Opioid induced hyperalgesia

Background and Objectives : The effects of midazolam, a benzodiazepine, on pain perception are complex on both spinal and supraspinal levels. It is not yet known whether remimazolam clinically attenuates or worsens pain. The present study investigated the effect of intraoperative remimazolam on opioid-induced hyperalgesia (OIH) in patients undergoing general anesthesia. Materials and Methods : The patients were randomized into three groups: group RHR (6 mg/kg/h initial dose followed by 1 mg/kg/h remimazolam and 0...

Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions...

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the μ-opioid (MOR) and sigma-1 (σ1 R) receptors are reported. Compound 23 exhibited good affinity to σ1 R (Ki  = 44.7 ± 7.05 nM) and high selectivity to σ2 R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED50  = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED50  = 5...

Oxycodone is the most prescribed opioid for pain management and has been available in clinics for almost a century, but effects of chronic oxycodone have been studied less than morphine in preclinical and clinical studies. Newly developed depression has been coupled with chronic oxycodone use in a few clinical studies, but no preclinical studies have investigated the pathogenesis of oxycodone-induced depression. Gut microbiome changes following oxycodone use is an understudied area, and interleukin-17A (IL-17A) is linked to both the development of mood disorders and regulation of gut microbiome...

The mechanisms of β -caryophyllene (BCP)-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute postsurgical pain model and evaluated its effect on the endocannabinoid system. Rats were treated with vehicle and 10, 25, 50, and 75 mg/kg BCP. Paw withdrawal responses to mechanical stimuli were evaluated using an electronic von Frey anesthesiometer. Endocannabinoids, including 2-arachidonoylglycerol (2-AG), were also evaluated in plasma and tissues using high-performance liquid chromatography-tandem mass spectrometry...

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4...

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4...

We discuss the use of an inpatient multi-day continuous intravenous ketamine infusion for the treatment of opioid-induced hyperalgesia (OIH) and high fentanyl requirements in the case of a patient with a background of fibromyalgia/central sensitisation syndrome who underwent a complicated post-operative course following a right below-knee amputation for high-grade myxoid fibrosarcoma. The patient was successfully tapered off a total fentanyl patch dose of 162 mcg/hour every 72 hours (morphine equivalent dose of 389 mg/day) to short-acting hydromorphone 2 mg orally two times per day as needed (equivalent of 8 mg morphine sustained-release twice per day) during a 2-week admission with only mild withdrawal symptoms...

Repeated use of opioid analgesics may cause a paradoxically exacerbated pain known as opioid-induced hyperalgesia (OIH), which hinders effective clinical intervention for severe pain. Currently, little is known about the neural circuits underlying OIH modulation. Previous studies suggest that laterocapsular division of the central nucleus of amygdala (CeLC) is critically involved in the regulation of OIH. Our purpose is to clarify the role of the projections from infralimbic medial prefrontal cortex (IL) to CeLC in OIH...

We investigated the role that innate immunological signaling pathways, principally nod-like receptors (NLRs) and inflammasomes, in the manifestation of the contradictory outcomes associated with opioids, namely hyperalgesia, and tolerance. The utilization of opioids for pain management is prevalent; nonetheless, it frequently leads to an increased sensitivity to pain (hyperalgesia) and reduced efficacy of the medication (tolerance) over an extended period. This, therefore, represents a major challenge in the area of chronic pain treatment...

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests-thermal gradient ring (5-30 °C, 5-50 °C, 15-40 °C, and 25-50 °C), dynamic cold plate (4 °C to -1 °C at -1 °C/min, -1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)-to measure hyperalgesia in a mouse protocol of heroin dependence...

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...

About 25 million American adults experience pain daily and one of the most commonly prescribed drugs to treat pain are opioids. Prolonged opioid usage and dose escalations can cause a paradoxical response where patients experience enhanced pain sensitivity. This opioid induced hyperalgesia (OIH) is a major hurdle when treating pain in the clinic because its underlying mechanisms are still not fully understood. OIH is also commonly overlooked and lacks guidelines to prevent its onset. Research on pain disorders and opioid usage have recognized potential epigenetic drivers of disease including DNA methylation, histone modifications, miRNA regulation, but their involvement in OIH has not been well studied...

2,6-di- tert -butylphenol (2,6-DTBP) ameliorates mechanical allodynia and thermal hyperalgesia produced by partial sciatic nerve ligation in mice, and selectively inhibits HCN1 channel gating. We hypothesized that the clinically utilized non-anesthetic dimerized congener of 2,6-DTBP, probucol (2,6-di- tert -butyl-4-[2-(3,5-di- tert -butyl-4-hydroxyphenyl)sulfanylpropan-2-ylsulfanyl]phenol), would relieve the neuropathic phenotype that results from peripheral nerve damage, and that the anti-hyperalgesic efficacy in vivo would correlate with HCN1 channel inhibition in vitro...

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0...

A re-examination of clinical principles of long-term opioid therapy (LTOT) for chronic pain is long overdue amid the ongoing opioid crisis. Most patients on LTOT report ineffectiveness (poor pain control, function and health) but still find deprescribing challenging. Although prescribed as analgesics, opioids more likely provide pain relief primarily through reward system actions (enhanced relief and motivation) and placebo effect and less through antinociceptive effects. The unavoidable physiologic LTOT dependence can automatically lead to a paradoxical worsening of pain, disability and medical instability (maladaptive opioid dependence) without addiction due to allostatic opponent neuroadaptations involving reward/antireward and nociceptive/antinociceptive systems...

OBJECTIVES: Many chronic pain conditions show evidence of dysregulated synaptic plasticity, including the development and maintenance of central sensitization. This provides a strong rationale for neuromodulation therapies for the relief of chronic pain. However, variability in responses and low fidelity across studies remain an issue for both clinical trials and pain management, demonstrating insufficient mechanistic understanding of effective treatment protocols. MATERIALS AND METHODS: In a randomized counterbalanced crossover designed study, we evaluated two forms of patterned repetitive transcranial magnetic stimulation, known as continuous theta burst stimulation (TBS) and intermittent TBS, during normal and central sensitization states...

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...

Neuropathic pain is one of the most debilitating forms of chronic pain, resulting from an injury or disease of the somatosensory nervous system, which induces abnormal painful sensations including allodynia and hyperalgesia. Available treatments are limited by severe side-effects and reduced efficacy in the chronic phase of the disease. Sigma-1 receptor (σ1R) has been identified as a chaperone protein, which modulate opioid receptors activities and the functioning of several ion channels, exerting a role in pain transmission...

BACKGROUND: Remifentanil and sufentanil are potent short-acting synthetic opioid analgesics. The administration of remifentanil has been associated with the incidence of opioid-induced hyperalgesia. Opioid-induced hyperalgesia may be alleviated when opioids, such as morphine, are switched to sufentanil. Therefore, this retrospective observational study aimed to compare the effects of remifentanil and sufentanil on postoperative pain in patients undergoing robotic gynecological surgery...