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Literature Review: February 2024

Feb 8, 2024, 00:00 AM by Bhavana Yalamuru, MBBS, Harsha Shanthanna, MD, PhD, FRCPC, and Vinita Singh, MD, MS

Cite as: Oweida A, Singla P. Literature review - February 2024. ASRA Pain Medicine News 2024;49.

Editor’s note: “Literature Review” is a feature designed to provide you with brief summaries of recent articles of interest, particularly from sources that our readers might not normally consume.

Chronic Pain

Treatment Delay From Onset of Occipital Neuralgia Symptoms to Treatment with Nerve Decompression Surgery: A Prospective Cohort Study

Hazewinkel MHJ, Remy K, Black G, et al. Pain Med 2023;23:pnad154.

Summary by Bhavana Yalamuru, MBBS

Introduction: Occipital neuralgia (ON) is a disabling clinical condition for which surgical decompression is a low-risk procedure, but it is not routinely performed. This study aims to evaluate the time interval between onset of ON symptoms and nerve decompression surgery, compare costs between operative and non-operative management, and report the results for decompression surgery.

Methods: A multicenter prospective study was conducted between 2012 and 2022. Patient surveys were conducted preoperatively and postoperatively at 3 months, 12 months, and yearly. Patient demographics, onset of symptoms, previous treatments, work status, pre and postoperative pain intensity (0-10), frequency (pain days per month), and pre and postoperative pain duration in hours were collected. Primary endpoint was the number of years from onset of symptoms to occipital nerve decompression surgery. The secondary endpoints were cost comparison between conservative management and surgery.

Results: Out of 1,112 subjects who underwent screening for surgery, 226 (73%) underwent surgery. The average time between onset of symptoms and surgery was 19 years (7.1-32). Surgery reduced the median number of pain days by 57% (17 days, 0-26, p<0.001), decreased median pain intensity by 44% (4 hours, 2-8; p<0.001), and median pain duration in hours by 50% (12, 2-23, p< 0.001). The mean cost of non-operative management annually was $28,728.82 ($16,419.42-$41,198.41) whereas the average cost of surgery was $12,000.00.

Key Point: Occipital neuralgia is a debilitating condition for which decompression surgery should be considered earlier in the treatment algorithm to prevent morbidity and decrease healthcare costs in patients refractory to conservative management.

Topical Co-Application of Hyaluronan with Transdermal Drug Delivery Enhancers Attenuates Inflammatory and Neuropathic Pain

Bonet IJM, Araldi D, Green PG, et al. Pain 2023;164(12):2653-64.

Summary by Harsha Shanthanna, MD, PhD, FRCPC

Introduction: High-molecular-weight (HMW) hyaluronan is widely used for intraarticular knee injection in osteoarthritis. The authors had previously demonstrated that intradermal application of HMW hyaluronan produces anti-hyperalgesia. As hyaluronan has poor skin penetration, its efficacy when combined with drug delivery enhancers needs to be tested.

Methods: Experiments were performed on male and female rats. The inflammatory pain model was based on injection of prostaglandin E2, and the neuropathic pain model was based on chemotherapy induced peripheral neuropathy (CIPN) using oxaliplatin and paclitaxel. The penetration was tested in combination of HMW hyaluronan with three different transdermal delivery systems, dimethyl sulfoxide (DMSO), protamine or terpene, and using low molecular weight hyaluronan as well. Hyperalgesia was tested using mechanical nociceptive thresholds.

Results: Topical application of HMW hyaluronan (500 to 1200 kilo Dalton (kDa)) with DMSO markedly reduced prostaglandin E2 (PGE2) hyperalgesia in both male and female rats. With CIPN, hyaluronan with DMSO attenuated hyperalgesia in male rats but lacked efficacy in female rats. However, this estrogen-based effect was reversed after ovariectomy or with intrathecal administration of an oligodeoxynucleotide antisense to G-protein–coupled estrogen receptor (GPR30) mRNA, making it work. The anti-hyperalgesic effects were not observed with 70-120 KDa hyaluronan. The attenuation of CIPN hyperalgesia with hyaluronan in combination with protamine and terpene was more prolonged than with DMSO. Lastly, repeated administration of topical hyaluronan prolonged the duration of anti-hyperalgesia.

Key Point: Topical hyaluronan when combined with appropriate biological skin penetration enhancers induces marked anti-hyperalgesia for both inflammatory and CIPN in preclinical models and could be considered for evaluation in clinical studies.

Neurocognitive Effect of Biased µ-Opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine

Moss L, Hijma H, Demitrack M, et al. Anesthesiology 2023;139(6):746-56.

Summary by Vinita Singh, MD, MS

Introduction: The µ-opioid receptor activation results in G-protein coupled signaling pathway, associated with analgesia as well as engagement of β-arrestin pathway associated with opioid related side effects. Oliceridine is a new class of opioids biased towards the G-protein coupled signaling pathway only. This randomized clinical trial presents a pharmacokinetics and pharmacodynamics comparison of morphine and oliceridine.

Methods: Twenty volunteers received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects per dose), morphine (5 or 10 mg; cohorts of 10 subjects per dose), or placebo each at least 7 days apart. Pharmacokinetic (neurocognitive and cold pressor test) and pharmacodynamics (plasma drug concentrations) measures were obtained and analyzed before and after dosing at regular intervals. Two neurocognitive tests were conducted, saccadic peak velocity test (saccadic eye movements tracking a moving dot) and body sway, which served as an adverse effect measure. The cold pressor pain threshold served as an analgesic effect measure. The utility function was defined as the probability of the desired analgesic effect minus the probability of an adverse effect.

Results: The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was superior to that of morphine over the concentration range 15 to 50 ng/ml (p<0.01).

Key Point: Oliceridine, a biased opioid ligand, shows a higher probability of providing analgesia than neurocognitive adverse effects when compared to morphine.

Acute Pain

by Jeffrey Grzybowski, MD, Monika Nanda, MBBS, MPH, FASA, Marcelle Blessing, MD

Effects of pecto-intercostal fascial block combined with rectus sheath block for postoperative pain management after cardiac surgery: a randomized controlled trial

Wang L, Jiang L, Jiang B, et al. BMC Anesthesiol 2023;23(1):90.

Summary by Jeffrey Grzybowski, MD

Introduction: Severe pain following sternotomy for cardiac surgery can lead to numerous complications. Opioid-sparing efforts have led to the application of fascial regional techniques, such as pecto-intercostal fascial block (PIFB) to achieve analgesia without consideration of heparinization. Many patients refer to subxiphoid drains as the most painful site after open-heart surgery. This single-center, randomized, controlled trial hypothesizes that the addition of a rectus sheath block (RSB) to PIFB would reduce opioid consumption and achieve better analgesia following sternotomy.

Methods: Sixty adult patients undergoing elective cardiac surgery with a median sternotomy were randomized at a 1:1 ratio to either the PIFB + RSB group (received 20 ml 0.3% ropivacaine plus 2.5 mg dexamethasone on each side for PIFB and 15 ml 0.3% ropivacaine plus 2.5 mg dexamethasone on each side for RSB) or the PIFB group (20 ml 0.3% ropivacaine plus 2.5 mg dexamethasone on each side for PIFB and 15 ml normal saline on each side for RSB). Blocks were performed under ultrasound guidance after induction of general anesthesia. Postoperatively, all patients received patient-controlled intravenous analgesia (PCIA) with a standard regimen of hydromorphone. Pain was assessed using a 10-point numeric rating scale at rest and cough at 12, 24 and 48 hours after surgery.

Results: Fifty-four patients were analyzed (27 in each group). Intravenous opioid consumption at 24 hours was 2.33 +/- 1.77 mg in the PIFB + RSB group vs 3.81 +/-2.24 mg in the PIFB group (p=0.010). Consumption at 48 hours was 4.71+/-2.71 mg in the PIFB + RSB group vs 7.25+/-3.76 mg in the PIFB group (p=0.006). The pain score did not differ between the two groups at rest or cough at 12, 24, and 48 hours. Additionally, there were no significant differences in any secondary outcomes measured, including time to extubation, length of hospital stay, or levels of inflammatory biomarkers.

Key Point: Combining single shot PIFB with RSB decreased opioid consumption up to 48 hours; however, the effect on early recovery following sternotomy, including pain scores, was unclear.

Effect of Pecto-Intercostal Fascial Block on Extubation Time in Patients Undergoing Cardiac Surgery: A Randomized Controlled Trial

Wang L, Jiang L, Xin L, et al. Front Surg 10:1128691.

Summary by Monika Nanda, MBBS, MPH, FASA

Introduction: The study investigates the effectiveness of PIFB in reducing extubation time post-cardiac surgery. PIFB is presented as a feasible alternative to epidural and paravertebral block, especially in heparinized patients where traditional methods pose a risk of hematoma.

Methods: This single-center, randomized, controlled trial involved 50 patients undergoing elective open cardiac surgery. Participants were randomized to receive either PIFB (with ropivacaine and dexamethasone) or saline after induction of general anesthesia. The primary outcome was the extubation time, and secondary outcomes included opioid consumption, postoperative pain scores, and length of hospital stay.

Results: The study reported shorter extubation times (9.4 hours vs 12.1 hours, p=0.03) and reduced intraoperative opioid consumption in the PIFB group. Pain scores while coughing were lower in the PIFB group at 12 hours post-surgery with no significant differences in length of hospital stay or adverse events rates between groups.

Key Point: PIFB effectively reduced extubation times and opioid requirements in cardiac surgery patients, demonstrating its potential as a safer, efficient analgesic technique in cardiac anesthesia.

Pain Control with Regional Anesthesia in Patients at Risk of Acute Compartment Syndrome: Review of the Literature and Editorial Review

Lam D, Pierson D, Salaria O, et al. J Pain Res 2023;16:635-48.

Summary by Marcelle Blessing, MD

Introduction: While the use of regional anesthesia has proliferated, the use of regional anesthesia for patients at risk for acute compartment syndrome (ACS) due to high-risk fractures remains controversial. Concerns remain about the potential to mask pain, a cardinal symptom of ACS. There is a paucity of available literature on the subject. This article attempts to use the available literature to provide guidance for the use of regional anesthesia in trauma patients and to summarize the current consensus guidelines.

Methods: The authors reviewed all cases of compartment syndrome with regional anesthesia, patient-controlled analgesia (PCA), or epidural anesthesia in the literature and whether these modalities of pain control were seen as contributing to a delayed diagnosis of ACS. The authors looked at 15 cases in the literature of ACS where the patient had a peripheral nerve block (PNB) and looked at how the PNB affected the patient’s awareness of pain as a symptom of ACS.

Results: In most cases of ACS where a PNB was used, the PNB did not mask the development of ischemic pain or diagnosis of ACS. Also, several cases in the literature were identified where PCA or epidural anesthesia masked symptoms of ACS and potentially delayed the diagnosis.

Key Point: Regional anesthesia may be underutilized for trauma patients. Existing case reports suggest that in most situations peripheral nerve blocks do not completely mask the pain of ACS. Even though PCA is assumed to be a more conservative option in the trauma patient, it may delay the diagnosis of ACS.

Marcelle Blessing
Marcelle Blessing, MD, is an assistant professor of anesthesiology at Yale New Haven and Bridgeport Hospitals. She is also the director for quality and safety for regional anesthesia, the director of regional anesthesia for the YNHH Saint Raphael Campus and the director of anesthesia for Reproductive Endocrinology and Infertility in Connecticut.
Jeffrey S. Grzybowski, MD, is an assistant professor in the department of Anesthesiology at the University of Wisconsin School of Medicine and Public Health System in Madison, WI.
Dr. Monika Nanda
Monika Nanda, MBBS, MPH, is a professor of anesthesiology at the University of North Carolina School of Medicine. 
Harsha Shanthanna, MD, PhD, is a professor in the department of anesthesia at St. Joseph’s Hospital at McMaster University in Ontario, Canada.
Dr. Vinita Singh
Vinita Singh, MD, MS, is board-certified in anesthesiology and pain medicine. She is the director of Cancer Pain and co-director of research for the Pain Division at Emory University in Atlanta, GA.
Bhavana Yalamuru, MBBS, is an assistant professor in the pain division at the University of Virginia in Charlottesville.
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