (TKA) has not been well explored. The purpose of this study is to assess whether perioperative synovial fluid or blood plasma cytokine levels are associated with reduced early post-TKA range of motion. METHODS: A total of 179 patients with end-stage idiopathic osteoarthritis undergoing TKA were enrolled in this prospective cohort study. Synovial fluid and blood plasma were collected prearthrotomy and plasma was collected longitudinally in the postacute care unit and on postoperative days (PODs) 1 and 2. Stiffness was defined as ≤95° range of motion measured with a goniometer at 6 weeks (±2 weeks). RESULTS: Thirty-two of 162 (19.8%) patients analyzed were stiff at 6 weeks postoperatively. Postoperative plasma levels of 9 cytokines (Eotaxin3, IL-5, IL12_23p40, IP10, VEGF, IL-7, IL-12p70, IL-16, IL-17a) were significantly different between stiff and nonstiff patients on POD1 and/or POD2. An association between preoperative plasma and synovial fluid cytokine levels and the development of postoperative stiffness was not detected. CONCLUSION: The results of this study suggest that there is a distinct acute postoperative cytokine response profile in patients who develop stiffness 6 weeks after TKA. This profile was characterized by significant differences in levels of 9 cytokines over the first 2 postoperative days. These results identify cytokines that are potential biomarkers for risk of early stiffness after TKA and may play a role in the pathophysiology of this outcome.

Minocycline Before Aortic Occlusion Reduces Hindlimb Motor Impairment, Attenuates Spinal Cord Damage and Spinal Astrocytosis, and Preserve Neuronal Cytoarchitecture in the Rat.

OBJECTIVES: Spinal cord ischemia secondary to trauma or a vascular occlusive event is a threatening phenomenon. The neuroprotective properties of minocycline have been shown in several models of central nervous system diseases and after spinal cord ischemia; however, the benefit of using the drug requires additional confirmation in different animal models. Astrocytes are essential as regulators of neuronal functions and for providing nutrients. The authors hypothesized that astrocytes in the spinal cord may be an important target for minocycline action after ischemia and thus in the prevention of secondary spreading damage. DESIGN: A prospective, randomized animal study. SETTING: University research laboratory, single institution. PARTICIPANTS: Adult male Sprague Dawley rats, weighing between 400 and 450 g. INTERVENTIONS: A model of spinal cord ischemia in the rat was used for this study to determine whether a single, high-dose (10 mg/kg) of minocycline protects against damage to the neuronal cytoskeleton, both in the white and gray matter, and whether it reduces glial fibrillary acidic protein levels, which is an index for prevention of astrocyte activation during ischemia. Thirty minutes before thoracic aorta occlusion, minocycline was administered for 18 minutes using a 2 F Fogarty catheter. MEASUREMENTS AND MAIN RESULTS: Minocycline given prophylactically significantly mitigated severe hindlimb motor impairment and reduced glial fibrillary acidic protein plus astrocytosis in both the white and gray matter of the spinal cord, caudal to the occlusion. Neuronal histologic cytoarchitecture, which was severely and significantly compromised in control animals, was preserved in the minocycline-treated animals. CONCLUSIONS: This study's data imply that minocycline may attenuate reactive astrocytosis in response to injury with better neurologic outcome in a model of spinal cord ischemia in rats. The data suggest that future use of minocycline, clinically, might be advantageous in surgeries with a potential risk for paraplegia due to spinal cord ischemia.

Cannabinoid 1 receptor knockout mice display cold allodynia, but enhanced recovery from spared-nerve injury-induced mechanical hypersensitivity.

BACKGROUND: The function of the Cannabinoid 1 receptor (CB1R) in the development of neuropathic pain is not clear. Mounting evidence suggest that CB1R expression and activation may contribute to pain. Cannabinoid 1 receptor knockout mice (CB1R-/-) generated on a C57Bl/6 background exhibit hypoalgesia in the hotplate assay and formalin test. These findings suggest that Cannabinoid 1 receptor expression mediates the responses to at least some types of painful stimuli. By using this mouse line, we sought to determine if the lack of Cannabinoid 1 receptor unveils a general hypoalgesic phenotype, including protection against the development of neuropathic pain. The acetone test was used to measure cold sensitivity, the electronic von Frey was used to measure mechanical thresholds before and after spared-nerve injury, and analysis of footprint patterns was conducted to determine if motor function is differentially affected after nerve-injury in mice with varying levels of Cannabinoid 1 receptor. RESULTS: At baseline, CB1R-/- mice were hypersensitive in the acetone test, and this phenotype was maintained after spared-nerve injury. Using calcium imaging of lumbar dorsal root ganglion (DRG) cultures, a higher percentage of neurons isolated from CB1R-/- mice were menthol sensitive relative to DRG isolated from wild-type (CB1R+/+) mice. Baseline mechanical thresholds did not differ among genotypes, and mechanical hypersensitivity developed similarly in the first two weeks following spared-nerve injury (SNI). At two weeks post-SNI, CB1R-/- mice recovered significantly from mechanical hypersensitivity, while the CB1R+/+ mice did not. Heterozygous knockouts (CB1R+/-) transiently developed cold allodynia only after injury, but recovered mechanical thresholds to a similar extent as the CB1R-/- mice. Sciatic functional indices, which reflect overall nerve health, and alternation coefficients, which indicate uniformity of strides, were not significantly different among genotypes. CONCLUSION: Cold allodynia and significant recovery from spared-nerve injury-induced mechanical hypersensitivity are two novel phenotypes which characterize the global CB1R-/- mice. An increase in transient receptor potential channel of melastatin 8 channel function in DRG neurons may underlie the cold phenotype. Recovery of mechanical thresholds in the CB1R knockouts was independent of motor function. These results indicate that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of robust cold allodynia but is not involved in motor impairment following spared-nerve injury in mice.

AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain.

BACKGROUND: AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive. METHODS: The authors studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain. The authors measured the effect of AMPAkines on sensory and depressive symptoms of pain using mechanical hypersensitivity and forced swim tests. The authors asked whether AMPA receptors in the nucleus accumbens (NAc), a key node in the brain's reward and pain circuitry, can be a target for AMPAkine analgesia. RESULTS: Systemic administration of CX546 (n = 13), compared with control (n = 13), reduced mechanical hypersensitivity (50% withdrawal threshold of 6.05 ± 1.30 g [mean ± SEM] vs. 0.62 ± 0.13 g), and it reduced depressive features of pain by decreasing immobility on the forced swim test in PI-treated rats (89.0 ± 15.5 vs. 156.7 ± 18.5 s). Meanwhile, CX546 delivered locally into the NAc provided pain-relieving effects in both PI (50% withdrawal threshold of 6.81 ± 1.91 vs. 0.50 ± 0.03 g; control, n = 6; CX546, n = 8) and persistent postoperative pain (spared nerve injury) models (50% withdrawal threshold of 3.85 ± 1.23 vs. 0.45 ± 0.00 g; control, n = 7; CX546, n = 11). Blocking AMPA receptors in the NAc with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione inhibited these pain-relieving effects (50% withdrawal threshold of 7.18 ± 1.52 vs. 1.59 ± 0.66 g; n = 8 for PI groups; 10.70 ± 3.45 vs. 1.39 ± 0.88 g; n = 4 for spared nerve injury groups). CONCLUSIONS: AMPAkines relieve postoperative pain by acting through AMPA receptors in the NAc.