BACKGROUND: Peripheral nerve blocks effectively alleviate postoperative pain. Animal studies and human research suggest that opioid tolerance may reduce the effectiveness of local analgesics. The reduced effectiveness has been observed in opioid-tolerant humans and animals undergoing spinal and infiltration anaesthesia with both lidocaine and bupivacaine. However, the impact on peripheral nerve blocks in humans has not been evaluated. This study aims to assess the onset time and duration of a radial nerve block in opioid-tolerant individuals compared to opioid-naive individuals. We hypothesise that peripheral nerve blocks may be less effective in producing sensory and motor blockades in opioid-tolerant individuals compared to their opioid-naive counterparts.
METHODS: Twenty opioid-tolerant individuals will be matched by sex and age with opioid-naïve counterparts. Participants will receive an ultrasound-guided radial nerve block. The primary outcome is the difference in the duration of sensory nerve blockade between the two groups. The secondary outcomes include the onset time of sensory blockade, onset time of motor blockade, and difference in duration of motor nerve blockade.
CONCLUSIONS: This study will compare the effectiveness of a peripheral nerve block between opioid-tolerant and opioid-naïve individuals. Any found differences could support a specific postoperative protocol for opioid-tolerant individuals regarding the use of peripheral nerve blocks.

First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.

Cannabinoid CB2 agonists show therapeutic efficacy without unwanted CB1-mediated side effects. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB2 receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice and in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f), but were absent in mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB2f/f and CX3CR1CRE/+; CB2f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB2f/f mice, but not AdvillinCRE/+; CB2f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our findings have potential clinical implications.

UNASSIGNED: Total knee arthroplasty (TKA) is a standard surgical procedure for individuals with debilitating knee arthritis. Effective postoperative pain management is essential for successful recovery, although traditional opioid-based methods have limitations.
UNASSIGNED: This study aimed to compare the efficacy of Apotel and remifentanil patient-controlled analgesia in managing postoperative pain after TKA.
UNASSIGNED: This double-blind, randomized, controlled clinical trial took place at Amir-al-Momenin and Qods Hospitals in Arak, Iran, spanning from June 2022 to September 2023. Sixty-two eligible patients scheduled for knee joint replacement were randomly assigned to receive either Apotel (Group A) or remifentanil (Group R) as part of multimodal analgesia administered via a pain pump for postoperative pain relief in TKA. The study assessed hemodynamic parameters, pain levels (measured using the Visual Analog Scale), analgesic duration, and narcotic consumption. Statistical analyses were performed using SPSS v.27 and Plotly.
UNASSIGNED: Subjects exhibited no statistically significant differences in age, gender distribution, duration of surgery, or anesthesia. The hemodynamic status assessment in the recovery room showed no significant differences in SPO2, PR, or MAP between the groups. However, remifentanil demonstrated superior effectiveness in reducing pain over 24 hours post TKA surgery compared to Apotel, as evidenced by lower average Visual Analog Scale (VAS) scores (P < 0.001), longer duration without the need for narcotic painkillers (P < 0.001), and lower cumulative opioid analgesic consumption in Group R (P < 0.001).
UNASSIGNED: Remifentanil demonstrates superior pain control in a multimodal pain management approach compared to Apotel, providing sustained pain reduction over 24 hours post-surgery. Moreover, remifentanil offers longer-lasting pain relief and results in lower cumulative narcotic painkiller consumption compared to Apotel.

In the cancer pain setting, ketamine has been typically employed as a co-analgesic for opioid refractory and neuropathic pain. One controversial topic is whether subanesthetic ketamine be considered when managing opioid refractory cancer pain. In this \"Controversies in Palliative Care\" article, three clinicians independently answer this question. Specifically, each clinician provides a synopsis of the key studies that inform their thought processes, share practical advice on their clinical approach, and highlight the opportunities for future research. Three independent clinicians reported a divergence of opinion regarding the usefulness of subanesthetic ketamine for managing opioid refractory cancer pain. All investigators acknowledged the lack of high-quality trials. All agreed on the need for adequately powered trials, the development of standardized methodology, and the exploration of any patient sub-populations that may benefit from ketamine for cancer related pain.

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signalling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signalling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management.

Agmatine, a decarboxylated form of L-arginine, prevents opioid analgesic tolerance, dependence, and self-administration when given by both central and systemic routes of administration. Endogenous agmatine has been previously detected in the central nervous system. The presence of a biochemical pathway for agmatine synthesis offers the opportunity for site-specific overexpression of the presumptive synthetic enzyme for local therapeutic effects. In the present study, we evaluated the development of opioid analgesic tolerance in ICR-CD1 mice pre-treated with either vehicle control or intrathecally delivered adeno-associated viral vectors (AAV) carrying the gene for human arginine decarboxylase (hADC). Vehicle-treated or AAV-hADC-treated mice were each further divided into two groups which received repeated delivery over three days of either saline or systemically-delivered morphine intended to induce opioid analgesic tolerance. Morphine analgesic dose-response curves were constructed in all subjects on day four using the warm water tail flick assay as the dependent measure. We observed that pre-treatment with AAV-hADC prevented the development of analgesic tolerance to morphine. Peripheral and central nervous system tissues were collected and analyzed for presence of hADC mRNA. In a similar experiment, AAV-hADC pre-treatment prevented the development of analgesic tolerance to a high dose of the opioid neuropeptide endomorphin-2. Intrathecal delivery of anti-agmatine IgG (but not normal IgG) reversed the inhibition of endomorphin-2 analgesic tolerance in AAV-hADC-treated mice. To summarize, we report here the effects of AAV-mediated gene transfer of human ADC (hADC) in models of opioid-induced analgesic tolerance. This study suggests that gene therapy may contribute to reducing opioid analgesic tolerance.

Prolonged exposure to opioids causes an enhanced sensitivity to painful stimuli (opioid-induced hyperalgesia, OIH) and a need for increased opioid doses to maintain analgesia (opioid-induced tolerance, OIT), but the mechanisms underlying both processes remain obscure. We found that pharmacological block or genetic deletion of HCN2 ion channels in primary nociceptive neurons of male mice completely abolished OIH but had no effect on OIT. Conversely, pharmacological inhibition of central HCN channels alleviated OIT but had no effect on OIH. Expression of C-FOS, a marker of neuronal activity, was increased in second-order neurons of the dorsal spinal cord by induction of OIH, and the increase was prevented by peripheral block or genetic deletion of HCN2, but block of OIT by spinal block of HCN channels had no impact on C-FOS expression in dorsal horn neurons. Collectively, these observations show that OIH is driven by HCN2 ion channels in peripheral nociceptors, while OIT is driven by a member of the HCN family located in the CNS. Induction of OIH increased cAMP in nociceptive neurons, and a consequent shift in the activation curve of HCN2 caused an increase in nociceptor firing. The shift in HCN2 was caused by expression of a constitutively active μ-opioid receptor (MOR) and was reversed by MOR antagonists. We identified the opioid-induced MOR as a six-transmembrane splice variant, and we show that it increases cAMP by coupling constitutively to Gs HCN2 ion channels therefore drive OIH, and likely OIT, and may be a novel therapeutic target for the treatment of addiction.

The quality of postoperative pain management is still considered insufficient in many cases, also in surgical ophthalmology. Complex constellations and comorbidities, such as pre-existing chronic pain, opioid consumption and opioid use disorders represent a special challenge due to psychosocial influencing factors and sometimes psychological and psychiatric comorbidities but also due to pharmacological effects, such as the development of opioid tolerance, the opioid-induced hyperalgesia. This review article aims to impart knowledge on aspects of these comorbidities and the perioperative management to improve the treatment skills of ophthalmologists in the management of pain in these complex patients.
UNASSIGNED: Die Qualität der postoperativen Schmerztherapie gilt nach wie vor in vielen Fällen als unzureichend, so auch in der operativen Ophthalmologie. Komplexe Konstellationen und Komorbiditäten wie Patienten mit vorbestehenden chronischen Schmerzen, Opioidvormedikation und Abhängigkeitserkrankungen stellen dabei aufgrund von psychosozialen Einflussfaktoren und teils psychologischer und psychiatrischer Komorbidität, aber auch aufgrund von pharmakologischen Effekten wie beispielsweise der Toleranzentwicklung von Opioiden, der opioidinduzierten Hyperalgesie, eine besondere Herausforderung dar. Die folgende Übersicht hat zum Ziel, Kenntnisse zu diesen Komorbiditäten und zum perioperativen Umgang zu vermitteln, um damit die Behandlungskompetenz der Augenärzte für die Schmerzbehandlung bei diesen komplexen Patienten zu stärken.

Opioids are widely used in treating patients with acute and chronic pain; however, this class of drugs is also commonly abused. Opioid use disorder and associated overdoses are becoming more prevalent as the opioid crisis continues. Chronic opioid use is associated with tolerance, which decreases the efficacy of opioids over time, but also puts individuals at risk of fatal overdoses. Therefore, it is essential to identify strategies to reduce opioid tolerance in those that use these agents. The gut microbiome has been found to play a critical role in opioid tolerance, with opioids causing dysbiosis of the gut, and changes in the gut microbiome impacting opioid tolerance. These changes in turn have a detrimental effect on the gut microbiome, creating a positive feedback cycle. We review the bidirectional relationship between the gut microbiome and opioid tolerance, discuss the role of modulation of the gut microbiome as a potential therapeutic option in opioid-induced gut dysbiosis, and suggest opportunities for further research and clinical interventions.