Opioid-induced Hyperalgesia Research Articles

The Use of Stem Cell Therapy to Reverse Opioid Tolerance.

Opioid tolerance (OT) and opioid-induced hyperalgesia (OIH) are major challenges in medicine. Here we report that transplantation of mesenchymal stem cells (MSCs) prevented and reversed OT and OIH in rats and mice. The preventive and therapeutic effects were long-lasting and consistent across different assessment schemes. Both intrathecal and intravenous transplantations were effective and safe. This emerging therapeutic strategy has thus shown promise to impact clinical practice and improve the efficacy and safety of opioid therapy.

Optimizing the care model for an uncomplicated acute pain episode in sickle cell disease.

The pathophysiology, clinical presentation, and natural history of acute pain in sickle cell disease are unique and require a disease-centered approach that also applies general principles of acute and chronic pain management. The majority of acute pain episodes are managed at home without the need to access health care. The long-term consequences of poorly treated acute pain include chronic pain, adverse effects of chronic opioid usage, psychological maladjustment, poor quality of life, and excessive health care utilization. There is no standard protocol for management of an acute pain crisis in either the hospital or the community. The assumptions that severe acute pain must be managed in the hospital with parenteral opioids and that strong opioids are needed for home management of pain need to be questioned. Pain management in the emergency department often does not meet acceptable standards, while chronic use of strong opioids is likely to result in opioid-induced hyperalgesia, exacerbation of chronic pain symptoms, and opioid dependency. We suggest that an integrated approach is needed to control the underlying condition, modify psychological responses, optimize social support, and ensure that health care services provide safe, effective, and prompt treatment of acute pain and appropriate management of chronic pain. This integrated approach should begin at an early age and continue through the adolescent, transition, and adult phases of the care model.

Opioid use disorder and misuse: A review of the epidemiology and medical implications for pediatric anesthesiologists.

This educational review presents an overview of opioid use disorder, misuse and overdose among adolescents, and the clinical implications for anesthesiologists. It provides definitions, discusses the epidemiology worldwide, (focusing on North America), and emphasizes the clinical implications of patients with chronic opioid exposure, including perioperative pain management, as well as opioid overdose and prolonged use of opioids after acute exposure. In the USA, opioid use disorder and negative outcomes related to opioids rose dramatically from 1999-2010; concomitantly heroin use and fatal overdoses have increased as heroin use is associated with the disordered use of licit opioids. Among adolescents and young adults, opioid use disorder is significant, with continued increases in disordered use specifically among young adults. Acute opioid intoxication may have multiple medical implications in addition to respiratory depression, and children are susceptible to acute intoxication via accidental ingestion of prescription opioids. Novel opioid formulations, such as acetyl fentanyl, with unpredictable pharmacology may also be present in acute intoxication. Chronically, opioid use presents challenges for safe and adequate pain management, in the presence of opioid-induced hyperalgesia and differential tolerance as well as mental health issues including depression and anxiety. Predictors of prolonged opioid use in adolescents and adults after surgery is an area of ongoing research. Young patients encountered by pediatric anesthesiologists may be involved in diversion and disordered use of opioids. Increased awareness among anesthesiologists is important, as perioperative discussions often provide an opportunity to detect at risk patients.

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

Repeated use of opioids can lead to the development of analgesic tolerance and dependence. Additionally, chronic opioid exposure can cause a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may drive continued or escalated use of opioids to manage worsening pain symptoms. Opioid-induced hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the cognitive/motivational dimension of pain in a state of opioid dependence and withdrawal, we employed a recently developed non-reflex-based method for measuring pain avoidance-like behavior in animals (mechanical conflict avoidance test). Adult male Wistar rats were administered an escalating dose regimen of morphine (opioid-dependent group) or repeated saline (control group). Morphine-dependent rats exhibited significantly greater avoidance of noxious stimuli during withdrawal. We next investigated individual relationships between pain avoidance-like behavior and alterations in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoidance-like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain regions. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain.

Inhibition of β-ARK1 Ameliorates Morphine-induced Tolerance and Hyperalgesia Via Modulating the Activity of Spinal NMDA Receptors.

Our previous study has proposed that increased presynaptic NMDARs activities play pivotal roles in the development of opioid tolerance and hyperalgesia, and blocking spinal NMDARs attenuates chronic morphine-induced synaptic plasticity and behavior. However, the cellular signaling mechanisms remain to be investigated. The aim of this research was to address the role of β-ARK1 in opioid analgesia. Opioid tolerance and hyperalgesia was induced by daily systemic morphine injections in rats for eight consecutive days. Whole-cell voltage-clamp was employed to record spontaneous EPSCs and evoked-AMPA-EPSCs in dorsal lamina II neurons. Strikingly, brief application of 1μM morphine decreased the percentage of inhibition and was followed by a large LTP in the amplitude of monosynaptic evoked-AMPA-EPSCs in opioid-tolerant rats. There was no effect on these responses by postsynaptic dialysis of the G-protein inhibitor. Incubation with the NMDAR blocker AP5 potentiated morphine-induced inhibition and attenuated washout potentiation after cessation of morphine in the amplitude of AMPA-EPSCs. Incubation with β-ARK1 inhibitor had the same effect on these responses. Incubation with β-ARK1 inhibitor diminished NMDAR hyperfunction-increased glutamatergic synaptic transmission and enhanced the analgesic effect of morphine. Intrathecal injections of β-ARK1 inhibitor significantly attenuated opioid-induced hyperalgesia and tolerance. β-ARK1 plays a pivotal role in the development and maintenance of opioid tolerance and hyperalgesia. Blockade of β-ARK1 activation ameliorates morphine tolerance and hyperalgesia via regulating the activity of spinal NMDARs. These findings provide electrophysiological evidence and useful insights regarding the mechanistic action of β-ARK1 inhibitor as a potential anti-hyperalgesic agent to improve the efficacy of opioid therapies.

Low-dose buprenorphine infusion to prevent postoperative hyperalgesia in patients undergoing major lung surgery and remifentanil infusion: a double-blind, randomized, active-controlled trial

BackgroundPostoperative secondary hyperalgesia arises from central sensitization due to pain pathways facilitation and/or acute opioid exposure. The latter is also known as opioid-induced hyperalgesia (OIH). Remifentanil, a potent μ-opioid agonist, reportedly induces postoperative hyperalgesia and increases postoperative pain scores and opioid consumption. The pathophysiology underlying secondary hyperalgesia involves N-methyl-D-aspartate (NMDA)-mediated pain pathways. In this study, we investigated whether perioperatively infusing low-dose buprenorphine, an opioid with anti-NMDA activity, in patients receiving remifentanil infusion prevents postoperative secondary hyperalgesia. MethodsSixty-four patients, undergoing remifentanil infusion during general anaesthesia and major lung surgery, were randomly assigned to receive either buprenorphine i.v. infusion (25 μg h−1 for 24 h) or morphine (equianalgesic dose) perioperatively. The presence and extent of punctuate hyperalgesia were assessed one day postoperatively. Secondary outcome variables included postoperative pain scores, opioid consumption and postoperative neuropathic pain assessed one and three months postoperatively. ResultsA distinct area of hyperalgesia or allodynia around the surgical incision was found in more patients in the control group than in the treated group. Mean time from extubation to first morphine rescue dose was twice as long in the buprenorphine-treated group than in the morphine-treated group: 18 vs 9 min (P=0.002). At 30 min postoperatively, patients receiving morphine had a higher hazard ratio for the first analgesic rescue dose than those treated with buprenorphine (P=0.009). At three months, no differences between groups were noted. ConclusionsLow-dose buprenorphine infusion prevents the development of secondary hyperalgesia around the surgical incision but shows no long-term efficacy at three months follow-up.

Role of endogenous melatoninergic system in development of hyperalgesia and tolerance induced by chronic morphine administration in rats

Morphine is a widely used analgesic for various types of pain. However, its efficacy is impeded by development of hyperalgesia and tolerance. Melatonin has antinociceptive effect and is involved in morphine-induced hyperalgesia and tolerance but the mechanism of its involvement remains to be defined. In this study, we established a rat model of morphine-induced hyperalgesia and tolerance. We determined the serum level of melatonin and expression of μ-opioid receptor (MOR), melatonin receptor (MT1, MT2) and protein kinase C γ(PKCγ) in the spinal dorsal horn of the rats with morphine-induced hyperalgesia and tolerance. Comparing with control group (n=6), the group (n=6) of rats with morphine-induced hyperalgesia and tolerance exhibited a significant lower serum melatonin level, reduction in expression of the MT1, but up-regulation of the PKCγ in the spinal dorsal horn. These results may facilitate revealing the mechanism of opioid-induced hyperalgesia and tolerance and exploring new therapeutic remedy for pain management.

Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease.

BackgroundN-methyl-D-aspartate receptor activation has been implicated in the pathobiology of inflammatory, nociceptive and neuropathic pain, opioid tolerance, opioid-induced hyperalgesia, and central sensitization. Some of those mechanisms underlie sickle cell disease(SCD)-associated pain.MethodsWe conducted an exploratory cohort study of SCD patients who during vaso-occlusive episodes (VOEs) received subanesthetic doses of the N-methyl-D-aspartate receptor antagonist, ketamine, as an adjunct to opioids. We sought to identify predictors of changes in pain scores and of the percentage of ketamine infusions associated with meaningful changes (≥20% reduction) in pain and opioid consumption.ResultsEight-five patients received 181 ketamine infusions for VOE-associated pain. Combined with opioids, ketamine yielded significant decrease in pain scores and opioid consumption. Ketamine administered to males and to younger patients yielded greater pain score decrease compared with females (P=0.013) and older patients (P=0.018). Fifty-four percent of infusions yielded meaningful reductions in pain scores, and in multivariate analysis, sex, age group, pain location, and infusion duration independently predicted pain score changes.ConclusionThis study suggests that in SCD patients admitted with VOE-associated pain, ketamine has age- and sex-dependent effects. These data can inform sample and effect size calculations for controlled trials to determine which SCD patients would benefit most from ketamine.

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease.

Acute vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Multiple complex pathophysiological processes can result in pain during a VOC. Despite significant improvements in the understanding and management of SCD, little progress has been made in the management of pain in SCD, although new treatments are being explored. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment of VOC pain, but new classes of drugs are being tested to prevent and treat acute pain. Advancements in the understanding of the pathophysiology of SCD and pain and the pharmacogenomics of opioids have yet to be effectively utilized in the management of VOC. Opioid tolerance and opioid-induced hyperalgesia are significant problems associated with the long-term use of opioids, and better strategies for chronic pain therapy are needed. This report reviews the mechanisms of pain associated with acute VOC, describes the current management of VOC, and describes some of the new therapies under evaluation for the management of acute VOC in SCD.

Histoire de la kétamine et du psychédélisme

Ketamine's history begins in the fifties in Detroit, at Parke-Davis laboratories. In 1956, Maddox synthetized phencyclidine or PCP. Domino studied PCP effects in animals and in 1958, Greifenstein made the first trials of PCP in humans under the name of Sernyl. Sernyl elicited severe excitation with a prolonged postoperative recovery. Because of its psychedelic effects, it became a street-drug under the name of “angel dust”. Calvin Stevens synthesized ketamine in 1962. The drug was studied in humans in 1964, by Domino and Corssen who described the so-called “dissociative anesthesia”. Ketamine was patented in 1966 under the name of Ketalar for human use and was administered to soldiers during the Vietnam war. The psychedelic effects and the arrival of propofol prompted the shelving of ketamine. However, the discovery of the NMDA-receptor and its non-competitive inhibition by ketamine revolutionized the pathophysiology of hyperalgesia and mental functioning. In early 1990s, the discovery of opioid-induced hyperalgesia elicited a paradigm shift in the management of pain, and a comeback of ketamine, as an anti-hyperalgesic drug. Ketamine is nowadays under the spotlight in the field of treatment-resistant depression and has been proposed as a potential fast antidepressant in patients with high suicidal risk.

Genetic deletion of microglial Panx1 attenuates morphine withdrawal, but not analgesic tolerance or hyperalgesia in mice

ABSTRACTOpioids are among the most powerful analgesics for managing pain, yet their repeated use can lead to the development of severe adverse effects. In a recent study, we identified the microglial pannexin-1 channel (Panx1) as a critical substrate for opioid withdrawal. Here, we investigated whether microglial Panx1 contributes to opioid-induced hyperalgesia (OIH) and opioid analgesic tolerance using mice with a tamoxifen-inducible deletion of microglial Panx1. We determined that escalating doses of morphine resulted in thermal pain hypersensitivity in both Panx1-expressing and microglial Panx1-deficient mice. In microglial Panx1-deficient mice, we also found that acute morphine antinociception remained intact, and repeated morphine treatment at a constant dose resulted in a progressive decline in morphine antinociception and a reduction in morphine potency. This reduction in morphine antinociceptive potency was indistinguishable from that observed in Panx1-expressing mice. Notably, morphine tolerant animals displayed increased spinal microglial reactivity, but no change of microglial Panx1 expression. Collectively, our findings indicate microglial Panx1 differentially contributes to opioid withdrawal, but not the development of opioid-induced hyperalgesia or tolerance.

Ameliorative response to detoxification, psychotherapy, and medical management in patients maintained on opioids for pain.

The prevalence of opioid-induced hyperalgesia (OIH) among patients maintained on opioids for chronic non-malignant pain has not been estimated. As a contribution toward establishing its prevalence, we report a case series of opioid maintained patients whose pain tolerance was measured by the cold pressor test at baseline. A case series of 117 patients who had undergone detoxification was reviewed retrospectively. Most patients (n = 108) and selected non-addicted support persons who accompanied them (controls; n = 37) had cold pressor time (CPT) assessments at baseline. Twenty patients had a repeat CPT after 1 month. When 61 patients completed one month abstinent reported pain was improved (51%), unchanged (46%), or worse (3%). Baseline CPT was 48 sec for patients and 102 sec for controls, suggesting that opioid maintained patients were more pain sensitive than opioid naïve controls. CPT increased for 90% of 1-month completers, suggesting improved pain tolerance. Ameliorative response to detoxification, psychotherapy, and medical management, as defined as the absence of worsening pain with removal of opioids, was 97% in this population. The difference in CPT between opioid maintained patients and controls, and the response to detoxification, psychotherapy and medical management suggest the possibility that the prevalence of OIH may be high. This study adds to the growing evidence that chronic opioid treatment contributes little to the management of chronic pain and in fact appears to frequently make it worse. (Am J Addict 2017;26:738-743).

Opioid-induced hyperalgesia in clinical anesthesia practice: what has remained from theoretical concepts and experimental studies?

This article reviews the phenomenon of opioid-induced hyperalgesia (OIH) and its implications for clinical anesthesia. The goal of this review is to give an update on perioperative prevention and treatment strategies, based on findings in preclinical and clinical research. Several systems have been suggested to be involved in the pathophysiology of OIH with a focus on the glutaminergic system. Very recently preclinical data revealed that peripheral μ-opioid receptors (MORs) are key players in the development of OIH and acute opioid tolerance (AOT). Peripheral MOR antagonists could, thus, become a new prevention/treatment option of OIH in the perioperative setting. Although the impact of OIH on postoperative pain seems to be moderate, recent evidence suggests that increased hyperalgesia following opioid treatment correlates with the risk of developing persistent pain after surgery. In clinical practice, distinction among OIH, AOT and acute opioid withdrawal remains difficult, especially because a specific quantitative sensory test to diagnose OIH has not been validated yet. Since the immediate postoperative period is not ideal to initiate long-term treatment for OIH, the best strategy is to prevent its occurrence. A multimodal approach, including choice of opioid, dose limitations and addition of nonopioid analgesics, is recommended.

Monitoring of nociception, reality or fiction?

There are currently various projects underway that attempt to monitor the nociceptive responses caused by surgical stress and ensure patients the best analgesic conditions. The systemic response to surgical stress has repercussions in the postoperative period, such as worse pain control, delayed recovery, greater complications, longer stay in resuscitation and hospital units, and increased healthcare costs. However, treatment with higher doses of opioids than necessary may lead to slower awakening, increased drowsiness and adverse effects, as well as situations of postoperative opioid-induced hyperalgesia. There are 2 large groups of nociceptive monitoring according to the origin of the theoretical objective of monitoring response to the stimulus, that may derive from changes in the electroencephalogram or the response of the autonomic nervous system.

Perioperative Ketamine Infusion is Effective in Reversing Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia (OIH) is a condition of nociceptive sensitization caused by exposure to opioids, which is characterized by a paradoxical response whereby patients receiving opioids for the treatment of pain actually become more sensitive to pain as a direct result of opioid therapy. There is increasing evidence showing OIH presents a clinical challenge in acute, chronic, and cancer pain settings. Both clinical and animal studies have shown that glutamate N-methyl-D-aspartate (NMDA) receptors may play a key role in OIH, and pre-application of ketamine, an NMDA receptor antagonist, or a co-administration of ketamine and opioids, can prevent OIH. However, no reports have shown if ketamine can reverse OIH once it occurs. We present a case of a 56-year-old male with a past medical history of DM-2 with severe peripheral neuropathy, recurrent osteomyelitis of the left foot, hypertension, dyslipidemia, chronic neck and right arm pain due to cervical spondylosis, status post 4 times of cervical discectomy, and fusion surgeries for cervical radiculopathy. He was prescribed to high doses of opioids (morphine 60 mg, orally every 8 hours and hydrocodone/acetaminophen 10/325 mg, as needed up to 4 times daily) for approximately 10 years. He underwent left below-knee amputation due to uncontrolled osteomyelitis. The patient had worsening stump pain with an increasing dose of opioids and phantom pain on post-operative day one, and he developed OIH, diagnosed as escalating pain reports with every opioid dose increase. A ketamine infusion (loading dose of 10 mg IV bolus, then 20 mg/ hour IV infusion) was used after total cessation of opioid use for post-operative analgesia for 3 consecutive days and the patient recovered from his obvious OIH, with his stump pain and phantom pain well-controlled by opioid administration on post-operative day 5. In our case, the blockage of NMDA receptors by ketamine might quickly restore the balance between opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems by deactivation of the latter, which may help the patient recover from OIH rapidly. While it is possible that ketamine may help facilitate patients’ recovery from OIH in addition to its ability to prevent OIH, this clinical observation must be tested in future prospective studies. Key words: Opioids, ketamine, opioid-induced hyperalgesia, phantom pain, post-amputation, post-operative

Opioid-induced Hyperalgesia: Myth or Burgeoning Public Health Crisis

Opioid-induced Hyperalgesia: Myth or Burgeoning Public Health Crisis

Advance in research on opioid-induced hyperalgesia

Background Opioids are the most commonly used drugs for the treatment of perioperative analgesia and chronic pain. But they are double-edged swords due to the paradoxical phenomenon called opioids-induced hyperalgesia (OIH, which is an increased sensitivity to pain caused by opioids exposure. Objective This review on OIH research to date would offer a more precise picture of OIH. It also benefits to clinical therapy by using opioids more reasonable. Content This review is to illustrate classification, diagnosis, mechanism and management of OIH. Trend So far, many aspects about OIH are not entirely clear, such as diagnosis, mechanism and management. To better understand the significance of OIH and make better guidelines for opioid administration, further pay attention to OIH and deeper researches on OIH are needed. Key words: Opioids; Hyperalgesia

Low-Dose Ketamine for Postoperative Pain Management

Ketamine, an anesthetic agent, is gaining attention as an analgesic for the management of acute and chronic pain conditions. Perianesthesia nurses may expect to see ketamine's use increase as more anecdotal and evidence-based experience is gained with its use for pain management. Unlike opioids, ketamine supports respirations while supporting hemodynamic function; moreover, the agent has potential for decreasing opioid-induced hyperalgesia. Ongoing clinical evidence continues to support ketamine's use for analgesia, thus it may be argued that the current Food and Drug Administration classification for ketamine as an anesthetic agent is outdated, and patients would be better served by a reclassification of this medication to include its use for analgesic purposes. This continuing education article provides an overview of ketamine, its side effects, and the possible adverse reactions so perianesthesia nurses may be prepared to care for postsurgical patients who receive ketamine for analgesic purposes.

Pain sensitivity and analgesic use among 10,486 adults: the Troms\xf8 study

BackgroundIncreased pain sensitivity is a putative risk factor for chronic pain and consequently for analgesic use. Conversely, analgesic use may be a cause of increased pain sensitivity, e.g., through opioid-induced hyperalgesia. We aimed to study the association between pain sensitivity and analgesic use in a general population, and to test the hypothesis that increased baseline pain sensitivity is a risk factor for future persistent analgesic use.MethodsThe Tromsø Study (2007–08), a population-based health study, was linked with eight years of prescription data from the Norwegian Prescription Database. The cold pressor test was completed in 10,486 participants aged 30+ years, and we used cold pressor endurance time as a proxy measure of pain sensitivity. Cross-sectional associations with different measures of analgesic use were assessed. Furthermore, a cohort of 9,657 persons was followed for 4.5 years.ResultsIn the cross-sectional analysis, increased pain sensitivity was associated with analgesic use; regular users of opioids alone were more pain sensitive than regular users of non-opioid analgesics. Increased baseline pain sensitivity was a risk factor for persistent analgesic use, i.e., using non-steroidal anti-inflammatory drugs, paracetamol, or opioids for ≥ 90 days and proportion-of-days-covered ≥ 40% (HR = 1.22, 95% CI 1.06-1.40), although not statistical significant after confounder adjustment.ConclusionsIncreased pain sensitivity was associated with analgesic use in general, and reduced pain tolerance was found for both opioid and non-opioid analgesic users. The data suggest that hyperalgesia is an effect of analgesics, whereas pain tolerance has little impact on future analgesic use.