Pain medicine basics: Articles

Abstract
Purpose of review: Neuromodulation approaches have been a part of a revolution in migraine therapies with multiple devices approved or in development. These devices vary in the nerve(s) being targeted, implantable versus noninvasive form factors as well as their effectiveness for acute pain reduction or migraine prevention. This review will summarize these recent advancements and approaches that are being developed which build upon prior work and improved technology that may help enhance the effectiveness as well as the patient experience.

Recent findings: Both noninvasive and implantable devices primarily targeting cranial nerves have shown the ability to help alleviate migraine symptoms. Multiple prospective and retrospective studies have demonstrated clinically meaningful reductions in headache intensity with noninvasive approaches, while prevention of migraine demonstrates more modest effects. Implantable neuromodulation technologies focusing on occipital and supraorbital stimulation have shown promise in migraine/headache prevention in chronic migraine patients, but there is a need for improvements in technology to address key needs for surgical approaches.

Summary: Electrical neuromodulation approaches in the treatment of migraine is undergoing a transformation towards improved outcomes with better technologies that may suit various patient needs on a more individualized basis.

Abstract
Complex regional pain syndrome (CRPS) presents postinjury with disproportionate pain and neuropathic, autonomic, motor symptoms, and skin texture affection. However, the origin of these multiplex changes is unclear. Skin biopsies offer a window to analyze the somatosensory and vascular system as well as skin trophicity with their protecting barriers. In previous studies, barrier-protective exosomal microRNAs were altered in CRPS. We here postulated that tissue architecture and barrier proteins are already altered at the beginning of CRPS. We analyzed ipsilateral and contralateral skin biopsies of 20 fully phenotyped early CRPS patients compared with 20 age- and sex-matched healthy controls. We established several automated unbiased methods to comprehensively analyze microvessels and somatosensory receptors as well as barrier proteins, including claudin-1, claudin-5, and claudin-19. Meissner corpuscles in the skin were bilaterally reduced in acute CRPS patients with some of them lacking these completely. The number of Merkel cells and the intraepidermal nerve fiber density were not different between the groups. Dermal papillary microvessels were bilaterally less abundant in CRPS, especially in patients with allodynia. Barrier proteins in keratinocytes, perineurium of dermal nerves, Schwann cells, and papillary microvessels were not affected in early CRPS. Bilateral changes in the tissue architecture in early CRPS might indicate a predisposition for CRPS that manifests after injury. Further studies should evaluate whether these changes might be used to identify risk patients for CRPS after trauma and as biomarkers for outcome.

Abstract
The human brain is a dynamic system that shows frequency-specific features. Neuroimaging studies have shown that both healthy individuals and those with chronic pain disorders experience pain influenced by various processes that fluctuate over time. Primary dysmenorrhea is a chronic visceral pain that disrupts the coordinated activity of brain's functional network. However, it remains unclear whether the dynamic interactions across the whole-brain network over time and their associations with neurobehavioral symptoms are dependent on the frequency bands in patients with primary dysmenorrhea during the pain-free periovulation phase. In this study, we used an energy landscape analysis to examine the interactions over time across the large-scale network in a sample of 59 patients with primary dysmenorrhea and 57 healthy controls at different frequency bands. Compared to healthy controls, patients with primary dysmenorrhea exhibit aberrant brain dynamics, with more significant differences in the slow-4 frequency band. Patients with primary dysmenorrhea show more indirect neural transition times due to an unstable intermediate state, whereas neurotypical brain activity frequently transitions between two major states. This data-driven approach further revealed that the brains of individuals with primary dysmenorrhea have more abnormal brain dynamics than healthy controls. Our results suggested that unstable brain dynamics were associated with the strength of brain functional segregation and the Pain Catastrophizing Scale (PCS) score. Our findings provide preliminary evidence that atypical dynamics in the functional network may serve as a potential key feature and biological marker of patients with PDM during the pain-free phase. PERSPECTIVE: We applied energy landscape analysis on brain-imaging data to identify relatively stable and dominant brain activity patterns for patients with primary dysmenorrhea(PDM). More atypical brain dynamics were found in the slow-4 band and were related to the strength of functional segregation, providing new insights into the dysfunction brain dynamics.

Abstract
Numerous, and often largely overlapping, observational pain assessment tools have been developed specifically to assess pain in older adults with dementia under the assumption that a specialized approach is necessary to evaluate pain in this population. However, this assumption has never been tested empirically. As an empirical test of this implicit assumption, our goal was to compare existing tools for people living with dementia (with respect to psychometric properties), not only against each other, but also against a tool developed for a different population with cognitive impairments. Videos of older adults with severe dementia recorded in long-term care settings were coded for pain behaviors in the laboratory. Trained coders coded pain behaviors in video segments of older adults with dementia during a quiet baseline condition as well as during a physical examination (designed to identify painful areas), using various observational pain assessment tools. An observational measure of agitation was employed to facilitate the assessment of discriminant validity. Consistent with our expectations, all pain tools (including the tool developed for younger people with cognitive impairments) successfully differentiated between painful and non-painful states, with large effect sizes. This was the first study to compare tools specifically developed to assess pain in people living with dementia to a tool developed for a different population. Given that all tools under study showed satisfactory psychometric properties when tested on persons with dementia, this study suggests that the assumption that different tools are necessary for different populations with cognitive impairments cannot be taken for granted. PERSPECTIVE: This article challenges an implicitly held assumption that specialized tools are needed to assess pain in different populations with cognitive impairments. Given commonalities in pain expression across populations, further research is needed to determine whether population-specific tools are needed.

Abstract
Background: The present study sought to determine the prevalence of chronic non-cancer pain (CNCP) among older adult inpatients with polypharmacy. It also aimed to analyse prescription patterns and assess the therapy adequacy and patient complexity for those with and without CNCP.

Methods: This 4-year longitudinal study examined data from an exhaustive acute care hospital register on home-dwelling older adult patients (≥65) with polypharmacy. Commonly known combinations of potentially inappropriate medications were used to estimate therapy adequacy. Patient complexity was evaluated by comparing number of comorbidities and investigating physical and cognitive deficits.

Results: We determined a prevalence of CNCP of 9.7% among all older adult inpatients with polypharmacy, rising to 11.3% for those aged ≥85. Overall, CNCP patients were prescribed more drugs and had more comorbidities and physical and cognitive deficits than patients without CNCP. Older adult patients with CNCP received more analgesics, greater quantities of opioids, paracetamol and co-analgesics and elevated opioid dosages. Older adult patients with CNCP aged ≥85 received fewer analgesics, opioids, non-steroidal anti-inflammatory drugs and co-analgesics but more paracetamol. Older adult patients with CNCP were prescribed more potentially inappropriate medications involving opioids. In particular, 24.5% received an opioid and a hypnotic (benzodiazepine or Z-drug), and 8.6% received an opioid and a gabapentinoid.

Conclusion: Observed differences in medication use between older adult inpatients with or without CNCP may be relevant for clinical practice. Potentially inadequate co-prescribing (such as hypnotics and opioids) affects a higher proportion of patients with CNCP and may have serious unintended consequences.

Significance statement: This study describes differences in prescription patterns between people with and without chronic non-cancer pain in a large dataset of 20,422 discharges. The differences found may be relevant to clinical practice. In particular, high co-prescribing of opioids and hypnotics may have serious unintended consequences. Greater physical and cognitive deficits may indicate greater patient complexity, and appropriate interventions need to be developed to improve the management of this vulnerable patient group.

Abstract
Background: Methadone is used as a perioperative analgesic in the management of postoperative pain. Despite positive outcomes from randomized trials favoring methadone, concerns about its safety persist, particularly regarding respiratory depression (RD) and excessive sedation. In this study, we compared the incidence of naloxone administration between patients administered intraoperative methadone and those administered intraoperative morphine as a measure of severe RD. Time spent at the postanesthesia care unit (PACU) was used as a proxy variable for excessive sedation.

Methods: This was a retrospective cohort study including all patients aged ≥18 years who underwent surgery between March 2019 and March 2023 at Aarhus University Hospital, Denmark. We assessed the association between intraoperative administration of either methadone or morphine and postoperative naloxone administration within the first 24 hours using logistic regression (primary outcome). An analogous linear regression model was used for the secondary outcome of time spent in the PACU after surgery. Patients were weighted using propensity scores to adjust for potential confounding variables.

Results: A total of 14,522 patients were included in the analysis. Among the 2437 patients who received intraoperative methadone, 15 (0.62%) patients received naloxone within the first 24 hours after surgery compared to 68 of 12,0885 (0.56%) who received intraoperative morphine. No statistical difference was observed in the odds of naloxone administration between patients administered methadone or morphine (adjusted odds ratio 95% confidence interval [CI], 1.21 [0.40-2.02]). Patients who were administered intraoperative methadone had a mean PACU length of stay (LOS) of 334 minutes (standard deviation [SD], 382) compared to 195 minutes (SD, 228) for those administered intraoperative morphine. The adjusted PACU LOS of patients administered intraoperative methadone was 26% longer compared to those administered intraoperative morphine (adjusted ratio of the geometric means 95% CI, 1.26 [1.22-1.31]).

Conclusions: The incidence of naloxone administration to treat severe RD was low. No difference was observed in the odds of naloxone administration to treat severe RD between patients administered intraoperative methadone or intraoperative morphine. Intraoperative methadone was associated with longer stays at the PACU; however, this result should be interpreted with care. Our findings suggest that intraoperative methadone has a safety profile comparable to that of morphine with regard to severe RD.

Abstract
Background and objective: Since targeted treatment for gastrointestinal pain is elusive, identifying the mechanistic underpinning of this pain type is important. Facilitation of spinal neuronal responses underpins certain pain types, and the psychophysical temporal summation of pain (TSP) paradigm provides a proxy measure of spinal facilitatory processes. Our aim was to systematically review whether facilitated TSP is a feature of gastrointestinal pain in patients with, or pain-free people experiencing experimentally induced, gastrointestinal pain.

Databases and data treatment: EMBASE, MEDLINE, PsychInfo, CINAHL, and Web of Science were systematically searched, from inception to July 2023, for human studies reporting TSP paradigm outcomes in the context of gastrointestinal pain. The Appraisal tool for Cross-Sectional studies was used for quality assessment and applied independently by two researchers.

Results: Fifteen papers consisting of cross-sectional (n = 6), case-control (n = 8), and retrospective cohort (n = 1) studies, were included. Thirteen studies investigated TSP in people with gastrointestinal pain with (n = 5) or without (n = 8) defined pathology. Two studies evoked TSP by repetitive gut stimulation in people undergoing abdominal medical procedures. Preliminary evidence showed that facilitated TSP correlated with the presence of functional gastrointestinal pain in women, and those with a history of trauma. No effect was observed in people with inflammatory bowel disease, although it was often unclear if they experienced pain.

Conclusions: It is not possible to conclude whether facilitated TSP is a feature of gastrointestinal pain. We recommend that subgroup findings are corroborated and that TSP paradigms are standardized in order that direct comparisons between studies may be made.

Significance statement: Evidence indicated that pain facilitatory processes, as evidenced by a facilitated TSP outcome, contribute to functional gastrointestinal pain in women and those with a history of trauma. However, heterogeneity of study populations and paradigms precluded statistical synthesis and findings would need be corroborated. Studies exploring facilitatory processes in people with inflammatory bowel diseases did not report significant results, but pain is not a given in these conditions and, conversely, may be driven by peripheral inflammation during active disease. This should be taken in consideration in future explorations.

Abstract
Pain science education can be used as part of treatment and prevention for chronic pain in children. We assessed the effectiveness of pain science education on knowledge, beliefs, attitudes, and behaviors in children and the people that care for children. We set a minimum criterion for education to address pain biology knowledge. We included studies aimed at both treatment and prevention of chronic pain. We conducted searches using five databases. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. Data were pooled using a random-effects meta-analysis or assessed using a narrative synthesis. The certainty of evidence was assessed using the GRADE. We screened 14505 records and included seven studies involving 351 caregivers and 1285 children. Four studies were included in meta-analyses. We found low certainty evidence that PSE has a large beneficial effect on caregiver knowledge and beliefs compared to alternative education (SMD=1.14 (95%CI: 0.88 to 1.42; I²=0%). We found no difference in functional disability in children with chronic pain after PSE (FDI score MD=0.73 (95%CI: -0.81 to 2.27; I=0%). Narrative syntheses showed low certainty evidence for improved knowledge and beliefs in children with preventative and treatment effects. Overall we found few studies, and along with high risk of bias, this significantly contributed to the low certainty of findings. The effect of learning pain science for both preventative and treatment effects in children, carers and the child/carer dyad remain mostly unknown. This review was prospectively registered with PROSPERO (CRD42022344382) on 22 July 2022. PERSPECTIVE: This review examines the effect of pain science education (PSE) on pain-related knowledge, beliefs, attitudes, and behaviors in children and the people that care for children (0-18). The findings contribute to knowledge about pain treatments and health promotion for caregivers of children with and without chronic pain. Clear recommendations for improving the quality of evidence in future studies are outlined.

Abstract
Objectives: The management of pain patients has not evolved as rapidly as envisioned when IASP was founded almost 50 years ago. We sought to identify factors that could contribute to this situation, with a focus on concepts of pain and the education of pain physicians.

Methods: Relevant literature describing new strategies for diagnosing and managing high impact chronic pain patients was reviewed.

Results: It appears that the acute-chronic dichotomy has outlived its usefulness and pains should be identified as of peripheral origin or due to central processing errors. Pains of peripheral origin and those of central processing errors require different diagnostic and therapeutic strategies.

Discussion: Peripheral treatments and opioids are not effective for central pains. When the cause of the pain lies in the central nervous system, a more centrally focused approach is needed to minimize wasteful pursuit of peripheral causes. The education and training of pain physicians should reflect the skills needed to address these two very different clinical problems.

Abstract
Both endocannabinoid (EC) and endogenous opioid systems are involved in nociceptive processing and may work together synergistically based on preclinical models. This study evaluated the interactive effects of preoperative beta-endorphin concentrations (a key analgesic endogenous opioid) in cerebrospinal fluid (CSF) and ECs (CSF and plasma 2-arachidonoylglycerol [2-AG] and plasma anandamide [AEA]) on postoperative opioid use and pain intensity in a prospective cohort of n = 112 pregnant patients undergoing scheduled cesarean delivery. Maternal blood and CSF samples were collected preoperatively for beta-endorphin and EC assays. Patients completed measures of outpatient opioid use (number of tablets used and days of use) and average pain intensity at 2 weeks postoperatively. Results of general linear model analyses controlling for maternal age, BMI at time of delivery, and race revealed significant multiplicative interactions between EC and beta-endorphin concentrations on number of opioid tablets used (based on pill count), days of opioid use, and total milligram morphine equivalents used in the 2 week follow-up period. Elevated preoperative plasma and CSF 2-AG predicted reduced outpatient opioid analgesic use particularly for patients low in CSF beta-endorphin. Similar analyses for pain intensity at 2-week follow-up indicated a significant interaction (p<.02) characterized by higher preoperative beta-endorphin concentrations being associated with lower subsequent pain only for individuals with low preoperative plasma AEA concentrations. Further exploration of interactions between EC and endogenous opioid inhibitory systems as they influence responses to opioid analgesics in other clinical pain populations may help guide development of precision pain management approaches. PERSPECTIVE: In the postoperative setting of patients undergoing cesarean delivery, elevated endocannabinoids were linked to reduced outpatient opioid analgesic use in individuals who had low endogenous opioid concentrations in cerebrospinal fluid. Further exploration of interactions between these two inhibitory systems as they impact on responses to pain management interventions appears warranted.

Abstract
Oxytocin 1 is a neuropeptide broadly implicated in social relationships and behavior. OT also exerts antinociceptive and pain-reducing effects in both humans and rodents. Recent research in rodents demonstrates that these effects can be peripheral and local. In human studies, intravenous OT has reduced visceral pain and subcutaneous injection of OT has reduced postsurgical pain. However, the local effects of subcutaneous OT on experimental pain have not been studied. We conducted a two-session crossover study during which healthy adults received a subcutaneous injection of synthetic OT (4mcg/2ml) or saline placebo (isotonic saline 2ml), in a randomized and double-blinded manner. 18 participants completed full study procedures. We hypothesized that 10 min after injection, OT would reduce measures of acute mechanical pain, pressure pain, and heat pain perception. Subcutaneous OT significantly reduced ratings of heat pain intensity and unpleasantness (both p < 0.01), but did not alter mechanical pain, pressure pain, or heat pain threshold (all p > 0.05). Changes in heat pain were observed only on the injected arm and not on the contralateral arm, confirming a localized mechanism. These findings confirm the ability of OT in or near the skin to modulate nociceptive processes in cutaneous tissues in human adults, opening exciting avenues for further mechanistic research as well as potential clinical applications for acute pain. The study purpose, targeted condition, study design, and primary and secondary outcomes were pre-registered in ClinicalTrials.gov (NCT05326776: "Peripheral Oxytocin and Touch (POPP)"). PERSPECTIVE: This randomized-controlled trial showed that a subcutaneous injection of oxytocin can reduce perception of heat pain tested with a thermode. Oxytocin did not alter mechanical or pressure pain, or thresholds for perceiving heat pain. These findings are relevant to scientists and clinicians seeking non-addictive local drug treatments for pain.

Abstract
Neuropathic pain (NP) is a prevalent condition often associated with heightened pain responsiveness suggestive of central sensitization. Neuroimaging biomarkers of treatment outcomes may help develop personalised treatment strategies, but white matter (WM) properties have been under-explored for this purpose. Here we assessed whether WM pathways of the default mode network (DMN: medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), precuneus (PCu)) and descending pain modulation system (periaqueductal gray (PAG)) are associated with ketamine analgesia and attenuated temporal summation of pain (TSP, reflecting central sensitization) in NP. We used a fixel-based analysis (FBA) of diffusion weighted imaging data to evaluate WM microstructure (fiber density, FD) and macrostructure (fiber bundle cross-section) within the DMN and mPFC-PAG pathways in 70 individuals who underwent MRI and TSP testing; 35 with NP who underwent ketamine treatment and 35 age- and sex-matched pain-free individuals. Individuals with NP were assessed before and 1-month after treatment; those with ≥30% pain relief were considered responders (n=18), or otherwise as non-responders (n=17). We found that WM structure within the DMN and mPFC-PAG pathways did not differentiate responders from non-responders. However, pre-treatment FD in the anterior limb of the internal capsule correlated with pain relief (r=0.48). Moreover, pre-treatment FD in the DMN (left mPFC-PCu/PCC; r=0.52) and mPFC-PAG (r=0.42) negatively correlated with changes in TSP. This suggests that WM microstructure in the DMN and mPFC-PAG pathway is associated with the degree to which ketamine reduces central sensitization. Thus, fixel metrics of WM structure may hold promise to predict ketamine NP treatment outcomes. PERSPECTIVE: We used advanced fixel-based analyses of MRI diffusion-weighted imaging data to identify pre-treatment white matter microstructure associated with ketamine outcomes including analgesia and markers of attenuated central sensitization. Exploring associations between brain structure and treatment outcomes could contribute to a personalized approach to treatment for individuals with neuropathic pain.

Abstract
Nociplastic pain, characterized by abnormal pain processing without an identifiable organic cause, affects a significant portion of the global population. Unfortunately, current pharmacological treatments for this condition often prove ineffective, prompting the need to explore new potential targets for inducing analgesic effects in patients with nociplastic pain. In this context, toll-like receptors (TLRs), known for their role in the immune response to infections, represent promising opportunities for pharmacological intervention because they play a relevant role in both the development and maintenance of pain. Although TLRs have been extensively studied in neuropathic and inflammatory pain, their specific contributions to nociplastic pain remain less clear, demanding further investigation. This review consolidates current evidence on the connection between TLRs and nociplastic pain, with a specific focus on prevalent conditions like fibromyalgia, stress-induced pain, sleep deprivation-related pain, and irritable bowel syndrome. In addition, we explore the association between nociplastic pain and psychiatric comorbidities, proposing that modulating TLRs can potentially alleviate both pain syndromes and related psychiatric disorders. Finally, we discuss the potential sex differences in TLR signaling, considering the higher prevalence of nociplastic pain among women. Altogether, this review aims to shed light on nociplastic pain, its underlying mechanisms, and its intriguing relationship with TLR signaling pathways, ultimately framing the potential therapeutic role of TLRs in addressing this challenging condition.

Abstract
Objectives: This study aimed to compare the analgesic effects of continuous femoral nerve block (FNB), femoral triangle block (FTB), and adductor canal block (ACB) following total knee arthroplasty (TKA). The goal was to identify the most effective nerve block technique among these three.

Methods: Patients undergoing TKA were randomly assigned to one of three groups: FNB, FTB, or ACB. Nerve blocks were administered preoperatively, with catheters placed for patient-controlled nerve analgesia (PCNA). The primary endpoint was the Numeric Rating Scale (NRS) score at movement at 24 hours post-surgery. Secondary endpoints included NRS scores at rest and movement, quadriceps strength, Timed Up and Go (TUG) test performance, range of motion (ROM), effective PCNA utilization, and opioid consumption at various post-surgery time points.

Results: Of the 94 valid datasets analyzed (FNB: 31, FTB: 31, ACB: 32), significant differences were observed in the primary endpoint (H=7.003, P=0.03). Post-hoc analysis with Bonferroni correction showed that the FNB group had a significantly lower median pain score (3 [2-4]) compared to the ACB group (4 [3-5], Bonferroni-adjusted P=0.03). Regarding secondary endpoints, both the FNB and FTB groups had lower NRS scores than the ACB group at various time points after surgery. Quadriceps strength and TUG completion were better in the FTB and ACB groups. There were no statistically significant differences among the groups for the other endpoints.

Discussion: Continuous FTB provides postoperative analgesia comparable to FNB, but with the advantage of significantly less impact on quadriceps muscle strength, a benefit not seen with FNB. Both FTB and ACB are effective in preserving quadriceps strength postoperatively.

Abstract
Migraine is a complex and highly incapacitating neurological disorder that affects around 15% of the general population with greater incidence in women, often at the most productive age of life. Migraine physiopathology is still not fully understood, but it involves multiple mediators and events in the trigeminovascular system and the central nervous system. The identification of calcitonin gene-related peptide as a key mediator in migraine physiopathology has led to the development of effective and highly selective antimigraine therapies. However, this treatment is neither accessible nor effective for all migraine sufferers. Thus, a better understanding of migraine mechanisms and the identification of potential targets are still clearly warranted. Voltage-gated calcium channels (VGCCs) are widely distributed in the trigeminovascular system, and there is accumulating evidence of their contribution to the mechanisms associated with headache pain. Several drugs used in migraine abortive or prophylactic treatment target VGCCs, which probably contributes to their analgesic effect. This review aims to summarize the current evidence of VGGC contribution to migraine physiopathology and to discuss how current pharmacological options for migraine treatment interfere with VGGC function. PERSPECTIVE: Calcitonin gene-related peptide (CGRP) represents a major migraine mediator, but few studies have investigated the relationship between CGRP and VGCCs. CGRP release is calcium channel-dependent and VGGCs are key players in familial migraine. Further studies are needed to determine whether VGCCs are suitable molecular targets for treating migraine.

Abstract
Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of β-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.

Abstract
Background: Lumbar disc herniation (LDH), as one of the most common causes of lower back pain, imposes a heavy economic burden on patients and society. Conservative management is the first-line choice for the majority of LDH patients. Traditional Chinese medicine (TCM) is an important part of conservative treatment and has attracted more and more international attention.

Study design: Evidence-based guideline.

Methods: We formed a guideline panel of multidisciplinary experts. The clinical questions were identified on the basis of a systematic literature search and a consensus meeting. We searched the literature for direct evidence on the management of LDH and assessed its certainty-generated recommendations using the grading of recommendations, assessment, development, and evaluation (GRADE) approach.

Results: The guideline panel made 20 recommendations, which covered the use of Shentong Zhuyu decoction, Shenzhuo decoction, Simiao San decoction, Duhuo Jisheng decoction, Yaobitong capsule, Yaotongning capsule, Osteoking, manual therapy, needle knife, manual acupuncture, electroacupuncture, Chinese exercise techniques (Tai Chi, Baduanjin, or Yijinjing), and integrative medicine, such as combined non-steroidal anti-inflammatory drugs, neural nutrition, and traction. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement.

Conclusion: This is the first LDH treatment guideline for TCM and integrative medicine with a systematic search, synthesis of evidence, and using the GRADE method to rate the quality of evidence. We hope these recommendations can help support healthcare workers caring for LDH patients.

Abstract
Purpose: Adequate post-cesarean delivery analgesia can be difficult to achieve for women diagnosed with opioid use disorder receiving buprenorphine. We sought to determine if neuraxial clonidine administration is associated with decreased opioid consumption and pain scores following cesarean delivery in women receiving chronic buprenorphine therapy.

Methods: This was a retrospective cohort study at a tertiary care teaching hospital of women undergoing cesarean delivery with or without neuraxial clonidine administration while receiving chronic buprenorphine. The primary outcome was opioid consumption (in morphine milligram equivalents) 0-6 h following cesarean delivery. Secondary outcomes included opioid consumption 0-24 h post-cesarean, median postoperative pain scores 0-24 h, and rates of intraoperative anesthetic supplementation. Multivariable analysis evaluating the adjusted effects of neuraxial clonidine on outcomes was conducted using linear regression, proportional odds model, and logistic regression separately.

Results: 196 women met inclusion criteria, of which 145 (74%) received neuraxial clonidine while 51 (26%) did not. In univariate analysis, there was no significant difference in opioid consumption 0-6 h post-cesarean delivery between the clonidine (8 [IQR 0, 15]) and control (1 [IQR 0, 8]) groups (P = 0.14). After adjusting for potential confounders, there remained no significant association with neuraxial clonidine administration 0-6 h (Difference in means 2.77, 95% CI [- 0.89 to 6.44], P = 0.14) or 0-24 h (Difference in means 8.56, 95% CI [- 16.99 to 34.11], P = 0.51).

Conclusion: In parturients receiving chronic buprenorphine therapy at the time of cesarean delivery, neuraxial clonidine administration was not associated with decreased postoperative opioid consumption, median pain scores, or the need for intraoperative supplementation.

Abstract
Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 μg) induced short-term (<24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7-/- or Trpa1-/- mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 μg), induced persistent mechanical allodynia for >2 weeks, which was abolished in Tlr7-/- mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b-induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator.

Abstract
Mindfulness interventions have become popular in recent decades, with many trials, systematic reviews, and meta-analyses of the impact of mindfulness-based interventions (MBIs) on pain. Although many meta-analyses provide support for MBIs, the results are more mixed than they at first appear. The aim of this umbrella review was to determine the strength of evidence for MBIs by synthesizing available meta-analyses in pain. We conducted a systematic search in 5 databases and extracted data from published meta-analyses as the unit of analysis. For each outcome, we reported the range of effect sizes observed across studies and identified the largest meta-analysis as the "representative" study. We separately analysed effect sizes for different pain conditions, different types of MBIs, different control groups, and different outcomes. We identified 21 meta-analyses that included 127 unique studies. According to Assessment of Multiple Systematic Review ratings, the meta-analyses ranged from very strong to weak. Overall, there was an impact of MBIs on pain severity, anxiety, and depression but not pain interference or disability. When conditions were considered in isolation, only fibromyalgia and headache benefited significantly from MBIs. Mindfulness-based interventions were more efficacious for pain severity than passive control conditions but not active control conditions. Only pain severity and anxiety were affected by MBIs at follow-up. Overall, our results suggest that individual meta-analyses of MBIs may have overestimated the efficacy of MBIs in a range of conditions. Mindfulness-based interventions likely have a role in pain management but should not be considered a panacea.

Abstract
Chronic overlapping pain conditions (COPCs) by definition frequently co-occur, perhaps reflecting their shared etiologies. Their overlapping nature presents a methodological challenge, possibly masking associations between COPCs and health outcomes attributable to either general or specific processes. To address this challenge, we used population-based cohort data to evaluate the predictive validity of a bifactor model of nine self-reported COPCs by assessing its association with incident pain-related clinical diagnoses; pain-relevant pharmacotherapy; and other health outcomes. We obtained data from a 2005-2006 study of Swedish adult twins linked with health data from nationwide registers through 2016 (N = 25,418). We then fit a bifactor model comprising a general COPC factor and two independent specific factors measuring pain-related somatic symptoms and neck and shoulder pain. Accounting for age, biological sex, and cancer, the general factor was associated with increased risk of all pain-related outcomes (e.g., COPC diagnosis aOR, 1.71; 95% CI [1.62, 1.81]), most mental health-related outcomes (e.g., depression aOR, 1.72 [1.60, 1.85]), and overdose and mortality (e.g., all-cause mortality aOR, 1.25 [1.09, 1.43]). The somatic symptoms specific factor was associated with pain-relevant pharmacotherapy (e.g., prescribed opioids aOR, 1.25 [1.15, 1.36]), most mental health-related outcomes (e.g., depression aOR, 1.95 [1.70, 2.23]), and overdose (e.g., nonfatal overdose aOR, 1.66 [1.31, 2.10]). The neck and shoulder pain specific factor was weakly and inconsistently associated with the outcomes. Findings provide initial support for the validity and utility of a general-factor model of COPCs as a tool to strengthen understandings of co-occurrence, etiology, and consequences of chronic pain. PERSPECTIVE: This article presents associations between a novel measurement model of chronic overlapping pain conditions (COPCs) and various health outcomes. Findings provide support for measuring pain across multiple domains rather than only measuring pain specific to one physical location in both research and clinical contexts.

Abstract
Pain is a significant health issue, and pain assessment is essential for proper diagnosis, follow-up, and effective management of pain. The conventional methods of pain assessment often suffer from subjectivity and variability. The main issue is to understand better how people experience pain. In recent years, artificial intelligence (AI) has been playing a growing role in improving clinical diagnosis and decision-making. The application of AI offers promising opportunities to improve the accuracy and efficiency of pain assessment. This review article provides an overview of the current state of AI in pain assessment and explores its potential for improving accuracy, efficiency, and personalized care. By examining the existing literature, research gaps, and future directions, this article aims to guide further advancements in the field of pain management. An online database search was conducted via multiple websites to identify the relevant articles. The inclusion criteria were English articles published between January 2014 and January 2024). Articles that were available as full text clinical trials, observational studies, review articles, systemic reviews, and meta-analyses were included in this review. The exclusion criteria were articles that were not in the English language, not available as free full text, those involving pediatric patients, case reports, and editorials. A total of (47) articles were included in this review. In conclusion, the application of AI in pain management could present promising solutions for pain assessment. AI can potentially increase the accuracy, precision, and efficiency of objective pain assessment.

Abstract
Objectives: Understanding adolescent perspectives on prescribed opioids in the context of medical care for acute pain is needed to prevent opioid-related adverse outcomes. We explored factors that may influence opioid decision-making and use behaviors among adolescents prescribed opioids for acute pain.

Methods: We conducted semi-structured interviews with nineteen adolescents (63% females, ages 12-17) prescribed opioids upon discharge from surgery or intensive care unit admission. Interview transcripts were coded using inductive thematic analysis.

Results: Five themes were identified: "Opioid use to reduce extreme pain and facilitate acute recovery"; "Familiarity with risks and negative effects of opioids"; "Assessment of opioid risk based on individual characteristics and use behaviors"; "Careful balance of risks, benefits, and symptoms when taking opioids"; "Importance of trusted adults for adolescent opioid management". Adolescents commonly believed opioids are only appropriate for severe pain that cannot be managed with other strategies. Most (but not all) adolescents were aware of addiction and other potential opioid harms, and generally disapproved of misuse. However, a few adolescents would consider taking unprescribed opioids for severe pain. Adolescents wanted to be well informed for opioid decision-making, considering guidance from trusted adults.

Discussion: Adolescents often demonstrated active and sound participation in shared opioid decision-making, influenced by complex integration of inputs and self-reflection. Conversely, potential factors that could contribute to risky behaviors included low personal risk perceptions, uncertainty about what constitutes opioid misuse, and avoidance of prescribed opioids despite extreme pain. Future studies may explore associations of adolescents' opioid decision-making with longer-term pain and opioid-related outcomes.

Abstract
Background: Open-label placebos (OLP) prescribed without deception and with a convincing rationale have been shown to evoke powerful treatment effects. Patients' treatment expectations seem to influence the magnitude of the effect.

Objective: We examined if two different OLP rationales increased pain tolerance and reduced pain intensity and unpleasantness in a standardized heat pain experiment.

Methods: Participants (N = 71) who self-reported reoccurring pain for at least the last 3 months were randomly assigned to one of three groups. We compared a personal-emotional and a scientific-matter-of-fact rationale with a control group (CG) that received the same placebo without any rationale. The rationale suggested a desensitizing effect on pain perception and improved pain coping of the placebo, whereas in the CG it was introduced as an ointment for measurement. The primary outcomes were pre-post changes in pain tolerance, expected and experienced pain intensity and unpleasantness.

Results: Participants showed a decrease in expected pain intensity, but not expected pain unpleasantness for both rationales. There were no differences in pain tolerance and experienced pain intensity and unpleasantness.

Conclusions: Our study suggests that evoking positive treatment expectations is not sufficient to elicit an OLP response. Possibly, the magnitude of expectations change in this study was not powerful enough to evoke an OLP effect. Additionally, it is possible that OLP effects in pain are unrelated to positive treatment expectations. The failure of OLP in our study is in contrast to a number of previous studies examining the effects of OLP in experimental and clinical pain.

Significance: This study provides evidence that positive treatment expectations are not sufficient to evoke an open-label placebo effect in a standardized heat pain experiment. We showed that two different rationales improved participants treatment expectations, but failed to evoke a placebo effect in comparison to a control group that received the same placebo, labelled as an ointment to improve measurement quality.

Abstract
Background: The prevalence of long-term opioid use after orthopaedic surgery varies from 1.4% to 24% and has mostly been studied with prescription data, making it difficult to estimate the size and impact of the problem. This study aims to assess the prevalence and predictors of long-term postoperative opioid use in a high volume and tertiary orthopaedic centre by using online patient reported measures.

Methods: This Dutch prospective cohort study was conducted among adult patients who underwent any type of orthopaedic surgery from June to August 2021. Six months after surgery patients were invited to complete an online survey on current opioid use and patients' willingness to taper opioids. The demographics, clinical factors and preoperative opioid use were extracted from the patient file.

Results: In total, 607 patients (mean age 61.2 years, 63.4% female) completed the survey. Seventy-six patients (12.5%) used opioids 6 months after surgery of which 20 (3.3%) did not use opioids before surgery. The median (Q1-Q3) postoperative daily dose after 6 months was 29.9 mg (10.0-76.1) morphine equivalents. Most of them (88.2%) wanted to taper opioids. Affected body region (OR's: 6.84-12.75) and pre-operative opioid use (OR = 35.33) were significant predictors of long-term opioid use.

Conclusion: The prevalence of long-term postoperative opioid use was 12.5%; one in thirty patients became a new long-term opioid user. Pre-operative opioid use and affected body region were predictive for long-term opioid use. These findings, together with the observation that long-term opioid users want to taper opioids, emphasize the relevance of prevention, recognition and tapering support in the perioperative setting.

Level of evidence: Level II.

Significance: Short-term opioid use can unintentionally progress to long-term opioid use. The prevalence of long-term opioid use after orthopaedic surgery varies widely and is mostly prescription-based, making it difficult to estimate the magnitude of the problem. This study assessed long-term postoperative opioid use in a full breadth orthopaedic population using patient reported measures, making conclusions much more robust. The prevalence of long-term postoperative opioid use in this study was 12.5%.

Abstract
Objectives: Our purpose was to explore the effect of remifentanil on acute and chronic postsurgical pain after cardiac surgery.

Methods: Randomized controlled trials (RCTs) were retrieved in electronic databases such as PubMed, Cochrane Library, CNKI databases, Scopus, and Web of Science. A systematic review, meta-analysis, trial sequential analysis (TSA) was performed. Basic information and outcomes were extracted from the included studies. The primary outcome was chronic postsurgical pain. Secondary outcomes were scores of postsurgical pain and morphine consumption within 24 hours after cardiac surgery. Our risk of bias assessment was based on the Cochrane risk of bias tool version 2 (ROB 2.0). The overall quality of the evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Results: Seven studies consisting of 658 patients were enrolled in the meta-analysis. A single study had a high risk of bias and two studies had a moderate risk of bias. The incidence of chronic postsurgical pain (four studies [415 patients]; RR, 1.02 [95% CI, 0.53-1.95]; P =0.95; I2=59%; TSA-adjusted CI, 0.78-1.20) and the postsurgical pain score (two studies [196 patients]; MD 0.09 [95% CI, -0.36-0.55]; P =0.69; I2=0%; TSA-adjusted CI, -0.36-0.55）were not statistically different between the two groups. However, morphine consumption (six studies [569 patients]; MD 6.94 [95% CI, 3.65-10.22]; P<0.01; I2=0%; TSA-adjusted CI, 0.00-0.49) was higher in the remifentanil group than in the control group.

Discussion: There was not enough evidence to prove that remifentanil can increase the incidence of chronic postsurgical pain after cardiac surgery, but interestingly, the results tended to support a trend toward increased complications in the intervention group. However, there was moderate-certainty evidence that the use of remifentanil increases the consumption of morphine for analgesia, and more direct comparison trials are needed to inform clinical decision-making with greater confidence.

Abstract
Purpose: Evaluate benefits and harms of education/advice for chronic primary low back pain (CPLBP) in adults to inform a World Health Organization (WHO) standard clinical guideline.

Methods: Electronic databases were searched for randomized controlled trials (RCTs) assessing education/advice compared with placebo/sham, usual care, or no intervention (including comparison interventions where the attributable effect of education/advice could be isolated). We conducted meta-analyses and graded the certainty of evidence.

Results: We screened 2514 citations and 86 full text RCTs and included 15 RCTs. Most outcomes were assessed 3 to 6 months post-intervention. Compared with no intervention, education/advice improved pain (10 RCTs, MD = -1.1, 95% CI -1.63 to -0.56), function (10 RCTs, SMD = -0.51, 95% CI -0.89 to -0.12), physical health-related quality of life (HRQoL) (2 RCTs, MD = 24.27, 95% CI 12.93 to 35.61), fear avoidance (5 RCTs, SMD = -1.4, 95% CI -2.51 to -0.29), depression (1 RCT; MD = 2.10, 95% CI 1.05 to 3.15), and self-efficacy (1 RCT; MD = 4.4, 95% CI 2.77 to 6.03). Education/advice conferred less benefit than sham Kinesio taping for improving fear avoidance regarding physical activity (1 RCT, MD = 5.41, 95% CI 0.28 to 10.54). Compared with usual care, education/advice improved pain (1 RCT, MD = -2.10, 95% CI -3.13 to -1.07) and function (1 RCT, MD = -7.80, 95% CI -14.28 to -1.32). There was little or no difference between education/advice and comparisons for other outcomes. For all outcomes, the certainty of evidence was very low.

Conclusion: Education/advice in adults with CPLBP was associated with improvements in pain, function, HRQoL, and psychological outcomes, but with very low certainty.

Abstract
Background: Opioid dose titration is a fundamental process of opioid therapy in cancer pain.

Aims: To assess data opioid dose titration.

Methods: The principal opioid dose titration methods, outcomes, and modalities of administration regarding the different opioid preparations were examined in different clinical contexts.

Results: Most studies suggested that opioid-naive patients should be started at doses of 15-30 mg/day of oral morphine equivalents. Opioid-tolerant patients may receive low or higher doses of oral morphine equivalents, depending on the level of opioid tolerance. Generally, dose increments of 30%-50% seem to be indicated to start dose titration. Some patients with severe excruciating cancer pain may present as an emergency requiring a rapid application of powerful analgesic strategies. The intravenous use of opioids may circumvent this problem providing a faster pain relief, due to the large availability and rapid achievement of effective plasma concentrations.

Discussion: Opioid dose titration is a delicate passage in patients with cancer pain. This approach may be different according to different clinical conditions. Opioid dose titration requires expertise to optimize cancer pain management while minimizing the development of adverse effects.

Conclusion: While most approaches are meaningful and partially supported by existing literature, more studies are necessary to establish advantages and disadvantages in different clinical conditions. Optimization of opioid dose titration is of paramount importance.

Significance: This review provides the most recent insights on the different modalities of opioid dose titration in cancer pain management.

Abstract in English, French
Purpose: In children, the relationship between the dose of intraoperative opioid and postoperative outcomes is unclear. We examined the relationship between intraoperative opioid dose and postanesthesia care unit (PACU) pain scores and opioid and antiemetic administrations.

Methods: We performed a single-institution retrospective cohort study. Patients who were aged < 19 yr, had an American Society of Anesthesiologists Physical Status of I-III, were undergoing one of 11 procedures under general anesthesia and without regional anesthesia, and who were admitted to the PACU were included. Patients were analyzed by quartiles of total intraoperative opioid dose using multivariable regression, adjusting for confounders including procedure. An exploratory analysis of opioid-free anesthetics was also performed.

Results: Three thousand, seven hundred and thirty-three cases were included, and the mean age of included patients was 8.3 yr. After adjustment, there were no significant differences between the lowest and higher quartiles for first conscious pain score, mean pain score, PACU opioid dose, or PACU length of stay; in addition, estimated differences were small. Patients in higher quartiles were estimated to be more likely to receive antiemetics, significantly so for those in the second quartile. Patients in the lowest quartile received significantly more intraoperative nonopioid analgesics. In the exploratory analysis, no significant difference in PACU pain scores was found in cases without intraoperative opioids.

Conclusions: Children who received lower doses of intraoperative opioids did not have worse PACU pain outcomes but required fewer antiemetics and received greater numbers of nonopioid analgesics intraoperatively. These findings suggest that lower doses of intraoperative opioids may be administered to children as long as other analgesics are used.

Abstract
Persistent pain is a major public health issue - estimated to affect a quarter of the world's population. Public understanding of persistent pain is based on outdated biomedical models, laden with misconceptions that are contrary to best evidence. This understanding is a barrier to effective pain management. Thus, there have been calls for public health-based interventions to address these misconceptions. Previous pain focussed public education campaigns have targeted pain beliefs and behaviours that are thought to promote recovery, such as staying active. However, prevailing pain-related misconceptions render many of these approaches counter-intuitive, at best. Pain Science Education improves understanding of 'how pain works' and has been demonstrated to improve pain and disability outcomes. Extending Pain Science Education beyond the clinic to the wider community seems warranted. Learning from previous back pain-focussed and other public health educational campaigns could optimise the potential benefit of such a Pain Science Education campaign. Pain Science Education-grounded campaigns have been delivered in Australia and the UK and show promise, but robust evaluations are needed before any firm conclusions on their population impact can be made. Several challenges exist going forward. Not least is the need to ensure all stakeholders are involved in the development and implementation of Pain Science Education public messaging campaigns. Furthermore, it is crucial that campaigns are undertaken through a health equity lens, incorporating underrepresented communities to ensure that any intervention does not widen existing health inequalities associated with persistent pain. PERSPECTIVE: Public misconceptions about pain are a significant public health challenge and a viable intervention target to reduce the personal, social, and economic burden of persistent pain. Adaptation of Pain Science Education, which improves misconceptions in a clinical setting, into the public health setting seems a promising approach to explore.

Abstract
Objectives: This study aimed to assess levels and predictors of self-efficacy and motivation to change opioid use among a community sample of patients using opioids for CP, as well as patient-reported barriers to pursuing opioid discontinuation.

Methods: Participants with a variety of chronic pain conditions, recruited from ResearchMatch.org, completed a battery of electronic, self-report questionnaires assessing demographic and medical characteristics, pain treatment history, and levels of readiness, self-efficacy, and other attitudes toward reducing or discontinuing opioid use. Multiple regression analyses and analyses of variance were conducted to examine predictors of readiness and self-efficacy to change opioid use. A modified version of rapid qualitative analysis was utilized to analyze themes in participant responses to an open-ended item about "what it would take" to consider opioid discontinuation.

Results: The final sample included N=119 participants, the majority of whom were female (78.2%), Caucasian (77.3%), and well-educated. Readiness and self-efficacy to decrease or stop opioid use were fairly low on a 0-10 Visual Analog Scale (2.6-3.8) and significantly higher to decrease than stop (P<0.01). Higher readiness to change was predicted by lower pain severity and higher concern about opioids, whereas higher self-efficacy was predicted by shorter pain duration. Results from the qualitative analyses revealed that availability of an alternative treatment option was the most commonly cited requirement to consider opioid discontinuation.

Discussion: Patients with lower pain severity, shorter duration of pain, and higher concerns about opioids may be a prime target from a motivation standpoint for interventions addressing opioid tapering and discontinuation.

Abstract
Objectives: Severe postoperative pain requiring opioid treatment has been reported in 20-40% of hemorrhoidectomy patients. Compared to morphine, nalbuphine offers better hemodynamic stability, a lower risk of respiratory depression, and a lower potential for addiction. Nalbuphine was developed from intravenous form into an oral form (PHN131) to alleviate moderate-to-severe pain.

Methods: A randomized, double-blind, placebo-controlled, multiple-dose, parallel-design trial was conducted to evaluate the safety and efficacy of PHN131 in patients undergoing hemorrhoidectomy. Eligible patients were randomly assigned to receive either PHN131 soft capsules containing nalbuphine hydrochloride 60 mg or placebo capsules. Intramuscular diclofenac was the rescue analgesic. Pain was measured by the area under the curve of mean Visual Analog Scale (VAS) pain intensity scores.

Results: VAS results in patients receiving PHN131 were significantly lower than placebo group scores through 48 hours postoperatively (149.2±75.52 vs. 179.6±65.97; P=0.0301). According to Brief Pain Inventory Short Form scores, the impact of pain on quality of life was significantly smaller for the PHN131 group than for the placebo group. Time to the first use of diclofenac postoperatively was significantly longer in the PHN131 group than in the placebo group. The cumulative dosage of diclofenac in the PHN131 group was only around half of that in the placebo group (P<0.0001). Drug-related adverse events were mild-to-moderate and resolved by treatment end. No drug-related severe adverse events were observed.

Discussion: Our findings demonstrate that PHN131 is effective and well-tolerated in the treatment of moderate-to-severe pain and may provide another option for patients to control their pain.

Abstract
Background: Postsurgical pain is a key component of surgical recovery. However, the genetic drivers of postsurgical pain remain unclear. A broad review and meta-analyses of variants of interest will help investigators understand the potential effects of genetic variation.

Methods: This article is a systematic review of genetic variants associated with postsurgical pain in humans, assessing association with postsurgical pain scores and opioid use in both acute (0 to 48 h postoperatively) and chronic (at least 3 months postoperatively) settings. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from 2000 to 2022 for studies using search terms related to genetic variants and postsurgical pain in humans. English-language studies in adult patients examining associations of one or more genetic variants with postsurgical pain were included. The primary outcome was association of genetic variants with either acute or chronic postsurgical pain. Pain was measured by patient-reported pain score or analgesic or opioid consumption.

Results: A total of 163 studies were included, evaluating 129 unique genes and 594 unique genetic variants. Many of the reported significant associations fail to be replicated in other studies. Meta-analyses were performed for seven variants for which there was sufficient data (OPRM1 rs1799971; COMT rs4680, rs4818, rs4633, and rs6269; and ABCB1 rs1045642 and rs2032582). Only two variants were associated with small differences in postsurgical pain: OPRM1 rs1799971 (for acute postsurgical opioid use standard mean difference = 0.25; 95% CI, 0.16 to 0.35; cohort size, 8,227; acute postsurgical pain score standard mean difference = 0.20; 95% CI, 0.09 to 0.31; cohort size, 4,619) and COMT rs4680 (chronic postsurgical pain score standard mean difference = 0.26; 95% CI, 0.08 to 0.44; cohort size, 1,726).

Conclusions: Despite much published data, only two alleles have a small association with postsurgical pain. Small sample sizes, potential confounding variables, and inconsistent findings underscore the need to examine larger cohorts with consistent outcome measures.

Abstract
Purpose: The study aims to compare the analgesic efficacy of two analgesic interventions, continuous paravertebral (PVB) nerve block alone with continuous paravertebral and intercostal nerve block (PVB/ICB) in patients undergoing thoracotomy.

Methods: A total of 70 patients undergoing thoracotomy were randomly enrolled in either continuous paravertebral nerve block (PVB) group or in continuous paravertebral and intercostal nerve block (PVB/ICB) group and received corresponding blocks. Analgesic efficacy measured by Visual Analog Scale (VAS) pain score, hemodynamic effects, total narcotic consumption, sedation score, patient's length of stay in hospital and patient's satisfaction with the analgesic technique were recorded.

Results: Demographic characteristics of the patients were similar in both groups. The mean VAS pain score was not statistically significant in both groups at 24 h. The mean pulse rate and blood pressures were comparable in both groups for the first 24 h. Nalbuphine consumption was significantly higher in PVB group as compared to PVB/ICB group at 1 h (p = 0.01), 6 h (p = 0.03) and 12 h (p = 0.009) and 24 h (p = 0.03). The mean total nalbuphine consumption in the PVB group was higher (28.29 mg vs. 22.63 mg) and statistically significant then PVB/ICB group (p = 0.03). The total tramadol consumption as a rescue analgesic was higher in the PVB group (131.42 mg) as compared to PVB/ICB group (120 mg) after 24 h but not statistically significant (p = 0.17).

Conclusion: Continuous paravertebral nerve block with intercostal nerve block provides effective post-operative pain relief after thoracotomy with reduced narcotic consumption compared to continuous paravertebral nerve block alone.

Keywords: Acute pain; Analgesics; Bupivacaine; Nalbuphine; Nerve block; Opioid; Pain; Thoracotomy; Tramadol.

Abstract
The procedure-specific postoperative pain management (PROSPECT) working group develops evidence-based pain management recommendations. PROSPECT methodology is unique and rigorous. However, several limitations were recognised that needed to be addressed, and several new factors were identified that improved PROSPECT methodology. The aim of this article is to present updated PROSPECT methodology for development of recommendations for procedure-specific pain management, focusing on the methodological revisions we will implement. In future, included randomised clinical trials will need to be prospectively registered on a publicly accessible clinical trials database and the study design, including the primary outcome in the registration, should coincide with that in the published manuscript. Placebo-controlled studies in which the analgesic intervention of interest is solely paracetamol, non-steroidal anti-inflammatory drugs, cyclo-oxygenase-2-specific inhibitors or opioids will not be included. Studies comparing one drug in a particular class with another in the same class will also not be included. Future projects will use the Cochrane Collaboration risk of bias tool for quality of reporting of methodology and results. A modified Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach will be used for grading of level of evidence and strength of recommendations. Finally, the updated PROSPECT methodology addresses several other limitations and implements new factors that all add rigour and transparency to developing procedure-specific pain management recommendations.

Keywords: analgesia; evidence-based medicine; methodology; postoperative pain; recommendations.

Abstract
Oxycodone is a commonly prescribed opioid for postoperative pain. However, there has been a marked increase in the use of tapentadol over the previous decade due to a perceived superior safety profile of tapentadol compared to oxycodone. There is limited real-world evidence on the safety of tapentadol compared to oxycodone after surgery. The primary objective was to examine the impact of tapentadol compared to oxycodone use on the incidence of opioid-related adverse drug events after surgery. Data for adult surgical patients receiving tapentadol or oxycodone during hospitalisation between 1 January 2018 and 31 December 2021 were collected from electronic medical records of three tertiary metropolitan hospitals in Australia. The primary outcome was the incidence of opioid-related adverse events. Patients receiving tapentadol or oxycodone were matched using nearest-neighbour propensity score matching. In the matched cohorts (n = 1,530 vs. n = 2,775; mean [standard deviation, SD] age 62.3 [17.0] years vs. 61.9 [SD 17.9] years; 43% vs. 45% male for the tapentadol vs. oxycodone groups, respectively), patients given tapentadol experienced a similar incidence of adverse events overall (14.4%, 220/1530 vs. 12.6%, 349/2775; p = 0.100; 95% CI -0.35% to 3.95%),. Secondary outcomes included an increased risk of delirium (2.7%, 41/1,530 vs. 1.3%, 37/2,775), arrhythmias (3.4%, 52/1,530 vs. 2.2%, 62/2,775), and length of hospital stay (5 [range1-201] vs. 4 [range 1-226] days) compared with oxycodone use. Further real-world studies are warranted to determine the impact of tapentadol use on a broad range of patient outcomes. PERSPECTIVE: This study provides an early signal that tapentadol use may be associated with an increased risk of some adverse events and a longer length of stay. Further research is needed to examine the impact of tapentadol use on a broad range of patient outcomes in clinical practice settings.

Abstract
Purpose: Diversion of controlled substances in the perioperative setting is an ongoing challenge, with consequences for patients, anesthesiologists, perioperative staff, and health care facilities alike. Perioperative environments are at high risk for diversion, since controlled substances are frequently handled in these settings, with varying levels of oversight. In this narrative review, we summarize strategies for preventing diversion of controlled substances in perioperative settings (i.e., operating rooms, endoscopy suites, and postanesthesia recovery units).

Source: We performed a targeted literature search in PubMed MEDLINE, Embase, Scopus, Web of Science, the Cochrane Register of Controlled trials, and the Cochrane Database of Systematic Reviews, as well as a manual search for additional references. We used terminology related to drug diversion, drug abuse, anesthesiologists, pharmacists, physicians, operating room personnel, and controlled substances.

Principal findings: Many strategies have been described for preventing diversion in perioperative settings, and these are broadly categorized into: education, distribution, auditing, or provider screening. Some of these approaches may be time- and resource-intensive. There is limited evidence to inform anesthesia departments' choice of which strategies to adopt.

Conclusion: Although awareness of perioperative controlled substance diversion has been improving, there are too few data to suggest an optimal approach. Anesthesia departments will need to work collaboratively with hospital pharmacies and actively select strategies that are reasonable given local resources.

Abstract
Background: Chronic neck pain (CNP) is a common musculoskeletal disorder. Pain neuroscience education (PNE) is a promising nonpharmacological intervention for CNP, however, its effectiveness remains unclear. This systematic review and meta-analysis aimed to evaluate the effectiveness of PNE in treating CNP.

Methods: Electronic databases from inception to February 2023 were searched for randomized controlled trials (RCTs) on the effects of PNE on CNP. The primary outcome was the change in pain intensity, and the secondary outcome was improvement in kinesiophobia, standardized using Hedges' g. Two authors independently scrutinized eligible articles, extracted data and assessed quality; a random-effects model was employed for data pooling.

Results: In total, seven RCTs comprising 479 participants were included and demonstrated that PNE significantly reduced pain intensity (Hedges' g = -0.730, 95% CI = -1.340 to -0.119, p = 0.019, I2 = 89.288%). Subgroup analysis revealed that the adult group experienced significant pain reduction after PNE, whereas the adolescent group did not. PNE also reduced kinesiophobia which was evaluated in four of seven RCTs (Hedges' g = -0.444, 95% CI = -0.735 to -0.154, p = 0.003, I2 = 36.822%). The meta-regression analysis indicated that an increased intervention duration contributed to greater pain reduction. No adverse events were reported following PNE or the control treatment.

Conclusions: PNE effectively reduced pain intensity and kinesiophobia in patients with CNP. A longer PNE time leads to greater pain reduction and is more effective in adults than in adolescents. Further studies are required to examine the long-term effects on CNP management.

Significance: This is the first meta-analysis evaluating the effectiveness of treating chronic neck pain with pain neuroscience education. Pain neuroscience education is successful in reducing pain and decreasing kinesiophobia in the chronic neck pain population. Longer treatment time leads to greater pain reduction.

Abstract
Opioid analgesics prescribed for the management of acute pain following orthopaedic surgery may lead to unintended long-term opioid use and associated patient harms. This study aimed to examine the prevalence of opioid use at 90 days after elective orthopaedic surgery across major city, regional and rural locations in New South Wales, Australia. We conducted a prospective, observational cohort study of patients undergoing elective orthopaedic surgery at five hospitals from major city, regional, rural, public and private settings between April 2017 and February 2020. Data were collected by patient questionnaire at the pre-admission clinic 2-6 weeks before surgery and by telephone call after 90 days following surgery. Of the 361 participants recruited, 54% (195/361) were women and the mean age was 67.7 years (standard deviation 10.1 years). Opioid use at 90 or more days after orthopaedic surgery was reported by 15.8% (57/361; 95% confidence interval (CI) 12.2-20%) of all participants and ranged from 3.5% (2/57) at a major city location to 37.8% (14/37) at an inner regional location. Predictors of long-term postoperative opioid use in the multivariable analysis were surgery performed at an inner regional location (adjusted odds ratio 12.26; 95% CI 2.2-68.24) and outer regional location (adjusted odds ratio 5.46; 95% CI 1.09-27.50) after adjusting for known covariates. Long-term opioid use was reported in over 15% of patients following orthopaedic surgery and appears to be more prevalent in regional locations in Australia.

Abstract
Background: Orthopedic patients report pain as their main symptom complaint. Subjective pain experience is correlated with self-reported psychological state such as distress.

Purpose: This study tests whether scores from a measure of mindful attention are associated with subjective pain levels and if psychological distress scores function as a mediation path.

Methods: During routine visits to a single orthopedic clinic in East Los Angeles, 525 patients were recruited to participate in the study. Participants reported on measures of pain (Universal Pain Assessment Tool, UPAT), mindful attention (Five-Facet Mindfulness Questionnaire, FFMQ) and psychological distress (Depression, Anxiety, and Stress Scale, DASS). We used Pearson correlation to examine relationships between FFMQ and UPAT scores, and mediation analyses to test indirect effects of DASS scores as a mediation path.

Results: The average age of the sample was 54 years (range 18-98), 61% were male, and 64% were non-Hispanic White individuals. The locations of injury were shoulder (72%), elbow (21%) and clavicle or wrist (7%). 91% reported mild or greater pain in the past two weeks (M = 4.2 ± 2.5, range 0-10) and 49% reported mild or more severe distress symptoms (DASS: 13.0 ± 11.5). FFMQ scores inversely predicted UPAT scores (β = 0.-22, p < 0.01) mediated through DASS scores. DASS subscale scores for depression (β=-0.10, p = 0.02) and stress (β=-0.08, p = 0.04) but not anxiety (β=-0.03, p = 0.33) produced significant indirect effects. FFMQ acting-with-awareness and non-judging subscales had the largest effect on depression and stress DASS subscale scores.

Conclusions: We find statistical support to suggest distress-particularly depressed mood and stress-mediates the association between mindful attention and pain intensity among orthopedic patients. A disposition of mindful attention may counter distress ailments that exacerbate subjective pain, and this has possible implications for mindfulness training interventions offered to orthopedic patients.

Abstract
There is an increase in outpatient procedures and this trend will continue in the future. For hemorrhoidectomy, it is the standard of treatment in many health care systems. Perioperative management including adequate pain control is of paramount importance to ensure successful ambulatory surgery. This study investigates the role and effect of morphine compared to short-acting opiates applied before, during, or after proctological interventions and with focus on hemorrhoidectomy. A retrospective analysis of a prospective database was conducted comparing two populations. The control cohort received morphine (Yes-Mô) intra- and postoperatively, while the intervention group did not receive morphine (No-Mô) between January 2018 and January 2020. Both cohorts were balanced by propensity score matching. The outcomes were postoperative pain measured by numeric ratings scale (NRS) one hour postoperatively, pain 24 h postoperatively, success rate of outpatient management, and complication rate including postoperative nausea and vomiting as well as urinary retention. The intervention population comprised 54 patients and the control group contained 79 patients. One hour after surgery, patients in No-Mô reported lower NRS (1.44 ± 1.41) compared to Yes-Mô (2.48 ± 2.30) (p = 0.029). However, there was no difference in NRS 24 h postoperatively (No-Mô: 1.61 ± 1.41 vs Yes-Mô: 1.63 ± 1.72; p = 0.738). 100% of No-Mô was managed as outpatients while only 50% of Yes-Mô was dismissed on the day of the operation (p = < 0.001). There was no difference in postoperative complications (including postoperative nausea and vomiting (PONV) and urinary retention) between the two groups (PONV No-Mô 7.4% vs Yes-Mô 5.6%, p = 1.0 and urinary retention No-Mô 3.7% vs Yes-Mô 7.4%, p = 0.679). No-Mô received an oral morphine equivalent of 227.25 ± 140.35 mg intraoperatively and 11.02 ± 18.02 mg postoperatively. Yes-Mô received 263.17 ± 153.60 mg intraoperatively and 15.97 ± 14.17 mg postoperatively. The difference in received morphine equivalent between the groups was not significant after matching for the intraoperative (p = 0.212) and postoperative (p = 0.119) received equivalent. Omission of perioperative morphine is a viable but yet not understood method for reducing postoperative pain. Omission of morphine leads to a lower use of total morphine equivalent to attain satisfactory analgesia. The reduction of the overall opiate load and using opiates with a very short half-life potentially leads to a reduction of side effects like sedation. This in turn promotes discharge of the patient on the day of surgery. Omission of morphine is safe and does not increase postoperative complications.

Abstract
Background: Worldwide, there is an increasing trend of performing more complex operations in a day care setting, usually driven by economic considerations. Provision of appropriate pain relief is still inadequate in this setting. Poor pain control and adverse effects of opioids provided for pain control are common reasons for readmission, with human and economic consequences. The aim of this review was to develop evidence-based protocol for pain management of day surgery in a resource limited setting.

Method: After formulating the key questions, scope, and eligibility criteria for the articles to be included, advanced search strategy of electronic sources from data bases and websites was conducted. Screening of literatures was conducted with proper appraisal checklist. This review was reported in accordance with preferred reporting items for systematic reviews and meta-analysis (PRISMA) 2020 statement.

Results: A total of 333 articles were identified from data bases and websites using an electronic search. 45 articles were removed for duplication and 87 studies were excluded after reviewing titles and abstracts. At the screening stage, 73 articles were retrieved and evaluated for eligibility. Finally, 40 studies met the eligibility criteria and were included in this systematic review.

Conclusion: Day surgery encourages patients to mobilize soon after surgery and empowers them to manage their own pain. Thus, preoperative patient education and high-quality perioperative pain management are paramount. With increasing healthcare demands for more day-case procedures, multi-modal analgesic techniques in the perioperative period with good extension of analgesia into the postoperative discharge period are essential.

Abstract
Background and objective: Pruritus (also known as itch) is defined as an unpleasant and irritating sensation of the skin that provokes an urge to scratch or rub. It is well known that opioid administration can cause pruritus, which is paradoxical as itch and pain share overlapping sensory pathways. Because opioids inhibit pain but can cause itching. Significant progress has been made to improve our understanding of the fundamental neurobiology of itch; however, much remains unknown about the mechanisms of opioid-induced pruritus. The prevention and treatment of opioid-induced pruritus remains a challenge in the field of pain management. The objective of this narrative review is to present and discuss the current body of literature and summarize the current understanding of the mechanisms underlying opioid-induced pruritus, and its relationship to analgesia, and possible treatment options.

Results: The incidence of opioid-induced pruritus differs with different opioids and routes of administration, and the various mechanisms can be broadly divided into peripheral and central. Especially central mechanisms are intricate, even at the level of the spinal dorsal horn. There is evidence that opioid receptor antagonists and mixed agonist and antagonists, especially μ-opioid antagonists and κ-opioid agonists, are effective in relieving opioid-induced pruritus. Various treatments have been used for opioid-induced pruritus; however, most of them are controversial and have conflicting results.

Conclusion: The use of a multimodal analgesic treatment regimen combined with a mixed antagonist and κ agonists, especially μ-opioid antagonists, and κ-opioid agonists, seems to be the current best treatment modality for the management of opioid-induced pruritus and pain.

Significance: Opioids remain the gold standard for the treatment of moderate to severe acute pain as well as cancer pain. It is well known that opioid-induced pruritus often does not respond to regular antipruritic treatment, thereby posing a challenge to clinicians in the field of pain management. We believe that our review makes a significant contribution to the literature, as studies on the mechanisms of opioid-induced pruritus and effective management strategies are crucial for the management of these patients.

Abstract
Background: Oliceridine (Olinvyk®) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. We determined the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test.

Methods: The study had a randomized, double-blind, placebo-controlled, partial block 3-way crossover design. Experiments were performed in 20 male and female volunteers. Subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose) or placebo on three separate occasions. Prior to and following dosing, neurocognitive tests, cold pressor test and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as measure of benefit, slowing of saccadic peak velocity and increased body sway as measures of neurocognitive harm.

Results: The oliceridine and morphine C50's, i.e. the effect-site concentrations causing 50% effect, were: antinociception 13±2 and 23±7 ng/mL, saccadic peak velocity 90±14 and 54±15 ng/mL, and body sway 10±2 and 5.6±0.8 ng/mL, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI 0.17-0.7; p<0.01) for saccadic peak velocity and 0.33 (0.16-0.50; p<0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5-77 ng/mL, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from zero from 0-100 ng/mL. Over the concentration range 15-50 ng/mL the oliceridine utility was superior to that of morphine (p < 0.01). Similar observations were made for body sway.

Conclusions: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

Abstract
Background: Nefopam is a centrally acting antinociceptive drug; however, the underlying mechanisms are not fully understood. This study investigated the supraspinal mechanisms of nefopam.

Methods: The effects of intraperitoneally administered nefopam were assessed in rats using the formalin test, and the mechanisms were investigated by intrathecal or intra-nucleus raphe magnus (NRM) pre-treatment with the serotonin (5-HT) receptor antagonist or 5-HT2 receptor antagonist. The change in extracellular 5-HT levels was measured by spinal cord microdialysis.

Results: Intraperitoneally administered nefopam showed antinociceptive effects in the rat formalin test, which were reversed by intrathecal pre-treatment with 5-HT receptor antagonist dihydroergocristine. Microdialysis study revealed that systemic nefopam significantly increased 5-HT level in the spinal dorsal horn. Pretreatment of cinanserin, a 5-HT2 receptor antagonist, into the NRM blocked the antinociceptive effects of intraperitoneally delivered nefopam. Direct injection of nefopam into the NRM mimicked the effects of systemic nefopam, and this effect was reversed by intra-NRM cinanserin pre-treatment. The increase in spinal level of 5-HT by systemic nefopam was attenuated by intra-NRM cinanserin pre-treatment.

Conclusion: The antinociceptive effects of systemically administered nefopam are mediated by 5-HT2 receptors in the NRM, which recruit the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn.

Significance: This study revealed supraspinal mechanisms of nefopam-produced analgesia mediated by 5-HT2 receptors in the NRM recruiting the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. These observations support a potential role for nefopam in multimodal analgesia based on its distinct mechanisms of action that are not shared by the other analgesics.

Abstract
Background: Chronic pain is a major cause of suffering and disability and is often associated with psychiatric complications. Current treatments carry the risk of severe side effects and may lead to limited or no relief at all in a relevant portion of this patient population. Preliminary evidence suggests that classical psychedelics (e.g. LSD and psilocybin) may have analgesic effects in healthy volunteers, and in certain chronic pain conditions and observational studies reveal that they are used in naturalistic settings as a means to manage pain.

Methods: In order to gain insight on the effectiveness of such compounds in chronic pain conditions, we set up a survey addressed to chronic pain patients inquiring about psychedelic use and the relief levels achieved with both conventional treatments, full psychedelic doses and microdoses. We analysed data related to five conditions selected based on diagnostic homogeneity within each of them: fibromyalgia, arthritis, migraine, tension-type headache and sciatica.

Results: Except for sciatica, volunteers reported that psychedelics led to better pain relief compared to conventional medication in all examined conditions. More specifically, full doses performed better than conventional medication. Microdoses led to significantly better relief compared to conventional medication in migraines and achieved comparable relief in the remaining three categories. Implications for future research are discussed.

Conclusions: Full doses and microdoses may hold value in the treatment of some specific chronic pain conditions.

Significance: Psychedelic substances are receiving increasing attention from the scientific literature because of evidence showing beneficial effects on several measures related to mental health in clinical samples and healthy volunteers samples. Previous evidence suggests that people suffering from chronic pain are using psychedelics to seek relief and the present paper presents the results of a survey study investigating their use and analgesic effects among individuals suffering from fibromyalgia, arthritis, migraine, tension-type headache and sciatica.

Abstract
Oxytocin is widely used to prevent atonic postpartum haemorrhage after caesarean delivery. Initial treatment failure rates are high and inadequate dosing may contribute. Excessive doses, however, are associated with serious adverse effects. The pharmacokinetic data from this context are sparse and there is a lack of data in the immediate postpartum minutes after an initiating bolus. The pharmacodynamic data from this context are exclusively from dose-effect studies, with some suggesting that higher doses of oxytocin are required to provide adequate uterine tone in obese compared with non-obese women. We aimed to perform a pharmacokinetic and pharmacodynamic study that would facilitate more precise weight-based oxytocin dosing. We measured arterial oxytocin concentration, uterine tone and haemodynamic parameters in 25 women in the first 40 min after exogenous oxytocin administration at elective caesarean delivery. Serum oxytocin concentrations varied considerably between individuals. We constructed a one-compartment pharmacokinetic model of exogenous oxytocin deposition, after its administration with an initiating bolus and a maintenance infusion, at elective caesarean delivery. Body weight was evaluated as a potential covariate but was not included in the model due to lack of statistically significant reduction in the objective function. We calculated the volume of distribution and clearance (mean [coefficient of variation]) as 156.1 l [18%] and 83 ml.s-1 [32%] but found no within-individual correlation between serum oxytocin concentration and uterine tone or haemodynamic parameters. In conclusion, we observed a large variation in serum oxytocin concentrations between individuals receiving similar doses of oxytocin and were unable to establish weight-based dosing of exogenous oxytocin at caesarean delivery. Our findings suggest that future studies on oxytocin pharmacokinetics would need large sample sizes. In the absence of such data, oxytocin dosing should continue to be guided by uterine tone assessments and adjusted according to a strategy based on the best evidence from dose-effect studies.

Abstract
Background: What 'acceptable pain' means may be different for everyone and dependent on the moment and the context. In this text, we explore the concepts of pain acceptability and acceptance. We explain why we need to better explore (un)acceptable pain, to eventually facilitate pain assessment and management.

Methods: Using different approaches and perspectives (with examples and application from multiple disciplines, i.e. orthopaedics, psychology, pharmacological therapy), we discussed anecdotal examples and included a systematic, scoping and literature review.

Results: We rejected the idea that in the context of chronic pain, acceptability, disability and manageability overlap neatly. Additionally, we rejected the validity of pain intensity rating scales to sufficiently explore individuals' experience of pain. In the one study that met our criteria, a definition of 'acceptable pain' was dropped as participants deemed it inappropriate because it did not address the significant challenges associated with pain. This is important, however, because the acceptability of pain may precede, follow and/or inform the 'pain acceptance' process, which is an important concept associated with better outcomes.

Conclusions: Very little is known regarding what 'acceptable pain' may mean to people living with pain. Qualitative studies may improve our understanding of individuals' perceptions, perspectives and expectations as we do not know, for the moment, what 'acceptable pain' may mean to a particular person and, potentially, regarding a specific treatment or other contextual aspects that are not captured with currently used scores and quantitative measures.

Significance: What does 'acceptable pain' mean may differ between people with painful experiences and may depend on contextual factors. Pain acceptability may be distinct from manageability, and may precede, follow and/or inform the 'pain acceptance' process. This text, rigorously based on a review of the existing literature, defends the idea that acceptable pain should be better studied.

Abstract
Objective: This study aims to determine the effectiveness of pregabalin for control of symptoms in mild to moderate idiopathic Carpal tunnel syndrome (CTS).

Methods: In this randomized, placebo-controlled trial, 146 mild to moderate idiopathic CTS patients were randomized into pregabalin (n=74) and placebo group (n=72). Per protocol analysis was done in 131 patients; pregabalin (n=65) and placebo (n=66). Drug titration dose was 50 mg once daily for 1st week, twice daily for 2nd week and thrice daily for next 6 weeks. Primary outcome included change in Symptom Severity Scale (SSS) and Functional Status Scale (FSS) of Boston Carpal Tunnel Questionnaire after 8th week. Secondary outcome was the change in clinical and electrophysiological grading after 8 weeks of therapy.

Results: There was a statistically significant improvement in the mean SSS (14.92±3.72 vs. 16.55±4.45; P=0.025) and FSS (10.77±2.64 vs. 12.0±2.55; P=0.007) in the pregabalin group after 8 weeks. Mean clinical and electrophysiological grading changed significantly from 2.3±0.7 to 2.1±0.8 (P=0.001) and 1.9±0.7 to 1.8±0.8 (P=0.020) respectively in pregabalin group but not in placebo group.

Discussion: This study demonstrates that pregabalin is effective in ameliorating symptoms and improving functional outcomes in mild to moderate idiopathic CTS.

Abstract
Guidelines recommend consideration of modification, tapering, or discontinuation of long-term, full-agonist opioid therapy when harms outweigh benefits; one alternative to tapering or discontinuing full-agonist opioids for the management of chronic pain is switching to the partial agonist buprenorphine. As the use of buprenorphine for pain expands, understanding the patient experience during and after transition to buprenorphine is critical. We conducted 45- to 60-minute semi-structured qualitative interviews with 19 patients to understand the experiences of patients with chronic pain actively maintained on buprenorphine after previously receiving full-agonist, long-term opioid therapy. Patients were recruited from two medical centers via provider referral. Through thematic analysis, five overall themes were identified, including satisfaction with buprenorphine, the importance of preconceptions about buprenorphine, experiences with transitions, patient-provider communication, and potential contributions to racial disparities in pain care. While we heard a range of experiences, most patients were satisfied with buprenorphine, reporting either equivalent pain control to their previous regimens, or reporting less analgesia but improved functioning due to reduction in side effects (e.g., mental clarity). Patients also emphasized the importance of a non-judgmental, patient-centered approach, including education about the risks and benefits of buprenorphine. The few black patients interviewed all reported limited access to pain care, which is consistent with the well-documented existence of racial disparities in access to pain treatment. As buprenorphine is used more frequently for pain management, provider education focused on pain treatment disparities, patient-centered approaches informed by motivational interviewing, and increasing acceptance of buprenorphine as an option for pain are needed. PERSPECTIVE: Qualitative analyses of patient experiences transitioning from full-agonist opioids to buprenorphine for chronic pain revealed general satisfaction. Patients reflected on functioning, tradeoffs between analgesia and side effects, patient-centered care, and access to treatment, highlighting how future research should focus on outcomes valued by patients.

Abstract
Background: Despite widespread use of opioid therapy in outpatient palliative medicine, there is limited evidence supporting its efficacy and safety in the long term. Objectives: We sought to improve overdose risk scores, maintain pain reduction, and preserve patient function in a cohort with severe chronic pain as we managed opioid therapy for a duration of four years in an outpatient palliative care clinic. Design: Over four years, we provided ongoing goal-concordant outpatient palliative care, including opioid therapy, using quarterly clinical encounters for a patient cohort with chronic pain. Setting/Subjects: The project took place in the outpatient palliative medicine clinic of a regional cancer center in Orlando, Florida (United States). The subjects were a cohort group who received palliative care during the time period between July 2018 and October 2022. Measurements: Key metrics included treatment-related reduction in pain intensity, performance scores, and overall overdose risk scores. Secondary metrics included cohort demographics, average daily opioid use in morphine milligram equivalents and categorization of type of pain. Results: In 97 patients, we observed a stable mean treatment-related reduction in pain intensity of 4.9 out of 10 points over four years. The cohort showed a 2-point (out of 100) improvement in performance scores and an 81-point (out of 999) reduction in mean overall overdose risk score. Conclusions: We present evidence that providing outpatient palliative care longitudinally over four years offered lasting treatment-related reductions in pain intensity, preservation of performance status, and reduction in overall overdose risk.

Abstract
Purpose of review: Continuous peripheral nerve blocks (cPNB) decrease pain scores and opioid consumption while improving patient satisfaction following ambulatory surgery. This review focuses on the history and evolution of ambulatory cPNBs, recent developments in infusion technology that may prolong the duration of analgesia, optimal choice of cPNB for various surgical procedures, and novel analgesic modalities that may prove to be alternatives or supplements to cPNBs.

Recent findings: The primary factor limiting the duration of an ambulatory cPNB is the size of the local anesthetic reservoir. Recent evidence suggests the use of automated boluses, as opposed to continuous infusions, may decrease the rate of consumption of local anesthetic and, thereby, prolong the duration of analgesia. Utilizing a long-acting local anesthetic (e.g. ropivacaine) for initial block placement and an infusion start-delay timer may further increase this duration.

Summary: Patients undergoing painful ambulatory surgery are likely to have less pain and require fewer opioid analgesics when receiving a cPNB for postoperative analgesia. Advances in electronic pumps used for cPNBs may increase the duration of these benefits.

Abstract
Introduction: Tonsillectomy is associated with significant pain and post-operative pain control is often unsatisfactory. This study sought to evaluate the effect of peritonsillar infiltration of tramadol-ketamine combination, tramadol alone and ketamine alone on post-tonsillectomy pain in children.

Patients and methods: A randomized double-blinded interventional study involving 90 patients aged 3-15 years of American society of anesthesiologists I or II physical status scheduled for elective adenoidectomy, tonsillectomy or adenotonsillectomy at JUTH was conducted. Patients were randomized into one of three groups: group I received tramadol 2mg/kg, group II received ketamine 1mg/kg plus tramadol 2mg/kg and group III received ketamine 1mg/kg only all made up to 2mls with normal saline and 1ml given per tonsillar bed. All patients had standard general anaesthesia with endotracheal intubation and monitoring. Data was analyzed using Epi-info version 7.1.5 with p £ 0.05.

Result: The analysis of data showed that the mean ages of the participants in group I, II and III were 5.70±2.00, 5.69±3.22 and 4.47±2.01 years respectively (p-value=0.091). Group II had significantly lower pain scores, longer time to first request of analgesia, earlier oral intake and discharge from the hospital compared to the group that received either tramadol or ketamine alone. Minimal side effects were noted across all the groups in the study.

Conclusion: Peri-tonsillar infiltration of tramadol-ketamine combination immediately after tonsillectomy (but before extubation of patients) significantly decreased post-tonsillectomy pain without increasing the incidence of side effects compared to tramadol or ketamine alone in children undergoing adenotonsillectomy.

Abstract
Introduction: Ultrasound-guided peripheral nerve blockade is a common pain management strategy to decrease perioperative pain and opioid/general anesthetic use. In this article our goal was to systematically review publications supporting upper extremity nerve blocks distal to the brachial plexus. We assessed the efficacy and safety of median, ulnar, radial, suprascapular, and axillary nerve blocks by reviewing previous studies.

Methods: We searched MEDLINE and Embase databases to capture studies investigating these nerve blocks across all specialties. We screened titles and abstracts according to agreed-upon inclusion/exclusion criteria. We then conducted a hand search of references to identify studies not found in the initial search strategy.

Results: We included 20 studies with 1,273 enrolled patients in qualitative analysis. Both anesthesiology (12, 60%) and emergency medicine (5, 25%) specialties have evidence of safe and effective use of radial, ulnar, median, suprascapular, and axillary blocks for numerous clinical applications. Recently, multiple randomized controlled trials show suprascapular nerve blocks may result in lower pain scores in patients with shoulder dislocations and rotator cuff injuries, as well as in patients undergoing anesthesia for shoulder surgery.

Conclusion: Distal upper extremity nerve blocks under ultrasound guidance may be safe, practical strategies for both acute and chronic pain in perioperative, emergent, and outpatient settings. These blocks provide accessible, opioid-sparing pain management, and their use across multiple specialties may be expanded with increased procedural education of trainees.

Abstract
Background: Opioid use has increased substantially as a treatment for chronic pain, although harms from long-term opioid therapy outweigh the benefits. More knowledge about factors associated with long-term opioid use is needed. We aimed to investigate the association between socioeconomic status and long-term opioid use in the period 2010-2019.

Methods: This was a nested case-control study in which the cases were all persons ≥18 years with long-term opioid use, that is use of opioids for more than 3 months (N = 215,642). Cases were matched on gender, age and index year (first long-term use period) with four controls who filled at least one opioid prescription, but never developed long-term opioid use in the study period (N = 862,568). We performed a logistic regression analysis adjusted for relevant confounders, stratified on age groups (18-67 years and 68 years and above).

Results: In the younger age group, long-term opioid use was associated with low education (adjusted odds ratio, aOR = 1.54; 95% confidence interval, CI [1.51-1.57]), low income (1.33 [1.31-1.36]), being unemployed (1.40 [1.38-1.42]) and receiving disability pension (1.36 [1.33-1.38]). Weaker associations were found for living in a single-person household or in a dense geographical area. Similar associations were found for the older age group.

Conclusion: We found that low socioeconomic status was associated with long-term opioid use both among people in working age and older people. These results indicate a need for social and financial support for non-pharmacological treatment of chronic pain among people with lower socioeconomic status.

Significance: This study shows that people with low socioeconomic status are at higher risk of developing long-term opioid use. In the clinical setting, physicians should consider socioeconomic status when prescribing opioids for chronic pain. Non-pharmacological treatment options funded by public health services should be prioritized to those with low socioeconomic status as long-term opioid use in chronic pain patients is not recommended.

Abstract
Objective: We aimed to compare the labor analgesia effects of nonpharmaceutical analgesia and pharmaceutical analgesia on parturient women.

Methods: One hundred and four parturient women with spontaneous births were selected and randomly divided into pharmaceutical and nonpharmaceutical analgesia groups. Before and after analgesia, the Visual Analogue Scale (VAS), parturient satisfaction with analgesia, serum pain stress factors (substance P [SP], neuropeptide Y [NPY], nerve growth factor [NGF], and prostaglandin E2 [PGE2]), duration of labor, vaginal bleeding at 2 h postpartum, postpartum urinary retention and dysuria incidence, Apgar score of 1 min and 5 min after birth, and neonatal cord blood gas analysis (pH, partial pressure of oxygen [PO2 ], partial pressure of carbon dioxide [PCO2 ], and lactate [Lac]) were compared in the two groups.

Results: VAS scores were lower and the analgesia satisfaction was higher in the pharmaceutical analgesia group than in the nonpharmaceutical analgesia group (all p < .05). Serum levels of SP, NPY, NGF, and PGE2 in the pharmaceutical analgesia group were lower than those in the nonpharmaceutical analgesia group (all p < .05). The first and second stages of labor were longer and the bleeding volume at 2 h postpartum was greater in the pharmaceutical analgesia group than those in the nonpharmaceutical analgesia group (all p < .05). Reduced Lac and PCO2 levels and increased PO2 level were found in the pharmaceutical analgesia group in comparison to the nonpharmaceutical analgesia group (all p < .05).

Conclusion: This study demonstrates that the analgesic effect and neonatal condition of the pharmaceutical analgesia are better than the nonpharmaceutical analgesia, but the labor duration and postpartum bleeding volume of the pharmaceutical analgesia are greater than those of the nonpharmaceutical analgesia.

Abstract
Introduction: This study aimed to compare remimazolam to propofol in psychomotor recovery after total intravenous anesthesia (TIVA) using the Trieger dot test.

Methods: Sixty-six patients who were scheduled to undergo endoscopic sinus surgery with American Society of Anesthesiologists (ASA) physical status I or II were randomly allocated to the remimazolam (group R) or propofol group (group P). In group R, all patients received flumazenil postoperatively. After discontinuation of anesthetic agents, the time to eye opening, response to verbal commands, extubation, and discharge from the operation room were measured. Psychomotor recovery was assessed using the Trieger dot test before induction and at 0, 30, 60, 90, 120, 150, and 180 min after anesthesia.

Results: The time to eye opening, response to verbal commands, extubation, and discharge from the operation room were significantly longer in group P compared to group R (group P: 9.8 ± 3.2 min, 11.5 ± 3.4 min, 12.7 ± 3.4 min, 18.1 ± 4.2 min; group R: 6.5 ± 2 min, 7.3 ± 2.6 min, 8.4 ± 2.9 min, 13.2 ± 3.2 min; respectively, p < 0.05). In the Trieger dot test, the number of dots missed was significantly increased in group R compared to group P at 30, 60, 90, and 120 min after discharge from the operation room (group R: 20.5 ± 9.3, 16 ± 8.8, 14.9 ± 11.1, 14.3 ± 10.8; group P: 14.6 ± 7.8, 10 ± 7.1, 8.7 ± 7.3, 7.3 ± 5.7; respectively, p < 0.05). The maximum distance of dots missed was significantly increased in group R compared to group P at 30 min after discharge from the operation room (group R: 3.9 ± 2.8; group P: 2.7 ± 1.6; p < 0.05).

Conclusion: Our results suggest that remimazolam with flumazenil leads to rapid recovery following anesthesia; however, it may cause delayed psychomotor decline.


Full citation:
Shimizu T, Takasusuki T, Yamaguchi S. Remimazolam Compared to Propofol for Total Intravenous Anesthesia with Remifentanil on the Recovery of Psychomotor Function: A Randomized Controlled Trial [published online ahead of print, 2023 Jul 25]. Adv Ther. 2023;10.1007/s12325-023-02615-w.

Abstract
Opioid-induced catatonia is underrecognized and poorly understood in the literature. An 81-year-old woman with chronic kidney disease stage III taking sertraline underwent surgery with general anesthesia, receiving fentanyl, hydromorphone, and ketamine. Postoperatively, she was unresponsive, rigid, and cataleptic with pinpoint pupils. Symptoms resolved with a naloxone infusion suggesting opioid-induced catatonia as the leading diagnosis. Differential diagnoses and etiologies discussed reveal a possible multifactorial catatonia mechanism involving opioids, ketamine, and serotonin. Anesthesiologists should consider these potential interactions when using opioids for management of vulnerable patients.

Abstract
Background: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain.

Methods: OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone-naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516).

Percutaneous nephrolithotomy (PCNL) is presently the preferred method for managing renal calculi. Visceral pain from the kidney and ureter and somatic pain from the incision site are the primary causes of immediate postoperative pain following PCNL. Poor pain control is associated with unwanted consequences such as patient discomfort, delayed recovery, and prolonged hospital stay. Recently, the erector spinae plane (ESP) block has been used in many thoracic and abdominal surgeries for the control of postoperative pain. This study aimed to assess the effectiveness of the ultrasound-guided ESP block following PCNL. Methodology This was a prospective, double-blind, randomized controlled study including 60 patients who were scheduled for elective PCNL under general anesthesia.

Ideal sedation and analgesia strategies for fiberoptic bronchoscopy have not been found. At present, propofol based sedation strategy still has some defects, such as respiratory depression and blood pressure drop. It is difficult to meet the requirements of safety and effectiveness at the same time. The aim of this study was to compare the clinical efficacy of propofol/remifentanil with propofol/esketamine for patient sedation during fiberoptic bronchoscopy.

Migraine oscillates between different states in association with internal homeostatic functions and biological rhythms that become more easily dysregulated in genetically susceptible individuals. Clinical and pre-clinical data on migraine pathophysiology support a primary role of the central nervous system (CNS) through 'dysexcitability' of certain brain networks, and a critical contribution of the peripheral sensory and autonomic signalling from the intracranial meningeal innervation. This review focuses on the most relevant back and forward translational studies devoted to the assessment of CNS dysfunctions involved in primary headaches and discusses the role they play in rendering the brain susceptible to headache states.

Full citation:
Rolfzen ML, Wick A, Mascha EJ, et al. Best Practice Alerts Informed by Inpatient Opioid Intake to Reduce Opioid Prescribing After Surgery (PRIOR) - A Cluster Randomized Multiple Crossover Trial [published online ahead of print, 2023 May 8]. Anesthesiology. 2023;10.1097/ALN.0000000000004607.

Keywords: Chronic pain; cognitive therapy; hypnosis; low back pain; moderators.

Keywords: anesthesia; critical care medicine; healthcare management; surgery.

Keywords: Conservative management; Greater trochanteric pain syndrome; Visual analogue pain score.

Keywords: anxiety; arterial blood gas; emergency department; nocebo; pain; positive therapeutic communication; therapeutic communication.

Abstract
Background: Low back pain (LBP) is a major cause of disease burden around the world. There is known clinical variation in how LBP is treated and addressed; with one cited reason the lack of availability, or use of, evidence-based guidance for clinicians, consumers, and administrators. Despite this a considerable number of policy directives such as clinical practice guidelines, models of care and clinical tools with the aim of improving quality of LBP care do exist. Here we report on the development of a repository of LBP directives developed in the Australian health system and a content analysis of those directives aimed at deepening our understanding of the guidance landscape. Specifically, we sought to determine: (1) What is the type, scale, and scope of LBP directives available? (2) Who are the key stakeholders that drive low back pain care through directives? (3) What content do they cover? (4) What are their gaps and deficiencies?

Methods: We used online web search and snowballing methods to collate a repository of LBP policy documents collectively called 'directives' including Models of Care (MOC), information sheets, clinical tools, guidelines, surveys, and reports, from the last 20 years. The texts of the directives were analysed using inductive qualitative content analysis adopting methods from descriptive policy content analysis to categorise and analyse content to determine origins, actors, and themes.

Results: Eighty-four directives were included in our analysis. Of those, 55 were information sheets aimed at either healthcare providers or patients, nine were clinical tools, three were reports, four were guidelines, four were MOC, two were questionnaires and five were referral forms/criteria. The three main categories of content found in the directives were 1. Low back pain features 2. Standards for clinical encounters and 3. Management of LBP, each of which gave rise to different themes and subthemes. Universities, not-for-profit organizations, government organisations, hospitals/Local Health Districts, professional organisations, consumers, and health care insurers were all involved in the production of policy directives. However, there were no clear patterns of roles, responsibilities or authority between these stakeholder groups.

Conclusion: Directives have the potential to inform practice and to contribute to reducing evidence-policy-practice discordance. Documents in our repository demonstrate that while a range of directives exist across Australia, but the evidence base for many was not apparent. Qualitative content analysis of the directives showed that while there has been increasing attention given to models of care, this is not yet reflected in directives, which generally focus on more specific elements of LBP care at the individual patient and practitioner level. The sheer number and variety of directives, from a wide range of sources and various locations within the Australian health system suggests a fragmented policy landscape without clear authoritative sources. There is a need for clearer, easily accessible trustworthy policy directives that are regularly reviewed and that meet the needs of care providers, and information websites need to be evaluated regularly for their evidence-based nature and quality.

Abstract
Background: The effectiveness and safety of opioid-free anesthesia (OFA) regimens in distinct types of surgeries remain controversial. In this study, we investigated whether OFA could reduce the occurrence of chronic postoperative pain in patients receiving video-assisted thoracoscopic surgery (VATS).

Methods: We conducted a 2-center, randomized, controlled trial from September 2021 to January 2022. A total of 162 lung tumor patients scheduled to undergo VATS were randomly divided into an opioid-based anesthesia (OA) group and an OFA group. The OA group received general anesthesia combined with thoracic epidural block using morphine, while the OFA group received general anesthesia combined with thoracic epidural block using esketamine. Patient-controlled epidural analgesia (PCEA) was used after surgery (ropivacaine and morphine for the OA group versus ropivacaine and esketamine for the OFA group). The primary end point was chronic pain rates at 3 months after VATS, which were analyzed using a logistic regression model. The secondary end points were chronic pain rates at 6 months, acute pain rates at 24 hours and 48 hours postoperatively, postoperative side effects, and perioperative variables.

Results: The final analysis included 159 patients. Acute postoperative pain at 24 hours occurred in 0 of the 79 (0%) patients in the OA group and 10 of the 80 (17.5%) patients in the OFA group (odds ratio, 52.14; 95% confidence interval [CI], 6.47-420.10; P < .001). Acute postoperative pain at 48 hours occurred in 3 of the 79 (3.8%) patients in the OA group and 2 of the 80 (2.5%) patients in the OFA group (odds ratio, 2.07; 95% CI, 0.99-4.32; P = .053). In this study, none of the patients had moderate or severe pain in either group at 3 and 6 months postsurgically. Mild chronic postoperative pain at 3 months occurred in 27 of the 79 (34.2%) patients in the OA group and 14 of the 80 (17.5%) patients in the OFA group (odds ratio, 3.52; 95% CI, 1.49-8.31; P = .004). At 6 months, mild chronic pain still occurred in 23 of the 79 (29.1%) patients in the OA group and 9 of the 80 (11.3%) patients in the OFA group (odds ratio, 5.55; 95% CI, 2.01-15.33; P = .001). In addition, the OFA group included fewer patients with side effects, including nausea, vomiting, and pruritus, within 48 hours after surgery.

Conclusions: Replacement of opioids by esketamine, intraoperatively as intravenous injection and epidural infusion and postoperatively as epidural infusion, reduces the incidence of mild chronic postoperative pain and side effects in patients after VATS.

Keywords: Bispectral index; liver transplantation; living donor liver transplant; propofol.

Keywords: Adverse Drug Event; Analgesics; Burns; Opioid; Pain.

Keywords: Analgesia; Emergency department; Pre-hospital; Sufentanil; Systematic review.

Keywords: Acute pain; Multimodal pain control; Naltrexone; Opioids; Post-surgical pain.

Keywords: Duloxetine hydrochloride; gallbladder neoplasms; morphine; pain; postoperative.

Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities, remain poorly understood. We tested the hypothesis that intravenous morphine and hydromorphone differ in onset, magnitude, duration and variability of analgesic and ventilatory effects

Abstract
Workplace violence is any physical assault, threatening behavior or other verbal abuse directed toward persons at work or in the workplace. The incidence of workplace violence in healthcare settings in general and more specifically the pain clinic is thought to be underestimated due to hesitancy to report, lack of support from management and healthcare systems, and lack of institutional policies as it relates to violence from patients against healthcare workers. In the following article, we explore risk factors that place clinicians at risk of workplace violence, the cost and impact of workplace violence, how to build a violence prevention program and lastly how to recover from violence in the practice setting.