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Optimizing the use of ketamine to reduce chronic postsurgical pain in women undergoing mastectomy for oncologic indication: study protocol for the KALPAS multicenter randomized controlled trial

Wang, Jing; Doan, Lisa V; Axelrod, Deborah; Rotrosen, John; Wang, Binhuan; Park, Hyung G; Edwards, Robert R; Curatolo, Michele; Jackman, Carina; Perez, Raven; ,
BACKGROUND:Mastectomies are commonly performed and strongly associated with chronic postsurgical pain (CPSP), more specifically termed postmastectomy pain syndrome (PMPS), with 25-60% of patients reporting pain 3 months after surgery. PMPS interferes with function, recovery, and compliance with adjuvant therapy. Importantly, it is associated with chronic opioid use, as a recent study showed that 1 in 10 patients continue to use opioids at least 3 months after curative surgery. The majority of PMPS patients are women, and, over the past 10 years, women have outpaced men in the rate of growth in opioid dependence. Standard perioperative multimodal analgesia is only modestly effective in prevention of CPSP. Thus, interventions to reduce CPSP and PMPS are urgently needed. Ketamine is well known to improve pain and reduce opioid use in the acute postoperative period. Additionally, ketamine has been shown to control mood in studies of anxiety and depression. By targeting acute pain and improving mood in the perioperative period, ketamine may be able to prevent the development of CPSP. METHODS:Ketamine analgesia for long-lasting pain relief after surgery (KALPAS) is a phase 3, multicenter, randomized, placebo-controlled, double-blind trial to study the effectiveness of ketamine in reducing PMPS. The study compares continuous perioperative ketamine infusion vs single-dose ketamine in the postanesthesia care unit vs placebo for reducing PMPS. Participants are followed for 1 year after surgery. The primary outcome is pain at the surgical site at 3 months after the index surgery as assessed with the Brief Pain Inventory-short form pain severity subscale. DISCUSSION/CONCLUSIONS:This project is part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, a nationwide effort to address the opioid public health crisis. This study can substantially impact perioperative pain management and can contribute significantly to combatting the opioid epidemic. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT05037123. Registered on September 8, 2021.
PMCID:10797799
PMID: 38243266
ISSN: 1745-6215
CID: 5624462

AMPAkines have site-specific analgesic effects in the cortex

Zhu, Elaine; Mathew, Dave; Jee, Hyun Jung; Sun, Mengqi; Liu, Weizhuo; Zhang, Qiaosheng; Wang, Jing
Different brain areas have distinct roles in the processing and regulation of pain and thus may form specific pharmacological targets. Prior research has shown that AMPAkines, a class of drugs that increase glutamate signaling, can enhance descending inhibition from the prefrontal cortex (PFC) and nucleus accumbens. On the other hand, activation of neurons in the anterior cingulate cortex (ACC) is known to produce the aversive component of pain. The impact of AMPAkines on ACC, however, is not known. We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats. Furthermore, AMPAkines did not modulate the nociceptive response of ACC neurons. In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC.
PMCID:10860473
PMID: 37921508
ISSN: 1744-8069
CID: 5635122

A peptidomimetic modulator of the CaV2.2 N-type calcium channel for chronic pain

Gomez, Kimberly; Santiago, Ulises; Nelson, Tyler S; Allen, Heather N; Calderon-Rivera, Aida; Hestehave, Sara; Rodríguez Palma, Erick J; Zhou, Yuan; Duran, Paz; Loya-Lopez, Santiago; Zhu, Elaine; Kumar, Upasana; Shields, Rory; Koseli, Eda; McKiver, Bryan; Giuvelis, Denise; Zuo, Wanhong; Inyang, Kufreobong E; Dorame, Angie; Chefdeville, Aude; Ran, Dongzhi; Perez-Miller, Samantha; Lu, Yi; Liu, Xia; Handoko,; Arora, Paramjit S; Patek, Marcel; Moutal, Aubin; Khanna, May; Hu, Huijuan; Laumet, Geoffroy; King, Tamara; Wang, Jing; Damaj, M Imad; Korczeniewska, Olga A; Camacho, Carlos J; Khanna, Rajesh
Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Cav2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A1R2
PMCID:10666126
PMID: 37972067
ISSN: 1091-6490
CID: 5608032

Lived experiences of maintaining self-identity among persons living with young-onset dementia: A qualitative meta-synthesis

Tang, Xueting; Wang, Junqiao; Wu, Bei; Navarra, Ann-Margaret; Cui, Xiaoyan; Wang, Jing
BACKGROUND:The self-identity of persons with young-onset dementia (YOD) is affected by the disease progression. However, the lived experience of maintaining self-identity along the disease trajectory is understudied. This meta-synthesis integrated qualitative data on the challenges, coping strategies, and needs of persons living with YOD and how their experiences affected their self-identity over time. METHODS:Four English (PubMed, Scopus, CINAHL, PsycINFO) and two Chinese (CNKI and Wanfang) electronic databases were searched for published literature peer-reviewed from the time of database inception to 2022. We used thematic analysis to extract and synthesize data from the literature concerning the long-term lived experiences of persons living with YOD. RESULTS:A total of five peer-reviewed publications were eligible for inclusion in this meta-synthesis study. We identified four themes: (1) declining cognitive function and a prolonged diagnostic process threaten the self-identity of persons living with YOD, (2) struggling to accept the diagnosis of YOD and maintain self-identity, (3) maintaining self-identity and the normalcy of life through social support and person-centered care, and (4) living with YOD through self-development and self-identity reshaping at a later stage of the disease. CONCLUSIONS:Persons living with YOD experience challenges maintaining their self-identity throughout the disease trajectory. These challenges are affected by their cognitive function, experiences of personal and social stigma associated with the disease, perceived social support, and person-centered care. Study findings have implications for developing tailored supportive programs for persons living with YOD at various stages of the disease trajectory.
PMID: 37646673
ISSN: 1741-2684
CID: 5610092

Anterior cingulate cortex regulates pain catastrophizing-like behaviors in rats

Jee, Hyun Jung; Zhu, Elaine; Sun, Mengqi; Liu, Weizhuo; Zhang, Qiaosheng; Wang, Jing
Negative pain expectation including pain catastrophizing is a well-known clinical phenomenon whereby patients amplify the aversive value of a painful or oftentimes even a similar, non-painful stimulus. Mechanisms of pain catastrophizing, however, remain elusive. Here, we modeled pain catastrophizing behavior in rats, and found that rats subjected to repeated noxious pin pricks on one paw demonstrated an aversive response to similar but non-noxious mechanical stimuli delivered to the contralateral paw. Optogenetic inhibition of pyramidal neuron activity in the anterior cingulate cortex (ACC) during the application of repetitive noxious pin pricks eliminated this catastrophizing behavior. Time-lapse calcium (Ca2+) imaging in the ACC further revealed an increase in spontaneous neural activity after the delivery of noxious stimuli. Together these results suggest that the experience of repeated noxious stimuli may drive hyperactivity in the ACC, causing increased avoidance of subthreshold stimuli, and that reducing this hyperactivity may play a role in treating pain catastrophizing.
PMCID:10576271
PMID: 37833814
ISSN: 1756-6606
CID: 5604422

Oxytocin promotes prefrontal population activity via the PVN-PFC pathway to regulate pain

Liu, Yaling; Li, Anna; Bair-Marshall, Chloe; Xu, Helen; Jee, Hyun Jung; Zhu, Elaine; Sun, Mengqi; Zhang, Qiaosheng; Lefevre, Arthur; Chen, Zhe Sage; Grinevich, Valery; Froemke, Robert C; Wang, Jing
Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.
PMID: 37023755
ISSN: 1097-4199
CID: 5463882

A prototype closed-loop brain-machine interface for the study and treatment of pain

Zhang, Qiaosheng; Hu, Sile; Talay, Robert; Xiao, Zhengdong; Rosenberg, David; Liu, Yaling; Sun, Guanghao; Li, Anna; Caravan, Bassir; Singh, Amrita; Gould, Jonathan D; Chen, Zhe S; Wang, Jing
Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain-machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing) and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top-down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviours caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms.
PMID: 34155354
ISSN: 2157-846x
CID: 4932012

Pain, from perception to action: A computational perspective

Chen, Zhe Sage; Wang, Jing
Pain is driven by sensation and emotion, and in turn, it motivates decisions and actions. To fully appreciate the multidimensional nature of pain, we formulate the study of pain within a closed-loop framework of sensory-motor prediction. In this closed-loop cycle, prediction plays an important role, as the interaction between prediction and actual sensory experience shapes pain perception and subsequently, action. In this Perspective, we describe the roles of two prominent computational theories-Bayesian inference and reinforcement learning-in modeling adaptive pain behaviors. We show that prediction serves as a common theme between these two theories, and that each of these theories can explain unique aspects of the pain perception-action cycle. We discuss how these computational theories and models can improve our mechanistic understandings of pain-centered processes such as anticipation, attention, placebo hypoalgesia, and pain chronification.
PMCID:9771728
PMID: 36570771
ISSN: 2589-0042
CID: 5392372

Temporal pain processing in the primary somatosensory cortex and anterior cingulate cortex

Sun, Guanghao; McCartin, Michael; Liu, Weizhuo; Zhang, Qiaosheng; Kenefati, George; Chen, Zhe Sage; Wang, Jing
Pain is known to have sensory and affective components. The sensory pain component is encoded by neurons in the primary somatosensory cortex (S1), whereas the emotional or affective pain experience is in large part processed by neural activities in the anterior cingulate cortex (ACC). The timing of how a mechanical or thermal noxious stimulus triggers activation of peripheral pain fibers is well-known. However, the temporal processing of nociceptive inputs in the cortex remains little studied. Here, we took two approaches to examine how nociceptive inputs are processed by the S1 and ACC. We simultaneously recorded local field potentials in both regions, during the application of a brain-computer interface (BCI). First, we compared event related potentials in the S1 and ACC. Next, we used an algorithmic pain decoder enabled by machine-learning to detect the onset of pain which was used during the implementation of the BCI to automatically treat pain. We found that whereas mechanical pain triggered neural activity changes first in the S1, the S1 and ACC processed thermal pain with a reasonably similar time course. These results indicate that the temporal processing of nociceptive information in different regions of the cortex is likely important for the overall pain experience.
PMCID:9817351
PMID: 36604739
ISSN: 1756-6606
CID: 5410092

Single-Dose of Postoperative Ketamine for Postoperative Pain After Mastectomy: A Pilot Randomized Controlled Trial

Doan, Lisa V.; Li, Anna; Brake, Lee; Ok, Deborah; Jee, Hyun Jung; Park, Hyung; Cuevas, Randy; Calvino, Steven; Guth, Amber; Schnabel, Freya; Hiotis, Karen; Axelrod, Deborah; Wang, Jing
Background and Objectives: Perioperative ketamine has been shown to reduce opioid consumption and pain after surgery. Ketamine is most often given as an infusion, but an alternative is single-dose ketamine. Single-dose ketamine at up to 1 mg/kg has been shown to reduce symptoms of depression, and a wide range of dosages has been used for pain in the emergency department. However, limited data exists on the tolerability and efficacy of a single-dose of ketamine at 0.6 mg/kg for pain when administered immediately after surgery. We conducted a pilot study of single-dose ketamine in patients undergoing mastectomy with reconstruction, hypothesizing that a single-dose of ketamine is well tolerated and can relieve postoperative pain and improve mood and recovery. Methods: This is a randomized, single-blind, placebo-controlled, two-arm parallel, single-center study. Thirty adult women undergoing mastectomy with reconstruction for oncologic indication received a single-dose of ketamine (0.6mg/kg) or placebo after surgery in the post-anesthesia care unit (PACU). Patients were followed through postoperative day (POD) 7. The primary outcome was postoperative pain measured by the Brief Pain Inventory (BPI) pain subscale on POD 1 and 2. Secondary outcomes include effects on opioid use, PROMIS fatigue and sleep, mood, Quality of Recovery-15, and the Breast Cancer Pain Questionnaire. Results: Side effects were minor and not significantly different in frequency between groups. The ketamine group reported lower scores on the BPI pain severity subscale, especially at POD 7; however, the difference was not statistically significant. There were no statistically significant differences between ketamine and placebo groups for the secondary outcomes. Conclusion: A single-dose of ketamine at 0.6mg/kg administered postoperatively in the PACU is well tolerated in women undergoing mastectomy and may confer better pain control up to one week after surgery. Future studies with larger sample sizes are necessary to adequately characterize the effect of postoperative single-dose ketamine on pain control in this population.
SCOPUS:85150750594
ISSN: 1178-7090
CID: 5447712