Opioid-induced Hyperalgesia Research Articles

KEA-1010, a ketamine ester analogue, retains analgesic and sedative potency but is devoid of Psychomimetic effects

BackgroundKetamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents.MethodsKEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was further undertaken in morphine tolerant rats. Behavioural aberration was assessed following intravenous injection in rats undergoing TFL assessment and in auditory pre-pulse inhibition models.ResultsKEA-1010 demonstrated an ED50 similar to ketamine for loss of righting reflex following bolus intravenous injection (KEA-1010 11.4 mg/kg [95% CI 10.6 to 12.3]; ketamine (racemic) 9.6 mg/kg [95% CI 8.5–10.9]). Duration of hypnosis was four-fold shorter in KEA-1010 treated animals. KEA-1010 prolonged thermal tail flick responses comparably with ketamine when administered de novo, and augmented morphine-induced prolongation of tail flick when administered acutely. The analgesic effect of KEA-1010 on thermal tail flick was preserved in opioid tolerant rats. KEA-1010 resulted in increased paw-withdrawal thresholds in a rat paw incision model, similar in magnitude yet more persistent than that seen with fentanyl injection, and additive when co-administered with fentanyl. In contrast to ketamine, behavioural aberration following KEA-1010 injection was largely absent and no pre-pulse inhibition to acoustic startle was observed following KEA-1010 administration in rats.ConclusionsKEA-1010 provides antinociceptive efficacy in acute thermal and mechanical pain models that augments standard opioid analgesia and is preserved in opioid tolerant rodents. The NMDA channel affinity and psychomimetic signature of the parent compound ketamine is largely absent for KEA-1010.

Ketamine and lidocaine infusions decrease opioid consumption during vaso-occlusive crisis in adolescents with sickle cell disease.

Recurrent exposure to opioids can lead to development of opioid tolerance and opioid-induced hyperalgesia through activation of N-methyl-D-aspartate receptors. N-methyl-D-aspartate receptor antagonists ketamine and lidocaine can modulate development of opioid tolerance and OIH. This study evaluated the utility of ketamine and/or lidocaine in decreasing opioid consumption during acute pain episodes in adolescents with sickle cell disease. There has been an increased effort to promote opioid-sparing pain relieving methods given the ongoing opioid epidemic. There have been six studies published over the past decade that highlight the ability of ketamine to reduce opioid consumption in the management of sickle cell disease-related pain, primarily in adult patients. There has been one study (2015) that demonstrated a similar benefit with lidocaine, however this was also in adult patients. We retrospectively evaluated treatment with ketamine and/or lidocaine infusions in adolescents hospitalized for vaso-occlusive crisis (VOC). Patients served as self-controls using a comparison with a previous control admission for VOC. The use of ketamine and/or lidocaine as adjuncts to opioids resulted in lower daily opioid consumption in three of four patients. Our study suggests that ketamine and/or lidocaine infusions may be useful adjuncts in reducing opioid exposure during VOC pain.

Determination of acute tolerance and hyperalgesia to remifentanil constant rate infusion in dogs undergoing sevoflurane anaesthesia

ObjectiveTo determine if acute opioid tolerance (AOT) or opioid-induced hyperalgesia (OIH) could develop and limit the remifentanil-induced reduction in the sevoflurane minimum alveolar concentration (MAC). The response to mechanical nociceptive threshold (MNT) was evaluated and related to OIH. Study designA crossover, randomized, experimental animal study. AnimalsA total of nine Beagle dogs. MethodsThe dogs were anaesthetized with sevoflurane in 50% oxygen. Baseline sevoflurane MAC was measured (MACb1). Remifentanil (0.3 μg kg–1 minute–1) or 0.9% saline constant rate infusion (CRI) was administered intravenously (IV). Sevoflurane MAC was determined 20 minutes after CRI was initiated (MACpostdrug1), 30 minutes after MACpostdrug1 determination (MACpostdrug2) and after 1 week (MACb2). The MNT was determined at baseline (before anaesthesia), 3 and 7 days after anaesthesia. An increase of MACpostdrug2 ≥0.25% compared to MACpostdrug1 was considered evidence of AOT. A decrease in MNT at 3 and 7 days or an increase in MACb2 or both with respect to MACb1 were considered evidence of OIH. ResultsRemifentanil CRI reduced sevoflurane MACpostdrug1 by 43.7% with respect to MACb1. MACpostdrug2 was no different from MACpostdrug1 with the saline (p = 0.62) or remifentanil (p = 0.78) treatments. No significant differences were observed in the saline (p = 0.99) or remifentanil (p = 0.99) treatments between MACb1 and MACb2, or for MNT values between baseline, 3 and 7 days. Conclusion and clinical relevanceIn dogs, under the study conditions, remifentanil efficacy in reducing sevoflurane MAC did not diminish in the short term, suggesting remifentanil did not induce AOT. Hyperalgesia was not detected 3 or 7 days after the administration of remifentanil. Contrary to data from humans and rodents, development of AOT or OIH in dogs is not supported by the findings of this study.

Pharmacological Characters of Oliceridine, a μ-Opioid Receptor G-Protein-Biased Ligand in Mice.

A major advancement in the field of analgesic pharmacology has been the development of G-protein-biased opioid agonists that display less respiratory depression than conventional drugs. It is uncertain, however, whether these new drugs cause less tolerance, hyperalgesia, and other maladaptations when administered repeatedly. The archetypical µ-opioid receptor agonist morphine and, separately, the G-protein-biased µ-opioid receptor agonist oliceridine were administered to mice. These drugs were used in models of acute analgesia, analgesic tolerance, opioid-induced hyperalgesia, reward, and physical dependence. In addition, morphine and oliceridine were administered for 7 days after tibia fracture and pinning; mechanical allodynia and gait were followed for 3 weeks. Finally, the expression of toll-like receptor-4 and nacht domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NALP3) and interleukin-1β mRNA were quantified in spinal tissue to measure surgical and drug effects on glia-related gene expression. We observed using the tail flick assay that oliceridine was a 4-fold more potent analgesic than morphine, but that oliceridine treatment caused less tolerance and opioid-induced hyperalgesia than morphine after 4 days of ascending-dose administration. Using similar analgesic doses, morphine caused reward behavior in the conditioned place preference assay while oliceridine did not. Physical dependence was, however, similar for the 2 drugs. Likewise, morphine appeared to more significantly impair the recovery of nociceptive sensitization and gait after tibial fracture and pinning than oliceridine. Furthermore, spinal cord toll-like receptor-4 levels 3 weeks after fracture were higher in fracture mice given morphine than those given oliceridine. Aside from reduced respiratory depression, G-protein-biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.

Remifentanil-Induced Secondary Hyperalgesia Is Not Prevented By Preoperative Acetazolamide Administration In Patients Undergoing Total Thyroidectomy: A Randomized Controlled Trial.

PurposeAcute administration of remifentanil may lead to opioid-induced hyperalgesia (OIH). Studies in mice suggest that OIH is mediated by impaired anionic homeostasis in spinal lamina I neurons due to a down-regulation of the K+-Cl− co-transporter KCC2, which was reverted using acetazolamide (ACTZ), a carbonic anhydrase inhibitor. We propose that ACTZ prevents remifentanil-mediated OIH in humans.Patients and methodsWe conducted a randomized, double-blind, placebo-controlled clinical trial between December 2016 and September 2018. Patients were randomly allocated to receive ACTZ (250 mg of ACTZ 2 h before surgery) or placebo. To detect hyperalgesia, mechanical pain threshold (MPT) were measured before and after surgery using hand-held von Frey filaments in the forearm. Anesthesia was maintained with remifentanil at a target effect site of 4.5 ± 0.5 ng/mL, and sevoflurane at an end-tidal concentration of 0.8 MAC corrected for age.ResultsIn total, 47 patients completed the study. Both groups were comparable in the baseline characteristics and intraoperative variables. Baseline MPT were similar in both groups. However, MPT in the forearm significantly diminished in the time in both groups. Finally, postoperative pain and morphine consumption were similar between groups.ConclusionBoth groups developed remifentanil-mediated OIH at 12–18 h after surgery. However, ACTZ did not prevent the MPT reduction in patients undergoing total thyroidectomy.

A High Dose of Fentanyl May Accelerate the Onset of Acute Postoperative Pain.

Fentanyl is a popular intraoperative analgesic linked with the development of opioid tolerance (OT) or opioid-induced hyperalgesia (OIH). The development of OIH or OT may lead to several issues such as delayed healing after surgery and timely discharge. Moreover, it causes discomfort in patients with higher pain scores, greater use of analgesics, and other associated side effects. The current study aimed at determining whether the amount of intraoperatively administered fentanyl affects the onset of acute postoperative pain. The current retrospective study was conducted on 56 patients undergoing laparoscopic sleeve gastrectomy. In patients receiving relatively large doses of fentanyl intraoperatively (over 3 µg/kg body weight), the onset of acute postoperative pain accelerated significantly, in comparison with the ones receiving lower doses.

Low‐ versus high‐dose intraoperative opioids: A systematic review with meta‐analyses and trial sequential analyses

Opioid-induced hyperalgesia is a state of nociceptive sensitisation secondary to opioid administration. The objective of this meta-analysis was to test the hypothesis that high-dose intraoperative opioids contribute to increased post-operative pain and hyperalgesia when compared with a low-dose regimen in patients under general anaesthesia. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and rated the certainty of evidence with the Grading of Recommendations, Assessment, Development and Evaluation system. Only trials investigating pain outcomes and comparing two different dosages of the same intraoperative opioid in patients under general anaesthesia were included. The primary outcome was pain score (analogue scale, 0-10) at 24post-operative hours. Secondary outcomes included pain score and cumulative intravenous morphine equivalents (mg) consumed at 2post-operative hours, together with mechanical pain threshold (g·mm-2 ). Twenty-seven randomised controlled trials, including 1630 patients, were identified. Pain score at rest at 24post-operative hours was increased in the high-dose group (mean difference [95% CI]: -0.2 [-0.4, -0.1]; trial sequential analysis-adjusted CI: -0.4, -0.02; low certainty of evidence). Similarly, at 2post-operative hours, both pain score (mean difference [95% CI]: -0.4 [-0.6, -0.2]; low certainty of evidence) and cumulative intravenous morphine equivalents consumed (mean difference [95% CI]: -1.6mg [-2.6, -0.7]; low certainty of evidence) were significantly higher in the high-dose group. Finally, the threshold for mechanical pain was significantly lower in the high-dose group (mean difference to pressure [95% CI]: 3.8g·mm-2 [1.8, 5.8]; low certainty of evidence). There is low certainty of evidence that high-dose intraoperative opioid administration increases pain scores in the post-operative period, when compared with a low-dose regimen.

Remifentanil for abdominal surgery is associated with unexpectedly unfavorable outcomes.

Insufficient perioperative pain treatment is known as a highly predictive risk factor for the development of chronic postoperative pain. Remifentanil is an ultrashort-acting opioid that provides quick and efficient analgesia but is associated with the induction of opioid-induced hyperalgesia. Despite these well-known characteristics, this substance is being increasingly used in anesthesia and in a variety of medical fields, such as intensive-care medicine and obstetrics. The aim of our study was to reveal whether remifentanil influences postoperative pain, the requirement for postoperative analgesics, and requirement of antiemetics (as indirect indicator of postoperative nausea and vomiting), as well as the effects on time to extubation and length of stay in the postanesthesia care unit in daily clinical routine. From an electronic medical records database of 55,693 anesthesias, we analyzed data from all patients receiving intraabdominal surgery (visceral, gynecological, and urological) under general anesthesia or combined general-epidural anesthesia by propensity score matching. The administration of remifentanil was associated with higher postoperative pain scores despite a higher requirement of postoperative analgesics. Additional epidural analgesia was not able to avoid this finding. The intraoperative use of remifentanil is associated with a deterioration of pain levels and postoperative analgesic requirement, wherefore the potential benefit of this substance seems to be outweighed by its potential disadvantages. Especially in operative procedures in which high postoperative pain scores are expected, the unreflective use should be critically questioned.

Opioid-Induced Tolerance and Hyperalgesia.

Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.

Hyperalgesia and fentanyl dosing in on-pump coronary artery bypass grafting

Introduction Opioids have many known side-effects. However opioid-induced hyperalgesia (OIH), as a result of central sensitization, remains more obscure. The increase in hyperalgesia is dose-related and postoperatively an increased secondary wound hyperalgesia may be a factor in the development of chronic or persistent pain. This prospective, randomized and double-blind clinical trial aims to investigate the effects of fentanyl on secondary wound hyperalgesia in patients undergoing on-pump coronary artery bypass grafting. Methods Secondary wound hyperalgesia was investigated between two study-groups, respectively a low dose bolus group (n = 14, 3mcg/ kg) and a continuous infusion group (n = 17, Shibutani). The primary endpoint of this study was the area of secondary wound hyperalgesia after 24 hours. The area was measured using a Von Frey filament (256mN). Additionally we looked at hyperalgesia after 48 hours and we investigated following secondary endpoints: time to extubation, ICU/hospital length of stay, PONV, pain scores, the need for additional analgesia and the total dose of opioids administered 24 and 48 hours after surgery. This study is a subgroup analysis of a larger study, in which the possible association between the area of secondary wound hyperalgesia and persistent pain at 3, 6 and 12 months after surgery will be investigated. Results The examination of preliminary results showed no statistically significant difference for the area of secondary wound hyperalgesia after 24 hours (p = 0.3268). However the results became significant after 48 hours, where the area of secondary wound hyperalgesia was smaller in the low dose bolus group (p = 0.0389). No significant differences were found for the other secondary endpoints. Discussion There was less secondary wound hyperalgesia in the low dose bolus group after 48 hours, although at 24 hours this was not statistically significant. These findings are the result of preliminary data. We need to wait for the definitive results of hyperalgesia and for the results regarding chronic pain to draw any conclusions about the clinical significance of OIH.

Postoperative Pain Responses in Dental Patients on Chronic Opioid Therapy

It is estimated that 5 to 8 million Americans use opioids daily for the management of chronic pain. Yet, opioid therapy for chronic pain is not an evidence-based intervention, and it is increasingly apparent that outcomes are poorer for patients taking opioids (pain severity, functionality, quality of life) (1). A theorized explanation for these poor outcomes is the phenomenon of opioid-induced hyperalgesia (OIH) (2), defined as increased sensitivity to pain related to chronic opioid use, and which may interfere with desired pain relief in the chronic pain patient. This study was designed to compare pain responses and analgesic need in a sample of dental patients on chronic opioid therapy vs. not on opioid therapy, the first study of its kind. A total of 40 adult dental surgical patients are being enrolled in the study, 20 of whom are on opioid therapy for chronic pain, all undergoing a dental surgical procedure with a similar expected trauma rating, and standardized postoperative non-opioid pain management. Those in the opioid group are taking a regular daily dose of opioids ≥ 50mg morphine equivalents/day for ≥ 3 months and those in the control group have not taken an opioid medication within 3 months. Exclusion criteria include active substance use disorder; severe psychiatric disorder; neurological or psychiatric illness that would affect pain responses; history of GI ulcers; NSAID allergy; poor liver or kidney function; or pregnancy. Prior to the surgical procedure, pain perception is measured using 2 standardized experimental pain assays (cold-pressor testing; quantitative sensory testing) to detect OIH. To determine how OIH may affect postoperative pain responses, patient-reported pain severity and documentation of all analgesic consumption for the first 72 hours are collected. If preoperative opioid use is found to result in increased postoperative pain severity, clinical implications may include anticipation of increased analgesic need or preoperative opioid taper.

Withdrawal from an opioid induces a transferable memory trace in the cerebrospinal fluid.

Opioids are the most powerful analgesics available to date. However, they may also induce adverse effects including paradoxical opioid-induced hyperalgesia. A mechanism that might underlie opioid-induced hyperalgesia is the amplification of synaptic strength at spinal C-fibre synapses after withdrawal from systemic opioids such as remifentanil ("opioid-withdrawal long-term potentiation [LTP]"). Here, we show that both the induction as well as the maintenance of opioid-withdrawal LTP were abolished by pharmacological blockade of spinal glial cells. By contrast, the blockade of TLR4 had no effect on the induction of opioid-withdrawal LTP. D-serine, which may be released upon glial cell activation, was necessary for withdrawal LTP. D-serine is the dominant coagonist for neuronal NMDA receptors, which are required for the amplification of synaptic strength on remifentanil withdrawal. Unexpectedly, opioid-withdrawal LTP was transferable through the cerebrospinal fluid between animals. This suggests that glial-cell-derived mediators accumulate in the extracellular space and reach the cerebrospinal fluid at biologically active concentrations, thereby creating a soluble memory trace that is transferable to another animal ("transfer LTP"). When we enzymatically degraded D-serine in the superfusate, LTP could no longer be transferred. Transfer LTP was insensitive to pharmacological blockade of glial cells in the recipient animal, thus representing a rare form of glial cell-independent LTP in the spinal cord.

Tolerability and safety of strong opioid analgesics in children and adolescents with incurable oncological diseases

Relevance. One of the basic tasks of palliative medical care is to control pain in an incurable patient. To administer strong opioid analgesics as basic pain management in terminal patients, a treating physician must understand the risk of opioid-related adverse effects. According to the World Health Organization, the occurrence of the pain syndrome and importance of correct analgesic therapy in children and adolescents with incurable oncological diseases are underestimated.Purpose. To improve the quality of palliative medical care provided to children and adolescents with incurable oncological diseases.Materials and methods. A retrospective and prospective study was carried out. 400 patients with incurable oncological diseases aged 0 months to 20 years (median 9 years) were included into the study from June 2014 to December 2017, in particular, 235 boys and 165 girls (189 patients with extracranial solid tumors, 117 patients with CNS tumors and 94 patients with hemoblastoses). The study was approved by the Independent Ethics Committee and the Council of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Protocol No. 5 dated May 21, 2013). Of 284 patients with the pain syndrome, 227 (80%) of children and adolescents aged 0–20 years (median 12 years) used strong opioid analgesics (morphine hydrochloride, morphine sulfate and transdermal therapeutic system with fentanyl) for pain relief. Their dosage was set in accordance with WHO 2012 recommendations related to the management of persisting pain syndrome in children. To estimate the severity of adverse events (AE) when strong opioids were used (nausea, vomiting, constipation, skin itching, urinary retention and respiratory failure), the CTCAE (Common Terminology Criteria for Adverse Events) displays Grades 1 through 5. Opioid-induced hyperalgesia and opioid-induced neurotoxicity were estimated by clinical signs (absence or presence of a symptom).Results. Of 227 patients, 59 (26%) patients had AE associated with the administration of strong opioid analgesics: 11.5% of cases for constipation, 7.5% cases for nausea, 4% of cases for pruritus, 2.2% of cases for urinary retention, 0.44% of cases for opioid-induced hyperalgesia, 0.44% of cases for opioid-induced neurotoxicity. No respiratory failure was noted when strong opioid analgesics were used. In the majority of cases (95%), the registered AE were mild and required no termination of therapy with opioid analgesics. Of 284 patients, 281 (98.9%) underwent analgesic therapy with complete pain management.Conclusion. Strong opioid analgesics are safe and effective in children and adolescents with incurable oncological diseases.

Pain Response to Cannabidiol in Opioid-induced Hyperalgesia, Acute Nociceptive Pain and Allodynia By Using a Model Mimicking Acute Pain in Healthy Adults

Pain Response to Cannabidiol in Opioid-induced Hyperalgesia, Acute Nociceptive Pain and Allodynia By Using a Model Mimicking Acute Pain in Healthy Adults

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia.

Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 μg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 μg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nm) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a μ-opioid receptor (MOR)-dependent increase in [Ca2+]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4+ and IB4- neurons. This sensitizing effect of fentanyl was reversed in weakly IB4+ DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH.SIGNIFICANCE STATEMENT Clinically used μ-opioid receptor agonists such as fentanyl can produce hyperalgesia and hyperalgesic priming. We report on an in vitro model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid-naive and opioid-primed animals, and provide evidence for the important role of nociceptor μ-opioid receptor-mediated calcium signaling and peripheral protein translation in the weakly IB4-binding population of nociceptors in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.

Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming.

In addition to analgesia, opioids produce opioid-induced hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E2 hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C ε (PKCε) AS-ODN also prevented LDM-induced hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4+ and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKCε, HDM-induced analgesia, and priming are neither TLR4 nor PKCε dependent. OIH produced by LDM is mediated by both IB4+ and peptidergic nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4+ and peptidergic nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed.SIGNIFICANCE STATEMENT Opioid-induced hyperalgesia (OIH) and priming are common side effects of opioid agonists such as morphine, which acts at μ-opioid receptors. We demonstrate that OIH and priming induced by systemic low-dose morphine (LDM) share action at Toll-like receptor 4 (TLR4) and signaling via protein kinase C ε (PKCε) in common, whereas systemic high-dose morphine (HDM)-induced analgesia and priming are neither TLR4 nor PKCε dependent. OIH produced by systemic LDM is mediated by isolectin B4-positive (IB4+) and peptidergic nociceptors, whereas priming is dependent on a different class of nociceptors. Priming induced by systemic HDM is, however, mediated by both IB4+ and peptidergic nociceptors. Our findings may provide useful information for the use of low-dose opioids combined with nonopioid analgesics to treat pain and opioid use disorders.

Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens.

The benefits of opioid-based treatments to mitigate chronic pain can be hindered by the side effects of opioid-induced hyperalgesia (OIH) that can lead to higher consumption and risk of addiction. The present study advances the understanding of the molecular mechanisms associated with OIH by comparing mice presenting OIH symptoms in response to chronic morphine exposure (OIH treatment) relative to control mice (CON treatment). Using RNA-Seq profiles, gene networks were inferred in the trigeminal ganglia (TG), a central nervous system region associated with pain signaling, and in the nucleus accumbens (NAc), a region associated with reward dependency. The biological process of nucleic acid processing was over-represented among the 122 genes that exhibited a region-dependent treatment effect. Within the 187 genes that exhibited a region-independent treatment effect, circadian rhythm processes were enriched among the genes over-expressed in OIH relative to CON mice. This enrichment was supported by the differential expression of the period circadian clock 2 and 3 genes (Per2 and Per3). Transcriptional regulators in the PAR bZip family that are influenced by the circadian clock and that modulate neurotransmission associated with pain and drug addiction were also over-expressed in OIH relative to CON mice. Also notable was the under-expression in OIH relative to CON mice of the Toll-like receptor, nuclear factor-kappa beta, and interferon gamma genes and enrichment of the adaptive immune processes. The results from the present study offer insights to advance the effective use of opioids for pain management while minimizing hyperalgesia.

Controversies on the endoscopic and surgical management of pain in patients with chronic pancreatitis: pros and cons!

Pain is the dominating symptom of chronic pancreatitis (CP) causing impairment of quality of life, decreased activity, unemployment and major healthcare costs.1 Opinions differ on the best strategy to treat...

Case report: possible opioid-induced hyperalgesia in a cat

Opioid-induced hyperalgesia is a recognised phenomenon in human medicine and in experimental animal studies. This case report describes a cat that appeared to have an increased nociceptive response when treated with opioids. Withdrawal of opioid analgesia resulted in improvement in the pain score. This case emphasises the need to tailor analgesia to individual cases, consider multi-modal analgesia and alerts veterinary surgeons to the possibility of opioid-induced hyperalgesia.

Opioid-Induced Hyperalgesia in the Nonsurgical Setting: A Systematic Review.

Opioid-induced hyperalgesia (OIH) is a phenomenon that causes an increased pain sensitization and perception of pain to noxious stimuli secondary to opioid exposure. While this clinical effect has been described in the surgical setting, it is unclear if OIH occurs in the nonsurgical setting. To review the available literature which evaluated OIH in nonsurgical settings. A comprehensive literature search was performed using PubMed (January 1946-July 2017) using a variety of keywords for OIH. This review included randomized controlled trials with objectives to identify OIH in the nonsurgical setting. The clinical outcomes of interest were identification of OIH, adverse events, and impact of OIH on opioid consumption. The search identified 8 studies that fulfilled the criteria. Six studies enrolled healthy male volunteers, 1 study used chronic low-back patients, and another used heroin-dependent treatment-seeking adults. Studies used various opioids and dosages, including remifentanil, alfentanil, fentanyl, morphine, methadone, and buprenorphine. Three primary experimental pain induction models were used to evaluate for OIH. Measured outcomes included hyperalgesia area, pain threshold, and pain tolerance. All 5 studies that used the electrical stimulation model identified OIH as a significant outcome. However, only 2 of 5 studies using the cold pressor model and 1 of 3 studies using the heat pressor model identified OIH. None of the trials explored clinical outcomes, such as effects on opioid consumption. Most included studies identified OIH as a significant outcome within the nonsurgical setting. However, due to conflicting conclusions and various limitations, the clinical impact of OIH could not be assessed. Clinicians should monitor for effects of OIH in the nonoperative setting because there is insufficient evidence from the available literature to conclude that OIH is consistently observed in this setting.